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receptors to forget


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How an open-access trove of data on
Calcium sensor synaptotagmin-3 helps
Britons is unlocking the genetics of weaken synaptic strength and supports
IN BRIEF disease, behavior, and physical traits forgetting By N. J. Mandelberg and R. Tsien
8 What to expect in 2019 By J. Kaiser and A. Gibbons


The half-million people in the Synthetic photorespiration bypass
11 THE WORLD DEBATES OPEN-ACCESS increases crop yield
UK Biobank hold the genetic
MANDATES By M. Eisenhut and A. P. M. Weber
legacy of Neanderthals—and clues
Spurred by European funders behind ▶ RESEARCH ARTICLE P. 45
to how we are still evolving
Plan S, many countries consider similar
By A. Gibbons
moves By T. Rabesandratana 33 REALLY COOL NEUTRAL PLASMAS
▶ PODCAST Properties of laser-cooled neutral


INSIGHTS plasmas can be used to model high–
energy-density plasmas By S. Bergeson
▶ REPORT P. 61
Indonesia’s mountains could be cause of
current glacial age By P. Voosen PERSPECTIVES POLICY FORUM

INTO SPEECH Modeling human crowds as a fluid TO OCEAN SUSTAINABILITY

Fed data from invasive brain recordings, allows prediction of group behavior A common pledge and review system is
algorithms reconstruct heard and By N. T. Ouellette needed By B. Neumann and S. Unger
spoken sounds By K. Servick ▶ REPORT P. 46
Once considered outlandish, the idea Recording of forest soundscapes Seeking solutions to Cold War divisions,
that plants help their relatives is taking can help monitor animal biodiversity in the mid-20th century NATO embraced
root By E. Pennisi for conservation environmentalism By D. Degroot
By Z. Burivalova et al.
As first data roll in from Hayabusa2, Genomics study informs about Lassa Globalization and AI are primed to
engineers plan descent to rocky surface fever epidemiology By N. Bhadelia disrupt tomorrow’s workplace, argues
By D. Normile ▶ REPORT P. 74 an economist By J. Peha

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 3

Published by AAAS
33 & 61
4 JA N UA RY 2 0 1 9 • V O LU M E 3 6 3 • I S S U E 6 4 2 2
Ultracold plasma

CHALLENGING TRANSITIONS 27 & 46 An elephant-sized Late Triassic
synapsid with erect limbs
T. Sulej and G. Niedźwiedzki

DNA fragility in the parallel evolution
of pelvic reduction in stickleback fish
K. T. Xie et al.
39 From Science and other journals Structure of the posttranslational
Sec protein-translocation channel

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complex from yeast
42 OPTICS S. Itskanov and E. Park
Exceptional points in optics and
photonics M.-A. Miri and A. Alù 88 PROKARYOTIC IMMUNITY
REVIEW SUMMARY; FOR FULL TEXT: Functionally diverse type V CRISPR-Cas systems W. X. Yan et al.

Commensal-specific T cell plasticity
promotes rapid tissue adaptation to
Counter-propagating charge transport Examining author gender data
injury O. J. Harrison et al.
in the quantum Hall effect regime By Jeremy Berg
44 NEUROSCIENCE 57 NANOMATERIALS Lessons from the ‘real world’
Synaptotagmin-3 drives AMPA receptor Fluorine-programmed nanozipping to By Barbara A. Wanchisen
endocytosis, depression of synapse tailored nanographenes on rutile TiO2
strength, and forgetting A. Awasthi et al. surfaces M. Kolmer et al.
61 ATOMIC PHYSICS Artist’s rendering of an
Laser cooling of ions in a neutral early morning in Silesia,
plasma T. K. Langin et al. Poland, during the Late
Synthetic glycolate metabolism Triassic. The elephant-
pathways stimulate crop growth and sized dicynodont
64 NEUROSCIENCE Lisowicia bojani,
productivity in the field P. F. South et al.

A collicular visual cortex: Neocortical a distant cousin of

space for an ancient midbrain visual present-day mammals,
structure R. Beltramo and M. Scanziani plods slowly through
the woodland as gracile theropod dinosaurs
70 CLIMATE CHANGE search for prey. In the foreground, the
REPORTS mammalian ancestor Hallautherium moves
The Little Ice Age and 20th-century
46 CROWD DYNAMICS deep Pacific cooling cautiously along a branch. Lisowicia, the
Dynamic response and hydrodynamics of G. Gebbie and P. Huybers largest known dicynodont, had upright
polarized crowds N. Bain and D. Bartolo limbs and walked with an erect gait,
▶ PERSPECTIVE P. 27; VIDEO 74 VIROLOGY similar to modern mammals. See page 78.
Metagenomic sequencing at the Illustration: Julius Csotonyi
49 CHEMICAL PHYSICS epicenter of the Nigeria 2018 Lassa
Rovibrational quantum state resolution fever outbreak L. E. Kafetzopoulou et al. Science Staff ..................................................6
of the C60 fullerene P. B. Changala et al. ▶ PERSPECTIVE P. 30 Science Careers ...........................................94

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INFORMATION FOR AUTHORS See Ottoline Leyser, U. of Cambridge Maria Zuber, MIT

6 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
Corrected 4 January 2019. See full text.


Examining author gender data

previously reported results of a study on au- compared with 16% in the physical sciences and 22% in
thor gender in Science ( other fields. The values for corresponding authors are
content/355/6323/329) that was based on the ex- 19, 12, and 20%, respectively.
amination of a random sample of approximately The gender distributions for papers that were pub-
2600 authors for which gender was inferred by lished can be compared with those for the overall sub-
painstaking analysis of websites and similar sourc- missions pool. The acceptance rates for Reports were
es. Unfortunately, this approach does not scale not significantly different for female as compared to
well to large samples necessary for many analyses. male first authors for papers submitted in 2016 and Editor-in-Chief,
We have since initiated systematic efforts to examine 2017, although significant differences were observed Science Journals.
gender distributions of key populations of authors and favoring male authors from 2011 to 2015. Further work
reviewers for the Science family of journals using addi- is in progress to determine if these disparities are

Downloaded from on January 7, 2019

tional data and tools and plan to use this information due to gender biases in reviews, editorial decisions,
to guide policy develop- or other factors such as
ment and other appro- Acceptance rates for Reports by gender of frst authors institutional differences
priate steps to address and preferences. Signifi-
any gender disparities. 0.100 cant differences in Re-
Since our initial study, port acceptance rates by
we have collected gender gender of corresponding
and other demographic authors were observed
information voluntarily in 2012, 2014, and 2015.
from approximately 5000 We can also examine
Acceptance rate

individuals (authors and other article types. For

reviewers). To extend this 0.050 example, the fraction
dataset further, we’ve of female correspond-
used first name–based ing authors for Perspec-
gender inference software tives (driven largely by
that we validated and editorial invitations to
calibrated with accurate Perspective authors and,
datasets, as described in indirectly, peer review-
the accompanying Sci- 0.00 ers) grew steadily from
encehound post (https:// 2010 2011 2012 2013 2014 2015 2016 2017 19 to 26% from 2010 to 2017. The Science news
sciencehound/2019/01/03/new-tools-for-gender- team’s analysis of data regarding its use of women and
analysis). The automated tool provides inferred genders men as sources and in quotes in its stories reveals an
for more than 70% of the authors of both published and increase in the fraction of quoted female sources from
rejected Science papers submitted from 2010 to 2017. approximately 20% to more than 30% over the course
Based on comparisons with the individual-provided of 2018.
dataset, these inferred genders are more than 93% ac- With these data and tools in place, we are now well
curate on an individual basis. Furthermore, the inferred positioned for further analyses and actions that ad-
gender information can be extended to populations dress gender disparities. We plan to examine the gender
with gender distributions that appear to be more than distribution of our peer reviewers. Social science stud-
98% accurate. ies indicate that women and men tend to have similar
The fractions of male and female authors for Re- gender biases, based on their perceptions of the gender
ports submitted to Science are nearly constant over the distribution of the population that they are examining.

8-year period examined. Twenty-five ± 1% of the first Nonetheless, ensuring that gender distributions for re-
authors are female, while 18 ± 1% of the correspond- viewers approximate those for authors is good practice,
ing authors are female, consistent with the results from and peer reviewers do get access to exciting scientific
our earlier analysis. These figures reflect the weighted results and are often invited to write Perspectives. We
averages across the different fields covered by Science. plan to share these and other analyses and encourage
Separating submissions by field reveals that 30% of first others to perform and share similar examinations.
authors of submissions in the life sciences are female, –Jeremy Berg


SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 7

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Downloaded from on January 3, 2019


AREAS TO WATCH the ice’s structure and the water and land
beneath it, using everything from seismo-
meters to instrument-carrying seals. Both
What’s coming up in 2019 missions will benefit from revitalized satel-
lite coverage, as two satellites launched last

cientists in Europe and the United States face an uncertain year, the Ice, Cloud, and Land Elevation
political landscape in the new year, which could affect fund- Satellite-2 and the Gravity Recovery and
ing and collaborations. The threat is most acute in the United Climate Experiment Follow-on, which
measure ice height and mass, respectively,
Kingdom, which plans to exit the European Union in March begin to beam science data back home.
but has not settled on the terms of its departure. Some big re-
search findings could share the headlines, however, including
A science whisperer for Trump
the first clear images of the supermassive black hole at the heart of
SCIENCE POLICY | For 2 years, President
our galaxy, from astronomers in an international collaboration called Donald Trump has been making decisions
the Event Horizon Telescope. Science’s news staff forecasts other involving science and innovation without
areas of research and policy likely to make news this year. input from a White House science adviser.
Meteorologist Kelvin Droegemeier, whom

Trump nominated in late July 2018 to

of Arctic Climate, hosting researchers fill that void, was awaiting final Senate
All eyes on polar ice from 17 countries. They’ll study how polar approval at press time. The question is
| If you want to
C L I M AT E S C I E N C E clouds, ocean dynamics, and first-year ice what his arrival will mean for the adminis-
understand Earth’s warming future, look formation contribute to the Arctic’s shift tration’s handling of an array of technical
to the poles. This year, scientists in two to ice-free summers. Then, near year’s challenges, from regulation of human
international projects will heed that call. end, researchers from the United States embryo engineering and self-driving cars
In September, researchers will position a and United Kingdom will fan out across to combatting cyberterrorism and foster-
German icebreaker, the RV Polarstern, to the remote Thwaites Glacier, the part of ing a more tech-savvy workforce. Some
freeze in Arctic sea ice for a year’s stay. the Antarctic ice sheet most at risk of col- science-soaked issues may already have
The ship will serve as the central hub lapsing into the ocean and driving up been settled, such as leaving the Paris cli-
for the €120 million Multidisciplinary sea levels, in the first full season of a mate accord and forsaking the Iran nuclear
drifting Observatory for the Study $50 million, 5-year effort. They’ll probe deal. But many others remain unresolved,

8 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
The RV Polarstern, shown the team will loft a balloon into the strato-
here on a 2013
Seeking new physics in the muon sphere, where it will release 100 grams
polar research cruise, | By studying the
PA R T I C L E P H YS I C S of reflective particles—probably calcium
will spend a winter magnetism of a particle called the muon, carbonate, the chalky ingredient in antacid
frozen in Arctic sea ice. physicists hope to find results this year tablets. Flying back through the plume,
that could point to new particles or forces, the balloon will observe its cooling effect.
something they have craved for decades. Solar-radiation management, as it’s known,
Scientists at Fermi National Accelerator is controversial. It does not reduce the
Laboratory (Fermilab) in Batavia, Illinois, built-up carbon dioxide that drives climate
are examining whether the muon—a change and ocean acidification, and there’s
heavier and shorter-lived cousin of the no accepted international governance.
electron—is more magnetic than theory
predicts. The Muon g-2 experiment found
a hint of such an excess when it ran at Divided we stand?
Brookhaven National Laboratory in Upton, SCIENCE POLICY | You’ll need a Ouija
New York, from 1997 to 2001. Physicists board to predict how U.S. science will fare
moved the experiment’s 15-meter-wide this year under a divided government, with
electromagnet to Fermilab in 2013, Democrats now in control of the House of
upgraded the apparatus, and started to Representatives while Republicans retain
record data in January 2018. A first result

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could be one of the biggest stories in particle
physics this year, with the world’s biggest
atom smasher, Europe’s Large Hadron
Collider, idled for 2 years of upgrades.

A fine-grained look inside cells

| In cell biology, higher
resolution means more gets revealed. Now,
scientists are ready to use new combina-
tions of tools and techniques to provide
close-up looks at components inside
cells in unprecedented detail, and in 3D. With control of the U.S. House of Representatives,
including how to deal with Chinese espio- Already, researchers can analyze DNA, Democrats will likely examine environmental policies.
nage at U.S. universities without stifling proteins, RNA, and epigenetic marks in
global scientific cooperation. single cells. This year, multidisciplinary the Senate with President Donald Trump
teams plan to combine those methods in the White House. There are the known
with advances in cryoelectron tomography, flashpoints—Democrats challenging the
New rights for alleged harassers labeling techniques to trace molecules, Trump administration on its environment
#METOO | This year, the U.S. Department and other types of microscopy to see and energy policies, for example. Spending
of Education may finalize controver- subcellular structures and processes. For cuts will be on the table as lawmakers
sial proposed rules that would reduce example, a multifaceted technique for face tight budget caps mandated by a 2011
universities’ liability for policing sexual imaging and staining DNA could shed law. Then there are the what-ifs, including
harassment and sexual assault and give new light on how chromosomes fold. And whether the Supreme Court will throw out
more rights to the accused. The regula- the blended methods could yield clearer a citizenship question on the 2020 census
tions, proposed in November 2018, would pictures at the molecular level of how cells and lawmakers can suspend partisan bick-
change how institutions investigate such divide and change shape, and how gene ering long enough to pass an infrastructure
allegations under the landmark 1972 activity affects structure and function. package that would boost U.S. innova-
law known as Title IX. They wouldn’t tion. A few science-savvy new members of
be responsible for investigating most Congress hope to lend a hand.
off-campus incidents of harassment or Solar dimming gets a test
assault, and the standard of evidence | A geoengineering
for confirming allegations of on-campus technique to curb global warming by New GM mosquitoes take off
misconduct could rise. The definition of temporarily dimming the sun’s rays could | The first release of

sexual harassment would be narrowed get its first, modest field experiment this genetically modified (GM) mosquitoes in
from “unwelcome conduct of a sexual year. In solar geoengineering, vast amounts Africa is set to happen in Burkina Faso
nature” to “unwelcome conduct on the of reflective aerosol particles would this year, an initial step in a planned “gene
basis of sex that is so severe, pervasive, be sprayed into the high atmosphere, drive” strategy against malaria. It will be
and objectively offensive that it effec- mimicking the cooling effects of volcanic the first release of GM mosquitoes of the
tively denies a person equal access” to eruptions. The Stratospheric Controlled genus Anopheles, which transmits the
education. And defendants’ lawyers will Perturbation Experiment, led by climate parasite responsible for the disease. The
be able to cross-examine accusers. The scientists at Harvard University, will test gene drive approach, under development at
department is accepting comments on the the idea in a small, controlled way. If its the nonprofit consortium Target Malaria,
proposals until 28 January. plans are approved by an advisory board, would spread mutations through the wild

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 9

Published by AAAS

population that knock out key fertility to living descendants. Some warn, however,
genes or reduce the proportion of female The next planetary mission that widespread adoption of similar methods
insects, which transmit disease. But the | In July, NASA will chart
S PAC E S C I E N C E could be used to coerce communities into
first GM Anopheles mosquitoes released its next major step in planetary science genetic testing. In France, a government-
won’t bear such mutations and aren’t when it selects the next billion-dollar mis- commissioned report recommended in
intended to cut down the population. sion under its New Frontiers program. The November 2018 that over the next 5 years,
Researchers will let out fewer than agency will choose between two finalists. French museums work with colleagues in
10,000 genetically sterilized males to Dragonfly would send a semiautonomous Africa to repatriate tens of thousands of
observe how they survive and disperse quad-copter to fly across the surface of cultural artifacts looted during colonial rule
in the wild and to help introduce the Titan, the saturnian moon sculpted by if their countries of origin ask for them.
concept of GM mosquitoes to regulators rivers of liquid methane. The copter would
and community members. search for clues of chemical reactions that
could lead to life. The Comet Astrobiology Disease crisis looms for swine
Exploration Sample Return mission would | Pig farmers—
Nations size up biodiversity return gases and ice from the nucleus of and perhaps some bacon lovers—will anx-
| Three years in the mak-
C O N S E R VAT I O N the comet 67P/Churyumov-Gerasimenko. iously scan the headlines this year for news
ing, a $2.4 million assessment of Earth’s Such samples, likely unaltered for billions of African swine fever (ASF). Harmless to
biodiversity and ecosystems will be pub- of years, could provide a window into the humans, the viral disease is highly infec-
lished in May. By evaluating trends over role comets played in delivering water and tious and lethal among pigs, causing serious
50 years in indicators such as species organic compounds to Earth in its economic damage through culls and trade

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extinctions and extent of marine pro- early history. bans. ASF made major jumps in Europe last
tected areas, it will chart progress toward year, turning up for the first time in pigs and
international goals on biodiversity wild boar in Bulgaria and in boar in Belgium
conservation—and, in many places, how A push to return museum holdings and Hungary. The virus can jump from boar,
far short the world is falling. Experts RESEARCH ETHICS | Researchers are which are difficult to manage, to swine.
from 50 nations have participated in a beginning new efforts to return bones and Germany, Denmark, and other major pork
review of scientific literature and govern- cultural artifacts collected for study and producers are on high alert. Most worrisome
ment data conducted under the auspices as museum specimens to the peoples from was the first detection of the virus in China,
of the Intergovernmental Science-Policy whom they were obtained, often without a long-dreaded development in the country
Platform on Biodiversity and Ecosystem consent. Expect renewed debate on this with the world’s largest pig population. China
Services. The report, the first since a issue, as after centuries of exploitative col- has recorded more than 80 outbreaks since
similar effort in 2005, will forecast the lecting, some researchers use new methods August 2018, including in boar. Authorities
future of species on the planet under to collaborate with those communities, and have clamped down on the transport of pigs,
business-as-usual and other scenarios. also expand efforts to return objects of art. culled more than 630,000,and last month
The new assessment is intended to A study from Australia published last month reportedly banned pig farming where wild
inform the next generation of biodiversity showed ancient DNA can be used to reliably boar are present. Despite these efforts, the
targets, due in 2020. link the remains of Aboriginal ancestors virus could still explode in China and else-
where in Asia.

A global assessment will

examine endangered China eyes bioethics overhaul
species, which include the BIOETHICS | China is likely to tighten its
ploughshare tortoise in rules for genetic engineering of humans,
Madagascar. including the creation of heritable traits,
in the wake of an uproar over such work in
2018. A Chinese scientist named He Jiankui
announced in November 2018 that he modi-
fied a gene in embryos that led to twin baby
girls. The modification is meant to protect
them and their descendants from HIV infec-
tion, a feat widely condemned in China and
worldwide as unethical, unjustified, and
possibly harmful to the babies. Most coun-
tries ban or outlaw such experiments. In
China, however, what is apparently the most
relevant regulation was enacted in 2003 and

never updated to cover advances in gene

editing. Since the announcement, numerous
Chinese researchers, ethicists, and officials
have called for an overhaul of the country’s
bioethics laws and regulations, although
no agency or institution has been named
to lead the effort. Another question for this
year is whether He will face sanctions.

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The world debates open-access mandates

Spurred by European funders behind Plan S, many countries consider similar moves

By Tania Rabesandratana ary 2020, has drawn support from many to OA, says librarian Jeffrey MacKie-Mason,
scientists, who welcome a shake-up of a pub- the chief digital scholarship officer at the

ow far will Plan S spread? lishing system that can generate large prof- University of California, Berkeley.
Since the September 2018 launch its while keeping taxpayer-funded research Robert-Jan Smits, the European Com-
of the Europe-backed program to results behind paywalls. But publishers (in- mission’s OA envoy in Brussels, who is one
mandate immediate open access (OA) cluding AAAS, which publishes Science) are of the architects of Plan S, says publishers
to scientific literature, 16 funders in concerned, and some scientists worry that have stalled by emphasizing the need for
13 countries have signed on. That’s Plan S could restrict their choices. broad participation. “The big publishers
still far shy of Plan S’s ambition: to con- If Plan S fails to grow, it could remain told me: ‘Listen, we can only flip our jour-
vince the world’s major research funders a divisive mandate that applies to only a nals [to OA] if this is signed by everyone. So
to require immediate OA to all first go on a trip around the world
published papers stemming from “[Plan S] is perhaps our best chance to and come back in 20 years. Then
their grants. Whether it will we can talk again,’” Smits recalls.
reach that goal depends in part transform the publishing industry soon.” “Some people try to do anything to
on details that remain to be set- Jeffrey MacKie-Mason, University of California, Berkeley keep the status quo.”
tled, including a cap on the au- OA mandates are nothing new:
thor charges that funders will pay for OA small percentage of the world’s scientific In Europe, 74 research funders require that

publication (Science, 30 November 2018, papers. (Delta Think, a consulting company papers be made free at some point, up from
p. 983). But the plan has gained momen- in Philadelphia, Pennsylvania, estimates 12 in 2005, according to the Registry of
tum: In December 2018, China stunned that the first 15 funders to back Plan S ac- Open Access Repository Mandates and Poli-
many by expressing strong support for counted for 3.5% of the global research ar- cies. But existing policies typically allow a
Plan S (Science, 14 December 2018, p. 1218). ticles in 2017.) To transform publishing, the delay of 6 or 12 months after initial publica-
This month, a national funding agency in plan needs global buy-in. The more funders tion, during which papers can remain be-
Africa is expected to join, possibly followed join, the more articles will be published in hind a publisher paywall.
by a second U.S. funder. Others around the OA journals that comply with its require- Plan S requires immediate OA; it also in-
world are considering whether to sign on. ments, pushing publishers to flip their jour- sists that authors retain copyright and that
Plan S, scheduled to take effect on 1 Janu- nals from paywall-protected subscriptions hybrid journals, which charge subscrip-

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 11

Published by AAAS

tions but also offer a paid OA option, sign government research funder and two na- National Institute of Informatics in Tokyo,
“transformative agreements” to switch to tional science libraries issued strong state- an adviser to the Japan Alliance of Univer-
fully OA. ments backing Plan S’s goals. “China needs sity Library Consortia for E-Resources, says
Some European funders think Plan S to contribute to international open access that despite interest from funders and li-
goes too far. “We and many German [or- [and] open its research results to its own braries, OA has yet to gain much traction
ganizations] think that we should not be people,” says Zhang Xiaolin of Shanghai- in his country.
as prescriptive as Plan S is,” says Wilhelm Tech University in China, who chairs the South America has a strong tradition
Krull, secretary general of the Volkswagen Strategic Planning Committee of the Chi- of OA repositories and fee-free publish-
Foundation, a private research funder in nese National Science and Technology Li- ing, often with government subsidies.
Hannover, Germany. The country is Eu- brary. Even if Chinese organizations do not Bianca Amaro, president of LA Referencia,
rope’s top producer of scientific papers, join Plan S formally, similar OA policies in a Santiago-based Latin American network
ahead of the United Kingdom and France, China would have a “huge, perhaps deci- of repositories, says Plan S takes a more
whose main funding agencies have signed sive impact on the publishing industry,” “systemic view” than previous policies, and
on to Plan S. Germany’s biggest MacKie-Mason says. she values its pledge to monitor APCs and
federal funding agency, DFG, For now, North America is their impact—a worry for lower-income
said it supports Plan S’s goals Paper players not following suit. The Bill & countries. “We’ll see how Europe handles
but prefers to let research- Melinda Gates Foundation was this,” she says.
Percentages of the
ers drive the change. Other world’s 2016 science
the first Plan S participant out- Of course, MacKie-Mason says, not every
funders, including the Esto- articles by country side Europe, and another pri- funding agency will agree that Plan S is the
nian Research Council, say the vate funder may follow. But U.S. best way to universal OA. “But some will

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timeline is too tight, and they federal agencies are sticking to agree it’s good enough and perhaps our best
will reconsider joining when policies developed after a 2013 chance to transform the publishing indus-
Plan S’s impact is clearer. White House order to make try soon,” he says. It comes in the wake of
Other European funders are peer-reviewed papers on work often incremental OA initiatives in the past
18.6 China
weighing pros and cons. Spain’s they funded freely available 15 years, and some disagreement about the
science ministry says it is analyz- within 12 months of publication best route to OA.
ing the potential repercussions (Science, 10 April 2015, p. 167). “In the OA movement, it seems to a lot of
of Plan S on the country’s science “We don’t anticipate making people that you have to choose a road: green
and finances, and on research- any changes to our model,” said or gold or diamond,” says Colleen Campbell,
ers’ careers. FNRS, the fund for Brian Hitson of the U.S. Depart- director of the OA2020 initiative at the Max
scientific research in Belgium’s ment of Energy in Oak Ridge, Planck Digital Library in Munich, Germany,
Wallonia-Brussels region, is United Tennessee, who directs that referring to various styles of OA. “Publish-
waiting for Plan S to announce States agency’s public access policy. ers are sitting back laughing at us while we
its cap on article-processing Nor are the three main fed- argue about different shades” instead of
charges (APCs), the fees for pub- eral research funders in Canada focusing on a shared goal of complete, im-
lishing in OA journals, which the ready to change their joint 2015 mediate OA. Because of its bold, stringent
coalition’s funders have pledged 4.8 India
OA policy. Plan S is “a bold and requirements, she and others think Plan S
to pay. “We’re not ready to com- aggressive approach, which can galvanize advocates to align their ef-
mit if the costs are too high,” says is why we want to make sure forts to shake up the publishing system.

4.5 Germany
Véronique Halloin, secretary- we’ve done our homework to The Plan S team predicts steady growth
general of FNRS, whose exist- 4.3
United ensure it would have the best ef- in the coming months. Funders will dis-
ing OA mandate caps APC re- Kingdom fect on Canadian science,” says cuss Plan S in São Paulo, Brazil, at the May
imbursement at €500—which 4.2 Japan Kevin Fitzgibbons, executive meeting of the Global Research Council,
Halloin admits is on the low side. director of corporate planning an informal group of funding agencies. Al-
Many await the European 3 France and policy at Canada’s Natural though Smits will leave the European Com-
Commission’s policy: Although 3 Italy Sciences and Engineering Re- mission in March, the Plan S coalition is
its grants represent a small 2.8 South Korea
search Council in Ottawa. seeking a replacement who can keep the
percentage of research funding Outside Europe and North momentum going.
2.6 Russia
in Europe, its OA rules can in- America, funders gave Science “The combined weight of Europe and
fluence national mandates. The 2.5 Canada mixed responses about Plan S. China is probably enough to move the sys-
commission’s research chief, 2.3 Brazil India, the third biggest pro- tem,” says astrophysicist Luke Drury, of the
Carlos Moedas, supports Plan 2.3 Spain ducer of scientific papers in Dublin Institute for Advanced Studies and
S, and its 7-year funding pro- 2.2 Australia the world, will “very likely” the lead author of a cautiously supportive
gram Horizon Europe, which join Plan S, says Krishnaswamy response to Plan S by All European Acad-
will begin in 2021, contains VijayRaghavan in New Delhi, emies, a federation of European academies
general statements of support principal scientific adviser to of sciences and humanities.
for OA. Plan S’s rules will go India’s government. But the If Plan S does succeed in bringing about a
into the program’s model con- Other
Russian Science Foundation fairer publishing system, he says, a transition
tract for grants, Smits says. 25.1 is not planning to join. South to worldwide OA is sure to follow. “Some-
Smits has found unexpected Africa’s National Research body has to take the lead, and I’m pleased
support from China, which Foundation says it “supports that it looks like it’s coming from Europe.” j
now produces more scientific Plan S in principle,” but wants
papers than any other coun- to consult stakeholders before With reporting by Jefrey Brainard, Sanjay
try. Last month, China’s largest signing on. Jun Adachi of the Kumar, Dennis Normile, and Brian Owens.

12 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
In some wet tropical mountains, carbon dioxide is
captured and flushed out of the atmosphere.

90 million and 50 million years ago lined up

neatly with the collisions of a chain of island
volcanoes in the now-vanished Neo-Tethys
Ocean with the African and Asian continents.
A similar collision some 460 million years
ago formed the Appalachians, but it was
thought to have taken place in the subtropics,
where a drier climate does not favor weather-
ing. By reanalyzing ancient magnetic fields
in rocks formed in the collision, Macdonald’s
team found the mountains actually rose deep
in the tropics. And their uplift matched a
2-million-year-long glaciation. “They’re de-
CLIMATE veloping a pretty compelling story that this
was a climate driver in Earth’s past,” says Lee

Tropical uplift may set Kump, a paleoclimatologist at Pennsylvania

State University in University Park.

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But those cases could be exceptions. So the

Earth’s thermostat team compiled a database of every tectonic

“suture”—the linear features left by tectonic
collisions—known to contain ophiolites,
Indonesia’s mountains could be cause of current glacial age those bits of volcanic sea floor, over the past
half-billion years. Based on magnetism in
By Paul Voosen changes in the planet’s temperature are gov- each suture’s rocks and a model of continen-
erned by shifts in CO2, and that plate tecton- tal drift, they mapped their ancient latitudes

ate the cold? Blame Indonesia. It may ics somehow drives those shifts as it remakes to see which formed in the topics, and when.
sound odd, given the contributions the planet’s surface. But for several decades, “We were surprised that this is not as compli-
to global warming from the country’s researchers have debated exactly what turns cated as we thought,” Macdonald said.
270 million people, rampant defores- the CO2 knob. Many have focused on the vol- The team compared the results to records
tation, and frequent carbon dioxide canoes that rise where plates dive beneath of past glaciations and found a strong cor-
(CO2)-belching volcanic eruptions. But one another. By spewing carbon from Earth’s relation. They also looked for declines in
over much longer times, Indonesia is sucking interior, they could turn up the thermostat. volcanism, which might have cooled the cli-
CO2 out of the atmosphere. Others have emphasized rock weathering, mate. But their influence was much weaker,
Many mountains in Indonesia and neigh- which depends on mountain building driven Macdonald said.
boring Papua New Guinea consist of ancient by plate tectonics. When the mountains Kimberly Lau, a geochemist at the Univer-
volcanic rocks from the ocean floor that contain seafloor rocks rich in calcium and sity of Wyoming in Laramie, calls the work
were caught in a colossal tectonic collision magnesium, they react with CO2 dissolved “exciting in idea and novel in execution.” Lee,
between a chain of island volcanoes and a in rainwater to form limestone, which is however, would like to see direct evidence
continent, and thrust high. Lashed by tropi- eventually buried on the ocean floor. Both from ancient sediments that the collisions
cal rains, these rocks hungrily react with CO2 processes matter; “the issue is which one is drove up rock weathering. “They have to go
and sequester it in minerals. That is why, changing the most,” says Cin-Ty Lee, a volca- to the sink and study those,” he says. And a
with only 2% of the world’s land area, Indo- nologist at Rice University in Houston, Texas. recent study challenges the mountain ther-
nesia accounts for 10% of its long-term CO2 Having the right rocks to drive the CO2- mostat idea with evidence for the importance
absorption. Its mountains could explain why chewing reaction is not sufficient. Climate of volcanoes. The study used ages from thou-
ice sheets have persisted, waxing and wan- matters, too. For example, the Siberian Traps, sands of zircons, durable crystals that can in-
ing, for several million years (although they a region that saw devastating volcanic erup- dicate volcanic activity, to show that upticks
are now threatened by global warming). tions 252 million years ago, are rich in such in volcanic emissions were the dominant
Now, researchers have extended that rocks but absorb little, says Dennis Kent, a force driving the planet’s warm periods. It’s
theory, finding that such tropical mountain- geologist at Rutgers University in New Bruns- likely both teams have at least one hand on
building collisions coincide with nearly all of wick, New Jersey. “It’s too damn cold,” he the truth, adds Lee, who contributed to the
the half-dozen or so significant glacial periods says. Saudi Arabia has the heat and the rocks zircon paper.

in the past 500 million years. “These types of but lacks another ingredient. “It’s hotter than The beauty of his team’s model, Macdonald
environments, through time, are what sets Hades but it doesn’t rain.” Indonesia’s loca- said at the end of his talk, is that it explains
the global climate,” said Francis Macdonald, tion in the rainy tropics is just right. “That is not just why glacial times start, but also why
a geologist at the University of California, probably what’s keeping us centered in an ice they stop. A hothouse Earth appears to be
Santa Barbara, when he presented the work age,” Kent adds. the planet’s default state, prevailing for three-
last month at a meeting of the American Geo- Over the past few years, Macdonald and fourths of the past 500 million years. An
physical Union in Washington, D.C. If Earth’s his collaborators have searched for other Indonesia-style collision may push the global
climate has a master switch, he suggests, the times when tectonics and climate could have climate into a glacial period, but only for a
rise of mountains like Indonesia’s could be it. conspired to open an Indonesia-size CO2 while. Mountains erode and continents drift.
Most geologists agree that long-term drain. They found that glacial conditions And the planet warms again. j

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 13

Published by AAAS


Computers turn neural signals into speech

Fed data from invasive brain recordings, algorithms reconstruct heard and spoken sounds

By Kelly Servick removal of a brain tumor, when electrical words aloud. Meanwhile, electrodes re-
readouts from the exposed brain help sur- corded from the brain’s speech planning ar-

or many people who are paralyzed and geons locate and avoid key speech and motor eas and motor areas, which send commands
unable to speak, signals of what they’d areas. Another is when a person with epi- to the vocal tract to articulate words. The
like to say hide in their brains. No one lepsy is implanted with electrodes for several network mapped electrode readouts to the
has been able to decipher those sig- days to pinpoint the origin of seizures before audio recordings, and then reconstructed
nals directly. But three research teams surgical treatment. “We have, at maximum, words from previously unseen brain data.
recently made progress in turning 20 minutes, maybe 30,” for data collection, According to a computerized scoring sys-
data from electrodes surgically placed on Martin says. “We’re really, really limited.” tem, about 40% of the computer-generated
the brain into computer-generated speech. The groups behind the new papers made words were understandable.
Using computational models known as neu- the most of precious data by feeding the Finally, neurosurgeon Edward Chang and
ral networks, they reconstructed words and information into neural networks, which his team at the University of California,

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sentences that were, in some cases, intelli- process complex patterns by passing infor- San Francisco, reconstructed entire sen-
gible to human listeners. mation through layers of computational tences from brain activity captured from
None of the efforts, described in papers in “nodes.” The networks learn by adjusting speech and motor areas while three epi-
recent months on the preprint server bioRxiv, connections between nodes. In the experi- lepsy patients read aloud. In an online test,
managed to re-create speech that 166 people heard one of the sen-
people had merely imagined. In- tences and had to select it from
stead, the researchers monitored among 10 written choices. Some
parts of the brain as people ei- sentences were correctly identi-
ther read aloud, silently mouthed fied more than 80% of the time.
speech, or listened to recordings. The researchers also pushed the
But showing the reconstructed model further: They used it to
speech is understandable is “defi- re-create sentences from data
nitely exciting,” says Stephanie recorded while people silently
Martin, a neural engineer at the mouthed words. That’s an impor-
University of Geneva in Switzer- tant result, Herff says—“one step
land who was not involved in the closer to the speech prosthesis
new projects. that we all have in mind.”
People who have lost the abil- However, “What we’re really
ity to speak after a stroke or waiting for is how [these meth-
disease can use their eyes or ods] are going to do when the pa-
make other small movements tients can’t speak,” says Stephanie
to control a cursor or select Riès, a neuroscientist at San Diego
on-screen letters. (Cosmologist Epilepsy patients with electrode implants have aided efforts to decipher speech. State University in California who
Stephen Hawking tensed his studies language production. The
cheek to trigger a switch mounted on his ments, networks were exposed to recordings brain signals when a person silently “speaks”
glasses.) But if a brain-computer interface of speech that a person produced or heard or “hears” their voice in their head aren’t
could re-create their speech directly, they and data on simultaneous brain activity. identical to signals of speech or hearing.
might regain much more: control over tone Mesgarani’s team relied on data from five Without external sound to match to brain ac-
and inflection, for example, or the ability to people with epilepsy. Their network analyzed tivity, it may be hard for a computer even to
interject in a fast-moving conversation. recordings from the auditory cortex (which sort out where inner speech starts and ends.
The hurdles are high. “We are trying to is active during both speech and listening) Decoding imagined speech will require “a
work out the pattern of … neurons that turn as those patients heard recordings of stories huge jump,” says Gerwin Schalk, a neuro-
on and off at different time points, and infer and people naming digits from zero to nine. engineer at the National Center for Adap-
the speech sound,” says Nima Mesgarani, a The computer then reconstructed spoken tive Neurotechnologies at the New York
computer scientist at Columbia University. numbers from neural data alone; when the State Department of Health in Albany. “It’s
“The mapping from one to the other is not computer “spoke” the numbers, a group of really unclear how to do that at all.”
very straightforward.” How these signals listeners named them with 75% accuracy. One approach, Herff says, might be to give
translate to speech sounds varies from per- Another team, led by neuroscientists feedback to the user of the brain-computer

son to person, so computer models must Miguel Angrick of the University of Bremen interface: If they can hear the computer’s
be “trained” on each individual. And the in Germany and Christian Herff at Maas- speech interpretation in real time, they may
models do best with extremely precise data, tricht University in the Netherlands, relied be able to adjust their thoughts to get the
which requires opening the skull. on data from six people undergoing brain result they want. With enough training of
Researchers can do such invasive record- tumor surgery. A microphone captured both users and neural networks, brain and
ing only in rare cases. One is during the their voices as they read single-syllable computer might meet in the middle. j

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Sunflowers are among a number of plants that appear

Do plants favor their kin? to recognize and help kin.

the plants grown with kin put out more

Once considered outlandish, the idea that plants help their flowers, making them more alluring to pol-
linators. The floral displays were especially
relatives is taking root big in plants in the most crowded pots of rel-
atives, Torices and his colleagues reported
By Elizabeth Pennisi better, a finding that suggested family ties on 22 May 2018 in Nature Communications.
can be exploited to improve crop yields. “It Torices, now at King Juan Carlos Univer-

or people, and many other animals, seems anytime anyone looks for it, they find sity in Madrid, calls the kin effects “altruis-
family matters. Consider how many a kin effect,” says André Kessler, a chemical tic” because each individual plant gives up
jobs go to relatives. Or how an ant will ecologist at Cornell University. some of its ultimate seedmaking potential
ruthlessly attack intruder ants but res- From termites to people, kin-specific be- to expend more energy making flowers. In
cue injured, closely related nestmates. haviors have evolved over and over in ani- the end, he suspects, more seeds are fertil-
There are good evolutionary reasons mals, showing there is a strong advantage ized overall in the closely related pots.
to aid relatives, after all. Now, it seems, fam- to helping relatives pass on shared genes. Doubts linger. Is a plant identifying genetic
ily feelings may stir in plants as well. Dudley reasoned that the same evolutionary kin, or simply recognizing that its neighbor is
A Canadian biologist planted the seed of forces should apply to plants. Not long after more or less similar to itself? “I do not think
the idea more than a decade ago, but many researchers proved that plants can distin- that there has been convincing evidence for
plant biologists regarded it as heretical— guish “self” from “nonself” roots, she tested kin recognition in plants yet,” says Hélène
plants lack the nervous systems that enable whether they could also pick out and favor Fréville, a population biologist studying crops
animals to recognize kin, so how can they kin. She grew American searocket (Cakile at the Montepellier outpost of the French Na-
know their relatives? But with a series of edentula), a succulent found on North tional Institute for Agricultural Research.
recent findings, the notion that plants re- American beaches, in pots with relatives or Sagebrush bushes (Artemisia tridentata)
ally do care for their most genetically close with unrelated plants from the same popu- have provided some strong clues, however.
peers—in a quiet, plant-y way—is taking lation. With strangers, the searocket greatly When injured by herbivores, these plants
root. Some species constrain how far their expanded its underground root system, but release volatile chemicals that stimulate
roots spread, others change how many flow- with relatives, it held these competitive urges neighboring sagebrush to make chemicals
ers they produce, and a few tilt or shift their in check, presumably leaving more room for toxic to their shared enemies. Ecologist
leaves to minimize shading of neighboring kin roots get nutrients and water. The claim, Richard Karban at the University of Califor-
plants, favoring related individuals. published in 2007, shocked colleagues. A few nia, Davis, wondered whether kin were pref-
“We need to recognize that plants not sharply criticized the work, citing flawed sta- erentially warned. His group had already
only sense whether it’s light or dark or if tistics and bad study design. found that sagebrush plants roughly fall into
they’ve been touched, but also whom they Since then, however, other research- two “chemotypes,” which mainly emit ei-

are interacting with,” says Susan Dudley, a ers have confirmed her findings. Recently, ther camphor or another organic compound
plant evolutionary ecologist at McMaster working with Moricandia moricandioides, called thujone when their leaves are dam-
University in Hamilton, Canada, whose a Spanish herb, Rubén Torices and his col- aged. The team showed that the chemotypes
early plant kin recognition studies sparked leagues at the University of Lausanne in are heritable, making them a potential kin
the interest of many scientists. Switzerland and the Spanish National Re- recognition signal. In 2014, the researchers
Beyond broadening views of plant be- search Council demonstrated cooperation reported that when volatiles from a plant
havior, the new work may have a practical in flowering. After growing 770 seedlings in of one chemotype were applied to the same
side. In September 2018, a team in China pots either alone or with three or six neigh- type of plant, those plants mounted stronger
reported that rice planted with kin grows bors of varying relatedness, the team found antiherbivore defenses and had much less

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Published by AAAS

insect damage than when the volatiles were yields. His lab studies rice varieties that give PLANETARY SCIENCE
applied to a plant of the other chemotype—a off weed-killing chemicals in their roots.
hint of a kin effect.
The mustard Arabidopsis thaliana has
provided another clue. About 8 years ago,
Right now, they don’t have high enough
yields to replace commonly grown variet-
ies that require herbicides. But in 3-year-
Jorge Casal, a plant biologist at the Univer-
sity of Buenos Aires, noticed that Arabidopsis
long field tests, kin-recognizing versions of
these self-protective rice varieties produced mission faces
plants growing next to relatives shift the ar- a 5% increase in yield when grown with kin,
rangement of their leaves to reduce shading rather than unrelated plants, Kong and col-
of their neighbors, but don’t do that when the leagues reported in late September 2018 in
neighbors are unrelated. How they sense the
presence of relatives was a mystery, however.
The plants do have light sensors, and
New Phytologist. To test the approach on a
larger scale, he and his colleagues are plant-
ing “kin” seedlings of the weed-killing strain
in 2015, Casal’s team discovered that the together in paddy fields in South China. As first data roll in from
strength of reflected light striking nearby Brian Pickles, an ecologist at the Uni-
leaves signaled relatedness and triggered versity of Reading in the United Kingdom, Hayabusa2, engineers plan
the rearrangements. Relatives tend to proposes that kin recognition could even descent to rocky surface
sprout leaves at the same height, bouncing help forests regenerate. By tracing flows
more light onto each other’s leaves. By shift- of nutrients and chemical signals between
ing leaves to reduce how much they shade trees connected by underground fungi, he By Dennis Normile, in Yonago, Japan

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apan’s Hayabusa mission made his-
tory in 2010 for bringing back to Earth
the first samples ever collected on
an asteroid. But the 7-year, 4-billion-
kilometer odyssey was marked by
degraded solar panels, innumerable
mechanical failures, and a fuel explosion that
knocked the spacecraft into a tumble and
cut communications with ground control for
2 months. When planning its encore, Haya-
busa2, Japan’s scientists and engineers were
determined to avoid such drama. They made
components more robust, enhanced commu-
nications capabilities, and thoroughly tested
new technologies.
But the target asteroid, Ryugu, had fresh
surprises in store. “By looking at the details
of every asteroid ever studied, we had ex-
Initially disbelieved, Susan Dudley’s work on plant kin recognition is winning over more biologists. pected to find at least some wide flat area
suitable for a landing,” says Yuichi Tsuda,
each other, the relatives cumulatively grow showed that the firs preferentially feed Hayabusa2’s project manager at the Japan
more vigorously and produce more seeds, their kin and warn them about insect at- Aerospace Exploration Agency’s Institute
his team found. “There is no other case of tacks. The finding suggested a family of firs of Space and Astronautical Science (ISAS),
kin recognition in plants where the cue, would grow faster than unrelated trees. which is headquartered in Sagamihara. In-
the receptors, and the fitness consequences To some biologists, the emerging picture stead, when the spacecraft reached Ryugu
have been established,” Casal says. of communicating, cooperating plants is in June 2018—at 290 million kilometers
Since then, he has shown that when sun- still based on thin evidence. Laurent Keller, from Earth—it found a cragged, cratered,
flower kin are planted close together, they, an evolutionary biologist at the University boulder-strewn surface that makes land-
too, arrange themselves to stay out of one of Lausanne who has shown that some ap- ing a daunting challenge. The first sam-
another’s way. The sunflowers incline their parent signs of kin recognition in Arabidop- pling touchdown, scheduled for October,
shoots alternately toward one side of the sis can instead stem from innate differences was postponed until at least the end of this
row or the other, Casal and his colleagues among the plants, calls for more rigor in month, and at a symposium here on 21 and
reported in 2017 in the Proceedings of the studies. “People have started to realize that 22 December, ISAS engineers presented an
National Academy of Sciences. Taking ad- it is important to think carefully about the audacious new plan to make a pinpoint
vantage of the effect, they planted 10 to design of the experiment to rule out other landing between closely spaced boulders.
14 related plants per square meter—an un- potential explanations,” he says. “It’s breathtaking,” says Bruce Damer, an
heard of density for commercial growers— Keller is keeping an open mind and pre- origins of life researcher at the University of
and got up to 47% more oil from plants that dicts stronger evidence of plant kin rec- California, Santa Cruz.
were allowed to lean away from each other ognition will emerge. Karban is already Yet most everything else has gone accord-

than plants forced to grow straight up. convinced. “We are learning that plants are ing to plan since Hayabusa2 was launched
Chui-Hua Kong, a chemical ecologist at capable of so much more sophisticated be- in December 2014. Its cameras and detec-
the China Agricultural University in Beijing, havior than we had thought,” he says. “It’s tors have already provided clues to the
is exploiting a similar effect to boost rice really cool stuff.” j asteroid’s mass, density, and mineral and

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Published by AAAS
elemental composition, and three rovers to conduct comparative studies of these two studies that can reveal much more about
dropped on the asteroid have examined asteroid brothers,” Watanabe says. the asteroid’s age and content. ISAS engi-
the surface. At the symposium, ISAS re- Geologist Stephen Mojzsis of the Univer- neers programmed the craft to perform
searchers presented early results, including sity of Colorado in Boulder is not convinced autonomous landings, anticipating safe
evidence of an abundance of organic ma- such asteroids will prove to be the source of touchdown zones at least 100 meters in di-
terial and hints that the asteroid’s parent Earth’s water; there are other theories, he ameter. Instead, the biggest safe area within
body once held water. Those findings “add says, including the possibility that a giant the first landing zone turned out to be just
to the evidence that asteroids rather than Jupiter-like gaseous planet migrated from 12 meters wide.
comets brought water and organic materi- the outer to the inner solar system, bringing That will complicate what was already a
als to Earth,” says project scientist Seiichiro water and other molecules with it around nail-biting operation. Prior to each landing,
Watanabe of Nagoya University in Japan. the time Earth was formed. Still, findings Hayabusa2 planned to drop a small sphere
Ryugu is 1 kilometer across and 900 me- on Ryugu’s shape and composition “scien- sheathed in a highly reflective material to be
ters top to bottom, with a notable bulge tifically, could be very important,” he says. used as a target, to ensure the craft is mov-
around the equator, like a diamond. ing in sync with the asteroid’s rotation.
Visible light observations and com- Gravity then pulls the craft down gen-
puter modeling suggest it’s a porous tly until a collection horn extending
pile of rubble that likely agglomerated from its underside makes contact with
dust, rocks, and boulders after another the asteroid; after a bulletlike projec-
asteroid or planetesimal slammed tile is fired into the surface, soil and
into its parent body during the early rock fragments hopefully ricochet into

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days of the solar system. Ryugu a catcher within the horn. For safety,
spins around its own axis once every the craft has to steer clear of rocks
7.6 hours, but simulations suggest that larger than 70 centimeters.
during the early phase of its forma- During a rehearsal in late October,
tion, it had a rotation period of only Hayabusa2 released a target marker
3.5 hours. That probably produced the above the 12-meter safe circle; unfor-
bulge, by causing surface landslides tunately, it came to rest more than
or pushing material outward from the 10 meters outside the zone. But it is
core, Watanabe says. Analyzing surface just 2.9 meters away from the edge of
material from the equator in an Earth- a second possible landing site that’s
based laboratory could offer support 6 meters in diameter. Engineers now
for one of those scenarios, he adds. If plan to have the craft first hover above
the sample has been exposed to space the target marker and then move lat-
weathering for a long time, it was erally to be above the center of one
likely moved there by landslides; if it of the two sites. Because the naviga-
is relatively fresh, it probably migrated tion camera points straight down,
from the asteroid’s interior. the target marker will be outside the
So far, Hayabusa2 has not detected camera’s field of view as Hayabusa2
water on or near Ryugu’s surface. But descends, leaving the craft to navigate
its infrared spectrometer has found on its own.
signs of hydroxide-bearing minerals “We are now in the process of se-
that suggest water once existed either lecting which landing site” to aim for,

on the parent body or on the asteroid, says Fuyuto Terui, who is in charge
says Mutsumi Komatsu, a planetary ma- of mission guidance, navigation, and
terials scientist at the Graduate Univer- control. Aiming at the smaller zone
sity for Advanced Studies in Hayama, means Hayabusa2 can keep the target
Japan. The asteroid’s high porosity also Hayabusa2 imaged its shadow during a rehearsal descent (top). A marker in sight until the craft is close
suggests it once harbored significant close-up shows a surface strewn with boulders (bottom). to the surface; the bigger zone gives
amounts of water or ice and other vola- more leeway for error, but the craft
tile compounds that later escaped, Watanabe Some new details come from up-close will lose its view of the marker earlier in
says. Asteroids such as Ryugu are rich in car- looks at the asteroid’s surface. On 21 Sep- the descent.
bon as well, and they may have been respon- tember, Hayabusa2 dropped a pair of rovers Assuming the craft survives the first
sible for bringing both water and carbon, the size of a birthday cake, named Minerva- landing, plans call for Hayabusa2 to blast a
life’s key building block, to a rocky Earth II1A and -II1B, on Ryugu’s northern hemi- 2-meter-deep crater into Ryugu’s surface at
early in its history. (Comets, by contrast, are sphere. Taking advantage of its low gravity another site a few months later, by hitting it
just 3% to 5% carbon.) to hop autonomously, they take pictures with a 2-kilogram, copper projectile. This is
Support for that theory, known as the late that have revealed “microscopic features of expected to expose subsurface material for
heavy bombardment, comes from another the surface,” Tsuda says. And on 5 October, observations by the craft’s cameras and sen-
asteroid sample return mission now in Hayabusa2 released a rover developed by sors; the spacecraft may collect some mate-
progress. Early last month, NASA’s OSIRIS- the German and French space agencies that rial from the crater as well, using the same
REx reached asteroid Bennu, which is analyzed soil samples in situ and returned horn device. There could be a third touch-
shaped like a spinning top as well and, the additional pictures. down, elsewhere on the asteroid. If all goes
U.S. space agency has reported, has water The ultimate objective, to bring aster- well, Hayabusa2 will make it back to Earth
trapped in the soil. “We’re lucky to be able oid samples back to Earth, will allow lab with its treasures in 2020. j

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Published by AAAS

How an open-access trove of
data on Britons is unlocking

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the genetics of disease,
behavior, and physical traits
By Jocelyn Kaiser and Ann Gibbons

n early 2017, epidemiologist Rory the encrypted files. Then, on 19 July 2017, long-running controversies about the ap-
Collins at the University of Oxford in they released a final encryption key, firing plication of genetics to behavior in people.
the United Kingdom and his team the starting gun for a scientific race. When the Manchester-based UKB en-
faced a test of their principles. They Within a couple of days, one U.S. group rolled its first volunteer 13 years ago, some
run the UK Biobank (UKB), a huge had done quick analyses linking more than critics wondered whether it would be a
research project probing the health 120,000 genetic markers to more than waste of time and money. But by now, any
and genetics of 500,000 British peo- 2000 diseases and traits, data it eventu- skepticism is long gone. “It’s now clear
ple. They were planning their most ally put up on a blog. Only 60,000 markers that it has been a massive success—largely
sought-after data release yet: genetic had previously been tied to disease, says because the big data they have are being
profiles for all half-million participants. human geneticist Eric Lander, president made widely available,” says Oxford de-
Three hundred research groups had signed and director of the Broad Institute in Cam- velopmental neuropsychologist Dorothy
up to download 8 terabytes of data—the bridge, Massachusetts. “[They] doubled Bishop, a participant. Other biobanks are
equivalent of more than 5000 streamed that in a week.” bigger or collect equally detailed health
movies. That’s enough to tie up a home Within 2 weeks, others had begun to data. But the UKB has both large numbers
computer for weeks, threatening a key goal post draft manuscripts on the bioRxiv pre- of participants and high-quality clinical
of the UKB: to give equal access to any print site. By now, those data have spawned information. It “allows us to do research
qualified researcher in the world. dozens of papers in journals or on bioRxiv, on a scale that we’ve never been able to do
“We wanted to create a level playing firming up how particular genes contrib- before,” says Peter Visscher, a quantitative
field” so that someone at a big center with ute to heart disease, diabetes, Alzheimer’s, geneticist at the University of Queensland
a supercomputer was at no more of an ad- and other conditions, as well as genes’ role in Brisbane, Australia.
vantage than a postdoc in Scotland with a in shaping personality, depression, birth The crucial ingredient, however, may be

smaller computer and slower internet link, weight, insomnia, and other traits. More open access. Researchers around the world
says Oxford’s Naomi Allen, the project’s chief controversially, data from the trove also can freely delve into the UKB data and rap-
epidemiologist. They came up with a plan: pointed to DNA markers linked to educa- idly build on one another’s work, resulting
They gave researchers 3 weeks to download tion level and sexual orientation, stoking in unexpected dividends in diverse fields,

18 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS

diet and smoking with the development of In 2015, his team released the first batch
disease over time. The model was the famous of genetic data on a subset of 150,000 par-
Framingham Heart Study, a long-term study ticipants. Then came the July 2017 release
that initially analyzed 5200 residents of of full genotyping data for all 500,000. Two
Framingham, Massachusetts, seeking factors months later, Benjamin Neale’s group at the
that influence heart disease. The UKB proj- Broad Institute put up its blog doubling the
ect, which has received $308 million in fund- number of markers linked to traits and dis-
ing so far from the Wellcome Trust medical orders, as well as a web browser for looking
charity, the U.K. government, and disease up specific markers. “We viewed it as a ser-
foundations, “was going to be like Framing- vice to the community,” Neale says.
ham, only 100 times bigger,” says principal
investigator Collins. TODAY, about 7000 researchers have reg-
From 2006 to 2010, the UKB enrolled istered to use UKB data on 1400 projects,
500,000 people aged 40 to 69 through the and nearly 600 papers have been published.
United Kingdom’s National Health Service. Some studies simply link behaviors and dis-
Mailed invitations were sent widely, includ- ease, for example reporting that drinking
ing to people in poor and ethnically diverse more coffee can reduce mortality but that
areas of cities such as Birmingham. But in
the end, participants were “anybody you
could persuade,” Collins says. Investigators Engine of productivity

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sampled their blood and urine, surveyed Published papers based on the UK Biobank’s bounty
their habits, and examined them for more of health and genetics data are piling up fast, in part
than 2400 different traits or phenotypes, in- because the data are freely available.
cluding data on their social lives, cognitive
state, lifestyle, and physical health.
The blood samples yielded DNA for ge-
nomic analyses. Links to other U.K. data-
bases added information such as cancer 200
diagnoses, deaths, and hospitalizations. “If
you’re talking about common phenotypes, 150
the Biobank shines,” Lander says. “There’s
arm fat, smoking behavior, miserableness, 100
neurotic behavior, time on your computer,
UK Biobank Principal Investigator eating behavior, drinking behavior.”
Rory Collins stands amid Other biobanks have comparably rich
stored biospecimens from the health data, such as deCODE Genetics’s de-
project’s half-million participants. tailed database on Iceland’s population and 0
biobanks run by U.S. health care provid- 2013 2014 2015 2016 2017 2018
ers. Some, such as the U.S. Million Veteran
such as human evolution (see story, p. 21). Program and the DNA testing company binge-watching TV is associated with more
In a crowdsourcing spirit rare in the hyper- 23andMe, are bigger. But in most cases re- colon cancer. But most studies compare the
competitive world of biomedical research, searchers can use these databases only by genomes of people with some trait or dis-
groups even post tools for using the data collaborating with their creators. ease with those without it, in order to home
without first seeking credit by publishing In contrast, the Wellcome Trust and U.K. in on genes that influence that attribute;
in a journal. Medical Research Council insisted that any these projects are known as genome-wide
“The U.K. is getting all of the world’s researcher approved by the UKB board, association studies.
best brains” to study its citizens, says anywhere in the world, be able to download The result, every few days, is a new pa-
Ewan Birney, director of the EMBL Euro- anonymized data sets on all 500,000 par- per using UKB data to link particular gene
pean Bioinformatics Institute in Hinxton, ticipants. (Users pay a relatively modest fee variants to a disease or trait—arthritis, type
U.K., and a member of the UKB’s steering of $2500 and agree to return their raw data, 2 diabetes, depression, neuroticism, heart
committee. The U.K. focus is also the proj- results, and code to the UKB after publish- disease. “It’s so easy for people who don’t

ect’s chief downside, as it explores just one ing. They also sign a legal agreement not to collect their own data,” says statistical genet-
slice of humanity: northern Europeans. It try to reidentify any participant.) icist Danielle Posthuma of Vrije University in
holds data for only about 20,000 people “It was a novel concept,” says Collins, who Amsterdam, who studies brain diseases. By
of African or Asian descent, for example. says he’s lost track of the times someone has combining data from the UKB and other col-
Yet as new papers appear every few days, asked him after a talk whether he’s inter- lections, investigators can amass samples of
researchers say the UKB remains a shin- ested in collaborating. “I have to say, ‘You a million people or more, amplifying the sig-
ing example of the power of curiosity un- just request the data.’ To some extent people nal of gene variants with subtle effects. For
leashed. “It’s the thing we always dreamed don’t believe it.” some diseases, dozens or hundreds of genes
of,” Lander says. The aim is to maximize the scientific pay- appear to play a role. The genetic links are
off: “By making data available to 100 people suggestive correlations; establishing cause
THE UKB WAS ANNOUNCED in the early 2000s around the world, we can get a lot more re- and effect will take more genetics work and
as a classical epidemiological study—the search done than if I sit here and do one lab studies, which could reveal new disease
kind used to associate risk factors such as study a year with the data,” he says. pathways that might be drug targets.

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Published by AAAS

In the near term, the large sample sizes THE UKB’S UNUSUAL DESIGN does have some enrolled 33,000 Britons of Bangladeshi
are boosting the power of “polygenic” risk limitations. The big one: Ninety-four per- and Pakistani ancestry. In his experience,
scores, which calculate a person’s disease risk cent of participants are white. “It’s really South Asians in the United Kingdom are
by combining many genetic markers. For ex- good if you’re British or European,” Lander less likely to respond to mailed invitations.
ample, one study published in August 2018 says. But, “If you’re an American without His project achieved success by approach-
in Nature Genetics drew on the July 2017 European ancestry or an African or Asian, ing potential participants in person—
data to devise risk scores for five diseases, in- you’re going to be poorly serviced by the sometimes in their native language—in
cluding breast cancer and heart disease. The new polygenic risk scores.” Nor will scores “trusted” settings such as health clinics
authors, at Massachusetts General Hospital for traits such as educational attain- and community centers.
in Boston and the Broad Institute, found that ment be meaningful in people with non- Collins and other geneticists hope other
a surprisingly high 8% of people of European European ancestry. biobanks can help fill the gap. For exam-
descent have at least a threefold elevated risk The mailed invitation recruitment strat- ple, the Wellcome Trust is now the main
for heart disease. And up to 6% have a three- egy didn’t work as well as hoped, says funder of the China Kadoorie Biobank,
fold increase in risk for one of the four other Collins, who notes that young, low-income, with data on 515,000 people from main-
diseases, suggesting they should be screened white men are also scarce in the database. land China, belonging to 10 ethnic groups.
early and consider lifestyle changes or other “We were aiming to get heterogeneity, but In the United States, the All of Us biobank
measures that could improve their odds. it’s difficult.” funded by the National Institutes of Health
The most provocative studies have probed Bishop blames the project’s slant toward (NIH) aims to use community outreach to
for genetic influences on human behavior. higher income, healthy, white people on help enroll at least half of its 1 million par-
ticipants from minority groups, and like

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the UKB, promises to make data freely
Long-term investment available. The Human Heredity & Health
Nearly 2 decades after U.K. funding organizations proposed a large, long-term health study, the database is in Africa initiative has 70,000 participants
paying off richly; its timeline is punctuated by massive, open-access data releases. Meanwhile, participants age so far across the continent, with funding
and develop diseases, adding power and momentum to the project. from NIH and the Wellcome Trust. “There
are ways of fixing this up. But we’ve got a
March 2000 October 2015 July 2017 March 2019 long ways to go,” Birney says.
Expert panel proposes cohort Imaging data Genotyping Exome data on 50,000 Meanwhile, the UKB’s riches are grow-
study of 500,000 adults. available for 5000. data on to be released. ing. About half of the participants’ pri-
April 2002 March 2012 May 2015 released. 2020 mary care data, including clinical data
Wellcome Trust and U.K. UK Biobank Genotyping data on All exome and prescriptions, will become available
government announce initial resource 150,000 released. data released.
funding of £45 million. launches. next spring. The UKB has also done MRI
scans of the brains, hearts, and abdomens
of 25,000 participants, with plans to scan
100,000; researchers are examining and
2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020
annotating the images.
Collins has been promoting the UKB’s sci-
Recruitment of participants entific treasure in Silicon Valley in Califor-
nia, where he hopes bioinformatics experts
One, published in Nature Genetics in July a lack of incentives for participants—they will dig in and come up with unexpected
2018, drew on the UKB and 23andMe to pin don’t get even a small payment or the findings. The genetic data are ballooning,
down genetic contributions to a person’s promise of receiving their test results. The too: Several companies are now sequenc-
level of education. Together, 1300 genetic people attracted to the project were those ing the exomes, or protein-coding regions,
markers accounted for 11% of the variability with enough spare time to participate or of all UKB participants, and the United
among individuals, the researchers found. “who [wanted] to help research,” she says. Kingdom’s public Sanger Institute is se-
That’s comparable to certain environmental One problem is that many immigrants quencing whole genomes from 50,000 vol-
influences in the UKB sample, such as fam- to the United Kingdom have little experi- unteers. Unlike the genotyping data, which
ily income, which predicted just 7% of the ence with the research world, says Naveed don’t usually point to specific genes, the
variance in educational attainment among Sattar, an adviser to the UKB and a clinical sequences will allow researchers who have
participants; and mother’s education level, researcher and epidemiologist at the Uni- found a genetic marker linked to a disease
which predicted 15%. Another study pre- versity of Glasgow. “Most first generation to quickly zero in on the causative gene and
sented at a meeting last fall found four ge- Asians simply have no prior experience see the specific mutations at work.
netic markers that appear to have a strong of what research is and that it may help Because of the $150 million cost of this
influence on whether a person has had sex their community and their children in the sequencing work, the UKB had to compro-
with someone of their own sex at least once future,” he says. Surveys have found that mise on open access: Companies have 9 to
(Science, 26 October 2018, p. 385). immigrants are often suspicious of par- 12 months to use the exome data before
Such studies are raising concerns that ticipating in research—perhaps because of they are made widely available. But Collins
genetic tests could be used to screen em- unethical past studies in some countries, and his team, as well as geneticists around

bryos for desired traits or discriminate or concern that genetic findings could be the world, are already gearing up for the
against individuals with certain genetic used to discriminate. wide release of the first batch of exome
profiles. That would be a misuse of the Engaging such groups is possible, says data on 50,000 participants. Again, they’ll
findings, say the researchers who identi- geneticist David Van Heel of Queen Mary allow time for the download, then release a
fied these links. They stress that the prob- University of London, who heads the code. The starting gun in the next scientific
abilities mean little on the individual level. Genes & Health study, which so far has race is set for March. j

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The half-million people in the UK Biobank hold the genetic legacy
of Neanderthals—and clues to how we are still evolving
By Ann Gibbons

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eanderthals are still among us, get their rubber-gloved hands on enough Among participants in the UK Biobank are people
Janet Kelso realized 8 years ago. people’s genomes to detect the relatively whose Neanderthal DNA predisposes them to traits
She had helped make the momen- rare bits of Neanderthal DNA, much less such as propensity to sunburn, staying up late,
tous discovery that Neanderthals to see whether or how our extinct cousins’ depression, smoking, and feeling lonely.
repeatedly mated with the ances- genetic legacy might influence disease or
tors of modern humans—a find- physical traits. could actually look and say: ‘We see a Ne-
ing that implies people outside of But a few years ago, Kelso and her col- anderthal version of the gene and we can
Africa still carry Neanderthal DNA leagues at the Max Planck Institute for measure its effect on phenotype in many
today. Ever since then, Kelso has Evolutionary Anthropology in Leipzig, people—how often they get sunburned,

wondered exactly what modern humans Germany, turned to a new tool—the UK what color their hair is, and what color
got from those prehistoric liaisons—beyond Biobank (UKB), a large database that their eyes are,’” Kelso says. They found
babies. How do traces of the Neanderthal holds genetic and health records for half Neanderthal variants that boost the odds
within shape the appearance, health, or per- a million British volunteers (see story, that a person smokes, is an evening person
sonalities of living people? p. 18). The researchers analyzed data from rather than a morning person, and is prone
For years, evolutionary biologists couldn’t 112,338 of those Britons—enough that “we to sunburn and depression.

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Kelso is one of many researchers who are used proprietary electronic records of 28,000 psychiatric and lifestyle traits.” Those rich
turning troves of genetic and medical data on Americans. His team was the first to publish, data have also made the UKB a hunting
living people into windows on human evolu- reporting Neanderthal DNA variants that ground for clues to evolutionary changes
tion. In addition to unearthing archaic DNA, raise the risk of depression, skin lesions, that have shaped people’s genomes in the
the studies are pinpointing genes that natu- blood clots, and other disorders in people past few generations—and may even be do-
ral selection may now be winnowing out of today (Science, 12 February 2016, p. 648). In- ing so today.
the gene pool and other genes—for example spired by Capra’s study, Kelso jumped in, be-
those linked to fertility—that it may be fa- coming the first to use UKB data to publish A FEW YEARS AGO, Molly Przeworski of Co-
voring. Among the most fruitful of the data Neanderthal gene variants in living people. lumbia University and Joe Pickrell of the
sources is the UKB, which makes its data ac- Her results suggest that although some Ne- New York Genome Center in New York City
cessible to researchers, no matter where they anderthal gene variants may have been op- met for lunch near Columbia’s campus. Talk
are and what their field. Its giant database timal for active lives outdoors in prehistoric turned to aging and Alzheimer’s disease.
is “a magical new resource that [will] help Europe, they may be problematic for people Pickrell had been writing a blog, where he
us answer a whole bunch of hard questions now, who live mostly indoors in artificial had discussed studies showing that between
we’re struggling with now because all of the light and get less exercise. the ages of 70 and 85, carriers of the ApoE4
data has been under lock and key,” says allele, which boosts the risk of Al-
population geneticist Jeremy Berg, a zheimer’s and cardiovascular disease,
postdoc at Columbia University. “It is a died at about twice the rate of non-
step beyond other databases.” carriers. The pair wondered whether
For the UKB architects, who designed other gene variants affect survival so

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it for biomedical research, the evolu- dramatically—and whether natural
tionary discoveries are an unexpected selection is weeding them out.
bonus. “No one was thinking about When it comes to natural selection
Neanderthal traits when we designed in humans, most studies have only
the protocol,” says molecular epidemio- been able to detect dramatic cases
logist Rory Collins of the University of thousands or millions of years ago
Oxford in the United Kingdom, who is in genes of known function. Now,
principal investigator of the UKB. “The Pickrell and Przeworski wondered
experiment [is] working well beyond whether they could detect genetic vari-
people’s expectations.” ants that affect survival today—and
whether natural selection in recent gen-
NEANDERTHALS SNEAKED INTO the UKB erations has been weeding out harmful
in 2013, when Harvard University pop- ones or favoring beneficial ones.
ulation geneticist David Reich was in To do this, they realized they’d need
Oxford to give a talk. His host, Oxford data on DNA as well as on traits like
geneticist Peter Donnelly, was oversee- participants’ age at death. For statis-
ing the design of chips to identify genes tical confidence, they’d need a giant
of interest in blood samples like those sample size—at least 100,000—to de-
in the UKB. Donnelly asked Reich tect how the frequency of common al-
whether he’d like to add Neanderthal Janet Kelso fshed for Neanderthal gene variants in the UK Biobank. leles varied in people of different ages.
variants to a custom chip used to geno- Databases like the UKB were the an-
type the UKB participants; that would allow Groups led by Kelso and Sankararaman swer. “We suddenly realized that the some of
Reich and others to fish for rare Neanderthal are now looking for links between Nean- these databases were large enough to let us
variants in half a million people. “David was derthal DNA and traits in genotyped data study selection in contemporary humans,”
very enthusiastic,” Donnelly recalls. from 500,000 people—the total UKB data Przeworski says.
Soon after, Reich and his postdoc, Sriram set, which was released in July 2017. Al- They soon got access to genetic and health


Sankararaman, emailed Donnelly a wish list ready, they are learning that Neanderthal data on 57,696 people in the Resource for
of variants to add to the chip: 6000 relatively alleles help cause baldness and mental ill- Genetic Epidemiology Research on Aging
rare alleles likely to come from Neander- ness and boost certain immune functions, database at Kaiser Permanente in Oakland,
thals. Their calculations suggested the UKB Sankararaman says. Meanwhile, another California, and 117,648 individuals in the
was big enough to include enough carriers team has found variants that help explain UKB’s 2015 data release. They sorted partici-
of these variants so researchers could probe why modern humans’ heads are round, in pants into 5-year age intervals, and looked
the function of the genes. “Imagine 1% of the contrast to the elongated, football-like shape at the frequency of many alleles, including
population has a Neanderthal variant,” says of Neanderthal skulls (Science, 14 Decem- ApoE4, in each age group, as well as how the
Sankararaman, now a computational geneti- ber 2018, p. 1229). Those researchers plan variants correlated with 42 traits potentially
cist at the University of California (UC), Los to combine forthcoming MRI brain scans associated with early death or long life, such
Angeles. “If you’re looking at half a million of 100,000 UKB participants with genetic as cardiovascular disease, cholesterol levels,
people, you’re looking at enough copies of data to probe the genetic basis of brain dif- asthma, age at puberty, and menopause.
that variant in enough individuals [5000] so ferences between us and our extinct cousins. Nearly all the variants they examined
you can detect subtle effects.” Capra says when it comes to scanning persisted at the same frequency even into
At the same time, computational bio- and understanding DNA from Neander- old age, suggesting they had no large ef-
logist Tony Capra at Vanderbilt University in thals, the UKB cohort offers even more ana- fect on survival. That implies natural se-
Nashville had the same bright idea to search lytical power than the medical databases he lection has efficiently weeded out harmful
for Neanderthal DNA in a large database. He used, because it covers “a broader range of variants, even if they act only in old age—

22 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
perhaps, Przeworski speculates, because traits in women and men that might have in- Using other databases, researchers had
the variants curb older men’s fecundity. fluenced fertility, such as age of first birth, found that the number of genes that con-
Or perhaps the hypothesized benefit that age of menopause, height, weight, body tribute to tallness in Europeans increased
healthy grandmothers confer on grandchil- mass, blood pressure, and education. They on a cline from south to north. Many re-
dren was at work. found 23 traits in women and 21 in men searchers, including Berg, had concluded
The researchers did find two genes that linked to having more children. Not surpris- that northern Europeans had inherited
suddenly became rare at older ages, suggest- ingly, mothers who gave birth early and had those genes from an ancient migration—
ing they were harmful. One was ApoE4: As late menopause—and therefore had a longer that of the Yamnaya herders who migrated
expected, fewer carriers—especially women— reproductive span—were more fertile. So from the Eurasian steppe to central Europe
lived past age 80. Also, fewer men with a vari- were women who were heavier and shorter, about 4000 years ago. Berg and others sug-
ant of the CHRN3 gene that makes it harder perhaps because shorter bodies are more gested natural selection had favored tall-
to quit smoking survived past the age of 75 energy efficient, leaving a bigger reserve for ness in the Yamnaya or their ancestors,
than did men without the variant. pregnancy and nursing. and ancient DNA reveals that the Yamnaya
The researchers concluded that natural Visscher and his colleagues then set out were tall.
selection has not yet had time to eliminate to identify the genetic basis of these fertility- But now, with UKB data, population ge-
these two alleles, perhaps because changes linked traits. They analyzed data from neticist Graham Coop of UC Davis and his
in the environment and human behavior 157,807 of the women and 115,902 of the colleagues, including Berg, are challenging
only recently made them deadly (Science, men. As predicted, they found that the most that finding. In a bioRxiv preprint posted in
20 May 2016, p. 876). For example, the fertile women had higher frequencies of al- June 2018, they analyzed genetic and height
CHRN3 allele wouldn’t have affected sur- leles that tend to make them shorter and data on 500,000 people from the 2017 UKB

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vival until many men were smoking. And heavier. In men, greater fertility was asso- data release. With so many people from
women who were more active in the past ciated with more alleles that contribute to similar backgrounds, the researchers could
might have been less vulnerable to the a higher body mass index and hand-grip identify more height alleles, as well as note
cardiovascular diseases caused by differences in diet, disease, and
ApoE4, Przeworski speculates. the environment. They found that
The researchers spotted another “No one was thinking about Neanderthal northerners had no more tall vari-
intriguing pattern. Genetic variants traits when we designed the protocol.” ants than southerners.
that lead to early puberty also be- “It’s true people in northern
came rarer in older age groups. Nat- Rory Collins, University of Oxford Europe are taller on average, but
ural selection may have preserved there is no evidence this has any-
those variants even though they shorten life strength. That suggests men with genes that thing to do with natural selection,” Berg
span because they also boosted fertility. make them taller and bulkier have more kids says. He speculates that northerners’ height
than sedentary types, whether because of fe- might be an environmental effect, perhaps
A LONG LIFE, though, is much less important male choice, some health-related reason, or from a diet richer in protein, or from fewer
to evolution than fertility. When it comes the men’s own preference. childhood or prenatal illnesses.
to the game of evolution, in fact, the per- Not all traits linked to fertility are physi- Although UKB data cast doubt on natural
son who has the most kids wins by pass- cal or likely to have a big genetic component: selection’s role in that case, they do suggest
ing on the most genes. With the advent of Among women who had their first child later that evolution has favored genes for short-
birth control, people in industrial societies in life, those who had more education and ness in pygmy populations on the island of
have more control than ever over their own did better on an intelligence test had more Flores in Indonesia. Visscher and colleagues
fertility—but new studies zeroing in on the babies. This may be because better-educated scanned the DNA of Flores people for genes
genes underlying fertility show the forces of couples tend to be wealthier and can afford the UKB had linked to short stature. They
selection may still be at work. more children. found that Flores pygmies carry more such
Multiple studies have suggested that when But the fact that genes linked to traits gene variants than their closest relatives in
food sources became more reliable in indus- thought to increase fertility are indeed more New Guinea and East Asia, suggesting evo-
trialized societies, women began to mature common in fertile people backs up the idea lution favored genes for shortness on the
faster, weigh more, give birth to their first of recent selection on our genomes, even as island (Science, 3 August 2018, p. 439). All
child earlier, and enter menopause later—all both the environment and humans’ prefer- these studies have generated “huge buzz
traits possibly linked to having more babies. ences for mates and families are changing. among evolutionary biologists about how
But researchers have been unable to tie those “The UK Biobank allows us to show that nat- biobanks can provide very deep informa-
trends to underlying genes to get direct evi- ural selection not only took place in the past, tion about the genetics of different popula-
dence of natural selection. Quantitative ge- but it’s still ongoing,” Visscher says. tions and their evolution,” Kelso says.
neticist Peter Visscher and his colleagues at She hopes to work with researchers de-
the University of Queensland in Brisbane, TEASING OUT natural selection from other signing databases in Africa and Asia to
Australia, realized they could use the UKB factors shaping genes can be tricky, how- identify archaic DNA in those populations.
to see firsthand which gene variants under- ever, especially when multiple genes work Thanks to the success of the Neanderthal
lie those traits in people today, and whether together to influence complex traits, such work, many researchers are eager for data
they are really linked to fertility. as height. About 5000 gene variants si- from Melanesians, because they have inher-
They searched the UKB’s full cohort for multaneously influence a person’s height, ited traces of DNA from Denisovans—the
people who had the most babies to see what some boosting it, some reducing it, says mysterious cousins of Neanderthals who
traits they share, and what genes correlate Jian Yang, a statistical geneticist at the lived in Siberia more than 50,000 years ago.
with those traits. They documented the University of Queensland. The UKB’s huge “That would be amazing, to get Denisovan
number of live births for women over age database allows researchers to find new DNA from more living people [in biobanks].
45 and men over age 55. Then, they analyzed variants and explore their impact and origins. That’s our dream,” Kelso says. j

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 23

Published by AAAS
Be prepared
The greatest challenge during my
transition from a teaching assistant to
an assistant professor in a large public
university was the teaching responsibil-
ity. Whereas teaching assistants focus
only on the subject matter and a small
LET TERS group of students, a professor must select
textbooks, prepare syllabi, coordinate lab-
oratory experiments, teach large classes,
handle teaching assistants, manage the
course website, and accommodate athletes’
schedules and students with disabilities.
By taking courses on teaching, I devel-
oped skills in communication, evaluation
and assessment, education psychology,
academic advising, and student accommo-
dations. For me, preparation was the key
to a smooth transition.

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Niluka D. Wasalathanthri
Department of Chemistry, University of Connecticut,
Storrs, CT 06269, USA.

Postdocs are expected to perform as expe-

rienced researchers. This can be challenging
given the dependence of Ph.D. students
on their supervisors for scientific ideas
and experimental designs. To excel as a
postdoc, I advise thoroughly reviewing the
literature. Read the relevant papers com-
pletely, especially the methods sections.
This will greatly enhance your ability to
design your own experiment.
Syed Shan-e-Ali Zaidi
Plant Genetics Lab, Gembloux Agro-Bio Tech,
University of Liège, Gembloux, 5030 Namur, Belgium.

After juggling my experiments and man-

aging a small lab of 10 members as a
graduate student, I now focus solely on
meeting the needs of a 75-person lab.
Although I work far fewer hours now, I
must work much faster in a shorter time
frame. My excellent mentors and my
management experience eased my transi-
tion. To succeed as a lab manager, I advise
others to get as much regulatory, person-

Challenging transitions
nel management, and ordering experience
as possible.
Elena Mahrt
Center for the Genetics of Host Defense,
We asked young scientists these questions: Have you ever encountered University of Texas Southwestern Medical Center,
Dallas, TX 75390, USA.
a particularly stark diference between an old and new position Email:
in your education or career? What was the diference between the

positions, and what advice would you give to someone making As a scientist, I could focus on research,
but my transition to a professor role
a similar transition? Here, respondents share the challenges they faced came with new responsibilities. Instead
when they took on new responsibilities and roles, changed fields, of simply reading a publication to plan
or moved to new places. To others in similar situations, they advise: new experiments, I now read with an eye
toward how to explain the concepts to a
Be confident, prepared, and patient; communicate; and always ask student. A scientist might manage a group
for help when needed. —Jennifer Sills of 5 to 10 researchers, whereas a teacher

24 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
manages students ranging from under- and maintaining connections to your Transitioning from a dental school in India
graduates to postdoctoral fellows. As a original field. to a business school in the United States was
scientist, I could remain silent and work Fengbo Li tough. Looking back, I was not adequately
out problems internally. As a teacher, I Zhejiang Academy of Agricultural Sciences, prepared to appreciate the teaching peda-
have to talk constantly, yet remain calm. Hangzhou, Zhejiang 310021, China. gogy in a business school, which was in
Sudhakar Srivastava stark contrast to what I had been exposed to
Institute of Environment and Sustainable in dental school. Difficulties adapting to the
Development, Banaras Hindu University, Varanasi, When I transitioned from a master’s degree
Uttar Pradesh 221005, India. surroundings, environment, and culture of
program in Colombia to a Ph.D. program in
Email: a different country further compounded my
the United Kingdom, I encountered cultural
problems during my first year of graduate
shock and language barriers. To address
The training of a physician focuses on the studies. To those in a similar predicament,
these challenges, I acknowledged the differ-
familiarity with medical knowledge and I would recommend being a good listener,
ences, maintained an open dialogue with
clinical guidelines, whereas solid statis- setting achievable goals for each day, focus-
peers and supervisors to ensure accurate
tics and a programming background are ing on seemingly small activities, being
communication, and tried to view setbacks
required to become a data scientist. To detail oriented, and asking for help if you
with perspective. I also surrounded myself
make the transition, I joined a Ph.D. pro- need any. You will be surprised at how much
with other multilingual people who could
gram after medical school; spent 3 years people are willing to help those coming from
relate to the process of learning another
taking classes on statistical inference, a different country.
language and its frustrations, and I looked
machine learning, and computational for academic role models who weren’t native Veerasathpurush Allareddy
biology; and participated in programming College of Dentistry, University of Illinois at Chicago,
English speakers. Rather than compare

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Chicago, IL 60612, USA. Email:
contests with undergraduates. As a result, myself to others who had different back-
I benefited from both the medical domain grounds or experience, I took pride in my When I transitioned from undergraduate
knowledge and the quantitative skills I ability to overcome obstacles. to postgraduate (Ph.D.) studies, there was a
learned in my journey.
Maria Fernanda Torres Jimenez substantial change in my effort-reward sys-
Kun-Hsing Yu Department of Biological and Environmental tem. In high school and college, the harder
Department of Biomedical Informatics, Sciences, University of Gothenburg, and Gothenburg
Harvard Medical School, Boston, MA 02115, USA. Global Biodiversity Centre, Gothenburg, Sweden. I studied, the better results I would get. In
Email: Email: contrast, as a Ph.D. candidate, substantial
effort does not always mean a visible reward
right away. I realized that outcomes do not
Find community depend on me alone but also on supervisors,
When I transitioned from one field in available resources, and even luck. My advice
biology to another, I had to acclimate is to try to find small, perhaps unexpected,
to subtle differences between fields, rewards from that effort and to be patient
such as strategies for collaboration and because a long-term important reward is
publication. Anyone who is planning likely still to come.
to change fields should make sure that Carmen Romero-Molina
the new workplace has a good working Department of Biochemistry and Molecular
Biology, University of Seville, 41012 Seville, Spain.
environment. It would have been impos- Email:
sible for me to get started without the
help of colleagues willing to teach me
the nuances of my new field. In return, Trust yourself
I taught them skills I had developed in I transitioned from a position as a special-
my original field. ist in the pharmaceutical industry to a
Karin S. L. Johansson position as a Ph.D. student. I went from
Institute of Technology, University of Tartu, 50411
Tartu, Estonia. Email:
solving day-to-day tasks with short dead-
lines to doing research projects lasting for
After finishing my Ph.D., I made a career
Be patient several years. Sometimes, when weeks and
transition from aquaculture to entomol- As a premedical student, I focused on even months go by without results, I have
ogy. I had to abandon a decade of fish obtaining high exam scores and a compet- to remind myself that I made the transition
research experience and start studying itive GPA. When transitioning to medical to challenge myself and develop my skills.
school, I realized that I was now studying Remembering the reason that I’m here helps
insects from scratch. Within the ento-
for my future patients, not an exam score. me overcome frustration and setbacks.
mology community in China, however,
a new researcher has little chance to get The expectation that I would retain all Signe Mosegaard
Research Unit for Molecular Medicine,
a research grant, and my career stalled. the information I learned for a lifetime of Aarhus University, DK-8200 Aarhus N, Denmark.

When our institute decided to launch clinical practice was daunting. I believe Email:
a new aquaculture research program, I it is important for students making this
returned to the aquaculture field without transition to prepare themselves not just I left a research assistant position in a
hesitation and reconnected and collabo- for the sprint to the next exam but for the 20-member lab to do my Ph.D. as the sole
rated with colleagues and old friends in “marathon” that is medical training. member of a new lab. Our productivity
the aquaculture community. To those Cody Lo depended on my effort, and I understood
transitioning from one field to another, I University of British Columbia, Vancouver, BC V6T both the responsibility and the opportunity
recommend being prepared for setbacks 1Z3, Canada. Email: the position entailed. I advise others to start

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 25

Published by AAAS

a Ph.D. with a secure and honest vision more we serve as role models, push societal stakeholders with substantially differ-
of what they want to achieve. Otherwise, acceptance of equality, and improve condi- ent levels of expertise, expectations, and
all the distractions in the world will not tions for future academic mothers. backgrounds on a daily basis. Excellent
be comfort enough during the difficult or Christine D. Bacon oral and written communication skills
unexpected moments. Department of Biological and Environmental are essential to ensure that messages are
Sciences, University of Gothenburg, Gothenburg, delivered clearly, precisely, and effi-
Steven M. Heaton Sweden. Email:
Department of Biochemistry and Molecular ciently. Understanding the organizational
Biology, Biomedicine Discovery Institute, landscape also plays a crucial role in effec-
Monash University, Clayton, VIC 3800, Australia. When I started my Ph.D. project, I depended tive communication, and the academic
Email: on guidance from my supervisor. When I platform does not provide that type of
transitioned to postdoctoral work, I had complex environment. Thus, I believe
Medical school was like drinking from a fire to independently navigate my research
hose. There was so much to learn; the more internships and industrial co-op positions
schedule, including both long-term and are the best opportunities for postgradu-
efficient I was, the better. When I transi- short-term goals. It was up to me to stay
tioned to graduate school during my M.D./ ate students who would like to get true
engaged, focus on my goals, and change exposure to the industrial atmosphere and
Ph.D. training, the rules for success were direction when appropriate. Self-navigation
less clear. My research mentor often tells me to improve their soft skills.
driven by intrinsic motivation helped me
to be creative, but there is no textbook for Dhanuka Wasalathanthri
find success as a postdoctoral researcher. Sanofi US, Fiskdale, MA 01518, USA.
creativity. Testing the boundaries of science Email:
Sha Yu
requires experiments or techniques that you School of Biological Sciences, Seoul
have never done before, and when you try National University, Seoul 8826, South Korea.

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When I was a graduate student, it was
new things, you often fail. The key, I believe, natural and helpful to vent my nega-
is to work on questions that truly interest tive feelings about incomplete tasks to
you. Genuine scientific curiosity can form When I first transitioned from Ph.D. to
someone in our group. After transition-
the foundation for sustained perseverance. postdoc, the most challenging difference
ing to a position as an adviser, I realized
Asking “Why?” can turn failed experiments was the change in expectations. As a Ph.D.
that I had to express my frustration more
into new opportunities. It turns out that student, I benefited from my supervisor’s
constructively. Expressing pessimism to
graduate school is also like drinking from helping hand and the understanding that
the graduate students can affect them,
a fire hose, but the fun part is you get to my colleagues would tolerate mistakes. As
sometimes more than we expect. Although
choose what you drink. a postdoc, I had to face the expectation that
I still share my concerns, I now try to lay
Jonathan Joon-Young Park
I could produce high-impact results with
out the problems and possible solutions
Department of Genetics, Yale University minimal supervision.
School of Medicine, New Haven, CT 06520, USA.
without emphasizing my feelings, and I
Emre Ozan Polat encourage the students to work together to
Email: ICFO–The Institute of Photonic Sciences,
Castelldefels, 8860 Barcelona, Spain. solve problems.
For academics, transitioning to parenthood Email: Wei Wang
can be daunting. During the first years of Fujian Institute of Research on the Structure
of Matter, Chinese Academy of Sciences, Fuzhou,
my child’s life, I experienced academia Fujian 350002, China. Email:
with a new perspective. We have traveled Communicate effectively
to conferences and field work all over the When I left my position as a graduate During my Ph.D., I started a medical
world. With the help of patient colleagues, research assistant in academia to begin device company. The transition from
supportive family and friends, conference work as a scientist in industry, I learned scientist to entrepreneur was challenging
day care, and a strong will, I have tried my that industry requires complex com- because the business world was com-
best to be an active member of my scientific munication skills. I have to engage and pletely new to me. Young scientists in
community. The more we participate, the communicate with internal and external a similar position, conflicted between a
comfortable academic trajectory and
the unknown startup world, should
not hesitate to reach out to those more
experienced. You will be surprised at
the insights a quick phone call, email,
or coffee chat can generate. In graduate
school, while you’re learning about the
scientific process of hypothesis design and
testing, explore what it takes to translate
new ideas into market-ready products.
It is never too early to learn how to
become a good salesperson. The ability to

pitch an idea effectively will help you

communicate your science more success-
fully in any setting.
Divyansh Agarwal
Perelman School of Medicine, University
of Pennsylvania, Philadelphia, PA 19104, USA.

26 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
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CROWD DYNAMICS A human crowd supports a wave-like transmission

of information when the crowd is modeled as a single

Flowing crowds entity rather than a composite of individuals.

years, researchers have attempted to con-

Modeling human crowds as a fluid allows strain these assumed rules by measuring real
animal groups (6–9). However, this approach
prediction of group behavior is fraught. Data can be hard to come by for
many reasons—including, in the case of hu-
By Nicholas T. Ouellette a continuum “hydrodynamic” model of the mans, substantial ethical considerations.
crowd as a whole and then constrain it with More fundamentally, extracting individual

ollective behavior of social animals, observational data collected from marathon interaction rules from observations of group
particularly coordinated group move- runners. This approach circumvents many behavior is a complex, nonlinear inverse
ments, is one of the most striking of the sometimes-questionable assumptions problem, so drawing reliable conclusions in a
phenomena in the natural world, as that have previously been made and provides model-free way is often impossible.
anyone who has been enthralled by a roadmap for constructing an empirically Rather than thinking about a group as a
flocks of starlings or schools of sar- grounded theory of collective behavior. composite of individual agents with their
dines can attest. Research in this broad, in- The dominant paradigm for describing own rules, a group can instead be considered
terdisciplinary field has recently exploded, collective behavior is agent-based model- as an entity itself. The properties of the group
with motivations ranging from understand- ing. Each individual in a group is treated as certainly emerge from interactions between
ing the biological basis of social behavior an “agent” that follows a set of rules to de- the individuals, but to model these properties,
(1) to developing algorithms for designing termine its behavior. Most commonly, these it is not necessary to know where they come
and controlling swarms of robots (2). There rules include instructions to not stray too from. In this sense, collective behavior can
is good reason to think that the behavior far from the group, to avoid collisions, and, be treated analogously to how the mechan-
of human crowds is quite similar to these for directed motion, to move in the same ics of materials are modeled. To describe how
animal groups and that studying humans direction as nearby agents (5). Agent-based water flows, one does not need to consider
might help elucidate the origins of crowd models have succeeded in qualitatively re- molecular interactions; rather, one can apply
panic and other dangerous instabilities that producing patterns observed in real animal conservation laws for a macroscopic amount
can lead to injury or loss of life (3). All these groups (1), providing strong evidence that lo- of water and constrain them with empirical

goals require modeling, both as a check on cal interaction alone is sufficient to drive the observations (in the case of hydrodynamics, a
our understanding and as a predictive tool formation of group-level coherent behavior. linear constitutive law that relates stress and
for analyzing new situations. On p. 46 of this However, pattern isn’t everything, and just strain rate). Such an approach cannot cap-
issue, Bain and Bartolo (4) describe a pow- because a model’s output qualitatively looks ture the behavior of water molecules, but if
erful new way to model human crowds. In- acceptable does not mean that the model is the goal is to formulate a predictive theory of
stead of focusing on individuals, they build right. There is also reason to be skeptical of hydrodynamics, they are not necessary.
this approach because it requires a priori as- Bain and Bartolo have essentially followed
Department of Civil and Environmental Engineering, Stanford sumptions about animal behavior that are at this approach for human crowds. They be-
University, Stanford, CA 94305, USA. Email: least oversimplified if not incorrect. In recent gin with generic equations of motion for the

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 27

Published by AAAS

continuum crowd density and velocity start-

ing from mass and momentum conservation.
To gather the necessary information to con-
strain these equations, they made a series of
observations of a large number of people in a
confined space—in this case, runners at the
start of major marathons who are strongly
constrained by geometry (along a street) and
by the control of race officials. Runners are
typically allowed to start the race in small
groups according to their expected speed.
The authors quantitatively analyzed videos of
runners at the start of races and found that
each starting event (when officials let runners
start to advance toward the starting line) trig-
gered an upstream-propagating wave of den- CONSERVATION
sity and velocity perturbations through the
crowd. In other words, the crowd supported
a wave-like transmission of information (in
this case, the start of the race). The proper-
The sound of a tropical forest
Recording of forest soundscapes can help monitor animal

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ties of this wave provided the information
needed to constrain the equations of motion,
which in turn enabled predictions about the
biodiversity for conservation
dynamics of other crowds without resorting
to any assumptions about human behavior. By Zuzana Burivalova1, Edward T. Game2,3, to conserving biodiversity. Continuing ad-
That’s a very important outcome, including Rhett A. Butler4 vances in spectral imagery and lidar (light
for those interested in modeling potentially detection and ranging) reveal progressively

dangerous situations such as crowd panic. onservation areas around the world finer levels of forest change, but they still re-
The approach of Bain and Bartolo opens aim to help conserve animal biodiver- main a proxy for animal biodiversity rather
many avenues for future work for collective sity, but it is often difficult to measure than a direct measure of it (4).
behavior researchers more generally. For ex- conservation success without detailed Repeated on-the-ground surveys can
ample, it should inspire studies that pinpoint on-the-ground surveys. High-resolu- provide the required information to assess
a group response to perturbations—such as tion satellite imagery can be used to animal biodiversity. However, such sur-
the traveling waves launched by the start- verify whether or not deforestation has oc- veys are expensive, cover limited ground,
ing events of a marathon race—to constrain curred in areas dedicated for conservation and may be affected by the biases of indi-
continuum models. Some studies along these (1). Such remote sensing analyses can reveal vidual experts. One possible alternative is
lines have already been done, such as char- forest loss and, in some cases, severe forest the use of bioacoustics, which can detect
acterizing the response of starling flocks to degradation, such as through fragmenta- animals by their vocalizations. Depending
predators (10), of ants to mechanical stresses tion and intensive selective logging, espe- on vegetation structure and the vocaliz-
(11), and of midge swarms to sensory cues (12). cially if it includes the construction of roads ing species, acoustic recorders can detect
More work is necessary to incorporate these or camps. However, conservation benefit is animal calls and song from several hun-
findings into dynamical continuum models determined not only by forest loss but also dred meters away (5). Autonomous sound-
that avoid the need for a priori assumptions by the level of degradation in those forests recording devices are now available from
about animal behavior. Ultimately, such mod- left standing. Bioacoustics—specifically the several companies as small units that are
els may even be an effective way to determine recording and analysis of entire sound- inconspicuous to humans. They can be
the local interactions themselves because any scapes—is an emerging tool with great programmed to record either continuously,
agent-based model must approach the con- promise for effectively monitoring animal if there is sufficient solar power or cellular
tinuum model as a limiting case. j biodiversity in tropical forests under vari- network signal for direct transmission of
ous conservation schemes (2, 3). data to cloud storage, or at given intervals,
Even forests that appear intact in satellite if battery power and data storage are lim-
1. J. K. Parrish, L. Edelstein-Keshet, Science 284, 99 (1999).
2. M. Rubenstein, A. Cornejo, R. Nagpal, Science 345, 795 imagery can have low biodiversity conserva- iting factors (6). Several multiyear record-
(2014). tion value because of effects such as canopy ings have now been completed (7).
3. D. Helbing, I. Farkas, T. Vicsek, Nature 407, 487 (2000).
4. N. Bain, D. Bartolo, Science 363, 46 (2019). simplification, understory fires, invasion by Selected times of the day can convey a
5. C. W. Reynolds, Comput. Graph. 21, 25 (1987). exotic species, or overhunting. These forms disproportionately large amount of infor-
6. Y. Katz, K. Tunstrøm, C. C. Ioannou, C. Huepe, I. D. Couzin, of degradation are difficult to monitor re- mation about the resident biodiversity; for

Proc. Natl. Acad. Sci. U.S.A. 108, 18720 (2011).

7. J. E. Herbert-Read et al., Proc. Natl. Acad. Sci. U.S.A. 108, motely with satellite imagery, resulting in example, mornings and evenings have been
18726 (2011). a common but faulty assumption that con- found to be particularly important for de-
8. W. Bialek et al., Proc. Natl. Acad. Sci. U.S.A. 109, 4786 (2012).
9. J. G. Puckett, D. H. Kelley, N. T. Ouellette, Sci. Rep. 4, 4766 serving forest cover is necessarily equivalent tecting differences between forests that are
(2014). used in different ways by humans (8). With
10. A. Procaccini et al., Anim. Behav. 82, 759 (2011). 1 further developments in energy and data
11. M. Tennenbaum, Z. Liu, D. Hu, A. Fernandez-Nieves, Nat. Woodrow Wilson School of Public and International Affairs,
Mater. 15, 54 (2016). Princeton University, Princeton, NJ 08540, USA. 2The Nature storage and transmission, continuous re-
12. R. Ni, J. G. Puckett, E. R. Dufresne, N. T. Ouellette, Phys. Rev. Conservancy, South Brisbane, QLD 4101, Australia. 3School of cording is likely to become the norm.
Lett. 115, 118104 (2015). Biological Sciences, University of Queensland, St. Lucia, QLD
4072, Australia., Menlo Park, CA 94026, USA. Relative to on-the-ground surveys, bio-
10.1126/science.aav9869 Email: acoustics is inexpensive, making it more

28 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
Hornbills, such as this rhinoceros hornbill in protected forests should be determined scape composition due to climate change
Bukit Tigapuluh National Park, Sumatra, not just by how much forest loss has been might be beyond the direct control of the
Indonesia, have prominent vocalizations that avoided, but also by the level of biological companies, but abrupt and quick change in
can be identified in soundscapes. integrity of those forests left standing. Bio- soundscapes is more likely to be attributable
acoustics has the potential to provide this to management. In these cases, other mea-
feasible to repeat measurements over time. information (see the figure). sures (such as prevention of hunting, refor-
Also, the results are not influenced by in- Advances in bioacoustics, as well as the esting edges or the degraded areas of the
dividual researchers’ biases or simply by robustness and affordability of sound- conserved zone with native species, or curb-
the presence of observers in the field. The recording devices, make it possible for ing fires) would be called for by auditors,
method offers the possibility to monitor companies or independent consultants to who are typically involved in independent
multiple taxonomic groups at the same time deploy sound recorders in areas of forest verification of a company’s commitments.
(all vocalizing birds, mammals, insects, and maintained by a company under legal re- Because of the enormous size of the
amphibians), as opposed to, for example, quirements, certification, or a zero-defores- acoustic datasets and the computational
camera traps. Finally, the data can be reana- tation commitment. If the soundscape of a power required to analyze them, there is
lyzed in the future with improved algorithms forest spared from conversion were becom- a need for a global organization to host a
or to search for specific acoustic features. ing more impoverished and altered beyond global acoustic platform, which would al-
Analysis of human-made sounds can help to the natural variation of the soundscape low direct, on-the-fly analysis. The develop-
clarify how sounds from machinery (such as baseline, on-the-ground survey would be ment of such a data hosting and analysis
tractors, bulldozers, and chainsaws) affect warranted. Slow, gradual changes in sound- platform should be a priority, together with
habitat quality and to track illegal human the collection of regional soundscape base-

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activities, such as gunshots from poachers or lines by scientists. Such baselines would
chainsaws in illegal logging (9). How soundscape monitoring be especially useful for understanding and
Acoustic data from soundscapes can be accounting for the natural seasonal and in-
analyzed in many ways (10). Various indi-
can aid conservation terannual variation of soundscapes, as well
This diagram shows how bioacoustics monitoring
ces can be calculated that characterize the as for comparison of the industry-protected
could be implemented in a concession governed
soundscape for each time and frequency by a corporate conservation commitment or
forest soundscapes with the closest avail-
unit (11, 12). Alternatively, individual spe- sustainability certification. Soundscape recordings able undisturbed sites.
cies can be identified by experts, algorithms would be compared to each other over time, Nongovernmental organizations and the
(13), or deep learning (14). as well as to regional baselines from the closest conservation community need to be able
Soundscape analysis using indices ap- available intact forest landscapes. to truly evaluate the effectiveness of con-
pears most suitable to monitor the general servation interventions. Many (but not all)
state and recovery of forests, because it does companies want to be able to provide objec-
not require site-specific species lists (8). Ran- tive, consistent, and easy-to-share evidence
dom forest models based on multiple acous- documenting their conservation efforts, at
tic indices can predict species richness with a low cost. Environmentally aware consum-
very high accuracy (11). However, further ers may feel more confident about purchas-

studies linking on-the-ground biodiversity ing from brands that can show the results
surveys to soundscape indices are needed of their conservation efforts, on top of their
from a wide variety of forest types and hu- certification logo or zero-deforestation
man disturbances to determine whether commitment. The scientific community
such indices can be generalized. In areas will benefit from a huge tranche of data on
Soundscape of a forest that
where hunting is important, the recordings ecological communities across the tropics.
belongs to a nearby plantation
could also be used to determine the presence committed to zero deforestation It is therefore in the interest of certification
or absence of the hunted species (typically bodies to harness the developments in bio-
large mammals and birds) using individual acoustics for better enforcement and effec-
species recognition algorithms. tiveness measurements of their schemes. j
Bioacoustics has particular potential in
the context of industry sustainability cer-
1. H. K. Gibbs et al., Conserv. Lett. 9, 32 (2016).
tification and zero-deforestation commit- 2. J. Sueur, A. Farina, Biosemiotics 8, 493 (2015).
ments, both of which have become popular, 1 Comparison 3. B. Krause, A. Farina, Biol. Conserv. 195, 245 (2016).
widely publicized conservation strategies (1, over time 4. M. M. C. Bustamante et al., Glob. Change Biol. 22, 92
15). Companies involved in such industries 5. K. Darras, P. Pütz, Fahrurrozi, K. Rembold, T. Tscharntke,
as palm oil, beef, soy, and pulp and paper Biol. Conserv. 201, 29 (2016).
production commit to not cause any defor- 6. A. Rodriguez et al., Ecol. Inform. 21, 133 (2014).
7. S. H. Gage, A. C. Axel, Ecol. Inform. 21, 100 (2014).
estation through their industrial develop- 8. Z. Burivalova et al., Conserv. Biol. 32, 205 (2018).
ment. Typically, this means that any new 2 Comparison 9. C. Astaras, J. M. Linder, P. Wrege, R. D. Orume, D. W.
plantation, ranch, or farm can only be devel- Macdonald, Front. Ecol. Environ. 15, 233 (2017).
to a regional
10. J. L. Deichmann et al., Biotropica 50, 713 (2018).
oped in an area that is already deforested or baseline 11. R. T. Buxton et al., Conserv. Biol. 32, 1174 (2018).
heavily degraded. In some countries, such 12. L. M. Ferreira et al., J. Ecoacoust. 2, PVH6YZ (2018).
as Brazil, companies are legally obliged to 13. A. P. Hill et al., Methods Ecol. Evol. 9, 1199 (2018).
14. D. Stowell, Y. Stylianou, M. Wood, H. Pamuła, H. Glotin,
protect parts of their concessions from de-
Methods Ecol. Evol. 10.1111/2041-210X.13103 (2018).
forestation. However, precise definitions of 15. S. Brown, D. Zarin, Science 342, 805 (2013).
zero deforestation are often missing (15).
The conservation benefit of such industry- 10.1126/science.aav1902

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 29

Published by AAAS

INFECTIOUS DISEASE phylogenetic homology). Another recent

study from the current outbreak of Lassa fe-

Understanding Lassa fever ver in Nigeria has drawn similar conclusions

using more traditional genetic sequencing
technology (7).
Genomics study informs about Lassa fever epidemiology Despite the critical epidemiological clues
provided by both studies, it is helpful to keep
in mind that the narrative of Lassa fever is
By Nahid Bhadelia sense of the bigger picture. In the biological driven by where the testing for the disease
world, longer reads of genomic information occurs. Owing to the high number of asymp-

assa fever is a viral hemorrhagic fever also provide invaluable information about tomatic cases and the nonspecific symptoms
prevalent in West Africa that has been structural variations and epigenetic modifi- mimicking myriads of infectious diseases in
gaining international attention as an cations between individual organisms. How- the region in patients who actually become
emerging infectious disease with the ever, with longer reads comes greater error sick, establishing the true burden of Lassa
potential to cause epidemics (1). Con- rates, which appear to improve with repeated fever in Nigeria and other West African coun-
firmed and suspected cases of Lassa reads of the same genetic material, as long as tries has been near impossible (8). The dis-
fever have been steadily rising in Nigeria it is of high-enough quality and quantity (5). ease is mainly spread through contact with
over the past 3 years. Laboratory-confirmed With its compact size, portability, and quick the urine and feces of multimammate rats in
cases have increased from 106 in 2016 to 143 turnaround time, the device can be rapidly the household setting, a human-vector inter-
in 2017 and had already reached 562 by No- deployed in outbreak areas where laboratory face that happens mostly in poor communi-

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vember 2018 (2). Part of defining the scope of ties and in rural areas. Unfortunately, these
the problem is trying to assess whether this are also communities with considerably less
is a true increase in the number of people af- access to health care, and, because diagnos-
flicted by the infection, due to either changes tic testing for Lassa fever is only available
in the virus itself or the geographical spread at a handful of reference laboratories, it is
of the vector (rodents of the Mastomys spp.), thought that many suspected patients are
or a reflection of higher rates of detection either never tested or only tested after a de-
and diagnosis secondary to the increased lay (9). Conversely, ~80% of suspected cases
attention and interest of clinicians and labo- tested in 2018 were actually negative for
ratorians (1). Lassa fever outbreaks illustrate Lassa fever (2).
the issues associated with the response and Because of a lack of access to laboratory
management of emerging infectious diseases: testing, a sizeable portion of the world’s
How do you plan the public health, clinical, LASV (blue) is spread by rat urine and droppings and population, particularly in resource-limited
and community responses to a disease while infects humans through ingestion or inhalation. areas, is simply treated on the basis of symp-
you are still learning about the epidemiology, tomatology for common infectious diseases
pathophysiology, and the ecological factors capacity may not exist for genomic sequenc- such as malaria or cholera rather than tested
contributing to the spread of the pathogen? ing and when samples cannot be exported on presentation to confirm the underlying di-
On page 74 of this issue, Kafetzopoulou et out of the country for analysis (4). Its uses agnosis (10). This paradigm allows emerging
al. (3) present the results of a rapid genomic include not only sequencing to evaluate vi- infectious diseases to circulate in populations
study of Lassa virus (LASV) from the cases ral evolution and chains of transmission but without initial detection. Hence, the real test
of 2018, which have improved understanding also, as the authors highlight, identification of emerging microbial detection techniques
of how the disease has been spreading in Ni- of multiple cocirculating viruses in patient will be how accurate, affordable, and amena-
geria and have led to informed and targeted samples. The technology has already been ble to widespread use they are and whether
disease-control strategies. The study also fur- used in outbreaks with other pathogens, in- they can test both for common endemic in-
ther describes the use of a new and compact cluding Ebola virus (6). fectious diseases as well as rarer pathogens
genomic sequencing device, which may start Kafetzopoulou et al. used this technology of high concern, such as viral hemorrhagic
playing a larger role in defining other emerg- to compare the phylogenetic differences be- fevers. To get the true sense of the disease
ing infectious disease outbreaks in real time. tween the strains of viruses from 120 con- burden and deaths from these emerging in-
The device generates exponentially longer firmed LASV samples from Nigeria from fectious diseases, to really solve the problem
reads of genetic material than traditional the spring of 2018. With the increase in the of Lassa fever, we still need diagnostic tech-
sequencing and offers some remarkable number of total cases as well as clusters of nologies closer to the point of care, and ev-
advantages over existing next-generation cases in recent years, one of the concerns has erywhere patients get sick. j
sequencing platforms (4). To date, sequenc- been whether the virus has changed, allow-
ing the genomes of organisms has been like ing Lassa fever to transmit between humans
1. L. Roberts, Science 359, 1201 (2018).
printing individual pages of a novel in the more easily. By examining the level of genetic 2. Nigeria Centre for Disease Control, “Weekly epidemiologi-
wrong order (many of which end with the diversity between viruses in each of the dif- cal report: Epi week 1, week 46” (2018).

3. L. E. Kafetzopoulou et al., Science 363, 74 (2019).

same words and phrases) and trying to put ferent samples, alongside epidemiological 4. H. Lu et al., Genom. Proteom. Bioinf. 14, 265 (2016).
the story together with guess work. The de- information about the cases, the authors 5. A. D. Tyler et al., Sci. Rep. 8, 10931 (2018).
vice allows researchers to instead print out demonstrated that most of the viral genomes 6. J. Quick et al., Nature 530, 228 (2016).
7. K. J. Siddle et al., N. Engl. J. Med. 379, 1745 (2018).
whole chapters, making it easier to get a were different enough from each other that 8. C. Houlihan, R. Behrens, BMJ 358, j2986 (2017).
they had to have come from humans infected 9. R. S. Dhillon et al., Lancet Infect. Dis. 18, 601 (2018).
Section of Infectious Diseases, Boston University 10. A. M. Caliendo et al., Clin. Infect. Dis. 57 (suppl. 3), S139
by different rodents, rather than from those (2013).
School of Medicine and National Emerging Infectious Diseases
Laboratories, Boston University, Boston, MA, USA. infected through transmission from other
Email: humans (which would have greater shared 10.1126/science.aav8958

30 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS

Weakening synapses to cull memories

Calcium sensor synaptotagmin-3 helps weaken synaptic strength and supports forgetting

By Nataniel J. Mandelberg and tioning in mice can be deactivated through dant at postsynaptic regions, is endocytosed
Richard Tsien optogenetically induced LTD and reactivated when neurons are stimulated, binds directly
with LTP (6). LTP occurs when the activity of to GluA2 receptors, and controls their inter-

rom correct answers on a school exam the presynaptic neuron causes a large influx nalization. Awasthi et al. show that SYT3 has
to a loved one’s birthday, we have all of Ca2+ into the postsynaptic neuron. It mani- a functional impact on synaptic plasticity. In-
forgotten things we wish we had not. fests as an increased number of a-amino- duction of LTP was unaffected by Syt3 gene
The ability to forget, however, is a 3-hydroxy-5-methyl-4-isoxazolepropionic deletion in mice, whereas the decay of LTP
feature rather than a flaw of how our acid (AMPA) type 2 subunit–containing glu- and the induction of LTD, both reliant on
brains work. As the celebrated author tamate (GluA2) receptors at the spine, mak- GluA2 receptor endocytosis, were abolished.
Jorge Luis Borges wrote about a man inca- ing the postsynaptic neuron more responsive Notably, SYT3 binds Ca2+ at 5- to 20-fold
pable of forgetting, Funes the Memorious (1), to input from the presynaptic cell. By con- lower concentrations (8) than does SYT1,
“I suspect, however, that he was not very ca- trast, LTD is driven by smaller Ca2+ events which participates in postsynaptic recruit-

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pable of thought. To think is to ment of GluA2 receptors in LTP
forget differences, generalize, (7). Taken together, these find-
make abstractions.” Although Switching between remembering and forgetting ings (5, 7, 8) align with a model
Funes’s example is literary, it 2+
In this model, different SYT isoforms with different Ca affinities (8) determine that attributes the different Ca2+
contains a grain of truth. Neuro- whether GluA2 receptors should be added to synapses, which strengthens them requirements of LTP and LTD
scientists have traditionally paid (LTP), or removed, which weakens them (LTD). This contributes at the synaptic level to their structurally divergent
more attention to how the brain to the decision in the brain of whether a memory should be encoded or forgotten. Ca2+ sensors. Other players, such
remembers than how it forgets, as calmodulin kinases and cal-
but there is increasing clarity Synaptic Memory Synaptic cineurin, may also participate
LTP LTD Forgetting
about mechanisms and roles of strengthening formation weakening in the all-important molecu-
forgetting (2, 3). By forgetting, lar decision between synaptic
we prioritize and separate the strengthening and weakening.
useful from the irrelevant and Work is needed to further inte-
more easily reorganize informa- grate postsynaptic vesicle cycling
tion to learn (4). On page 44 of GluA2 receptor and signaling biochemistry.
this issue, Awasthi et al. (5) show Awasthi et al. show that
that the Ca2+-sensing protein these circuit-level findings have
synaptotagmin-3 (SYT3) is es- SYT1 in vivo relevance by training
sential for synaptic weakening Clathrin mice to find target locations.
and link this molecular process AP-2 When Syt3 was deleted, the
to beneficial forgetting in mice. SYT3 mice learned the target loca-
A compelling association tion as well as the wild-type
exists between memory and GluA2 receptor GluA2 receptor mice did but, when the target
changes in neuron connectivity. exocytosis endocytosis was moved, showed impaired
Neurons are linked by synapses, forgetting of the initial location,
structures in which boutons Stimulation strength reflected by an unwillingness
from the axon of the upstream Calcium
to leave the target’s original
(presynaptic) neuron communi- location. These results extend
cate with spines on dendrites of reports that GluA2 receptor
the downstream (postsynaptic) endocytosis mediates memory
neuron via neurotransmitter release. If the and reflects the removal of GluA2 receptors loss (9) and that blocking this endocytosis
presynaptic neuron reliably drives the activ- from the synapse through endocytosis, weak- preserves memories (10), by showing that
ity of the postsynaptic neuron, the synapse’s ening the connection. this process is mediated by SYT3 in vivo.
strength, or weight, increases through long- To clarify the mechanism of GluA2 recep- Awasthi et al. go on to demonstrate that
term potentiation (LTP). However, if the ac- tor endocytosis, Awasthi et al. looked closely this inability to forget hinders behavioral
tivities of the neurons are poorly correlated, at members of the synaptotagmin family of flexibility, much as in Borges’s story of Funes.
the connection weakens through long-term Ca2+-sensitive proteins. Synaptotagmins con- The mice were again tasked with finding a

depression (LTD). Controlling LTP and LTD trol the exocytosis of presynaptic vesicles (full hidden platform in a pool of water, but the
in rodents drastically affects memories they of neurotransmitters) from the bouton, and location of the platform was changed every
have formed: Previously learned fear condi- postsynaptic SYT1 and SYT7 are required for day. Mice in which Syt3 was deleted persisted
glutamate receptor exocytosis in LTP (7). Aw- with former platform locations rather than
asthi et al. show that SYT3 has key qualifi- seeking new ones, as if unable to distinguish
Langone Medical Center, New York University,
New York, NY, USA. Email:; cations to be the arbiter of LTD through its between a past memory and a new, immedi- regulation of GluA2 receptors: SYT3 is abun- ately relevant experience.

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 31

Published by AAAS

The study of Awasthi et al. highlights the METABOLISM

importance of vesicle cycling on both sides of
the synapse. Clarification of the cell biology
of how postsynaptic weights are weakened
shifts the spotlight to questions about the
Improving crop yield
spatiotemporal allocation and reallocation of Synthetic photorespiration bypass increases crop yield
such weights. We speculate that the internal-
ized glutamate receptor vesicles are a synap-
tic resource too precious to waste and can be By Marion Eisenhut and strongly enhanced biomass production in
redistributed among nearby dendritic spines Andreas P. M. Weber field trials, suggesting that this could be used
to strengthen nearby postsynapses (11), much to improve crop yields.

as vesicles of neurotransmitters can be real- he enzyme ribulose 1,5-bisphosphate Photorespiration is an essential metabolic
located among presynaptic boutons along an carboxylase-oxygenase (RuBisCO) is repair pathway in all organisms that perform
axon (12). This study begins to show how neu- one of the most abundant proteins oxygenic photosynthesis, from cyanobacte-
rons might use similar tools pre- and post- on Earth. During photosynthesis, it ria, through algae, to land plants (2, 4). Core
synaptically to channel resources to the most assimilates atmospheric CO2 into bio- photorespiratory metabolism comprises nine
important synapses while culling synapses mass and hence is a major driver of the enzymatic steps that are distributed over
that no longer encode relevant information. global carbon cycle. However, the enzyme is chloroplast, peroxisome, and mitochondrion
The work of Awasthi et al. has a close yet catalytically imperfect. It accepts not only CO2 within a plant cell. It converts detrimental
unexplored relationship to pathological pro- as a substrate, but also O2, which leads to the 2-PGlycolate into the Calvin-Benson cycle

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cesses in neuropsychiatric and neurodegen- formation of a toxic byproduct, 2-phospho- intermediate 3-PGlycerate and thereby re-
erative disorders. The exaggerated removal of glycolate (2-PGlycolate) (1). The metabolic turns 75% of otherwise unusable carbon to
glutamate receptors, including GluA2 recep- pathway photorespiration detoxifies 2-PGly- photosynthetic metabolism. However, during
tors, is a feature of Alzheimer’s disease (AD) colate, and it is essential for performing pho- this salvage pathway, 25% of previously fixed
(13) and potentially linked to the associated tosynthesis in an O2-containing atmosphere. CO2 gets lost, and energy is consumed (see
forgetting. This process involves protein in- Importantly, photorespiration causes a 20 to the figure). Hence, albeit essential, photo-
teracting with C kinase-1 (PICK1), another 50% yield penalty, depending on the environ- respiration is also considered a wasteful and
mediator of GluA2 receptor endocytosis (14), mental conditions and the type of photosyn- inefficient process (2). Accordingly, photores-
but the role of SYT3 and the relationships thesis employed (2). Multiple attempts have piration has been identified as a prime target
between PICK1, SYT3, and other proteins in- been undertaken to overcome this yield pen- for engineering to improve crop yields, and
volved in GluA2 receptor endocytosis remain alty and thereby increase biomass production diverse strategies have been developed to im-
unclear. This pathophysiological endocytosis in plants, with limited success to date. On prove photosynthetic efficiency by reducing
could contribute to the memory loss experi- page 45 of this issue, South et al. (3) present a photorespiration and/or enhancing the CO2
enced by AD patients, and we speculate that synthetic pathway that fully detoxifies 2-PG- fixation processes. Some of these attempts
pharmacological interventions that restore lycolate inside plant chloroplasts. Transgenic are inspired by naturally occurring CO2-
normal GluA2 receptor endocytosis could tobacco plants expressing this pathway show concentrating mechanisms present in, for
help mitigate these defects. Furthermore, be- example, cyanobacteria and algae. Others are
havioral inflexibility is a hallmark of autism Institute of Plant Biochemistry, Cluster of Excellence on Plant based on implementing synthetic metabolic
Science (CEPLAS), Heinrich Heine University Düsseldorf,
spectrum disorders (ASD) and might be as- Universitätsstrasse 1, 40225 Düsseldorf, Germany. routes to redirect the canonical pathway of
signed to deficits in forgetting, as supported Email: CO2 assimilation and photorespiration (5).
by five fruitfly models of ASD risk genes (2).
In another study, patients with ASD were
asked to choose the location of a stimulus. Engineering wasteful photorespiration into a beneficial process
Although they performed equally well as the The fixation of O2 by RuBisCO in chloroplasts leads to high rates of photorespiration and a concomitant loss of
control patients, the ASD patients showed CO2 from mitochondria. A synthetic bypass and the restricted activity of PLGG1 allow metabolism of glycolate with
extra reversion back to the original location release of CO2 inside of the chloroplasts, which promotes CO2 fixation by RuBisCO and improves yield.
even after the stimulus location changed (15).
Elucidation of mechanisms of this inflexibil-
Synthetic bypass
ity will benefit from the insights that Awasthi
et al. have elegantly provided. j O2 Pyruvate
RuBisCO O2 RuBisCO
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Plant cell Photorespiration high Photorespiration reduced
10.1126/science.aaw1675 CO2 loss Promotes CO2 assimilation

32 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
South et al. revisited two previously estab- were introduced into the model crop tobacco, ATOMIC PHYSICS
lished synthetic bypasses of photorespiration which was investigated not only in growth
(6, 7) and tested a newly designed pathway
in genetically modified tobacco plants. These
pathways aim to completely metabolize the
chambers and greenhouses, but also in field
trials. Thus, the yield gains manifested in an
agriculturally relevant scenario and not only
Really cool
photorespiratory metabolite glycolate, which
is generated from 2-PGlycolate by phospho-
in controlled environments.
Importantly, the synthetic pathways open neutral
glycolate phosphatase within the chloroplast.
They release CO2 close to RuBisCO (not in mi-
tochondria, as in natural photorespiration)
new avenues for reevaluating long-standing
hypotheses regarding the importance of
photorespiration beyond detoxification of
to increase the ratio of CO2 to O2 fixation.
Alternative pathway (AP) 1 originates from
2-PGlycolate. Photorespiration is considered
indispensable for photosynthesis in an O2-
Properties of laser-cooled
the bacterium Escherichia coli and uses five containing atmosphere, and mutants defec- neutral plasmas can be
enzymes that oxidize glycolate via glyoxylate
and tartronic semialdehyde to glycerate (6).
tive in photorespiration can only survive in a
high-CO2 atmosphere (10). Genetic suppres-
used to model high–energy-
The second bypass, AP2, uses three enzymes sor screens on such mutants have been un- density plasmas
that convert glycolate via glyoxylate and ma- successful to date. The study of South et al.
late to acetyl–coenzyme A (CoA). AP2 also demonstrates that a photorespiratory pheno-
requires the expression of catalase for de- type (repression of PLGG1) can be suppressed By Scott Bergeson
toxification of hydrogen peroxide that results by metabolic engineering. The true reason or

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from conversion of glycolate to glyoxylate by reasons for the indispensability of photorespi- lasmas are supposed to be hot. Hy-
glycolate oxidase (7). AP1 and AP2 were previ- ratory metabolism are intensely debated and drogen nuclei undergo fusion in the
ously shown to increase biomass (6, 7). AP3 include the detoxification of 2-PGlycolate; Sun because plasma temperatures
was newly designed by South et al. In AP3, carbon salvage; biosynthesis of the amino and pressures are so high. On page
only two transgenes had to be introduced into acids glycine and serine (11); generation of 61 of this issue, Langin et al. (1) re-
the plant chloroplast: a glycolate dehydroge- activated C1-units; and protection from pho- port on a completely different kind
nase that converts glycolate into glyoxylate toinhibition and dissipation of excess excita- of plasma by photoionizing a laser-cooled
derived from the green alga Chlamydomonas tion energy (2, 12, 13). The work of South et al. gas of strontium atoms. The ion tempera-
reinhardtii was redirected to tobacco chloro- indicates that plant metabolism adapts to the ture is a chilly 0.05 K, so thermal speed of
plasts, and similar to AP2, a malate synthase synthetic pathways and compensates for re- the ions is equivalent to a person taking a
was expressed to convert glyoxylate to malate duced flux through the peroxisomal and mi- brisk walk. Surprisingly, the properties of
and eventually to acetyl-CoA via the native tochondrial parts of native photorespiration. this low-density, low-temperature plasma
chloroplast-resident nicotinamide adenine This implies that 2-PGlycolate detoxification provide clues about the workings of high–
dinucleotide phosphate (NADP)–malic en- and carbon recycling are the critical functions energy-density physics relevant for fusion
zyme (see the figure). Using the green algal of photorespiration. power research.
glycolate dehydrogenase instead of plant Recently, the optimization of a mecha- A very simple description of a plasma is
glycolate oxidase prevents production of nism that protects plants from excess light, that it is an ionized gas. In equilibrium, ion-
hydrogen peroxide, and hence additional ex- nonphotochemical quenching (NPQ), which ization occurs when the temperatures are
pression of catalase is unnecessary. is dissipation of excess excitation energy as high enough and when charged particles
Two important differences from the origi- heat, afforded appreciable yield gains (14). It in the plasma are moving fast enough that
nal pathway designs (6, 7) represent major is important to test whether a combination of collisions tear electrons away from their
advances. Besides introducing a synthetic by- engineered photorespiration with optimiza- parent atoms and ions. The Boltzmann
pass, South et al. also reduced the expression tion of NPQ will enable additive yield gains. equation is the main tool for modeling
of PLASTIDIAL GLYCOLATE/GLYCERATE Realizing the yield gains afforded by the syn- the plasma environment (2). With a hand-
TRANSPORTER 1 (PLGG1) (8). This modifica- thetic bypass in crops will require genetic ful of approximations and extensions, this
tion was suggested previously (9) to increase engineering because the required enzymes and related equations successfully describe
the potential of synthetic bypasses, because it are not present in plant genomes and hence processes used to create integrated circuits,
restricts the export of glycolate from chloro- cannot be targeted by breeding or genome light neon signs, and generate colorful
plasts and hence promotes its consumption editing technologies. j flames. This success is somewhat surprising
by the synthetic bypass. A larger portion of because the collisions occur through Cou-
glycolate is decarboxylated within the chloro- lomb interactions, which are long-range
1. T. J. Erb, J. Zarzycki, Curr. Opin. Biotechnol. 49, 100 (2018).
plast by the synthetically engineered bypass, 2. H. Bauwe et al., Trends Plant Sci. 15, 330 (2010). interactions and lead to many-body effects,
leading to enhanced CO2 fixation activity of 3. P. F. South et al., Science 363, eaat9077 (2019). but the Boltzmann equation is based on
4. M. Eisenhut et al., Proc. Natl. Acad. Sci. U.S.A. 105, 17199
RuBisCO. This comes with an impressive yield (2008). two-body collisions in a low-density envi-
gain of more than 40%. Importantly, yield 5. A. Bar-Even, Plant Sci. 273, 71 (2018). ronment. However, effective collision cross
improvements positively correlated with the 6. R. Kebeish et al., Nat. Biotechnol. 25, 593 (2007). sections that include many-body effects can
7. A. Maier et al., Front. Plant Sci. 3, 12 (2012).
expression levels of the introduced enzymes, 8. T. R. Pick et al., Proc. Natl. Acad. Sci. U.S.A. 110, 3185 (2013). be calculated (with help from Chapman,
which highlights the importance of high and 9. A. P. Weber, A. Bräutigam, Curr. Opin. Biotechnol. 24, 256 Enskog, Bogoliubov, and others), so these
balanced expression of the transgenes. Typi- 10. C. R. Somerville, Plant Physiol. 125, 20 (2001). kinetic theories can often give very accurate
cal annual yield gains in crop breeding are 11. R. M. Benstein et al., Plant Cell 25, 5011 (2013). results (3, 4).
below 2%; hence, the synthetic pathway holds 12. A. Kozaki, G. Takeba, Nature 384, 557 (1996).
13. M. Eisenhut et al., Mol. Plant 10, 47 (2017).
potential for a step change in yield improve- 14. J. Kromdijk et al., Science 354, 857 (2016). Department of Physics and Astronomy,
ment by genetic modification of crops. In Brigham Young University, Provo, UT 84602, USA.
contrast to earlier work (6, 7), the pathways 10.1126/science.aav8979 Email:

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 33

Published by AAAS

The foundation of this treatment rests (5). In fusion-class plasmas, for example, shown how to laser-cool ions in a neu-
on a hierarchy of length scales. The Debye the non-ideal limit is approached in the tral plasma, which overcomes a critical
length lD is the distance over which elec- early stages of the plasma evolution dur- roadblock in the field of strongly coupled
trons rearrange their positions so that there ing compression and early heating of the plasma physics. Although photoionized
is zero electric field inside the plasma. This system, and G ~ 1. The traditional concept laser-cooled gases are initiated with essen-
length must be shorter than the extent of the of a collision becomes problematic because tially zero kinetic energy, the ions instantly
plasma but longer than the average distance lD ≈ aWS ≈ r0. experience strong accelerating forces
between ions in the plasma, the so-called The plasmas created by Langin et al. are from neighboring ions and heat up. This
Wigner-Seitz radius aWS. These constraints similar to high–energy-density plasmas be- “disorder-induced heating” limits G to val-
ensure that there are many particles in a lD- cause they have comparable values of G (6). ues near 2 (11), but laser-cooling the plasma
sized sphere so that Boltzmann’s statistical Thermodynamic properties of plasmas can ions makes it possible to manipulate the
assumptions about collisions will hold. The be expressed in terms of G, so all plasmas value of G. Thus, collision physics in this
Debye length must also be orders of magni- with a given value of G are thermodynami- system can serve as a check on benchmark
tude longer than the classic distance of clos- cally similar. Thus, these ultracold neutral calculations. It also means these low-
est approach r0, which can be thought of as plasmas can help probe the frontier of fu- temperature plasmas can be used as simu-
the minimum distance between two ions in sion science (see the figure). Measurements lators for high–energy-density plasmas.
a head-on collision. of collision properties (momentum trans- In what seems like a paradox, the ultra-
Treatments like the Boltzmann equa- fer, thermal relaxation, diffusion, collision cold neutral plasmas of Langin et al. can
tion are valid when lD >> aWS >> r0. This cross sections, Coulomb logarithms, and help us understand collision parameters in
high–energy-density plasma science. Un-

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der dense fusion plasma conditions, these
What cold plasmas can say about hot ones parameters are nearly impossible to mea-
The properties of neutral plasmas created by Langin et al. inform models of plasmas at higher temperature and sure directly. Even with the best computer
pressure when they have similar values of the strong-coupling parameter G. simulations, it is challenging to compute
the values of these parameters with confi-
Cold-atom plasma Fusion dence. Extensions of kinetic theories into
the strongly coupled regime, which are vali-
dated through modeling of plasmas, will fa-
Laser-driven Laser cilitate computer modeling of more complex
Computational ignition and technologically interesting plasmas.
As laser-cooled plasmas become physically
larger or reach longer confinement times, it
⌫ Hydrogen
may be possible to initiate and study clas-
sic plasma instabilities (12) or to initiate
Laser cooling and and characterize bump-on-tail distribution
High temperature
interrogation relaxations (13). These systems could also
and pressure
Making cold measurements Modeling hot problems
lead to higher-brightness focused-ion beam
Spectroscopic studies of cold neutral plasmas allow These parameters improve models of laser-driven sources (14), which perhaps could be use-
measurement of many parameters that are difcult nuclear fusion because the two plasmas have ful in ion implantation or x-ray source de-
to obtain from high–energy-density plasmas. similar parameterized collision rates. sign. For very large values of G = 172, the
ions will form a Coulomb crystal. Perhaps
regime is that of “ideal” plasmas, and all related quantities) can be made in these in that configuration, it will be possible to
plasmas that obey these conditions are low-temperature, low-density plasmas and engineer massively entangled states useful
similar. An equivalent way to express these then directly applied to computer models of for quantum computation or for high-preci-
foundational assumptions in plasma sci- plasmas with similar values of G. sion metrology. j
ence uses characteristic energies instead These plasmas do not constitute the first
of lengths. The average kinetic energy per laser-cooled ions, which were reported by
1. T. K. Langin, G. M. Gorman, T. C. Killian, Science 363, 61
particle is approximately KE ≈ kBT, where the groups of Dehmelt (7), Wineland (8), (2019).
kB is Boltzmann’s constant and T is the and others in the 1970s. Nor are these the 2. P. L. Bhatnagar, E. P. Gross, M. Krook, Phys. Rev. 94, 511
plasma temperature. For singly charged coldest ions reported; the ion trapping and (1954).
3. S. D. Baalrud, J. Daligault, Phys. Rev. Lett. 110, 235001
ions, the average nearest-neighbor electri- quantum information community achieve (2013).
cal potential energy per particle is U = e2/ mean temperatures approaching the zero- 4. L. G. Stanton, M. S. Murillo, Phys. Rev. E 93, 043203 (2016).
(4p«0aWS), where e is the electron charge point energy of the trap (9). Ultracold neu- 5. R. P. Drake, High-Energy-Density Physics (Springer, ed. 2,
Heidelberg, 2018).
and «0 is the permittivity of free space. The tral plasmas have also been reported, and 6. T. K. Langin et al., Phys. Rev. E 93, 023201 (2016).
ratio of these two energy scales is called Killian and co-workers have contributed 7. W. Neuhauser, M. Hohenstatt, P. Toschek, H. Dehmelt,
the strong-coupling parameter G ; U/KE to the development of this field (10). These Phys. Rev. Lett. 41, 233 (1978).
8. D. J. Wineland, R. E. Drullinger, F. L. Walls, Phys. Rev. Lett.
= r0/aWS, basically the cube root of density are, however, the coldest neutral plasmas 40, 1639 (1978).
divided by temperature. The basic assump- yet reported, and neutrality means that the 9. T. Rosenband et al., Science 319, 1808 (2008).

tion of kinetic plasma theories is that G << strong laboratory fields associated with ion 10. T. C. Killian et al., Phys. Rev. Lett. 83, 4776 (1999).
11. Y. C. Chen et al., Phys. Rev. Lett. 93, 265003 (2004).
1, that is, conditions of low density and high trapping are absent.
12. P. W. Terry, Rev. Mod. Phys. 72, 109 (2000).
temperature. The presence of those fields typically 13. D. V. Dylov, J. W. Fleischer, Phys. Rev. Lett. 100, 103903
When the foregoing hierarchy of length dominates the ion motion for trapped (2008).
or energy scales is not met, the plasma is ions and obscures the underlying inter- 14. D. Murphy et al., Nat. Commun. 5, 4489 (2014).

said to be “non-ideal” or “strongly coupled” esting plasma physics. Langin et al. have 10.1126/science.aau7988

34 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
Commitments have been made to improve
tracking of products from tuna (such as
Atlantic bluefin tuna) from vessel to final buyer.

action and indirect appeals to countries or

intergovernmental bodies to adopt ocean
governance reforms. By November 2018, the
number of contributions registered through
the UN’s registry of voluntary commitments
(8), a web-based site that remains open for
new registrations and updating on progress,
had grown to 1478.
The pledging of voluntary commitments
across government, civil society, and the pri-
vate sector also stands at the heart of the Our
Ocean conferences. Although not directly
P OLICY FORUM linked to the 2030 Agenda, the Our Ocean
Conference series is complementing efforts of
the UN process and has a strong topical rela-
OCEAN GOVERNANCE tionship to SDG 14 (9). In total, 305 commit-

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ments for action were announced at the 2018

From voluntary commitments conference, covering six topical strands: ma-

rine protected areas, climate change, sustain-
able fisheries, marine pollution, sustainable
to ocean sustainability blue economy, and maritime security (10). At
the Our Ocean Conference 2017, hosted by
the European Union in Malta, 437 announce-
A common pledge and review system is needed ments for “tangible and measurable commit-
ments” had been made toward ocean health
By Barbara Neumann and Sebastian Unger A SURGE OF OCEAN COMMITMENTS and sustainability (9, 11), including a large
The UN Ocean Conference had encouraged number from the private sector. Although

oluntary commitments by states, gov- state and nonstate actors to submit com- smaller in the number of commitments than
ernmental or nongovernmental orga- mitments to advance implementation of the UN process, the Our Ocean conferences
nizations, and other actors, aiming to Sustainable Development Goal (SDG) 14 succeed particularly in mobilizing financial
deliver outcome-oriented activities, and associated targets (4). Part of a compre- resources or pledges for creation of new ma-
have become a well-recognized mech- hensive framework of 17 interlinked goals rine protected areas.
anism in international sustainability under the UN’s 2030 Agenda for Sustain-
policy (1–3). For ocean governance, the call- able Development (5), SDG 14 calls on states A TRANSFORMATIVE TOOL?
ing for and pledging of voluntary commit- and the global community to “conserve and Though not replacing state measures to im-
ments could become a game changer, with sustainably use the oceans, seas and marine plement legally binding agreements, we be-
two major international processes harness- resources for sustainable development.” It is lieve that voluntary commitments hold great
ing such voluntary contributions in recent underpinned by 10 specific targets address- additional potential for driving transforma-
years: the Our Ocean conferences, an annual ing marine pollution, conservation, ocean tive change for the ocean. They mobilize ac-
high-level series initiated by U.S. Secretary acidification, fisheries, benefits for Small Is- tions and means for improving ocean health,
of State John Kerry in 2014, and the United land Developing States, small-scale fisheries, support the creation of new partnerships
Nations (UN) Ocean Conference, which took scientific knowledge and marine research, across different sectors and actor groups, and
place for the first time in June 2017. Such and international law. facilitate learning processes and exchange
calls and commitments provide opportuni- More than 1300 voluntary commitments of innovative practice. By lowering barriers
ties to raise awareness, promote engage- for ocean action, such as measures for com- to address complex cross-cutting problems,
ment, and catalyze political will for action bating marine pollution or strengthening the nonbinding nature of voluntary commit-
on the part of states as well as public and capacity for marine research, were made at ments also helps to overcome established but
private sectors. However, without effective the UN Ocean Conference by governments, problematic sectorial approaches in ocean
and transparent review systems, it is diffi- the UN system, civil society organizations, governance. Voluntary commitments also

cult to link pledged commitments to actual academia, the scientific community, and the create normative pressure (1, 12) and increase
implementation. Quality control and ensur- private sector (6). Despite the open call for expectations to play an active role in improv-
ing that commitments are effective and im- contributions, the majority of commitments ing ocean health.
pactful will be difficult to achieve. A uniform registered were still made by governmental However, central oversight is needed to
global process is required to register and as- actors and civil-society organizations (7). ensure that promises are kept. Without a
sess commitments, including consistent re- But they also include innovative initiatives transparent and rigorous pledge and review
porting and monitoring systems with clear from the private sector and philanthropic system for all ocean-related commitments,
targets, baselines, and review systems. organizations such as the Tuna 2020 Trace- there is a risk of double-announcing in vari-
ability Declaration or the Seafood Business ous forums or creating a flurry of low-impact
Institute for Advanced Sustainability Studies (IASS), 14467 for Ocean Stewardship (SeaBOS) platform, or short-term activities that do not deliver
Potsdam, Germany. Email: which seek change both through collective progress on targets. Other critical challenges

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 35

Published by AAAS

associated with voluntary commitment pro- other ocean-related SDGs and targets. ments should be reported to and assessed
cesses are accountability, enforcement, effec- To identify trends and to measure distance by the UN’s High-level Political Forum on
tiveness, and progress accounting (2, 13). and progress to targets, this global registry Sustainable Development and reflected in
The pledging processes under the UN should be linked to baseline data in exist- the Global Sustainable Development Report.
Ocean Conference and the Our Ocean series ing databases and assessment processes on The registry should also seek synergies with
seek to address these challenges to a certain the state of the marine environment. For reporting systems for other goal-based policy
extent through their individual registrations example, the World Database on Protected frameworks such as the UN Paris Agreement
procedures that request the formulation of Areas, which is run by the UN Environment on climate change.
commitments along defined criteria. Our World Conservation Monitoring Centre Both the UN Ocean Conference process
Ocean 2018, for the first time, published a (UNEP-WCMC) and the International Union and the Our Ocean series will continue to col-
report seeking to describe progress on com- for Conservation of Nature (IUCN), the UN’s lect voluntary commitments toward the next
mitments made under previous Our Ocean World Ocean Assessment, or the UN Food UN Ocean Conference planned for 2020 and
conferences (14), and the UN’s registry of and Agriculture Organization’s world fishery the upcoming Our Ocean conferences in Nor-
voluntary commitments invites pledging en- and aquaculture statistics could provide the way (2019) and Palau (2020). And there have
tities to provide updates on progress through necessary information. been first discussions of possible coordina-
their website (8). But the two registry systems In addition, independent scientific data tion of the two commitment systems, a prom-
are neither harmonized in terms of the data and assessments such as the Ocean Health ising prospect for developing an orchestrated
gathered nor in the standards for acceptance Index (15) or the MPAtlas of the Marine Con- post-2020 strategy for ocean sustainability
and registration of commitments. This lack servation Institute could be taken into ac- with a uniform global pledge and review sys-
of robust and consistent tracking and report- count. The UN Decade of Ocean Science for tem for voluntary ocean commitments. j

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ing processes, and missing links to existing Sustainable Development (2021 to 2030), an RE FERENCES AND NOTES
environmental baseline data, impede assess- upcoming global effort to boost international 1. B. Guy, Econ. Soc. Rev. (Irel.) 45, 223 (2014).
ments of transformative effects and overall cooperation in ocean sciences, could help to 2. P. Pattberg, O. Widerberg, Ambio 45, 42 (2016).
3. M. Beisheim, A. Ellersiek,“Partnerships for the 2030 Agenda
progress toward goals. further strengthen the knowledge base of the for Sustainable Development: Transformative, inclusive and
A centralized registry, however, is needed review process. accountable?” (SWP Research Paper, Berlin, 2017).
to learn whether voluntary commitments Under the proposed strategy and a central 4. United Nations,“Voluntary Commitments for the implemen-
tation of Goal 14” (2017); https://sustainabledevelopment.
produce desired outcomes on the ground, registry, pledging of voluntary commitments
to identify trends, and to facilitate adjust- could take place throughout the year and be Conference%20-%20Guidance%20on%20Voluntary%20
ments of policies. If kept separately, a com- highlighted on an annual basis at the Our 5. United Nations,“Transforming our world: The 2030
petition between pledging systems with Ocean conferences or other high-level meet- Agenda for Sustainable Development. UNGA Resolution A/
diverging objectives, different standards, ings of states and relevant actors such as the RES/70/1” (Resolution adopted by the General Assembly on
25 September 2015 70/1, New York, 2015).
and a general lack of monitoring and ac- UN Environment Assembly. Comparability of 6. IISD,“Summary of The Ocean Conference: 5-9 June 2017”
countability may obscure their potential for commitments and assessment of impact and (Earth Negotiations Bulletin, vol. 32, 2017); http://enb.iisd.
improving ocean health and governance. progress would be facilitated through com- 7. Division for Sustainable Development, M. Vierros, R.
mon reporting formats. The registry would Buonomo,“In-depth analysis of Ocean Conference
BUILDING BLOCKS FOR POST-2020 be evaluated and commitments assessed Voluntary Commitments to support and monitor their
implementation. 14 Life Below Water” [Department of
As 5 of 10 SDG 14 targets mature in 2020 every 3 years at the UN Ocean Conference, Economic and Social Affairs (DESA)], United Nations, New
and—possibly with the exception of the tar- providing an accountability moment for the York, 2017);
get to conserve at least 10% of coastal and global community. This would also aid the 8. United Nations,“The Ocean Conference Registry of
marine areas (7)— will most likely not be steering of calls for action into directions Voluntary Commitments” (2018); https://oceanconference.
achieved by then, the coming years will be where topical or geographical gaps have been
9. European Commission,“Our Ocean Conference 2017. Final
critical for achieving the ocean goal. A cred- identified, and the aligning of actions on report” (2017);
ible post-2020 strategy is therefore needed international, regional, and national scales. ooc-2017-report.pdf.
10. Ministry of Marine Affairs and Fisheries, Republic of
to support the implementation of SDG 14, Bringing together these different types of Indonesia,“Our Ocean Commitments” (2018); https://
ideally harmonized with the post-2020 bio- data and information, such a common pledge
diversity framework currently developed and review system could determine whether 11. European Commission,“Our Ocean 2017 commitments”
under the Convention on Biological Diversity the global community is on track to achieve ooc-2017-list-of-commitments_en.pdf.
(CBD). One of the key building blocks for the goals set for the ocean and help to orches- 12. M. Stafford-Smith et al., Sustain. Sci. 12, 911 (2017).
13. J. Foti,“Promises kept: Ensuring ambition and account-
such a strategy could be a unified and com- trate further action. ability through a Rio+ 20 ‘compendium of commitments’”
prehensive global registry for voluntary com- The registry should be hosted by an in- (Working paper, WRI, 2012).
mitments. The existing pledging schemes ternational body and be maintained and 14. Ministry of Marine Affairs and Fisheries, Republic
of Indonesia,“Progress of Our Ocean Conference
and registries of voluntary commitments updated regularly in close cooperation with Commitment” (2018);
under the UN Ocean and the Our Ocean competent global and regional organizations, files/progress_commitment.pdf.
15. B. S. Halpern et al., PLOS ONE 12, e0178267 (2017).
conferences would lend themselves as strong ensuring transparent access to data and
starting points to developing such a global information. This could be supplemented ACKNOWL EDGMENTS
registry and reporting mechanism. by independent reviews from scientific in- We thank participants of the 2017 Potsdam Ocean Governance
The role of this new system would be to stitutions and nongovernmental organiza- Workshop for their contributions on the topic, and are grateful to
the following experts for their input and reflections: M. Caldwell,
take stock of voluntary commitments; report tions. The registry would provide grounds J. Hammersland, D. Herr, M. Knigge, M. Kobayashi, A. Mondré, H.
on progress on implementation; provide for developing and applying indicators and Schopmans, and T. Thiele. We thank L. von Pogrell, J. Pütz, and S.
transparency and independent verification; analytical frameworks for monitoring and Heinecke for support in researching data. This work is supported
by the German Federal Ministry of Education and Research
provide joint quality criteria for voluntary evaluating performance and impacts, and as- (BMBF) through its Research for Sustainable Development
commitments; identify trends and highlight sist in sharing of good practices. program (FONA), and the Federal State of Brandenburg.
thematic and geographical gaps; and ana- Regular assessments of the pledge and
lyze distance and progress to SDG 14 and review process for voluntary ocean commit- 10.1126/science.aav5727

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NATO’s efforts stopped short of confronting the
environmental degradation caused by warfare.

another round of environmental research,

with obvious strategic applications.
After the rise of Ronald Reagan and Mar-
garet Thatcher led NATO to again de-empha-
size environmental research, the collapse of
the Soviet Union led the CCMS to support
efforts to rehabilitate defunct Cold War mili-
tary bases. Environmental research at NATO
lives on but faces challenges amid the alli-
ance’s increasing focus on the “cybersphere.”
In the end, Turchetti convincingly argues
not only that militaries fostered the emer-
gence of modern environmental sciences but
also that they long set the agenda for ma-
B O OKS et al . jor research programs in its disciplines. His
analysis of the American role within NATO
is especially compelling. Far from a Cold War

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hegemon, the United States in Greening the
HISTORY OF SCIENCE Alliance could only achieve its objectives
with the cooperation of often-reluctant allies.

A military alliance goes green Skeptics will note, however, that American
officials repeatedly determined when, and
how, NATO would pursue environmental re-
Seeking solutions to Cold War divisions, in the mid-20th search and policy.
The protagonists of Greening the Alliance
century NATO embraced environmentalism are scientists in the upper echelons of Cold
War military and diplomatic institutions.
By Dagomar Degroot search with obvious strategic applications, This focus makes for a richly detailed story of
it actually exacerbated divisions among political maneuvering and high-minded ide-

ar and preparation for war have the allies. als, yet it also deprives Turchetti’s narrative
long led militaries to exploit, In 1966, Turchetti argues, growing dissat- of context that might have given it greater
transform, and degrade environ- isfaction with NATO’s science program came significance. Politicians and military officers
ments. How ironic, then, that at to a head. The rise of environmentalism, the are rarely mentioned by name, and ordinary
the height of the Cold War, the sinking of the tanker SS Torrey Canyon, and people who may have shaped the course of
North Atlantic Treaty Organiza- the political opportunism of Richard Nixon scientific research, such as North Sea fisher-
tion (NATO)—the most powerful military all led to an American push for a new kind of men resistant to early oceanographic surveys,
alliance ever assembled—emerged as a lead- environmental research at NATO. Enter the rarely receive much attention.
ing proponent of environmental- “Committee on the Challenges of Key scientific controversies discussed in
ism. Simone Turchetti’s Greening Modern Society” (CCMS), estab- Greening the Alliance—the possibility of nu-
the Alliance is the first book to lished in 1969 to fund research clear winter, for example—frequently appear
explain the surprising rise, re- into toxicology, devastated ecosys- with little explanation, and Turchetti opts not
peated revision, and possible tems, and environmental moni- to compare NATO’s environmental programs
decline of NATO’s environmental toring. Research pioneered by with similar and simultaneous efforts in
research program. the committee steadily advanced other western institutions. (Neil Maher has
Turchetti organizes his book a brand of environmentalism recently revealed that NASA similarly strug-
chronologically. After insightful that prized scientific rationalism gled to implement an “environmental turn”
passages on sources and meth- Greening the Alliance rather than the radical counter- in the 1970s, for example.) Moreover, because
Simone Turchetti
ods, he traces the diplomatic University of Chicago culture of the grassroots environ- Turchetti rarely explains the scope and sig-
tensions and maneuverings that, Press, 2018. 263 pp. mentalist movement. nificance of NATO’s environmental science
in 1958, led representatives of Yet, Turchetti explains that Eu- program within the broader development
the United States and Britain to cooperate ropean allies repeatedly stalled CCMS initia- of 20th-century science, it is difficult for the
in securing support for a new NATO Sci- tives, which in any case never confronted reader to know just how important the activi-
ence Committee. Supporting environmen- the environmental impact of military activi- ties of the CCMS really were.
tal research, they hoped, would promote ties. When the CCMS exposed new divisions Written in workmanlike prose, Green-
parallel diplomacy to repair deepening di- within NATO, American support withered, ing the Alliance is therefore a book that will

visions among the alliance’s 12 signatories. and the alliance’s commitment to environ- primarily appeal to a relatively small group
Yet because the committee sponsored re- mentalism seemed to fade. By that time, of historians and political scientists. Yet for
however, emerging weapons systems in the those specialists, it succeeds in telling a new
United States and the Soviet Union increas- and critically important story. j
The reviewer is at the Department of History,
Georgetown University, Washington, DC 20057, USA. ingly demanded constant environmental
Email: surveillance. This new reality encouraged 10.1126/science.aav1863

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 37

Published by AAAS


Robots, telework, and the jobs of the future

Globalization and AI are primed to disrupt tomorrow’s workplace, argues an economist

By Jon Peha will now have to compete with accountants The Globotics Upheaval
around the world. An accountant whose Globalization, Robotics,
and the Future of Work

n the conference room of a popular San primary advantage is the ability to detect
Francisco–based magazine, journal- complex patterns in financial data will have Richard Baldwin
Oxford University Press,
ists and editors walk through the door, to compete with machine-learning software 2019. 300 pp.
gathering for a staff meeting. One col- that never sleeps or asks for a raise.
league, however, rolls in on two large For people hoping to choose a profession
motorized wheels. that won’t soon be replaced, Baldwin recom-
“EmBot” is a human-sized robot that mends those that require physical proximity fast for society to absorb. Baldwin portrays
shows live video of Emily Dreyfus, a staff and that take advantage of distinctly human the progress of telepresence and AI as sud-
writer who lives 3000 miles away. But qualities, such as creativity, social awareness, denly becoming rapid, but these technolo-
EmBot is more than a face on a screen. It ethics, and empathy. AI robots cannot (yet) gies have been progressing for decades.

Downloaded from on January 3, 2019

can turn toward whomever is speaking or write articles for Science, for example, and Thanks to the vast expansion of un-
chase a colleague of Dreyfus’s down the they are terrible preschool teachers. dersea fiberoptic cables in the 1990s,
hall. EmBot is an example of the telep- Disruptive change can lead to backlash. widespread adoption of the Internet, and
resence technology that Richard continuous improvement in col-
Baldwin, author of The Globotics laboration software, we already live
Upheaval, believes will cost many with many effects of telepresence.
workers in wealthy nations their Multinational companies routinely
jobs, allowing them to be replaced hire the most competitive workers
with “telemigrants” from abroad. anywhere in the world and use this
But even telemigrants face stiff technology to move jobs to work-
competition in the emerging econ- ers rather than moving workers to
omy. EmBot has software-based jobs. Similarly, AI algorithms have
cousins that use artificial intelli- already replaced humans in many
gence (AI) to perform tasks we once endeavors, including monitor-
thought required highly skilled hu- ing everything from surveillance
mans, from searching for the legal video to credit card purchases, just
precedents of a patent dispute to as websites have all but replaced
spotting cancer in a magnetic reso- travel agents.
nance image. So far, there has been workplace
Baldwin’s thesis is that globaliza- change but little true upheaval. Both
tion and AI robots constitute a “glo- telepresence and AI technology are
botics” tidal wave that will shake the still making impressive progress,
foundation of middle-class prosper- but The Globotics Upheaval pro-
ity in wealthy nations. This, he ar- vides no way to judge whether the
gues, will lead to social upheaval, just pace of advancement will eventually
as 19th-century steam engines and exceed what society can absorb.
mechanical looms created workplace A remote reporter for the Toronto Star greets a co-worker. Nonetheless, Baldwin presents
disruptions that brought workers to a compelling view of the future
the streets in sometimes violent protest. Baldwin argues that 2016 vote outcomes of work and the serious challenges ahead
Although globotics will improve produc- favoring Brexit in the United Kingdom while there is still time to prepare. He
tivity and create new jobs, by some estimates and Donald Trump in the United States wisely argues that we must protect work-
cited in the book, it could also replace more were backlashes to globotics. Although ers, without necessarily protecting specific

than half of current jobs in a developed econ- this was not a period of high unemploy- jobs as they become outdated, and that we
omy. The effects will be uneven. ment—Trump was elected after 7 years of must do more to help those who’ve been
Some skilled workers will prosper as they solid economic growth that drove the U.S. displaced by technology reenter the work-
gain the ability to compete for jobs across unemployment rate from 10 to 4.6%—it is force and offer such individuals a strong
the globe; others will become obsolete. An possible that globotics could have contrib- safety net along the way.
accountant whose primary competitive ad- uted to low growth in wages. I would add education reform to the
vantage is that she lives within easy driving Although the book offers valuable in- prescription: Moving forward, schools and
distance of a commercial hub, for example, sights into the long-term impact that glo- universities should teach students to work
balization and AI will have on workers, with emerging technology rather than
The reviewer is at the Department of Engineering and Public the case that globotics will bring upheaval compete against it. j
Policy and the Department of Electrical and Computer
Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, is less convincing. Upheaval occurs when
USA. Email: technology advances at a pace that is too 10.1126/science.aav6273

38 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
Fluorinated aryl groups couple
to form nanographenes
Kolmer et al., p. 57

IN S CIENCE JOURNAL S Edited by Stella Hurtley

VIROLOGY mutually exclusive binding of

Sec63 and the ribosome to the
Mobile detection channel. —SMH
of Lassa virus Science, this issue p. 84
Lassa fever is a hemorrhagic viral
disease endemic to West Africa.
Usually, each year sees only a
smattering of cases reported, but C60 at high resolution
hospitalized patients risk a 15% It generally takes more energy
chance of death. Responding to for molecules to vibrate than to
fears that a 10-fold surge in cases rotate. A vibrational absorption
in Nigeria in 2018 signaled an band thus encompasses many
incipient outbreak, Kafetzopoulou distinct concurrent rotational
et al. performed metagenomic transitions, but these tend to blur
nanopore sequencing directly together when the molecules
from samples from 120 patients have more than a few atoms.
(see the Perspective by Bhadelia). Changala et al. succeeded in cool-
Results showed no strong ing C60 fullerenes sufficiently to
evidence of a new strain emerg- obtain rotational resolution within
ing nor of person-to-person a C–C stretching band. Success
transmission; rather, rodent hinged on careful optimization
contamination was the main of argon buffer gas flow. Such
source. To prevent future escala- quantum state–resolved features
tion of this disease, we need to could aid characterization of
understand what triggers the fullerene-type compounds in
irruption of rodents into human exotic environments such as
dwellings. —CA interstellar space. —JSY
Science, this issue p. 74; Science, this issue p. 49
see also p. 30

Making a strongly

Runners moving down Columbus Drive at the Chicago Marathon, October 2017 coupled plasma
translocon architecture Plasmas—gases of ionized
About a third of proteins are atoms and electrons—are
transported into endoplasmic naturally formed at high temper-
A crowd that flows like water reticulum by the universally
conserved Sec61 protein-
atures, such as those reached in
the interiors of stars. Describing

he behavior of large numbers of insects, animals, and
conducting channel. Itskanov plasmas theoretically is tricky
other flocks is often based on rules about individual inter-
and Park determined a cryo– when they are in the strongly
actions. Bain and Bartolo applied a fluid-like model to the
electron microscopy structure coupled regime; reaching that
behavior of marathon runners as they walked up to the
of the Sec complex from yeast, regime in the laboratory would
start line of the Chicago Marathon (see the Perspective by
which mediates posttranslational provide a valuable benchmark
Ouellette). They observed nondamping linear waves with the
translocation of many secretory for theory. To that end, Langin
same speed for different starting corrals of runners and at dif-
proteins across the endoplasmic et al. worked with a cold plasma
ferent races around the world. Their model should apply both
reticulum membrane. The study created out of atoms of stron-
to this type of polarized crowd as well as to other groups, which
reveals how Sec63 activates tium that were ionized by laser
may help guide crowd management. —BG
the Sec61 channel for substrate light (see the Perspective by
Science, this issue p. 46; see also p. 27 polypeptide insertion. The Bergeson). They used lasers to
structure also explains the cool the ions down to about 50

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 39

Published by AAAS

millikelvin, reaching the desired number, and proportion of the

strongly coupled regime. —JS population murdered, even when Edited by Caroline Ash
Science, this issue p. 61; compared to other 20th-century IN OTHER JOURNALS and Jesse Smith
see also p. 33 genocides. —PJB
Sci. Adv. 10.1126/
sciadv.aau7292 (2018).
A proto-mammalian giant
Early terrestrial amniotes evolved PROKARYOTIC IMMUNITY
into two groups: the sauropsids,
which led to the bird and dinosaur
Additional, diverse
lineages, and the synapsids, CRISPR systems
which led to mammals. Synapsids CRISPR systems have been
were diverse during the Permian revolutionizing molecular biol-
but were greatly reduced after the ogy. Mining the metagenomic
end-Permian extinction (about database, Yan et al. system-
252 million years ago). The few atically discovered additional
groups that survived into the subtypes of type V CRISPR-Cas
Triassic were mostly small and systems. The additional Cas12
retained a sprawling gait. Sulej effectors displayed a range of
and Niedźwiedzki, however, activities, including target and
describe a dicynodont from collateral cleavage of single-
the Late Triassic of Poland that stranded RNA and DNA, as well as
is as large as some coexisting double-stranded DNA nicking and
dinosaurs and appears to have cleavage. These diverse nuclease
had an erect gait—like modern activities suggest how an ancient A Raggiana bird-of-paradise
mammals. Thus, megaherbivores transposase may have evolved from the Southern Highlands,
in the Triassic were not only dino- into various type V effectors and Papua New Guinea
saurs. —SNV expand the nucleic acid detec-
Science, this issue p. 78 tion and genome-editing toolbox.
—SYM HUMAN GENETICS Sinclair et al. studied plants that
are unable to deliver Zn into their
Science, this issue p. 88
Alzheimer’s disease own xylem. The plant shoots were
Deadliest 100 days in admixed people thus internally starved regardless
DRUG DEVELOPMENT Several genes have been identi- of whether Zn was available from
of the Holocaust A long-lasting fied that increase the risk of the root. The Zn-starved shoots

More than 25% of the approxi- late-onset genetic disorders, signaled to roots to increase Zn
mately 6 million Jews murdered poison scavenger such as Alzheimer’s disease supplies. In response, the roots
during the Holocaust were killed Nerve agents are neurotoxic (AD). Specifically, the ApoE «4 up-regulated expression of the
in one 100-day period in 1942. compounds found in pesticides allele is associated with a higher genes encoding metal transport/
Stone used an unusual dataset and chemical weapons. They risk of developing AD. However, tolerance protein 2 (MTP2) and
of railway transportation records act by blocking the transmis- individuals of African ancestry heavy metal ATPase 2 (HMA2).
to show that during this period, sion of nerve impulses to the that carry this variant appear Local Zn deficiency in roots left
the Nazis murdered more than muscles, and exposure can be to be less prone to developing these same genes unaffected. It
1.47 million Jews, a kill rate that fatal within minutes. Zhang et al. AD. Rajabli et al. examined AD seems that Zn taken up in lateral
is 10 times higher than previous developed a nanoparticle-based cases and controls in admixed roots is transported into the
estimates. Contradicting contem- bioscavenger that breaks down individuals of Puerto Rican endoplasmic reticulum by MTP2,
porary analyses of the Holocaust, organophosphate nerve agents and African-American descent thus gaining access to the inter-
the author shows that Operation into innocuous compounds. and found that individuals who cellular symplastic network. The
Reinhard was exceptionally Prophylactic treatment of rats carried an African ApoE «4 Zn then progresses from outer
violent in its extreme kill rate, and guinea pigs confirmed background had less risk of epidermal cells toward the core
low immunogenicity developing the disease. It seems of the root, where it is exported
and good biodistribu- the African variant of ApoE «4 by HMA2 into the xylem for trans-
tion. Treated animals contains protective genetic port to the shoot. The shoot asks
were protected from variants. —LMZ for what it needs, and the root
repeated exposure PLOS Genet. 14, e1007791 (2018). delivers. —PJH
to the nerve agent Plant Cell 30, 2463 (2018).
sarin over 7 days. This
nanoscavenger might
thus help prevent nerve- Essential metal for plants
agent poisoning in Although zinc (Zn) is an essen- Roots of acne
Transport records have been analyzed to at-risk subjects. —MM tial micronutrient for plants and Most people experience a bout
estimate the number of Jews murdered by the Sci. Transl. Med. 11, humans, much of the world’s of acne at some stage in their
Nazis in 1942. eaau7091 (2019). agricultural land is deficient in Zn. life. For an unlucky few, the skin

40 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
more than 48 days. The pres-
EVOLUTION ence of the smaller nanoparticles
in muscle tissue suggests that
Sing on high, dance the particles can cross epithelial
membranes. —JFU
on the floor Environ. Sci. Technol. 52, 14480 (2018).

he frugivorous, polygamous, and
wildly glamorous birds of para-
dise are a puzzle to evolutionary
biologists. What is sexual selection Ending a relationship
acting on to result in such extremely When deciding to end a relation-
visual, behavioral, and aural diversity ship, people may consider the
among these related species? Ligon et feelings of their partners as well as
al. analyzed 961 video clips, 176 audio their own. Joel et al. investigated
clips, and 393 museum specimens. They whether decisions to break up
concluded that females are selecting on are driven in part by perceptions
the combined sensory assault from song, of a partner’s dependence on the
display, and plumage color, resulting in relationship. They found that par-
a “courtship phenotype.” Although all ticipants were less likely to initiate
elements are required for successful a breakup with their partners when
courtship, there is room for variation they felt that their partners were
depending on environmental constraints. more dependent on the relation-
Song predominates in the canopy, where ship for psychological well-being,
it is unimpeded by twigs and branches, even when participants were
unsatisfied in the relationship. Even
whereas flashy behavioral display is most
participants who were actively
effective on the gloomy forest floor. —CA
considering breaking up with their
PLOS Biol. 16, e2006962 (2018).
partners were less likely to do so if
they felt their partners depended
on the relationship. These results
condition feels relentless and at predicted environmental whereas smaller nanoparticles suggest that people exhibit costly,
can evade treatment. Petridis concentrations. The authors use are dispersed through the entire prosocial preferences in relation-
et al. performed a DNA study of radiocarbon labeling to track the scallop body. After exposure to ships even when they may wish to
individuals with acne vulgaris nanoplastics within the scallop nanoplastics ceased, smaller leave them. —TSR
and found that those affected tissues. Uptake differs depending nanoparticles were no longer J. Pers. Soc. Psychol. 115, 805 (2018).
share similar, but surprising, on particle size: Larger nanopar- detected after 14 days, but some
genetic mutations. Homing in ticles accumulate in the intestine, larger nanoparticles persisted for
on 15 regions of the genome, OPPORTUNITY DENIED
they identified a series of culprit
genes that controlled hair
The inequality
growth and follicle formation. of innovation
This discovery lends weight to A lack of social capital can
the idea that hair follicle shape undermine a child’s likelihood of
creates a milieu susceptible becoming an inventor, regard-
to bacterial colonization and less of her inventive ability.
inflammation. —PNK Using U.S. patent records for
Nat. Commun. 9, 5075 (2018). 1.2 million inventors, combined
with tax records and other data,
Bell et al. show how children
PLASTIC POLLUTION from high-income families are
several times more likely to
Scallops seasoned become inventors than those

with nanoplastics from lower-income families, even

Microplastics are present in when they have comparable
marine environments worldwide. math abilities. Children who grow
As these particles break down up in areas where innovation and
further, they form nanoplastics, patenting are more common are
which are harder to detect. more likely to patent as well, and
Nanoplastics also can enter the particularly in the same class
environment directly from com- of technologies that had a high
mercial products such as paints innovation rate in their childhood
and cosmetics. Al-Sid-Cheikh communities. —BW
et al. investigate the uptake of The great scallop (Pecten maximus) reveals details about the uptake of Quart. J. Econ. 10.1093/
such nanoplastics by scallops nanoplastics by marine organisms. qje/qjy028 (2018).

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 41

Published by AAAS

ALSO IN SCIENCE JOURNALS Edited by Stella Hurtley

OPTICS IMMUNOLOGY NANOMATERIALS cortex and have a modulatory

role on cortical responses to
Exceptional points in Commensal-specific Nanographenes on oxides visual stimuli. Beltramo and
The growth of nanographene
optics T cells are flexible islands and ribbons on metal
Scanziani found a visual cortical
Many complex systems operate Barrier tissues, like the skin, are area that is entirely dedicated
surfaces can be accomplished
with loss. Mathematically, these sites where noninvasive com- to the superior colliculus. This
on single-crystal metal surfaces
systems can be described as mensal microbes constantly area can discriminate moving
through carbon-carbon coupling
non-Hermitian. A property of interact with resident T cells. visual stimuli that the “classical”
reactions, but the surfaces of
such a system is that there can These encounters can result primary visual cortex cannot.
oxides do not assist these reac-
exist certain conditions—excep- in commensal-specific T cell Thus, the superior colliculus, a
tions. Kolmer et al. show that
tional points—where gain and responses that promote, for phylogenetically ancient struc-
fluorinated aryl groups can be
loss can be perfectly balanced example, host defense and tis- ture, has its own projection in
coupled to form nanographenes
and exotic behavior is predicted sue repair. Harrison et al. show neocortex that provides this area
on the rutile surface of titanium
to occur. Optical systems gener- that subsets of skin-resident with exquisite feature-detection
oxide. The fluorine substitution
ally possess gain and loss and so commensal-specific interleukin- abilities not found in the classical
of the aryl groups was selected
are ideal systems for explor- 17A–producing CD4+ and CD8+ primary visual cortex. —PRS
so that as the carbon-fluorine
ing exceptional point physics. T cells have a dual nature: Science, this issue p. 64
bonds were thermally activated,
Miri and Alù review the topic of They coexpress transcription
a stepwise process sequentially
exceptional points in photonics factors that direct antagonistic
added aromatic rings around CLIMATE CHANGE
and explore some of the possible antimicrobial (type 17) and
a central aryl group until it was
exotic behavior that might be antiparasite and pro–tissue
completely substituted. —PDS
Deep Pacific cooling
expected from engineering such repair (type 2) programs. When Earth’s climate cooled consider-
Science, this issue p. 57
systems. —ISO skin is damaged, epithelial cell ably across the transition from
Science, this issue p. 42 alarmins license type 17 T cells the Medieval Warm Period to
to turn on type 2 cytokines. MESOSCOPIC PHYSICS the Little Ice Age about 700
Thus, commensal-specific type years ago. Theoretically, owing
NEUROSCIENCE 17 T cells can direct antimicro-
A backward current to how the ocean circulates, this
Two-dimensional materials in a
bial activity under homeostatic cooling should be recorded in
Forgetting and receptor conditions but rapidly turn on
magnetic field can exhibit the so-
Pacific deep-ocean tempera-
called quantum Hall effect. This
removal tissue repair in the context of
regime is characterized by cur-
tures, where water that was on
The trafficking of AMPA recep- injury. —STS the surface then is found today.
rents running along the edge of
tors to and from the surface Science, this issue p. 43 Gebbie and Huybers used an
the sample in the “downstream”
of postsynaptic membranes ocean circulation model and
direction determined by the sign
regulates synaptic strength observations from both the end
of the magnetic field. Lafont et
and underlies learning and PLANT SCIENCE of the 19th century and the end
al. studied electrical transport in
memory. Awasthi et al. found of the 20th century to detect
that the integral membrane
Fixing photosynthetic GaAs-AlGaAs heterostructures,
and quantify this trend. The
focusing on a previously less-
protein synaptotagmin-3 (Syt3) inefficiencies studied spin-unpolarized state
ongoing deep Pacific is cooling,
is predominantly found on In some of our most useful which revises Earth’s overall heat
in the fractional quantum Hall
postsynaptic endocytic zones crops (such as rice and wheat), budget since 1750 downward by
regime. By considering various
of neurons, where it promotes photosynthesis produces toxic 35%. —HJS
experimental configurations,
AMPA receptor internaliza- by-products that reduce its Science, this issue p. 70
they observed a component of
tion (see the Perspective by efficiency. Photorespiration
the charge current flowing in the
Mandelberg and Tsien). In Syt3 deals with these by-products,
opposite, “upstream” direction.
overexpressing or knockdown converting them into metaboli- EVOLUTION
neurons, synaptic transmis- cally useful components, but at
sion and short-term plasticity the cost of energy lost. South et
Science, this issue p. 54 DNA breakage and
were unchanged. However, in al. constructed a metabolic path- adaptation
neurons from Syt3 knock- way in transgenic tobacco plants NEUROSCIENCE Adaptation to new environments
out mice, synaptic long-term that more efficiently recaptures often occurs in similar ways
depression was abolished and the unproductive by-products
Another primary visual across different colonization
decaying long-term potentiation of photosynthesis with less cortex events. Stickleback fish repre-
endured. In Syt3 knockout mice, energy lost (see the Perspective Most functional studies in the sent a classic example of this, in
spatial learning was unaltered; by Eisenhut and Weber). In field visual system have focused on which repeated colonizations of
however, these animals showed trials, these transgenic tobacco the cortical representation of freshwater have resulted in the
signs of impaired forgetting and plants were ~40% more produc- the geniculo-striate pathway loss of pelvic hind fins. Previous
relearning during the water maze tive than wild-type tobacco that links the retina to the work has shown that a pelvic
spatial memory task. —PRS plants. —PJH cortex. The parallel collicular enhancer gene is involved. Xie et
Science, this issue p. 44; Science, this issue p. 45; pathway is believed to sparsely al. now show that this gene lies
see also p. 31 see also p. 32 project throughout the visual within a region of the genome

41-B 4 JANUARY 2019 • VOL 363 ISSUE 6422 SCIENCE

Published by AAAS
that is prone to double-stranded a common monogenic etiol-
DNA breakage owing to a high ogy for the “white plague.” The
thymine-guanine content. This current frequency of the P1104A
enhanced region of breakage allele in European popula-
could lead to enhanced mutation tions is significantly decreased
rates that facilitate repeated compared with its frequency in
adaptations to new environ- ancient European DNA samples.
ments. —SNV These findings suggest that
Science, this issue p. 81 negative selection against the
TYK2 P1104A allele by endemic
tuberculosis in Europe may have
CONSERVATION contributed to a slow genetic
purge of this susceptibility allele
The distinctive sound of a during recent millennia. —IW
biodiverse forest Sci. Immunol. 3, eaau8714 (2018).
Assessing the state of
biodiversity in a forest is a time-
consuming task that typically CANCER
requires detailed on-the-ground
surveys. In a Perspective,
Altering membrane
Burivalova et al. explain that potential for cancer
recordings of soundscapes Polymorphisms in the G pro-
can provide an easier route to tein–coupled receptor GPR35
this information. By record- are associated with increased
ing soundscapes from a forest risk for certain inflammatory
over time and comparing them diseases that can progress to
to a regional baseline, scien- cancer. Schneditz et al. found
tists can determine whether a that GPR35 promoted the activ-
forest’s ecosystem is healthy ity of Na+- and K+-dependent
or not. If the soundscape of adenosine triphosphatase
a forest spared from conver- (Na+,K+-dependent ATPase),
sion becomes impoverished a transmembrane pump that
and altered, an on-the-ground sets the membrane potential in
survey would be warranted. This cells. This effect was enhanced
approach may be particularly by a disease-associated GPR35
useful for companies interested variant. Stimulation of Na+,K+-
in sustainability certification ATPase activity by GPR35
or zero-deforestation commit- increased glycolysis and pro-
ments. —JFU liferation in intestinal epithelial
Science, this issue p. 28 cells. Na+,K+-ATPase deficiency
or treatment with a pepducin
targeting GPR35 decreased
TUBERCULOSIS tumor burden in mouse models
of intestinal cancer. —WW
Faulty kinase purged by Sci. Signal. 12, eaau9048 (2019).
Rare mutations in genes involved
in interferon-g–dependent
immunity underpin human
genetic susceptibility to severe
mycobacterial diseases,
including primary tuberculosis.
Boisson-Dupuis et al. investi-
gated whether two common
missense variants of the TYK2
Janus kinase that have impaired
catalytic activity conferred an
increased risk of tuberculosis.
Individuals homozygous for
the P1104A (proline to alanine
substitution at residue 1104)
variant of TYK2 are markedly
predisposed to developing
primary tuberculosis, defining

SCIENCE 4 JANUARY 2019 • VOL 363 ISSUE 6422 41-C

Published by AAAS

◥ lating the modal content of multimode lasers. In

REVIEW SUMMARY addition, adiabatic parametric evolution around
exceptional points provides interesting schemes
for topological energy transfer and designing
mode and polarization converters in photonics.
Lately, non-Hermitian degeneracies have also
Exceptional points in optics been exploited for the design of laser systems,
new nonlinear optics phenomena, and exotic

and photonics scattering features in open systems.

OUTLOOK: Thus far, non-Hermitian systems

Mohammad-Ali Miri and Andrea Alù* have been largely disregarded owing to the
dominance of the Hermitian theories in most
BACKGROUND: Singularities are critical points in photonics, given that optical gain and loss areas of physics. Recent advances in the theory
for which the behavior of a mathematical model can be integrated as nonconservative ingre- of non-Hermitian systems in connection with
governing a physical system is of a fundamentally dients to create artificial materials and struc- exceptional point singularities has revolution-
different nature compared to the neighboring tures with altogether new optical properties. ized our understanding of such complex sys-
points. Exceptional points are spectral singu- tems. In the context of optics and photonics,
larities in the parameter space of a system in ADVANCES: As we introduce gain and loss in in particular, this topic is highly important be-
which two or more eigenvalues, and their cor- a nanophotonic system, the emergence of ex- ◥
cause of the ubiquity of

Downloaded from on January 7, 2019

responding eigenvectors, simultaneously co- ceptional point singularities dramatically alters nonconservative elements
alesce. Such degeneracies are peculiar features the overall response, leading to a range of exotic Read the full article
of gain and loss. In this
of nonconservative systems that exchange functionalities associated with abrupt phase at http://dx.doi. regard, the theoretical de-
energy with their surrounding environment. transitions in the eigenvalue spectrum. Even org/10.1126/ velopments in the field
In the past two decades, there has been a though such a peculiar effect has been known science.aar7709 of non-Hermitian physics

growing interest in investigating such non- theoretically for several years, its controllable have allowed us to revisit
conservative systems, particularly in connec- realization has not been made possible until re- some of the well-established platforms with a
tion with the quantum mechanics notions of cently and with advances in exploiting gain and new angle of utilizing gain and loss as new
parity-time symmetry, after the realization loss in guided-wave photonic systems. As shown degrees of freedom, in stark contrast with the
that some non-Hermitian Hamiltonians ex- in a range of recent theoretical and experimental traditional approach of avoiding these elements.
hibit entirely real spectra. Lately, non-Hermitian works, this property creates opportunities for On the experimental front, progress in fabri-
systems have raised considerable attention ultrasensitive measurements and for manipu- cation technologies has allowed for harnessing
gain and loss in chip-scale photonic systems.
B Pump 1 Pump 2 C These theoretical and experimental develop-
ments have put forward new schemes for
a controlling the functionality of micro- and
µ nanophotonic devices. This is mainly based on
x the anomalous parameter dependence in the
response of non-Hermitian systems when op-
erating around exceptional point singularities.
µ Such effects can have important ramifications
A in controlling light in new nanophotonic device
designs, which are fundamentally based on en-
gineering the interplay of coupling and dis-
sipation and amplification mechanisms in

EP multimode systems. Potential applications of

CCW such designs reside in coupled-cavity laser
sources with better coherence properties, cou-
CW pled nonlinear resonators with engineered dis-
Parameter 1 Paramete persion, compact polarization and spatial mode
converters, and highly efficient reconfigurable
diffraction surfaces. In addition, the notion of
the exceptional point provides opportunities
Frequency to take advantage of the inevitable dissipation
in environments such as plasmonic and semi-
Ubiquity of non-Hermitian systems, supporting exceptional points, in photonics. (A) A conductor materials, which play a key role in
generic non-Hermitian optical system involving two coupled modes with different detuning, ±w1,2, optoelectronics. Finally, emerging platforms such
and gain-loss values, ±g1,2, coupled at rate of m. The real part of the associated eigenvalues in a two- as optomechanical cavities provide opportunities
dimensional parameter space of the system, revealing the emergence of an exceptional point (EP) to investigate exceptional points and their asso-
singularity. a1 and a2 are the modal amplitudes. (B to E) A range of different photonic systems, which
are all governed by the coupled-mode equations. (B) Two coupled lasers pumped at different rates.
ciated phenomena in multiphysics systems.

(C) Dynamical interaction between optical and mechanical degrees of freedom in an optomechan- The list of author affiliations is available in the full article online.
*Corresponding author. Email:
ical cavity. (D) A resonator with counter-rotating whispering gallery modes. CW, clockwise; CCW, Cite this article as M.-A. Miri and A. Alù, Science 363,
counterclockwise. (E) A thin metasurface composed of coupled nanoantennas as building blocks. eaar7709 (2019). DOI: 10.1126/science.aar7709

Miri et al., Science 363, 42 (2019) 4 January 2019 1 of 1


◥ theory of resonances in the context of atomic, mo-

REVIEW lecular, and nuclear reactions (11). Early exper-
iments on microwave cavities revealed the peculiar
topology of eigenvalue surfaces near exceptional
OPTICS points (12, 13). The emergence of spectral singular-
ities was also pointed out in the analysis of multi-
mode laser cavities (14, 15) and in time-modulated
Exceptional points in optics complex light potentials for matter waves (16).
Recently, interest in these peculiar spectral
and photonics degeneracies has been sparked in a particular
family of non-Hermitian Hamiltonians, the so-
called parity-time (PT) symmetric systems. A
Mohammad-Ali Miri1,2,3 and Andrea Alù4,3,5,1*
Hamiltonian is PT symmetric as long as it com-
mutes with the PT operator, that is, ½H; PT  ¼ 0,
Exceptional points are branch point singularities in the parameter space of a system at which
where the parity operator P represents a reflection
two or more eigenvalues, and their corresponding eigenvectors, coalesce and become
with respect to a center of symmetry and the time
degenerate. Such peculiar degeneracies are distinct features of non-Hermitian systems, which
operator T represents complex conjugation. It has
do not obey conservation laws because they exchange energy with the surrounding
been realized that PT-symmetric Hamiltonians,
environment. Non-Hermiticity has been of great interest in recent years, particularly in
despite being non-Hermitian, can support entirely
connection with the quantum mechanical notion of parity-time symmetry, after the realization
real eigenvalue spectra (17). More interestingly, it
that Hamiltonians satisfying this special symmetry can exhibit entirely real spectra. These
has been realized that commuting with the PT
concepts have become of particular interest in photonics because optical gain and loss can be

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operator is not sufficient to ensure a real spec-
integrated and controlled with high resolution in nanoscale structures, realizing an ideal
trum, as formally PT-symmetric Hamiltonians can
playground for non-Hermitian physics, parity-time symmetry, and exceptional points. As we
undergo a phase transition to the spontaneously
control dissipation and amplification in a nanophotonic system, the emergence of exceptional
broken symmetry regime, in which complex eigen-
point singularities dramatically alters their overall response, leading to a range of exotic optical
values appear. The phase transition happens as a
functionalities associated with abrupt phase transitions in the eigenvalue spectrum. These
result of a parametric variation in the Hamiltonian.
concepts enable ultrasensitive measurements, superior manipulation of the modal content of
Quite interestingly, the symmetry-breaking thresh-
multimode lasers, and adiabatic control of topological energy transfer for mode and
old point exhibits all properties of an exceptional
polarization conversion. Non-Hermitian degeneracies have also been exploited in exotic
point singularity (17–23).
laser systems, new nonlinear optics schemes, and exotic scattering features in open systems.
Although these theoretical explorations origi-
Here we review the opportunities offered by exceptional point physics in photonics, discuss
nated in the realm of quantum mechanics, optics
recent developments in theoretical and experimental research based on photonic exceptional
and photonics have proven to be the ideal plat-
points, and examine future opportunities in this area from basic science to applied technology.
form to experimentally observe and utilize the

rich physics of exceptional points (24–27). Owing
ermiticity is a property of a wide variety Hamiltonian. Generally, nonconservative phenome- to the abundance of nonconservative processes,
of physical systems, under the assump- na are introduced as small perturbations to photonics provides the necessary ingredients to
tions of being conservative and obeying otherwise Hermitian systems. Thus, the overall realize controllable non-Hermitian Hamiltonians.
time-reversal symmetry. Hermitian oper- behavior of non-Hermitian systems has been large- Indeed, dissipation is ubiquitous in optics, be-
ators play a key role in the theory of linear ly extracted from their Hermitian counterparts. cause it arises from material absorption as well
algebraic and differential operators (1–4), and However, recent investigations have revealed that as radiation leakage to the outside environment.
they are known to exhibit real-valued eigenvalues, non-Hermitian phenomena can drastically alter In addition, gain can be implemented in a locally
a property that stems from energy conservation. the behavior of a system compared to its Hermi- controlled fashion through stimulated emission,
For a set of dynamical equations described through tian counterpart. The best example of such devi- which involves optical or electrical pumping of
a Hermitian operator, the relation between initial ation is the emergence of singularities, so-called energy through an external source, or through
and final states is governed by a unitary operation. exceptional points, at which two or more eigen- parametric processes. Therefore, photonics pro-
Hermiticity has long been considered one of the values, and their associated eigenvectors, simul- vides a fertile ground to systematically investigate
pillars of mathematical and physical models, such taneously coalesce and become degenerate (5). non-Hermitian Hamiltonians and exceptional
as in quantum mechanics and electromagnetics. The term “exceptional point” was first intro- points. Recent theoretical developments in the
The elegance of such theories lies in powerful prop- duced in studying the perturbation of linear non- area of non-Hermitian physics have opened ex-
erties, including the completeness and orthogonality Hermitian operators (6), described by a general citing opportunities to revisit fundamental con-
of the eigenbasis of the governing operators (1). class of matrices H(z) parameterized by the com- cepts in nonconservative photonic systems with
However, these models are based on idealizations, plex variable z = x + iy, where x is the real part, gain and loss, such as lasers, sensors, absorbers,
like the assumption of complete isolation of a i is the imaginary unit, and y is the imaginary and isolators. In these systems, exceptional points
system from its surrounding environment. In prin- part. The eigenvalues sn(z) and eigenvectors open pathways for totally new functionalities and
ciple, nonconservative elements arise ubiquitously jyn ðzÞi of H can be represented as analytic func- performance. The interested reader may find
in various forms; thus, a proper description of a tions except at certain singularities z = zEP (EP, detailed overviews of non-Hermitian and, in par-
realistic physical system requires a non-Hermitian exceptional point). At such exceptional points, ticular, PT-symmetric systems in the context of
two eigenvalues coalesce, and the matrix H can optics and photonics in recent review papers
Department of Electrical and Computer Engineering, no longer be diagonalized. The physical impor- (28–32). In the present work, we discuss instead
The University of Texas at Austin, Austin, TX 78712, USA.
Department of Physics, Queens College of the City University
tance of exceptional points was pointed out in more broadly the concept of exceptional points
of New York, Queens, NY 11367, USA. 3Physics Program, early works (7, 8), in which the terminology of non- in non-Hermitian systems. In the following, we
Graduate Center of the City University of New York, New York, Hermitian degeneracy was used to distinguish provide an introduction to exceptional point
NY 10016, USA. 4Photonics Initiative, Advanced Science such critical points from regular degeneracies oc- physics and explain some of the fundamental
Research Center, City University of New York, New York, NY
10031, USA. 5Department of Electrical Engineering, City College
curring in Hermitian systems (9, 10). In addition, concepts associated with such critical points.
of The City University of New York, New York, NY 10031, USA. exceptional points were referred to as branch- We then draw the connection with optics and
*Corresponding author. Email: point singularities in investigating the quantum photonics and show the universal occurrence of

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 1 of 11


exceptional points in optical settings. Finally, we where w is the resonance frequency of the two coupling. Assuming, harmonic solutions of the
review recent theoretical and experimental ef- coupled modes, m is the coupling coefficient, and form ða1 ; a2 Þ ¼ ða1 ; a2 Þeisx , the eigenvalues of
forts in observing exceptional points in optics g is their decay rate. This particular choice of the system are
and their peculiar functionalities in practical Hamiltonian system, shown in Fig. 1A, represents
devices, presenting an outlook for the future of a large class of structures and devices of large
this exciting area of research. relevance in photonics, examples of which are sT ¼ wave  igave T m2 þ ðwdiff þ igdiff Þ2 ð2Þ
given in Fig. 1, such as coupled cavities (Fig. 1B)
Theoretical background (33), coupled waveguides (Fig. 1C) (34), polar- where wave = (w1 + w2)/2 and gave = (g1 + g2)/2,
We begin by investigating exceptional points in a ization states in the presence of small pertur- respectively, represent the mean values of res-
generic two-level system. Assuming that a1,2 are bations in an optical waveguide (Fig. 1D) (35), onance frequencies and loss factors, whereas
the modal amplitudes of two states that evolve counter-propagating waves in Bragg gratings wdiff = (w1 − w2)/2 and gdiff = (g1 + g2)/2 are the
with the variable x, representing the evolution (Fig. 1E) (36), wave mixing in nonlinear crystals differences between their resonance frequencies
time or propagation distance, the coupled mode (Fig. 1F) (37), coupled optical and mechanical and loss factors.
equations can be generally written as modes in an optomechanical cavity (Fig. 1G) (38), The Hamiltonian in Eq. 1 is a function of mul-
! ! and a two-level atom in a cavity (Fig. 1H) (39). tiple parameters. In Fig. 2, A and B, we evaluate
d a1 w1  ig1 m a1 In the case of coupled optical resonators, for the evolution of real and imaginary parts of the
ð Þ ¼ i instance, w1,2 in Eq. 1 represent the individual eigenvalues in the parameter space (wdiff, gdiff),
dx a2 m w2  ig2 a2
frequencies of each element, g1,2 describe their assuming a constant coupling coefficient m. An
ð1Þ loss or gain rate, and m represents the mutual exceptional point occurs when the square-root
term in Eq. 2 is zero, as the two eigenvalues co-
alesce. Assuming a real coupling constant, this

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happens for (wdiff = 0; gdiff = ±m). Figure 2, A and
B, highlights the interesting topology of the
branch point singularity at the exceptional point,
which has important implications in the optical
response of the system around this parameter
point, as we discuss in the following sections.
The two-body problem investigated here is the
simplest case of a non-Hermitian system. In gen-
eral, exceptional points appear ubiquitously in
systems with spatially discrete or continuous
degrees of freedom of multiple dimensionalities.
In principle, when more than two eigenvalue
surfaces are involved, it is also possible that more
than two surfaces simultaneously collapse at one
point, creating a higher-order exceptional point
(40, 41). A third-order exceptional point, for
example, is formed when three eigenvalues simul-
taneously coalesce. In this scenario, the square-
root dependence of the eigenvalues around the
exceptional point in Eq. 2 is replaced by a cubic
root. It is worth stressing that at an exceptional
point, the coalescing eigenvalues do not support
independent eigenvectors, implying that, in dis-
crete systems described by a matrix Hamiltonian,
the Jordan form is no longer diagonal (42). This is
notably different from accidental degeneracies,
which occur when two eigenvalues with different
eigenvectors cross. In a two-dimensional parameter
space, such accidental degeneracies appear when
two eigenvalue surfaces form a double cone or
“diablo,” forming diabolic points (43). In contrast
with exceptional points, at the diabolic points, the
eigenvectors remain linearly independent. Diabolic
points emerge in various Hermitian systems,
Fig. 1. A generic two-level system and its different realizations in optics and photonics. most notably in molecular reactions (44) and
(A) A schematic representation of a generic two-level system composed of two coupled entities. in the electronic band diagram of graphene (45).
(B) Two coupled optical cavities with spatially separated resonator modes. (C) Two evanescently Exceptional point singularities are closely
coupled optical waveguides with spatially separated waveguide modes. (D) Coupled orthogonal related to the phenomenon of level repulsion,
polarization states in an optical waveguide. (E) Counter-propagating waves in a volume Bragg grating. which has been originally explored in the con-
(F) Signal and idler frequency components in a parametric amplifier. (G) Photonic and phononic degrees text of quantum chaos, because it explains the
of freedom in an optomechanical cavity. (H) Coupling between a two-level atom and an optical cavity scarcity of closely spaced levels in Wigner dis-
mode. The different platforms represented in (B) to (H) can be treated under a unified model depicted tributions (46). In photonics, level repulsion is
schematically in (A).The universality of nonconservative processes in these settings calls for a systematic of great interest because it marks strong cou-
understanding of non-Hermiticity in a basic two-level system as a first step toward a rigorous bottom-up pling and hybridization between states, which is
approach for designing complex photonic systems in the presence of gain and loss. The arrows indicate manifested as a repulsion between closely spaced
electromagnetic waves, and different colors indicate different frequencies. eigenvalues when a parameter is adiabatically

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 2 of 11


change their behavior despite the fact that the

governing evolution operator preserves its sym-
metry. The behavior of the eigenvalues of a PT-
symmetric system is shown in Fig. 3A, highlighting
the bifurcation associated with the spontaneous
symmetry breakdown at the exceptional point.
In Eq. 1, we assumed that the coupling m is a real
parameter, whereas in principle, it can become
complex, involving dissipation. For instance, in
several scenarios, coupling between two states
is mediated through a continuum of radiation
modes, for which the energy partially leaks to
the outside environment (51). Examples include
radiative coupling between subwavelength nano-
particles (52) as well as channel-mediated coupling
of microring lasers (53). Independent of the cou-
pling mechanism, exceptional points also arise in
this case. According to Eq. 2, assuming a purely
imaginary coupling m = imi, exceptional points
emerge for (wdiff = ±mi; gdiff = 0). In this case, the
exceptional point arises for a frequency detuning

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equal to the mutual coupling between cavities.
The discussion on exceptional points pre-
sented so far has been built on Hamiltonian sys-
tems, or, in broader terms, on dynamical systems,
that evolve in time and space through a linear
operator. A large body of photonic systems,
however, are open, coupled to a continuum of
radiation modes, as in the case of optical wave-
Fig. 2. Exceptional points in a non-Hermitian two-level system. (A and B) Evolution of the real guides coupled to cavities or finite-sized scat-
(A) and imaginary (B) parts of the eigenvalues of the system described by Eq. 1 in the two- terers illuminated by impinging optical fields.
dimensional parameter space (wdiff, gdiff). These panels illustrate the exotic topology of the eigenvalue Such systems are better described through a
surfaces near an exceptional point singularity. (C to E) Eigenvalues versus wdiff for different values of scattering matrix, which directly relates outgoing
gdiff, that is, cross sections of the surfaces depicted in (A) and (B). Owing to the presence of the waves and incoming waves. The scattering matrix
exceptional point (gdiff = gEP; wdiff = wEP), depending on the value of the secondary parameter, can be compared with the time-evolution oper-
different parameter dependence is observed for the eigenvalues. (C) For gdiff > gEP, level repulsion ator, that is, U ¼ expðiHxÞ in Hamiltonian
occurs in the real part of the eigenvalues, whereas the imaginary parts cross. (D) For gdiff = gEP, the systems. Indeed, in a scattering medium without
real and imaginary parts coalesce at wdiff = wEP. (E) For gdiff < gEP, level crossing governs the real parts material gain or loss, the scattering matrix is
of the eigenvalues, whereas the imaginary parts repel each other. unitary, with all its eigenvalues located on the
unit circle (54). In the presence of loss and/or
gain, however, the norms are not preserved,
tuned (47). They typically occur near an excep- In the context of exceptional points, an espe- and the eigenvalues can, in general, be located
tional point in the real or complex parameter cially relevant class of non-Hermitian two-level inside or outside the unit circle. Quite interest-
space. For instance, Fig. 2, C to E, shows cross systems are those satisfying PT symmetry. In the ingly, similar to Hamiltonian systems, excep-
sections of the eigenvalue surfaces in Fig. 2, A context of quantum mechanics, a Hamiltonian tional points can also emerge in the scattering
and B, for different values of gdiff, highlighting H is PT symmetric when ½H; PT  ¼ 0, where P matrix formalism when two or more eigenvalues
level repulsion in either their real (Fig. 2C) or and T respectively represent parity and time and their associated eigenvectors coalesce (55).
imaginary part (Fig. 2E) for values of gdiff re- operators. In photonics, this corresponds to the A basic example is a PT-symmetric Fabry-Perot
spectively larger or smaller than the critical value case in which loss in one region is balanced by resonator involving two materials with balanced
gdiff = gEP, corresponding to the exceptional gain in another symmetric region (50). For the gain and loss (Fig. 3B). At a given frequency, for
point condition (Fig. 2D). Level repulsion in the two-level system of Eq. 1, considering that the an increasing gain and loss contrast, the scattering-
real (imaginary) part is accompanied by level parity and time operators respectively act as matrix eigenvalues bifurcate from the unit circle
crossing of the imaginary (real) part, as shown Pða; bÞ ¼ ðb; aÞ and T ða; bÞ ¼ ða ; b Þ, where a at an exceptional point singularity, as shown in
in Fig. 2, C to E (48, 49). At the critical condition and b are two variables, the conditions of PT Fig. 3B. Here, the exceptional point marks the
gdiff = gEP, both real and imaginary parts of the symmetry are satisfied for w1 ¼ w2 ≡ w and onset of the broken symmetry regime, in which
eigenvalues coalesce, and an exceptional point g1 ¼ g2 ≡ g. The response of this system is amplification of the wave excitation becomes the
is achieved. The different behavior in the three governed by the interplay of two major processes: dominant response of the PT-symmetric scatterer.
cases is determined by the topology of the in- the gain and loss contrast g and the mutual cou-
volved Riemann surfaces at the given cross sec- pling m. An exceptional point arises at the critical Exceptional points in photonics
tion. As a special case, level repulsion can arise condition m = g. Here, the exceptional point Exceptional points arise in several optical and
also in Hermitian systems, such as in the case of marks the onset of a transition from purely real photonic systems. In the previous section, we
two lossless optical resonators, in which level eigenvalues, associated with oscillatory solutions introduced a general class of two-level systems
repulsion occurs as we detune their resonance expðTijsT jxÞ, where x is the evolution variable, to described through coupled-mode equations, point-
frequency (33). Consistent with Fig. 2C, this purely imaginary eigenvalues associated with ing out the conditions to achieve a second-order
phenomenon is associated with an exceptional growing or decaying solutions expðTjsT jxÞ. This exceptional point. Integrated photonic waveguides
point in the complex parameter space, as we transition is often referred to as spontaneous and cavities, in particular, provide a controlla-
operate at gdiff = 0 < gEP. symmetry breaking, because the eigenvalues ble platform to observe exceptional points. In

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 3 of 11


the photonic bandgap closes, whereas the coupling

between counter-propagating waves becomes un-
idirectional (67). Unidirectional invisibility has
been observed in different settings, including in
integrated semiconductor waveguide gratings
(68), organic composite films (69), time-domain
lattices (59), and coupled acoustic resonators
(70). Similar ideas have been utilized in micror-
ing resonators to create integrated laser devices
supporting modes with definite angular momen-
tum when the system is biased at an exceptional
point (71). In addition, it has been shown that
properly engineered defects in microring reso-
nators can create an exceptional point that in-
stead induces chirality between counter-rotating
modes (72–74). It has also been shown that non-
Hermitian scattering systems operating around
the exceptional points can induce other interest-
ing phenomena, such as negative refraction (75)
and unidirectional cloaking (76, 77).
Fig. 3. PT symmetry in closed and open systems. PT-symmetric systems form an interesting Coherently prepared, multilevel warm atomic

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class of non-Hermitian settings, which share certain similarities with Hermitian systems. vapors provide another controllable platform
In the case of a two-level system (Fig. 1), PT symmetry is realized for w1 ¼ w2 ≡w and g1 ¼ g2 ≡g, to realize complex optical potentials. In such sys-
that is, when the individual levels share the same real part but exhibit opposite values of the tems, strong pump laser beams can create wave-
imaginary parts (gain and loss). (A) A PT-symmetric system of two coupled waveguides (top) guiding effects for weak probe beams where,
with gain (red) and loss (blue), and the corresponding eigenvalues (bottom) versus the gain-loss under proper detuning, both gain and loss can
contrast g. This figure reveals a transition in the eigenvalues from purely real (exact PT symmetry) be achieved in Raman-active systems (78). In this
to purely imaginary (broken PT symmetry). Interestingly, the PT symmetry–breaking threshold regard, the realization of complex potentials
point reveals all the properties of an exceptional point singularity. In this figure, the arrows represent supporting exceptional points have been theo-
the intensity of the eigenmodes in both the exact and broken PT regimes. (B) A PT-symmetric retically proposed in three- and four-level atoms
Fabry-Perot resonator (top) and the eigenvalues of its scattering matrix (bottom) evolving (79, 80) and experimentally demonstrated in
as a function of the frequency of excitation. In this case, an exceptional point marks a transition coupled atomic vapor cells (81), as well as in PT-
in the eigenvalue evolution, breaking away from the unit circle. The geometries of (A) and (B) symmetric optical lattices (82).
represent examples of Hamiltonian and scattering settings. Even though the discussion here is primarily
focused on linear operators, it is important to
integrated photonic platforms, exceptional points The peculiar properties of exceptional points also stress the relevance of exceptional points
and phase transitions have been observed in have also been investigated in open scattering in nonlinear systems. The connection of non-
coupled passive optical waveguides, where con- systems involving gain and loss. In particular, Hermiticity to nonlinear systems is multifold:
trollable loss in one of the channels was utilized it has been shown that a PT-symmetric Fabry- First, most nonlinear configurations in optics
(56) (Fig. 4, A and B). In the context of PT sym- Perot cavity, similar to the one discussed in Fig. and photonics are accompanied by losses, and
metry, spontaneous symmetry breaking at the 3B, can simultaneously act as a laser and a co- second, active devices are, by nature, nonlinear.
exceptional point was demonstrated in a coupled herent perfect absorber at the exceptional point Therefore, lasers, amplifiers, and saturable ab-
arrangement of optical waveguides with balanced (55, 62). This interesting behavior, occurring as sorbers are all examples of devices in which
gain and loss (50). In other works, coupled optical a result of the coalescence of a pair of poles and nonlinearity and non-Hermiticity coexist. In ad-
cavities with gain and loss were utilized to observe zeroes of the scattering matrix eigenvalue, has dition, nonlinear optical effects can create inter-
a PT-symmetric phase transition (57, 58) (Fig. 4, been recently demonstrated in an integrated actions between different wave components. A
D and E). The first demonstration of exceptional semiconductor resonator with active and passive high-intensity pump, for example, initiates energy
points in periodic structures was achieved in regions (63). Non-Hermitian optical gratings with exchange between lower-intensity wave compo-
time-domain lattices (59) (Fig. 4C), induced alternating layers of materials with different levels nents that are governed by a linearized operator.
through the propagation of short laser pulses of loss or gain reveal another interesting aspect Such an operator is, by essence, non-Hermitian,
in two coupled fiber loops of a slightly different of exceptional points (64, 65). In such systems, given the energy exchange between pump and
lengths with alternating gain and loss. This prop- whereas reciprocity enforces equal transmission probe through the nonlinearity.
agation creates a quantum walk of pulses gov- in both directions, the reflection coefficients can The interplay of nonconservative and non-
erned by PT-symmetric evolution equations, be completely different. In a Hermitian system, linear effects is of special interest, given that
described through a peculiar band structure as equal transmission coefficients also require equal optical materials with strong nonlinearities
in spatially periodic structures. In addition, ex- magnitude of the reflection coefficients, but in necessarily suffer from large absorption (83).
ceptional points have been demonstrated in pho- non-Hermitian systems, this is not the case. The Therefore, concepts from non-Hermitian
tonic crystal slabs (60), in which out-of-plane contrast in reflection amplitudes is maximized at physics are sought to provide strategies to take
radiation losses due to the finite thickness of the exceptional point, where the reflection from advantage of losses in such nonlinear materials.
the dielectric slab result in the merging of two one direction becomes zero and the reflection In this regard, the conjunctive use of nonlinear
eigenfrequency bands, inducing a ring of excep- from the other direction can be very large, thus processes with gain and loss have been sug-
tional points in the wave number space. Among inducing unidirectional invisibility (65). In a gested as a viable route to achieve optical non-
other realizations, exceptional points have also similar fashion, it has been shown that a two- reciprocity (84, 85). In addition, it has been
been experimentally demonstrated in chaotic layer structure with gain and loss can exhibit shown that laser systems exhibit exotic behavior
optical cavities (61). In all these photonic sys- one-way reflectionless behavior at a particular such as anomalous pump dependence near the
tems, operation around the exceptional points frequency, thus inducing an anisotropic trans- exceptional point singularity (86, 87), as well as
enables a singular optical response. mission resonance (66). At the exceptional point, reduced lasing threshold with increased losses

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 4 of 11


Fig. 4. Experimental demonstration of exceptional points in various band merging effect at the exceptional point was experimentally demon-

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optical settings. (A and B) Coupled integrated photonic waveguides (A) strated. PM represents a phase modulator that creates an effective
fabricated through a multilayer AlxGa1−xAs heterostructure (B), for which potential for the light pulses. (D and E) Coupled microring resonators with
thin layers of chromium of different widths were utilized to impart different gain and loss have been used to probe the exceptional point through the
amount of losses in one of the waveguides (56). In this setting, couplers mode splitting of the resonance eigenmodes (57, 58). In (D), the numbers
with different losses on one arm were used to observe mode symmetry indicate the four ports that are used to probe the system, and orange and
breaking beyond the critical loss contrast associated with the exceptional green arrows represent waves propagating in forward and backward
point. (C) The propagation of laser pulses in coupled fiber loops of slightly directions, respectively. [Credits: (A) and (B) reprinted with permission
different lengths (D L) with alternating gain and loss creates a quantum from (56), copyright 2009 by the American Physical Society; (C), (D),
walk of pulses which is governed by a PT-symmetric operator (59). In this and (E) reprinted from (59), (57), and (59), respectively, with permission
temporal lattice, the onset of complex eigenvalues associated with the from Springer Nature]

(88). The impact of non-Hermiticity on non- which goes from being real to complex valued. standard perturbation theory, however, does not
linear waves in bulk and periodic systems has Other well-known examples of exceptional points apply at such points. The perturbation problem
been also explored, after the realization that PT- in the wave number space are the cut-off fre- can be introduced as H ¼ H0 þ eH1 where we
symmetric potentials support optical solitons (89). quency of a closed waveguide or the edge of a want to find the behavior of the eigenvalues sn(e)
Indeed, although dissipative nonlinear systems photonic bandgap in periodic structures. In and eigenvectors jyn ðeÞi of H for e≪ 1, where e is
have been largely investigated (90), recent de- addition, a volume Bragg grating, in which alter- the perturbation parameter. In general, such a
velopments in the area of PT symmetry have nating layers of two different materials with perturbation problem can be divided into regular
sparked interest in the exploration of new in- refractive indices n1 and n2 create a photonic and singular problems (96). In the regular case, a
tegrated nonlinear systems combining gain and bandgap for a range of incoming frequencies, power-series solution with integral powers of e
loss (29, 91, 92). In addition, solitary waves in supports an exceptional point. In this structure, X

exists, that is, sðeÞ ¼ s0 þ cn en, where cn are
PT-symmetric potentials have been experimen- the wave number of the counter-propagating n¼1
tally demonstrated in time-domain lattices (93). waves follows a square-root dispersion in terms the series coefficients, with a finite radius of
Nonlinear wave-mixing processes, such as sum of the incoming wave frequency. Whereas in the convergence. However, in the case of an excep-
and difference frequency generation and optical propagation band the wavenumber is real, inside tional point singularity, such a solution does not
parametric amplification, are other examples of the bandgap it becomes complex, and an excep- converge. At a singularity, the exact solution at
non-Hermitian systems in which external cou- tional point marks this transition. Similar to the e = 0 is of a fundamentally different nature
pling through a pump beam mediates the inter- exceptional points emerging in complex poten- compared with its neighboring points e → 0
actions (94). tials, the photonic bandgap in gratings exhibits (96). At a second-order exceptional point, the
At this point, it is worth stressing that ex- interesting properties, such as a vanishing group series solution
ceptional points are not necessarily difficult to velocity (95). X
find in optical setups because they occur ubiq-
Applications in nanophotonics sT ðeÞ ¼ s0 þ ðT1Þn cn en=2 ð3Þ
uitously in the wave number space, even in con-
servative systems in which no gain or loss is The exotic properties of exceptional points open
involved. In these scenarios, a part of a Hermitian interesting possibilities for advanced light ma- exists, where s0 is the eigenvalue at the ex-
system can be considered non-Hermitian, be- nipulation. In this section, we present an overview ceptional point. The radius of convergence of
cause it exchanges energy with the rest of the of some of the recent theoretical and experimental this series in the complex e plane is deter-
system. Possibly the best-known example of developments in the exploration of exceptional mined by the nearest exceptional point. In a
these trivial exceptional points is the total in- points for applications in photonics. As in other similar manner, for a kth-order exceptional
ternal reflection at the interface of two materials. areas of physics, in photonics, perturbation theory point the nth term in the perturbation series
In this case, light transmitted at the interface of is an important mathematical tool to tackle a is en/k, with a dominant first-order term of e1/k.
two media critically depends on the incidence range of problems without having to deal with For small perturbations, this term is considera-
angle of the impinging light. In particular, at a complex full-wave equations. Owing to the sin- bly larger than the linear term e, which occurs
critical angle, a phase transition occurs in the gularity at exceptional points, as well as the di- at regular points, enabling extra sensitivity to
propagation wave number of the second medium, mensionality collapse in the eigenvector space, the parameter e of a system when biased at the

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 5 of 11


exceptional point singularity. This property has (100) (Fig. 5B). Although it has been pointed out laser cavities (104). A common issue in laser
been proposed to achieve enhanced mode split- that enhanced sensitivity at the exceptional point systems is that often several transverse or long-
ting between counter-propagating whispering does not necessarily correspond to enhanced itudinal modes may simultaneously lase. In this
gallery modes of a microring resonator in the precision in sensing instruments (101) and that regard, it has been suggested to complement the
presence of nanoparticles (97). The prospect of quantum noise should be considered to assess active multimode laser cavity with a passive ca-
utilizing exceptional points for enhanced mode the ultimate performance of these exceptional vity that ideally exhibits an equal amount of loss.
splitting has been experimentally demonstra- point sensors (102), sensors appear to be an In this scenario, the overall level of loss is in-
ted in microtoroid cavities (98, 99) (Fig. 5A). In interesting application area for these concepts. creased in the entire system, given that each mode
addition, integrated microring resonators with In this area, it has also been shown that a scaled overlaps with the loss region, and thus the gain
externally controllable perturbations have been form of PT symmetry can be used for enhanced threshold is expected to increase. However, a large
utilized to induce second- and third-order excep- sensor telemetry (103). discrimination between lasing thresholds of dif-
tional points, where ½ and ⅓ power-law expo- Another interesting application of exceptional ferent modes is obtained at the exceptional point
nents in mode splitting have been demonstrated points is mode discrimination in multimode supported by this PT-symmetric system. In this
case, the modes are split into two classes that are
equally distributed between the active and pas-
sive regions, as well as modes that are localized
either in the gain or loss cavity. The first class of
modes remains neutral, whereas the modes lo-
cated in the gain enter the gain regime. As a result,
the passive cavity prevents some of the modes
from lasing. More interestingly, this structure

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creates a large discrimination between the lasing
thresholds of the fundamental mode with its
closest competing counterpart. Assuming g0 and
g1 to be the gain coefficients for fundamental and
competing modes, respectively, in the coupled-
cavity system, the discrimination is governed by
g02  g12, which can be considerably larger than
g0 − g1 in a single laser cavity. This approach has
Fig. 5. Demonstration of enhanced perturbation near an exceptional point singularity. been utilized to enforce single longitudinal-
(A) Sensing a nanoparticle with a microtoroid resonator biased at an exceptional point (99). Blue mode operation in coupled microring lasers
arrows and curve indicate light pulses propagating in counter-rotating whispering gallery modes, and (105) (Fig. 6A) and in single rings with embedded
the red arrow and curve indicate a backscattering pulse due to the presence of additional scatterers active-passive gratings (106) (Fig. 6B). Similar
(shown with two gray circles), which help to bias the system at an exceptional point. (B) Three strategies have been utilized to filter out trans-
coupled microring resonators creating a third-order exceptional point (100).k represents the verse modes in ring resonators with large cross
strength of coupling between adjacent microrings. [Credits: (A) and (B) reprinted from (99) and sections (107), in optically and electrically pumped
(100), respectively, with permission from Springer Nature] stripe lasers (108, 109) (Fig. 6C), and in microdisc

Fig. 6. PT-symmetric laser arrangement

and its different realizations. (A) Coupled
active-passive microring resonators (105),
with a scanning electron microscope (SEM)
image shown at the bottom. (B) SEM image
of a microring resonator with an embedded
gain-loss grating (106). (C) SEM image of
coupled stripe lasers (109). (D) A schematic
of integrated coupled microring lasers (left)
and a photograph of the fabricated system
(right), where the scale bar represents 200 mm
(111). PM, phase modulator; SOA, semi-
conductor optical amplifier. [Credits: (A)
and (B) reprinted from (105) and (106),
respectively, with permission; (C) reprinted
from (109) with permission from John Wiley
and Sons; (D) reprinted from (111) with
permission from Springer Nature]

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 6 of 11


lasers (110). In addition, integrated coupled mi- pological properties. That their optical properties also been presented (118). An interesting prob-
croring lasers have been demonstrated with are related to a topological feature makes the lem in this context is to adiabatically change the
single-mode operation at telecommunication wave- response inherently robust to disorder and im- parameters of a non-Hermitian system such that
lengths (111) (Fig. 6D). perfections. Analogously, exceptional points rep- the exceptional point is dynamically encircled, as
As illustrated in Fig. 7A, an interesting aspect resent an interesting example of topological depicted in Fig. 7B. In a Hermitian system, when
of exceptional points consists of their exotic features arising in simple coupled dynamical adiabatically changing the parameters along a
topological features in the parameter space. This systems as a result of the interplay between closed path, the two eigenvectors are bound to
discussion falls into the broad context of topo- interaction and dissipation. According to Fig. 7A, return to their original form, apart from acquir-
logical photonics, an area of optics research that a loop of eigenvalues that encircle a base point ing a possible geometric phase (120). In the case
has produced considerable excitement in recent identifies a topological object, given that it can- of non-Hermitian systems, instead, parametric
years. Inspired by the unusual physics of topo- not be continuously deformed to a single point cycling an exceptional point interchanges the
logical insulators in condensed-matter physics, without crossing the base point. instantaneous eigenvectors, whereas only one
topological phenomena in photonics have been The rigorous analysis of these features can be picks up the geometric phase (13, 121–123). In
shown to arise in sophisticated periodic struc- carried out using results from condensed-matter principle, this behavior does not occur, even for
tures, ranging from gyromagnetic photonic crys- physics, in which the topological band theory of arbitrarily slow dynamic cycling of the excep-
tals (112), arrays of helical waveguides (113), arrays non-Hermitian Hamiltonians has been rigorously tional point, given that the adiabatic theorem
of microring resonators (114), bianisotropic or investigated in (118). Specifically, it was shown breaks down in case of non-Hermitian systems.
magnetized metacrystals (115), dielectric chiral that non-Hermitian band structures exhibit a Indeed, under such conditions, depending on
metasurfaces (116), and time-modulated lattices topological invariant associated with the gra- the direction of rotation, one of the two eigen-
(117). In these systems, highly unusual photon dient of the band in momentum space (119). states dominates at the end of the parametric
transport, characterized by one-way propagation Inspired by the periodic table of topological cycle. This interesting topological response pro-

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along the edges of the sample, arises within insulators, a systematic classification of topo- vides a scheme for topologically robust energy
bandgaps delimited by bands with distinct to- logical phases of non-Hermitian systems has conversion between different states.
On the basis of this principle, topological
energy transfer has been recently demonstra-
ted in a multimode optomechanical cavity in
which two mechanical modes of a membrane
are coupled and coherently controlled through
a laser beam (124) (Fig. 7C). In addition, dynam-
ical cycling of exceptional points is explored in a
microwave waveguide in which a robust asym-
metric transmission between even and odd modes
is demonstrated (125) (Fig. 7D). In addition, it has
been shown that this concept can provide op-
portunities for polarization manipulation (126, 127).
In particular, one can create an omnipolarizer in
which the output light is polarized along a
specific direction irrespective of the polarization
of the input state (Fig. 7E). For propagation along
the opposite direction, on the other hand, the out-
put is populated in the orthogonal polarization.

Conclusions and outlook

The peculiar features of exceptional points, as-
sociated with their unusual parameter dependence
in the eigenvalue spectrum of non-Hermitian
systems, enable exciting opportunities for a wide
range of applications. These applications arise in
scenarios in which interaction among different
modes in the presence of dissipation and/or amp-
lification is involved. In such circumstances,
coupling and gain-loss mechanisms can be
Fig. 7. Chiral mode conversion through dynamically cycling an exceptional point. (A) The engineered and utilized to induce and control
eigenvalue surfaces near an exceptional point (left). Although a loop of eigenvalues containing exceptional points, to take advantage of the strong
a base point can be continuously deformed into a circle, it cannot be shrined into a point without and anomalous parameter dependence of the
crossing the base point (right) (118, 119). p1 and p2 represent two parameters. (B) Two different system around them.
possibilities of encircling an exceptional point (EP) cycling along opposite directions. (C) The We envision future opportunities to exploit
experimental probing of the complex eigenvalues of two mechanical oscillators driven adiabatically these singular responses in photonics for ad-
through optical fields (124). The cross indicates the location of the exceptional point. (D) Asymmetric vanced dispersion engineering. As a relevant
conversion between the even and odd modes of a waveguide, when the loss and detuning are recent example, level repulsion in the group
adiabatically controlled in order to encircle an exceptional point (125). Blue and red curves indicate velocity dispersion between coupled cavities has
two modes of the waveguide, and the arrow indicates the direction of propagation. (E) An adiabatic been used to control the modal dispersion of an
conversion between orthogonal polarization states (126). Green arrows show the propagation individual cavity. This has been utilized to create
direction, yellow arrows indicate the polarization state, P is the pumping, and w is the channel width. anomalous dispersion, which is of great impor-
[Credits: (A) reprinted with permission from (118), copyright 2018 by the American Physical Society, tance in four-wave mixing and parametric fre-
and (119); (C) and (D) reprinted from (124) and (125) with permission from Springer Nature; (E) quency comb generation (128–130). However,
reprinted with permission from (126), copyright 2017 by the American Physical Society] the full potential of coupled waveguide or cavity

Miri et al., Science 363, eaar7709 (2019) 4 January 2019 7 of 11


arrangements for dispersion manipulation is dress the current challenges in integrated laser different spatial orders (135). As a result, adia-
still largely unexplored, and multiple coupled sources by taking advantage of the strong pa- batic tapering of the waveguide width along the
cavities or metamaterials may be envisioned to rameter dependence of such structures near propagation direction can efficiently convert
take full advantage of exceptional points in the exceptional points. polarization states as well as spatial-mode orders
context of dispersion engineering. Mode conversion in a compact integrated (136, 137). As shown schematically in Fig. 8C, the
In a similar fashion, coupled-cavity arrange- photonic device is another important function- inclusion of selective gain and loss in such
ments offer exciting prospects to design new ality that can largely benefit from exceptional geometries provides an alternative degree of
semiconductor lasers with highly desired func- points, in terms of reduced footprint and inherent freedom to control the mode-conversion ef-
tionalities. Although modern semiconductor laser robustness to disorder. Even though rigorous op- ficiency. In addition, hybridization between mul-
sources exist in the entire optical spectrum, their timization techniques allow for inverse design tiple modes through higher-order exceptional
coherence properties are not sufficient for many of such structures, often resulting in complex points can initiate the simultaneous conversion
applications. In particular, key requirements for structures that require advanced fabrication among a large number of modes. The full ram-
laser sources, such as stable and narrowband fre- technologies, alternative designs with reduced ifications of these concepts become very pow-
quency operation, as well as frequency tunability, complexity are highly desirable. In this vein, erful new tools in photonic engineering.
can be achieved through coupled-cavity geo- adiabatic perturbation of a structural parameter The quest for integration of optical setups on a
metries (131–134) (Fig. 8B). Even though this inducing an exceptional point–induced control- chip requires integrated implementation of
scheme has been previously applied to semi- lable level repulsion can provide a simple ap- fundamental elements such as laser sources
conductor lasers at specific frequencies, it re- proach for hybridization and adiabatic exchange with critical power and coherence demands, iso-
mains to be explored in other, arguably more of modes. Recently, it has been shown that in lators and circulators, mode convertors, and so
practical, sources and at different frequencies. optical ridge waveguides with different cladding on. In this regard, multimode structures have
In this regard, coupled-cavity techniques in and buffer materials, varying the waveguide proven to provide a great opportunity to achieve

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conjunction with non-Hermitian designs pro- width induces a strong coupling between trans- desired functionalities and realize compact de-
vide an exciting strategy to systematically ad- verse electric and magnetic polarizations of vices. This trend naturally calls for a bottom-up
approach in designing photonic devices in an
abstract modal picture in which three ingre-
dients are relevant: (i) modal detuning, (ii) mode
coupling, and (iii) modal gain and/or loss. The
role of the first two processes has been largely
explored in the past in the context of coupled-
mode theory. The third mechanism, on the other
hand, has been largely unexplored. As we dis-
cussed in this survey, the interplay of these
phenomena can result into totally new oppor-
tunities for photonics, associated with the emer-
gence of exceptional points that notably alter
the eigenvalue surfaces. Therefore, notions from
exceptional point physics can provide new de-
signs for realizing multimode integrated photonic
devices. This creates opportunities for theoretical
and experimental research focused on exploring
the fundamental bounds of accessible perform-
ance, such as bandwidth and sensitivity, of
photonic devices operating at exceptional points.
It is worth stressing that inducing exceptional
points through gain and loss imposes difficulties
in experimental photonics. This is because op-
tical gain is limited to certain materials and is
not generally compatible with all platforms, and
loss is generally undesired for various purposes.
At the same time, suitable settings for investigat-
Fig. 8. Application of exceptional points in multimode photonic integrated circuits and new ing and fruitfully exploiting exceptional points
platforms to investigate exceptional points. (A to C) Applications. (A) Hybridization of arise in systems that inherently involve optical
eigenfrequencies in coupled microring resonators (top) creates two branches with strong dispersion gain or loss, such as semiconductor lasers, sat-
(bottom) (130). The anomalous dispersion can be utilized for frequency comb generation. (B) urable absorbers, and plasmonic structures, among
Wavelength manipulation in three coupled-cavity lasers through a strong dispersion at a third-order others.
exceptional point (133). (C) Level repulsion of modes with different polarization provides an Along different lines, remaining to be inves-
opportunity for compact polarization mode conversion (135, 136). A parametric evaluation of the tigated are the interesting physics arising from
eigenmodes of a rib waveguide (top left) versus the waveguide width reveals a level repulsion the propagation of classical light at exceptional
between transverse electric (TE) and transverse magnetic (TM) polarizations (bottom). Therefore, point singularities. Recent theoretical investiga-
tapering of the waveguide width over a finite distance (top right) can result in an adiabatic tions, for example, suggest dynamical slowing
polarization conversion. (D to F) New platforms. (D) Multimode optomechanical cavities provide and stopping of light in coupled waveguides at
a flexible platform for investigating exceptional points. (E) Exciton-polaritons in semiconductor exceptional points (138), as well as photonic
cavities offer an alternative multiphysics structure for realizing exceptional points. (F) Coupled catastrophe in optical lattices (139). In addition,
nanoantennas can be designed as non-Hermitian building blocks of optical metasurfaces. a point of interest would be to explore these
[Credits: (A) reprinted from (130) with permission from Springer Nature; (B) reprinted from phenomena in new platforms. An emerging play-
(133) with permission from AIP Publishing; (C) reprinted with permission from (135) and (136), ground to explore the rich physics of exceptional
copyright 2011 and 2012, respectively, Optical Society of America] points is provided by hybrid photonic platforms

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Miri et al., Science 363, eaar7709 (2019) 4 January 2019 11 of 11


◥ the context of tissue challenges such as chitin

RESEARCH ARTICLE SUMMARY injection or insect bites, commensal-specific
RORgt+ T cells were able to produce type 2
cytokines (IL-5 and IL-13). The spontaneous
release of type 2 cytokines by these cells was
also observed in the context of local defects
Commensal-specific T cell in immune regulation associated with impaired
regulatory T cell function. Alarmins associated

plasticity promotes rapid tissue with tissue damage and inflammation, such
as IL-1, IL-18, IL-25, and IL-33, were able to
superimpose a type 2 effector program on
adaptation to injury ON OUR WEBSITE

both TC17 and TH17 cells
in the context of T cell re-
Oliver J. Harrison, Jonathan L. Linehan, Han-Yu Shih, Nicolas Bouladoux, Read the full article ceptor engagement. Using
Seong-Ji Han, Margery Smelkinson, Shurjo K. Sen, Allyson L. Byrd, Michel Enamorado, at http://dx.doi. an IL-17A fate-mapping
org/10.1126/ strategy, we found that
Chen Yao, Samira Tamoutounour, Francois Van Laethem, Charlotte Hurabielle,
science.aat6280 IL-17A–committed RORgt+
Nicholas Collins, Andrea Paun, Rosalba Salcedo, John J. O’Shea, Yasmine Belkaid* ..................................................
T cells and their IL-17A−
INTRODUCTION: Barrier tissues are con- challenges relies on rapid and coordinated local RORgt counterparts both produced type 2
stitutive targets of environmental stressors responses tailored to both the microenviron- cytokines in response to tissue alarmins. Such

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and are home to a highly diverse microbiota. ment and the nature of the instigating injury. cellular plasticity allows commensal-specific
When the immune system encounters these Our study explored whether commensal-specific type 17 cells to promote IL-17A–mediated
noninvasive microbes, one possible result is T cells can act as tissue sentinels, allowing rapid antimicrobial defense under homeostatic con-
the induction of cognate T cell responses that adaptation to defined injuries, and how dys- ditions, as well as tissue repair in an IL-13–
control various aspects of tissue function, in- regulation of these responses may have path- dependent manner in the context of tissue
cluding antimicrobial defense and tissue re- ogenic consequences. injury.
pair. Given the extraordinary number of antigens
expressed by the microbiota, a substantial frac- RESULTS: Homeostatic encounters with com- CONCLUSION: Our work describes a tissue
tion of barrier tissue–resident T cells are ex- mensal microbes promoted the induction of checkpoint that relies on the remarkable
pected to be commensal-specific, accumulating commensal-specific interleukin-17A (IL-17A)– plasticity and adaptability of tissue-resident
over time in response to successive exposure to producing T cells [CD4+ (TH17) and CD8+ (TC17)] commensal-specific T cells. We propose that
new commensals. Because barrier tissues are that persisted as tissue-resident memory cells. this feature may also have important implica-
defined by the constitutive coexistence of com- Surprisingly, commensal-specific T cells were tions in the etiology of tissue-specific inflam-
mensals and commensal-reactive lymphocytes, characterized by coexpression of classically an- matory disorders. The extraordinary number
any understanding of tissue homeostasis, re- tagonistic transcription factors (RORgt and of both commensal-derived antigens and T cells
sponse to injury, and tissue-specific pathologies GATA-3) that control the respective expression at barrier sites suggests that the ability of
must occur in the context of this fundamental of type 17 and type 2 programs. Consequently, commensal-specific T cells to functionally
dialog. commensal-specific T cells displayed a hybrid adapt to injury may play a fundamental role in

RATIONALE: The skin serves as a primary

chromatin landscape that underlies the co-
expression of a broad type 2 transcriptome,
controlling tissue physiology.

interface with the environment and is conse- including the type 2 effector cytokines IL-5
The list of author affiliations is available in the full article online.
quently a constitutive target of environmental and IL-13. Notably, during homeostasis, RORgt+ *Corresponding author. Email:
stressors mediated by physical damage or in- T cells expressed type 2 cytokine mRNA without Cite this article as O. J. Harrison et al., Science 363, eaat6280
vasive pathogens. Tissue protection from these subsequent protein translation. By contrast, in (2019). DOI: 10.1126/science.aat6280

Homeostasis Tissue injury Impaired regulation


Antimicrobial Poised type 2 Wound Tissue

defense immunity repair Inflammation

Il5, Alarmins
IL-17A IL-13
Il13 mRNA IL-1 IL-5
IL-18 IL-13
Commensal-specific Alarmin-licensed Foxp3+ Treg
CD4+ and CD8+ T cells T cell plasticity

Poised type 2 immunity of commensal-specific T cells promotes rapid adaptation to tissue injury. Commensal-specific T cells produce
IL-17A under homeostatic conditions for antimicrobial defense while harboring a poised type 2 transcriptome. Tissue injury licenses type 2
immune potential of commensal-specific type 17 T cells, thereby promoting tissue repair. Impaired immune regulation unleashes type 2
cytokine production from commensal-specific CD8+ TC17 cells.

Harrison et al., Science 363, 43 (2019) 4 January 2019 1 of 1


◥ defined injury remains unknown. Here, we ex-

RESEARCH ARTICLE plored the unique features of commensal-specific
T cells and how their distinct wiring might
promote physiological or pathological tissue
IMMUNOLOGY adaptation.

Acute injury licenses type 2 cytokine

Commensal-specific T cell production from commensal-specific
type 17 T cells
plasticity promotes rapid tissue The skin is home to a number of resident lympho-
cytes, some of which recognize the microbiota

adaptation to injury (4, 6–8). We first assessed whether commensal-

specific T cells could develop as nonrecirculat-
ing tissue-resident memory cells (TRM), a subset
Oliver J. Harrison1, Jonathan L. Linehan1*, Han-Yu Shih2, Nicolas Bouladoux1,3, of memory T cells previously shown to accumu-
Seong-Ji Han1, Margery Smelkinson4, Shurjo K. Sen5, Allyson L. Byrd1*, late in tissues upon pathogen encounter and
Michel Enamorado1, Chen Yao2, Samira Tamoutounour1, Francois Van Laethem6†, promote local immunity (9). Staphylococcus
Charlotte Hurabielle1,7, Nicholas Collins1, Andrea Paun8, Rosalba Salcedo9, epidermidis colonization of the skin promotes
John J. O’Shea2, Yasmine Belkaid1,3‡ the noninflammatory accumulation of both CD4+
[T helper 1 (TH1) and TH17] and CD8+ T cells
Barrier tissues are primary targets of environmental stressors and are home to the largest [T cytotoxic 1 (TC1) and TC17] (4). A large fraction

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number of antigen-experienced lymphocytes in the body, including commensal-specific (>80%) of these S. epidermidis–specific poly-
T cells. We found that skin-resident commensal-specific T cells harbor a paradoxical clonal CD8+ T cells are nonclassically restricted
program characterized by a type 17 program associated with a poised type 2 state. Thus, (6). S. epidermidis–specific CD8+ T cells can be
in the context of injury and exposure to inflammatory mediators such as interleukin-18, tracked via the use of a peptide–major histocom-
these cells rapidly release type 2 cytokines, thereby acquiring contextual functions. Such patibility complex (MHC) tetramer (f-MIIINA:
acquisition of a type 2 effector program promotes tissue repair. Aberrant type 2 responses H2-M3) (6) and newly generated T cell receptor
can also be unleashed in the context of local defects in immunoregulation. Thus, (TCR)–transgenic mice (BowieTg). Both tools
commensal-specific T cells co-opt tissue residency and cell-intrinsic flexibility as a means recapitulate the S. epidermidis–specific polyclonal
to promote both local immunity and tissue adaptation to injury. CD8+ T cell response, including cytokine po-
tential, skin-homing, and distribution of the tis-

sue residency markers CD69 and CD103 (9) (Fig. 1,
arrier tissues are constitutive targets of T cell responses (1–4). This tonic recognition pro- A to C). To assess tissue residency, we generated
environmental stressors as well as primary motes a highly physiological form of adaptive S. epidermidis–colonized parabiotic mice, which
sites of exposure to symbiotic and patho- immunity that can control distinct aspects of establish chimerism through joint circulation
genic microbes. As such, under homeosta- tissue function, including antimicrobial defense (10) (fig. S1A). In contrast to lymphoid organs,
sis, barrier tissues are home to vast numbers and tissue repair (5, 6). Because of the extraor- where cells equilibrated, f-MIIINA:H2-M3+ CD8+
of antigen-experienced lymphocytes. The numer- dinary number of antigens expressed by the T cells within the skin were host-derived (97.1 ±
ous and diverse microbes that colonize these microbiota, a substantial fraction of barrier tissue- 2.4%) and coexpressed CD103 and CD69 (Fig. 1,
tissues, referred to as the microbiota, play a fun- resident T cells are expected to be commensal- D and E). Thus, commensal-specific T cells can
damental role in the induction and quality of specific, accumulating over time in response to develop as long-lived tissue-resident memory
these local immune responses, including those successive exposure to new commensals. This T cells.
that are directed at the microbiota itself (1–4). understanding of host-microbiota interactions Given the fundamental role of the skin as a
Indeed, far from being ignored, microbes at all has important implications for our understand- protective barrier, we sought to determine the
barrier surfaces are actively recognized by the ing of host immunity and pathologies. Because impact of environmental stressors on commensal-
immune system. Encounters with noninvasive barrier tissues are defined by the constitutive specific tissue-resident T cells. After colonization,
symbionts can lead to the induction of cognate coexistence of commensals (and associated anti- S. epidermidis–specific polyclonal CD8+ T cells
gens) and commensal-reactive lymphocytes, our were identified as T-bet + CCR6 − TC1 cells or
Mucosal Immunology Section, Laboratory of Parasitic Diseases,
understanding of tissue homeostasis, response to RORgt+CCR6+ TC17 cells [of which ~30% have
National Institute of Allergy and Infectious Diseases, Bethesda, injury, and tissue-specific pathologies must occur interleukin (IL)–17A production potential] (Fig.
MD 20892, USA. 2Molecular Immunology and Inflammation in the context of this fundamental dialog. 1, F and G). Although the intradermal injection
Branch, National Institute of Arthritis and Musculoskeletal and The skin serves as a primary interface with of chitin or sand fly (Lutzomyia longipalpis)
Skin Diseases, Bethesda, MD 20892, USA. 3NIAID Microbiome
Program, National Institute of Allergy and Infectious Diseases,
the environment and is consequently a consti- bites had no impact on the potential for IL-17A
Bethesda, MD 20892, USA. 4Biological Imaging, Research tutive target of environmental stressors medi- and interferon (IFN)–g production by TC17 and
Technology Branch, National Institute of Allergy and Infectious ated by physical damage, invasive pathogens, TC1 cells, respectively (Fig. 1H), both stressors
Diseases, Bethesda, MD 20892, USA. 5Leidos Biomedical impaired immune regulation, or the nutritional revealed a surprising potential for the produc-
Research Inc., Basic Science Program, Cancer and Inflammation
Program, Frederick National Laboratory for Cancer Research,
state of the host. Tissue protection from these tion of IL-5 and IL-13 from S. epidermidis–
Bethesda, MD 20892, USA. 6Experimental Immunology Branch, challenges relies on rapid and coordinated local elicited TC17 cells, including f-MIIINA:H2-M3+
National Cancer Institute, Bethesda, MD 20892, USA. 7Inserm responses tailored to both the microenvironment CD8+ T cells (Fig. 1, H and I, and fig. S1, B and
Unité 976, Hôpital Saint-Louis, Paris, France. 8Intracellular and the nature of the instigating injury. Recently, C). Increased type 2 cytokine production after
Parasite Biology Section, Laboratory of Parasitic Diseases,
National Institute of Allergy and Infectious Diseases, Bethesda,
the discovery that cells such as innate lymphoid chitin or sand fly challenge was also observed
MD 20892, USA. 9Cancer and Inflammation Program, National cells (ILCs) can rapidly respond to mediators from RORgt-expressing CD4 + T cells (TH17)
Cancer Institute, Bethesda, MD 20892, USA. released during tissue damage has provided a elicited by S. epidermidis (fig. S1D). Thus, RORgt+
*Present address: Department of Cancer Immunology, Genentech, framework to begin to understand this phenom- T cells (both CD8+ and CD4+ T cells) elicited
South San Francisco, CA 94080, USA. †Present address: Institut
de Génétique Moléculaire de Montpellier, University of Montpellier,
enon. Whether tissue-resident T cells, particu- by encounter with a commensal may have the
CNRS, Montpellier, France. ‡Corresponding author. Email: larly those specific to commensals, can also act unexpected potential to produce type 2 cytokines as tissue sentinels allowing rapid adaptation to in response to defined tissue challenges.

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 1 of 11


A Polyclonal B Polyclonal
CD8+ T cells BowieTg T cells f-MIIINA:H2-M3+ T cells CD8+ T cells BowieTg T cells f-MIIINA:H2-M3+ T cells
23±3 2±1 20±4 2±1 18±2 3±1 18±2 66±6 19±3 73±8 11±1 72±5


22±5 24±2 26±4 10±4 7±5 12±4

IFN-γ CD69
C CD8α CD45.1 CD8α CD45.1

150µm 50µm

CD49f DAPI CD8a CD45.1 (BowieTg)

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f-MIIINA:H2-M3+ T cells CD8+ T cells CD8+ T cells CD8+ T cells
f-MIIINA:H2-M3+ (% Host)

100 7±2 88±2

Tc17 16±5



Tc1 47±5
25 34±8
0 7±1


CD69 T-bet CCR6 CCR6


H 30 30 10 ** 6 **
8 ** **
IL-17A+ (%)

IL-13+ (%)
IFN-γ+ (%)

IL-5+ (%)

20 20 4

10 10 2

0 0 0 0

nd in

nd n
i.d PB l

i.d . PB l


.C S

.C S



nd in

nd n


nd in

nd n

nd in

nd in
i.d PB l

. P rl
. r

i.d PB l

i.d . PB l

i.d PB l

i.d PB l
.C S

.C S
.C S

.C S

.C S

.C S
Sa hiti

. r
. r

. r

. r
i.d Ct

i.d Ct

Sa hiti
Sa hit

Sa iti

i.d Ct

i.d Ct
i.d Ct

i.d Ct

i.d Ct

i.d Ct
Sa hit
Sa hit

Sa hit

Sa hit
i.d B

Tc1 Tc17 Tc1 Tc17 Tc1 Tc17 Tc1 Tc17

Fig. 1. Acute injury licenses type 2

I CD8+ T cells CD8+ T cells
cytokine production from commensal- i.d. PBS i.d. Chitin i.d. PBS i.d. Chitin
specific type 17 cells. (A to C) S. epidermidis–
41±7 0.4±0.3 43±5 4±2 43±6 0.2±0.1 41±4 2±1
specific TCR-transgenic CD8+ T cells (BowieTg)
were adoptively transferred to wild-type mice


before colonization with S. epidermidis. (A)

Representative contour plots of IL-17A and
IFN-g production potential; (B) expression of
tissue residency markers CD69 and CD103 by 0.2±0.1 0.4±0.3 0.1±0.1 0.4±0.2
indicated CD8+ T cell populations; (C) repre-
IL-5 IL-13
sentative confocal imaging volume projected
along the z axis of epidermal skin from S. epidermidis–colonized mice. (D and E) colonized wild-type mice were exposed to bites from sand flies (L. longipalpis)
Conjoined pairs of S. epidermidis–colonized CD45.1 and CD45.2 mice were or injected intradermally (i.d.) with PBS or chitin. (H) Frequencies of TC1
analyzed 90 days after parabiosis surgery for cellular origin and phenotype. and TC17 cells with cytokine-producing potential from the skin of S.
(D) Frequency of host-derived f-MIIINA:H2-M3+ CD8+ T cells in indicated epidermidis–colonized wild-type mice after skin injury. (I) Representative
tissues; SLN, skin-draining lymph nodes. (E) Representative contour plot of contour plots of IL-5 and IL-13 production potential by CD8+ T cells from
CD69 and CD103 expression by skin f-MIIINA:H2-M3+ CD8+ T cells. (F) the skin of S. epidermidis–colonized wild-type mice after skin injury.
Representative contour plot of RORgt and T-bet expression by CD8+ T cells Numbers in representative plots indicate means ± SD. Bar graphs show
from the skin of S. epidermidis–colonized wild-type mice. (G) Representative means ± SD. Data represent at least two experiments with four to six mice
contour plots of RORgt, CCR6, and IL-17A expression by CD8+ Tcells from the per group. **P < 0.01 (one-way ANOVA with Holm-Šidák multiple-
skin of S. epidermidis–colonized wild-type mice. (H and I) S. epidermidis– comparison test).

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 2 of 11


Fig. 2. Local defects A S. epidermidis - CD8+ T cells C

in immunoregulation
51±5 0.7±0.3 5±2 48±5
unleash type 2
immunity from


T cells. (A) Represent-
ative contour plots of 0.8±0.3 9±2
RORgt and GATA-3
Isotype GATA-3 Foxp3 DAPI CD8α
expression by skin
CD8+ T cells from B D E
S. epidermidis–colonized S. epidermidis C. albicans Foxp3YFP-CreGata3fl/wt Foxp3YFP-CreGata3fl/fl
100 RORγt
wild-type mice. (B) Rep-

Foxp3+ LDTF+ (%)

Iso Iso *** GATA-3 27±4 36±5 21±3 13±5
Th17 Th17 80
resentative histogram T-bet

% max

plots of GATA-3 60

expression by RORgt+ 40

CD4+ TH17 cells from 20

3±2 8±4
the skin of commensal- 0


Lu T
ym P
M s

Li N

M d
Bl er
colonized wild-type CD25


Th siL



mice. (C) Representa-
tive confocal imaging F G H I

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volume-projected YFP-Cre YFP-Cre 15 15 50 15 ** 100 Foxp3YFP-CreGata3fl/fl
Foxp3 Foxp3 ** ** **

Eosinophils (%)
along the z axis of
CD4+ IL-5+ (%)

Skin inflammation
CD4+ IL-13+ (%)

Basophils (%)

penetrance (%)
fl/wt fl/fl 40
Gata3 Gata3
epidermal skin from 10 10 30
S. epidermidis–colonized 50
SLN 20
Foxp3gfp mice. (D) Fre- 5 5 5
quencies of Foxp3+ Treg Foxp3YFP-CreGata3fl/wt
0 0 0 0
cells coexpressing PLN 0
Skin Skin Skin Skin 0 100 200 300
lineage-defining Spleen
Age (days)
YFP-Cre fl/wt YFP-Cre fl/fl
transcription factors Foxp3 Gata3 Foxp3 Gata3
(LDTFs) within indicated
tissues of naïve wild- J K L Foxp3YFP-CreGata3fl/wt Foxp3YFP-CreGata3fl/fl
type mice. VAT, visceral Foxp3YFP-CreGata3fl/wt Foxp3YFP-CreGata3fl/wt Foxp3YFP-CreGata3fl/fl
adipose tissue; cLP, 2.5 *** 2.5 ***

CD8+ IL13+ (x103)

20±3 0.4±0.3 26±5 7±2
colonic lamina propria; 2.0 2.0CD8+ IL-5+ (x103)

siLP, small intestinal 1.5 1.5

lamina propria; MAT, 1.0 *
mesenteric adipose *
0.5 0.5
tissue; SLN, skin- 3±1 3±2
draining lymph node; 0 0
YFP-Cre fl/fl
Foxp3 Gata3 IL-5 Naïve S. epi Naïve S. epi
PP, Peyer’s patch; PLN,
para-aortic lymph
node; MLN, mesenteric
M Foxp3YFP-CreGata3fl/wt Foxp3YFP-CreGata3fl/fl Foxp3YFP-CreGata3fl/wt Foxp3YFP-CreGata3fl/fl

lymph node; BM, bone 51±5 0.6±0.3 52±6 5±2 44±5 0.7±0.5 46±6 4±3

marrow. (E) Represent-


CD8 T cells

ative contour plots of

Foxp3 and CD25
expression by skin

0.3±0.1 0.5±0.3 0.5±0.4 0.7±0.5

CD4+ T cells from naïve
Foxp3 YFP-Cre
Gata3 fl/wt
4±2 54±4 0.5±0.2 50±7 4±3 49±7 0.5±0.4 48±9 4±2
and Foxp3YFP-CreGata3fl/fl
BowieTg Donor

BowieTg Donor

mice. (F) Representative BowieTg

cutaneous lymphadeno-
pathy in Foxp3YFP-Cre-
Gata3fl/fl compared to 0.3±0.1 0.2±0.1 0.7±0.4 0.3±0.1
IL-5 IL-13
control mice. (G) Fre-
quencies of IL-5– and IL-13–producing skin CD4+ T cells from naïve of IL-5– and IL-13–producing CD8+ T cells from the skin of S. epidermidis–
Foxp3YFP-CreGata3fl/wt and Foxp3YFP-CreGata3fl/fl mice. (H) Frequencies colonized Foxp3YFP-CreGata3fl/wt and Foxp3YFP-CreGata3fl/fl mice.
of skin eosinophils and basophils from naïve Foxp3YFP-CreGata3fl/wt and (M) Representative contour plots of IL-5 and IL-13 production by CD8+ Tcells in
Foxp3YFP-CreGata3fl/fl mice. (I) Cumulative incidence of skin inflammation Foxp3YFP-CreGata3fl/wt and Foxp3YFP-CreGata3fl/fl mice adoptively transferred
among naïve Foxp3YFP-CreGata3fl/wt and Foxp3YFP-CreGata3fl/fl mice. with BowieTg T cells before colonization with S. epidermidis. Numbers in
(J) Representative histological micrograph of skin tissue from naïve representative plots indicate means ± SD. Each dot represents an individual
Foxp3YFP-CreGata3fl/wt and Foxp3YFP-CreGata3fl/fl mice. Scale bars, 250 mm. mouse. Data represent at least two experiments with three to seven mice per
(K) Representative contour plots of CD8b expression and IL-5 production group. Cumulative skin inflammation data (I) represent 25 mice per genotype.
potential by TCRb+ T cells from the skin of S. epidermidis–colonized *P < 0.05, **P < 0.01, ***P < 0.001 as calculated using Student t test [(G), (H)]
Foxp3YFP-CreGata3fl/wt and Foxp3YFP-CreGata3fl/fl mice. (L) Total numbers or one-way ANOVA with Holm-Šidák multiple comparison test [(D), (L)].

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 3 of 11


Local defects in immunoregulation vealed colocalization of S. epidermidis–induced were associated with discrete elevated fre-
unleash type 2 immunity from CD8+ T cells and Foxp3+ Treg cells (Fig. 2C). quencies and absolute numbers of eosinophils
commensal-specific T cells As such, we assessed the possibility that skin and basophils in the skin of Foxp3YFP-CreGata3fl/fl
Flow cytometric analysis revealed that TC17 cells Foxp3+ Treg cells could limit type 2 cytokine mice relative to control mice (Fig. 2H and fig.
coexpressed GATA-3, the lineage-defining tran- production by commensal-specific type 17 cells. S2L). Of note, and in agreement with a skin-
scription factor (LDTF) for both TH2 cells and Because complete ablation of Foxp3+ Treg cells specific defect, naïve Foxp3YFP-CreGata3fl/fl mice,
group 2 ILC (ILC2) (Fig. 2A). Such a phenotype results in severe local and systemic inflamma- with an endogenous skin microbiota but not
was also detected among the very few CD8+ tory responses and aberrant accumulation of S. epidermidis, spontaneously developed severe
T cells present in the skin of naïve mice (fig. TC1 cells within the skin (11) (fig. S2, D and E), we skin inflammation (but not systemic inflamma-
S2A), and coexpression of RORgt and GATA-3 used an approach allowing for a tissue-specific tion) with ~70% penetrance by 8 months of age
by S. epidermidis–specific BowieTg CD8+ T cells defect in immunoregulation. Within the skin, (Fig. 2, I and J).
was restricted to the skin and not detectable Treg cells express high levels of GATA-3 (but not To assess the possibility that T cells producing
in secondary lymphoid organs; these findings other LDTFs) (Fig. 2D and fig. S2F), a factor type 2 cytokines within the skin of these mice
suggested that GATA-3 expression is imprinted that contributes to Treg cell stability and fitness are commensal-specific, we colonized young
within the tissue microenvironment (fig. S2B). (12–15). In mice in which Treg cells were condi- Foxp3YFP-CreGata3fl/fl mice (before inflammation)
This phenotype was conserved across T cell tionally deleted of GATA-3 (Foxp3YFP-CreGata3fl/fl), and control mice with S. epidermidis and tracked
lineages and distinct microbial exposures. Nota- Foxp3+ cells were reduced in frequency and ex- the fate of S. epidermidis–specific T cells. Adop-
bly, TH17 cells elicited by skin colonization with hibited decreased Foxp3 and CD25 expression tively transferred BowieTg CD8+ T cells (as well
S. epidermidis or Candida albicans also expressed in the skin, but not in other tissues (Fig. 2E as host polyclonal S. epidermidis–induced CD8+
GATA-3 (Fig. 2B and fig. S2C). Thus, homeostatic and fig. S2, G and H). Consistent with this ob- T cells) expressed IL-5 and IL-13 proteins in the
encounter with bacterial or fungal commensal servation, by 10 weeks of age, skin-draining skin of Foxp3YFP-CreGata3fl/fl mice but not con-

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microbes can lead to the development of cells lymph nodes (but not other lymphoid structures) trol mice (Fig. 2, K to M). By contrast, the ability
with a paradoxical phenotype characterized by were enlarged, and the skin compartments (but of S. epidermidis–elicited CD8+ T cells to produce
the coexpression of classically antagonistic tran- not other tissues) of these mice were charac- IL-17A or IFN-g was unaffected (fig. S2M). Nota-
scription factors. terized by a selective increase in the number bly, type 2 cytokine production by S. epidermidis–
The skin is highly enriched in Foxp3+ regu- of T cells producing IL-5 and IL-13 (Fig. 2, F and specific polyclonal and adoptively transferred
latory T (Treg) cells (5), and confocal imaging re- G, and fig. S2, I to K). Enhanced type 2 responses BowieTg CD8+ T cells remained restricted to cells

Global ATAC-seq analysis Ifng Il17a Il17f
200 350
Tc1 Tc17 Naïve Memory

Tc17 Tc17
Enriched 200 350
motifs Tc1 Tc1
100 250

Tc17 Tc17
100 250
Tc17 specific RORγt Tc1 Tc1
Tc1 specific
Eomes D E
Canonical CD8 Rad50 Il5 Il4 Il13
100 25

Tc1 and Tc17 Tc17 Tc17

100 25
Tc1 Tc1
50 75


50 75
Tc1 Tc1
-1kb 0 +1kb

GATA-3 binding motif GATA-3 binding motif

Eo 6

Il1 21
Tb g

G 3

Il1 2
Kl es

Il1 b
Il1 r
R a

C f


Il1 c


Pr 1




r l1



Il13 Promoter/TSS (RPM)

Il5 Promoter/TSS (RPM)

80 * 60

Tc1 60
1 Tc17 20

0 0
type 17 type 1 type 2 17 c1 17 Tc1
Tc T Tc

Fig. 3. S. epidermidis–specific TC17 cells express a broad type 2 the right. (B to E) Genomic tracks of ATAC-seq and RNA-seq signal profiles
signature. TC17 (CD8+CCR6+) and TC1 (CD8+CCR6−) cells were isolated in TC17 and TC1 cells across signature cytokine genes. Genomic location of
by FACS from the skin of S. epidermidis–colonized wild-type mice for TC17-specific regulatory elements with GATA-3 binding motifs are denoted by
transcriptomic and epigenetic analysis by RNA-seq and ATAC-seq. ATAC-seq red triangles. (F) Heat map of lineage-specific signature genes expressed
signals from canonical naïve and memory CD8+ T cells were from lymphoid by TC17 and TC1 populations. (G) Chromatin accessibility at transcription
tissue. (A) Global comparison of ATAC-seq signals in S. epidermidis–induced start site (promoter ± 500 bp) of Il5 and Il13 in TC17 and TC1 cells. Bar graphs
TC17 and TC1 and canonical naïve and memory CD8+ T cells. Representative show means ± SD. Sequencing data represent two or three independent
transcription factor binding motifs enriched in indicated groups are listed on biological replicates. *P < 0.05 (Student t test).

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 4 of 11


A B Ccr6 Rorc Tbx21

Merge IL-17AFM+ Tc17

tSNE 2

20 Il17a Il13 Il5


tSNE 2
−20 0
CCR6- Tc1 IL-17AFM- Tc17
−40 −20 0 20 40 −20
tSNE 1
−40 −20 0 20 40
tSNE 1

C Tc17 D
IFN-γ IL-17A IL-5 IL-13 Tc17 Tc17

IL-17A Protein
IL-17A Protein
1±1 2±1 11±3 19±4 0.3± 0.2±0.1 0.2± 0 28±5 0.2±0.1 27±6 4±2
0.2 0.1

Downloaded from on January 7, 2019

0.5±0.3 5±1 12±3 10±2 0.3±0.1 16±5

mRNA IL-5 Protein IL-5 mRNA

E Tc17 Tc17 F
mRNA relative expression

Il5 Il13 Il17a

IL-17A Protein

CreERT2Gata3 fl/fl
IL-17A Protein

28±4 0.3±0.2 23±5 4±2 30 30 90

* * ** ** * Vehicle
20 20 60

10 10 30

0.4±0.3 14±3
0 0 0
IL-13 Protein IL-13 mRNA Tc1 Tc17 Tc1 Tc17 Tc1 Tc17

Fig. 4. S. epidermidis–specific TC17 cells harbor a poised type 2 tran- production potential and Il5 or Il13 mRNA expression by TC17 cells from the
scriptome. (A and B) TC1 (CD8+CCR6−), IL-17AFM+ TC17 (CD8+CCR6+eYFP+), skin of S. epidermidis–colonized wild-type mice. (F) S. epidermidis–colonized
and IL-17AFM− TC17 (CD8+CCR6+eYFP−) cells were isolated by FACS from the CreERT2Gata3fl/fl mice received tamoxifen or vehicle control before cell
skin of S. epidermidis–colonized Il17aCreR26ReYFP (IL-17AFM) mice and sorting of skin TC1 and TC17 cells. Gene expression in the indicated
analyzed by scRNA-seq. (A) tSNE plots of scRNA-seq expression highlighting populations was assessed by quantitative reverse transcription polymerase
TC1 (gray), IL-17AFM+ TC17 (orange), and IL-17AFM− TC17 (blue) populations. chain reaction (qRT-PCR). Numbers in representative plots indicate means ±
(B) Expression of LDTFs and cytokine genes projected onto a tSNE plot. SD. Flow cytometric data represent at least two experiments with four to
(C) Representative dot plots of cytokine protein production potential and six mice per group. qRT-PCR data represent three biological replicates
mRNA expression by TC17 cells from the skin of S. epidermidis–colonized of eight pooled mice per group. *P < 0.05, **P < 0.01 (one-way ANOVA with
wild-type mice. (D and E) Representative dot plots of IL-17A and IL-5 or IL-13 Holm-Šidák multiple-comparison test).

expressing CCR6; this result shows that in the tissue (16). Regulatory elements unique to skin relative to TC1 cells (Fig. 3, D to G, and fig. S3C).
context of local immune defects, type 2 cytokines TC17 or TC1 cells were enriched in binding sites Furthermore, TC17 cells expressed a broad type 2
can be unleashed from RORgt-committed T cells for RORgt, and for T-bet and Eomes, respectively transcriptome, including a LDTF (Gata3) and
(Fig. 2M). Thus, impaired local immunoregu- (Fig. 3A), consistent with subset-specific expres- cytokine and chemokine receptors (Ccr8, Il1rl1,
lation promotes type 2 cytokine production by sion of these LDTFs (Fig. 1F). Elevated chroma- and Il17rb), but neither Il4 nor Il10 mRNA, as
commensal-specific type 17 cells—a property that tin accessibility and transcript abundance of the previously described for tissue-derived TH2 cells
may predispose tissue to inflammation. signature cytokines Ifng, Il17a, and Il17f also (18) (Fig. 3F and fig. S3D). The type 2–associated
confirmed the clear distinction between TC1 and cytokine amphiregulin (Areg) was detectable in
S. epidermidis–specific TC17 cells harbor TC17 cell subsets (Fig. 3, B and C, and fig. S3, A both cell subsets, albeit at higher abundance in
a poised type 2 transcriptome and B). Among regulatory elements unique to TC17 cells (fig. S3D). As such, commensal-specific
To gain insight into the transcriptional and epi- TC17 cells, we identified previously described TC17 cells express a broad type 2 transcriptome
genetic landscape of commensal-specific T cells GATA-3–binding sites within Il13 and the Rad50/ under homeostatic conditions.
under homeostatic conditions, we identified TH2 locus control region (17) (Fig. 3, D and E). Of S. epidermidis–induced TC17 cells, ~30%
global regulatory elements shared between, and Consequently, TC17 cells demonstrated elevated displayed the potential for IL-17A production
unique to, S. epidermidis–specific polyclonal TC17 chromatin accessibility at type 2 immune gene (Fig. 1G), supporting the idea of possible pheno-
(CCR6+) and TC1 (CCR6−) cells from the skin and loci encoding Il5 and Il13 and expressed ele- typic heterogeneity. However, using cells from IL-
naïve and memory CD8+ T cells from lymphoid vated levels of Il5 and Il13 mRNA transcripts 17A fate-mapping mice (IL-17AFM–Il17aCreR26ReYFP)

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 5 of 11


and single-cell RNA sequencing (scRNA-seq), IL-1a significantly increased the ex vivo pro- are found during allergic asthma and helminth
t-distributed stochastic neighbor embedding duction of IL-17A from TC17 cells in the context infection (25–29). Previous studies also demon-
(tSNE) projection of TC1, IL-17AFM+ TC17, and of TCR stimulation (Fig. 5A). As previously re- strated plasticity of effector TH17 cells to convert
IL-17AFM− TC17 cells demonstrated consider- ported, IL-18 and IL-33 promoted IFN-g pro- to TH1, follicular helper (TFH), and Treg cell
able transcriptional overlap between IL-17AFM+ duction by TC1 cells (23, 24) (Fig. 5B). Notably, phenotypes in a context-dependent manner
and IL-17AFM− TC17 cell fractions, with type 2 several alarmins promoted the production of (26, 30, 31). Our work supports the idea that
cytokine mRNA–expressing cells present in both IL-5 (IL-18, IL-25, and IL-33) or IL-13 (IL-1a, such plasticity may be a fundamental fea-
fractions (Fig. 4, A and B, and fig. S4A). Thus, IL-1b, IL-18, and IL-33) (Fig. 5, C and D). IL-25 ture of tissue-resident commensal-specific T
commensal-specific TC17 cells, including those potently promoted the production of IL-5 but cells. To specifically address this point, we used
already committed to IL-17A production, can be not IL-13 (Fig. 5, C and D), supporting the idea IL-17AFM mice to assess in vivo the heritage of
superimposed with the expression of a type 2 that distinct classes of injury may have differ- TC17 cells licensed for type 2 cytokine produc-
transcriptome. Furthermore, in situ hybridiza- ent impacts on commensal-specific T cell re- tion. In line with the finding that both IL-
tion for mRNA detection by flow cytometry sponses. Strikingly, IL-18, a cytokine widely 17AFM− and IL-17AFM+ TC17 cells display poised
revealed that Il5 and Il13 transcripts, but not linked to the initiation of type 1 responses, was Il5 and Il13 mRNA expression (Fig. 4, B to E),
protein, were expressed selectively by TC17 cells particularly potent at eliciting the release of IL-18 triggered type 2 cytokine production
from the skin of S. epidermidis–colonized mice both IL-5 and IL-13 from TC17 cells ex vivo from both TC17 and TH17 cells regardless of
(Fig. 4C and fig. S4B). In line with our scRNA- (Fig. 5, C and D). IL-18 also promoted IL-17A whether they had previously expressed IL-17A
seq data (Fig. 4B and fig. S4A), Il5+ and Il13+ production by TC17 cells, further supporting (IL-17AFM+ and IL-17AFM−) (Fig. 6, A and B).
cells were found within both IL-17A–producing the idea that this alarmin can superimpose Thus, within commensal-induced TC17 and TH17
and IL-17A–nonproducing fractions of TC17 cells type 2 responses upon a precommitted type 17 cell populations, plasticity among IL-17AFM+ cells
(Fig. 4, D and E); this suggests that during ho- program (Fig. 5A). Under these conditions, IL- and local licensing of IL-17AFM− cells both con-

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meostasis, commensal-specific TC17 cells express 4 and IL-10 were undetectable (fig. S5B), but tribute to alarmin-mediated induction of type 2
type 2 cytokine mRNA without subsequent pro- both TC1 and TC17 cells produced amphiregu- cytokine production.
tein translation. The inducible deletion of Gata3 lin upon TCR stimulation, a response that was Although a few reports have suggested that
at the peak of the CD8+ T cell response to S. also enhanced by IL-18 (fig. S5C). Type 2 re- IL-18 can potentially promote type 2 and reg-
epidermidis revealed that sustained GATA-3 ex- sponses to IL-18 were not restricted to CD8+ T ulatory responses (32–34), this cytokine is more
pression by TC17 cells was required for the consti- cells nor to S. epidermidis–elicited cells. Indeed, widely considered to promote type 1 immunity.
tutive expression of Il5 and Il13, but, as expected, skin CD4+ T cells induced by S. epidermidis or In support of a major role for IL-18 in the
not for Il17a (Fig. 4F). Thus, S. epidermidis–specific C. albicans colonization (including TH17 cells) promotion of skin type 2 responses, IL-18 in-
TC17 cells express a poised type 2 transcriptome also produced higher levels of IL-5 and IL-13 jection promoted type 2 cytokine production
dependent on continued GATA-3 expression. upon IL-18 and TCR stimulation in vitro (fig. S5, not only by T cells but also by ILC2, as re-
Accordingly, type 2 cytokine competency D to F). Thus, such poised type 2 potential may cently described (Fig. 6C) (35). In contrast to
(mRNA expression) and licensing (stimuli- be the norm for type 17 commensal-specific T transient ILC2 responses, induction of type 2
induced protein production) are temporally cells raised under homeostatic conditions. In cytokine expression by T cells was sustained
decoupled in S. epidermidis–elicited TC17 cells— this context, local inflammatory factors includ- up to 4 days after injection (Fig. 6C). Thus,
a process likely involving the posttranscriptional ing IL-1, IL-18, IL-25, and IL-33 can superimpose type 2 cytokine licensing by IL-18 may have a
regulation of cytokine mRNA stability and pro- a type 2 effector program. profound effect on skin physiology via the
tein translation. Under inflammatory conditions, To assess the impact of a single defined broad impact of a defined alarmin on both
previous work revealed that distinct stimuli alarmin on commensal-specific T cells, we next tissue-resident commensal-specific T cells and
can govern competency and licensing of type 2 focused on the impact of IL-18 in vivo. A single ILC2 (35). Indeed, IL-18 injection promoted
immunity within injured tissues, ensuring injection of IL-18 licensed both IL-5 and IL-13 an IL-5–dependent eosinophil accumulation
tissue-restricted effector function during path- protein production by S. epidermidis–elicited within the skin compartment of S. epidermidis–
ogen infection (19). Recent findings also suggest TC17 (including f-MIIINA:H2-M3+ cells) and colonized mice (Fig. 6D and fig. S6A). Thus,
that IFN-g production by CD8+ T cells is actively CD4+ T cells (including TH17 cells) (Fig. 5, E to tissue-resident commensal-specific type 17 T
regulated at the level of translation, thereby G, and fig. S5, G and H). Type 2 cytokine li- cells can adapt to defined injury by direct sen-
preventing chronic immune activation (20–22). censing by IL-18 occurred at the expense of sing of alarmins and inflammatory mediators.
IL-17A production, suggesting dynamic regu- Because of the known contribution of type 2
Alarmins license type 2 cytokine lation of cytokine production by commensal- immunity and IL-13 in particular to tissue re-
production by commensal-specific specific TC17 and TH17 cells in vivo (Fig. 5, E pair, we next used a model of skin wounding
TC17 cells to G). The ability of TC17 and TH17 cells to pro- to assess the potential contribution of commensal-
Our work proposes that such a phenomenon duce type 2 cytokines in response to IL-18 was specific type 2 cytokine licensing to this funda-
may also apply to commensal-specific T cells dependent on T cell–intrinsic IL-18R1 signaling mental process. Although IL-13 did not contribute
generated under homeostatic conditions. To (Fig. 5, H and I) and was sustained up to 60 days to the healing process in unassociated mice,
identify the factors capable of licensing poised after colonization (fig. S5I). After chitin injection, IL-13 neutralization or genetic Il13 deficiency
type 2 immunity from commensal-specific T cells, type 2 licensing of TC17 and TH17 cells was also impaired S. epidermidis–accelerated wound re-
we used an ex vivo screening approach, stimu- IL-18R1 signaling–dependent (Fig. 5, H and I); pair (Fig. 6, E and F). Adoptive transfer of wild-
lating TC17 and TC1 cells with cytokines and these findings support the idea that in defined type BowieTg CD8+ T cells rescued this defect
alarmins previously shown to be associated with inflammatory settings, IL-18 alone may be suf- in an IL-13–dependent manner (Fig. 6F). In agree-
tissue damage. Cytokine stimulation alone did ficient to impose this response. ment with the role of IL-13 in tissue repair
not promote type 2 cytokine production by skin (36), whole-tissue RNA-seq of skin after wound-
T cells, demonstrating that these cells cannot be Commensal-specific T cell plasticity and ing revealed an IL-13–dependent transcriptional
licensed in a TCR-independent manner (fig. S5A). IL-13 production promote wound repair signature dominated by pathways associated
Because commensal microbes persist within The co-production of cytokines associated with with muscle contractility and extracellular matrix
the skin, this result is consistent with the ex- distinct T cell subsets can occur during inflam- reorganization (Fig. 6G and fig. S6B). Notably, in
pectation that exposure to alarmins will occur mation. For example, IL-17A+IFN-g+ cells are line with the fact that punch biopsies can trigger
in the context of antigen exposure. However, present during intestinal and central nervous the release of numerous factors able to license
in line with the role of IL-1 within the skin (4), system inflammation, and IL-17A+IL-4+ cells type 17 cells (Fig. 5, C and D), IL-18 was insufficient

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 6 of 11


A B C ** D
** *
2.0 150 200
** 500 **
* ** *
IL-17A (ng/ml)

** *

IFN-γ (ng/ml)

IL-13 (pg/ml)

IL-5 (pg/ml)
1.5 150
1.0 100
0.5 50

0 0 0 0

IL α
IL ia

IL 8
IL 5
TS 33
IL β
IL α

IL α

IL α
IL ia

IL 8
IL 5
TS 33

IL ia

IL 8
IL 5
TS 3

IL ia

IL 8
IL 5
TS 3
IL β

IL β

IL β






Tc17 Tc1 Tc17 Tc17

E Tc17 F CD4+ CCR6+ CD4+ CCR6+ CD4+ CCR6- CD4+ CCR6-

i.d. PBS i.d. IL-18 i.d. PBS i.d. IL-18 i.d. PBS i.d. IL-18
25±4 0.2±0.1 16±5 4±2 22±4 1±0.3 10±3 3±2 3±1 0 2±1 0.3±0.1


Downloaded from on January 7, 2019

0.6±0.3 15±3 2±1 17±5 3±1 18±4

IL-5 IL-5

G * H
20 ** 30 25 i.d. PBS 20 * 8
** 10

IL-5+ Tc17 (%)

IL-13+ Tc17 (%)

20 i.d. IL-18 *
IL-17A+ (%)

15 * 6
IFN-γ+ (%)
IL-13+ (%)
IL-5+ (%)

15 20
10 5 10 4
5 5 2

0 0 0 0 0 0
Tc1 Tc17 Tc1 Tc17 Tc1 Tc17 Tc1 Tc17 PBS IL-18 Chitin PBS IL-18 Chitin
Il18r1 Cd4 Il18r1fl/fl Cre
Fig. 5. Tissue alarmins license type 2 cytokine production from commensal-specific
I 20 8
T cells. (A to D) TC17 (CD8+CCR6+) and TC1 (CD8+CCR6−) cells were isolated from * *

IL-13+ Th17 (%)

the skin of S. epidermidis–colonized wild-type mice and cultured in vitro with agonistic
IL-5+ Th17 (%)

15 * 6 *
anti-CD3e mAb and the indicated cytokines. Cell culture supernatants were assayed
for cytokine production after 24 hours of culture. (E) Representative contour plots 10 4
of IL-5 and IL-17A production potential by S. epidermidis–induced TC17 cells after i.d.
injection with PBS or IL-18. (F) Representative contour plots of IL-5 and IL-17A production 5 2
potential by skin CD4+Foxp3− T cells from S. epidermidis–colonized wild-type mice after
i.d. injection with PBS or IL-18. (G) Frequencies of TC17 and TC1 cells with indicated 0 0
cytokine production potential from the skin of S. epidermidis–colonized wild-type mice PBS IL-18 Chitin PBS IL-18 Chitin
after i.d. injection of PBS or IL-18. (H and I) Frequencies of TC17 (H) and TH17 (I) cells with
Il18r1fl/fl Cd4CreIl18r1fl/fl
indicated cytokine production potential from the skin of S. epidermidis–colonized
Cd4 Il18r1
Cre fl/fl
and control mice after i.d. injection with PBS, IL-18, or chitin. Numbers in
representative plots indicate means ± SD. Bar graphs show means ± SD. Data represent at least two experiments with three to six mice per group.
*P < 0.05, **P < 0.01 as calculated using one-way [(A) to (D), (G)] or two-way [(H), (I)] ANOVA with Holm-Šidák multiple-comparison test.

to promote these responses (fig. S6C). Thus, the Our results show that adaptation of tissue to and contextual functions including tissue repair.
poised type 2 immune potential of commensal- injuries can also be mediated by immunity to Thus, we describe a tissue checkpoint that relies
specific TC17 cells allows for local adaptation to the microbiota, a fundamental but poorly under- on the remarkable plasticity and adaptability of
injury, thereby promoting tissue repair. stood class of immunity. Notably, we found that tissue-resident commensal-specific T cells. We pro-
homeostatic immunity to bacteria or fungal com- pose that this feature may also have important
Conclusion mensals is characterized by the coexpression of implications in the etiology of tissue-specific
Barrier tissues are constitutively exposed to en- paradoxical programs, allowing commensal- inflammatory disorders. Given the extraordinary
vironmental stressors and are primary targets of specific T cells, when entering and persisting number of both commensal-derived antigens and
chronic inflammatory disorders. The mainte- within tissues, to adopt a type 17 program com- T cells at barrier sites, such a feature may represent
nance of tissue integrity and function represent patible with tissue homeostasis and immunity a fundamental component of host immunity.
a complex challenge that requires both resilience while maintaining a type 2–poised state. As such,
and adaptation. Under steady-state conditions, in the context of injury and consequent exposure Materials and methods
tissue resilience is, in part, mediated by innate to inflammatory mediators and cognate antigens, Mice
and adaptive immunity to the microbiota, which commensal-specific T cells rapidly release type 2 Wild-type (WT) C57BL/6 Specific Pathogen
reinforces barrier function and immunity (5). cytokines, allowing these cells to exert pleiotropic Free (SPF) mice were purchased from Taconic

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 7 of 11


A i.d. PBS i.d. IL-18

IL-17AFM+ Tc17 B CD4+ CCR6+ IL-17AFM+
* IL-17A+ 30 ** IL-17A+
29±2 0.4±0.2 15±4 3±2 * IL-17A+IL-5+ IL-17A+IL-5+

Cytokine+ (%)
* IL-5+ ** IL-5+

Cytokine+ (%)
20 20
CD8+ T cells **
eYFP (Il17aFM)

10 10

0.6±0.4 12±4
0 0
IL-5 PBS IL-18 PBS IL-18

i.d. PBS i.d. IL-18 IL-17A FM-

Tc17 CD4 CCR6 IL17AFM-
+ +

30 IL-17A+ 30 IL-17A+
15±3 0.4±0.1 9±3 2±1 * IL-17A+IL-5+
IL-17A+IL-5+ **

Cytokine+ (%)

Cytokine+ (%)
* IL-5+ IL-5+

20 * 20

10 10 **
0.5±0.3 15±4
0 0
IL-5 PBS IL-18 PBS IL-18


Epidermal tongue (x 103 µm)

ILC2 Isotype

Downloaded from on January 7, 2019

6 3 CD4+
4 * * Isotype 2.0 * * anti-IL-13
IL-13+ Cells (x103)
IL-5+ Cells (x103)


Eosinophils (x104)
Tc17 3 1.5
4 2
2 1.0
2 1
1 0.5

0 0 0 0
0 24 48 72 96 0 24 48 72 96 S. epidermidis

i.d. IL-18

hours post IL-18 injection hours post IL-18 injection


F Naive S. epidermidis WT
Epidermal tongue (×103 µm)

** *** * * IL-13-dependent pathways

Extracellular matrix organization
1.5 Striated muscle contraction

1.0 Muscle contraction

Degradation of extracellular matrix
-8 -6 -4 -2 0
0 Fig. 6. Commensal-specific T cell plasticity and IL-13 production
Enrichment score
+ promote wound repair. (A) Representative contour plots for gating
g + (Log10 p adjusted)
e pe ieT -13
no transfer
owi oty w -IL strategy of CCR6 and eYFP (enhanced yellow fluorescent protein)
B is B o t i
T T an expression by CD8+ T cells from the skin of S. epidermidis–colonized
Il17aCreR26ReYFP (IL-17AFM) mice after i.d. injection of PBS or IL-18.
Contour plots represent IL-5 and IL-17A production potential of IL-17AFM+ TC17 (CD8+CCR6+eYFP+) or IL-17AFM− TC17 (CD8+CCR6+eYFP−) T cells after
i.d. injection of PBS or IL-18. (B) Frequencies of TH17 cells with IL-17A– or IL-5–producing potential from the skin of S. epidermidis–colonized IL-17AFM
mice after i.d. injection of PBS or IL-18. (C) Absolute cell number of IL-5– and IL-13–producing lymphocyte subsets in the skin of S. epidermidis–colonized
wild-type mice after i.d. injection of IL-18. Data are means ± SD of five mice per group. (D) Absolute number of eosinophils from the skin of S. epidermidis–
colonized wild-type mice after i.d. injection with PBS or IL-18, and i.p. injection with anti–IL-5 or isotype control. (E and F) Naïve and S. epidermidis–colonized
wild-type and Il13−/− mice, with or without adoptive transfer of BowieTg CD8+ T cells before colonization and isotype or anti–IL-13 antibodies at the time of
wounding, were subjected to back-skin punch biopsy. Epithelial tongue length of wound bed–infiltrating keratinocytes was quantified 5 days after wounding.
(G) Pathway analysis using differentially expressed genes between d3 isotype and d3 anti–IL-13 wounding groups was performed using Enrichr and graphed
according to enrichment score for significant Reactome biological processes. Numbers in representative plots indicate means ± SD. Bar graphs show
means ± SD. Data represent at least two experiments with three to seven mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 as calculated using one-way [(A),
(B), (D)] or two-way [(E), (F)] ANOVA with Holm-Šidák multiple-comparison test.

Biosciences. Gata3fl/fl (37), Foxp3YFP-Cre (38) and NIAID-Taconic Exchange. Tcra+/− mice were American Association for the Accreditation of
Il17aCre (26) have been previously described and generated by breeding Tcra−/− mice with C57BL/6 Laboratory Animal Care (AAALAC)–accredited
were generously provided by J. Zhu (NIAID, NIH), WT mice. Foxp3DTR (B6.129(Cg)-Foxp3tm3(DTR/GFP) animal facility at NIAID and housed in accord-
A. Rudensky (Memorial Sloan Kettering Cancer Ayr/J) (11) and R26ReYFP (B6.129X1-Gt(ROSA) ance with the procedures outlined in the Guide
Center), and B. Stockinger (Francis Crick Insti- 26Sortm1(EYFP)Cos/J) (43) mice were purchased for the Care and Use of Laboratory Animals. All
tute), respectively. Foxp3gfp (39), CD45.1 (B6.SJL- from The Jackson Laboratory. CD4CreIl18r1fl/fl experiments were performed at NIAID under an
Ptprca Pepcb/BoyJ), Tcra−/− (B6.129S2-Tcratm1Mom/J) and Il18r1fl/fl control mice were kindly provided Animal Study Proposal (LPD-11E or LPD-68E)
(40), CD45.1 Rag1−/−, Il13−/− (41), and CreERT2- by G. Trinchieri (NCI, NIH). All mice were bred approved by the NIAID Animal Care and Use
Gata3fl/fl mice (42) were purchased from the and maintained under SPF conditions at an Committee. Sex- and age-matched mice between

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 8 of 11


6 and 35 weeks of age were used for each was removed and mice were joined at the joints. tured directly ex vivo in a 96-well U-bottom plate
experiment. The skin of the two animals was then connected in complete medium (RPMI 1640 supplemented
and sutured together. Animals were kept on oral with 10% fetal bovine serum, 2 mM L-glutamine,
Commensal culture and colonization antibiotics for 2 weeks and remained conjoined 1 mM sodium pyruvate, 1 mM nonessential amino
Staphylococcus epidermidis NIHLM087 (44) was for 90 to 95 days before analysis. Analysis was acids, 20 mM HEPES, 100 U/ml penicillin, 100 mg/
cultured for 18 hours in Tryptic Soy Broth at performed on ear pinnae skin tissue. ml streptomycin, and 50 mM b-mercaptoethanol)
37°C. Candida albicans (8) was cultured for and stimulated with 50 ng/ml of phorbol myris-
18 hours in Tryptic Soy Broth at 37°C (shaking Acute intradermal challenge tate acetate (PMA) (Sigma-Aldrich) and 5 mg/ml
180 rpm). For colonization with commensal S. epidermidis–colonized mice were anesthetized of ionomycin (Sigma-Aldrich) in the presence of
microbes, as before (45), each mouse was topically with ketamine-xylazine and injected intrader- brefeldin A (1:1000, GolgiPlug, BD Biosciences)
associated by placing 5 ml of culture suspension mally (10 ml per ear pinnae) with either sterile for 3 hours at 37°C in 5% CO2. After stimulation,
(approximately 109 CFU/ml) across the entire PBS (vehicle control), 250 ng of carrier-free re- cells were assessed for intracellular cytokine pro-
skin surface (approximately 36 cm2) using a sterile combinant IL-18 (R&D Systems), or 500 ng of duction as described below.
swab. Application of commensal microbes was chitin (Sigma-Aldrich). Unless otherwise indicated,
repeated every other day a total of four times. Skin skin tissue was analyzed for cytokine production Flow cytometric analysis
tissue was analyzed 14 days after initial coloniza- potential 48 hours after injury. Single-cell suspensions were incubated with com-
tion, unless otherwise indicated. binations of fluorophore-conjugated antibodies
Sand fly bite exposure against the following surface markers: CCR6 (29-
Inducible deletion of Gata3 S. epidermidis–colonized mice were exposed to 2L17), CD3e (145-2C11), CD4 (RM4-5), CD8b (53-
Deletion of Gata3 in CreERT2Gata3fl/fl mice was sand fly bites as described (48). Briefly, mice were 6.7), CD11b (M1/70), CD19 (6D5), CD44 (IM7),
induced by intraperitoneal injection of 5 mg anesthetized with ketamine-xylazine. Twenty fe- CD45 (30-F11), CD45.1 (A20), CD45.2 (104), CD69

Downloaded from on January 7, 2019

tamoxifen in a corn oil–ethanol (90:10) mixture male Lutzomiya longipalpus were transferred to (H1.2F3), CD103 (2E7), MHCII (M5/114.15.2), TCRb
daily for 3 days before cellular isolation and sub- plastic vials (volume 12.2 cm2, height 4.8 cm, di- (H57-597), and/or Thy1.2 (30-H12) in Hank’s buf-
sequent analysis. ameter 1.8 cm) covered at one end with 0.25 mm fered salt solution (HBSS) for 20 min at 4°C (RT for
of nylon mesh. Specially designed clamps were 30 min for CCR6) and then washed. LIVE/DEAD
Global Treg cell depletion used to bring the mesh end of each vial flat Fixable Blue Dead Cell Stain Kit (Invitrogen Life
Naïve or S. epidermidis–colonized Foxp3DTR mice against the ear, allowing flies to feed on exposed Technologies) was used to exclude dead cells. Cells
received ~1 mg (50 mg/kg) of diphtheria toxin skin for a period of 1 hour in the dark at 26°C and were then fixed for 30 min at 4°C using BD Cytofix/
(Sigma-Aldrich) in phosphate-buffered saline 50% humidity. The number of flies with blood Cytoperm (Becton Dickinson) and washed twice.
(PBS), or PBS alone, by intraperitoneal (i.p.) meals was employed as a means of checking for For intracellular cytokine staining, cells were
injection on days 3, 5, 7, and 9 after initial S. equivalent exposure to bites among animals. At stained with fluorophore-conjugated antibodies
epidermidis colonization. Flow cytometric anal- indicated time points after exposure, tissues were against IFN-g (XMG-1.2), IL-5 (TRK5), IL-13
ysis of skin leukocytes was performed 12 days analyzed for cytokine production. (eBio13A), and IL-17A (eBio17B7) in BD Perm/Wash
after initial colonization. Buffer (Becton Dickinson) for 60 min at 4°C. For
Ex vivo cytokine screening transcription factor staining, cells were fixed and
Generation of BowieTg mice CD4+ and CD8+ T cell subsets from the skin of permeabilized with the Foxp3/Transcription Fac-
Tcra+/− mice were colonized with S. epidermidis, S. epidermidis– or C. albicans–colonized mice tor staining buffer set (eBioscience) and stained
and CD8+CCR6+ T cells were isolated from skin were isolated by FACS (> 97% purity) and cul- with fluorophore-conjugated antibodies against
tissue by fluorescence-activated cell sorting (FACS) tured for 24 hours in the presence of cytokines Foxp3 (FJK-16s), GATA-3 (L50-823 or TWAJ),
and subjected to single-cell sequencing of TCR a (IL-1a, IL-1b, IL-18, IL-25, IL-33, or TSLP; R&D RORgt (B2D), or T-bet (eBio4B10) for 45 min at
and b chains (46). Clonal TCR pairs were identified Systems) (10 ng/ml) and presence or absence of 4°C. Each staining was performed in the presence
and used in a hybridoma reconstitution screen- TCR stimulation (1 mg/ml plate bound anti-CD3 of purified anti-mouse CD16/32 (clone 93) and
ing assay to identify S. epidermidis–reactive TCR mAb, clone 145-2C11). Culture supernatants were purified rat gamma globulin (Jackson Immuno-
heterodimers. A single S. epidermidis–specific TCR assayed for cytokine production by FlowCytomix research). All antibodies were purchased from
pair was cloned into a hCD2-expression vector bead array (eBioscience). eBioscience, Biolegend, BD Biosciences, or Miltenyi
(47) and used to generate TCR-transgenic mice Biotec. Cell acquisition was performed on a BD
(BowieTg), to track S. epidermidis–specific T cells Tissue processing Fortessa X-20 flow cytometer using FACSDiVa
in vivo. Cells from the skin-draining lymph nodes, spleen, software (BD Biosciences) and data were analyzed
Tg +
and ear pinnae were isolated as described (6). using FlowJo software (TreeStar).
Adoptive transfer of Bowie CD8 T cells Cells from lymph nodes and spleen were mashed
BowieTg mice were backcrossed to a CD45.1 Rag1−/− through a 70-mm cell strainer to generate single- RNA staining
background to exclude the possibility of dual cell suspensions. Ear pinnae were excised and Skin tissue single-cell suspensions were analyzed
TCR expression and facilitate identification of separated into ventral and dorsal sheets. Ear for mRNA and protein expression using the
transferred cells. Recipient mice (CD45.2) re- pinnae were digested in RPMI 1640 media sup- PrimeFlow RNA assay (eBioscience) and standard
ceived 4 × 105 BowieTg CD45.1 Rag1−/− CD8+ T cells plemented with 2 mM L-glutamine, 1 mM sodium mouse probe sets for Ifng, Il5, Il13, and Il17a, as
by intravenous injection 24 hours before the first pyruvate, 1 mM non-essential amino acids, 50 mM per manufacturer’s instructions for 96-well-plate
application of S. epidermidis. b-mercaptoethanol, 20 mM HEPES, 100 U/ml of staining.
penicillin, 100 mg/ml of streptomycin, and
Parabiosis experiments and surgery 0.25 mg/ml of Liberase TL purified enzyme blend Tetramer-based cell enrichment
Congenically distinct, age- and weight-matched (Roche), and incubated for 90 min at 37°C and 5% f-MIIINA:H2-M3-specific CD8+ T cells from sec-
mice were co-housed for 2 weeks before coloniza- CO2. Digested skin sheets were homogenized ondary lymphoid organs were subjected to magnetic
tion with S. epidermidis. Both mice were colonized using the Medicon/Medimachine tissue homog- bead based enrichment, as previously described
to control for bacterial spread. Forty days after enizer system (Becton Dickinson). (49). Briefly, spleen and lymph node cells from
initial colonization, parabiosis surgery was per- parabiotic pairs were stained for 1 hour at room
formed as described (10). Briefly, mice were sedated In vitro restimulation temperature with f-MIIINA:H2-M3-streptavidin-
and longitudinal incisions were made from the For detection of basal cytokine potential, single- phycoerythrin (PE) tetramer. Samples were then
elbow to the knee joint of each mouse. Excess skin cell suspensions from various tissues were cul- incubated with anti-PE beads (Miltenyi Biotech)

Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 9 of 11


and enriched for bead-bound cells on magnetized Single-cell RNA sequencing analysis or 1 mg of anti–IL-5 monoclonal antibody (clone
columns. Sequence reads were processed and aggregated TRFK5, BioXCell) or rat IgG1 isotype control
using Cell Ranger software. Aggregated data were (clone TNP6A7, BioXCell), or 1 mg of anti–IL-18
RNA-sequencing and further analyzed using Seurat (55). monoclonal antibody [clone SK113AE-4 (57)] or
transcriptome analysis isotype control by i.p. injection 1 day before skin
T cells were isolated by flow cytometric cell sorting Confocal microscopy injury.
from the ear skin tissue of C57BL/6 mice 2 weeks Ear pinnae were split with forceps, fixed in 1%
after colonization with S. epidermidis NIHLM087. paraformaldehyde in PBS (Electron Microscopy Total tissue RNA-seq
Groups included: TC1 (Viable Lineage−CD45+ Sciences) overnight at 4°C, and blocked in 1% A ~1-mm skin region surrounding the wound
CD90.2+TCRb+CD8b+CCR6−) and TC17 cells (Viable BSA + 0.25% Triton X in PBS for 2 hours at room site was microdissected at indicated time points
Lineage−CD45+CD90.2+TCRb+CD8b+CCR6+). temperature. Tissues were first stained with anti- after wounding, submerged in RNAlater (Sigma-
Sorted cells were lysed in Trizol reagent and CD4 (RM4-5, eBioscience), anti-CD8a (clone 53- Aldrich), and stored at −20°C. Total tissue RNA
total RNA isolated by phenol-chloroform extrac- 6.7, eBioscience), anti-CD45.1 (A20, eBioscience), was isolated from skin tissue using the RNeasy
tion with GlycoBlue as a co-precipitant (7 mg per anti-CD49f (GoH3, eBioscience), and/or anti-GFP Fibrous Tissue Mini kit (Qiagen), as per manu-
sample; Life Technologies). Single-end libraries (A21311, Life Technologies) antibodies overnight facturer’s instructions. A 3′ mRNA sequencing
were prepared with 0.25 to 1 mg of total RNA at 4°C, washed three times with PBS and then library was prepared using 200 to 500 ng of total
using the TruSeq RNA Sample Preparation Kit stained with 4,6-diamidino-2-phenylindole (DAPI, input RNA with the QuantSeq 3′ mRNA-Seq
V2 and sequenced for 50 cycles with a HiSeq Sigma-Aldrich) overnight before being mounted Library Prep Kit FWD for Illumina (Lexogen) as
2500 instrument (4 to 6 samples multiplexed with ProLong Gold (Molecular Probes) antifade per manufacturer’s instructions. Libraries were
per lane; Illumina). Sequencing quality of the reagent. Ear pinnae images were captured on a quantified using an Agilent Tapestation (High
raw read data was assessed using FASTQC Leica TCS SP8 confocal microscope equipped Sensitivity D1000 ScreenTape) and Qubit (Thermo

Downloaded from on January 7, 2019

v0.11.5. Using a custom Perl script, 10 bp were with HyD and PMT detectors and a 40× oil ob- Fisher Scientific). Libraries (n = 20) were pooled at
trimmed from the 3′ end of the 50-bp reads. Sub- jective (HC PL APO 40×/1.3 oil). Images were equimolar concentrations and sequenced on an
sequently, FASTQ files were used as input for analyzed using Imaris software (Bitplane). Illumina Nextseq 500 using the High Output v2
RSEM v1.3.0 (50) (internally configured to use kit (75 cycles). Resultant data was demultiplexed
the bowtie aligner, v1.1.1). Expected read counts Back-skin wounding and epifluorescence on Illumina Basespace server using blc2fastq
from RSEM were imported into the DESeq2 microscopy of back-skin wounds tool. The reads from the Illumina Next-seq se-
Bioconductor package (51), normalized using the Tissue wounding and quantitation of wound quencer in fastq format were verified for qual-
geometric-mean based approach built into this healing were performed as previously described ity control using FastQC software package,
package and then tested for differential expres- (56). Briefly, male mice in the telogen phase of aligned to mouse GRCM38 using RSEM package
sion between groups using a Wald test with mul- the hair cycle were anesthetized and punch biopsies (50) calling STAR aligner (52). The RSEM expected
tiple testing correction using Benjamini-Hochberg performed on back skin. Dorsal hair was shaved counts were rounded to the nearest integer value
false discovery. with clippers and a 6-mm biopsy punch was used and the transcripts with zero counts across all
to partially perforate the skin. Iris scissors were samples filtered out. Differential expression anal-
ATAC sequencing and epigenome analysis then used to cut epidermal and dermal tissue to ysis and principal components analysis was per-
T cells were isolated as for RNA sequencing. create a full thickness wound in a circular shape. formed using DESeq2 (51).
ATAC-seq was performed according to a published Back-skin tissue was excised 5 days after wound-
protocol (16). ATAC-seq reads from two biological ing, fixed in 4% paraformaldehyde in PBS, incu- Statistics
replicates for each sample were mapped to the bated overnight in 30% sucrose in PBS, embedded Groups were compared with Prism V7.0 software
mouse genome (mm10 assembly) using STAR (52). in OCT compound (Tissue-Tek), frozen on dry (GraphPad) using the two-tailed unpaired Stu-
Duplicate reads were removed using FastUniq ice, and cryo-sectioned (20-mm section thickness). dent t test, one-way analysis of variance (ANOVA)
(53), and reads mapping to mitochondrial loci Sections were fixed in 4% paraformaldehyde in with Holm-Šidák multiple-comparison test, or two-
removed based upon ENCODE blacklists. Regions PBS, rinsed with PBS, permeabilized with 0.1% way ANOVA with Holm-Šidák multiple-comparison
of open chromatin were identified by MACS Triton X-100 in PBS (Sigma-Aldrich), and blocked test where appropriate. Differences were considered
(version 1.4.2) using a P-value threshold of 1 × for 1 hour in blocking buffer (2.5% Normal Goat to be statistically significant when P < 0.05.
10−5. Only regions called in both replicates were Serum, 1% BSA, 0.3% Triton X-100 in PBS). Pri-
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Harrison et al., Science 363, eaat6280 (2019) 4 January 2019 11 of 11


◥ into plasma membranes, but synaptotagmin-3

RESEARCH ARTICLE SUMMARY (Syt3) internalizes from postsynaptic membranes.
Stimulating AMPA (a-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic) or NMDA (N-methyl D-
aspartate) receptors induces internalization of
AMPA receptors (which mediate most of the
Synaptotagmin-3 drives AMPA fast synaptic transmission in the brain) and Syt3.
This raised the intriguing possibility that Syt3

receptor endocytosis, depression of mediates activity-induced internalization of recep-

tors to weaken synapses and cause forgetting.
We imaged Syt3 using an isoform-specific anti-
synapse strength, and forgetting body, tested its role in receptor trafficking using
electrophysiological methods in brain slices
Ankit Awasthi*, Binu Ramachandran*, Saheeb Ahmed, Eva Benito, Yo Shinoda, and neuronal cultures, and tested its role in
Noam Nitzan, Alina Heukamp, Sabine Rannio, Henrik Martens, Jonas Barth, forgetting using spatial memory tasks in mice.
Katja Burk, Yu Tian Wang, Andre Fischer, Camin Dean†
RESULTS: Syt3 is on postsynaptic membranes
at endocytic zones, which are clathrin-rich
INTRODUCTION: Memories are stored as mo- synaptic plasma membrane. These receptors regions close to the postsynaptic density. Syt3
lecular and cellular changes in the brain. Synap- mediate synaptic transmission by transduc- binds the GluA2 AMPA receptor subunit and

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ses, the nodes of connection between neurons, ing presynaptically released neurotransmitters ◥ also binds AP2 and BRAG2,
can store memories by virtue of their ability to into an electrical signal. Neuronal activity two proteins implicated
tune the efficacy of communication between strengthens synapses by inserting receptors or Read the full article in activity-dependent in-
neurons. This property of synaptic plasticity weakens synapses by removing receptors at http://dx.doi. ternalization of AMPA
makes it possible for the brain to store and from the postsynaptic membrane. Receptor org/10.1126/ receptors via clathrin-
retrieve memories—to replay patterns of elec- trafficking is controlled through calcium in- science.aav1483 mediated endocytosis.
trical activity that occurred during an impor- flux into the neuron; however, the calcium Syt3 does not affect basal
tant event. Forgetting leads to the inability to sensors mediating this control are not known. AMPA receptor trafficking. However, knock-
retrieve memories by making them latent or ing out Syt3—or expressing calcium-binding–
decaying them below any useful quality. How- RATIONALE: Synaptotagmin proteins sense deficient Syt3—abolishes AMPA receptor
ever, what determines whether a memory is calcium to trigger membrane fusion. Stimulat- internalization induced by AMPA, NMDA, or
forgotten? A mechanism is the regulation of ing neuronal cultures elicits a calcium-mediated electrophysiological stimulation of long-term
neurotransmitter receptor numbers on the post- externalization of most synaptotagmin isoforms depression of synaptic strength. It also blocks
the AMPA receptor internalization that nor-
Escape position 1 Escape position 2 Previous escape position AMPA receptor mally decays long-term potentiation of synap-
tic strength. These effects are mimicked in a
Recorded field EPSP (readout of synaptic strength) Dendritic spine Mouse
wild-type background through acute appli-
cation of the Tat-GluA2-3Y peptide, which
competitively inhibits binding of Syt3 to a
tyrosine-rich (3Y) motif on the cytoplasmic
tail of GluA2. In spatial memory tasks, mice in
Wild-type which Syt3 was knocked out (Syt3 knockout
mice) learn escape positions normally but
persevere to previously learned positions,
which can be explained by a lack of forget-
ting previously acquired memories. Inject-
ing the Tat-GluA2-3Y peptide in wild-type
mice mimics the lack of forgetting of spatial
memories, and this effect is occluded in
Syt3 knockout mice.

CONCLUSION: The persistence or degra-

Syt3 KO dation of memories is governed by a poorly
understood molecular machinery. We have
discovered a distinct synaptotagmin isoform
that triggers calcium-mediated internalization
of AMPA receptors, resulting in a weakening
of synaptic transmission and forgetting of
Syt3 knockout mice do not forget. Both wild-type mice and Syt3 knockout mice can learn
an escape position in the water maze, in which corresponding synapses are strengthened
spatial memories in mice.

through the increase of AMPA receptors. These synapses are weakened by the removal The list of author affiliations is available in the full article online.
of receptors if the memory is no longer needed—for example, when a new escape position is *These authors contributed equally to this work.
†Corresponding author. Email:
learned. Syt3 knockout mice cannot remove receptors and therefore cannot forget previous Cite this article as A. Awasthi et al., Science 363, eaav1483
escape positions. (2019). DOI: 10.1126/science.aav1483

Awasthi et al., Science 363, 44 (2019) 4 January 2019 1 of 1


◥ Results
RESEARCH ARTICLE Syt3 is on postsynaptic
plasma membranes
To examine the location of Syt3, we developed
NEUROSCIENCE a highly specific antibody (fig. S1, A and B) that
recognized a single band in brain homogenates,

Synaptotagmin-3 drives AMPA which was absent in Syt3 knockouts; an antibody

developed by Neuromab showed similar results
(Fig. 1A). Syt3 was most abundant in adipose
receptor endocytosis, depression of tissue, heart, and brain (fig. S1C), where it was
found in the hippocampus, cortex, thalamus, and

synapse strength, and forgetting striatum (fig. S1D). Expression in the brain began
embryonically and remained high throughout
adulthood (fig. S1E). Immunostains revealed Syt3
Ankit Awasthi1*, Binu Ramachandran1*, Saheeb Ahmed1†, Eva Benito2,3, Yo Shinoda1‡, signal on neuronal cell bodies and dendrites in
Noam Nitzan1, Alina Heukamp1§, Sabine Rannio1, Henrik Martens4, Jonas Barth2,3, the CA1 (Fig. 1B), CA3, and dentate gyrus (fig. S1F)
Katja Burk1, Yu Tian Wang5, Andre Fischer2,3, Camin Dean1¶ in wild-type, but not Syt3 knockout, hippocam-
pal slices.
Forgetting is important. Without it, the relative importance of acquired memories in a To localize Syt3 subcellularly, we expressed
changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to cytosolic green fluorescent protein (GFP) in cul-
postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma tured hippocampal neurons and immunostained

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membranes in response to stimulation. AMPA receptor internalization, long-term for Syt3 and MAP2 to distinguish dendrites (MAP2-
depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required positive) from axons (GFP-positive/MAP2-negative).
calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory Syt3 signal was predominantly detected in den-
tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of drites (90.2 ± 3.0% of total signal) compared with
forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of axons (9.8