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Gain

of Function Research: The Second Symposium: Day 1


Session 1: Welcome and Opening Remarks

Harvey Fineberg: This is a scientific symposium, organized by the National Academies at the request of
the National Institutes of Health to assist the NSABB and the Nation in preparation for dealing with Gain
of Function research. Over the course of these two days, we'll have an opportunity to speak with one
another about this challenging problem. Our aim is to try to assist the NSABB to prepare its
recommendations to help the nation, and indeed, other nations of the world to deal with the problem. At
this point, I want to welcome, not only those of you that are here, but also all who are listening in on the
Web cast. Look forward to an active and engaging two days with you. To begin our program, we have an
opportunity to hear a welcome and some opening comments from individuals who represent a variety of
pertinent organizations, who are related to the sponsorship and oversight of the work that we're doing in
the course of these two days. First, it's my great pleasure to introduce and to welcome the President of the
National Academy of Sciences, Dr. Ralph J. Cicerone. Ralph, the floor is yours.
Ralph Cicerone: Thank you, Dr. Fineberg. Welcome to the National Academy of Sciences building. Over
the years, in this building, there have been convened any number of discussions, such as this, on
important topics of the day, and sometimes of the decade, where scientific underpinnings of an area with
great potential benefit also lead to complexities. So, in one sense, this kind of discussion is common here.
Nonetheless, we're very, very happy to host all of you from so many different countries, and different
parts of the United States, as well as the Web presence that Dr. Fineberg just mentioned. The meeting is
sponsored by the National Institutes of Health Welcome Trust, and the McArthur Foundation, we're very
appreciative of their stepping forward on these occasions. Excuse me. I am aware of some of the
controversies in GoF research and policy brought forth by people with very different points of view who
see different ways to weigh the potential benefits versus the potential risks of this kind of research, so the
discussion should be very interesting today.
And, as Dr. Fineberg just said, a major goal of this gathering is to allow people to discuss these different
points of view, and to respond to draft policies from the National Scientific Advisory Board on
Biosecurity, which we refer to as NSABB, because they definitely want to hear from scientific
community medical professionals and the public to find out how policies might maximize the benefits of
this research, while minimizing the risks. Well, here at the National Academy of Sciences, and the
National Academy of Medicine, and our National Academy of Engineering, we're very pleased to do a
small part in convening this distinguished group, and we look forward to the discussions. There's nothing
like informed public opinion to hone public policies, and occasionally to review them. So, thank you once
again, and Dr. Fineberg, thank you for the opportunity to be here.
Thank you very much, Ralph. It's now my pleasure to call upon Margaret Hamburg, the Foreign Secretary
of the National Academy of Medicine for greeting, on behalf of the NAM. Thank you.
Peggy Hamburg: Well, thank you very much. It's a pleasure to be here. I want to echo the welcome of
Ralph Cicerone, the distinguished President of the National Academy of Sciences. And, I'm representing
Victor Dzau, the President of the National Academy of Medicine, formerly known as the Institute of
Medicine, and as was mentioned, I am now the Foreign Secretary. The topic of this meeting is one that is
enormously important with ramification for other areas of research, and certainly for other parts of the
world as well. It's one that I've actually been involved with for a number of years from a number of
different perspectives, and I was just reflecting that actually, back in 2002, I worked for a foundation that
funded a project, a committee on research standards and practices to prevent to prevent the destructive
application of bio-technology, that then released a report in 2004, that became finally known as the Think
Report. But, it was that report that actually made a recommendation, a set of recommendations, but that
led to the creation of the NSABB.

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And, of course, an important focus of today's meeting will be on the recommendations being made by the
NSABB in the GoF research arena, so there's a very important and continuing nexus between the work of
the Academies, the impact of the Academies on science advise to government, government activities, and
the continuing back and forth, which is so key. As Foreign Secretary of NAM, I really do want to
underscore the important dimensions of the discussion around GoF research, and the discussions today,
because clearly these are issues that extend beyond borders, the research itself, and the disease that are
being addressed through the research efforts as well. So, it's wonderful that colleagues have come from all
over the world to participate today, and I think it's important to recognize that the work being done is
intended in response to policies of the US government, but will have much broader implications for
activities around the world, and of course, global enterprise, research is a global enterprise.
I want to also underscore, and I want it to be brief, because there's so much that needs to be done over the
next two days working with all of you, but I want to underscore the importance of this meeting. I think
you all understand it, but you know, there have been many ongoing policy discussions, and important
actions that have been taken, but over the last year and a half, maybe a little longer now, there has been
work in specifically looking at what should be the policy framework, what kinds of approaches should be
taken, to address this issue of GoF research. And, I think that this meeting really is an opportunity to look
at the policy frameworks and approaches that are being put forward. And to think about what kind of
concrete next steps can happen, because we need to move from talking about the issue to really
implementing policies and strategic approaches that will help to support scientific progress, but will also
recognize critical public health needs, both risks and benefits, so that we can find a path forward that will
really make a difference to promote and protect health for all. So, thank you all for your willingness to
participate, and as I said, this really is an important meeting where your work, your contribution to the
discussion, your perspective and experiences, can make a real and enduring difference. Thank you.
Spectacular. Thank you very much, Peggy. And, now to offer a word on behalf of the office of Science
and Technology, it's my pleasure to call on Dr. Jo Handlesman. Jo, thank you.
Jo Handelsman: Well, thank you Dr. Fineberg, and thank you all for being here. I bring greetings on
behalf of the White House. As you probably know, we've been tracking this issue very carefully for the
last year and a half, and I wanted to make a few comments about the larger process in which this meeting
plays a very important role. So I thank the National Academies for having this meeting, and all of you for
participating, either in the flesh, or on the Web, because I think this is going to be a landmark meeting. As
Dr. Hamburg alluded to, there have been a few of those, in the last couple of decades, on topics related to
this, and I think this is one that will really direct our future in important ways. As you know, the White
House has been focusing on this issue for about a year and a half now, and we want to figure out policy
that will be an effective way of keeping the life sciences vibrant and active, but also protecting safety and
security across the globe.
So, in the last few years, the life sciences and policy communities have wrestled with concerns of creating
new pathogens, and particularly those that could trigger pandemics. We've also suffered a series of biosafety and Biosecurity lapses in some of our premier Federal labs, and that has generated certain
questions in the public about the safety of the research that we're doing, and how it affects the public. So,
in response, the Director of OSTB, John Holdren, and the Homeland Security Advisor, Lisa Monaco,
initiated a series of inter-agency reviews and initiatives with a letter that came out about a year and a half
ago. Most relevant to this gathering, the laboratory incidents that prompted the reassessments and the
evaluation of the risk benefit evaluation that underpins the funding of certain types of GoF research. The
greatest concern focused on respiratory pathogens, the obvious ones are MERS, SARS, and certain strains
of Flu. So, on October 17th, 2014, the US government announced the launch of a deliberative process to
assess the potential risks and benefits associated with GoF studies. During that process, the government

Gain of Function Research: The Second Symposium: Day 1


institutes a pause in funding for certain kinds of GoF experiments involving Flu, SARS, and MERS, but
there were several exceptions to that pause, so that critical research could proceed.
Two organizations that were asked to play a key role, and that brings us to why we're here today, were
first the NSABB, the National Science Advisory Board for Biosecurity, was asked first to draft a set of
recommendations on a conceptual approach to the evaluation of the proposed GoF studies that brought
concern to the scientific community, and the broader public. These will then be reviewed by the broader
life science community. We also asked NSABB to serve as the official Federal Advisory body for
providing advice to the HHS Secretary. Second, we asked the National Academy of Sciences to do a
number of things, first to convene two public meetings that would facilitate broad discussions of the
issues associated with GoF research. The first was very early in the deliberative process, and that was to
examine the underlying scientific and technical issues that are the source of current discussion and debate
over GoF. And, then the second is why we're here today, and that's a symposium that's towards the end of
the deliberative process to discuss the draft recommendations that NSABB is proposing, and to discuss
the future of policy for GoF research. So, I'll let my colleague, Carrie Wall, and that's to tell you more
about the deliberative process, how it's proceeded, and the status of NSABB's work. And, that will set the
stage for the symposiums discussions.
But, I wanted to skip ahead to the final process. Once the recommendations, after they've been modified,
based on this discussion, and on other public input, they will form the basis for public policy that will
replace the current pause on research on GoF. So, on behalf of the White House, and all my colleagues
there, on behalf of OSTB, and John Holdren, it's Director, I want to thank you for being part of this broad
process that involves many agencies, and the public, and remind you to, as Dr. Hamburg did, that your
input is absolutely critical, and I urge you to take an active role in this discussion because we need every
point of view that we can get to identify the risks, to mitigate those risks, and to proceed in protecting
scientific autonomy, discovery and innovation, public health, national security, and other critical issues
that are part of GoF research. So, thank you all for being here.
Thanks, Jo. Thank you very much, Jo, for explaining so clearly the mandate and opportunity at the
conference, and making such a wonderful opening to our next speaker who is Carrie Wolinetz, speaking
on behalf of the National Institutes of Health.
Carrie Wolinetz: Let me echo the thanks to my colleagues, the National Academies for convening us here
today. As well as to, my Federal colleagues, and the members of the NSABB who have been working so
hard and vigorously on this entire process. So, I want to just start off with, I think, very important points,
that the viruses are out to get us. I think that I'd be interested in a show of hands, how many of you have
uttered or heard the words, Zika, in the past 24 hours? It's by way of illustration. And, I think it is also
very important to emphasize over and over again, how important life science research is into addressing
the challenges presented by infectious pathogens, in terms of developing new counter-measures, vaccines,
treatments, strategies, for prevention, and it is because of this, the US government supports a robust and
diverse life sciences portfolio.
The National Institutes of Health is clearly a big part of that but we're joined by many other agencies in
that regard. Equally true is the recognition that with that robust investment in life sciences research,
comes a certain amount of risk in working with dangerous pathogens, and manipulating dangerous
pathogens, and the responsible conduct of that research requires thoughtful and deliberative thinking of
how we maximize the benefits of the research, while reducing the inherent risks of that research, and
being very thoughtful about oversight processes. So, as was mentioned by Dr. Handelsman, there have
been a number of incidents that have really focused the US government's attention on bio-safety and
Biosecurity, and there have been a number of activities and reports produced by the US government over
the past year, 18 months, to really address and examine, and consider additional policies and oversight

Gain of Function Research: The Second Symposium: Day 1


mechanisms, to ensure that the life science research that we support is in fact conducted in the most
responsible way going forward. And, I'm going to focus today on the details of this GoF deliberative
process, which brings us all together today.
So, GoF research is a common tool in life science research. This is a common practice in micro-biologists
as they try to understand fundamental scientific related to disease, related to infections, and pathogens,
and GoF studies have a great deal of potential in helping us understand the fundamental nature of most
pathogen interactions. They allow us to take a look at the landscape of pathogens out there and guess
whether or not they may have pandemic potential. They inform our public health and preparedness efforts
in many ways. And, as I already mentioned, they further our counter-measure development. So, GoF
research, I think it's important to emphasize, is not itself a boogeyman, it is a common scientific practice,
but there are certain GoF experiments which have ways, relevant concerns about their safety going
forward. And, specifically the question of whether or not pathogens that we're engineering in our
laboratories could pose a pandemic threat if they were deliberately, or accidentally released from the lab,
or could the information that we gain from those studies actually be misused in some way as to present a
threat.
And, that brings us to a couple of important policy questions, which is the conversation today is
continuing. Under what conditions could, or should, these studies be safely conducted? And, the sort of
broader question of should we be conducting these studies at all if they in fact pose significant safety or
security risks?
So, this process has already been alluded to, but I just want to go into it a little bit more depth. The
deliberative process to develop GoF policy was accompanied by a pause in certain types of GoF research,
particularly with strains of Influenza, MERS, and SARS so that we can all collectively take a deep breath
and think about how we move forward safely and securely with these studies. I think, as Dr. Handelsman
mentioned, it's important to note that there was an exception mechanism for this pause to allow research
that was critical to public health to go forward, which I think is important to recognize. The GoF
deliberative process has had a number of moving parts. The NSABB has served as, sort of, the official
convening body to orchestrate all of these, and they've received a number or really critical inputs, and
continue to receive a number of critical inputs, including a risk benefit assessment, I'm sure you've all got
your highlighted copies with you, so we can talk about it additionally today.
The first symposium of the National Academies, which was already mentioned, which was an important
venue for hear diverse public opinion, and all of these inputs have fed into the National, the NSABB's
recommendations, in terms of how the US government should think about policy moving forward. So, the
charge to the NSABB is really, sort of, two-fold. First to advise on the development of this risk benefit
assessment, which ultimately was feeding back into the process. And, then the next step, which is where
we are today, providing recommendations to the US government on a conceptual approach that would
allow us to evaluate proposed GoF studies, in terms of whether or not we should be funding them. And,
to look at that visually, I know this is a very, very busy slide, but sort of the you-are-here is at this second
purple diamond, the National Academy is. So, the NSABB has deliberated, they've received all these
various inputs, the risk benefit analysis, we've heard from the public, we've received ethical analysis,
there have been a lot of in-depth discussions, many of the folks in this room, I know have been involved
in those, and the NSABB has put forward some draft recommendations, which we'll be discussing today,
and ultimately we'll be finalizing those recommendations.
Once those recommendations are finalized, they'll be transmitted to the US government, and has already
been mentioned, will serve as the foundation for policy going forward, in terms of developing an
approach, a mechanism, a policy, to help us think through how, and if we should fund these studies going
forward, and what we put in place to oversee and mitigate risk. So, I think it's important to note that we

Gain of Function Research: The Second Symposium: Day 1


are still open for input at this point. The recommendations are drafts. Today's meeting is going to be very
important I think, and hearing further thoughts about the recommendations, about policy process. They're
available, of course, on our Web site. We welcome emails at any time, if a thought occurs to you at four
AM, you know, feel free to email them. My colleague, Chris Viviani, Executive Secretary of the NSABB,
will be up at four AM reading those vigorously. And, so we really value the perspective of the public, of
the scientific community in informing this process, it's very important. So, just some additional resources,
if you're interested and I'll end there, and look forward to today's discussion. Thank you.
Thank you very much, Carrie. Thank you very much, Carrie, for a wonderful overview, and clearly laying
out the purpose and s that this meeting will serve.

Session 2: Overview of the NSABB Working Paper

Harvey Fineberg: We can move directly into our first session, which is an overview of the draft NSABB
policy framework, and the key questions that we're going to be trying to come to grips with in the course
of our time together today and tomorrow. As was evident from Carrie's remarks particularly, the NSABB
is moving down the final common pathway toward the development of guidelines and recommendations
for the conduct of GoF research, its support and, indeed its dissemination. All of these were factors of
consideration in the NSABB deliberations, and we're very fortunate to be able to begin this session with
an overview presentation about the NSABB state of progress, by Samuel Stanley, who is the chair of the
NSABB. Dr. Stanley, the floor it yours. After you finish, stay up here and we'll have a conversation.
Thanks.
Sam Stanley: So, good morning everyone. I want to begin also by thanking the National Academies for
organizing this meeting. I think the first GoF symposium, hosted by the Academies, played a very
important role in informing NSABB's recommendations for the risk benefit assessment, and I'm really
looking forward to a very informative meeting over the next two days. Am I audible OK in the back? Yes?
Great, thank you. So, I'm going to be discussing NSABB's progress towards developing recommendations
about the funding, and oversight of GoF studies. Since the (inaudible) process, over one year ago as
you've heard, the board has been extremely busy. In January, we released and discussed our draft report,
which contains our preliminary findings and recommendations. I'm going to provide a brief overview of
that report. I would also point out to you the entire report, which I think has been available, both in front,
and is available on our website. I have to tell you that a tremendous amount of effort went into that report,
I'm very pleased with it at this stage, but of course it's not finished. It's a draft, as we said, and the
discussions today and tomorrow will be critical to our deliberations moving forward, and I hope will help
us to finalize our recommendations.
At the end of my presentation, I'm going to present a few outstanding issues that hopefully will be
discussed over the next few days. And again, these are vital to our deliberations. As you've heard on
October 2014, the NSABB was issued a two-part charge related to GoF studies. First we were asked to
advise on and design the conduct of risk and benefit assessments for GoF studies. The board
accomplished this task in May of last year, when we approved our framework for conduction risk and
benefit assessments. This framework served to guide Gryphon Scientific, as they conducted the risk and
benefit studies. Our second task was to provide recommendations to the United States government on a
conceptual approach for evaluating proposed GoF studies. My presentation, today, focused on these draft
findings and recommendations. The major elements of the NSABB draft reports are shown here. In
addition to our findings and recommendations, it also describes our analysis of the risk benefit
assessment, and our examination of the current policy landscape. We also devote a section to the
discussion of ethical values that are important to consider when funding certain GoF studies. The report

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also details our process and summarizes the important stakeholder input we received during our
deliberations. As I said before, this document is still a work in progress, and while working group has met
since the last NSABB meeting, we will wait until after this meeting to issue an updated draft.
In general, the working group is focused on three major areas, risk and benefits, ethics, and policy
analysis. I highlight on this slide a few key inputs, but this list is certainly not comprehensive. Gryphon's
risk benefit assessment provided quantitative and qualitative information that helped us evaluate the
potential risks and benefits of GoF studies. And ethics analysis, written by Professor Michael Selgelid,
was important to our consideration of ethical issues, and decision frameworks that relate to the funding of
GoF studies.
We also examined relevant domestic and International policies, related to bio-safety, bio-security, and
dual-use research to determine whether and how they might apply to GoF studies. Importantly,
underpinning all our analysis has been the perspective of stakeholders. We have sought input at a number
of public meetings, including today's, and have received several comments in writing. And this input,
again, has been essential to our deliberations.
Gryphon Scientific presented its risk benefit assessment at our January meeting. Gryphon's presentation,
and our discussion, is archived on the NSABB website. I would urge all that are interested to view that
session of our meeting. The risk benefit assessment represents a truly monumental amount of work, 1,009
pages, and I commend Gryphon for putting together a rigorous and comprehensive report. Gryphon's
analysis, as we will hear from Marco in the next session, consisted of three main parts. An assessment of
bio-safety risks associated with GoF research, a bio-security risk assessment that included analysis of
information risks, and an analysis of the potential benefits of GoF research, to public health. Rather than
detail NSABB's analysis of the risk benefit assessment, I thought instead I would describe, how the board
has used the information from Gryphon's study. First, it allowed us to understand the relative risks
associated with certain types of GoF studies. The study allowed us to compare whether certain
experimental manipulations increased risk. If so, we were able to make determination about whether that
increase was significant.
Of course, there are many caveats associated with interpreting this assessment. Two that stood out to the
NSABB involved uncertainty, and the comparative nature of the assessment. Gryphon utilized real data
whenever possible. However, any risk assessment contains unknown and inherent uncertainty. Therefor
Gryphon relied on assumptions and estimations about the likelihood or magnitude of an event occurring.
To address some of this uncertainty, Gryphon performed a relative risk assessment. They compared the
risks associated with potential lab accidents involving the GoF strain, with the risks associated with the
same accident involving a wild type strain. This is informative, but the lack of comprehensive estimates,
or baseline absolute risks, makes interpreting the bio-safety risks a challenge. All that said, the risk
assessment did allow NSABB to identify GoF studies that entailed the greatest risks. You will note in our
report that we describe GoF studies of concern. These are substantive studies that NSABB suggests
should require additional pre-funding review, and ongoing oversight. Gryphon's benefit assessment also
provided a comprehensive review of the positive benefits, and the barriers to realizing benefits associated
with GoF studies. This, along with Gryphon's discussion of alternative approaches to GoF studies,
allowed us to better understand the scientific and public health value of this type of research.
The NSABB has focused a lot of attention on ethical issues associated with funding, and conducting GoF
studies. We recognized early on, that interpreting the risk benefit assessment would require weighing
benefits in light of risks, and making determinations about policy recommendations. Moreover, those that
would make future decisions about whether to fund individual studies, will face similar problems. These
decisions are essentially value and ethical judgments. To inform discussions about values, an ethics white
paper was commissioned, that was designed to review the relevant ethics literature, discuss important

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values relevant to this type of research, and propose decision-making frameworks that may be considered
when evaluating GoF research proposals.
As I mentioned before, this task was undertaken by Dr. Michael Selgelid, an ethicist at Monash
University, who has studied the dual-use issue for many years. His paper was very informative, and was
presented at our meeting in January. The NSABB identified a number of important substantive values
listed on this slide, including social justice, scientific freedom, and respect for persons, to name a few.
These are values that are important when considering whether to fund a GoF study that entails significant
risks. We also identified procedural values, including public participation, transparency, and
accountability that are very important for any process reviewing proposals involving GoF studies.
The NSABB spent a significant amount of time considering the current Federal policy landscape, as it
applies to GoF studies. We examined the policies listed here, and focused particularly on how they relate
to GoF work. These policies are discussed in detail, in our draft report, so I'll simply touch on some of
NSABB's overall conclusions. First, there are multiple policies in place for managing risk throughout the
research cycle; this includes mechanisms for pre-funding review, as well ongoing Federal and institutional
oversight of funded projects. However, the effectiveness of the policies depends on proper
implementation and compliance at both the Federal and institutional levels. Importantly, variations in the
scope and applicability of the policies results in different levels of oversight, depending on the pathogen,
and the specific GoF experiment.
Taken together, our analysis of the risk and benefits, out consideration of ethics, our analysis of the policy
landscape, and the input from stakeholders, the NSABB tried to distill our thinking into five key findings.
Finding one, there are many types of GoF studies, and not all of them have the same level of risk. Only a
small subset of GoF studies, GoF studies of concern, entail risks that are potentially significant enough to
warrant additional oversight. Later, I will describe the attributes that constitute GoF research of concern.
The next two findings are related. Finding two, the United States government has policy frameworks in
place for managing risks associated with life science research. If these policies are implemented
effectively, they can serve to mitigate risks and provide oversight to many GoF studies.
However, in finding three, we note that oversight policies vary in scope and applicability. This means that
current oversight is not sufficient for all GoF studies that raise concern. This figure illustrates how
different pathogens are covered under different policies. We see, for instance, that Avian Influenza, H5N1,
is subject all of the relative, all of the relevant policies, including pre-funding review at the health and
human services level for GoF studies involving enhanced transmission ability. However, research
involving other Influenza strains, and SARS and MERS strains, for example, are subject to varying
degrees of oversight. For most studies with these pathogens, the level of oversight is appropriate, however
there could be GoF research of concern involving these, or other agents, that are not subject to sufficient
oversight policies.
The NSABB's fourth finding is that there are life science experiments that should not be conducted on
ethical and public health grounds, if the potential risks are not justified by the potential benefits. Funding
decisions should be based on consideration of both the risks and benefits associated with the specific
experiments in question. Finding five, notes that bio-safety and bio-security issues associated with GoF
studies are essentially similar to those issues associated with all high containment research. But, we know
since GoF research of concern could entail high and potentially unknown risks, a commitment to a culture
of biosafety and biosecurity is critically important. With these findings in mind, the NSABB developed its
draft recommendations. The first recommendation is that proposals involving GoF research of concern
should be reviewed carefully for biosafety and biosecurity implications, as well as for potential benefits,
prior to determining whether they're acceptable for funding. If funded, such projects should be subject to
ongoing oversight at both the Federal and institutional levels.

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As part of this recommendation, the NSABB recognized three attributes that would define a study of GoF
research of concern. Studies anticipated to generate pathogens with all three of these characteristics,
should be subject to additional review, prior to making a funding decision. They should also be monitored
carefully throughout the course of the research if funded. GoF research of concern would be a study that
can be anticipated to generate a pathogen that is, one, highly transmissible in a relevant mammalian
model, two, highly virulent in a relevant mammalian model, and three, is likely more capable of being
spread among human populations than currently circulating strains of the pathogen. The first two
characteristics are intended to involve the concept of the threshold. That is, the generated pathogen would
need to be highly transmissible, and highly virulent. Studies of pathogens with moderate virulence and
transmissibility entail risks of course, but in general, those risks can be managed through existing
mechanisms. The third criterion is intended to capture the concept of pandemic potential. That is, a
pathogen could spread rapidly among human populations, either because there's no population immunity,
no available counter-measures, or for some other reason.
The NSABB articulated seven principles that should guide subsequent funding decisions for GoF research
of concern. The expectation would be that in order to funded, a proposal would need to be in line with
these principals. The first is that the research proposal has been evaluated by a peer review process, and
had been determined to be scientifically meritorious. This concept of scientific merit is very important,
and any study that entails significant risk, must be considered good science if it is to be conducted. The
second principle is that the risks and benefits should be evaluated, and the risks be justified, in light of the
benefits. Importantly, risks should be mitigated wherever possible if the plan is to be funded. The third
principle, there are no feasible alternatives to address the same scientific question in a manner that poses
less risk. This principle would require an explicit consideration of alternative approaches, or experimental
designs, prior to funding a GoF study of concern.
The fourth principle states that an investigator and institution proposing the research have the
demonstrated capacity to carry it out safely and securely. This would include adequate resources, security,
trained personnel, occupational health and safety procedures, and the ability to adapt to unanticipated
results. Number five is that the research information, that is anticipated to be generated from the project,
will be broadly shared in order to realize its potential benefits to global health. Principle six states that the
research should be supported through funding mechanisms that include appropriate oversight of all
aspects of the research. And, the final principle is that proposed research should be ethically justifiable.
This would mean that the broader ethical values and principles should be considered when reviewing a
GoF study of concern.
It is important to note that the ethical values, described a few slides back, are embodied we believe, by a
number of the principles listed here. This slide shows a new figure that does not appear in our draft report.
We wanted to present it here for your consideration. The working group has developed this figure over the
past few weeks, to better illustrate the review process that is envisioned for GoF research and concern.
The process would begin with investigators and institutions considering whether a research proposal
might entail GoF research of concern. Investigators could flag their proposals as potentially involving
GoF research of concern. Next a proposal would receive a standard scientific merit review. Proposals that
are identified as meritorious, and likely to be funded, would then be examined by the Federal funding
agency to determine if their project constitutes GoF research of concern. Projects anticipated to generate a
pathogen with all three of the attributes I described, would be sent for a higher level review, before they
could be funded.
We envision a multidisciplinary review involving broad expertise, including scientific, public health,
national security, biosafety, ethical, legal, and other areas. We envision a Federal level review that would
not be conducted by the specific program that would fund the work, but rather a group that could bring in

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experts to bear, from across the Federal government. These reviews would likely be informed by the
investigators proposing the studies, as well as the agency that is considering funding it. Only proposals
that are in line with all seven of the principles described by NSABB would be considered or funding.
Proposals that are determined to be acceptable for funding, could then be funded, and could proceed in
accordance with ongoing Federal and institutional oversight. It is important, importantly it envisioned that
during the higher level review process, that additional risk mitigation measures could be identified, and if
necessary, required as a condition for funding.
Our second draft recommendation states that in general, oversight mechanisms for GoF research of
concern should be incorporated into existing policy frameworks, rather than entirely new mechanisms and
policies. The working group felt that existing policies, if implemented effectively, could provide an
appropriate foundation for oversight. Of note however, as mentioned before, the level of oversight
provided by existing framework varies by pathogen. For some pathogens, existing oversight frameworks
are robust, and additional oversight mechanisms would generally not be required. For other pathogens,
existing oversight frameworks are less robust, and may require updating. Recommendation three speaks
to a need for a continued regular review and re-evaluation of projects involving GoF research of concern.
As we know, research is dynamic, and what is necessarily anticipated, does not always materialize. The
risk benefit profile of a study can change as the work progresses. In addition, policies and risk mitigation
measures should also be re-evaluated to ensure that risks are being adequately managed, and oversight
remains commensurate with risk. Recommendation number for encourages the United States government
to continue its effort to strengthen bio-safety and bio-security for all research involving pathogens.
Continuing to build a culture of responsibility will promote the safe conduct of research, including GoF
studies of concern.
I thought I would conclude by noting a number of questions that the NSAAB, and our working group,
have been considering. We sought input on these questions in January, and I hope our panelists today can
address them as well. I won't go through the all, but they're available in the NSABB draft report. As the
working group has continued its work since the January NSABB meeting, these and other questions have
continued to arise. Of note, question two refers to oversight mechanisms. And, the working group has
been considering whether linking oversight to Federal funding is the optimal approach, or whether
approaches that would cover non-Federally funded research would be necessary of feasible. I will also
note question three here, which is a new question the working group has begun to consider. The question
asks what type of body should be tasked with the high level review of GoF research of concern. Would a
FACA-like committee be desirable, or as now envisioned by NSABB, can such reviews be accomplished
by Federal agencies, or other groups internal to the United States government?
This slide lists other questions that we have been thinking about, and your input today on these, and other
questions, will help the working group finalize its draft. We've begun the planning stages for our next
NSABB meeting, and we expect the board to convene on May 24th to discuss, and possibly vote on an
updated report. A notice about this meeting will be forthcoming in the Federal register, and meeting
materials will be made available beforehand. I'll end by encouraging people to submit their comments to
NSABB at our email address. And, I want to thank the Academies again; I'm looking forward to the
presentations from an outstanding group of panelists, and to a very interesting next two days. Thank you.
Fineberg: Thank you very, very much, Dr. Stanley. We really appreciate the cogent and clear overview,
when it's very, very evident that the NSABB has been, not only diligent, but comprehensive and inclusive
in the way that you have approached the task, and I think all of us can be very appreciative to you for
your leadership, as well as to every member of the NSABB for bringing us to this point. We hope in the
course of this day, and tomorrow, to be able to provide some additional insights and input. I think the
seven questions, that you've outlined at the end, represent a very adequate framework to help guide some

Gain of Function Research: The Second Symposium: Day 1


of our discussion, and I'd like to make just a couple of introductory comments, if I may, and to share with
the group the thinking of the planning committee that tried to organize this discussion, so as to enable us
to come to grips most fully, and completely, with the questions and challenges that we're all trying to
understand and to illuminate in the course of these days. I think, personally that a really important starting
point question is one that you asked us about as to what does qualify, and should qualify, for research of
concern.
In fact, in my mind I think, you know we use the abbreviations GoF, I sometimes think we ought to be
also identifying GOFROC, which is GoF Research of Concern, because exactly what is it that would lead
us to want to focus additional attention on a particular subset of GoF research? And, I think this is not a
point to gloss over. It's a very fundamental question, and as you enumerate, the committee has tried to
come to grips with this, and I think quite helpfully identified three dimensions according to which a
particular research program, or project, could qualify as being of concern. I might note that sometimes we
use words like, of greatest concern or of concern, and I think it's a really important question about
defining a threshold when you move from a research program, which does not evoke a set of additional
concerns to one that does. To put it another way, one way of thinking about the scientific research
enterprise overall, is to imagine a starting point at which we all believe that research, in general, is a good
thing, because it is a good thing for science to uncover and discover truths of nature.
And, the scientific merit of any research program that examines, and seeks to discover truths of nature
intrinsically, is a good thing. At the other extreme, another starting point would be that there's a class of
investigation that evokes sufficient concern, either from a scientific point of view, or from an ethical point
of view, or from a broader social point of view, that would lead that research intrinsically to begin as
questionable, and where the burden of proof would be on the advocates of the research to justify its
continuance.
So, on the one side, a possible starting point is, science is good, when do we question whether it should
go forward, and on the other end, a class of research is so dangerous and ill-conceived that it takes a lot of
effort to demonstrate why it should go forward. The NSABB has offered these three dimensions of
transmissibility, virulence, and resistance, as a way of defining a subset of GoF studies that warrant
attention. Or, to put it in terms as I've been describing, where the burden of proof falls on the investigator
and the champion of the research, to document why it should go forward. One of the features about this
which I'd like to raise as a question is, it doesn't seem to take account of the starting point of
transmissibility, virulence, and resistance in the native organism, or the wild organism that one is
beginning with. In other words, if you have a very resistant organism that is very virulent if contracted,
and all you want to do is to test whether the function of transmissibility could be enhanced, why would
that be less of concern than starting with a less virulent, less resistant, less transmissible organism, and
trying to produce increased function along all three dimensions. In other words, conceptually, would it
make more sense perhaps, using these same three attributes, to think about zones of GoF where concern
enters, because any combination of the three, any one, two, or three, leads us to a zone of concern outside
of what the native organism represents, in terms of transmissibility, virulence, and resistance. I'd love to
get your thoughts about that as we open our discussion more widely.
A second point that I think is very important, and that was alluded to by Dr. Hamburg in her opening
remarks, and others, but which I think has to be foremost in our consideration, is that these policies, and
the decisions that NSABB will recommend, are National policies. And yet, the challenge is intrinsically a
Global challenge. In your remarks, Dr. Stanley, you talked about examining the regimes of biosafety and
biosecurity, and looking at those internationally as well as domestically. And I hope that in the course of
these two days, we will be able to examine more completely, with the help of all of the participants, the
issues related to a global regime to manage this class of research of concern, in addition and beyond any
national regime.

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Otherwise I think, and I would say it's the sentiment of the organizing committee that we won't have done
completely the necessary task of providing an adequate framework for the conduct of this research that
can go on anywhere in the world in the course of thinking about how to best organize and bring out the
elements that we hope will be useful in the deliberations of NSABB. The organizing committee is setting
up the program today to look at the frameworks of thinking about risk and benefit, and the overall
landscape of the policy environment in the US and abroad. Tomorrow, we have organized the program so
as to be able to delve more deeply into selected aspects of coming to grips with the problem. So, we're
going to be looking tomorrow at the science of safety and of public deliberation, very important both for
the ethical, as well of the practical effectiveness of policy. We're going to try to examine the ideas of best
practices, which the NSABB has enumerated in terms of its proposals, and we want to both tear that apart,
and build it back together from the vantage points of the biomedical, public health, and lay communities,
and we're going to deal with that.
We do hope to spend time specifically on governance, both domestically and globally. And then finally,
we'll try our best to take advantage of all the main ideas and insights that are raised in the course of these
two days, to bring together in a summary session that again, we hope will be of use to the, to the NSABB.
I'd like to take a moment as we get to the threshold of where we're going to invite comment and input
from all who are here, to remind everyone about the products that will come out of this meeting. There
will be, of course, the archived web cast. And, that will be available for anyone who wishes to re-examine
any part of the discussions that have gone on. We think that should be available, as an archive, by the end
of next week, and all participants will receive an announcement about its availability. There will also be a
complete transcript of what is said at this meeting. We hope that, that will be available by the end of this
month. And, that again will be posted and there will be an announcement of its availability.
The primary product of this consultative workshop will be a summary of the discussion. This is an
account of the presentations and of the comments that are offered by all those that are here, or that come
in to this group from those that are listening and participating on the web. The purpose of this meeting is
not to reach any collective views, much less shared conclusions or recommendations. Our purpose is to be
able to represent, in as coherent and effective a way, the central ideas and suggestions for the benefit of
the NSABB, the NIH, Government policy makers, and others who wish to take advantage. Keep in mind
that for the purpose of this meeting, only what is actually expressed at the meeting, can find its way into
the summary. So, if you would like to have your views or ideas included, you have to speak up. There
will, of course, be other opportunities, as we've been informed, to provide input separately to the NSABB,
and to the NIH, but for our purposes, for this meeting, we will take full advantage and do our best to fairly
and accurately represent the ideas that are raised at the meeting. When you do offer a comment, or pose a
question, we'll invite you to the microphone so that your words can be recorded. And, I would ask that
you would state your name, and a brief affiliation, so that we can accurately attribute the comments in the
course of doing the summary.
Similarly, we will ask that those that submit questions over the Web, or via Twitter, or other mechanisms,
identify themselves so that they can also be identified in the summary of this workshop. With that, let me
again thank you, Dr. Stanley, for a very cogent introduction, and we're now open to comment, questions,
and other advice from those who are present. Please come to either microphone that is set up on either
side of the seating, and we'll recognize people in turn. And, I will join you there. Sam, did you want to say
something?
Stanley: I did. I wanted, with your permission, to have Joe Kanabrocki from the University of Chicago,
and Kenneth Berns from the University of Florida, who chaired the working group, join me on stage.
Fineberg: Absolutely, please let me ask if you would both come forward, Joe and Ken, we welcome

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having your participation. And, let me turn to the first speaker at the microphone as they come up.
This is Abdulaziz Alagaili from Saudi Arabia. I'm a faculty member at King Saud University, a consultant
for the Ministry of Health and the Ministry of Agriculture. I'm very pleased to be here, and I'm happy to
see what's going on about GoF in the United States that, you know, everyone wants to make sure that, you
know, the researchers are following the rules. But I have a few comments that I might an address to the
audience. We see all these regulations happening in the United States, but what about other countries? Are
we thinking about other countries? From what I have seen, I work on MERS Co-V in Saudi Arabia, so I
get so many contacts from so many countries, and people are asking me for collaborative work. Some of
them, they have the money, and some of them are asking to prepare proposals, you know, to be submitted
to the government, mostly on MERS vaccines and something like that. So, for some scientists it's kind of
hard, there is a race between the scientists in the United States and outside, and everyone wants to catch
up, you know, we are the best group here, and you know, we need to accomplish something. So, there is a
race, and I'm afraid if someone thinks we have regulations in the US, lets move somewhere else to
another poor country where there are no regulations, and we can do all that research in those countries,
and no one is watching us. Its not about funding from the government of the United States?
There are so many companies, and they have money, and they want to get something done in a short time,
before someone else. So, they might go to another country and they do the research. And that happened
for me. I have been approached by, you know, several companies to develop vaccines, and they want to
do, like experimental infection on camels, and they said, "OK, let's do it in the desert," which is
something unusual. So, I see a competition between scientists, and they might do it in poor countries. This
is something else. And, sometimes, maybe, there is like a bridge to go over all these regulations by a US
scientist joining another group in Europe, in China, or somewhere else, and then you know, we are doing
all the research in that country, and there are no regulations. So, I'm not familiar with the regulations that
are proposed this time, so maybe it's not about funding only, it's about ethics. So, OK I have so many
difficult regulations with the United States, I'm going somewhere else. I'm joining other group in that
country, and then we'll do it, and we'll go over all these challenges. And, you know, my other point is
about GoF research that is, you know, in my opinion, it shouldn't be applied just to scientists at
universities or institutions, but also to be expanded to private companies. And, this is very important,
because they have the money, and they want to achieve their goals in a short time. Thank you so much.
Fineberg: Thank you very much for the comment and point. What I'd like to do is invite a number of
speakers, and then we'll turn to those that are here. Is that agreeable to you all?
Good morning. Piers Millet at Biosecure Ltd, and a global fellow at the Woodrow Wilson International
Center for Scholars here in DC. First of all, I'd like to thank NSABB for the excellent work that it's been
doing in this space. I have five comments on the draft working paper. The first one is how important it is
that NSABB opted to make recommendations broad enough to deal with any type of GoF research, more
broadly than the specific three types of viruses mentioned in the deliberative process. I would encourage
you to, as you move forward, and the US government as it reflects on this, to take, to set aside taxonomic
classifications and to avoid specifying specific agents. Second, I'm of the opinion that the existing
arrangements and frameworks may need more review than I see represented in your report. I think I will
come back to that after we've heard from Rocco, a little bit later on. Third of all, I wanted to point out the
International engagement on GoF will need to be a significant component moving forward.
That will require resources, it will need to be sustained, and it will need to be a two-way conversation.
The US government will need to listen very closely to its International partners. Whilst I like the concept
of thresholds on the three specific areas of GoF of concern, as listed in the report, I wonder whether the
barrier of requiring all three is too high, and whether if we look at approaches for prioritizing responses in
public health, and the development of counter-measures, perhaps two of those three would be enough to

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trigger greater oversight, if not a singular binary state of no oversight, or complete oversight.
And finally, in all areas involving health and security, I think it's important that both communities are
involved, so there have been some discussions moving forward of what International settings may be
appropriate to have those discussions. I would encourage you, and the US government, to look to balance
both health and security, and not to opt to move into one or other forum, and there for avoiding
perceptions of bias. Thank you.
Fineberg: Thank you very much. Let me move to the other side, and we'll alternate.
Gao: OK, thank you. George Gao, from the Chinese Center for Disease Control and Prevention, and also
the Chinese Academy of Sciences. So, from the report you cover, especially for the three major
experiments for the transmission of BDT, virulence and also for resistance. You know, last year, I think a
lot of people must have already read that paper, published from loss of function. So, while you are talking
about GOF, so now someone's doing some experiments for LOF. Why do you, you are such out for
experiment, you will never know. So, why do you expressly do your nutrition for a particular virus? For
example myself, I'm involved with H789 virus. It's very difficult to predict which method would reduce,
or increase, or enhance the virus ability, virulence of transmissibility. So, as I wonder, so why we are
talking a lot about GOF, should we also involve, you know, other experiments for LOF. That's a question
I, you know, get out so we can all discuss for the next day. Thank you.
Fineberg: Thank you very much. We'll go back here and alternate.
Jenna Ogilvie: Good morning. So, I am bringing a question from the Web. This is from Filipa Lensos. It's
briefly paraphrased for length. We are a group of International students in global health and social
medicine at Kings College, London. Key themes that have come up in our discussions relating to GoF
research concern relate to the lack of clear and convincing justifications for GoF of concern research,
global dimension of GoF research, and need for an International solution, and the potential for accidents,
abuse, and malpractice amongst others. A question for today's meeting is how will you ensure that the lay
public's voice, including ours, is heard and incorporated into the decision making process around GoF of
concern research?
Fineberg:Thank you, could you just repeat the third element that they had said they were studying.
Ogilvie: Sure, the potential for accidents, abuse, and malpractice.
Fineberg: OK, thank you.
Hi. Mark Lipsitch from Harvard Chan School of Public Health. Thank you for a helpful presentation. I
think that the possibly most essential issue that was raised, is the first question that Dr, Stanley addressed,
raised, which is have the criteria for GoF of concern been adequately laid out. And, I think there's been
some confusion about the three criteria. The three criteria were initially virulence, transmissibility, and
resistance, and it was a necessity to have all three. Today the resistance to counter measures seems to have
been dropped in favor of a new criterion that's also considered necessary, which is the criterion of being
more virulent or transmissible, I didn't completely catch it, but worse than things that are currently in
nature. I think the initial White House charge, the comments of the Infectious Disease Society of America
that were submitted recently, and common sense dictate that really the first two criteria alone together, but
without a third criterion, define GoF research of concern. Whether or not a novel agent that combines
those traits is worse than anything out there, is not really the issue, especially because it's hard to know
what's out there, or how we would define it, or what we would compare it to.

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Are we comparing it to the seasonal variant that's there now? Are we comparing it to all possible
pandemic flu's that have ever been? The comparison makes no sense to me, and it seems to me that no
one was pointing to these, to any third criterion, when they identified the work of Fouchier, Kawaoka, and
others as being of concern. And, adding a third criterion possibly rules out actually any of the studies that
people have been concerned about. So, I think the two criteria alone, on conceptual grounds, make sense,
and on empirical grounds of what we have actually been concerned about, make sense, and I think the
third is just a distraction.
Fineberg: Thank you. Please.
Nicolas Evans, University of Pennsylvania. I'd like to gauge the views of the NSABB members on two
issues presented here today. The first is how they see this proposed regulatory framework that happens
during the funding process interfacing with the Dual Use Research of Concern policy put forward by the
NIH in 2014 and implemented through 2015. The second is regarding the ethical values that were listed in
Professor Stanley's slides, and how they see that moving forward, in terms of these multidisciplinary
assessments that is purported to happen. It occurs to me that in the history of biomedical ethics and
human subjects research ethics, we bioethicists have often made reference to beneficence, and the benefits
of research, but actually articulating what those benefits are has been a very, very challenging process in
human subjects research, and so having those big four values plus two seems to be a much bigger
challenge again. Thanks.
Fineberg: Thank you.
Inglesby: Good morning. I'm Tom Inglesby from the University of Pittsburghs Medical Center. Thanks
for those presentations this morning. Just two comments. The first is I think there's a lot to commend in
the NSABB working group paper. In particular the finding that the current oversight structure is
insufficient for all we GOF studies of concern, I think that was finding three, I agree with that, it's
important. Another finding is that some research should not be conducted at all, the potential risks
outweigh benefits, which I agree with. I partially agree with the first recommendation in the working
group report, which is that studies of greatest concern generate highly transmissible, highly virulent virus,
and this has been discussed by a number of speakers. I do not really agree, or understand, the criterion
that was in the report before, it seems like it may not be in it now, but that experiments of concern also
have to be, quote, resistant to public health controls. I think if a virus is made to be highly transmissible
and highly virulent, that alone is the definition of being resistant to public health controls, and we should
not try to, kind of, pretzel ourselves into thinking about what another definition of public health controls
might be.
We don't control seasonal influenza at this point, and I think that speaks for itself. I don't agree with the,
something that I don't know was discussed this morning, but I think is in the reports still, which is that US
government funding is really the only mechanism of control of this work if it's deemed to be not
justifiable, risks versus benefits. I think we need to think about additional mechanisms, certainly the US
government is not the only entity that might fund these, it could be private research, it could be other
government research. So, I do think, just in keeping in the long view, funding or no funding is not a
sufficient mechanism of control if we determine that this does need to be controlled. And then finally, I
would just commend to the group that I think hopefully by the end of two days, we'll be talking broadly
about policy options. I know we're not, this is not decision meeting, and policies aren't going to be made
here, but I do think that we're getting to a point where policies will need to be made this summer, or
sometime at the conclusion of the process. So, I hope that we will be able to get to a discussion of
concrete policies, and to that end, I would say that my colleagues, Dr. Lipsitch, and Dr. Relman and I,
have circulated a document that suggests some possible policy options that might be useful for you to
consider. Thanks.

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Fineberg: Thank you very much. Let me just say that we're, although we're not going to be trying to do
any collective decision making, we definitely welcome specific guidance, and specific recommendations.
In fact, I would say the more specific the comments that any of us offers, the more likely it is to actually
be useful to the NSABB process. So, we welcome those specificities, specific elements as well. Please.
Megan Palmer: I'm a senior research scholar at the Center for International Security and Cooperation at
Stanford University, and I want to thank you for the discussion so far, and I'm looking forward to the
discussions the next two days. I wanted to note that many of the questions that came up as items for
further consideration in the NSABB draft report do recapitulate some of the central questions that were
charged to the committee at the beginning of this process, notably the adequacy of current oversight
institutions and the adequacy of the current dual-use research of concern frameworks. And also, whether
or not these oversight mechanisms, the discussion at the last NSABB meeting regarding how to establish
meaningful norms, either through strong red lines, or through these processes, came up as a central
question. I wanted to ask, considering that the notable focus of this meeting on what are best practices
around oversight, what were your key lessons, in either the limitations on expertise, or the limitations in
the process, that you came up against in trying to address these questions about the adequacy of
oversight? Are there things that you would like to see addressed, in the course of these panels, regarding
best practices for oversight, or any places where we aren't resourcing or gathering expertise currently?
Thank you.
Fineberg: Megan, just to clarify for a moment, when you talk about the adequacies, are you referring to
the policy levels, or the institutional and researcher levels? Is it more the policy process you were asking
about?
Palmer: I think it's both. I think this question of how do we gather the data that we need in order to assess
the adequacy of current policies and current institutions, and was this a problem even in the process of the
current deliberations.
Fineberg: Thank you, Keiji.
Keiji Fukuda, World Health Organization (WHO). So, first I want to thank the panel and the board for the
materials that you put together. They're really very well done, and I think the process to date has really
covered a lot of the issues. But, you know, coming from Geneva, there are a couple of things that I was
struck by. Let me put it this way. Coming from influenza and having worked on some of these viruses,
and then having worked on some of the issues, dual-use issues, which really came to the fore a few years
ago, you know, this is a bit of a precise discussion. It has to do with viruses; it has to do with GoF, but
beyond GoF, GoF of concern. I think, Harvey, in your remarks up there, you were saying something about
of concern, what does that mean? Coming from a global perspective, one of the things that I'm struck
by at that level is that I think of concern is really one of the critical issues here. It's easy to understand
why we focus on viruses, and particularly viruses with pandemic potential. But I think it's also clear that
if we take a further step backwards, there are studies that involve animals, there are studies that involve
genetic manipulation that go beyond viruses, and at the global level, it's probably hard to have an overly
precise discussion about any of these concerns. To give you an example, I think that if we look at
genetically modified food, which we're not talking about safety or so much security concerns, but still at
the global level, a lot of the issues that will be discussed are how it would relate to biological diversity,
what kind of impact does it have there, what kind of commercial impact does it have, what kind of
implications will it have in terms of food that will be grown and the requirements for that. So I'm just
raising these issues, because I think that, you know, as Piers indicated, this is not just a national issue, it's
become an international issue or it has International implications. I think that in looking ahead at how
such a discussion would unfold, I think that over the next couple of days, these kinds of issues will be

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helpful to address, and hear what is the scope and question, and is that going to be sufficient for taking it
forth International.
Fineberg: Thank you very much. Please.
Katherine Rhodes from the University of Cambridge Center for the Study of Existential Risks: So I work
broadly in the area of International governments of genetic resources, so I want to, again, make some
comments on the International situation. The first one is that as well as engaging with the health and
security fields, there'll be a need to engage with access and benefit sharing regimes in this area. The
second is to really think about your engagement with the scientific community. So, there was a meeting
about two weeks ago in the UK Parliament on How Safe is Pathogen Research. And, talking to people
there, who are doing some of the Influenza research, they were asking, "How could they get International
standards without having it dominated by the US process?" And, I think that was largely based on
misperception of the moment of what the US process is and a fear that that would incorporate bans of
certain classes of experiments. So, that's a perception coming from the scientific community at the
moment, and I think there's a need to make sure you're engaging, so that, you know, some of the
misperceptions, or misinformation is sort of dealt with.
Fineberg: Thank you very much. Please.
Michael Selgelid, Center for Human Bio-Ethics at Monash University: Thanks for all the great work on
this important issue. I have two main points. One concerns to the delineation of GoF research of concern.
You know, one might argue that there are not two kinds of GoF research, that which is of concern, and
that which is not of concern, but there's a whole spectrum pertaining to degrees of concern. So, one could
argue that GoF research is more or less concerning depending upon the degree to which the pathogen
created is more transmissible or not, more virulent or not, or more resistant or not to existing control
measures. Beyond existence of control measures, we should also keep in mind availability of control
measures that might exist. And the move, if I understand correctly, to a binary conception, is the idea that
we need to decide if it's concerning or not to decide if we're going to have extra scrutiny of the study or
not.
But, we're not forced into that situation, because we can recognize that there's more or less concerning
research, we can say The more concerning the research in question, the more extra scrutiny we need."
So, the response can be scaler, as well as the conceptualization of the research we're talking about. So, we
shouldn't forget about that. We should also keep in mind that that's maybe a more realistic way of
addressing this issue. Because I'm not sure where thresholds for transmissibility, or virulence, or
resistance would come from without pulling them out of a hat, right? So, what would be a scientifically
realistic way of setting these supposed thresholds? That's the first point.
The second point concerns the diagram that was presented about the process of addressing GoF research
of concern, and if I understood that correctly, first there's an evaluation of whether or not the study is
scientifically meritorious, and then there's looking at whether or not it's research of concern, and then
there's the side process that might happen, scrutinizing it with regard to concerns about it being of
concern, and then it either passes the test or not. It's either ruled out on grounds of concern about it being
a concern or not, and if it passes that test, then it gets to the box where it says, "Considered for funding."
This raises the question of whether or not, at that stage, the GoF aspect of the study should be taken into
consideration, cause what, because when it's considered for funding, presumably it's going to be in
competition with other studies that have gotten to that stage in the process, and you might think that
there's two studies that are equally scientifically meritorious, and that have both passed the test of not
being ruled out on grounds of being of concern, that other things being equal, it's better to fund a less
risky study, if we can't fund both. Thank you.

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Fineberg: Thank you very much. You're next.
John Steel, Emory University: Ive got an audit to anybody that works on the transmission of influenza.
So, my question is one relating to their entry finding, the GoF concern studies relate to viruses that are
highly transmissible. And, I just want to ask, how are you going to define highly? So, you're going from a
situation from non-transmissible or transmissible, to highly, which is if you want to say a semiquantitative definition. That may sound like it's a down-in-the-weeds question, but really it's when studies
are going to go in front of Institutional Biosafety Committees (IBCs), how do they decide what is highly
transmissible given that the animal models we use are fairly blunt. Is one out of three transmissions not
highly transmissible, but two out of three is? So, is it intention of the board to make some kind of
guidelines, in terms of a definition of highly transmissible, or is it more the intention to allow the IBC's to
decide that, and for the studies to work their way up from the bottom?
Fineberg: Thank you very much. I hope you've all been listening carefully, because there's a lot of
comment here to invite your response, and Joseph, maybe we could begin with you, and just work our
way down, if that's agreeable to everyone. I'd welcome your initial reactions to anything, but I hope that
the group particularly reflects on the array of perspectives around this core question of what qualifies as
being of concern. We've heard a number of points of view about that, question of whether all three criteria
are necessary, question of whether it's sensible to try to define thresholds as opposed to continuities,
which invites then a very practical question of what exactly defines a threshold, question of whether,
depending on where you start, then one of the three could be sufficient to make this research program of
concern, and so forth. So, we have a lot of comment just on that question, which I hope you'll come to.
Then, lots of observations and reflections on some of the, let's call it, international or global dimensions
of this, including the movement of researchers, the scope of research that might be related, the nature of
the governance processes, etcetera, and I would really welcome your comments as well on that, in
addition to the specific questions, or observations on regulatory framework and approach. So, Joseph, I'll
begin with you and real welcome all of your initial reflections.
Joe Kanabrocki: So, thank you. A lot of great points were made, and I think many of the comments made
really reflect the discussion that the working group had over these many months. We've struggled greatly
with a lot of these issues that you've raised here today. I'll begin by addressing the central question, the
three phenotypes that we're looking at here. It's been suggested that we've shifted our thinking on the third
criterion, and I don't think that's really true. I think in the way the original language was written, there was
misinterpretation of that to be limited to resistance only. And, really we meant to have that be taken more
broadly, such that it's about being capable of spread, of basically the pandemic issue, and you know, that
takes into consideration the background of the virus that's being managed, and whether there's hard
immunity potentially to that virus, and it's not just about resistance to counter-measures. So, the third
criterion was originally intended to be broader than it was interpreted, and again, we heard a number of
times this morning, the focus being on resistance, that wasn't our sole focus though.
Fineberg: Do you want to just discuss this point, I mean maybe we should stay on this point first, because
there are lots of vantage points? Let me just ask you directly, do you believe that all three attributes
should be present in order to put a proposed experiment in this category of concern, holding aside the
important observation about continuity? I would really love to hear your thoughts on this.
Berns: I guess I came from the point of view that what's important is what you wind up with. Several of
the attributes may have been there to start with, and so what we're really concerned about is the potential
for a pandemic. So the question of whether or not there are existing defense mechanisms, which would
inhibit the development of a pandemic, I think, is an important consideration, and I thought Tom Inglesby
made the point, we're not too terrific with seasonal flu, and that depends upon the year, of course, and

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which vaccine we're using. But I think that accepting that variability issue of whether or not, at least in
practice there's some way of blocking the spread, is an important consideration. So I think that third point
is actually a very important point.
Fineberg: Sam, did you want to comment on that?
Stanley: I think that what the working group was trying to drive at was, and I think it came out in the risk
benefit analysis as well, are you creating a risk that's above, significantly above an existing risk for that
pathogen? So in other words, we can say it's a slightly different strain or whatever, but for that pathogen
you're creating something that goes beyond the risks that already exist for that pathogen. If you take a
look at the example again, and influenza is the one that was utilized, changing it, and yet if the same
antivirals are still effective, if vaccine potentials are still effective, is that risk above the risk that's done
every day for people who are working with influenza? So why is this particular research then singled out,
if that ultimate risk doesn't look different? I think that's what was being driven at, is that you're creating
something again where there is not natural immunity, so it's a situation where if it's a H5N1, for example
that there is a natural immunity present, you now are able to transmit it much more effectively than it
could before, that's the result, then that does clearly, in my mind, translate to GoF research concern, it's
something one needs to deal with. If one was working with a seasonal flu strain, an altered one
component of it, and yet the same defenses were still in place, I can see the point, if it became much more
viral, that's a potential, so I can see the point there, and I think, you know, and I said, so I think there's
always been a question, is that last point an and or an or, for each of these criterion, and I think this is
what we want to discuss today.
Fineberg: I think it'll be interesting to hear other views in the course of the meeting. Ken I was taken with
your observation that it really depends on where you end up, that's crucial, not where you started and
what the trajectory is from there to the end. And I think that the questions about thresholds for policy
action, if you get very practical, is really not a trivial question, as was amplified by the comment about the
continuity of these attributes as well. Would you like to comment, any of you, on how are you thinking
about the relation between the process that you've been involved with for the US government, and the
NIH, and what is happening elsewhere in the world? Do you have any preliminary reflections on that? Is
it just beyond the mandate of your NSABB assignment, or how would you, how would you find it most
helpful, from the point of view of comments that we'll raise in the course of the next two days.
Berns: We've brought in people from the EU to talk to us about the EU approach to this question. And that
was very interesting and useful to the working group, which actually constitutes almost a majority of the
NSABB, it's a large group. So, that was helpful. I think two things struck me. One is that many places
around the world, in fact, have considered this issue. They're approaching it. I don't know that any other
country has instituted a moratorium on this research, which I think is a comment unto itself, stands by
itself. And, I think the fears that have been expressed by some that people who don't want to be bother by
a moratorium simply move elsewhere to do their, to do their work probably is a real concern, to a certain
extent. I think, but what all of this, sort of, glides over is the question that arose in a major way when we
considered the original H5N1 papers level, and that is the fact, the ability of people who are not part of
the normal organization to be able to do the research anyhow in this day and age, and this point was made
to me by Dr. ter Muelen this morning.
You can buy a CRISPR kit now, and so the ability to do lots of things at the molecular level is possible,
and so that's of some concern, and potentially more than bioterrorists per se might be a real source of
something coming out that we'd be unhappy with, because it's unlikely that the kinds of containment that
we assume in an institutional setting will exist in that type of research.
Fineberg: Yeah, I think that reflects the comment that Dr. Fukuda raised about the way this blends into

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research concerns completely outside the domain of infectious disease, never mind virus pandemic
potential. Sam, you want to add anything?
Stanley: It's clearly an International issue. But our primary task was to advise the US government, but I
think all members think NSABB, as well as those who sponsor us, believe that we do need to try and
strive for a global solution here, and that some type of harmonization essentially of these processes would
be extraordinarily valuable. And, that extends to the issues around biosafety. One of the things that, you
know, one of the important recommendations we've made is that we want to see standards of biosafety,
and that for research to go forward, that would be GoF Research of Concern, we want to see established
biosafety and biosecurity standards. And, so I think that's important as we look globally as well.
I think the United States is typically a leader in these areas, so I think developing policies, hopefully,
could serve as a way in which we could collaborate with other scientific organizations, as well as other
governments. I think both of those are going to be important. And, I think what was raised earlier, and
Ken just talked about, about the challenge of going outside federally funded research, I think is one that
we've tried to deal with as well. At least we have talked about ithow one captures industry research, and
so on. I think often the biotechnology industry tends to collaborate or comply on their own because of
Federal regulations, if not for liability reasons, if nothing else. So, I think in general there's not a huge
dichotomy between the groups, but I think that's another thing that we're thinking about as well is there
a way to expand, essentially, these type of processes so it captures more than just Federally funded
research?
Fineberg: Thank you.
Kanabrocki: I would just add that, you know, we've had a lot of the discussions around these three major
issues, and you know, the International aspect is obviously very critical, and we recognize that. There's
been this tension between the real threat versus what is our charge, and you know, our charge is really
limited to US funded research with GoF with pandemic potential, so that was really limited to the human
public health realm. That said, we had many discussions that took it beyond the human health
considerations. And so the funding piece, the International component part of it, and the public health
aspect, those are three things that we definitely spent a lot of time discussing, but going back to our
charge, there's some tension there.
Fineberg: Yes. Ken, you want to add something to that?
Berns: Yeah, I think that the challenge of International harmonization is a big one. I'd like to commend the
paper that was mentioned by Tom Inglesby and Mark Lipsitch, coauthored with a third person, which
offers several approaches that might be taken on the International level to try to approach this. I thought
the suggestions were cogent. I'm not sure how practical it really is, but I think it's a starting point to think
about this.
Kanabrocki: And, I would just add, I mean, international harmonization would be wonderful, but we
could start by having harmonization within the US, that would be a big help.
Stanley: And, I think the other thing I'd add is that a lot of the concepts that were developed by NSABB
for dual-use have found homes internationally as well. So, I think there has been an opportunity and
there's been cross-fertilization between other countries and their policies and what we do, but I think that
also gives me some hope that what we adopt in the US could find its way, assuming that it is viewed as an
appropriate response could find its way internationally.
Fineberg: Has the NSABB, in its deliberations, gone so far at this point, of identifying the actual, not

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simply directionalities of transmissibility, virulence, etc., but the actual way to think about when a
threshold of concern is passed, either in terms of, for example, a set of reference organisms, or in some
other numeric or quantitative way, or if you think about the actual assignment to a future group, maybe
yourselves, who are going to be asked, does this or does this not qualify, how will you judge? Have you
thought about that as yet?
Berns: I think those are two different questions. How you predict what the consequences are is a guessing
game. I mean you can say, "Well, this seems potentially dangerous." The trouble is how you calculate that
risk in a quantitative sense is challenging, and we saw that in the Gryphon report. And, so I don't know
that, I mean we can only, sort of, do it in a generic sense without being all that specific. I think the
question, which we grappled with more is the level at which that decision is going to be made. Does this
specific experiment constitute such dire GoF of concern that we don't think it should be done. And, and so
the issue is, should that final decision, if you will, be made inside the government, or in a FACA
approach?
And, I think the issue, I mean the NSABB is a FACA, but that's beside the point of the sense. But, I think
the efficiency sense, in a way, says that maybe it should be inside the government. But the public interest
in a transparency sense would argue very strongly for a FACA. I was on the IOM committee that looked
at the fate of the RAC, most recently, and that was the major reason that we suggested that Therec be
retained, because it was the only window that the public had into what was going on.
Fineberg: Yeah. Any final comments that you'd like to make on any of the other points that were raised,
before we conclude?
Stanley: I just echo what Joe said, that the externally thoughtful, and helpful in terms of their scope and
scale, and as we said, some of them we've wrestled with, others I think brought some new perspectives.
Kanabrocki: I was just going to say another major thing that we struggled with is how specific do we
want to be in our recommendations, or do we want to stay back at the more conceptual level, and that's,
we've gone back and forth on that. And, so again with some of the comments that were made were calling
for rather specific guidance, and we've struggled with whether that's going to be ultimately useful as
something that can be used for overall GoF research analysis.
Fineberg: Yes. It's very hard, when you're making the recommendations, to put yourself in the mindset of
the recipient, but if you did that and asked, "Well, how would I actually act?" Now, if I receive this, it
might help answer that question for you.
Great. I want to thank everyone who participated thus far. Please keep in mind we welcome your
comments and ideas throughout this meeting. I hope that we will provide abundance of input that will
enable NSABB to come to the fullest understanding, and put forward the most helpful final
recommendations that they can come up with. Thank you all for joining us in the opening session and
thank you all for participating. We will resume at eleven o'clock. We'll come back at eleven o'clock, one
half hour from now.

Session 3: Informing the Policy Framework: The Risk/Benefit Assessment


Hi, I am Chuck Haas from Drexel University. I'll be moderating this session.
The way in which we've organized this, we'll first have Dr. Rocco Casagrande go over some particular
questions that we posed with reference to the work that you heard talked about this morning that Gryphon

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did under his direction. Then we have three comments. We've changed the order of the comments a little
bit. Tony Cox will start off, then Kara Morgan, finished off by Adam Finkel. And then at the end,
hopefully, we'll have a goodly amount of time for questions. And what I'd like to do in the question period
is we'll alternate between two mics, taking one question at a time for however many we can take until the
end of the session.
So with that, let me introduce Dr. Casagrande to talk about lessons from the risk/benefit assessment.
I'd like to thank the Academy of Science for inviting me here today and to provide an opportunity to
discuss some of the lessons we've learned in the conduct of the risk and benefit assessment, and also
address some of the questions posed to me by the panel.
Just very briefly, I'll go over the risk and benefit assessments, the salient points that were made, as well as
some of the subtle changes that have been made from the draft that was presented at the last NSABB
meeting to the final, which will be posted at the end of the month. I'll talk about the lessons we've learned
and some data gaps we encountered during the conduct of the risk and benefit assessment.
And then two of the specific questions addressed to us were how the risk and benefit assessment could be
applied to specific experiments that might be proposed in the future. And then, as many of you who are
following this debate know, our choice of using the 1918 influenza strain as one of the comparators has
been the subject of much discussion; so I'd like to add some additional comments on that.
Just as a reminder, the purpose of our eight-month study was to provide data on the risks and benefits
associated with research on modified strains of the influenza viruses and coronaviruses. And that was
broken into three tasks, each of which was completely distinct as far as the data that was collected and the
analysis that was conducted.
One was a quantitative biosafety risk assessment. The second, which actually had two components, was a
biosecurity risk assessment; and the last was a benefit assessment. And, as I said, the assessment was
comparative. It was to determine the change in risk from research on gain-of-function pathogens
compared to research on wild type pathogens and also the change in benefits. The benefit assessment was
also comparative insofar as what are the benefits of gain-of-function research compared to its alternates.
Just very briefly, some of the most salient points one of the points was trying to address the public
discussion that conflated an accident in a laboratory or a mishap in a laboratory with a global pandemic.
And we tried to suss out all of the individual steps that are required to get from one to another.
So a mishap occurs a spill, a breach in a glove, et cetera then someone had to become infected. Then
that person had to either be unaware that they were infected or breach isolation protocols and mix with the
general population and successfully infect others. Those others had to infect many in the community, and
the infection had to escape local control and then cause an outbreak. And at each step, even for very
contagious pathogens, like a pandemic influenza strain or like a seasonal influenza strain, the chance that
it precedes the next step is not assured.
This is the summary that we provide of where risk inheres across the various modifications. In yellow, we
show some of the changes from the assessment that was published in December. And the changes
happened based on some data that was pointed to us by Kanta Subbarao in the last NSABB meeting,
some recent data that showed quite a high degree of cross protection afforded by exposure to the 2009
influenza against the 1918 influenza.
When we incorporated those data, it took some epidemiological calculations that will provide a little bit

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of additional length to the risk assessment. But when we incorporated that, we found that the 1918
influenza wouldn't be as transmissible as we initially thought, which then implies if one were to make it
more transmissible or to have it evade this immunity, that would increase its risk. So essentially the
experiments that are of concern of pandemic influenza virus mirror those of seasonal influenza virus,
which we'll get to in one of our lessons learned in the future, but further underscore the decision by the
NSABB to focus on those phenotypes.
Specifically, here is an example of the some of the data. If you look at the median global deaths that
would occur should a global pandemic be sparked by a 1918 influenza, the high degree of protection
afforded by exposure to the recent 2009 influenza actually reduces global deaths by a factor of about
1,000 compared to a strain that would be completely antigenically novel or of which the population would
be completely nave. Therefore, in making a 1918 influenza that is antigenically distinct from the wild
type one could increase risk significantly.
The other interesting thing about this is the 1957 H2N2 pandemic strain then becomes the most risky
strain because it would cause about 100 times more global cases because of its antigenic profiles, while
it's only one-tenth as deadly as the 1918 strain. And the riskiest modified stain is a 1918 H1N1 strain
modified that's modified to evade residual immunity simply because it has such a high case fatality rate.
So once again, all these changes just further serve to reinforce the phenotypes focused on by the NSABB.
Some of the other salient conclusions were that manipulating gain-of-function seasonal influenza strains
at BSL3 may compensate for the increase in risk posed by the modified strains, basically by decreasing
the risk of a laboratory-acquired infection in the first place. And that's essentially mostly by providing an
extra system of respiratory protection.
Also, we do highlight several experiments that could pose a risk theoretically; but many of them may not
be achievable or many of them might not have scientific merit. For example, a strain that can overcome
protective vaccination increases risk only if it can evade vaccine protection via immune modulation, not
by shifting the antigenicity profile of the pathogen. Once again, the scientific value of that experiment
might be questionable.
The scientific value of increasing the transmissibility of influenza virus beyond that of the most
transmissible strains or increasing the final titer beyond 1 times 10 to the 8th (1E8) PFU/ml is
questionable and also perhaps infeasible. Also, there is no model of transmission for the coronaviruses, so
manipulation of this trait is not currently achievable. And also, some have contended in some of the
comments we've received that SARS-CoV is much more transmissible than we modeled in the baseline;
and so further manipulation of that wouldn't have any risk.
When we're looking at the biosecurity risk assessment, some points are worth making or repeating. The
traits that drive the biosecurity risk are the same as those that drive biosafety risk. And that's because once
the incident occurs and there are infections in the population, the probability that the outbreak would
escape local control is driven by the same phenotypes.
The other important point is these biosecurity events seem to evolve the covert infection of the public,
meaning that there isn't an opportunity for isolation protocols and health-monitoring protocols that are
implemented on laboratory workers to curtail the risk of an outbreak. And so these biosecurity events,
were they to occur and infect someone, have a greater risk of sparking a global pandemic.
Because of that, the biosecurity risk, we contend, should be given as much weight, if not potentially more
so, than biosafety risk because each individual event that involves an infection has a greater chance of
becoming a global pandemic. And I want to emphasize here that the biosecurity events that we are talking

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about, the ones that we think are high-risk because they are probable and consequential, aren't that
someone would purloin the strains and create a weapon and intentionally infect the public, but that other
nefarious events would occur such as workplace violence, theft, stealing infected animals for animal
welfare purposes. These types of events that we see happening again and again in laboratories throughout
the U.S. are the ones that would drive the biosecurity risk.
On the information risk, we found that minimal information risk remains for gain-of-function studies in
the influenza viruses because the dual-use methods that would create more contagious, or more deadly, or
both, pathogens have already been published. There is significant information risk remaining for gain-offunction studies in the coronaviruses, but these studies are hampered by a lack of model systems. So the
bottom line here is that if we were to look at studies where the publication itself could be used to generate
information that would be leveraged by someone who has the intent to intentionally create a very
dangerous virus that there's minimal information risk remaining for influenza and that we don't have the
tools to leverage the information risk yet for the coronaviruses.
The other important point in the Information Risk section is that any information risk that exists in the
influenza and coronaviruses is not unique to those pathogens. We describe several other types of
pathogens that could be manipulated to create similar risks of modified strains.
And lastly, in the Benefit Analysis, I recommend that anyone who is very interested in this field read the
longer version of the benefit analysis that's there because the devil is in the details. However, we have
identified several benefits arising from gain-of-function research that have significant advantages over the
alternatives. The exact nature of those benefits, though, depends on the exact experiments that are being
conducted, and that's all described in the benefit assessment.
All right, so moving to the charge that we were given, what were the lessons learned in the gaps. There
were several lessons we learned during the executions of the risk and benefit assessment. For the sake of
time, I'm going to talk about the top four; and I'll talk about them in order.
The first was something we noticed during the conduct of the RBA which was then driven home by the
final pieces of data that were highlighted by Dr. Subbarao, which was that there is really an artificial
distinction between seasonal and pandemic influenza strains when we're dealing with biosafety risk. And
by that, I mean that the discussion thus far of these two types of pathogens has been distinct largely
because public health and policy stakeholders often compartmentalize pandemic and seasonal influenza
strains because they have very different risks when they first emerge.
However, after emergence, the pandemic strains contribute to the population and seasonal influenza
strains in the following years. And many of today's H1N1 strains of seasonal influenza are descendants of
the 1918 strain.
So the interesting thing is something that we learned during the conduct of this risk and benefit
assessment: the risk from a laboratory accident or a biosecurity incident with an older pandemic strain
must be understood in the context of the non-nave population, although all the epidemiological data we
have from these strains is largely from those initial outbreaks. So distinguishing that one pool of data, that
very robust data we have, and modifying it to account for our non-nave population is actually pretty
tricky, but one thing that we did in this final version of the report..
Anyway, there's no bright line between these strains, between the seasonal and old pandemic strains; so
risk is best understood as a single continuum. We have pandemic strains with case fatality rates that are
about that of seasonal influenza, and transmissibility about that of seasonal influenza; so the distinctions
begin to disappear. So all it does is create these artificial boundaries and additional complexity to any

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study without adding a lot of benefit.
And I want to point out that although it makes sense to consider them as one continuum for examining
older pandemic strains that have emerged in the past and are being studied currently, it's not true for risk
and benefit assessments that look at the risk of emergence. Should a new pandemic strain evolve in nature
for which we have no immunological experience, then that should be analyzed as a completely distinct
thing.
The other thing that hampered our study was a lack of data on human reliability assessment in life
sciences laboratories. We had data from other industries that demonstrated quite clearly that most failures
in safety equipment are due to human ignorance, carelessness, or neglect; it's not mechanical failures that
are driving these accidents that occur.
As an example here, faulty PAPRs are produced much more rarely than sound PAPRs are poorly worn,
poorly assembled, or poorly maintained by the personnel using them. Moreover, when we look in the life
sciences laboratories, most mechanical failures that occur are accompanied by some signal that a human
worker has to ignore, misunderstand, or intentionally override all of which have occurred to create a
dangerous situation. A mechanical failure by itself is not sufficient.
Additionally, in the life sciences enterprise -- unlike the nuclear, chemical or transportation sectors -mechanical failures by themselves aren't sufficient to cause an accident. In general, the accidents that we
see occurring that lead to infections in life sciences laboratories, there is a human error that initiates them.
The most common accidents that we see that drove infection risks were slips, spills, misuse of
centrifuges, and cuts, whereas it's not just pipes failing that cause a breach in a chemical plant, for
instance.
So despite the importance of human factors in driving the risk of accidents, we found extremely little data
on human factors and their relationship to accidents and infections in the life science enterprise. We did
find some data on animal bites and how human practices influence the frequency and severity of animal
bites in laboratories, but that's about it.
So our risk and benefit assessment had to analogize from human reliability data from other industries to
activities in the laboratory -- somebody misreading a dial on an airplane or in a nuclear plant, misreading
a dial on an autoclave, for instance.
And this shortcoming prevented an evidence-based and rigorous assessment of absolute risk, as was
pointed out by Dr. Stanley. We didn't have enough data to use our probabilistic risk assessment to say how
often a spill would occur such that an infection would happen because we don't know how often when
someone is using a microtiter plate the Pipette tip skips over the top of the well and sprays them; we don't
have those data.
We don't know when someone is doing a necropsy using scissors to cut open a mouse, how often they slip
and breach their gloves such that it causes an infection risk versus how often they just drop the scissors,
for instance. So this shortcoming prevented an absolute risk assessment from being created that was
actually evidence-based and defensible.
And I think though looking forward into the future to kind of improve biosafety analysis that's
undertaken, this shortcoming is addressable by primary research. Primary research on human factors in
the life sciences laboratories must be conducted to fill this data gap. And we've seen this research
conducted in very extensive studies that were undertaken in the transportation, nuclear and chemical
industries, which seem to have much less total possible consequences. When we're talking about a nuclear

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power plant accident, the consequences from that are certainly dire; but they don't match that of a
potential global pandemic. So the lack of investment in the human factors research in life sciences is
something that definitely needs to be addressed, and that would help any risk and benefit analysis in the
life sciences going forward.
We found the lack of a risk/benefit benchmark difficult to deal with in our risk and benefit assessment,
and I think that was echoed in a lot of the comments that you've heard already this morning and probably
will hear later on going forward.
Our study focused on the change in risk posed by the manipulation of a wild type pathogen into
something else, and we highlight how much risk increases for particular manipulations. However, that
increase is sometimes from a low level; for example, increased virulence or tighter in attenuated strains.
We could say the risk of an accident or of a global pandemic from the wild type pathogen is tenfold or a
hundredfold or a thousand fold higher. But is that sufficient to make it into a category that requires
additional oversight? For instance, given Dr. Stanley's comments this morning, does that allow the strain
to cross into the moderate category or the high-risk category?
Sometimes we found that the risk of a pandemic increases to a level posed by any wild type strain, and
that's what we highlighted in our risk assessment as well. However, most of the time for the
manipulations that we found, pandemic risk increases but to a level much less than that posed by the
worst pandemic strain, which we're now considering the 1957 H2N2 strain. So still, we have that problem
of a lack of a bright line.
So does it make sense to continue suspending funding of research that creates new risky strains while
continuing funding research on wild type pathogens that pose more pandemic risk? Does it matter if the
non-manipulated strains were created by nature? For instance, if you're just creating a new strain that has
more risk than the wild type strain, does it matter if you're working on a wild type strain that has
extremely high risk that nature created? Does it matter if nature created it once but it's now extinct? So
SARS-CoV no longer exists in nature and also neither does 1918 innfluenza. Does that matter? Should
that be considered?
And in the absence of agreed-to risk benchmarks for wild type strains, absolute or relative risk metrics for
any manipulated strain, we found difficulty in interpreting our studies. Once again, in a relative risk, we
could state that risk increases a hundred fold; we could even say risk increases to more than any wild type
pathogen or any particular wild type pathogen. But the so what is difficult to say without an agreed-to
benchmark saying this much risk is acceptable and this much risk is not acceptable.
Also, I think if you listen to the debate that has occurred to this point on gain-of-function research and on
the pathogen research enterprise, a lot of that debate seems to be people talking past each other about
whether they basically agree that the risk of working on wild type pathogens is acceptable simply because
nature created them versus those that don't agree that that is true. And I think you see a lot of people
talking past each other based on that baseline assumption that they disagree on.
Lastly, our risk and benefit assessment, the quantitative part at least, was restricted to the influenza
viruses and the coronaviruses. The Information Risk section had to look more broadly because a hostile
actor, an intelligent adversary, is free to choose whichever pathogen they want to achieve their ends. And
in this Information Risk section, we identified that manipulations of pathogens other than the influenza
and coronaviruses could pose similar levels of pandemic risk if it was driven by someone with nefarious
intent.
The remainder of our study, though, examined just one component of potential pandemic risk, just those

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particular pathogens, the full suite of which should be considered as part of a comprehensive risk and
benefit assessment. And the risk and benefit assessment should provide a set of benchmarks that look at
the highest tolerable risk of looking at pathogens that currently exist versus ones that are extinct or could
evolve -- like notional pathogens, theoretical pathogens. I think it makes sense to have two sets of
benchmarks there, but that's a policy decision.
Also how risk tolerance might change given different containment levels so what's acceptable to be
done at BSL3, BSL3 enhanced, and BSL4.
The second question that was posed to us was how the risk and benefit assessment would be applied to
specific experiments. And that's because, as was made clear this morning, decision-makers might be
asked to evaluate the risk and benefits posed by specific experiments, either in grant proposals or in
institutional reviews. I think both were positive in the discussion this morning.
The good news is that our risk and benefit assessment -- I've often described it essentially as an
encyclopedia. There are no conclusions at the end; it's just a set of data that shows how risk changes and
where benefits increase. So it can be used broadly going forward by those struggling with these decisions.
To understand the benefits -- I don't have it on the slide because it's pretty easy. -- you go to the Relevant
Benefits section and look at the discussion that's going on there and what are some of the arguments that
are made in support of some of these benefits; what are some of the alternatives that should be
considered; what are their relative strengths and weaknesses. And that would be a great starting off point
because at already at 500 pages or so, it's a broad review of the topic. Additional data for the specific
manipulation being proposed would need to be brought in, but it's a pretty good starting point there.
To understand risk, once again, I think the nature of the task here is to understand the potential risk or
reasonable, anticipated risk. One of the commenters this morning brought up the excellent point that
science is interesting because it's unpredictable. It's potential that you might think you would increase the
transmissibility or the pathogenicity of a virus but find out that you've attenuated it accidentally due to the
manipulation that occurred. But still, if the intent is to see what's driving transmissibility or pathogenicity,
if the intent is to create a strain that's more pathogenic, that's a reasonably anticipated change.
So the first step is to identify the strain that's worked on and to describe its properties that are relevant to
pandemic risk, those properties we were talking about this morning in the NSABB policy, then to
understand how the proposed experiment could alter any of these properties. Once again, science is
interesting because it's unpredictable; but what is the reasonably anticipated change.
And then using our Section 6.6 in the RBA, examine how the proposed change could affect the
probability of an outbreak escaping local control; and in Section 6.7, how that would affect global
consequences -- so the probability of an outbreak becoming a pandemic and also the consequences should
it become a pandemic. And then in a very simple way, that could be done by almost any reader of the risk
and benefit assessment. Simply multiply these two factors together to obtain what I would say is a
perspective on the change and risk. I'm not going to stay you should stick to that number because it's a
very simplistic way to interpret the risk and benefit assessment, but it's something to give you an idea.
So for some examples, I think the examples might be illustrative here. We provide an experiment. What's
the risk posed by experiments that include virulence factors from 1918 H1N1 influence into a 2009 H1N1
strain? We know that the 2009 strain wasn't that pathogenic compared to the 1918 strain, approximately
equivalent to a seasonal strain. So this experiment could be reasonably interpreted to possibly increase the
virulence.

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In Section 6.6, it's clear that changes in virulence don't increase the probability that an outbreak escapes
local control, which makes sense. And in Section 6.7, we find that the global consequences scale linearly
with case fatality rates basically, which makes sense. The more infections you have, if that doesn't change,
and the more likely an infected person is to die, the more the consequences increase.
Also because the case fatality rate of 1918 influenza was so high and that of 2009 was so low, there's a lot
of room for increase. So potentially, global consequences could increase by several orders of magnitude.
And then the simplistic way of interpreting this, since probability is unchanged and consequences could
increase by several orders of magnitude, risk could also increase by several orders of magnitude. It's a
very qualitative way to use the quantitative assessment that should be accessible to most users.
Another example is what is the risk posed by experiments that aim to create antigenically distinct strains
of a recently-circulated seasonal influenza strain? Section 6.6 has graphs, like you see on the right side at
the top, that show that antigenically distinct strains have a two- to threefold increase in risk of escape of
local control. So if you have at least one person mingling in the public, if it's completely antigenically
distinct from a seasonal strain that has somewhat recently circulated, that risk of it becoming a global
pandemic increases two- to threefold.
Section 6.7 shows that antigenically distinct strains may inflict tenfold more global deaths, which is
obvious. If people have already been exposed in previous flu seasons to the strain, they're going to be a lot
less susceptible to infection; and they're also going to be a lot less likely to transmit that infection to
others. Changing the antigenic properties of a seasonal influenza virus could increase the consequences
by tenfold. And so once again, taking a simplistic approach of just multiplying an increase in probability
and consequences together, suggests that risk might increase by roughly twenty- to thirtyfold via this
manipulation.
Now, there are a number of caveats here. One is that we don't know what a lab accident with a seasonal
influenza strain looks like. We don't know if the illnesses caused by the accident with seasonal influenza
would supplement or implant the infections from the next year. We don't know if this outbreak would
even be noticed, for instance; so there are a number of issues.
But most importantly, once again, we don't know if this increase, even though it's more than an order of
magnitude probably, puts this strain into the category of danger. If the change from an r naught of 1.2 to
1.6 changes its category from moderately transmissible to highly transmissible or if the increase in global
deaths by tenfold from a low level compared to a pandemic strain we're only talking about 1 million
global deaths total compared to 100 million for the most dangerous pandemic strains is that sufficient to
be considered high risk? We can just point to an increase in the risk and benefit assessment.
This slide basically says what I just said, with the additional point that does it matter if work is going on
down the hall on a wild type pathogen that poses a greater level of risk compared to this manipulated
seasonal influenza strain, let's say.
The relative risk information that we give, I think, is still pertinent and still sufficient to state that more
controls or measures should be taken to control infection risk on this modified pathogen than the wild
type pathogen. I think those types of decisions could be made definitely at the institutional level. So I
think that is still strong. But in the absence of the overall benchmarks and the absence of having a bright
line, yes, this hundredfold increase in risk puts it into the high-risk category, making broader decisions
might be difficult.
I think a lot of bench researchers we talked to might not be familiar enough with the epidemiological
properties of pathogens that they could properly characterize their strains by assigning case fatality rates

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or transmissibility values for the wild type pathogens. Some things that would help are some guides or
tools to easily obtain some parameter values for those wild type strains and perhaps a tool that helps them
just make the calculations.
Lastly and I think I still have about five minutes I'd like to address the use of the 1918 H1N1 strain as
the comparator. And I want to say the use of this comparator is only in our brief summary, in our
Executive Summary and in the little 10-page or so summaries of each of the sections that then go on for
100 pages. The rest of the 100 pages don't use any comparators. We just show how the change in any
property affects risk. We needed some kind of benchmark to basically quickly summarize 100 pages of
results in a couple of pages.
One thing that we heard from the public comments and we're changing is that we are going to provide
more comparators in the summaries; we're not just going to use 1918 H1N1 anymore. There will be others
that people can choose as other comparators. And once again, 1918 because of the data highlighted for us
in the last meeting won't be the highest risk anymore because of preexisting immunity.
The point is made though that we chose this comparator because at the time there was limited discussion;
there was some discussion, but limited discussions of the funding moratorium on work on wild type
versions of the 1918 pandemic strain. We chose this because at the time we were thinking it was the most
risky strain, so it would be decided as a reasonable benchmark as maximum allowable risk. If there's no
moratorium on work on this, then that's a good benchmark for maximum allowable risk; that's why we
chose it.
However, if you pick other strains, I think you could find different levels of risk. We have a new
comparator as I said, the 1957 H2N2 pandemic strain. Its initial transmissibility is likely 1.7, slightly
less than that of the 1918 strain when it broke out. There is low residual immunity against H2 strains in
the public right now. We estimate that the 1918 H1N1 strain, given the data that was shown to us from
animal models, if we extend that to an epidemiological modeling, we predict that it's r naught right now is
around 1.2, which is on the low end of seasonal strains.
The case fatality rate of this strain is about 0.5%, a little bit less, compared to up to 5% for the 1918
strain; and everything else is similar. So if we use this H2N2 strain as our comparator and, as I said,
we'll provide several in the final version of the risk assessment we find that increases in transmissibility
don't increase risk very much. So if you're already at an r naught value of 1.7, increasing that even further
barely influences risk; that's shown in many of the figures in Sections 6.6 and 6.7.
It's possible, since we have examples of pandemic influenza strains where the case fatality rate was
several percent, that one could increase risk by increasing its pathogenicity by a factor of 10 or more
given that there's some historical evidence that there is room there for increasing pathogenicity, whereas
the other parameters don't influence risk. So once again, if H2N2 is the only comparator, then
transmissibility drops out because increasing it from a higher level doesn't matter, whereas pathogenicity
still is important.
We could use any strain we want to as a comparator, but it's arbitrary. Given that there are no benchmarks,
no bright lines, we could pick a strain and show that if it poses more or less risk than wild type MERSCoV or 1918 flu or even polio virus or god knows what we could pick whichever comparators we like,
and it doesn't necessarily help inform the policy discussion. What I think is helpful is all of the data we
provide on exactly how risk increases from a relative level as you manipulate any of the phenotypes. That
helps policymakers focus on what the phenotypes of concern are and how much space there is for
increasing risk.

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Also I think it's helpful to determine if additional safety and security measures are needed compared to
wild type pathogens. But, importantly, it can't be used to determine necessarily if the risks are worth the
benefits overall.
And once again, the sensible comparators are benchmarks for the riskiest allowable research for existing
or novel pathogens potentially two different benchmarks at particular containment levels. And these
benchmarks, I think, should be applied regardless of the pathogen being studied -- regardless if it's
influenza or the coronaviruses, whatever the pathogen might be.
And I think that ended the comments. I just wanted to say that, as always, the risk and benefit assessment
is posted on our website. If you think that the main text is long, there are about 1,000 pages of additional
supplemental information that's there. And that's also one of the places where you'll be able to find the
revised version when it comes out. Thank you.
Haas: Thank you. Our first commenter will be Tony Cox of Cox Associates.
Cox: Well, first, thanks for a great presentation of a lot of information in a hurry. It's quite useful.
I think it's helpful to divide the information that we're getting this morning and background information
into two big chunks. One has to do with what I think of as risk assessment, which addresses the question:
How big is the risk?
And Rocco suggested, for example, that sometimes how big the risk is that's created by a change might be
found by multiplying together the change in probability that could occur and the change in consequence
that could occur. Of course, if zero change in either of those could occur, you wouldn't necessarily want to
think that the risk is zero. So it's possible that something other than multiplication for example, addition
of multiple scenarios might be useful. But the idea that we can at least put some numbers around, well,
how many people are at risk and risk of what fatalities or something else is quite useful.
The other big chunk of information would be what should be done about it? That's what I think of as the
risk management piece. And if we're uncertain about what the size of the risk is, we still may have some
clarity about what to do about it.
And in the few minutes I have, I want to look at the question of what to do about risk in the context of
particular proposals for funding that come in. I'd like to begin this risk management focus by warning
against a couple of things that I think are fallacies. One is if somebody says, "What is the maximum
tolerable risk or what is acceptable risk," it's a little bit like asking, "What's the maximum acceptable
price?" If I said to you, "What is the maximum acceptable price," you might very well say to me, "Well,
tell me -- price of what what are we talking about here?"
And if I say, "What is the maximum acceptable risk? Is it 1 times 10 to the minus 6th," you might say,
"Well, risk from what? What are the benefits that we're talking about? What are the costs of reducing the
risk?" I've often thought myself that there's no such thing as an acceptable risk if you could get rid of it
for free. I mean, why carry it? So we really have to look at costs and risks and benefits in combination to
have a meaningful statement.
Another area where I would urge caution, another fallacy actually, it's what's called "arbitrary coherence"
by some behavioral economists. It's the idea that, well, look, we're already accepting this; and that is
smaller than this, so shouldn't we accept that? By no means -- the question is: Do we have an attractive
risk cost/benefit comparison; is there something better that we can do instead?

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So the idea of using benchmarks or using existing or past scenarios might lead us towards enshrining a
bias towards the status quo or the past quo. In a way, it's got nothing to do with rational decision-making.
Rational decision-making says of all of the things we can do, which is most attractive?
So let me put up for consideration first a list of questions. The charge was given to some of us
commentators was to try to say something useful about how to decide what to do on whether or not to
fund a new proposal. And I think any such consideration will be enormously informed by the information
that Rocco presented, but that information alone, of course, stops short of saying, well, how are we going
to figure out what to do?
So rather than saying anything useful on this first slide, I'm just going to give you a list of questions that I
think can help to think productively about almost any kind of risk management decision.
The first and least good question is: Do the potential benefits of a proposed project outweigh its potential
risks?
That could be useful as a screening question. Let me say up front that there's not necessarily an objective
answer. Risks and benefits don't necessarily have commensurable units, and they do necessarily have
subjective components. What I mean by that is if I give you two probability distributions and say, "Which
one is better," decision analysis teaches us that in general, there's no answer to that question in general.
You need to know the risk attitude of the person making the decision. You need to know something about
tradeoffs.
But sometimes, as in the colorful picture that I've pasted from Google Images up there, sometimes it's
clear that one probability distribution lies to the right of another. And in that case, everybody who prefers
more to less or in the case of fatalities, prefers less to more ought to agree on which is better.
A more useful question of this screening question is the second question: Can we do something to
improve the risk/benefit profile of the project that's been submitted?
I'm going to skip over No. 3 who should decide but I'll note that it's very important. The BOGSAT
model, a bunch of guys sitting around a table, is not necessarily legitimate or acceptable to all
stakeholders. So there are great questions that have been, I think, sensitively addressed already by this
committee on what constitutes a legitimate decision process.
The thing that I find most interesting is No. 4: How should we decide?
And here I want to mention the concept of a decision rule. A decision rule is something that is input, takes
all the information that is available however lousy that might be. It says, okay, here is the information.
And as output, it makes a decision. For example, fund this, given that information; or say no, we're not
going to fund it given that information; or temporize say, we might fund it but we need more
information. And if more information is favorable, then we might fund it.
So mapping available information to decision, that's what I mean by a decision rule. And there are
different forms of decision rules. A useful thing, I think, to consider is what decision rules do we want to
use? This is a little bit of a different question from what decisions should we make in an individual case.
Here comes a project; you're in charge. What do you do? Do you accept it? Do you reject it? Or do you
say "I need to see some changes or get more information?"
Rather than answering that question one decision at a time, I think it may be more productive to say:
What decision rule do we want to use that when it's applied over a population of cases tends to have

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pretty good performance? And we can't find anything that is better performance.
So here I'm doing two things, and I only have three minutes left to do them. One is to say: What are the
questions that we should be asking? And this slide is an attempt to list some questions for focusing good
decision-making on a risk management problem. And then the other is not what questions should we be
asking, but what hints should we be giving?
And where I'm headed is the idea of, well, if we have enough information of the type that's already in the
risk/benefit analysis report to simulate the performance of decision rules, then we should do that. And we
should find the rules that will work best. So that's in a nutshell where I'm going.
Okay, Question No. 5 is: When should a decision be made?
And what's going on here is that it's worth asking should we collect more information before making a
funding commitment one way or another? I would contrast this point of view, which says how much
information do we need and what does the information need to say before we can determine whether this
is the best option available to us? I would contrast that first with how much information do we need to
decide whether the benefits outweigh the costs according to somebody's system of values? And I would
contrast it especially with are we above or below an acceptable risk threshold? I think that the acceptable
risk threshold is a lousy way of making decisions because it leaves out the tradeoffs about risks, costs,
benefits, and other options opportunity costs.
Speaking of opportunity costs, there is a different kind of cost to weighting, or perhaps benefit from
weighting, which comes from the collective or social aspect of decision-making here, which is if not us
now, maybe somebody else now or maybe somebody else later. Who else is going to be doing this
research and when, and are they going to share the results?
It seems to me that the answers to those questions looking at the social aspect or, if you're an analyst,
the gain theory aspects of research put a very different light on should we fund this now. If we don't
fund it now, maybe somebody will do it first. Is that good or bad? If they do it first and publish the results
and bear most of the risks, it might be a good thing to wait. On the other hand, if they'll discover
something that we'll really wish that we'd done first, then it might be a bad thing to wait.
My point in raising this question is just to focus from an emphasis on is this above or below a certain line
called maximum tolerable risk, a bad way of doing things, I think to what are the tradeoffs involved in
postponing a decision or making a decision sooner or making different kinds of decisions.
Lastly, how good was our decision?
We put all this thought into it. We tried to ask all the right questions; we tried to do the right thing. We
made a decision. Was it a good decision? We should set up and the concept of adapt of risk management
has already come out several times in the committee's deliberations but we should try to make sure that
we learn from experience. Too often, if you don't think about that, you don't do it.
Okay, I'm about out of time; so I'll put up a slide and say nothing about it other than if you understand the
situation well enough to simulate a bunch of cases, then in the privacy of your simulation model, you can
try to work out what decision rules are most productive averaged over a population basis. Possibly this
would be a useful way forward, possibly not. It depends on whether we have enough knowledge to be
able to do useful simulations.
Thank you.

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Haas: Thank you, Tony. Our second discussion will be Kara Morgan from Battelle.
Morgan: My first comment is that Tony and I have a lot consistency in our presentations, but we use a
slightly different lens. So maybe some of his comments resonated with some folks; maybe some of mine
will resonate with others. But I wanted to make that comment because it might sound different because of
the way I talk about it, but there's actually a lot of consistency.
The other thing I wanted to mention is Chuck and Adam and Tony and I are all colleagues from the
Society for Risk Analysis. But a lot of what we're talking about today also really connects to the Decision
Analysis Society. And Tony mentioned decision analysis as a tool. Really we were asked to talk about
how to link the analysis that was done the risk and benefit analysis to policymaking; and that is really
about decision-making. So you're taking technical information and using it to make decisions; so in that
sense, the decision analysis community is one that has a lot of relevance here as well.
The research and decision-making I'm not sure how many of you are kind of familiar with this area. I
know a lot of you are working in the government, but also more on the pure science side. And there has
actually been decades of work in the area of how to make decisions. And a lot of it was driven by
situations like this complex science and technology, lots of uncertainties, multiple stakeholders, really
important conflicting objectives, maybe conflicting values, situations where you might have severe
significant outcomes but with a low probability. Those all make for a situation that it's really hard to make
decisions about.
And the analysis is an important part of that, but I'm going to talk more broadly about the decision tools
that have been developed to help in exactly those kinds of situations because I think it's very relevant
here.
So I'm going to talk about three different decision frameworks, you might call them. Tony referred to
them as decision rules. And at the risk of sounding too academic, it's really very practical. It's deciding
how to decide, and I think that's part of maybe what's missing in some of these discussions. I heard a lot
of the comments today talked about different decision models. But since you guys aren't from that field
generally, maybe you don't even know that you're talking about different decision models; and that creates
more conflict.
So I just want to lay out three frameworks, but really making the point that they're not really three distinct
frameworks; they're kind of points on a continuum. And there's a lot of adaptation that can be made to any
of these frameworks to fit this particular situation, any particular situation.
And I also wanted to mention that there could be a tiering of these frameworks. So you might have one
framework or decision rule that you use initially to do some screening, to separate off some things that
you take to a higher level. We heard some comments this morning about analysis kind of fitting the
complexity, so you don't want to do overly complex analysis if you don't need to; so we can use a tiering
approach and apply different decision rules. In that way, some decision rules that might be overly simple
for some cases might be perfectly fine for other cases. So I'm going to talk about that in these three
frameworks.
The first one we've heard a bit about today already. This is really the most simple and therefore very
appealing decision rule, and it's still used in a lot of risk assessment contexts today. This fundamentally is
a decision about what level is acceptable in whatever metrics you're using to determine risk, whether its
mortality rate or a qualitative continuum. It's just a matter of saying we know that this is the place at
which things switch to being unacceptable. So everything lower than that is fine, and everything greater

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than that is not fine or maybe leads to another more complex decision rule.
Like I mentioned, this is very appealing. It's really easy to implement, incredibly transparent, very easy to
understand for folks that are not involved in the decision. You ideally would incorporate in your estimates
of those points on the line what the risk is you would be incorporating, your risk management options. So
in situations where there's a lot of agreement on kind of the effectiveness of those risk management
options to address risk, this is, again, a very appealing tool to use.
One of the things that has happened historically in the use of this decision rule is the acknowledgment that
there is always uncertainty in science. And so there might be some studies that lead you to say, okay, the
line is here; it's at 2, whatever your metric is. But we know that future studies might give us more
information, so we're going to add some safety factors to that 2 and make it 1, just to be extra safe. And in
cases where you're not losing something from that shift, that makes a lot of sense to do. Again, in the kind
of situations where the decision is clearer, that makes sense.
But in decisions where there is lots of uncertainty and maybe disagreement about the effectiveness of
those risk management options, moving that line to the left you end up potentially leaving a lot of benefit
on the table in that you're moving down to a level that is lower than what it needs to be; and so you're not
accruing the benefit from the things in that gap. So there's a potential to leave benefit on the table when
you take this bright line approach.
The other thing that it does not do is take into account benefit. So if you have something that's just over
the line but is incredibly beneficial, you would lose out on that benefit. So it doesn't take that into
account.
The other challenging thing is that you have to pick a level. And we've heard today this discussion, in this
context about where is the of concern line, what's that line that makes things of concern or not of concern.
And in this context, it sounds like there are a lot of challenges with that. There are some situations where
there are not challenges, where there is a clear place where you're okay with accepting the risk and where
you're not. In those cases, this is a very appealing approach; but again, being able to choose that line is an
important part of being able to apply this.
Another challenge is that of course this doesn't explicitly incorporate uncertainty that we know is present
in all risk assessments. And as I mentioned earlier, the use of safety factors has been one way to take
uncertainty into account, at least acknowledge the possible uncertainty. But the way it's incorporated into
this type of approach, like I said, it could leave some benefit on the table.
The next model I'll talk about is I think where the folks who commissioned this study were going, and the
idea of, well, we really need to take into account the benefits of the study; that's relevant to our decision.
It's not just about the level of risk, but we also want to take into account the degree to which this is
providing something valuable.
And of course there are many situations in society where we are willing to accept risk for some benefit. If
there weren't, we would all live in bubbles and never take cars or take planes or eat out at restaurants or
anything like that. So this idea of incorporating benefit to accept risk is very common in our society.
But there are a couple of challenges to this approach as well. While it does take into account these extra
criteria of benefit, which is an important kind of evolution getting to a more complex decision context,
these criteria of benefit should be acknowledged as having an important role in the decision. There are
challenges here.

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Of course, you need to be able to express the risk and benefit in terms that are comparable across different
events, which can be challenging to be able to put them on this scale. It's also better if you can have the
risk and the benefit in the same matrix, which again leads to the use of assumptions and other kinds of
things that add to the complexity of interpreting the results. For example, if you have cost in terms of
dollars but a benefit in terms of saving lives, and you have to compare those together, we know there are
tools for doing that; but it adds to the kind of levels of assumptions and potential concerns about value
judgments and so on that are being incorporated into the decision. So it does add those challenges.
The positives are, of course, that it does incorporate more criteria than just risk in the first example. But
you need to be able to compare the risks and benefits, which is challenging; and it does still require a
judgment about what's right. What is the ratio of risks to benefits that's right? So there is still this need to
have a place where you're willing to accept that benefit for that level of risk.
The last framework that I'll talk about is what I'm calling a deliberative criteria-based framework. And
this is really based on decades of work from the National Academies Institute of Medicine. There's a 1996
Understanding Risk report that talked about an analytic deliberative approach. My colleague in the
decision analysis here, Detlof von Winterfeldt, recently wrote a paper in the Proceedings of the National
Academy that talked about using this kind of framework.
And the idea here is that there is no bright line; there is no number that's acceptable, but that the process
would include an agreement on the criteria. So you would likely have at least one, if not more, criteria
related to risk and also related to benefit. So you might have different dimensions of risk and benefit that
you would include; but you also could include other criteria that are important to the decision-makers and
important to the stakeholders, thing that are more value-based than fact-based, things that have to do with
controllability which we know affect risk perception.
A lot of the things that have come up today in terms of potential things that should be taken into account
in the decision process could be captured as criteria here. So this would be kind of the initial work, to
decide what the criteria are so that each study that was being proposed could be evaluated on those
criteria.
And then those criteria would go to this analytic deliberative process with the stakeholders, decisionmakers, whatever the group of people that are really providing input to that including these observations
and perceptions that would be in the criteria based on facts in the analysis results, but also including the
criteria that could be more driven by values, ethical concerns, tradeoffs between those criteria -- so those
less observable, but still important factors that we've been hearing about today. And those criteria for each
study, those values and observations, would be discussed by the stakeholders, taken into account in a nonformulaic way; and a decision would be made. And then the experience from that decision would be fed
back into the process, and the stakeholders would continue to make these decisions.
So there are a lot of things that this approach gives us, but there are also a lot of things that it costs. So it's
obviously much more resource-intensive than the first approach. The first approach requires some set up,
but then you're pretty much good to go. You can just apply the factors and go on.
The second approach has a little bit more complexity, but is still relatively straightforward. This one, in
terms of the amount of resources used to implement it and manage and oversee it and learn from it, is
higher than those; so that's a tradeoff. But it does allow for kind of learning and adaptation of things that
we've talked about in terms of being important, to include in a process like this where there's so much
uncertainty and so much to learn as time goes forward; and it is a very collaborative process. And it's
designed to be collaborative. And so those are the positives about it.

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One of the initial questions this morning was: Under what conditions should this research be done? So
with that kind of question in mind, you can think about what are all the criteria that might be relevant to
that decision, including the analysis of course, but also potentially taking into account other values and
criteria that are important.
In conclusion, I just wanted to leave you with two key takeaways from my comments. The first is that
policymaking, decision-making, is a social process; it's not an analytical process. It's ideally informed by
an analytical process, especially in situations like this. And of course the analysis is very important to get
right and to keep updated and to have all the right things factored into it. But the analysis itself, as was
mentioned earlier, is not going to give you the answer. We need a process that's really going to help you
take that analysis, incorporate all the things that are important, and lead to a decision.
And the second thing I would mention, and this kind of follows on a little bit of what Rocco was talking
about in terms of the resources invested, I would argue that the decision framework, the decision rules,
and the decision process that are used are just as important as the analysis.
And when you think about it in terms of resources and time and attention and all the things that go into
the analysis, in my experience I was at the Food and Drug Administration for 10 years working in this
risk-based, decision-making world, and the focus is always on the analysis because we're scientists and
we're analysts and we want to know what the numbers are. And to pull it into this kind of recognition of
these decision rules is really important in terms of how this analysis is used. The decision process, the
criteria included all those things are going to have a big impact on the outcomes from this process. And
so I would just argue that that part of the work is just as important in terms of resources and time, and
maybe more important in some ways, than the analysis itself.
Haas: Thank you. Our final invited discussant is Adam Finkel from the University of Pennsylvania.
Finkel: I'm waiting for my slides to come up, but thank you; I'm always glad to be here. There they are.
I'm going to talk from my perspective as having been a regulatory official. I was in charge of the rule
making divisions at OSHA in the second half of the Clinton Administration, but I've also been doing work
generously funded by the Sloan Foundation on synthetic biology more generally, not so much on this
gain-of-function research per se.
And it's always easy to follow people like Tony and Kara. Tony and I went to college together many,
many years ago; and we agree completely on everything but specifics. But I certainly agree with his
whole presentation.
I want to try and find time to make five major points, some of which have been made already. First, that
both risk and benefit estimates want to be balanced in rigor with each other. They should be, I believe
whenever possible, quantitative. They should be humble with respect to uncertainty. They should be
explicit with respect to values. And particularly importantly, and the other two speakers have already said
this, they should be challenged in the service of a thoughtful decision rule.
Secondly, the benefit estimates need to be but can be made commensurable with risk estimates and should
be communicated with the same care. I'm going to try and argue briefly that a purely risk-based
prioritization system what to be concerned about, what to regulate, what to fund is inferior to a net
benefit prioritization rule. I'll talk briefly about transparency; Baruch's session tomorrow will talk much
more about that. And I'll try and introduce very briefly a much more general decision paradigm that I've
been calling solution-focused assessment.

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In the synthetic biology area in general, and from what little I've seen in just getting ready for this
presentation, this meeting, in the gain-of-function area, I think there are a lot of risk-like pronouncements
out there. And I would say also parenthetically benefit-like pronouncements, which I'll get to. A lot of
precise talk about outcomes, but very imprecise or even cavalier talk about probability, the slide on the
left showing the sort of very vague apocalyptic scenario but with no quantitation at all.
But there also may be many less easy to understand pronouncements that are very good on probability but
kind of fuzzy and cavalier about outcome. And I'll just mention on the right-hand image here the notion
that those Americans who chose to drive in roughly the year or 18 months after 9/11 of 2001, that those
folks who died on the highway "died needlessly" because they were irrational. That presupposes that the
death in the plane and the death in the car accident were commensurable and identical; and they're not.
The endpoint fatality is fatality, but the process that gets you there may be very different; it may be very
idiosyncratic person to person.
I think it's great that the Gryphon report is at least trying to get to quantitation. I find it really interesting
that the paper or written comments that Lynne Katz submitted are trying to get to absolute quantitation.
But you can see even from the two reports, even though one is more on a relative and one a more absolute
scale, that there is considerable difference of opinion about what these probabilities are. I've seen other
estimates that are even smaller, this famous 1 in 33 billion years estimate. But it's good, I think, that these
are out there from the outset.
We all know about prior examples, like the National Space Shuttle Program, where there were dueling
estimates of risk; but they were internal to the Agency and didn't get out to the public and to the decisionmakers really where they belong.
But of course dueling point estimates is really the antithesis of a thoughtful balancing of risk and
uncertainty. Uncertainty is the water in which we swim, and leaving it out is really a violation of first
principles.
So I think I'm going to skip over this slide -- I hope they'll make them available -- but this is very similar
to what Kara was saying. I developed at one point a hierarchy of 9 or 10 increasingly complex decision
rules, ranging from sort of a pure precautionary principle, which I've always been suspicious of. It's what
got us into the war in Iraq, among other things.
But I'm highlighting a couple of levels in this chain where we increasingly try both to quantify, to be
thoughtful about uncertainty, but also to be thoughtful with respect to how risk always varies across the
population. And if we just over aggregate and talk about expected fatalities and don't talk about the
distribution of those fatalities and the individual probabilities of harm, I think we're leaving out justice
and equity. And in my view, equity is efficiency. It's hard to provide maximum benefit if you're not
thinking about the benefit to the individuals who bear it or receive it.
This is too hard to explain in the time allotted, but the little red bar here is from an old paper of mine
taking issue with the dueling point estimate that Bruce Ames put out in the early '90s when the
controversy about Alar, the growth hormone in apples, was raging. And he said, why worry about that.
The aflatoxin in peanut butter is "18 times worse for you" than the Alar in the apple juice was. Now, that
estimate was not untrue; but I showed it was within a six or seven order of magnitude probability
distribution ranging on both sides of the line of equality.
So this mental model that risk assessment is good for comparison but not good for quantitation is like a
yardstick with the markers rubbed off. It really doesn't make sense because when uncertainties exist,
which they always do, and when they're uncorrelated, which they often are, it becomes X-squared as hard

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to compare things in the right rank order than to make a reasonable decision about one or the other.
I saw something on Rocco's slide about uncertainty canceling out, and that gives me the willies because I
think that's often not the case.
Moving on to benefit quickly, again, I'm kind of a novice to synthetic biology and even more so in gain of
function; but I think even the proponents, even the developers, don't do a very good job maybe because
they're squeamish or diffident about being advocates for their own work or their own livelihood but we
don't have a good language to talk about the tremendous benefit that these applications and products and,
in your case here, these fundamental gains in knowledge can provide.
So this is just kind of a human interest slide. This is three pictures of our daughter in vitro, in vivo Day 1
and now, more recently, an IVF baby. And we were fortunate enough to need IVF about 20 years after the
initial flurry of concern. But if some people had gotten their way in the late '70s, people would not have
been born. And what's the value? To us, it's priceless; and I think we need to do a better job of
communicating without shame, without sheepishness, the tremendous upsides of some of these
technologies.
Getting again back to both Kara and Tony's discussions of choice being the operative term rather than risk
in a vacuum, I guess I would just say maybe more starkly than the others have, I think the question, is it
safe, is kind of an impoverished, maybe even a vapid, question; and the more useful and ambitious
questions include, again in kind of ascending order, does this experiment or application have positive net
benefit? Compared to other ways to do it, does it have greater marginal net benefit than the alternatives?
And then I'm going to talk at the very end, if I have time, about asking even more ambitious questions.
But at this point I want to say, putting on my former OSHA administrator's hat, boy, it seems to me to that
I'm glad that Rocco talked as much as he did about the real day-to-day of working in a lab and trying to
do the job safer. But obviously, the application with maximal change in net benefit could be made better
still with mundane, very quotidian emphasis to basic aspects of safety in the lab. The best way to keep
these things from infecting the general population is to keep them from infecting workers. And this is
always the case in chemical risk assessment, nuclear. It's always the workers who bear the greatest brunt
of the risk and for whom the societal benefit could be sort of channeled through them by making them
safer.
I know very little about lab safety. OSHA has been very poor in this area; it's an underfunded,
overmatched agency. But we did pass a regulation in my time there in 2000 for the universal use of
inherently safe needle devices in health care settings. It's meant to apply to labs too; but my sense is that it
has not percolated very well into the lab setting. There are needle devices or self-sheeting needles and
other kinds of needleless systems. And that's just one example of drilling down to where the faults occur
and trying in the name of work protection but in the name of societal protection as well.
A brief mention of process and transparency my colleagues at Penn and I just finished a one-year
project funded by the oil and gas regulator in the province of Alberta looking at agencies around the world
under the rubric of best-in-class or regulatory excellence. And one of the things we learned from
stakeholders, both in Alberta and around this country, is that people obviously want transparency; they
want access to data in the information age. But what they really want, I think, by and large even more
than that is not just having information thrown at them, but I think the psychologists call this "apparency."
It's not just transparency, but it is having one's rationale and motivations be apparent.
The public wants to know why, not necessarily to know what. And agencies need to do a better job, even
when they say we disagree with the majority here, this is what we're doing, they need to say why we're

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doing it.
I'll say one more thing and then conclude. It always bothers me I talked to Kara a little bit about this
right before we went up I totally understand the reluctance of committees, especially committees that
are getting advised by people currently in the government -- to really rethink in a fundamental way the
organizational paradigm. But it always concerns me to see statements like, "The existing institutional
arrangements are pretty darn good. Here's a little mapping of all the turf that gets mapped onto different
functions. And we don't see any big gaps, so let's just improve around the margins but not tinker with the
organizational structure."
And I would just suggest that maybe this is an area where a more coordinated institutional structure
again, I see a tremendous possible vacuum here with the area of worker protection. But I'm not sure that
these agencies don't have a good history of communicating with each other well, don't have a good
history of ceding to another turf that it owns but really can't deal with as well as another agency so I
think some thought about fundamental reorganization might be worth at least discussing.
I'll just conclude by saying this is the place, the National Academy, a building where the 1983 paradigm
was developed, the so-called red book of risk assessment. It's been in force for now these 30-plus years.
And that paradigm is very common sensical. It says assess the risk first. But what's happened is that that
has degenerated into keep assessing the risk over and over, ad nauseam; and eventually, someone will say
enough is enough, let's make a decision (audio break).
risk assessment called the silver book. We talked in the last chapter about a more solution-first
paradigm of asking fundamental questions, what are we trying to do here, and then channel the
assessment in service of being able to discriminate among choices.
So my example of late has been the plastic water bottle. It has not much to do with anything with gain of
function, but I think it's a good analogy. I predict with some confidence that EPA and the other agencies
doing this will very gladly go on for many more years, many more decades, thinking about the plastic
water bottle problem as an endocrine disruptor problem. How can we limit, dial down, the leachability of
these plastics so that bisphenol A gets into the water in some acceptable concentration? They might say, as
they've begun to, maybe there's some other chemical that will be less harmful. It turns out that this phenol
H may be as harmful or more so.
But they're not asking the more fundamental question, why is the market producing 29 billion single-use
plastic water bottles with consequences for energy use, disposal, et cetera? When I was a kid, we didn't
have them because we had other ways of getting our ready access to cold drinking water. I'm not saying
we need to go back in the past and incentivize street corner water fountains or building water fountains,
but there are other ways to get this thing that falls from the sky than to bottle it up. And unless we're
willing to ask these sort of industrial policy questions, I think we're not going to ask the good questions
about GoF research that need to be asked in a risk/benefit decision context.
Thanks.
Haas: Thank you. With the indulgence of my Chair, we'll go to 12:45 p.m. I would ask people to come to
one of the two mics. I'll alternate from one mic to the other; and we'll go until whichever comes first no
more questions or 12:45 p.m. First question on this side?
Yes, thank you very much for the excellent presentations. I'm Jim Welch, I'm with the Elizabeth R. Griffin
Foundation. And I love hearing risk/benefit people, and I just have a simple question: At what point does
it become unacceptable that there is no national database or framework of laboratory near misses,

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accidents, or exposures?
Haas: Who'd like to take that?
Finkel: Well, easy question with an easy answer from my limited point of view, it's already
unacceptable. That's already something we should have had by now. So I would urge the committee to
think about that as a short-term start now.
Casagrande: Also, it did hamper our study quite significantly. That would have been one way to start
approaching an absolute risk assessment. Hand in hand with that needs to be a no-fault reporting system
because accidents do happen, and you can't disincentivize lab workers from reporting what needs to be
reported.
Haas: Question on this side?
Thank you. I'm Gigi Gronvall from the UPMC Center for Health Security. I'd like to comment on some of
the significant data gaps that were in the RBA for not only laboratory procedures but also human factors.
This is not the only circumstance where there are these data gaps for biosafety. This has come up in some
other newsworthy biological incidents for the inactivation of pathogens, which is that there just isn't a lot
of data out there.
And a lot of these data gaps could be really addressed by you can imagine, like a master's thesis or
Ph.D. thesis that would address a lot of these gaps. But that type of research and scholarship is not funded
currently. And so to that end, I think it would be valuable if the NSABB were to recommend that in order
to provide this kind of data that would be useful to the oversight of not only gain of function but other
infectious disease work synthetic biology, et cetera that there should be an explicit funding of this type
of scholarship.
One of the aspects that I find most valuable from the framework that NSABB produced, the draft
framework, is that it holds the need to do infectious disease research as a value. And I agree with that.
And I think it's my opinion that we should be encouraging universities and the university researchers to
take on infectious disease research, whether it's influenza or other types of infectious disease work. And
that we should be taking care not to further vulcanize influenza work.
But in order to do that, we need to give these scientists the tools that they need to be able to make their
labs continually safer. And when it comes to the laboratory database, I believe the U.S. Government has
made a commitment to do that, to have an accident and incident database that will be coming on in the
next couple of years. But more of this type of thing is certainly needed. Thank you.
Haas: Thank you. Responses from the panel? Okay, from my left side.
Piers Millet, Biosecure again. I'd like to start off by thanking Rocco for a wonderful real-time, or almost
real-time, example of why this resilience to public health impact or the impact of the public health
response is so important. The reconfiguring of the risk space to taking into account the comparative risk
between H1 and H2 influenza really demonstrated to me what we were talking about in the session before
coffee.
Secondly, I think there was a missed opportunity to explore opportunity costs; and we heard a little bit of
those from Dr. Cox with the risk/benefit analysis, especially the international angle. It's a shame that that
didn't look into questions about what impact has the moratorium on pause in research had on research in
other countries that have started doing this. Has it increased it? Has it decreased it?

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Or indeed, what perceptional responses might be expected from other countries around the world in
response to the U.S. deciding to either undertake gain-of-function research of concern, to regulate gainof-function research of concern or, indeed, stop gain-of-function research of concern.
And finally, my reading of the risk/benefit analysis on information risks suggests strongly to me that the
risks in that space are only minimal because worse things have already been released. And that suggests
that the existing system failed to identify those risks, failed to assess those risks, failed to manage those
risks; and that I find quite worrying and from that I infer that there may be other information risks
emerging. Rocco mentioned perhaps transmission of coronaviruses in the future when we have a better
animal model. Why would we expect the same system to do better at assessing and mitigating those risks?
And more broadly, what about other information risks in biosecurity? So I would suggest that as you just
heard from Adam Finkel that maybe the system as a whole needs to be looked at.
Haas: Thank you. Any reactions?
Casagrande: Just to the point of the information risk, when you look at the sources cited, had we done the
exact same study in 2002, we would have found that the information risk for influenza would have been
high. But it just turned out, as you said, about 14 or 15 dual-use studies were published between 2002 and
today. So your point is well-taken.
Haas: Question on this side?
I would like to follow up on the question of information. Viktoriya Krakovna from the Future of Life
Institute. If you could elaborate why the further publication of dual-use research of concern would not
pose further information hazards and general interest in your recommendation for a consistent publication
policy for such research. Thank you.
Haas: Any comment?
Casagrande: Our assessment, once again, was comparative given that someone looking to leverage dualuse information has the choice to use whatever is already published. So in this case, if methodologies that
are relatively easy to follow, relatively easy to replicate, have already been published, they could use
those as opposed to others that might be published in the future that get them to the exact same end. And
that's why there was a relatively low remaining information risk -- because studies had been published
that are actually relatively easy to replicate, much simpler than the ones published by Fouchier and
Kawaoka, that get to a significantly dual-use state. So since an intelligent actor can just pick whatever
suits them as far as their technological capabilities and also gets them to whatever their desired end state
is, that's why the remaining information risk as well.
Haas: Question on this side?
My name is Corey Meyer and I'm from Gryphon Scientific, and I led the benefit assessment component
of our RBA. First, I wanted to add one lesson learned from the work on the benefit assessment. And that
is that simply defining phenotypic changes of concern or even types of experiments of concern does not
distinguish between experiments that enhance a particular gain-of-function phenotype by generating
genetic changes that do not yet exist in nature and those that generate a phenotypic change that does exist
in nature but in a slightly different genetic context.
And so an example of the latter experiment would be seeing a mutation that was observed in a wild type
strain but introducing that mutation into your favorite lab strain in order to isolate its functional

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consequences. And determining whether the risks associated with those two types of experiments are
different is important for two reasons. One, it gets to the definition of what counts as gain-of-function
research of concern, what falls into that category. But also, the value of the alternative approaches that
depend on characterization of wild type viruses depends on whether that latter type of experiment
constitutes gain of function or not. Can you confirm a hypothesis generated based on analysis of
surveillance data in the laboratory or not? That determines the value of that alternative approach. So I
would urge the NSABB to continue addressing that issue when they move forward and kind of refining
their definition of what counts as gain-of-function research of concern.
And my second comment pertains to how to compare risks and benefits. While the benefits of gain of
function research to public health may be able to be expressed, at least qualitatively, in similar terms as
the risks, I'm not sure that's true for benefits of scientific knowledge. And so considering how to compare
risks to scientific knowledge benefits is important. And secondly, when thinking about public health
benefits, I want to underscore that while the risks of the research are immediate in that they are occurring
at the time the research is being conducted, the benefits to public health will be realized in the future. And
there is significant uncertainty in how long it will take for those benefits to be realized because translation
of basic science research into public health benefits is complex and depends on many other factors.
And so what exactly are you comparing to risks the ultimate public health benefits, the public health
benefits in five years? How you think about those uncertainties would be important to consider?
Haas: Thank you. Comments?
Finkel: I'll just say briefly on the last point, obviously as a whole, literature about discounting and time
value of benefits, I would say that that literature, especially with regard to very large risks and benefits,
the climate change literature is beginning, I think, to move certainly towards lower discount rates; in other
words, letting the future speak more loudly than we have allowed in the past. So that part is not at all
intractable.
It's what you said though about the value of scientific knowledge, where the benefits may be we can't
even ask the question because we don't know what. That's a real obviously important and difficult area.
But I think the necessary first step and I would commend to everybody's attention, I just saw it this
morning Professor Selgelid's white paper that's out there has a worked example of benefits in terms of
expected lives saved. I think that's really important to know.
If we're talking about finding the experiment with the relatively least risk, we need to be able to, at least
on an order of magnitude basis, be able to compare it to what the public health benefits, whenever they
accrue, might be expected to be. That's a probability times consequence issue that can be elicited from
experts and it ought to be tried, even though it's very hard to do.
Casagrande: Regarding the uncertainty of future benefits though, I think the really daunting part isn't just
how much to discount potential lives saved in the future due to a new drug but to have any kind of
certainty or any kind of estimate on how likely a scientific discovery is to lead to that public health
benefit. That's, I think, one of the trickiest aspects of assessing this. Let's say you find new drug targets.
As anyone who worked in drug discovery knows, the uncertainty from a new drug target to actual lives
saved in any timeframe is unknowable.
Cox: And it depends on what other research is done.
Casagrande: True, absolutely.

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Morgan: And just to add to that, I was going to say even experiments that aren't successful, you learn
from them. So how do you account for that part of scientific knowledge that's contributing to something
that you can't directly connect?
This side?
John Steel, Emory University. I think you're actually answering the question I was afraid to ask. And that
is, Rocco, you did this great risk/benefit analysis, the comparative one. But in terms of maybe absolute
benefits, what we can estimate relatively well is that every 25 to 50 years, a pandemic will emerge and
may kill 1 million to 100 million people. So if you were advising the NSABB in terms of the risk benefit
as a community not doing research that could lead to potentially ameliorating these deaths, kind of
considering those numbers be integrated into the RBA as it is, or does the NSABB have to consider that
in parallel? And if it's a parallel consideration, how much reach should that be given? As an experiment,
less intuitively, I think that's a major consideration. But I'd like to know the panel's opinion.
Casagrande: Well, I think in our initial approach to risk/benefit assessment, we weren't going to provide
those data on the historical consequences of flu and coronaviruses. But the NIH asked us to include a
whole chapter on exactly what the impact has been, the consequences have been, and the frequency with
which they occur. And I think that is there to provide an additional piece of evidence for the deliberations.
And I think the framework explicitly recognizes that risk that we're trying to buy down by pathogen
research in general, so it's an important consideration.
And also, when I was talking about needing a benchmark against which to think about risk, that was
explicitly in terms of the potential benefits that could be provided, which is why I think we need more
than one benchmark one for pathogens that are currently circulating. Like I think we can accept more
safety risk from working on MERS because that's still causing morbidity and mortality, and probably less
from SARS because it doesn't exist in nature anymore. It could reemerge, and then even potentially even
less risk from a pathogen that's theoretical, one that we could create in a laboratory but we've never seen
before in nature.
So I think there needs to be a sliding scale, given these potential benefits, some of which could be realized
any day now because we're still suffering from them; and others either have suffered in the past and others
are theoretical.
Haas: Question on this side?
Megan Palmer, Center for International Security and Cooperation at Stanford University: I first wanted to
commend Gryphon Scientific for outlining specifically where there were gaps in data and how that led to
uncertainties on being able to draw strong conclusions. And I wanted to thank the other panelists for also
highlighting areas in both the process and the types of expertise that we solicit on these questions that
may also lead to the inability to draw conclusions that have, as Adam suggested, apparency and
legitimacy in the process.
I wanted to second Gigi Kwik Gronvall's recommendations and requests from the Board to highlight the
need to address the data gaps and to cultivate a wider breadth of expertise on folks that can comment on
risk analysis. I think that's critically important. But I also wanted to draw some attention to an underlying
issue that also appeared in reviews ongoing around U.S. biosafety and biosecurity systems that look at
what is considered sensitive information in the life sciences and our current policies around that.
So I wanted to first ask Rocco if those issues and how those issues around what we deem sensitive
information use ought to be an immediate risk or an immediate issue with making your assessments and

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what you see to be a long-term risk, and recommend to the Board that they perhaps draw attention to
these issues of what we consider to be sensitive information and to what extent we'll have discussions
about security in the life sciences in public as something they try and ask whether or not our current
institutions are sufficient to resolve. Thank you.
Casagrande: Well, it's an excellent question. It's a daunting one. This problem has been thrown about for a
very long time. I was involved in 2001 with the Controlling Dangerous Pathogens Working Group that
was run by John Steinbruner, in which that was the central focus. How do you potentially I don't want to
say prevent, but control the publication of research with significant dual utility, especially since
publication is usually the last step in disseminating the information? And it's an extreme challenge.
I think the DURC policy that was recently published begins to address it; but obviously, we've seen some
failings in the past. And I don't think we have enough evidence yet that the future will be much different
than the past as far as a lack of publication of dual-use information. I mean, as a community, we continue
to be surprised that experiments get done and then published; and we notice them sometime after their
published for their significant dual utility. And so the past makes the future seem kind of bleak; but
hopefully, there will be further work done on controlling that because as our tools get more and more
powerful, potentially the dual utility could increase.
Haas: In the interest of time, I can just take one more question from this mic. I apologize to everybody in
line.
Marc Lipsitch from the Harvard School of Public Health: I think the focus on net benefits or unique
benefits of this research compared to GOF of concern compared to alternatives that would be otherwise
engaged in is crucial, and it risks getting lost in this discussion. The fact that GoF of concern research can
find us certain scientific findings implies neither that those scientific findings can only be found by gainof-function of concern research rather than other methods, nor that those scientific findings have
immediate public health benefits.
My comments spoken and written at the last NSABB go into this in much more detail, but I would just
mention that every single one of the mutations and phenotypes that have been identified, through at least
the two best known of the gain of function experiments, had been previously identified and noticed as
phenotypes or mutations of concern in safe experiments done prior to this GoF work. So the confirmation
that they were important in the gain of function context was new, but their identification and their utility,
whatever that utility is, although unproven so far for public health prediction, was there already. So the
net benefit for public health is much smaller than the net knowledge.
Haas: Thank you. Any responses?
Casagrande: Well, I think one of the more interesting and data-driven aspects of the project was in the
benefits assessment, where Dr. Myers and my other colleagues collected data from stakeholders, the
translators of the research. Not just theoretically how could some of the experiments and experimental
data be used, but what is done today? What do people actually use, how do they make their decisions,
how does it feed into their framework?
So understanding exactly how work is done was an important piece of data on how scientific information
is used to guide decisions in public health and medicine. And I commend people who are interested in that
question to read that part of the benefits assessment.
Finkel: I'll just say I totally agree. I hope it's not lost again, I'm novice to this particular set of
discussions; and I'm not saying anything pejorative about what's happened before here. But I will say I've

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seen many other arenas where there is sort of good invocation of these more common sense principles
that it shouldn't just be worst things first, worst risk first; it has to be done in a comparative context. And
then it's sort of relegated to a chapter that says all the right things. But then ultimately people fall back on
the, well, even the very term "of concern," you've got to come up with an acronym or something that's
pithy. But concern is relative to what? To me, it's of concern if something is imposing risk where
something could be reaping the same benefit with much less risk. That's the concern; it's not the size of
the risk in isolation.
Haas: Okay, let me thank the entire panel and the audience commenters.

Session 4: The Policy Landscape: United States


My name is Michelle Mello. I'm a Professor of Medicine and Law at Stanford. And it's my pleasure to
host a panel today which includes some very experienced commentators from both government and
research institutions.
Key Findings 2 and 3 of the NSABB report addressed the adequacy of the policy frameworks in the
United States. And the second finding indicates that the frameworks overall are effective; yet Finding 3
suggests that their adequacy for managing the risks associated with gain of function research of concern
may vary, depending on which pathogen we're talking about.
So there's seems to be plenty to discuss on the panel today about where the policy frameworks may and
may not be adequate or optimal for addressing these risks. To that end, we've asked our speakers to
reflect, depending on their institutions, on the issues facing Federal agencies in administering this
regulatory framework, as well as some of the strengths and weaknesses in our current policy framework
and opportunities for optimizing our oversight of this area of research.
The speakers' bios are in your packet. I won't belabor introductions, but we'll just start simply with Dr.
Jerry Epstein, who is Deputy Assistant Secretary for Chemical, Biological, Radiological, and Nuclear
Policy at the Department of Homeland Security. Thank you.
Epstein: Thank you very much, Michelle. And thanks to the Academies for giving me the opportunity to
speak with you today. I am the Ex-Officio Member of the NSABB from the Department of Homeland
Security, and I've been working closely with the working group as it's developed the proposals that we're
here to discuss today.
It's not the role of an Ex-Officio Member to tell an Advisory Board what to advise; that's why we have
outside advisors. So I'm not going to be providing opinions on what I or what the HS thinks of what
they've given us. But it is our job to try and provide technical and policy support, and help make sure that
whatever recommendations they do provide are in a form that will be most useful to the U.S. Government
when it takes this up and has to come up with an ultimate policy.
I've been asked today to help describe the existing policy landscape that affects gain-of-function research.
So I'm going to talk about a variety of proposals, some of which I think are very familiar here, some of
which are less so, in terms of a context within which life science research is already being done today.
And I'll try to touch on those areas in which it overlaps with recommendations made by the working
group.
First though, let me just very briefly summarize that. We've had a very good discussion of that already. In
terms of the working group's proposed gain-of-function policies, I have it characterized by a number of

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different questions.
First, who is covered by it? Directly, it affects institutions that receive U.S. Government funding. In terms
of which pathogens are covered by the proposal, as has been noted earlier, it's not a list of pathogens but
rather a set of criteria, experiments which are reasonably anticipated to produce a pathogen meeting the
criteria on transmission, virulence, and spread in human populations would be capture by the NSAB
proposal so again, not a specific list of agents. And in this respect, it's unlike the funding moratorium we
now have in place, which is agent-specific.
Which activities are to be governed by the proposal are, again, those reasonably anticipated to generate a
pathogen with those problems that was not Freudian, I hope but with those criteria.
And what does the proposal require of research proposals which are found to be in that set is that there are
seven principles to be satisfied before funding is to be released. And then once it goes through the
standard funding process and is evaluated compared to other possible funding claimants, the research
would then undergo appropriate Federal and institutional oversight policy.
So in a nutshell, I hope that has not mischaracterized what the working group has recommended.
In terms of the policy landscape, there is no existing set of policies that addresses this particular set of
research. That's indeed why we've asked the NSABB to come up with a proposal. As characterized here or
the skein of function of concern us not something that in total is overseen by existing policies; but there
are a number of things in place which touch on bits and pieces. So let me go over a bit of them now.
In terms of the existing policy context, I want to differentiate between those which are in effect by force
of law and therefore affect all researchers in the United States as opposed to those which are, say, a
condition of Government funding, which would directly affect only the recipients of that funding. And of
course there are indirect effects, as has been mentioned earlier, in other areas. But directly, a funding hook
would only affect recipients of U.S. funding.
Those parts of the existing context that affect all of us by law are ones I've selected here. First of all, are
the statutes in place to prohibit biological weapons development? This prohibits work with biological
agents for use as a weapon or in types and quantities that are not reasonably justified for a legitimate
purpose. Nothing specifically about this statute says anything about gain-of-function research. And
presumably, if that research is being done for legitimate, bona fide research purposes, which is an actual
explosive provision that is permitted in this law, it would not be affected by this. But it does provide the
context and the ability of the Federal Government should there be egregious acts of use, the development
of a biological agent as a weapon, this would permit prosecution of that.
This law is also the mechanism by which the United States implements the Biological Weapons
Convention, an international treaty which prohibits development or acquisition of biological weapons.
That is not just a treaty, but it's a violation of U.S. law by virtue of this provision. This provision does not
have anything specific about types of activity or agents that would be deemed use as a weapon. It's a very
subjective determination and for that reason would become very difficult to prosecute someone, even if
there were activity that seemed hard to justify.
And partly for that reason, the Select Agent Regulations were developed in response to a second statute.
This is a comprehensive set of safety and security requirements governing any use of certain listed
pathogens. And here you have to be registered, you have to be vetted by the Government, the institution
has to have permission to use those agents, there are requirements on the safety and security and incident
response having to do with use of these pathogens. And here, one does doesn't have to prove intent. If one

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is found with one of these agents and one has not registered with the Government, that is a violation of a
law.
When that law was passed, it was also fully recognizing there are legitimate and important reasons why
these agents need to be used. And so there's a process by which research institutions and people can
become vetted and approved to work with these agents. But it does provide a bar for people who are not
within that scheme.
Of the GoF pathogens that have been discussed in this context, only two of them actually 1918 flu and
highly pathogenic avian influenza -- fall under these regulations. Again, this is a pathogen-specific
regulation; and those are the two pathogens which have been discussed in this area -- for example, in
Griffin's risk/benefit assessment, picking out those specific influenza strains. I'm sorry; I'm jumping ahead
to the DURC policies. SARS is also a subagent and would be covered by that; MERS is not. So these,
again, are pathogen-specific.
A third area of legislation which binds everybody in the United States is export controls. These affect the
export of certain listed pathogens from the United States or the communication of certain nonpublic,
proprietary information which could, for example, include information on how to develop a particular
strain of a pathogen if that were not published in the open literature.
Things that are published in the course of fundamental research are not affected by these export controls,
but it is a set of statutes and regulations that could have some bearing on the ability to do and disseminate
biological research.
Then there are a number of policies which are attached to Government funding, as we've already
discussed. I don't want to say very much about these because I think they are largely familiar. We have a
policy for Oversight of Life Sciences Dual Use of Research of Concern. This is a mechanism by which
the United States Government has established a set of procedures by which it will evaluate proposals in
terms of does it want to fund them or are there steps it should take to mitigate risks that the work being
proposed may offer.
This is also specific to a specific list of agents that is smaller than the Select Agent list. And it's a list that
only 1918 flu and H5N1 high-pathogen avian influenza are in the gain-of-function discussions, the only
overlap between that and the existing DURC policy in terms of Federal funding. So gain-of-function
research on any other organism would not be covered by this policy.
Then there is a more recent policy for the institutional Oversight of Life Sciences Dual Use of Research
of Concern that's triggered by the same list of agents. And whereas the first policy addresses the Federal
Government's decision to fund this work, this policy sets up a process by which institutions doing this
work would identify work that needed to be looked at, would establish review procedures inside the
institutions, and then would develop risk mitigation plans for particular proposals that required that.
A framework which in many respects is very similar to the structure NSABB's recommendation is a
framework developed by the department of Health and Human Services for certain H5N1 and actually
that's H7N9, not N7N9 influenza, sorry about that. Larry Kerr is going to be discussing that framework in
much greater detail, so I won't say much here.
And then there's a whole range of very extensive biosafety and biosecurity guidance that the CDC and
NIH have developed for use by anybody doing biological research. And I believe it's tied, as a term of
condition of US funding, to be obligatory for institutions receiving funding in terms of a whole process by
which research using potentially dangerous pathogens can be done safely for both those working on it in

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the laboratory as well as for the community. And these two in particular, the BMBL and the Recombinant
and Synthetic DNA Guidelines, all address research practices in terms of how to do them appropriately.
Again, this is formally tied to Government funding; but essentially, it constitutes a set of best practices.
And I do believe these are used widely around the United States, not for Government-funded work but for
relevant work, and indeed around the world. So even a policy only nominally having any force of that
sort, if that force is tied only to Government funding, it can have a much greater influence more broadly.
And then one other thing I want to talk a bit about; it's actually already been mentioned today. I called it
other. It's not Federal law; it's not really Federal funding guidance. But all research institutions that are
working with any potentially hazardous substance of course, not just restricted to biological organisms,
in fact not restricted to research institutions any entity working on something that could pose a risk to its
workers or to the neighborhood or to the environment has to do so in recognition of the fact that should
there be an accident that incurs damages in the community, that they can be held financially liable for
that. This includes harm not only to the institutions or employees but its harm to outside, the general
public.
And the extent to which an institution could be held liable may depend upon the degree to which there is a
regulatory structure in place and whether the institution had been complying with those regulations. These
can all be used to establish a standard of care and to establish a set of general industry practices, which
are all criteria that should this come to a trial and a lawsuit, may be part of an institution's defense. If it's
held to generally-accepted standards or complying with the generally-accepted standard of care, that may
be a means by which liability would not be incurred.
By the way, the big asterisk to my talk here is I am not a lawyer. So anything specifically I'm saying about
liability, you need to check with somebody who actually knows firsthand what they're talking about.
But I do want to say the importance of this because independent of law and independent of regulations,
this sets part of the context in which any research with potentially hazardous organisms would have to be
judged. And liability also depends on whether a reasonable person you find a lot of these reasonable
people in legal arguments would conclude that the institution had exercised due diligence in anticipating
possible harm and then mitigating against them.
So these are among the policy constructs or laws, statutes, regulations, policies that are in place. Now, any
additional development of policy and gain of function would have to be embedded in; and whether these
existing procedures would have to be modified to fit the new one or whether they would sit on top would
have to be determined as we went ahead.
Just to review very quickly, the NSABB's proposal is strictly tied directly to Federal funding and wouldn't
directly affect things outside. That would take legislation. The NSABB's proposal does not have a list of
specific agents, unlike many of the proposals I've talked about here.
As to biosafety and biosecurity requirements, there is no firm specific list of criteria other than in the
select agent regulations, which do require that institutions have biosafety in mind and take appropriate
care, with language such as is conveyed in the BMBL or such as conveyed in Federal guidance and other
Federal documents. So it's not a specific list of specific requirements, recognizing that biomedical
research has a lot of case-by-case determinations that have to be made in terms of what's appropriate in
what circumstance.
And one other thing I would like to flag, the NSABB's proposals in term of the generation research
likely to generate a pathogen described by those three criteria one question I might put out is what

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happens if research to generate such a pathogen has been proposed and has been approved by whatever
mechanism we go through, what would govern subsequent use of that same pathogen? Does that have to
go through another review, or does that then become sort of like part of the natural background and not
subject to any additional investigation?
Let me now turn it to my fellow panelists, and I'd be happy to discuss this further with you for additional
questions. Thank you.
Mello: Thank you very much. It's now my pleasure to welcome Dr. Lawrence Kerr, who is Director of
Pandemics and Emerging Threats for the Office of Global Affairs at DHHS.
Kerr: Thank you, Michelle. And thank you, Jerry, for the introduction. It is indeed an honor to be before
you as an Ex-Ex-Officio of the NSABB since its inception and joining you once again from my new
position in HHS. It's an honor to be here and to be able to talk about the specific framework that the
Department of Health and Human Services has put into effect and has been using for the past couple of
years on a very, very specific and narrow set of gain-of-function research specifically associated with the
H5N1 influenza. So we'll take the grand schemes and mechanisms that Jerry described and drill now into
the very, very specific framework that HHS has put in place.
It's daunting to speak in front of this audience of experts who have been thinking about this for going on
10-plus years now. And it's certainly unnecessary for me to talk about the mechanisms that ultimately
have led to the decisions. As we look at the research continuum from the concept of an idea through the
actual execution of that experiment in the lab to the publication that over time, each of us has recognized
that there are inflection points within this continuum where one could potentially address biosecurity
concerns.
But I think fairly early on, in conversations with the NASBB and with the science editors around the
world, that clearly the latter points of that research continuum one finds inflecting that those points to be
not only too difficult, too hard, but also too potentially dangerous to the research enterprise to try and put
biosecurity measures in place at the point of publication.
So if we back up in the entire spectrum to basically pre-award decisions, that is where HHS has really
focused based upon the recommendations of the NSABB to place its attention on the review process and,
in particular, post the 2011/2012 issues associated with H5N1 experiments, the so called gain-of-function
experiments of concern. That is where the particular framework had its origins and the way in which the
funding agencies of HHS chose to approach this in a pre-award review manner that ultimately decided
upon a departmental-level review for certain pathogens within that criteria, and I'll talk about that briefly.
I've talked about within specifically influenza H5N1, the highly-pathogenic AV influenza strain of
concern, that even within that category, the framework specifically addresses those experiments which are
going to go on to potentially create strains that have either increased transmissibility or increased
pathogenicity by respiratory droplets; and that's the key. So that if you're taking this world of experiments
of a specific pathogen and now you start to carve off what's going to be done with that experiment, we are
talking about a very narrow and defined set of experiments that have the potential to create these
organisms through gain-of-function techniques.
What one finds is what NIH, CDC and our other agencies those are the two major funding agencies -decided was that should these proposals come before them, that the funding agencies do an extra set of
level of review where they are specifically asking seven questions of that particular experimental
proposal. These criteria determine whether or not the proposal goes on to a departmental-level review that
I will describe in just a few minutes.

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It is important that the proposal, again, around the anticipated production of an H5N1 with increased
transmissibility or pathogenicity by respiratory droplets, has the following criteria. The virus anticipated
to be generated could be produced through revolutionary process. The research addresses a scientific
question with high significance to public health. There are no feasible alternative methods to address the
same scientific question. Biosafety risks to the laboratory workers and the public can be sufficiently
mitigated and managed. Biosecurity risks can be sufficiently mitigated and managed. The research
information is anticipated to be broadly share in order to realize its potential to global health. And the
research will be supported through funding mechanisms that facilitate appropriate oversight of the
conduct and communication of the research.
If the proposal for these specific pathogens meets all of these criteria, then the funding agency refers that
proposal to what is referred to as the HHG. You'll see why we use the acronym. HHG stands for the
Highly Pathogenic Avian Influenza H5N1 Research of Concern Working Group, HHG. I'll use up my
entire five minutes if I call it that.
The HHG is chaired by the Assistant Secretary of Preparedness and Response, Dr. Nicki Lurie. It has on it
12 experts comprising senior officials from HHS encompassing countermeasure development and
availability; national security and intelligence; law, domestic and international; public health preparedness
and response; select agent regulations; science and public health policy; funding agency representatives;
scientific expertise; global health; risk assessment; and ethics.
So for every proposal that comes before the HHG, the body is assembled. They review the scientific
content that has already been through scientific and technical merit review by the funding agency and put
forward to the Department. The HHG is then demanded to basically work through a set of criteria to
determine whether or not -- there is basically one of two decisions that come out of it. Either HHS
recommends the funding of the proposal, or it recommends not funding the proposal.
The criteria are that it reviews the funding agency's risk assessments of the potential for the creation of
the entity of concern; provide additional and multidisciplinary expertise to consider additional risk factors
that may alter the research risk assessment; determine which measures may be needed to mitigate risks;
take into account the overall HHS influenza portfolio of HPAI gain-of-function research; and ultimately,
recommend whether the proposal is acceptable for HHS funding.
So in the course of the past couple of years where, again, this narrowly-defined set of research proposals
have come forward, only a handful of proposals meeting these criteria have ultimately come before the
HHG and have been individually reviewed. And what you find is actually the full spectrum of what you
might expect from a review process if it's working well.
There were some proposals that received full approval by the working group and were recommended
funding to the funding agency director. There were funding proposals or scientific proposals that were
received in which individual experiments were rejected by the committee and were recommended to the
funding agency that those not be funded.
It also defines why those decisions were made and the potential to mitigate them if they could be
addressed by the funding agency with the research investigator.
In conclusion I don't want to take up much time that basically is the overall framework that has been
put in place. It has only been used a few times. It is very narrow to the specific subset of H5N1 influenza
research that I have described. And with that, I will conclude and take any questions that you have later.
Thank you.

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Mello: Thank you. In a roomful of people who can really fling an acronym around, I think you just won
the gold medal. Next I'm pleased to present Dr. Richard Frothingham, who is from Duke University,
where he directs the NIAID Regional Biocontainment Lab and chairs the Institutional Biosafety
Committee.
Frothingham: Thank you for the invitation. I can be coming from a very different perspective, mostly
someone who has been doing this dual-use review as part of an IBC working with IBC members,
working with investigators and hopefully there will be some perspectives that will be helpful from our
experience.
We began reviewing dual-use research back in 2003 when the NIH funded the Southeast Regional Center
of Excellence for Emerging Infections and Biodefense (SERCEB), one of the Regional Centers of
Excellence. And within the SERCEB, they funded a Policy, Ethics and Law Core. And one of their
mandates was to review the research coming forward for dual use. That was an idea that they had. They
thought it was time to begin that process. And they also reached out to IBCs in the region. And I think
virtually all the IBCs from the member institutions came on board and said, oh, yes, we'll review dual use.
And Duke, UNC, Emory, started reviewing things for dual use, just in general. And they brought some
training materials and taught us something about how to do it.
There's a publication in science just describing some of our practical experiences what worked, what
didn't, how the process went. And you can pull that up if you're interested in that experience.
For GoF review by the Duke IBC, we started that a couple of years later. In 2005, we added the seven
famous questions about the seven categories of experiments that could raise concern. And we also added a
generic segment of anything else that would pose issues of dual use.
We did training for the IBC members in 2006, using the SERCEB module. And so we've been reviewing
protocols. And we do rDNA review. As you can imagine, our IBV also does Select Agents. We do BSL3
review, and we review anything that somebody wants us to. So that's how we've gotten these protocols.
And so just some of the pathways one of the questions is what is the on ramp, as it were. And in
addition to the questions on the IBC form and the concerns that are identified, really, IBC members are
probably the most like to identify these. We have gotten queries from NIH study sections and program
officers, so that's another process that has come to us, as you can imagine.
I want to give you a couple of examples of some gain-of-function research that we have looked at, at
Duke. I know many of you have examples of how you've dealt with these. And it's an imperfect and
complicated system; every case is a little bit different.
The first one that I became aware of was actually one that came through prior to IBC taking this on. And
that was an investigator at Duke who proposed to do some cytokine research with ectromelia. And this is
kind of the classical example of a gain-of-function that is problematic, putting cytokines into ectromelia.
And the dual-use concerns were raised by the NIH study section. The investigator had not really dealt
with them in the grant application. And the investigator just, I guess, got gun shy and just pulled it back;
and he stopped doing it, just pulled back completely.
That's not to say that it couldn't have gone forward -- if discussion had good forward, if there was a good
justification. We never saw that application, and I can't really speak to why it was justified or not; but that
was an experience. And going forward, this has been sort of a cautionary tale to say, hey, as PIs, we think
maybe it's helpful for you to think about these things before going forward.
And the second one listed there, we see this all the time. All of our bacterial pathogenesis folks are

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dealing with virulence factors. They are manipulating bacteria putting things in, taking things out in
hopes of attenuating or making more virulent various bacteria.
The reality is most of this research is gain of function in a sense. You've got a strain that suddenly
produces a colony forming unit at twice what the other strain did. But in many cases, these strains with
their souped-up virulence factors are not fundamentally different from the basic organism. They have the
same basic mechanism of causing disease, the same transmission, etc.
In any case, this is an example of one we reviewed. We reviewed it and we said, hey, we don't want you to
put 10 different antibiotic markers in the same strain. And if it comes to you from the clinic resistant to
five things, you can't put all the antibiotics into the same strain. But other than that, we thought the
research was fine. And the PI agreed that if they identified an unusual extenuation of virulence that they
would stop the research and bring it to our attention. That hasn't happened, and we've reviewed a number
of these types of applications.
We got a query from an NIH Program Officer related to a SERCEB project that involved adaptation of
dengue virus to grow in Drosophila cell lines, taking advantage of genetic tools available in Drosophila to
explore how the virus works, I guess. I don't know the details of what they wanted to do with that. And
this actually had been reviewed by the SERCEB growth agency adding dual use to it. But the NIH
Program Officer was reading the seven things and it says "Extending the host range of a pathogen." And if
you extend the host range to Drosophila cell culture, it sounds like it fits that criteria.
The Duke IBC reviewed it. We felt that since it was coming to us from NIH that we would like to think
about it ourselves, but we also recruited some external opinion/external advice on it. And the consensus
was uniform that this was not a particularly hazardous approach because when you adapt a virus to grow
in a cell culture, it virtually always loses virulence rather than becoming more virulent. And also
Drosophila is not going to become the new host. We just didn't see Drosophila transmitting dengue.
So the project proceeded, and we did this typical thing that we always do. We required the research
personnel to complete dual-use training, so they're at least familiar with this. And that's actually a step
forward because throughout this period, I would say that most of our PIs, when we ask them a question
about dual use, they are not really understanding exactly what we're asking about. They're thinking
biosafety usually; they're thinking even biosecurity a little bit, but not so much what is the concept of dual
use?
A recent one that we reviewed was an HIV infectious molecular clone pseudotyped with VSV-G, which
are envelope proteins that allow viruses to enter a wide variety of cells. And it's the common workforce
that we use for replication-deficient lentivirus and retrovirus factors. This is a replication competent
vector. And the researcher wanted to use this to put HIV infection-molecular clones into renal cells to
understand how does the renal reservoir work. And this is a one-cycle kind of thing because the VSV-G is
on a different plasmid from the infectious and molecular clone, so it's not expected to produce a virus that
propagates in that fashion. But the initial infection, the initial organism, the prep, the material would be
potentially more hazardous in that it can infect virtually all human cells including resting cells,
including cells that don't express CD4, etc. So there was a sense it might be a little bit more hazardous to
work with.
We actually went for external advice on this one as well and got some opinions from various people. And
in this particular one, we're beginning to move in areas that you've heard about today. We began to ask
sort of the question of: Can we work with this safely; what are the risks of this? And then the second
question was: Is this necessary and do you need to do this research?

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And got some opinions on both of those matters, went forward, the research is going forward. And the
IBC felt that it did need to be conducted under BSL3 conditions and also with rigorous administrative
controls. And that ended up with them recommending that it go on within the regional biocontainment
laboratory, where there's a lot of infrastructure along those lines.
Some of the lessons that we've learned along the way and I hear this from people otherwise, some of
these things; you've all experienced these as well. We do encounter gain-of-function studies. These are not
the gain-of-function studies that the NSABB is describing or that the HHS framework describes. These
are not at that level of heightened concern. And we've not encountered, as it were, gain-of-function
studies that are gain-of-function studies of concern.
And I've given you a new acronym here: GOF-SOC, which I thought was kind of nice. I was speaking
about six or eight years ago when the DURC abbreviation suddenly appeared in the handout that went to
the conference. And I was back there typing away, and I stuck it into my slides. And everyone said, "How
did you get that in there? We just released that."
Anyway, I don't know why it's not research of concern, it's studies of concern now, so it's GOF-SOC,
whatever that means. PIs in our experience have had a challenge in thinking about dual use. And dual use
is so broad and nebulous. All biomedical research has the potential of being misused. This gain of
function -- and particularly the gain of function that's being discussed today primarily -- is a very welldefined concept.
And I think in general, as we talk with our PIs about gain-of-function studies in the wide range of
microbiology, I think it's going to be a little bit easier for them to understand why we're concerned about
this and the potential for misuse kind of questions that arise from it.
Consensus is a big issue. And I heard Jerry talk about the reasonable person. And I've got some great IBC
members on our committee, and I'd like to think that they are all reasonable. They are independent; they
are smart; and they can imagine almost anything. They have great imaginations.
So in the realm of dual-use potential, what could go wrong? We can think of almost anything. And getting
consensus has been a challenge. When I went into this, I said, well, let's come up with some categories
and not dual use and insignificant and significant. And I was going to characterize, and I like to
characterize things; and that never worked. We could never get consensus on: Is this dual-use research; is
it dual-use research of concern; is it significant concern, et cetera? All that stuff, we could never get
consensus because we could always imagine some horrible misuse.
However, we could get consensus on going forward with risk mitigation strategies, modifications; those
things all happened. So where we were never able to reach consensus of this is not a problem, we were
able to say, well, let's talk about how we're going to manage this. And management worked across the
years.
Now, we've never had to deal with the really tough ones -- the ones that no matter what we do pose a
substantial real risk, as some of the things we're talking about today. And I'm concerned about the ability
of committees to gain consensus smart people to gain consensus on tough issues, and I don't have an
answer for you there.
We have often gotten external advice, and I think that's useful when we don't know what to do. It's also
useful as a way of eliminating some of the conception of conflict of interest bringing other people in,
getting their opinions so that it's not just all within your shop.

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How about the benefits? And I've shown you this graphic; we've been keeping tabs on this very closely.
These are identified episodes of misuse of Duke research to harm public health, agriculture, plants,
animals, environment, or material coming out of the dual-use research of concern. And so these episodes,
we're keeping track of them. And prior to our doing this review, we had none that we had identified; and
subsequently, similarly, we have had none.
It's hard to know if this is working. But I have put at the bottom some things where I think -- some of the
benefits that I think are there and I hope we never have one, of course.
Can we measure benefits? I think public trust and responsible science is maybe the biggest thing that
comes out of this, at least at the level of what we're working with is that people can know we are
reviewing these things; we are thinking about these issues; our PIs are thinking about these issues.
Also early review people talk about don't review it before the publication. Review it at the very early
stages can avoid wasted effort and frustration and maybe even improve the outcomes in the study
sections.
I have a few perspectives on the NSABB recommendations. I'm not an expert in this area, and you folks
have done so much work on this. I think gain of function is easier to understand than dual use. And in
many ways, I'm feeling like we ought to do more gain-of-function training training our PIs in this
concept as opposed to dual use, which can mean almost anything.
The proposed definition of gain-of-function studies of concern is really very much clearer than our
current dual research of concern definition. It says "could be directly misapplied," but how is it going to
be misapplied? Almost anything you could imagine.
This is very precise and I like that. I think the world of research in this should be small and definable.
There probably aren't hundreds of people wanting to do this research. I hope they don't fall through the
cracks. I mean, I hope they're all identifiable. Many of them are in institutions that have select-agent
programs; many of these are select agents. So I hope that expertise will be very helpful.
The current IBC or IRE mechanisms or entities I think are going to be important at the institutional level.
Thats not going to be the only part of the review, but I think that these groups are well-equipped. But I
think as we go forward, we should have a very low threshold for getting external advice -- whether that's
from the Federal Government, whether it's from other experts -- just to give us some ability to say we're
not just in our own sphere making these decisions.
One of the things that we recently did, we've been doing dual-use research within the IBC for now 13
years. We recently moved it to our institutional review entity, the entity we're required to have under the
U.S. Government Policy of Institutional Review of Dual-Use Research of Concern. So we have an
institutional review entity. It's a separate committee; it does not have public minutes. We post our IBC
minutes on the website; we don't post our IRE minutes. And we believe that dual-use research, it's not
always possible for it to be public because the very fact we're reviewing something actually might be
dual-use information.
But it should be transparent. I'm just listening to people here. You can see our IRE members, Institutional
Review Entity members, on the right side of the slide; and three of them are community members. So we
have a community presence on our Institutional Review Entity. You can see the other names there
supporting this. Funding for all of this work is institutional, and we have to pay for this; and it's real
expensive, as you can imagine, to do it right.

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Thank you. I guess I'm done. It doesn't progress; when I get to the end, it won't progress. It throws me out.
So I'll have a seat then.
Mello: Thank you very much. And our final presenter before we open it up for Q&A is Dr. Philip Potter
from St. Jude's Children's Research Hospital. He's a cancer researcher, who has participated for many
years in institutional governance of dual-use research of concern.
Potter: I'm going to set the stage here for why I'm included. I became the DURC Committee Chairman as
part of my IBC responsibilities. And DURC Committee reports to the IBC but does not actually publish
its minutes, similar to what Richard said, because we have no idea who is reading our minutes; and we
don't want the science to be generally publically disclosed.
You might be thinking why does St. Jude have a DURC Committee? Partly because we have a very large
flu program that goes on at St. Jude run by two established PIs. A large amount of money comes through
WHO and NIAID. And as part of that, we receive influenza-positive sample from all round the world. The
idea is to find out where those viruses are tracking, how they're being spread, what movements are
occurring, and are they something we need to worry about.
And to do that, we sequence these. They're then categorized based on those sequences, whether they fit
into the high-path or low-path category. And of course that then covers agents which are potentially
DURC and gain-of-function; and then based on that, there are biochemical and in vivo studies performed.
And frequently, viral segments are swapped around to find out what their function is. So as you can
imagine, that could quite clearly fit into the current category of DURC and potentially gain of function.
So how did we go about reviewing this approach? We set up a DURC Committee, which consists of a half
dozen established faculty who have specific expertise in the subject that's being discussed. In our case, it's
always flu of course. We have legal personnel; we have PR folks; we have members from IRB. We have a
really diverse group of individuals, and it's up to the PI to espouse how good their science is, risk and
benefits, so that everybody from the Committee, even from the lay person to a scientist, can understand
what the benefits are.
We've been through this process now for four or five years. We've maybe evaluated somewhere on the
order of 14 or 15 different projects. And really what the sort of consensus that has occurred is that we've
come up a sort of an internal set of guidelines that we like to use. So I've put no gain of function in virus
resistant to antiviral agents; that's of course DURC as well. So I'm using DURC and gain of function here
synonymously. That has to be a vaccine. We typically like to see protection of individuals working in that
area, so we'd like a vaccine to be available.
We run into difficulty evaluating gray areas, as you might imagine. And the biggest gray area for us is in
the DURC guidelines where one of the comments says "altering the host range and/or tropism." So if you
take a highly pathogenic virus and you make it less pathogenic, you've altered the tropism of the host
range; therefore, we have to evaluate that. If it had said "increasing," then that would have been okay, but
anything that drops in pathogenicity we also have to evaluate.
We've also mandated that ferret be used as the gold standard for biological testing. That may seem
obvious, but some PIs were only doing their experiments in mice to see what the mouse phenotype was.
But inadvertently, they might be generating something that was also more pathogenic in ferrets; so we just
insisted that they do those same studies in the ferret.
And to give you an example of something that happened, as was mentioned earlier about H7N9, that
framework came in, I guess, in probably 2012-2013. Almost exactly at the same time, we'd started to see

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these viruses being detected in samples arriving at St. Jude; and clearly PIs wanted to do studies on that.
But it occurred to us that the studies that might happen would be potentially as hazardous as something
being done with H5N1.
But unfortunately, H7N9 is not on the list of 15 agents that is covered by DURC; so it fell into this hole.
We, as a committee, categorized it as 'durc,' in lower case, because it wasn't officially from the
Government perspective DURC; but we realized that those results might just be as enabling as anything
else. So we went back to the investigator and said these are the concerns. As a result of that, the
investigator decided not to progress because we knew at that time additional guidance was coming along
the line, so we waited for that to be established.
So what about the current guidelines that have been provided by the NSABB? I think they provide a
really initial good draft, which will certainly help PIs and institutional officials in understanding this. I
guess the problem that everybody has mentioned so far is that this is a continuum; and as a result, there
are no specifics. It's all highly likely significant.
As somebody who has to sit down and review this information, that's problematic because there are no
clear guidelines, no clear milestones, for me to say yes or no. So I think the way that DURC has looked at
it is that we've looked at what the starting material is, and then we see whether that would potentially
increase that. And so the starting virus is nearly always our sort of baseline. I don't know how else we can
do it; but, clearly, we might run into issues at some point.
And the other thing is that one of the points that's in the document is that the pathogen generated is likely
resistant to control measures. So I think one of the things at St. Jude that the DURC Committee has
mandated is that your parental flu virus that you're going to do these studies on has to be sensitive to
oseltamivir before you start doing those experiments. Whether that is a good thing or not, I don't know;
but I think it gives us some level of potential safety if anything untoward would happen.
So these were the specific questions that Michelle asked me to address, and I've tried to cover them as
best I can. So where are the proposals likely to succeed based on what our experience is with DURC?
I think the criteria are well-founded. I think they cover the right attributes. I think the process that we go
through to evaluate this would be pretty straightforward based on our experience with the DURC
Committee. I think the expectations for the PI and for the committee as to what they have to look for and
how they look for it are clear. And I think that our DURC Committee likely has the expertise to assess
gain-of-function research. It's not a huge step here to do that.
So where are the major gaps and weaknesses? Clearly, DURC is for the 15 selected organisms; and that
included non-avian pathogenic influenza, and that was of course the H7N9. There is still some ambiguity.
We fall into this area of: Where do you start on the continuum and what is good and what is bad? I can't
answer that.
And I think one of the things that has arisen from our experience is that if the local entity believes
something is gain of function or DURC that doesn't specifically meet the criteria that is mandated by
NSABB or other, what do we do in that situation? Does the local entity have control over this science, or
is this a Government issue that requires going backwards and forwards? Does it go through NIH or
whoever the funding agency is to make that decision? I put this out because I think we're going to see
more of this as time goes on, and I'd really like the NSABB to at least try and address it.
And so what are the most important problems that I think need to be addressed?

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Well, I think whatever you decide and however you write it, it has to be crystal clear. It has to be obvious.
If you go through a decision tree like you had previously, you can't have 45 branch points in that decision
tree. It's got to be yes/yes/no because otherwise, as scientists, we're always looking for that stuff on the
edge that doesn't quite fit the hypothesis. You're going to be working around that edge if that's the
hypothesis.
And then I guess the other issue that comes to my mind is if the local entity has a problem, who do we
contact? Is there a group who oversees this, who would be our first point of call when I have to pick up
the phone and say, "I've got a scientist who wants to do this; who do I need to talk to, to get a reasoned
decision or response?"
And so my other concerns that weren't listed there I really think the problem with local description of
gain of function or DURC, if that system goes forward, you might end up with a patchwork of institutiondependent rules.
Now, St. Jude is fairly conservative. I think we tend to be more restrictive on our science than some other
places. But I think if you allow local decisions to be made which I think in some cases, you might have
to I don't want the system to become even more clouded than it already is.
And so to the last two points, I have to state here that I'm a scientists as well as an institutional official.
The last two comments are me as a scientist don't represent St. Jude's viewpoint. But really, as a
scientist, if a PI can really justify to me -- DURC Committee/IBC/U.S. Government -- that this is the best
experiment ever, is it up to me or anybody else to say, "No, you can't do that." It's a philosophical
question I think you have to think about, but I don't really want this to stymie the way we do science.
And then the last point is really just a validation of that comment. I think we are scientifically more
informed, based on the work that Yoshi Kawaoka and Ron Fourchier did five-six years ago about virus
genetics. If we didn't have that information, we might not be able to predict what would be coming down
the pipeline for viruses that we pull out of nature at the moment. So I think it's really something we have
to seriously consider. Thank you.
Mello: Thank you. Okay, we have about 35 minutes for questions and answers. And as before, if the
speakers would start by identifying yourselves, that would be helpful.
I'm Pat Fitch. I'm an NSABB Member. My comments represent my personal perspective, not that of the
Board.
I wanted to start by reinforcing some things that Rich and others said about institutional review entities.
We've had a similar experience in our organization where assigning the label DURC outside the strict
government definition became very challenging for the committee. And so as institutional official for that
committee, I switched their charter to instead approve the risk mitigation plan for projects rather than
spending their time around whether it defines as DURC or non-DURC. And so I think that's likely
become a very broad experience for lots of organizations.
Second, I have a question because I'm wrestling with this myself on the NSABB and I don't know the
answer. I think we talk a lot about the representation, in terms of accountability, of the sponsor and the
performing institution. And so these are organizations that might appreciate what it takes to do the work
and the opportunity cost of not doing the work scientifically in terms of the scientific community. But I
don't think we've talked specifically about the accountability of who owns it if something goes terribly
wrong and how they're represented in this process. And so I'd be curious about your perspectives on how
maybe to do that better than we've talked about in the past.

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Mello: One of you want to take that?
Frothingham: My first word is that things haven't gone horribly wrong -- which I'm really thankful for
so far; and we're doing our best. But one of the things that I've experienced over the years I have both
hats -- I'm the IBC Co-Chair, and then I'm also a scientist. And whenever my research comes forward, I
have to leave the room; and they really hold me to what I think is an extreme standard. It took four rounds
to get my plague work approved, just starting up with anyway, and that's frustrating.
However, when news stories would break about a problem here or a problem there, immediately our dean
wanted to know what we were doing. And I would generate these memos at five in the morning before the
news story would get to the dean saying "By the way, you're going to hear about this; and here's what we
do at Duke." When the USA Today report came out saying all these reports to the NIH Recombinant DNA
Advisory Committee had reported a lot of things, we actually felt pretty good about what we'd reported
and how we'd responded to it. So I think that laying the background very carefully, having the scientists
and the review people be independent from each other, and holding to a very high standard, it's
frustrating. But in the end, when push comes to shove, you're really glad that you have it there.
Epstein: Let me jump in. Pat, I think there are two answers to your question. And one of the reasons I
brought up liability is there's going to be a legal answer. If something goes horribly wrong, there are
going to be lawsuits; and the courts will determine that. But there's also a political answer. I think
Government employees and senior political officials have to have in the back of their mind, "What am I
going to tell Congress in the inevitable investigation?" So I think that's something that we also have to
recognize.
And just while I'm here, I want to have an additional word. I think I may have left a misimpression in
terms of select agents and safety. The actual language in the select agent regulations on safety is very
small, but the attention given to safety by the program when it registers specific institutions and when it
does inspections and by incorporating the entire BMBL by reference, there's a great deal of attention
given to safety. So let me not equate amount of words with the degree of attention.
Mello: Thank you.
Potter: I have a comment. I think a lot depends on how you construct the committees, and including your
IBC, to get as much input as you can at the beginning. So our IBC contains a lawyer, who is part of the
medical community and not affiliated with St. Jude. We also have the public health official for Shelby
County, which oversees Memphis. Those people bring a completely different perspective to the way that
we look at the protocols, and they raise things that there's no way we would ever contemplate. And I think
that's really good.
It also happens that the public health official is also our first point of contact if there ever is an exposure
at St. Jude, so she can coordinate the exit of those individuals from St. Jude; the safe transfer to an
isolation facility in a Memphis hospital. I think having all those pieces in place means that your likelihood
of events happening drops significantly.
And I think by thinking about those things, which aren't obvious from any of the regulations, but by
working through it and thinking about it in advance, you hopefully mitigate those opportunities.
Mello: Thank you.
Hi, this is Diane DiEuliis from National Defense University and the Department of Defense. Formerly at

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HHS, where I participated in the HPAI review group, we actually changed the name of that to be HHG
because our original acronym was called a bureaucratic troglodyte by Richard Paggett; so we called it the
HHG.
My question for the panel, I appreciate all the comments that were made regarding this idea of having the
difficulty with crystal clear definitions. And our experiences in the HHG were sort of like a lot of the
review of these proposals were sort of on a case-by-case basis, and each one seemed unique.
So my question for the group and for those who have reviewed these kinds of proposals in IBCs or other
places, we constantly say that if there is a dual-use gain-of-function study, is there an alternative means
for the investigator to do a study that takes them out of the risk range? And I wonder how much
experience we have with that? Were there any scenarios in which an alternative path of research was
recommended and could that get us closer to helping us define where some of these lines are? Thank you.
Potter: I think from St. Jude's perspective, that's why our DURC Committee has people who are lay
individuals. They're much more likely to ask those sorts of questions than the scientists are. And actually,
I think that's good. We have folks on our IRB who ask questions like that, who may not have specific
expertise in the sciences actually going on; but they're much more likely to ask the question Do you need
to do that in an animal model? Can you do that computationally? Can you do it this way? Which I think is
good. Again, it comes down, I think, to making what you think are reasonable choices of having people
on committee.
Now, of course when we actually meet as a committee to discuss this, anybody can raise whatever
concerns they have. But I think at that point, because the PI has been through this process and will go
through this process at quite some length these are two-hour meetings sometimes with an hour-long
discussion with the PI on the science they will have gone through every possible way of trying to do
that same experiment without using a potentially-hazardous model to get through. So I think the situation
has already been discussed at that point. So I think while that does come up and it is raised, most of the
time there isn't an obvious less what's the word I'm looking for there isn't a simpler or more effective
or easier way or safer way of doing that.
Frothingham: We've certainly had experiences where we have raised a concern and an investigator has
modified their plan. I think more with viral vectors than with these GoF pathogens. But I think it's a tricky
balance because when you're sitting there as a committee and you're saying, well, you're working with a
pretty safe lentiviral vector but there's another one that's safer, do you say to the scientist, "Do you need to
go retool with this safer one?" That scientist may not have a lot of margin in his research funding. He may
be getting pretty close to running out and needing to get his next grant and so forth. And sometimes I
think there is a balance to be had there. It turns out that both of them are exceptionally safe and so we say,
well, we'd like you to think about this for the future. But, no, we're not going to require you to use the one
with the inactivated LTR versus the other; we are going to focus a lot on your sharps precautions. So it's a
balance I think we have to keep so that science can move forward too.
Epstein: Richard, I was very struck by I think it was you made an example at one of these symposiums
several years ago where you had mentioned that something came up before your IBC and questions were
raised about the safety of that approach; and it was suggested to do a different approach. I think it had to
do with a neurotoxin. And the answer is that you did a different approach, but you did different science.
Frothingham: Yes. It was not the same science in a safer way. It was a different approach, and you got
different science out of it which I thought was very telling. And we actually just ask the question and
the researcher just sort of I don't like it when researchers just immediately cave and say, oh, okay, we
won't do it. That's not always the right answer. We just want to engage with you and help us understand

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why it needs to be done. But, yes, this was a subunit that is not toxic because it can't get into the cells by
itself. But you put it on a retroviral vector, and it goes into the cells. So that was the research being
pursued gain of function.
Greg Koblentz from George Mason University. First of all, let me say this has been a very helpful panel
and all very interesting presentations. And it ties nicely into a theme that came up this morning among the
previous speakers and some of the commenters about the need for learning from past experiences in this
domain as we move forward.
And I think Duke and SERCEB are to be commended for capturing some of their lessons and publishing
them in Science, but that was many years ago. And clearly, you have even more experience to draw upon
now. And I would suggest that we need for the HHS methodology, the St. Jude's experience, and Duke I
know there are other IBCs that also have taken this on very seriously a mechanism for capturing these
lessons in a more wholesale fashion as opposed to the kind of a retail model we have here. I think that
would go a long way to helping both the PIs understand what the possibilities are, helping understand
what is practical at the laboratory or scientific level, and for helping the people understand more broadly
the processes behind these risk assessment methodologies.
And there's one point that the gentleman from St. Jude brought up about the risk of a patchwork of
institution-dependent frameworks. From my perspective, that's not necessarily a bad thing because if you
have different organizations/institutions that can experiment with different ways of doing these review
processes and they try different approaches and methodologies and different types of members of their
committees, they might all learn something different. And if they share those experiences, then everyone
benefits from it as opposed to a cookie-cutter approach where everyone just tells exactly what HHS says
to the letter for the select agent they generate. Then there's no experimentation as to innovation; there's no
improvement.
So I think there is a value to having different approaches; but there needs to be a mechanism to kind of
gather those differences and have a processes of understanding, okay, which of these are actually
improvements and doing things better, and then some kind of mechanism to incentivize people to then
adopt those best practices moving forward.
So I realize you guys aren't NSABB, but that would be something to consider for building and how to
learn from this process we have gone through. And any future process we establish should have a
mechanism built in to provide that kind of (inaudible) work so we can all learn and adapt from it.
Mello: Would anyone care to take up the question of whether having varying standards from institution to
institution is a problem?
Kerr: I'll chime in and say I actually completely agree with Greg in terms of if you're going to have
different scaling capacities at different colleges and universities around the States. So the ability to have
one cookie-cutter model that will fit all of them, I think, is possibly nave.
If anything, taking the examples that have been garnered from the grassroots level and that are actually
working is what we as a government need to find out is there a common pattern that exists across all of
the models that are working that can be replicated and then molded to the individual university or
college's particular frames, customs, the research that they're doing. So I actually think that's a really great
suggestion.
Epstein: I agree with that with an asterisk. I think it would be useful to have consistency. If one
department and institution is issuing guidelines or doing processes which are clearly incompatible or in
sync with what someone else is doing, that's not a good situation. But in terms of how one prevents that, I

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cannot see the Government specifying a list of guidelines and specifications and rules and requirements in
such detail to prevent that from ever happening. I don't think we could ever come up with that.
If there's one thing we know about biology, it's very hard to force it into a box. So I think an inevitable
result of the whole field we're in is we're going to have to have some amount of interpretation and some
amount of variability. But rather than mandate consistency, I think the answer is to try and go towards
best practices if we can.
But here I'm noting the point that one of you gentlemen made about not wanting to release your IRE
minutes because when you're discussing dual-use implications of a project, those essentially could also be
dual use. So I'm torn between the obvious imperative for transparency; but at the same time, here is a list
of all the things we really worry about in our biological portfolio. And having that on a website for
everybody to see has a bit of a concern for me. So we have to have some way of identifying and share
best practices, but doing it so recognizing that we're not just worrying about safety and nature. But we're
worrying about people that are mining this to try and do us harm. That's always at least in the back of my
mind.
Mello: If I may push this forward just a little bit before we go to the next question, how do we know when
an oversight approach is working? Is the absence of a rare, catastrophic event in and of itself evidence
that we have an effective regulatory framework?
Epstein: I think it was Rich's point, I believe that public trust is essential. And if you have a process
which you can lay out and explain and people will go, oh, okay, I can see why you're doing that; that sort
of makes sense. That's one measure in the absence of did we or did we not have a disaster. So you have to
have an approach where one can see why we're doing it, one can see that the things we're doing seem
reasonable. And then basically you have to argue in terms of going through and saying, yes, this is an
appropriate response to this issue if you don't have the ability to collect data. I don't want to get the data
on this.
Kerr: I also think years of reproducibility and then evolution of your process to learn from best practices
and challenges along the way starts to define a pretty well-defined program that you can say, at least to
date, that nothing has fallen through the cracks always with that in the back of your mind, that you're on
guard for what's around the corner in either research developments or new pathogens of concern that you
have to be mindful of. That's part of the evolutionary process.
Frothingham: I think the presence of community members and their stature we have the County Health
Director on our committee as well, the Medical Director of Durham County Health Department. And
that's a good place to go for community members. One place that I think you can really go a long way
with so I think that discussing the details of dual-use research is itself dual-use information at some
level; it is a problem. There is a lot of dual-use information that is currently published out there, and no
one knows it because they don't look at it that way. You start talking about it and suddenly people realize,
oh, yes, there is information about that.
And when I go to ASM meetings, sometimes I'll walk up and tap someone on the shoulder and say, you
just gave out some dual-use information and we need to not do that. Don't tell me how you do this
methods from people who need methods, but don't tell the whole world whatever it was I told them not to
tell. And I've been aerobiology conferences where so much is out there. So we need to be careful about
dual-use information. It's out there; it's published; but it's not as obvious what it is.
Where do we get our credibility? One of the places we do it is in the other three pillars that we haven't
talked about a lot, which are the biosafety, protecting the worker; the biosecurity, protecting the

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environment; and the biocontainment, the structure around it. And all of that is under an umbrella of
administrative controls. And to develop a program that is excellent in those areas, that has the credentials
by the way, they should be ABSA credentialed individuals out there or National Registry of
Microbiologists, if Joe prefers.
But we need to have credentialed people who have the expertise who are running these programs, but we
need to have a structure that we can point to and say, yes, here's how we protect people. And focus on the
biosafety, the biosecurity and biocontainment because those are things that we can talk about a lot more
freely.
Mello: Thank you.
Kerr: Can I just chime in and say kudos to you for including a public health person because that's a person
that's often forgotten about in IRE. I often get a question of: How does an institution bring a security
person on board who actually understands the world of the security community?
Certain IREs have brought in their local WMD coordinator, who is a person who is trained in the security
and trained in the threat and risk assessment environment to be able to lend that perspective, sometimes
from an outside perspective to an institution. But those are often disciplines that we'd like to see
incorporated into that.
Frothingham: Our WMD Director I mean our local director provided our initial insider threat
awareness. And clearly, insider threat is what the real threat is; we all know that.
Potter: While they're part of our IBC, we have an FBI contact that comes regularly. We discuss with these
people so that they're aware of what's going on. They probably don't know the nitty-gritty because they
don't need to know that, but they are aware of our security facilities and how we coordinate.
Mello: Thanks for your patience.
Silja Voneky, University of Freiburg and German Ethics Council Harvard Law School Fellow at the
moment. I have a question to Gerald Epstein because I was very glad that you mentioned the liability
issue. And my question would be whether you have thought about a duty to be insured for research of
organizations that would have a duty to be insured against accidents. That would be another element of
cost/benefit ratio into this whole topic, I think. This would be my first question.
And the second question to Gerald Epstein as well you talked about the bioweapons and chemical
weapons treaties. And my question would be whether your department or the government thinks about an
initiative to either enhance these treaties in regard to gain-of-function research, dual-use questions, or
whether there should be another international treat.
Epstein: Let me duck the second question because there's an active interagency program within the
United States government looking at how these treaties should be strengthened, and lots of folks are
giving the various ways in which that might be done. But I won't have a specific answer as to that specific
proposal here.
On the duty to be insured, at least my department does require laboratories doing work with select agents
to have insurance; and that is one mechanism by which one can try and influence the behavior of
institutions. The problem with any insurance approach to particularly a security problem is being able to
come up with an actuarial calculation that if you do these things, then you will save money because bad
things won't happen. It's very tough to make that connection, and it's very hard for the insurance industry

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to issue rates that are commensurate with the risk.
But certainly from a safety point of view, I think that is a tool that is being used. Institutions facing
liability threats would need to procure insurance. And then whatever requirements the insurance
companies would place on that will modify behavior or reinforce good behavior by those institutions.
Mello: Okay. Dr. Bloom?
Barry Bloom: A comment and a question to Richard and Jerry Epstein. In the beginning, you began with
the three criteria. And I am really now quite puzzled by the third of those criteria. The original criterion
No. 3 in addition to transmissibility and virulence was that it be resistant to existing control measures.
And I was offended by that because while we may have Tamiflu in this country and vaccines for flu, in
Bangladesh or in Burkina Faso, they don't have the capacity to control things and I thought that
introduced a level of inequity.
The current formulation, as I gathered it from this morning, is that it have an increase in virulence,
transmissibility, or ability to spread in populations which, to me, is the exact same as transmissibility.
Why add a third criterion when it's already redundant with transmissibility? And I'd be grateful for you
and the NSABB in general to clarify that. And the fewer restrictions and the clearer they are, it seems to
me the better it is.
My question to the panel is which I thought was a wonderful panel is there a need for separate
institutional panels or even higher level panels for GoF and DURC? Would it make sense to consolidate
those activities and create a group of experts, since they seem to overlap?
Potter: So we don't have a GoF panel as yet. The history of GoF at St. Jude is that we had a big grant
submitted; it was funded; it was flagged by NIAID as having potential GoF science. And it was sent to St.
Jude and said, you need to evaluate the GoF in this. So we convened a committee of 15 or so senior
faculty -- senior administrative folks, IBC personnel, security individuals -- and we evaluated the science
and gave everybody a scoresheet; and there were maybe 10 or so projects that were up. And the question
was: Do you think this is gain of function?
And there was a whole range of 100% yes to 100% no to everything in between. And clearly, we realized
that this was never going to be an obvious, easy decision. We sent all that information to NIH. All the
non-gain of function came back and said, yes, you're happy to continue that. We as an institution decided
not to continue with any of the gain of function because it was hard to know exactly what the criteria were
on it and we were still under the pause, so that science has essentially been stopped.
Ultimately, I think what will happen is that GoF will be reviewed by our DURC Committee. We may well
add a couple more individuals who have expertise for potentially biosecurity, biocontainment to maybe fit
with that. It's still a work in progress, but I'm pretty sure that we have the right expertise at the moment.
We just might need to expand it to cover that separation.
Epstein: Let me take your first point; I now have the opportunity to duck two questions in a row. As an
Ex-Officio Member, I was relaying the NSABB working group's point, but I'm not the one to answer the
question. However, they are in the room here; and they heard your intervention. So I think you have had
the effect of speaking to the working group with that.
Mello: Thank you.
Allison Mistry with Gryphon Scientific: Jerry, my question is for you as well. I appreciated the policy

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landscape that you laid out for us, but I'm curious about your statement that the institutional DURC
policies or the Federal DURC policies don't cover this type of research. The summary for both policies
states that the list of organisms will be reviewed and expanded as necessary. So I'm wondering why we
wouldn't update those policies as needed, rather than create an entirely new policy that institutions need to
react to especially when they've been expected to set up these new systems, the IRE that the two
institutional representatives mentioned.
And also that policy, the scope is meant to address people who both fund and conduct research. So the
scope is as far as institutions, a little bit broader rather than just the funders. So I'm wondering if you
could speak to why we wouldn't just expand or repurpose that policy instead of creating a potentially
duplicative one with potentially a smaller scope.
Epstein: Sure, what I meant by not covered is as they are now; and that's largely because they're based on
a list of 15, 16, 17 specific agents. And that's the first test that one applies to see if those policies are
relevant. So if one isn't doing one of those listed agents, then one isn't even in the discussion. One could
well imagine expanding those policies in some way to capture this, and I think a lot of what I heard earlier
was requests to try and have an integrated approach and not have a lot of each's and every's.
Let me say one way though in which there is a kind of a difference in focus, and I'll refer to the select
agent regulations as well. The DURC policies and the select agent rules, which are predicated on lists of
agents, are predicated on what you start with. Gain of function is all about what you end up with.
So for example, on the select agent rules, if you take a non-select agent and transform it into an agent that
would be as scary or as relevant to the security community as the select agent, it doesn't make it a select
agent. So the policies that are triggered by a list of what you start with, really, unless they're modified in
some more general way, aren't able to accommodate things that might be outside the list. But by the time
you're done working on it ends up being something that would have been on your list if it had existed
initially. So it's sort of a philosophical approach on how those are done, and I think that would have to get
reconciled.
Mistry: All right, but just to remind you, the second screen is to cover the seven experiments of concern,
which do cover the GoF phenotypes.
Epstein: But you never get there if it doesn't pass the first screen, the way the policy is now configured.
Mistry: That's true, but the policy is explicitly in telling institutions that they are not limited to those 15. If
they are concerned about any organism, they are invited to apply this same methodology to those. It's not
limiting the institutions at all.
Epstein: No, it doesn't limit institutions; and we certainly do encourage that. But in terms of what the
Government has in expectation to require for recipients of funds, we can't hook that extra piece on.
Frothingham: I can comment a little bit on that. That's sort of the interrelationship of those because, as I
mentioned, Duke has been reviewing every research protocol for dual use, regardless of what pathogen it
is or anything. So we have covered the whole water all the way through. We certainly do not intend to
start putting all of our dual-use review that we do routinely for 10 applications a month into the U.S.
Government policy on institutional review of dual use research of concern pathway. That pathway is a
laborious pathway. If we need to go and if we need to get help, we'll get help; but there's a lot that goes
through that doesn't go down that pathway.
And I guess I can't picture a lot of institutions voluntarily saying, hey, I've got some Shigella research

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going on here that's kind of concerning me. Maybe I should go through this pathway and call up the
program officer and say, well, I've made it through the first and second and now I need to notify you. I
just don't see that happening. The policy is list-based. Select agents are list-based, and the U.S.
Government policy is list-based. And nobody adds to these lists unless they're forced to do so.
One question that comes up though and this is where the gain of function comes in: How broad should
this be? We've mentioned three or four pathogens; are there others? And I was also struck that the gain of
function framework of recommendations from the NSABB is limited to human health. And I wonder
about animal and plant issues as well. Certainly the select agent world covers a lot more than human
health just ideas to put out there.
Mello: Thank you.
Chris Park from the Department of State. Actually, just on this last issue to jump in on something I wasn't
actually intending to raise, but there's one other I think important distinction at least at the moment
between the GoF and DURC categories, and that is what gave rise to the funding pause, etc. It was not
just a concern that you were potentially producing enabling information that could be misused, which is
the underlying concern that drives the concept of dual-use research of concern. It was that we may have
underestimated the safety risks; that was, in fact, a central focus of many of those who were expressing
concern. It was clearly one of the elements that went into the decision.
It doesn't mean you couldn't develop a single tool that addressed both, but there are some different issues
going on in this discussion. And I think when you're trying to figure a solution out, it's really important to
keep in mind what you are trying to fix because you might actually need a different tool.
But actually what I wanted to comment on was that I was struck that every time there's a meeting on this
topic, there's a lot of focus on, well, we need clarity, we need clear, crisp definitions, etc. And yet what
struck me was as I listened to Dr. Kerr and Dr. Frothingham, and your descriptions of your processes
sounded actually very useful, very overall successful. And it occurred to me you were both in situations
where you don't really have that problem.
In Larry's case, the boundaries for what goes into that review process are pretty straightforward, at least as
I understand it; plus, it's somebody else's job to decide it needs to come to you guys for review, which is
always nice. And Duke has a very broad sort of ecumenical approach in terms of everything gets
reviewed. So the focus was on, well, what's the problem here? What are the benefits? What are the
alternatives? Which, from my perspective, is where I want the brain power going not into a definitional
exercise of does this fit in this box or doesn't it?
And at the same time, we hear we need this clarity; on the other, the places where we've tried that say
the DURC policy the first thing that happens, as people start pointing out, is, well, that fell outside, that
fell outside; there are gaps. So I worry that I we are trying to produce clarity in terms of creating a
category where you say does this require review, then there's a real risk that you wind up, in an effort to
achieve both clarity and a small, manageable category you either result in considerable ambiguity,
which people find frustrating, it's uneven, etc. or you wind up with something that's got some pretty
obvious holes.
So the question is whether it's maybe better to have a broader basket of stuff that gets reviewed, with the
understanding that what you do with it and how long it takes you to do it is going to vary very much
depending on some very practical considerations. Obviously, if there are big consequences attached to a
category, if it falls into Basket X it means it shall not be done, that's a different story. But I'm not at all
persuaded that's where we're headed. So just a thought that maybe sometimes we put too much effort on

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the definitional question rather than on what can be done about it.
The related question is I was also struck by a couple of the examples of things that have been done how
people have identified issues and what has been done. That's where I don't think we have a big enough
basket of examples of tools. And at the same time, we're now recognizing the fact that that review and the
considerations themselves are potentially dual use, so we're taking that information offline and doing it in
settings without minutes. It makes sense; but it seems to me we really need to find a way to, without
putting it on Facebook, share that information among review entities and the government to start
developing clear models.
I think one of the things that will take a lot of the sting out of this whole exercise is the extent to which
people can show successful ways of identifying/prioritizing/evaluating and particularly addressing risks
when they're identified. If we can do that, the whole process is going to get a lot less painful because
people will say, ah, I've seen a couple of examples; I've got an idea of how to deal with this.Whereas right
now, everybody seems to be doing it de novo.
Mello: Thank you. Well, there's a lot in there. Anyone want to dive in?
Frothingham: I think it's impossible to categorize the wide range of biological research that can be done.
And I think even in the very limited area of influenza, it's not going to be possible. I mean, this 500-page
document wow, I'm really impressed. And I'm sure that tomorrow someone will think of an experiment
that's not covered in it; that's what science is about. Every case is going to be a little bit different. It's also
what makes life interesting.
Potter: I think my concern is that the minute you start going down the dual use and likely gain of function
paths, if you do meet the second criterion, you have to then contact NIH; you then have to get approval.
The complexity grows significantly. What I don't want to happen in gain of function is that the first two
criteria are so sloppy that you're contacting NIH every time you want to do an experiment. I think that
really becomes an issue, and that's what I want to avoid.
Kerr: Chris, I would contend you're right, that whenever we're dealing with a very narrow scope, it
actually is much easier to define the framework. The thing that I would note from the previous
presentations is the power of having the discussion. I think one of the powers that you started over a
decade ago sensitizing your community, your staff, to having the conversation so that when you come
across something in 2015 that that Board can then take something new and can actually have a robust
discussion on does this meet your definition of dual-use research of concern?
But more importantly, what do you do about that? And to me, that's actually the more important part of
the conversation for not only the university and the PIs' and the laboratory workers' safety and security
but for, as you said, the peace of mind of the community members and their respect for the fidelity of
your process.
Epstein: I'm very struck by Dr. Frothingham's remarks and also as corroborated by Pat Fitch that it can be
a great deal of effort which is not necessarily useful, to decide whether a definition fits when that effort is
much more readily applied to what one does about it.
On the other hand, if one has a set of experiments which are designated as needing review because there
are particular concerns, particular risks, we are defining a category where we have to apply separate
scrutiny. So we are differentiating that set from everything else. I would like to have a continuum where
we don't have to bother with arbitrary definitions, let's just talk about what we need to do. But we do
recognize that there is a certain area of work where we need to do more than we need to do for everything

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else. And we don't want to make that consistent by having that level of scrutiny for every single thing we
do. So we want to differentiate the scrutiny given to things depending on the risk they pose. And
hopefully, without having a lot of definitions about is one in a box or not when that is irrelevant, but
recognizing one does have to make a distinction somewhere along the way. And so how do we help
reviewers decide what needs that scrutiny and what doesn't.
Mello: Thank you. I'm going to adjourn this discussion for now as we've reached the end of our session.
But we'll be picking our discussion of policy approaches back up at 3:45 p.m. after the break.

Session 5: The Policy Landscape: International Dimensions of GoF Research

Barry Bloom: The next session, please. It is very gratifying that much of the discussion of the earlier
sessions focused on questions regarding not only U.S. policy but the implications of that policy more
globally, and the recognition that science can be done in so many different places, with the potential for
good and harm; that it really is important to think about how, if there are possibilities for harmonizing
policies, regulations, and approaches to the questions of gain of function and other kinds of research.
First off, I would like to say we have an extraordinarily distinguished panel, and I wanted to thank each of
them for coming long distances to be able to participate in this meeting. Basically what I would like to
have them do, if they would, is to talk about how their agencies, organizations, councils, or countries have
thought about this issue, and their policies that have been developed, and recognizing that not only are the
gains and benefits from biomedical research universal but so are the risks for the people in different parts
of the worlds who have not contributed to the science or given their permission to do these experiments.
So we have both global opportunities and obligations.
And so if they would comment on how their organizations and agencies have thought about it. And if they
thought there were possibilities for harmonization of those, I would ask to what extent is whatever
policies the NSABB of the United States government agrees upon, to what extent will that be helpful and
influential, and to what extent, if there were such defined policies, they think there could be some
harmonization.
So with that is an introduction, I'd like to introduce Dr. Ruxandra Draghia-Akli from the European
Commission, if she would make a presentation of how they felt about it.
Draghia-Akli : Thank you very much for the introduction, and thank you for inviting us to give our
perspective, and, from my point of view, the European perspective on the issues linked to the gain of
function and dual use.
So I will start with a very brief presentation of our Research and Innovation Program because probably
many of you are not familiar with the intricacies of that, then the funding, or, to be more precise, the nonfunding of the gain of function, and we'll use research in this context. The ethics review, which is
intrinsically component of our review, not only for the gain of function and dual use but by and large for
all the projects that are submitted for funding under our programs, and then some considerations related to
the member states, the stakeholders in Europe, and their perspective on gain of function and dual use.
So Horizon 2020 is a very nice name for the European Union programs for research and innovation for
the period of 2014 to 2020. It has a budget of about $80 billion Euros, and, indeed, it has rationale that
research and innovation is very complex. This program is not addressing issues that can be addressed at
the national level, but, rather, a part is looking at funding similar to the National Science Foundation in

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the United States, and the big other part is, in fact, collaboration programs, transnational,
multidisciplinary programs. So in this overarching program we don't have one or another country
exclusively, but the 28 European countries, and then the associated countries to the program.
So to put it a little bit in the perspective, in the EU, overall we have approximately three fourths of the
U.S. total for federally funding R&D. But if you're looking at how that is distributed, in fact, the
collaborative Horizon 2020 says the program that is managed at the union level is relatively small. By
comparison, the member states programs, so each and every one, if you put them head to head, represent
the bulk of the funding for research and innovation, each of them having their own funding agencies with
their national rules and regulation, legislation that, in fact, is adapted to the national legislation by and
large.
So if we are looking at how the budget breakdown in the program of research and innovation is done, you
will see that a big part is linked to what we are calling "societal challenges," from which the health
demographic change and wellbeing, so the part that is linked to biomedical research is biggest. But there
are also another number of components of the programs; for instance, excellent science or industrial
leadership that can be touched by issues of gain of function or dual use.
So if we are looking, actually, at the EU-funded research in this area, I need to start by saying that the
purpose of the European R&D is always, for civil purposes, house use, so military or [inaudible] use is
always either not intended at all in the program or is an unintentional byproduct. So we do not have,
actually, specific cause where this gain of function or dual use are spelled out. Nevertheless, we do have a
lot of the topics research that is in the area of prediction of identification of modeling, of surveillance, of
newly emerging diseases in humans, as well of the zoonotic infections and the background emulated
strategies.
So we have undertaken an analysis of the current thousand-plus programs and projects that we do have in
the portfolio, and it turned out that, in fact, only about three projects have been identified as having
components that are linked to gain of function. So those are, in fact, by and large, large platforms. One is
linked to the management for emerging and reemerging infectious diseases. Another one is linked to the
preparedness, prediction, and prevention of emerging zoonotic viruses with pandemic potential, and then
we do have a project looking at the global onset of novel epidemics.
So these older projects started around 2010 and 2011. In the current program, we don't have any new
projects that have been launched in this area. Nevertheless, we are prepared and we have watched very
closely the discussion that was undertaken at the global level and, in particular, here in the United States
and our ethics review is quite nimble in detecting such potential issues. So during proposal preparation, in
the guidance for the applicants they are asked if the proposal has an exclusive civilian focus on research,
and if their research produces goods or information that will require export licenses in accordance with
the legislation on dual-use items.
All the proposals that are submitted go first through an ethical screening, so they're looked upon by
independent panels of specialists to see if they're addressing all the issues, and these specialists come
from very different backgrounds, so it's not exclusively medical doctors or PhDs. They're also attorneys,
philosophers, and patient representatives that are looking at each and every one of those proposals. And
then those proposals that have been identified as containing elements where we have to move a little bit
forward with our analysis not only for gain of function or dual use but also for stem cells, complicated
issues linked to clinical trials or with animal experimentation, they are going to full ethical assessment,
which means that each and every one of those proposals are going to be evaluated by at least five ethics
experts coming from this very diverse background.

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So at the end of the process we are separating the proposals into different categories. We have proposals
that are cleared so they can continue, and then they're evaluated on the science. We do have a conditional
clearance where the applicants are asked for additional materials to be submitted, including those that are
required by their national legislation, for instance, permits, or they do not require -- they do not pass this
evaluation so do not get the clearance, and those projects are not funded.
In fact, even in the model grant agreement, which is a contractual agreement with the applicants, it is very
clearly stated that all the research has to comply with the EU national or international law. So in a very
direct manner, it's putting the burden of proof on the applicants, including the host institution for those
particular projects.
Because the EU is a very complex -- it's a very complex setting, and I'm sure all the other speakers are
going to point to this issue -- we do respect what is called the "subsidiary principle," which is that the
national research funding is the national responsibility. We don't interfere into that. But, of course, the
regulations at the EU level have to be respected, including their implementation in the national
legislation. So, for instance, we do have an EU-wide regulation on export control, which is looking at all
of the components of technology transfer. So, here, I'm not talking exclusively about materials but also,
again, as we've heard before, information linked to the research that is undertaken.
So the different scientific communities have looked at the problem of gain of function very differently, so
at the end, the tie breaker was the European Academy Science Advisory Council, and I'm very sure that
you'll have a wonderful presentation after mine related to their findings. So we have looked at how the
stakeholders would view these experiments, and all the stakeholder consultation has acknowledged the
fact that we need to improve the awareness, to share the best practices among the members of the
scientific community, and to promote this culture of responsibility, given not only the potential for
accidental release and misuse but recognizing the fact that we are dealing with 28 different legislations
that we had to have and find common grounds.
So we have embraced the recommendations of the European Academy of Science Advisory Council,
which I'm sure that they are going to be developed. I'm just going to focus on one, because they
challenged us to give us a response to the problem of global collaboration, which is that we do really
believe that an international forum is needed to sustain the dialogue between the life sciences and the
policy-maker communities with the other stakeholders involvement.
So I'm talking not only about the fact that this legislation at the European level provides a framework, a
little bit like global framework in Europe, but that has been transposed in practical terms probably not
identical in each and every one of the member states, so we do have to find this common ground, and I'm
taking three examples of three member states that have implemented the processes differently. That does
not mean that the standards are not at the highest level. So, for instance, in the United Kingdom, in the
research institutions, the scientists must assess, themselves, the risks of their experiments. Of course at the
universities we'll ensure the training, we'll have the equipment, the facilities that are suitable for the
proper experimentation, and they will submit their research proposals to the local Biological Safety
Committee, so it's the equivalent of the institutional safety committees in the American universities.
These biological safety committees will be composed of members that have the appropriate knowledge.
They have the expertise and the experience to assess the proposals. And, again, they do not come
exclusively from life sciences. In Europe this is dialogue with the society at large, is very well
established, and we always have not only the attorneys but, really, the civil society involved in the
assessment of the experiments.
For work that is required in highly secure facilities, all these proposals, recommendations, must also be

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submitted to the senior management of the institution. And then the accepted proposals will be submitted
to the health and safety executive, with the purpose of this notification of intention to conduct individual
contained use activities. So it is a rather complicated process but, you know, hearing you from this
morning, I don't think that it is more or less complicated than what we have heard. I think that with
practice and with the analysis, case by case, of these proposals, research can, in fact, continue.
In the Netherlands, of course, this has been one of the points of contention as of the last few years. The
responsibility lies, first, with the researchers, but also with the host institution. So, again, we do have the
special facilities, the procedures. We have the training stuff, but this time around they are directly
supervised by the Biosafety office. All the proposals are first submitted to the Biosafety office that is
looking, both at the wild-type pathogens and the GMOs. I'm not going to enter into a long description of
the GMO regulation in Europe. It's quite complex. But, fortunately, or unfortunately, researchers would
also have to comply with those rules. And then we do have this element of training.
The proposals are then checked by inspection services of the relevant ministry, so, again, some of the
measures that have not been mentioned here today are, for instance, that in the difficult cases there are
formal scientific opinions, which are made public, and receive a formal permit from the ministry that is
based on the WHO guidance. And for all the researchers that are undertaking these types of experiments,
we are practical, so vaccination is compulsory, if effective vaccines are available.
Last but not least, I took the example of France, because there the supervision is done by a national
agency for safety of the drug and health products, so all the persons who are conducting operation
involving the use of human pathogens or toxins in on the toxic microorganisms must have help and
authorization from this specific body. So this time around you start from the top, from the ministry, and
not from the researcher or the institution. And this control of the use of the microorganism is related to
their belonging in the lab, so the simple fact that you have it in the lab, it has to be regulated irrespective
if you are going to attenuate it or make it more virulent. And there are quite a large number of limitations
and control to access; for instance, for foreign persons in the sensitive laboratories. So from these three
examples you can see that, in fact, in the different European countries, this EU large regulation has been
implemented differently.
So I'm not going to dwell on each and every one of the member states. It turns out that quite a number of
them have no rules, just the general framework. But my point is that, in general, we are dealing with case
by case. We do not have a long list of very specific definitions and patterns that we will use in each and
every one of the cases, and that, in fact, the variabilities also introduced by the various member state
legislation. All of our researchers will have to comply with all of that. Thank you.
Bloom: Thank you so much, and I'd like to call on, now, Dr. Volker ter Meulen who represents the
European Academy of Sciences Advisory Council.
Volker ter Meulen: Thank you very much for inviting me and giving me the possibility to summarize the
report, which the European Academy Science Advisory Council has prepared.
Let me first explain to you what is EASAC. Dr. Draghia-Akli has already referred to it; that we are an
advisory council giving advice to policymakers at the EU Commission and the EU Parliament. This
European Science Advisory Council was actually formed in 2001, and it will present all science
academies of the European member states, with the exception of Malta, Luxembourg, and Cyprus,
because they don't have initial science academies.
And the objective of this council is to take issues which are of importance of society and for politics and
prepare them in a way that the administrators in the EU Commission, but also the Parliamentary in the EU
are really getting informed about important issues and topics. But they should be informed before they

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vote. You must know that, for example in Europe, the European Parliament and European Commission
have tremendous influence of the government and about 70 to 80% of all decisions made in these bodies
have science background.
In addition to these member states, we do have the Science Academies of Norway and Switzerland. The
secretariat of the headquarters my academy, at the Leopoldina, in Germany and Holland, and the basic
areas in which we give advice is biosciences and health, environment, and energy, and of course, also in
the area of infectious diseases.
Now we were asked by the EU Commission, and by the previous chief scientific adviser in [indiscernible]
one-and-a-half years ago to deal with the issue of getting a function experiment due to the fact that, like in
the United States and Europe, the society was concerned about the experiments which are really carried
out in the United States and in the Netherlands, and we were asked to try advise the EU Commission and
make a report and recommendation and statement.
And in contrast to what you have heard today, the very impressive analysis and document by the NSABB
and by the colleagues who did a detailed analysis of influenza risk and benefits situation, we actually
prepared and tried to bring a consensus report to the EU Commission and to the Parliament in a way that
they would understand what is at stake, they would understand the problems, and they could see in which
way the science community would deal with these problems. So this is not a report which is similar to the
reports you have seen today, which you have seen are very impressive, it is more a report in a way how
you advise policymakers.
Now, what we did, of course, was bringing together in the working group, first of all, colleagues who had
a different opinion of about the issue, and you may recall that in the European newspaper, for a period of
time there were really controversial issues constantly bringing up on the front page. So we brought these
two groups the European virology group and the European vaccinologists together around the table, in
addition, with some influenza experts who performed biosafety, biosecurity ,ethics colleagues, et cetera,
and we dealt and tried to find out is there a consensus report possible. Also, to clarify the issues which are
still unresolved and to advise what additional analysis is needed to assess future options for the research
areas. And, of course, we also was dealing with the EU regulation that you just have heard, that they are
different in different member states. But the majority of all these states do have certainty for these types
of experiments, some sort of government body which has to be consulted and which has to give
permission to do such an experiment.
Now the first meeting took place in November, then we had several meetings afterwards, and we
presented our report in 2015. And what we wanted to do is, of course, to address a number of audiences.
In the first place, the audience was the EU Commission and the EU Parliament. Then, of course, the
Academies of Sciences as member states, because the advantages that a science academy of our member
states have good context to the national government, and as the government, of course, they would really
have an impact.
Let me just say one word about the advantage of having a consensus report, because our report must not
only be approved by all the working groups but also by all the science academies of the European
member states. My experience is when a politician who comes from one of the member states knows that
his own science academies has approved a document, which we have prepared, then the politician feels
much more comfortable when his own country has had a look at the report which has been written. This is
different in your country, where you're one country and where you can really decide for the entire country,
and not in Europe where you have 28 different member states which have a different opinion in many,
many aspects.

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So what did we address? So we tried, of course, to address issues which with have talked today about it;
self-governance and scientific responsibility. We had a long discussion about benefit-risk assessment, of
course, and were very impressed today to listen to these presentations by the colleagues, how they have
analyzed in detail different influenza strain relation to the benefit and risk. Of course we did a research
review and management system. We also talked about some pro and some con of a moratoria and
alternatives. Bioethics was a big issue, as were biosecurity and advisory issues, mechanism and advisory
body. Of course publication was an issue because you probably may have heard that in the Netherlands
the government stepped in and did not approve for a certain place of time the publication, which the
Dutch colleagues wanted to publish on the Gain X function experiments. And, of course, global context,
how to inform discussion and action wide work.
I hope that tomorrow we have a possibility to discuss harmonization. This very room already mentioned
the possibility how eventually, not only Europe and United States, we find the basis in how to handle
these types of experiments but we certainly need more. If we want to achieve something, it has to be
done. We have to try, how much we can achieve globally in countries in which such experiments are
carried out.
So in the following slides I'm presenting to you, I would like to describe what we see as a layered
approach to the responsibility and action in the view of EASAC, emphasizing the need to adopt this
layout approach, see, because we think this would help to spread good practice, increase accountability,
improve public trust, which I think is very important in research, and, of course, also document that the
science community itself has concerns about these experiments. We feel this is fundamentally important,
first and foremost, that countries, their research institution and researchers follow the rules and guidance
already in place that resides of established legislation and experience.
We are focused on neurology because this was the issue we were asked to deal with, but we feel that our
recommendation, of course, are also applicable, as we referred to today, with many example, the different
sessions that is broadly in microbiology research, and we agree, I can say, as what we have NSABB
interim conclusions that all life sciences as well, of courses, research especially have certain risk,
depending on the question, which will be dealt with the scientists. My final crucial points on this slide are
EASAC usually tries to produce, as I said, the consensus report, and I already explained why consensus is
important for us.
So what are the EASAC key messages on self-regulation and harmonization? Our scientists, of course,
have to accept responsibility for the safety, first of all, of themselves but their colleagues and the country
at large, and self-regulations are necessary first step, but that does not mean that each researcher is free to
decide for himself what procedures to follow. Self-regulation means that there are checks and balances
within the scientific community. Our EASAC report describes several examples of self-regulation, and
the opportunities for harmonizing procedures to spread good practice in research design, review, and
management.
Attention to key biosafety issues is imperative at all stages of endeavor, from the very beginning when
already formulating a research idea. Grant applicants will discuss the potential risk involving proposed
experiments, and funders should consider, on a case-by-case basis, whether research proposal has
scientific merit and whether the research can be safely conducted. Our EASAC accommodations are
consistent with the recommendation published by the NSABB working group in December, which in
general oversight mission is for GOF studies of concern should be incorporated into existing policy
frameworks, where those represent best practice. We also agree with the NSABB recommendation that
governments should continue their efforts to strengthen biosafety and biosecurity to foster a kind of
responsibility for all research involving pathogens.

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Benefit/risk assessment I mentioned already that this is a very complicated and difficult issue, and we
tried our best to discuss this, of course, and find a way in which we could really go forward. I still recall
the meeting we had in December, or the end of November last year, where some of you were already in
Hanover at the Foxland(?) Foundation where we were discussed the possibility can we find some sort of
an equation, either metric measurements in which one can really define risk and benefits. And of course, it
is an issue which is, as we heard today, so specific and so difficult in defining and leading to a way that I
must say that for the influenza virologists it could not be better presented, as we have heard today.
So views have varied, of course, also among working group on GOF research, and the question where
should it be quantified as near future gains to public health as described in terms of generation of new
knowledge. In either case it is difficult to quantify benefits, as I mentioned, in a metric way, that the large
amount of benefits to be compared directly with amount of risk. Risk assessment in itself is very
challenging. Task as exemplifies very well in the comprehensive Gryphon report. We heard this today.
What we emphasize in our EASAC report is the need for benefit and risk assessment to be a continuing
collective commitment to understand and share the issues. Our message here is also similar to the
NSABB one; that risk benefit profile needs to be reevaluated over time. However, it is also important for
us all to address other questions; for example, who should be doing the assessments, and how should their
subjectivity be taken into account? And how should the results of assessments then be taken into account
in informing policy development and strategic decisions.
How about key messages at the initial activities in the organization? One key topic of the discussion in
Europe in the last couple of years has been does EU, through its European commission, require a new
advisory or regulatory board to deal with these matters for research of concern? As you know, in the EU
research can be funded and conducted at the national level, and as we heard already from the previous
speaker, the addition collaborative research can be funded by the EU Commission currently through its
Horizon 2020 program. It is recommended that there is no need for new advisory body on biosafety
and/or biosecurity.
At the EU universal we have many regulations in place, but we heard the most important problem is
disease regulations are really put into operation in all member states, and there may be some problems
which have to be addressed, but you got a good example how it is done in the UK or in The Netherlands
or in France, and in similar way it's done in Germany, I can tell you. However, we also recommended that
all the countries that make up the EU should have a clear national advisory and governance measure and
procedure for assessing and managing biosafety and biosecurity risk.
The point they want to emphasize here is that either recommendation at the national level should have
some sort of legal powers. In order to ensure this happens consistently across EU, it is now a task for our
EU countries to share and implement good practice with regard to national oversights as part of the
layering of the roles and responsibility that I mentioned earlier.
So how does the EU currently manage research? I mean you have heard there are different -- and I don't
have to go into details on the slides -- different directives, which have been presented by Dr. DraghiaAkli, and these regulations are also, then, in addition, we are compromised by WHO and OACD
guidance, which developed IHO standards, and I'm sure you'll hear about this later on. And, of course,
there's a code of conduct, which is also described by different research organizations [inaudible]
organizations, in Leopardine, et cetera. And I had included documentation of how it is done. In England
you heard this, and there are actually three layers, the infrastructures, the institution assessment, the health
and safety executive, and Dr. Draghia-Akli has given you some more detail so I can skip this.
How about publication: Now publication, of course, is an important issue. And I mentioned already that
there have been some problems in Europe for the publication of what the Dutch research group tried to

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publish when they had their first publication. And this was stopped, actually, by the so-called European
Commission export controlling regulation, which we feel is inappropriate and ineffective behavior to
block publication. Unfortunately we have not discussed here during the day today, but maybe tomorrow
what is the best view about publication of such sensitive issues? How should we deal with it? And of
course, if an experiment is done in which all safety measurements are really taken and defined, at the end,
I think things could be published. But if there are data coming out which are very sensitive, I think it is a
question that which has not been really solved yet.
Public engagement is an important aspect, which we feel trust and openness, I think, are crucial for the
researchers in the institutions, and I think academies and others in the scientific communities have a
responsibility, have to try to get a public dialogue and be open, and we have discussed this already today
in different penance in some details. And, of course, EASAC is committed to do this also in the future -in the future.
So, as I conclude, we have made recommendation for the EU Commission and the EU Parliament and the
member states, and it was quite interesting to note, if I summarize it after we had contained this report and
after it had been distributed in the EU, in the science academies, and there have been active controversy
discussion in our newspapers ended, and this, I think, this has at least some positive effect we could
achieve. Thank you very much for your attention.
Bloom: Thank you so much for that, and in a world in which consensus on anything at a policy level
seems so remote, you've done a terrific job of achieving that, at least in this area of science. Let me turn
now to Dr. Silja Vneky at the German Ethics Council, if she would speak to us, and you can stand, if you
wish, or sit.
Silja Voneky: Yes, thank you very much. I'm very grateful to be here and to be part of this symposium.
And I have to say that I'm really impressed by the efforts that are made by the NSABB and the National
Academies of Sciences, and the government here in the U.S. to get the full picture of gain of function
research and how it will govern it in a justified way. And I will present the German Ethics Council
recommendation on these topics and more accurately it was a report on biosecurity freedom and
responsibility of research that was issued 2014, and you can find an English translation in the Internet on
the Council's website.
The German Ethics Council is an interdisciplinary independent council of experts whose 26 members are
appointed by the President of the German Parliament. And concerning the biosecurity opinion, the Federal
Ministries of Health asked the Ethics Council to investigate whether we are sufficiently prepared with
respect to the misuse of research from the biological sciences. And according to this task, we mainly look
to solve the problem of biosecurity. Biosecurity aims, as you all know, to prevent the intentional misuse of
gain of function research or gain of function research results. Biosafety on the other hand aims to prevent
the accidental release. We dealt with questions of biosecurity, and the deeper reason behind this is that
there are many more laws in Germany that govern biosafety concerns; for instance, laboratory safety
standards, then enhanced by security. Nevertheless, we are not stating that there's a dichotomy between
the area of biosecurity and biosafety. Quite to the contrary, means to ensure biosafety can promote more
biosecurity and vice versa.
And before I come to the main part of my presentation and lay out the five recommendations for future
governance of gain of function research, please allow me to stress a few other results from the report of
the council. First of all, we found that it's incoherent for the precaution of principles in a very soft version,
not the version you find here in the U.S. So the pre-caution principle version is a very soft version that
measures to evaluate and reduce the risk of gain of function studies of concern have to be taken by the
states, even if we cannot know or quantify the risk of the occurrence of damage. This means even in low

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or unknown probability high risk scenarios.
The same result can be derived from legally binding basic rights, as they are part of the different
Constitution of states, and the international human right treaties. This is the case, since the fundamental
rights of the researchers, the freedom of research, may be restricted in a proportional manner for
legitimate aims, and the states must protect the fundamental rights to life and health of the individuals and
the public. However, we found that the existing legal rules that govern gain of function research in
Germany and Europe are not fully sufficient, nor coherent. They either encompass unlimited areas of
biosecurity or they target special questions of biosafety like the German genetic engineering law.
One striking example is that, according to European Union law, and it was mentioned, a publication in the
area of bio security relevant gain of function research only needs a permit from the expert authorities if
it's published in a journal outside the European Union. Another example is, I think, research funding,
because within the European Union framework programs for research, the Horizon 2020, their most
specific restrictions for funding gain of function studies of concerns. Hence, there are quite significant
gaps in the legal framework of the international European and national level concerning gain of function
research.
Having said this, I come now to the main part of my presentation, where to go from here, and what are
our, the Council's, recommendations for the future governance of gain of function research? Our view is
that we should focus on five different areas of governance. The first aim should be to raise the level of
awareness of questions of biosecurity in the scientific community. The second level targets the elaboration
of a national biosecurity code of conduct. The third area governs research area. The fourth area displaces
recommendations for regulation in Germany. And the fifth names European and international initiatives.
All these recommendations do intertwine. Biosecurity and biosafety are problems that can neither only be
solved by self-regulation nor on a national level. So the first recommendation; target raising awareness in
the scientific community itself. And the idea is to promote -- and this is very kind of straight forward -- to
promote a touch of responsibility and proof of knowledge of researchers in the life sciences. Therefore,
questions of biosecurity should be integrated into the undergraduate and graduate curriculum.
Secondly, the council recommends the elaboration of a national biosecurity code of conduct that defines
the responsible manner of dealing with problems of biosecurity. Such codes are useful instruments of selfregulation, and standards that extend beyond the legal obligations should be established in the code. This
means that the full and concrete obligations, according to the ethics council, concrete obligations to
minimize risk should be tried in the code.
So research programs should be examined in order to establish whether the benefits are sufficient to
justify taking the risk involved, and there's broad consensus, I think. However, this is not a mere
risk/benefit evaluation, since it's of particular importance of the researchers to examine whether the
research carries an unreasonably high risk for protected rights, such as the life or health of people, and
perhaps we can discuss why this is not only risk/benefit. Should such an examination reveal that there's an
unreasonably high risk for protected rights, then the research should not be pursued. The same applies
with respect to publication and research cooperation programs.
And, in addition to this general standard, a sub-group of the ethics council, including myself, agreed that
it's decisive that the code of conduct should contain an additional threshold for gain of function studies of
concern. This should be the case for those experiments for which it's possible that the pathogenic effect of
a microorganism will be enhanced in such a manner that the danger of an epidemic or a severe disease for
humans is given. Such experiments should not be undertaken unless direct, concrete, and overwhelming
benefits for the protection of humans against dangers to life or health are probable. This is a decisive
threshold, I think, since otherwise the potential damage outweighs the potential benefit of the research

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program.
The third recommendation concerns the area of research funding. With respect to funding of gain of
function research, it should be ensured that had the scientists entrusted with the program management has
agreed to comply with the new code of conduct we propose. Research programs that are not justifiable
after risk/benefit assessment dealing with gain of function that is of concern should not be funded.
However, whether this is a case cannot be decided by the researcher or the funding party. If we have
experiments that pose high risks, they should previously be assessed by a new federal oversight body, the
so-called Dual Use Research of Concern Commission or DURC Commission, which has to be established
for this purpose, and this new commission should take consultative roles, consultative roles. It's not a
permanent procedure to DURC-relevant experiments in Germany, and they both should decide on the
research funding on Dual Use Research of Concern.
So, Dual Use Research of Concern should be defined in coherence with the international discussion as
research that has significant potential to give rise to knowledge, products, or technologies, which could be
directly misapplied as weapons of mass destruction. And here you see, I think, that the notion of dual use
research of concern overlaps a certain amount with the NSABB notion of gain of function of concern.
This new commission is an important part of the fourth recommendation as well. Here are the
recommendations for new regulation, which the council advocates has summarized. The commission
must, in the council's view, be and independent interdisciplinary commission that should include life
sciences and security experts, as well as biosecurity expertise from civil society. And up to now we do not
have such a commission in Germany or Europe.
We also recommend laying down a legal obligation for researchers to consult the commission before
conducting dual use research of concern. Furthermore, the commission should consult on further
measures for reducing risks, monitor DURC experiments, and evaluate research cooperation and
publications of DURC outcomes. However, and this is quite an easy misunderstanding, the commission
should not evaluate all gain of function research that is carried out in Germany, but, instead, only those
that fall into the area of dual use of research of concern, as only dual research of concern should be
regulated. In the council's view, a more precise definition is necessary.
In our recommendation, 4.1 -- and it's Page 184 of the English translation of the report -- ten groups of
research experiments are listed, which, considering the international discussion, pose the greatest risk; for
instance, work intended to enhance the harmful consequences of listed agents. But these experiments are
dual use research of concern if and only if they are done with certain dangerous agents. So, hence, the
German Ethics Council recommends a multi-layered approach for the recommendation.
First, we propose a definition of dual-use research of concern included in act of Parliament. Second, it's
important to specify this definition and define certain groups of experiments that should be listed in the
statutory ordinance or regulation, if you want to call it. And, third, we see the need for a list of agents that
is determined by the new commission itself. It's necessary that the list of agents has to be kept up to date
in accordance with the new knowledge in the life sciences, and, therefore, the list of agents shall not be
part of the legislation, but agreed upon by the new commission so that it can be modified if necessary.
And these are the four essential recommendations for the domestic area: raising awareness; second,
biosecurity of conduct; third, special rules for research funding; and, fourth, the establishment of a federal
oversight commission and federal consultation procedure for studies of concern.
And having said this, I want to stress as well that it would be a misconception to assume that the freedom
of research is disproportionately restricted if legal regulations beyond a code of conduct are laid down.

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Codes and legal regulations complement each other. Codes of conduct can be useful and instrumental
self-regulation, but they dot no have democratic legitimacy. And in the areas of research that pose greatest
risk, only there, only there, the legislator must decide on how to balance the fundamental rights. Lawbased regulations do not violate the freedom of research; on the contrary, it's an acknowledgment of the
significance of the effective basic rights. The freedom of research on the one side, and the duty to protect
life and health of the population.
I come to the fifth and last recommendation of the ethics council, and this refers to European and
international initiatives. Certainly, standards at the international, or at least European level, are generally
the most appropriate for solving the biosecurity and biosafety problems connected to gain of function
research. Therefore, the following is recommended: The discussion within the scientific community
concerning the possible benefits and risks of gain of function should be continue to be pursued in order to
reach a consensus on what constitutes responsible research.
One should also try to agree on a code of conduct on the European, or even international level. At the
European level, states should advocate, again, that gain of function research is only funded according to
the previously-mentioned criteria and that uniform standards are established for this kind in the research
in the member states. Furthermore, states should strive for an internationally binding definition and
classification of dual use research of concern, or if you prefer, the notion gain of function studies of
concern, including uniform laboratory safety classifications. It's not convincing, in my view, for
biosecurity and for biosafety, if, in one country, certain gain of high risk experiments can be performed in
laboratories with safety classifications two or three, but in other countries they only can be performed in a
few laboratories with safety classifications with four.
Lastly, the council sees lacuna in the current international treaty regime, and international treaty law does
not regulate in a sufficient way the specific biosafety and biosecurity problems. The bioweapons and the
chemical weapons conventions are relevant important treaties but have too many gaps in regard to
research aimed towards peaceful purposes, and, therefore, states should strive for the conclusion of the
treaty that defines the fundamental principles and limitations of gain of function research, or, as a first
step, at least an international soft law declaration. And I think a good example for quickly negotiate it. In
15 months early, soft law declaration, which is relevant to research, is the UNESCO universal declaration
on bioethics and human rights from 2005, which consists of 28 articles and links ethical principles to
international human rights. I think we could do this here as well. And this leads me to my conclusion.
Our goal, the Ethics Council goal, was to propose -- here hopefully clear, coherent, but, nevertheless,
flexible governance, system for reasonable standards of gain of function research. Let us open to future
developments and balance the freedom and responsibility of research, and there neither may be
disproportionate limits to research, nor shall possibilities for risk minimizations be neglected. It's certainly
difficult to assess the prospects of success of our recommendations.
Up to now, the German Federal Ministry of Research tries to solve the problem of gain of function
research and dual use by relying on the self-regulation code of conduct issued by the DFGE. It was
mentioned, the largest research funding organization in Germany, and the Leopoldina. This, however, is a
very broad dual-use code of conduct. It's a very important code of conduct, but it's a broad dual use code
of conduct, giving recommendations for handling security relevant research, and it's covering not only
natural sciences but, for instance, legal scholars as well. The code has to be implemented by the different
research institutions and universities, and up to now, I know of six universities and six other research
institutions which have adopted this code and set up special ethic commissions to implement it.
Apart from this, I had the impression when I was attending the Bioweapons Convention meeting in
Geneva in 2014, and when I left Germany last summer to go to Boston Harvard, that the German Office is
addressed in the topic of deal with biosecurity relevant research and existential risks in a broader sense

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and would support a national initiative in this field with like-minded states. I will have a meeting next
Friday in Berlin at the foreign office, and I could tell more after this, not today. I'm sorry. But thank you
so much for your attention so far, and if you have questions I'm happy to answer them.
Bloom: Thank you so much. An enormous amount of thought and effort is going into things in Europe,
which is enormously gratifying. Let me ask for our fourth speaker, Keiji Fukuda, to come to the platform.
Dr. Fukuda was assistant director general at the World Health Organization (WHO) for Human Security
and special advisor, if I remember, on influenza, which he knows a great deal about.
Fukuda: Thank you, Dr. Bloom. And I want to thank both the NSABB, and also the academy, for the
invitation to the meeting. It's really a pleasure to be here. And in return for that pleasure, I have a very
short talk. If we can go to the next slide.
I think that one factor that I wanted to add is give you a little bit of a context about why I ask some of the
questions that I did earlier in the morning. But I think that this meeting is focused on one of the issues
related to genetic technologies, but, in fact, there are other issues which are out there. So, for example,
here we are looking very much at how one may approach gain of function studies, what is the potential
for harm, and at the global level, it's really a broader sense of harm rather than just dual use in terms of
information, which is a concern.
But, for example, WHO has been asked formally by a country to address the issue of synthetic biology in
relationship to smallpox viruses. On the one hand, we have gain of function and it is modifying current
organisms, synthetic biology can look at gain of function. It is really not a difference in concept, but it is a
difference in application, which really bears some thought.
Now I think out of these discussions, you know, many of the recent discussions in 2012 and 2013, and
since then, including in the area of gain of function and with synthetic biology, have highlighted one of
the facts that we can talk a lot about laboratories for which regulations will be meaningful. And, in fact,
there are a lot of biosafety/biosecurity mechanisms and regulations put in place, but one of the realities
that we have to look at is that we are dealing with the phenomenon that technology is getting cheaper, doit-yourself laboratories are a reality in many parts of the world, and if we are thinking about outcomes, it
doesn't really matter whether something new comes from a laboratory or from a garage or something, and
that is part of the broader issue.
But in addition to that, a lot of these issues are raised from the perspective of human health, which, you
know, for many of us is paramount. But there are other perspectives and there are other initiatives. So if
we look at something called the "Nagoya protocol," in fact, from the environmental world there has been
a great deal of effort going into something called the "convention and biological diversity," which has its
own secretariat, its own member states. And as part of that, there is something which was agreed upon by
countries called the Nagoya protocol, and it is now in force, and, in effect, what it says is that the
movement of viruses ought to come under things such as prior consent.
So there should be agreements on viruses moving, and one of the immediate questions that just come up
is, well how does that work in terms of outbreaks or emergencies? How do you handle those kinds of
situations? And I think right now the answer is nobody is quite sure. It hasn't been tested. It hasn't been
brought up, and it hasn't really been worked through. But I know that from my colleagues in the EU and a
member of states there, and for a number of other countries, it is of concern, how does all of this fit
together.
In addition, some of you may know something called the pandemic influence preparedness framework.
But that framework also was focused very much on the movement of viruses, but more recently has

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focused on the question of the movement of genetic sequence information. And so, again, these are not
exactly the same issues, and one of the practical questions is to what degree are they linked? How does
the world address them? Do you address them one by one? Do you try to bundle them in some sort of
way? And if you do, how do you bundle them?
And I think one of the key issues here is that when we look at the broader range of concerns, there are
scientific concerns, health concerns, security concerns, but they are also broader social concerns, and all
of these discussions take place in a broad social context. And the connections between these issues are not
the same at one perspective versus another. And it makes it, I think, complex. Next slide. Oh, I am
controlling it here? Sorry.
So I think that all of those issues at the global level are one way, in one way or the other, quite important
and critical, but, in fact, there's little global awareness about them. There's not that much understanding of
what the implications are, how they fit together, and there is certainly no clear strategy right now about
how to address them. So as I mentioned, can these kinds of issues be addressed one by one in a
meaningful way or, in fact, do you have to look at them as middle linked issues and try to come up with a
broader approach to the solution? And I think this is critical at the policy level. The policy considerations
will not be exactly the same as the technical considerations.
So if we look at global discussions, I put down that they usually broaden. The more people talk together,
the more they meet, the more things are put on the table and discussions get bigger, the scope of things
simply gets bigger. So if we look at risk assessment, this is -- when it is well done, it is very much a
scientific and technical issue. The methodology for this is pretty well worked out, and it can be a precise
discussion. And so frequently we talk about risk assessment and risk management, but from my
perspective, there's really something in between, which is perception and the tolerant of risk.
And so when we look at risk perception, tolerance and management of what to do, these become very
much cultural issues. They're political issues. They are consensus-based agreements at the global level.
These are different than pure scientific discussions, but that is how policy is developed, and these are the
things that have to be taken into consideration when you are thinking about what we can do. I think I
killed it. Okay, I think this is my last slide.
So, option for going forward: So what do you do? What do you do in this kind of situation? What are the
options which are really out there? Well I think that for the international organizations, and certainly
WHO, we are in the position to convene countries, parties, experts, bring them together. And I think that
in terms of looking at the technical aspects of these issues which we are dealing with, it is certainly
possible to think about convening, and in doing so, framing out what are the issues, what may be the
principles in terms of approaching them. I think that there is confusion on definitions and terminology.
You know, we're talking about gain of function or gain of function of concern or dual use, and so all of
these have different meanings for people. I think these kinds of things can be worked out.
A second kind of approach to this sort of problem is implementing what may be considered WHO
programmatic activities, and so, for example, some of the ways in which we look at how laboratories and
companies handle things. There is a process called prequalification, which differences depend on the
product, which differs depending on the companies that we're dealing with. But, in essence, it's kind of
like a good housekeeping seal of approval. A lot of countries like it because they feel that if there has been
this process, it is a seal of quality that they can count on. And so it works out well in many instances. It is
extremely time consuming.
Another example of where there are programmatic activities doing these things are that, as part of the
resolutions on smallpox, WHO formally conducts examinations of the two smallpox repositories in the

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world, the one at CDC and at Vector Insitutute in Russia. And, again, these are formal programmatic
activities. But the point I want to make is that these are activities which are requested by countries, and so
they are stood up.
Now a third kind of approach to this sort of issue and which is one that I get -- or was asked in the past
many times, are can there be a framework approach to this? So, for example, we've already mentioned a
little bit about the BWC, the Biologic Weapons Convention. Another kind of framework is the
international health regulations. And so, certainly, these sorts of frameworks are possible. But these are
very time consuming. These are things which usually require years of negotiations to stand up. And if you
are really trying to address an issue which is constantly evolving and probably the science of genetics is
something which is something that is constantly evolving, I'm not quite sure it's the right approach to take
here.
But regardless of all these things, at the international organization level, what's a critical point is that these
activities can get addressed if there is member state support, and this is both in terms of visible political
support, which is brought up in the assembly or in other forum, as well as the funding needed to carry
them out. So let me stop there.
Bloom: Thank you very much. One is to say that there has been a remarkable amount of harmonization
from the presentations we've heard within Europe, and the question I would ask our panel to respond to is
to what extent is that process open to collaborations and harmonization with stuff that will come from the
United States or countries outside of Europe? So that would be my first question. I'll ask you to think
about that.
And the second, if you look at the slide that I brought, one of the rare examples of international
cooperation through WHO has been in this process of prequalification laboratories. So essentially no
developing countries, or very few, are prepared to purchase a drug from a company that they don't know
anything about, that they don't know is safe. And WHO has set up this process, which is quite elaborate,
as you can see from this is the WHO description of everything including experience of the companies, the
site inspection, the issues of conflicts, and if we could have the next one, a little more [inaudible] -- could
I have the next slide, please -- again, very detailed examination of the commercial laboratories that
produce drugs and vaccines.
And essentially the world has bought into the fact that not every company that makes a product can sell
them with impunity to any country in the world unless someone has guaranteed the safety and quality of
that. And the question is whether that represents an example, if the NSABB wishes to move forward, with
opening some of at the scene FGO experiments of concern, how does one limit the laboratories to those
that one has the greatest confidence would cause the least risk? And would this be seen as a precedent?
And those would be my questions. And I would turn to the panel for comments on harmonization with the
U.S. and a role for WHO with input from all the appropriate countries and agencies finding a way to
make open, transparent, to the world and the public what is being done but being done under conditions
that are at the highest quality of safety one can imagine.
ter Meulen: Thank you, Barry. I would say it is certainly very important to Europe and the United States,
as they try to find a way in which they agree on a strategic and concept way to bring maybe different
views together. I mean, the United States has its regulations, the European Union has its regulations. I,
myself, as European have a hard time to understand European regulations. They're very, very
complicated. I am not an insider in your regulations, but I already know it would be very important to
bring these things together, and one should find a way in which one, you know, having a simple way,
basic requirements put together, and agree on the basic requirements.

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And all what comes in addition, I think, may be added step by step. But if we start, let's say with 1,000
pages on the NSABB report, I can see that it will be a hard time, you know, to take that as a basis for
finding agreement. This is my experience of life. So I would say it would be good if we find some sort of
common denominator for things which are essential, and we heard them today, and use this as a first step
that Europe and the United States come together, and then I would say we try to invite the others. Because
I would say, worldwide, this type of experiment is not done in every country. The majority of developing
countries cannot do it because they don't have the outfit. So it is important to get these countries together.
For example, I represent a network at the present time as co-chair of 130 initial academies worldwide, and
the majority [indiscernible] academy partnership, and it includes science academies, over a hundred, and
medical academies, around 25 worldwide, and it would be probably worthwhile to bring them together on
the table, which we have, and find out in which country are these experiments done, then start after
Europe and United States have found an agreement, bring them together, and eventually get an agreement,
which, from the science academy's point of view, would be acceptable, because they have a much better
connection to their own government than we at the outside would have with the government. And
probably this would be a way I could think to go forward. But I agree it would be important if we do these
steps.
Bloom: I think we have a plan. Other comments? Ruxandra?
Draghia-Akli: Yeah. So in Europe we do have, now, a push to deregulation, in fact, or to better regulation.
So on one hand very many of the member states are complaining of the complexity of the system and the
fact that a lot of regulations have been piling up and nothing disappeared. On the other hand, in these
newer fields of activity, there are is a call to better work together and to find a common framework. So, at
least in the area of biomedical research and innovation, we are moving more and more, not only in
Europe, but together with the international partners on some type of voluntary frameworks. We are
deciding, in fact, on some guiding principles. And everyone can adhere if they want, and they are not
obliged if they don't. And we are taking it really step by step.
We have been very successful in working with the colleagues from the United States, in particular within
NIH, but some other federal agencies in multiple areas, including -- you know, so I'll give you an
example. We have an international consortium in working rare disease, and I know that it is much less
controversial. But we have 40 different funding agencies in that particular consortium. We had agreed on
a common framework, including very sensitive issues, such as data sharing and biosample sharing from a
population that is immediately identifiable. And all the funding agencies adhere to those principles.
Projects are funded by each individual funding agency, but all the researchers are pledging to follow those
particular guidance. And I think that keeping it inclusive, but, at the same time, flexible was the key of
success for these international initiatives.
Bloom: Silja?
Voneky: Yes, I think in regard to the openness of the process for a suggestion from the U.S., I have
stressed very much the biosecurity side. I think on the biosafety side we have a very robust framework in
Germany, and therefore, I'm not quite sure how much the U.S. could influence it. On the other hand, I
would agree with you Volker ter Muelen that if we have a very clear outcome in regard to the gain of
function studies of concern, in regard to the risk benefit, even the biosafety side could be informed, I
think, in Germany, and biosecurity in every case. So I think it's very important, what will be the outcome
of this discussion here.
In regard to the pre-qualifications of laboratories by the WHO and the question of harmonization, I think
harmonization of laboratory safety standards is very, very important, and I think an international kind of

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framework or inspection mechanism would be very feasible. However, the question is in regard to gain of
function studies of concern, what does it mean? Does it mean that every laboratory, which is safe,
according to these rules may is allowed to do these kind of studies without any case-to-case evaluation of
the certain experiments? And then I would say I don't know, because we are thinking about with benefit,
and it's not only about laboratory safety. So I think it's an important first step for harmonization.
I think it would be important in regard to gain of function studies of concern to have the highest safety
level, but never would I think we have still think whether there are questions of substantial rules on gain
of function studies of concern and whether there some limits to them or not.
Bloom: Keiji?
Fukuda: Barry, I'll restrict myself to the second question. I think prequalification works for a couple of
reasons. You have countries that very much want it. You have the target are products which, in general,
are stable. If you were making some kind of medicine or vaccine, it's not going to change very often. And
so you have a process, you have a set routine that you can go through and ask, you know, what's the GMP
process, and so on and so on. And so you can have a very nice approach to that.
I think gain of function assessments are, in order of magnitude, more complicated. You know, the
experiments for influenza are not necessarily going to be the same as they would be for another organism.
The laboratories will be different, and researcher interest will come up at one time or another, and funding
over a limited period of time is very much an issue, so moving -- and I would guess at any time in the
world, there may be some hundreds of such laboratories which could be looked at. And so I think that
operationally it would be extremely, extremely difficult for the organizations.
I think that this kind of discussion came up after the 2012/2013 period in those meetings, and I think that,
to be blunt, much of WHO's response was to say these really should be done at a national level, at a
global level. For any organization to handle that level of activity would be very taxing, very difficult.
Bloom: Terrific. The floor is open for questions and discussion. A question here.
Yes. Hi. My name is Gavin Huntley-Fenner. I'm a human factors risk analysis consultant, and I have a
question regarding prequalification of labs. I was wondering if you could talk about the relevant merits of
go through WHO versus going through an organization like ISO, particularly vis--vis would be looking
at consistent standards across academic and industrial labs and whether you feel there might be a benefit
to go one way versus the other way, maybe one might support the other. What are your thoughts about
that?
Fukuda: Sure. I can be very blunt here. I think the reason that WHO can pull this off is that countries trust
WHO. And so this is what we find consistently, particularly when we're dealing with lower- and middleincome countries. So if another organization, which has even greater capacities perhaps, is doing it,
there's always a kind of question, you know, is this really being done in a neutral way? And so I think that
WHO could certainly work through or have other people come in and perhaps contractors come in, but it
would have to be done very much as a WHO activity, in my opinion, having dealt with a lot of countries
and these sorts of issues.
Bloom: Thank you. Harvey?
Harvey Fineberg from the Gordon and Betty Moore Foundation: I'm thinking of how different countries
approve drugs and medical devices. Here where we have relatively high standards in many countries,
nevertheless the experience teaches that occasionally, even regularly, some countries will approve a given

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drug or device. Other countries will not yet approve it. Sometimes there is a matter of many years, and
maybe indefinitely between the approvals in one country or another. And that's an instance in which the
standards are relatively clear, the measurements are relatively straightforward, and the decision-making is
through a well-established process.
The gain of function situation, in a sense, has higher stakes because it would not be good for the world if
one country would approve a given experiment and another country will not. It is much different than if
one country approves a given drug for a period of time compared to a second, and the mechanisms to
establish, recognize, and carry out and implement these standards are much less clear cut, and we have
much less experience.
So with that, my question, challenge to the board, really to all of us, is how we could take concrete steps
over time to enhance the likelihood that there will be, in fact, harmonized standards, applications, and
decision-making in different countries for gain of function research.
Draghia-Akli: I think that the likelihood is relatively small in the short term, and this is because, as we've
heard here today, we are not agreeing on a definition. We have also listened in the previous session on the
number of examples, which have been considered case by case, where by and large they might have
entered into a degree of gain of function, but they were considered as being, if you are looking at the
risk/benefit analysis, quite safe. And that is a matter of interpretation.
It is also a matter of being based on a specific legislative system, and as you have pointed out, the
differences, for instance, in the drug or device approval are, in part, streaming from these very different
legislative processes; thus, at least from my experience from the European experience, this voluntary
harmonization, which was the basis of the creation of the European medicinal agency. Before, each of the
national agencies were approving the drugs one by one in each individual country, at least that assessment
step now is done in common at the European level.
Now we've moved to the next step. Are we going to be able to assess, at least partially in common, so the
health technology assessment? We are not even talking about the pairs and the reimbursement. So I would
look at your question as a step-by-step approach. If we could be on some general framework and some
general principles and definitions, maybe we can actually move that.
Volker ter Muelen: Well, Harvey, I think that an agreement between scientists about biosafety on the gain
of function experiment will be relatively easy. I think the world is a small group here and small groups in
Europe doing these types of experiments have the expertise; I think they will come together quite fast.
Then, of course, the biosecurity and going in this area, there, of course, you know, probably the
discussion will be longer. But in the end; I would envision this is relatively easy to find agreement.
The question will be whether we can convince our legal institutions we have, our ministries and our
complicated European arrangement of finding solutions, whether they would follow us. But I would say if
the scientists of Europe and the United States will do these experiments and will know each other, will
come up and develop a concept, I think this is a first step, which would be done. I would say, from there
on, I'm quite optimistic in step-by-step development.
The questions which I have are if we try to do it more globally, going to other countries, then I would say
this would be more complicated. But the first step would be an agreement between the U.S. and the EU. If
this is not achievable, we have no chance globally. But if we can achieve this, I think, and I am quite
positive, it would be the first important step to do.
Voneky: Yes, I think so, as well, because I think there are some structural advantages we have here in this
field of gain of function studies of concern, because it's not so much the private sector, it's more research

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done at universities, and the research as defined by the taxpayer in the end. So we have less market forces,
I think, in this area, and, therefore, I think we could have agreement, and I still dream of a
UNESCO/WHO soft law declaration. I don't know what the WHO thinks about it, but I think we could
agree on the main principle perhaps, on the risk benefit. Link it, perhaps to human rights, and have the
framework. And this should be done together with the scientists. For instance, UNESCO declarations
were first draft by the scientists, and then the state representative came in, so we could bring those
together, politics and science. I don't know. I hope so.
Fukuda: Well, Harvey, this is, I think, how I look at it. I think that, you know, resolutions don't have the
power. They're not binding. They're not regulation. I think that resolutions are perhaps possible. But I
think in this area it's still a little bit difficult, but I don't think there would be enough countries engaged on
the issue in terms of it.
And then I think regulations are certainly a step which is harder. I think that if the United States and
Europe were to agree, even that would be difficult. But I think to throw that open more broadly own a
global level would be very difficult. The way I think about this issue is a little bit how I think about
infection prevention and control. We have guidelines which are sound. They're well known. We have a
great need for it, and it's terrible in most places in the world. It's not implemented in at a very high level.
And I think one [O] the missing ingredients is that there are cultural issues. And here we have the culture
scientists. I think peer-to-peer pressure in this kind of area is very strong, and I think that the scientists
themselves know better than anybody what others are doing and whether it's risky or not.
For myself, I believe that much of the ability to handle this issue comes from whether the scientific
culture is that these experiments are really not acceptable unless there's a very good reason for it, which is
justifiable. I think publications have a role to play in developing this kind of culture. So, for me it seems
to be that would be, in many ways, how you get to where I think we all wanted to go.
Bloom: Thank you.
Michael Callaghan, Mass General Hospital: Harvey had set up most of my question for me, so I'll take it
farther, based on our international experience taking care of patients. I ran the DARPA's Biodefense
Program for eight years, which launched a series of international clinical trials programs for emergency
use against highly dangerous pathogens. The point is this, is that there's a dramatic shift in the revenue
potential of the Asian rim for the development of new antivirals and antimicrobials. A huge number of
those drugs -- we counted 64 in China -- were never intended for U.S. Licensure. But they're evoking
resistance patterns for agents that we are seeing in our hospitals. Pen, Carbapenem resistant,
neuraminidase resistant against antivirals that we don't even have in our stockpile and can't prescribe.
So there is actually, I think, a greater need to understand the motivation for that. And when you ask how
these companies are being supported, they're being supported by in-country bioventure, bioventure
capital, and there intention is to keep those profits in those markets secured in Asia, where the people are,
which has a dramatically expanding middle income population and which does self-pay.
So, as the demographics changes, I think we have to pivot with it in terms of understanding how you're
going to capture the market incentives, driving the forcible gain of function to get a winning compound
that's still going to be effective against an antiviral or antibacterial landscape that's highly resistant with
FDA approved drugs. So forcing gain of function is largely, in our experience, working extensively in
Asia, taking care of patients at the premier infectious disease centers in Asia is being driven by mid-sized
biotech, funded by regional venture capital, with no intention, again, to proceed with FDA regulatory
reuse.

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So how would you suggest that we engage the commercial sector and the venture sector in a way that can
help us at least get situational awareness of the drugs that are driving resistance when we have so little in
our arsenal? It's decreasing every year. I know it's a tough problem, but Harvey had taken the first part of
the problem away from us. So what are your thoughts?
Bloom: Please.
Draghia-Akli: So in Europe we do have the largest public/private partnership in the world. It's called
"Innovative Medicine Initiative." It is a partnership between the European pharmaceutical industry and
association and the European Commission. And it's very interesting that you're pointing out this issue of
antimicrobial resistance, because the biggest of the platforms is, in fact, dedicated to antimicrobial
resistance. In the various projects entering there -- so, again, it's half and half -- BARDA is contributing to
one of the programs. But one of the projects is looking at new business models, where there are no
incentives. Another one is setting up international clinical trial sites when, you know, you have your drugs
and you have a certain target. We have sites in 46 countries, about 300-and-something clinical trial sites.
I think that the incentives are not only on the public side, but we have found a modality where the various
enterprises are incentivized to work with each other. So this program, which is called "New Drugs for Bad
Bugs," is a program of 790 million Euros that, in fact, is shared between the industry and the public
funders. So that's one model.
I know that one of the sponsors of the meeting is the Wellcome Trust. We are working together with them,
and with the NIH, with our friends, the Canadians, with others, in establishing also a global network for
preparedness for emerging epidemics, it's called "GloPID-R." In fact, the meeting is going to be here in
Washington next week, the 14th and the 15th. So while I don't say that we have that the magic bullet, I'm
talking about the global community, I think that there is a lot of work, both incentivizing industry to
participate, finding new funding models, and the business models, and actually working together globally
to tackle some of these issues.
Bloom: Last two questions, first on that side.
Piers Millet: So it's not a question, it's a comment. I really start by thanking all the panelists for their
comments. I'm Piers Millet from Biosecure. I just wanted to take this opportunity to reflect the views of
the large part of the world, not reflected in this meeting. In particular, to just convey to you a couple of
short paragraphs from 112 states in a statement made pretty much every year to the biological weapons
convention, specifically on the issues of this meeting. And the statement reads that the non-align
movement on whose behalf this is made notes that there have been recent advantages demonstrating the
increasing sophistication of synthetic biology, together with other enabling technologies which have
benefits, together with a potential for use is contrary to the biological weapons convention.
Now all states must conduct such activities in a transparent manner in order to build the confidence of
other states. There is a need to regulate these activities to ensure they do not lead to any concerns related
to the ethics, safety, and security, as well as any other uses contrary to international law. That has assumed
added importance in the light of experiments that have taken place in highly contagious virulent strains
like H5N1, as well as the production of several new strains of viruses that are both contagious and more
deadly than the 1918 flu that killed almost 50 million people worldwide.
Such regulation must however be undertaken in a manner that does not hamper scientific and
technological developments in keeping with the spirit and letter of the Biological Weapons Convention,
which are of benefit, most especially to developing countries. So those are the views of at least 112
countries on this issue. Thank you.

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Bloom: Thank you very much. Dr. Gao.
George Gao, China CDC and Chinese Academy of Sciences: I also have two comments. I think the first
one, I want bigger support for, really, either WHO-led or UN-led regulation for this GoF, because think
about it, especially for the [inaudible] virus research, and the technique is not that high (inaudible). So,
you know, any lab, like in a lot of European countries, they can just do genetic modified [indiscernible]
virus so easy, so you will never know what happened with that recent result and your recombination.
As far as in China, we have our national -- kind of a regulation from the Ministry of Health. You are not
allowed to mix any two viruses together in case -- especially for the [inaudible] virus you have a reassortment occurs. So I think we need a UN- or WHO-led regulation like that, you know, because of
technique is not that high anymore.
And my second comment I was about to give for the last session. I think we have been discussing, this
panel and last panel, the whole thing about the policy-making. But I think the oversight or supervision of
the process is also very important. So you have policy and, you know, you have the regulation, who and
who will be, you know, the supervisor to guide, you know, to really do the survey for any experiment and
the whole process. I think at least as far as you know, and in China, this process, because they are
scientists. Scientists are human beings. So you need someone or some watchdog to really oversee or
supervise the whole process to make sure the regulation is really there. That's my two comments. Thank
you.
Bloom: Thank you very much. I would like to express my appreciation to a fantastic panel who has really
thought long and hard, and that they could come to the degree of consensus within a 28 different countries
in Europe, I think, should give us hope that we can reconcile, as has been suggested, policies that this
government will ultimately recommend here. I think the point that we just heard on the need for universal
consensus I would point out that the big problem that was raised with the biologic weapons convention
is that there is no enforcement. There is no enforcement.
The enforcement is just what we heard, the collegial interactions of science, the development of a
scientific consensus, and, to the extent possible, being open about what scientists are doing has had the
constraining power to keep work at least that we know about in biological weapons under control that was
not really thought of in 1972. So getting to consensus at the scientific level is one step for moving
forward to international consensus on this kind of work.
With that, I thank everybody for their attention and questions, and I believe we have refreshments; is that
right?
Thank you.

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