Toward a new paradigm for life

Beyond genetic determinism

By Richard Strohman
(Editings in bold and italics added by the editor of this PSRAST)

Human genome scientists shocked ... but why?

When the highly anticipated sequencing of the human genome was completed in
February, a headline in the San Francisco Chronicle announced: "Genome Discovery
Shocks Scientists." The discovery was that many fewer genes were found (30,000) for the
human genome than had been expected (100,000), and discussion focused on the wonder
of it all: that a fertile human egg could create such a different organism than a mouse egg,
where the human egg had only 300 unique genes not found in the mouse.

News articles also made much of the fact that many genes interacting with one another
seemed to be as important in determining human diseases as a few "major" genes.
Another bit of news was that there are more proteins and genes and this was a surprise
because of the accepted idea that each gene encodes a single protein.

But on all of these matters, except for the 300 unique human genes, the "discoveries"
were not new, nor were they shocking. We have seen suggestions of 30,000 to 40,000
genes for at least a year; we have known for some time that different species have highly
similar genomes--humans and chimps for example; and genetic interaction has been part
of freshman genetics for at least 30 years. Finally, we have known for years that DNA
sequences within one gene may be used in coding many proteins.

In short, many biologists, world wide, have known for decades that genetics alone is not
sufficient to explain life's complex outcomes, and that another kind of information
management system must be present (see below). For them, none of this news was a
surprise and we must ask why our HGP scientists appeared to be so shocked.

Perhaps it has to do with something more than just "surprising and challenging new
data." To me, it suggests nothing less than than the failure of genetic determinism: the
biological theory that complex characteristics of human beings are caused by specific
genes.

But after almost a century of life sciences dominated by this theory, and after ten years of
the HGP dedicated to finding the genes for human diseases, their diagnosis and cure, and
with the human genome finally sequenced, and biotechnologists and drug companies
standing by around the world to implement these diagnoses and cures-after all that, to
announce that the entire project was based on an incomplete and flawed theory would
have been much more than "shocking." It would have been a scandal.

So, instead of being appraised of deeper problems with the HGP, we have been distracted
by press reports of lesser failures having to do with mistakes concerning gene numbers
and comparisons of human beings with other species (neither of which is new).
Nevertheless, these disclosures are damning enough and led Craig Venter, the president
of Celera, the U.S. corporate group, partnered with the U.S. government and other
national DNA sequencing teams, to conclude: "This [the surprising findings] tells me
genes can't possibly explain all of what makes us what we are."

But, having said that, he and the other HGP leaders went on to describe how they would
develop new technologies that would enable researchers to read the "book of life" and
thereby describe the most complex diseases and behaviors in terms of causal genes. In
other words, the HGP leaders were saying that, in spite of the surprises, genetic
explanations would be found as promised.

Most of the observers who published comments following the February announcement of
the sequencing of the human genome, after their shock and surprise, fell back to genetic
determinism. One exception was the distinguished Harvard biologist Stephen J. Gould,
who wrote this in the New York Times: "The collapse of the one gene for one protein,
and one direction for causal flow from basic codes to elaborate totality, marks the failure
of [genetic] reductionism for the complex system we call cell biology."

So, at a minimum, and reading between the lines of the news reports and press
conferences with the HGP leadership last February, we may conclude that the theory
behind the technology to be applied to living cells is flawed. While it does tell us much
about our genome, it tells us little about who we are and how we got that way.

Where is the program for life?

If Gould and Venter are correct in saying that genes alone cannot tell us who we are, then
what will tell us? If the program for life is not in our genes, then where is it, and what is
it? Many of us have been saying for years that there is no program in the sense of an
inherited, pre-existing script ready to be read. Rather, inside each cell there are regulatory
networks of proteins that function to sense or measure changes in the cellular
environment and interpret those signals so that the cell makes an appropriate response.

Figure 1.The genetic determinist view of life.

Phenotype (function) = Genes x Environment

 DNA----------------- >>Proteins----------->> Function

The causal pathway is linear: proteins are encoded by DNA and therefore
DNA may be said to encode function. Environment acts as a trigger to
activate pre-set programs in DNA.

Ever since Watson-Crick and the double helix of DNA (1953) we have been working
with the genetic model in Fig.1. Now we realize there is another information processing
system in cells. This second informational system is co extensive with the cell itself,
consists of many interconnected signaling pathways and is described here under the
heading of "dynamics"; the part of dynamics having to do with control of gene expression
is, for historical reasons, called epigenetic regulation.

Figure 2. The epigenetic regulatory view

Phenotype = Genetics x Dynamics x Environment

DNA --------->> Proteins --------->> Function

Protein Control Networks

(Open to Environment)

Protein networks feedback information from the outside world to DNA, and
change patterns of gene expression in a context dependent manner.
"Dynamics" refers to regulatory networks of proteins that function partly to
connect signals from the environment to DNA where patterns of DNA
expression change. The control pathway of gene expression is not closed, one
way and linear as in Fig. 1: it is dynamic and circular (non-linear).

What, then, is the role of genes?

Genes specify information necessary to make proteins and the genome provides a
collective informational source. However, by itself a genome is passive: DNA, for
example cannot make itself, and cannot construct a protein never mind an actual cellular
function. DNA has been called the book of life by HGP scientists but for many other
biologists DNA is not a book but simply a collection of words from which a meaningful
story of life may be assembled.

In order to assemble a meaningful activity or story, a living cell uses a second

informational system. Let me give an example. We know that at least 100 genes are
related to a heart disease . These genes code for at least 100 proteins, some of which are
enzymes. So you have a dynamic/ epigenetic network of 100 proteins, many biochemical
reactions, and many reaction products. It is dynamic because it regulates changes in
products over time, and it is epigenetic because it is above genetics in level of
organization. The output from these networks change in response to signals from the
body and from the environment. And some of these changes feed back to DNA to
regulate gene expression. The key concept here is that dynamic/epigenetic networks have
a life of their own - they have network rules - not specified by DNA: and we do not
understand these rules.

In short, genetics alone does not tell us who we are, or who we can or will be. The new
findings of epigenetic or dynamic regulatory systems in cells describe an information
management system that we have known about for quite a while but are only now
beginning to understand. While, as Gould says, the genetic reductionist theory has
collapsed, the epigenetic, or dynamic, point of view retains genetics as part of a new
theory or paradigm for life, one that has striking implications for the future of the life
sciences.

The problem is part science and part philosophy

We must now ask two questions. First, where did the Human Genome Project go wrong?
That is, where did the mistaken idea originate that complex human diseases could be
traced to one or a few major genes? Second, why is the new science of gene
management-epigenetic-dynamic biology-not in the news?

In response to the first question, there are indeed some diseases that are traceable to
single genes. I worked on one, muscular dystrophy, for 25 years. This group of diseases
has provided a simple model for molecular medical genetics seeking answer in terms of a
simplified formula: one gene leads to one disease.

But that model is wrong because it has limited application, muscular dystrophy being one
of the few clear cases where it works. In these relatively simple diseases, a single
defective gene finds no redundancy, or back-up information, in the cell, and therefore the
gene may be said to the be the single cause-changing environments or behavior and
interactions with other genes are often of no consequence. But these diseases are rare; in
fact they account for only 2 percent of our disease load.

The mistake of the HGP was to use that simplified model to attack all diseases, including
the common (sporadic) diseases such as most cancer, heart disease, and bipolar disease
(manic depression). Together, those disease account for over 70 percent of our disease
load. For the vast majority of cases, human diseases are multifactorial: They are
influenced by many genes interatcting with one another and by a vast array of signals
forming the cellular environment (nutrient supply, hormones, electrical signals from other
cells, etc), and all of these will reflect the external world of the organism as a whole.
Thus, mutations in specific genes in one human body, given its genetic background (all
other interacting genes), might produce a disease; but in any other human body there
might be little or no disease. And each human being has a genetic background that is
unique.

In addition, many diseases will be altered when the conditions of life - the environment -
is altered, especially in early life. Why? Because, for those diseases involving many
genes, the effect of each gene is small, and loss of function for any one mutation may be
compensated by gene interaction and by environmental conditions. Environmental
change coupled with gene interaction can reverse some, but not all, simple diseases. For
common diseases, lung cancer is the most obvious example of environmental impact
where, even for long term smokers, the impact on life expectancy is vastly improved for
those who give up the habit. Even more telling is Spina bifida; long thought to be a
multifactorial genetic disease it is now actually known to be due to a vitamin (folic acid)
deficiency. Spina bifida is one of several potentially fatal neural tube diseases in which
there is failure of spinal cord or brain to close or to develop. In 1992 a large population
study concluded that 75% of some of these diseases could be eliminated by giving small
doses of folic acid, one of the B vitamins. If the 70 million women capable of becoming
pregnant were to take folic acid one month prior to conception many of these neural tube
diseases would disappear.

But HGP scientists thought, and still do, that they could find a small number of genes that
were the key to these diseases. However, this strategy is flawed, because for most
multifactorial diseases affected by many genes those genes have small, not large effects.
And genes with small effects are very hard to find. Even when found, one would have no
way of predicting the disease outcome unless one also knew the "initial conditions'
surrounding the developmental history of the individual. In addition, most multifactorial
diseases like cancer take many years, even lifetimes, to develop, and one would have to
know all the historical details to make predictions. Finally, the strategy is flawed because
it takes all causality back to genes rather than to genes coupled with dynamics: the
duration of exposure to changing environments. Here again lung cancer is instructive
since the disease is dependent on the dose (number of cigarettes) and the duration
(number of years) of exposure.

Our second question is: Why is the alternative to genetics-the dynamic-genetic

management of complex diseases-not in the news? The answer has as much to do with
philosophy and sociology as it does with science.

The dynamic-regulatory view of life is right now being tested in laboratories around the
world, and scientific journals bring weekly news of its progress. However, the full extent
of cellular regulatory networks is not understood, nor do we have knowledge of how the
cell as a whole integrates the output of these systems to produce an adaptive response to a
complex set of ever-changing external signals.

The transition from a genetic determinist paradigm to a new, more complex regulatory
paradigm will take much more time. Why? Because that is the way science works. In the
case we have been considering, the Human Genome Project starts as a technology
devoted to a determinist, gene-based view of life, and spends ten years sequencing the
genome. But scientists outside the HGP test various predictions along the way, and the
community of science and technology arrives at a much more complex picture of life and
of the genome that it started out with. That is called "normal science," and surprises are to
be expected.

Until we have a theory, or a paradigm, of life that is able to assimilate the contradictions
generated by the HGP and by the experimental community at large-one that is able to
explain what genetics alone cannot-we will have to move ahead with caution and with
every effort to put the dynamic regulatory science in place alongside the more familiar
genetics. But moving ahead with caution, and with an incomplete theory of life, is not
exactly newsworthy in today's atmosphere of certainty and instant rewards.

We must further understand that the HGP does not exist solely in the world of science.
Over the past ten years, it has developed strong relationships with corporate, social, and
economic interests, and has-willingly, I would say-become a tool of those interests. It has
given itself over to a propaganda stream of unprecedented dimension and has made
promises that play on the health aspirations of people everywhere. In addition, the
corporate world of biotechnology has investments of billions of dollars in the pipeline, so
withdrawal from the determinist position is extremely difficult. These are all clear facts,
confirmed in our daily news.

Where do we go from here?

If I face the facts, I conclude, along with many other scientists, that we are in the middle
of a biological revolution. We have a failed or, at the least, an incomplete scientific
paradigm called genetic determinism. At the same time, we have an alternative paradigm
called epigenetic-dynamics, which is extremely interesting but also incomplete.
Unfortunately, over the last 50 years we have allowed our research portfolio to become
unbalanced, heavily favoring genetics and ignoring dynamics. So it will be difficult to
change direction, if for no other reason than it will take a long time to train the next
generation of scientists who understand both the genetic-biological side of the problem
and the dynamics part-which will come from a nexus of biology with physics, chemistry,
engineering, and computational sciences. And any change away from the genetic-
determinist view will also be resisted by corporate socio-economic forces that will need
to push current HGP goals through the pipeline and bring to market whatever might
emerge. This resistance grows stronger as a result of corporate-biotech and university
alliances.

All this is part of a larger issue of paradigm shifts in biology. In the long run, the issue of
genetic determinism will only be settled when something like epigenesis-dynamics
becomes complete enough to challenge the present world view. For now, the important
problem before us is the technological problem defined by genetic engineering of
organisms in the light of an imperfect understanding of how the living cell actually
works. It must be emphasized that we simply do not understand how living cells
respond over time to their manipulation through genetic engineering, and thus the
error factor here remains large.

It seems to me that we must move ahead at several levels. The first as at the level of the
social science of biology, and the second is at the level of biological science itself. By
social science I mean the construction and imposition of scientific standards that should
constrain present and future attempts to genetically engineer or clone ourselves, our
children, other animals, and the plants that constitute the basis of our agriculture and
much more. If the announcements from the HGP tell us anything, they tell us that we
do not now how organisms make themselves. We are still, as many developmental
biologists have said, in the dark ages about how organisms regulate their genomes to
produce adults. The obvious ethical problem is thus framed by the science of what we
do not know and by the logical constraint that, while the scientific inquiry must go on,
the inevitable technological applications, whether in medical centers or in corn fields,
must stop-until the science assures us that we may proceed while doing no harm.

At the level of science itself, we must now ask what we want our life scientists to do next.
The technology already developed is superb: It can measure and show us things far
beyond our expectations of only a few years ago. But now we are reminded, once again,
that wider environment and complex cellular processes-and not just genes-all play
important roles in shaping our lives. The work of corporate biotechnology will go on; as
the Wall Street Journal reminds us, it is inevitable, as is human cloning, as is a future
gene-based medicine for the wealthy few who will then immunize themselves against
premature diseases and death. But that will be a false hope. Premature disease and death
will surely come if we allow a continued degradation of the very environment [here I
think I know what this means! The wider surround.] so necessary for the healthy
expression of genes now present in all of us.

But for the universities and the national science laboratories, none of this is inevitable. In
pursuit of a technology of genetic immortality, the HGP may be said to have put us on the
road to finding technological improvements for the genomes of a few, using resources
that could bring substantial benefits to all, if applied as preventive measures to the
general population. Emphasis on gene technology causes us to forget that a technology
called public health has already provided a model for the future. Public health technology
has given us nearly forty years of increased life expectancy in just the past 100 years-
without genetic engineering of any kind, proving that the genomes we all have are
already competent to provide us with a life expectancy at birth of 85 years. Providing, of
course, that we are provided with a world reflective of our conserved and adapted
genomes.

The university and national (public) laboratories may now choose to take up the quest for
new rules of complex adaptive systems we call life. We can choose to support work that
would allow us to discover constraints at the level of multi-cellular organisms,
populations, and ecological settings that could be violated only with great risk to
individual health, to stable ecosystems, to renewable resources, and to sustainable
agriculture. We might call ththe implementation of this science a "technology of nature".
We thought the program was in the genes, and then in the proteins encoded by genes.
But, as already mentioned, knowing all the individual proteins would not reveal a
program; for that you need to know the rules of protein networks that are coextensive
with the cell itself. The program location is the cell as a whole, and the cell, through
signaling pathways, is connected to larger wholes and to the external world. If we could
find the financial and other necessary inspiration, and the will to implement the additional
research, we would have a science and a technology-a university-industrial complex-that
everyone could invest in. The real question is: Who is the we who chooses, and who is
the we who decides the future of life?

The University of California (Cal), may have a profound impact in the resolution of this
question. Cal is designing a new program in graduate biology that is following a more
complex view of life than is embraced by a genocentric biology and that appears, from its
design nexus with the physical sciences, to have anticipated some of the deficiencies in
genetic determinism discussed here.

The academic plan for Cal's new biology program, while still on the drawing board,
apparently creates the correct interdisciplinary structure for the analysis of biological
dynamic systems. However, the program appears to remain focused on developing an
individual-oriented medical technology centered on molecular and other mechanical
devices and on genome informatics. And no one can argue with that.

But the University can also exercise a choice to expand its new program to include the
science and technology of nature we have discussed. It is within this perspective that we
will be able to define the larger issues of context-dependent individual development,
growth, and aging, as well as the evolution of populations, all of which remain at the
periphery of future plans for a post-genomic science, not only at Berkeley but at most
other universities eager to embrace the opportunities opened by the declining power of a
genocentric world view.

It seems relatively easy to obtain funding for the individual-oriented medical model, but
funding is much more difficult for the broader view of a context-bound model in which
the organisms of the world-plants and animals-grow and develop in a natural world of
lawful constraints, only one of which is genetic. The discovery and understanding of
those laws is the real next challenge beyond the genome. That is a long-range challenge,
and the important questions are: Who will lay down the challenge and who will pay for
the research and development needed to meet it? For the university it would require
requests for funding new research not popular with corporate interests or even with the
present leadership of our National Institutes of Health. Such requests could drive a
change in the direction of a new complex biology that includes genetics but is "beyond
the genome" as the single answer to life's questions.

Richard Strohman, Professor Emeritus of Molecular and Cell Biology at

University of California, Berkeley. He is among the working retired Cal
faculty, teaching freshman seminars and writing a book dealing with the
 issues in this article. He has been at Berkeley since 1959, serving as chair of
the nation's top-ranked zoology department and director of the Health and
Medical Sciences Program. In 1992, while on leave, he was research director
for the Muscular Dystrophy Association's fight against neuromuscular
disease. He is a frequent contributor to Nature Biotechnology, a leading
journals in the biotech industry.

Published on PSRAST.org on March 22, 2001 with the permission of the author.

Source: Physicians and Scientists for Responsible Application of Science and

Technology (PSRAST)
www.psrast.org