Science_2020_01_03

CONTENTS 71

3 JANUARY 2020 • VOLUME 367 • ISSUE 6473 What makes
knots tight?

CREDITS (FROM TOP): (IMAGE) V. P. PATIL ET AL.; (PHOTO) SCIENCE HISTORY IMAGES/AL AMY STOCK PHOTO; (PHOTO) TONY HEALD/MINDEN PICTURES 9 13 Congress again rejects Trump cuts, INSIGHTS
smiles on science agencies
Afterglow of a 1962 nuclear test in space 2020 spending bill increases research BOOKS ET AL.
budgets, but next year will be tougher as
NEWS lawmakers will have less to spend 20 Asimov at 100
By J. Merivs From epic space operas to rules for
IN BRIEF 14 Global polio eradication falters robots, the prolific author’s literary
in the final stretch legacy endures By J. Gunn
6 What’s coming up in 2020 Vaccine-derived outbreaks may force a
change in “endgame” strategy By L. Roberts PERSPECTIVES
PODCAST
F E AT U R E S 22 Uncovering the ART of antimalarial
IN DEPTH resistance
16 Fighting words A key mechanism of resistance to the
9 U.S. military tests radiation belt Virologist Roberto Burioni has become a antimalarial drug artemisinin is identified
cleanup in space celebrity in Italy by sparring with vaccine By D. Marapana and A. F. Cowman
Radio waves could sweep belts clean skeptics By D. Starr
of satellite-killing particles after nuclear RESEARCH ARTICLE p. 51
sneak attack By R. Stone 6
23 Majorana fermions go for a ride
10 Past megadroughts hit North Published by AAAS Evidence for propagating Majorana
and South America in tandem quasiparticles is found
Strong La Niña conditions drove in a topological superconductor
deep medieval droughts By P. Voosen By S. Tewari and T. D. Stanescu

11 Study pushes emergence of measles REPORT p. 104
back to antiquity
The virus may have entered the human 24 Building a carnivorous trap
population when cities grew large enough to Experiments and computations reveal
sustain outbreaks By K. Kupferschmidt developmental origins of cup-shaped leaves
By D. E. Moulton and A. Goriely
12 Computer scientist in line to
become next NSF director REPORT p. 91
Sethuraman Panchanathan would
succeed France Córdova By J. Mervis 3 JANUARY 2020 • VOL 367 ISSUE 6473 3

SCIENCE sciencemag.org

CONTENTS

26 Electrostatics affect the glow 30 83 Neuroscience PHOTO: MICHAEL ROBINSON CHAVEZ/THE WASHINGTON POST VIA GETTY IMAGES
Chromophore twisting is probed Dendritic action potentials and computation
with unnatural amino acids By C. Hu et al. RESEARCH ARTICLES in human layer 2/3 cortical neurons
A. Gidon et al.
REPORT p. 76 40 Nanoparticles
Oriented attachment induces fivefold twins 87 Archaeology
27 Cancer in sub-Saharan Africa by forming and decomposing high-energy Cooked starchy rhizomes in Africa
Knowledge of cancer in Africa brings needed grain boundaries M. Song et al. 170 thousand years ago L. Wadley et al.
diversity to improve health worldwide
By T. R. Rebbeck 45 Multiplex genomics 91 Plant science
Massively multiplex chemical transcriptomics Evolution of carnivorous traps from planar
29 Gene expression regulated by at single-cell resolution S. R. Srivatsan et al. leaves through simple shifts in gene
RNA stability expression C. D. Whitewoods et al.
The factor responsible for autoregulation 51 Malaria
of tubulin RNA stability is identified A Kelch13-defined endocytosis pathway PERSPECTIVE p. 24; PODCAST
By O. Shoshani and D. W. Cleveland mediates artemisinin resistance in malaria
parasites J. Birnbaum et al. 96 Evolutionary biology
REPORT p. 100 Protein-coding changes preceded
PERSPECTIVE p. 22 cis-regulatory gains in a newly evolved
POLICY FORUM transcription circuit C. S. Britton et al.
REPORTS
30 Sustainable minerals and metals 100 Tubulin
for a low-carbon future 59 Topological optics TTC5 mediates autoregulation of tubulin
Policy coordination is needed for global A single photonic cavity with two via mRNA degradation Z. Lin et al.
supply chains By B. K. Sovacool et al. independent physical synthetic dimensions
A. Dutt et al. PERSPECTIVE p. 29
LETTERS
64 Topological matter 104 Topological matter
34 NextGen Voices: Absence of evidence for chiral Majorana Evidence for dispersing 1D Majorana
Making science accessible modes in quantum anomalous Hall- channels in an iron-based
superconductor devices M. Kayyalha et al. superconductor Z. Wang et al.
RESEARCH
68 Superconductivity PERSPECTIVE p. 23
IN BRIEF Atomic manipulation of the gap in
Bi2Sr2CaCu2O8+x F. Massee et al. D E PA R T M E N T S
36 From Science and other journals
71 Applied physics 5 Editorial
REVIEW Topological mechanics of knots and Clarity in 2020 By H. Holden Thorp
tangles V. P. Patil et al.
39 Neuroscience 114 Working Life
Memory engrams: Recalling the past 76 Fluorescent proteins Strange dreams By Desiree Dickerson
and imagining the future Electrostatic control of photoisomerization
S. A. Josselyn and S. Tonegawa pathways in proteins M. G. Romei et al. ON THE COVER

REVIEW SUMMARY; FOR FULL TEXT: PERSPECTIVE p. 26 Immature trap of the
DX.DOI.ORG/10.1126/SCIENCE.AAW4325 carnivorous plant
79 Optics Utricularia gibba (~200
On-chip integrated laser-driven particle µm in width), illustrat-
accelerator N. V. Sapra et al. ing its two-layered
cellular structure. Such
cup-shaped leaves have
evolved multiple times
as a mechanism for trap-
ping animals. Analyzing U. gibba, researchers
used a combination of molecular genetics
and computer modeling to reveal how shifts
in gene expression domains can account for
repeated evolution of cup shapes from spe-
cies with planar leaves. See pages 24 and 91.
Image: Karen Lee and Claire Bushell

New Products..............................................110
Science Careers .......................................... 111

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EDITORIAL

Clarity in 2020

W e begin 2020 (or should I say 20/20) awash One of the questions I am often asked is how the Sci-
in references to ophthalmology. In that vein, ence journals correct or retract papers. With the rapid
we hope to make science clearer and bright- analysis that can happen on social media, these questions
er in the months ahead—which brings me are being raised faster than ever before. We don’t seek
to the issue of transparency. to hide from these efforts: Image sleuth Elisabeth Bik
The Science family of journals looks for- (@MicrobiomDigest) recently stated on Twitter that

ward to a year in which the editors will strive she needed a list of journal editors’ emails and I im-

for greater transparency and reproducibility in the sci- mediately responded with mine (which is not hard to H. Holden Thorp
Editor-in-Chief,
ence that we publish. Policies on conflicts of interest find at right). Science journals.
[email protected];
and professional behavior for authors are now uniform Science journals prefer to publish a retraction signed @hholdenthorp

across our journals and strengthen our standards for dis- by all authors. Deciding to retract in cases where not

closure. For the first time, we will require general disclo- all authors agree can require a lengthy investigation

sures from Science’s Board of Reviewing Editors; prior by universities. In such cases, we publish an Editorial

to this year, they were only asked to disclose conflicts Expression of Concern (EEoC) in the meantime, to

that arose for papers on which they were consulted. quickly alert readers that concerns have been raised

As readers of Science’s news section about the reported work. We hope

would know, I have been active for de- “…editors will that making this information avail-
cades in the biotechnology business able promptly helps mitigate the

and disclosed competing interests strive for greater waste of time, effort, and funds by
to the American Association for the researchers who might otherwise

Advancement of Science (AAAS, pub- transparency base future work on papers that
lisher of the Science journals) upon and reproducibility…” are later retracted. During my short
joining the editorial team. These inter- time as editor-in-chief, when we
ests are stated on my web bio (www. have contacted universities to be-
sciencemag.org/about/leadership- gin this process, I have been giving

and-management#HoldenThorp), a deadline by which we will decide

and I commit to keeping them updated for full public if we are going to proceed with an EEoC. After run-

disclosure. The Science journals believe that the com- ning academic units for the past 14 years, I know that

mercial application of scientific findings is critical to it sometimes takes a nudge to get things to the top of

gaining public support and to ensuring that scientists an inbox. We also publish an EEoC when authors alert

are involved in the realization of their ideas. At the us to problems with their published paper and need

same time, vigorous disclosure of these competing in- time to determine whether the findings hold. Authors

terests is a must. taking the initiative to correct the record strengthens the

We will also continue to strive for greater reproduc- integrity of the scientific enterprise.

ibility in the science that we publish. Last year, Science The year 2020 brings a presidential election to the

helped to develop a framework setting out minimal United States and a time of transition across the At-

expectations for materials, design, analysis, and re- lantic. There will be great opportunities for everyone

porting (MDAR) and also participated with other to stand up for science and for their beliefs. Break-

publishers in piloting a checklist that operational- throughs in all fields will continue with new ideas, in-

ized this framework (https://cos.io/blog/journals-test- sights, and applications, hopefully for the good of all

materials-design-analysis-reporting-mdar-checklist/). members of society and for the Earth that we cherish.

Authors were admirably enthusiastic about this pro- And it will be exciting for AAAS, as our new chief ex-

cess, and we are pleased to endorse the framework ecutive officer, Sudip Parikh, begins next week. I have

and implement the checklist this year for life science known Sudip for 25 years and look forward to his gen-

papers in Science. This should allow information to be erous and thoughtful leadership.

used by others seeking to reproduce findings and will

hopefully pave the way for more such standardization. –H. Holden Thorp

PHOTO: CAMERON DAVIDSON 10.1126/science.aba6293
3 JANUARY 2020 • VOL 367 ISSUE 6473 5
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NEWS

IN BRIEF

AREAS TO WATCH New goals for saving biodiversity PHOTO: TONY HEALD/MINDEN PICTURES

What’s coming up in 2020 CO N S E RVAT I O N | This year will see an
attempt to revitalize the ambitious Aichi
I ncessant political turmoil in the United Kingdom, United Biodiversity Targets, named for the city in
States, and other nations will likely last well into the new year, Japan where they were negotiated. Since
complicating many researchers’ work. The U.K. election last they were approved 10 years ago, there has
month made the country’s departure from the European Union been little to no progress in meeting most
a near-certainty, and its scientists now face losing EU science of those 20 goals, such as preventing the
grants and scientific collaborators. In the United States, a presi- decline of endangered species. That alarm-
dential election in November will determine the role of scientists ing situation was highlighted last year in
in future policy deliberations; many experts on climate change a major scientific assessment by another
and other environmental issues assert that the Trump administra- organization, the Intergovernmental
tion has ignored scientific evidence. In this section, Science’s news Science-Policy Platform on Biodiversity
staff forecasts other areas of policy and research likely to make and Ecosystem Services. But in October,
news this year amid the chaos, from dark matter detectors to new nations will have a chance to try to set a
efforts to rein in loss of species. more effective course when they meet in
Kunming, China, to review and revise the
6 3 JANUARY 2020 • VOL 367 ISSUE 6473 Convention on Biological Diversity,
the world’s flagship conservation pact.

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Despite long-standing Without stepped-up efforts, there is little can apply them to understand more about
biodiversity conservation hope the world can keep future warming older fossils lacking DNA, including the sex
plans, both African elephants below 2°C, the level scientists forecast and age of remains of enigmatic ancient
will produce catastrophic damage to hominins. Most hominins are known by
and African wild dogs human communities and ecosystems. bones and teeth alone, and proteins could
are listed as endangered. provide a new tool for sorting them in
Counting on the census family trees and to identify fragments too
small to classify. Although tooth enamel
D E M O G RA P H I CS | The U.S. government has offers the best source of ancient proteins,
conducted a decennial census since 1790. researchers are also extracting them from
But the 2020 census that kicks off on 1 April bones and hair. In addition, proteins can
faces unprecedented political challenges. reveal new information about artifacts
Although civil rights groups won a fight to made of plant and animal materials, and
block a question about citizenship that the researchers hope this year to analyze
Trump administration wanted to add, it parchment manuscripts and the beeswax
has ordered the Census Bureau to generate once used to seal documents. Scientists
the equivalent data using existing govern- are also analyzing residues on pots for
ment records so that states can use the more clues to whether early pastoralists in
information when they redraw boundaries the steppelands of Mongolia, for example,
for federal and state elections. Researchers drank camel or goat milk first—and what
fear that assignment may not be doable, people living on the edge of the Roman
and that the political debate has further Empire in England ate.
alienated those already hardest to count.
Demographers also worry that the census’
use of a new way to protect respondents’
privacy could distort analyses of demo-
graphic trends. At stake are not only how
more than $1.5 trillion in federal funds are
distributed each year, but also the integrity
of the nation’s largest statistical agency.

PHOTO: K. MCGRATH ET AL., SCIENTIFIC REPORTS 9, 11027 (2019) Crunch time for climate policy CRISPR’s big clinical tests Proteins in these
400-year-old bone
POLICY | The politics of climate change B I O M E D I C I N E | The CRISPR gene-editing fragments, found in
faces crucial moments this year. The tool faces key tests this year of its promise Iroquois settlements
Trump administration’s opposition to to treat cancer and genetic diseases. A small in Canada, revealed whether
regulations reducing fossil fuel emissions U.S. clinical trial is using CRISPR to disable they were animal or human.
has emerged as a primary talking point three genes in T cells that are then returned
for the president’s Democratic challengers. to a cancer patient’s body, an approach that ‘Foreign influence’ worries grow
One day after the U.S. presidential election could help these immune system soldiers
on 3 November, the country, the second stop malignant cells from growing and N AT I O N A L S ECU R I T Y | The political debate
largest emitter of greenhouse gases, is set extend patients’ lives. More results may also over how to respond to China’s emer-
to leave the Paris climate accord, although come from separate CRISPR cancer trials gence as a scientific superpower is likely
a Democratic president could quickly rejoin in China. Other researchers are working to to intensify this year. In the United States,
after taking office in 2021. Less than 1 week treat people with sickle cell disorder and some federal agencies have banned their
later, the United Nations will convene thalassemia by using the DNA editor to turn employees from participating in foreign
in Glasgow, U.K., for its most important on the gene for a fetal version of hemoglo- talent recruitment programs—an approach
climate summit since 2015, where nations bin to compensate for a defective adult form that China has used to connect with thou-
are expected to increase their pledges to of the oxygen-carrying protein; last fall, sci- sands of scientists—to prevent disclosure
cut greenhouse gas emissions—even though entists reported success in two patients and of information that could damage national
they are behind on meeting existing ones. in 2020 will present longer-term results for security and U.S. economic competitiveness.
a larger group. Another clinical trial in the Two new bodies created by Congress will
United States could show whether CRISPR work to harmonize practices across federal
improves vision in people with an inherited agencies and chew over how best to balance
disorder that causes progressive blindness. openness and security. U.S. academic lead-
ers are hoping to convince policymakers
Proteins tell ancient tales not to fence off certain types of research,
which they say would throttle U.S. innova-
A RC H A EO LO GY | Ancient proteins will tion. A new report to the National Science
shed new light this year on the identity
and behavior of humans and other animals
that lived more than 1 million years ago.
Proteins are more stable than DNA, and as
analytical methods improve, researchers

SCIENCE sciencemag.org 3 JANUARY 2020 • VOL 367 ISSUE 6473 7

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NEWS | IN BRIEF

Foundation says teaching students and only through the feeble weak nuclear force. person. Transplants from these edited pigs
faculty members about acceptable and This year, the XENON-NT detector, which to monkeys, a key test of safety and efficacy
unacceptable behavior is a better approach. contains 8 tons of frigid liquid xenon, will before human trials, have demonstrated
turn on in the subterranean Gran Sasso long-term viability in their new hosts.
Japan boosts neutrino efforts National Laboratory in Italy. At the Sanford
Underground Research Facility in South Exascale computer to debut
PA RT I C L E P H YS I CS | Japan is expanding Dakota, the LUX-ZEPLIN (LZ) detector,
neutrino research to better understand which contains 10 tons of liquid xenon, CO M PU T E R SC I E N C E | This year, China is
properties of the phantom particles and the will also power up. If XENON-NT and expected to win the race to build the world’s
cosmic processes that produce them. This the LZ see nothing in the next few years, first exascale computer, capable of carrying
spring, scientists will increase the sensitiv- dark matter hunters could push for bigger out 1 billion billion (1018) calculations per
ity of the 22-year-old Super-Kamiokande WIMP detectors or set their sights on other second, also known as an exaflop. Just which
neutrino observatory by doping water in hypothesized forms of dark matter. The supercomputer will be the first remains
its observation chamber with the rare- Italian lab’s future also remains uncertain, uncertain, as China has set up a competi-
earth metal gadolinium. The detector will as former lab officials face prosecution for tion between three institutions: the National
then watch for signals generated when allegedly allowing contamination of local Supercomputing Center of Tianjin, the
neutrinos from supernovae hit the water, drinking water. National Supercomputing Center in Jinan,
providing clues about the dynamics within and Dawning Information Industry Co., a
those exploding stars. Japan’s legislature Making xenotransplants survive manufacturer also known as Sugon. The
is expected to fund an even bigger step: new Chinese supercomputers, and others to
construction of the 72 billion Japanese yen B I O M E D I C I N E | The genome editor CRISPR follow in the European Union, Japan, and
($660 million) Hyper-Kamiokande. Ten is reinvigorating the beleaguered field of the United States, will be used to analyze
times larger than its predecessor, it will xenotransplantation, which aims to surgi- vast data sets from astronomical and genetic
capture that much more data about neutri- cally replace human organs or tissues with surveys, and will support the continued rise
nos emanating from the Sun, distant stars, ones harvested from animals such as pigs. of artificial intelligence. Some computer
and supernovae. Novel clinical trials of the strategy could scientists expected the exascale milestone
launch this year. Xenotransplantation to have come sooner; delays resulted in part
Dueling dark matter detectors has long promised to alleviate a chronic from the need to develop energy efficient
shortage of human livers, hearts, and other computer chips.
AST RO P H YS I CS | The race to detect organs. It could also provide corneas to cure
hypothetical particles of dark matter—the blindness and insulin-producing islet cells ALSO IN 2020
invisible stuff that binds together the galax- to replace those destroyed by diabetes. But
ies with its gravity—enters a new phase this time and time again in earlier tests, human ALZHEIMER’S DRUG The U.S. Food and
year with the startup of two powerful new immune systems have quickly destroyed Drug Administration will decide whether
underground detectors. Since the 1980s, the foreign transplants. Recent CRISPR to approve aducanumab, an antibody
physicists have used ever bigger and more experiments have modified genes in pigs drug designed to bust the brain-clogging
sensitive ones to search for so-called weakly to prevent or dampen human immune amyloid plaques of Alzheimer’s disease.
interacting massive particles (WIMPs), responses to their tissue and have removed The experimental treatment has shown
theorized to weigh 100 times as much as DNA from the porcine genome that could mixed success in clinical trials.
protons and to interact with other matter spawn potentially dangerous viruses in a
OCEAN CONSERVATION The United
Nations intends to finish plans for a PHOTO: MATTHEW KAPUST/SANFORD UNDERGROUND RESEARCH FACILITY
Decade of Ocean Science to begin in
2021. The goal is to coordinate work
by scientists around the world to help
improve ocean health. One expected
emphasis is mapping more of the world’s
vulnerable marine ecosystems and bio-
diversity hot spots and more of the
ocean’s bottom, only about 4% of which
has been charted in high resolution.

STEM CELL FUNDING California voters will
decide in November whether to allocate
$5.5 billion from bond sales to keep alive
the California Institute for Regenerative
Medicine. The funding agency was cre-
ated through a $3 billion ballot initiative
in 2004 to translate stem cell research
into new therapies.

The LUX-ZEPLIN dark matter detector is readied to record data at an underground lab in South Dakota. SCIENCEMAG.ORG/NEWS
Read more news from Science online.
8 3 JANUARY 2020 • VOL 367 ISSUE 6473
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IN DEPTH

Aurorae were seen widely
after Starfish Prime, a

1962 nuclear test in space.

SPACE PHYSICS

U.S. military tests radiation belt cleanup in space

Radio waves could sweep belts clean of satellite-killing particles after nuclear sneak attack

PHOTO: SCIENCE HISTORY IMAGES/ALAMY STOCK PHOTO By Richard Stone experiments—one now in orbit and two be- 10 years ago, we just know so much more
ing readied for launch in 2021—aim to gather about how these wave-particle interactions
T he U.S. military thought it had cleared data on how to drain high-energy electrons work,” says Geoff Reeves, a space physicist
the decks when, on 9 July 1962, it trapped by Earth’s magnetic field in radia- at Los Alamos National Laboratory.
heaved a 1.4-megaton nuclear bomb tion belts encircling the planet. The process,
some 400 kilometers into space: Or- called radiation belt remediation (RBR), al- Now, researchers are ready to try artifi-
biting satellites were safely out of ready happens naturally, when radio waves cial remediation, by beaming radio waves
range of the blast. But in the months from deep space or from Earth—our own into the belts. Physicists have tested using
that followed the test, called Starfish Prime, radio chatter, for example, or emissions the U.S. Navy’s very low frequency (VLF) an-
satellites began to wink out one by one, in- from lightning—knock electrons trapped in tenna towers, powerful facilities used to com-
cluding the world’s first communications Earth’s Van Allen radiation belts into the up- municate with submarines, says Dan Baker,
satellite, Telstar. There was an unexpected per atmosphere, where they quickly shed en- director of the Laboratory for Atmospheric
aftereffect: High-energy electrons, shed by ergy, often triggering aurorae. and Space Physics at the University of Colo-
radioactive debris and trapped by Earth’s rado, Boulder, and a lead investigator on the
magnetic field, were fritzing out the satel- “Natural precipitation happens all the Van Allen Probes. The antennae of the High-
lites’ electronics and solar panels. time,” says Craig Rodger, a space physicist frequency Active Auroral Research Program
at the University of Otago. But it would in Alaska and the giant dish of the Arecibo
Starfish Prime and similar Soviet tests not nearly be fast enough to drain nuclear- Observatory in Puerto Rico might also be en-
might be dismissed as Cold War misadven- charged radiation belts, where electron listed to generate cleansing radio beams.
tures, never to be repeated. After all, what fluxes can be millions of times higher than
nuclear power would want to pollute space in Earth’s Van Allen belts. An orbiting RBR platform, closer to the
with particles that could take out its own target, could be more effective. In June
satellites, critical for communication, naviga- Scientists got a glimpse of a potential 2019, the U.S. Air Force launched what it
tion, and surveillance? But military planners solution from NASA’s Van Allen Probes, bills as the largest uncrewed structure ever
fear North Korea might be an exception: It which launched in 2012 and ducked in and flown in space: the DSX dipole antenna.
has nuclear weapons but not a single func- out of Earth’s radiation belts until the mis- Nearly as long as a U.S. football field, DSX’s
tioning satellite among the thousands now in sion ended last summer. It offered a deep primary mission is to transmit VLF waves
orbit. They quietly refer to a surprise orbital dive into natural remediation processes, into the Van Allen belts and measure pre-
blast as a potential “Pearl Harbor of space.” showing how radio waves resonate with cipitating particles with onboard detectors.
high-energy electrons, scattering them “It’s a new way to prod the belts and explore
And so, without fanfare, defense scien- down the magnetic field lines and sweep- basic questions in space physics,” says DSX’s
tists are trying to devise a cure. Three space ing them out of the belts. “Compared to principal investigator, James McCollough at

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NEWS | IN DEPTH

the Air Force Research Laboratory. C L I M AT E
A team of scientists at Los Alamos and
Past megadroughts hit North
NASA’s Goddard Space Flight Center is and South America in tandem
spearheading a second experiment in VLF
precipitation. In April 2021, the team plans Strong La Niña conditions drove deep medieval droughts
to launch a sounding rocket carrying the
Beam Plasma Interactions Experiment, a By Paul Voosen But pinning down the exact timing wasn’t PHOTO: RODRIGO GARRIDO/REUTERS/NEWSCOM
miniature accelerator that would create possible in the 1990s. Ancient drought is
a beam of electrons, which in turn would F or 10 years, central Chile has been typically detected in variations in the width
generate VLF waves capable of sweeping gripped by unrelenting drought. With of tree rings, but tree ring records then were
up particles. Reeves, who leads the ex- 30% less rainfall than normal, verdant spotty. Since, however, tree ring scientists
periment, believes the compact electron landscapes have withered, reservoirs have put together “drought atlases” that
accelerator could ultimately be a better are low, and more than 100,000 farm provide consistent records for much of the
broom than a gigantic VLF antenna. “If we animals have died. The dry spell has world. “We’ll have most hemispheric land ar-
validate it with this experiment, we have a lasted so long that researchers are calling it a eas covered by the end of the year,” says Ed
lot more confidence we can scale it up to “megadrought,” rivaling dry stretches centu- Cook, a tree ring scientist at Columbia.
higher power,” he says. ries ago. It’s not so different from the decade-
long drought that California, some 8000 kilo- Steiger combined these records with
A third experiment would coax the at- meters away, endured until last year. thousands of other proxies for dryness
mosphere itself to kick up turbulent waves and temperature from trees, corals, ocean
that would draw down electrons. In the By analyzing tree ring records, scientists sediments, and ice cores, and fed them
summer of 2021, the Naval Research Labo- have now found evidence that such tandem into a global climate model. Aligning it-
ratory plans to launch a mission called the droughts are more than a coincidence: They self to the records, it generated a global
Space Measurements of a Rocket-Released are surprisingly common over the past 1200 view of the changing climate, even in
Turbulence. A sounding rocket will fly years, and they may often share a common places with sparse proxies. The model
into the ionosphere—an atmospheric layer cause—an abnormally cool state of the east- confirmed that, from 800 to 1600 C.E.,
hundreds of kilometers up that’s awash in ern Pacific Ocean known as La Niña. “We multiple megadroughts occurred simulta-
ions and electrons—and eject 1.5 kilograms did not expect there to be as much coher- neously across the hemispheres. “It’s there,”
of barium atoms. Ionized by sunlight, the ence as we see,” says Nathan Steiger, a paleo- Cook says. “Without question, it’s there.”
barium would create a ring of moving climatologist at Columbia University who
plasma that emits radio waves: essentially presented the work last month at a meeting Besides correlating the varied climate re-
a space version of a magnetron, the gadget of the American Geophysical Union. “They cords, the model also identified the key fac-
used in microwave ovens. just happen together.” The results suggest tors driving the climate variations. Steiger
that, in the future, extreme aridity could and his co-authors, including Cook, first
The missions should help show which strike all along the Americas’ western coast. used the new tool to look at megadroughts
RBR system is most feasible, although an in the U.S. Southwest. Their study, published
operational system may be years off. What- Evidence for synchronous, hemisphere- last year in Science Advances, is “amazing,”
ever the technology, it could bring risks. wide droughts first emerged in a 1994 study in says David Stahle, a tree ring scientist at the
A full-scale space cleanup might dump as Nature, which documented dead tree stumps University of Arkansas in Fayetteville. “It’s a
much energy into the upper atmosphere in the middle of lakes and rivers in both Pa- bit like … they took those black-and-white
as the geomagnetic storms caused by the tagonia and California’s Sierra Nevada. For films and colorized them.” They found that
Sun’s occasional eruptions. Like them, trees to grow in stream- and lakebeds, the megadroughts in the Southwest were in-
it could disrupt airplane navigation and droughts must have lasted for decades, and fluenced by three factors: an anomalously
communication. And it would spawn heaps at least one of these megadroughts seemed to warm North Atlantic Ocean, small global
of nitrogen oxides and hydrogen oxides, have hit both continents simultaneously. temperature rises driven by factors such as
which could eat away at the stratospheric
ozone layer. “We don’t know how great
the effect would be,” says Allison Jaynes,
a space physicist at the University of Iowa.

Besides safeguarding against a nuclear
burst, RBR technology could have a ci-
vilian dividend, Jaynes notes. NASA and
other space agencies have long wrestled
with shielding astronauts from the Van
Allen belts and other sources of radia-
tion on their way to and from deep space.
VLF transmitters might be used to clear
out high-energy electrons just before a
spacecraft enters a danger zone. “When
we become more active space travelers,”
she says, “it could provide a safe passage
through the radiation belts.” j

Richard Stone is senior science editor at the
Howard Hughes Medical Institute’s Tangled Bank
Studios in Chevy Chase, Maryland.

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Ongoing drought INFECTIOUS DISEASES
has dried up
a lagoon near Study pushes emergence of
measles back to antiquity
Santiago, Chile.
The virus may have entered the human population when
cities grew large enough to sustain outbreaks

By Kai Kupferschmidt, in Berlin century B.C.E., rather than in medieval
times, as previous research had suggested.
PHOTO: KAI KUPFERSCHMIDT/SCIENCE a brightening Sun, and, especially, La Niña. O n 3 June 1912, a 2-year-old girl at the
The cold cousin of El Niño, La Niña can per- Charité University Hospital here died The work is technically brilliant, says
sist for years, deflecting rainstorms away of pneumonia following a measles evolutionary biologist Mike Worobey of the
from their usual tracks. infection. The next day, doctors took University of Arizona: “Just being able to
out her lungs, fixed them in forma- get the measles virus out of these old, wet
In the new work, the team finds that La lin, and added them to a collection specimens. That sets the stage for all sorts
Niña is almost the sole driver of the South of anatomical specimens started by Rudolf of exciting work.” Monica Green, a historian
American megadroughts. And because La Virchow, the “father of pathology.” There of infectious diseases at Arizona State Uni-
Niña affects conditions on both sides of the they languished for more than 100 years— versity, Tempe, calls the sequencing “very
equator, it could plausibly trigger simultane- until Sebastien Calvignac-Spencer, an impressive” as well but says the study lacks
ous droughts in both hemispheres. evolutionary biologist at the Robert Koch enough data points to “provide decisive
Institute, came across them in the basement answers” about measles’ emergence. The
Jessica Tierney, a paleoclimatologist at of Berlin’s Museum of Medical History. authors agree. They hope sequences from
the University of Arizona, says this mar- antiquity, preserved in naturally mummi-
riage of proxy records and models is a Calvignac-Spencer and his team took a fied or frozen bodies, may one day do so.
powerful tool for understanding past cli- sample from the lungs, isolated RNA from
mates. “Nathan has really been leading the it, and subsequently pieced together what Measles, which killed an estimated
way on that,” she says. But she cautions is the oldest known genome of the measles 142,000 people in 2017, is one of the most in-
that models don’t perfectly simulate the La virus. Its sequence helped them shed light fectious human diseases. But when, where,
Niña cycle. It’s also uncertain whether the on a much earlier period in measles’ history. and how it became a human pathogen is
link between La Niña and distant droughts In a study slated for submission to the pre- still debated. The closest relative of the
is a stable dynamic that lasts centuries or print submitted bioRxiv this week, the team measles virus is one that causes rinderpest,
might change over time. And the random- concludes that the virus may have entered a disease that affected cattle, deer, buffalo,
ness of weather is always a factor: The cur- the human population as early as the fourth and other even-toed ungulate species before
rent South American drought, for example, it was eradicated in 2011. Most researchers
has endured through both El Niño and La Scientists assembled a measles virus genome from believe both viruses had a common ances-
Niña conditions. the preserved lungs of a girl who died in 1912. tor that infected cattle. “The challenge is
that … measles has left so few clear traces in
Nor is it clear how the drought patterns historical disease descriptions,” Green says.
will change as climate warms. A warming
atmosphere alone seems certain to make Because measles spreads so fast and in-
megadroughts more frequent, especially in fection confers lifelong immunity, scientists
the Southwest. But scientists remain divided estimate it needs populations of 250,000 to
on how climate change will affect the El a half-million people to avoid burning itself
Niño-La Niña cycle. Models suggest El Niño out. Historians believe that the largest cit-
will dominate, but in the past few decades, La ies reached that size around the fourth cen-
Niña has seemed to be more frequent. “There tury B.C.E. But when researchers in Japan
are still camps,” says Daniel Griffin, a paleo- used available genomes of the measles and
climatologist at the University of Minnesota. rinderpest viruses to build a phylogenetic
“I see people trying to hold their noses for tree, enabling them to date the branches,
consensus statements.” they concluded in 2010 that measles didn’t
emerge until the 11th or 12th century C.E.
As bad as the drought in Chile is today, it
barely qualifies as a megadrought when com- The uncertainty stems in part from a
pared with the medieval ones, which were surprising lack of historic sequences. Only
longer and more severe. Clearly, there was three genomes from measles viruses occur-
something about that period that switched ring before 1990 are known; the oldest is
off in recent centuries, Cook says. If that pat- one isolated in 1954 that was turned into the
tern somehow came back, with greenhouse first measles vaccine. So Calvignac-Spencer
warming amplifying it, Cook says, “then turned to the Berlin museum, whose shelves
things could get quite catastrophic.” j are filled with thousands of tissues and or-
gans floating in formalin-filled glass cases,
like aquariums of human anatomy.

Formalin fixes tissue by cross-linking

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NEWS | IN DEPTH

proteins and other large molecules, includ- TRUMP ADMINISTRATION
ing RNA, which the measles genome is
made of. To extract RNA from such samples, Computer scientist in line
scientists use techniques pioneered about to become next NSF director
10 years ago by cancer researchers inter-
ested in formalin-fixed biopsies. “We put Sethuraman Panchanathan would succeed France Córdova
them at 98° for 15 minutes and that breaks
the cross-links,” Calvignac-Spencer says. By Jeffrey Mervis One of those jobs is being a member of PHOTO: ARIZONA STATE UNIVERSITY
This also breaks up RNA, but modern meth- the National Science Board (NSB), NSF’s
ods allow scientists to sequence the frag- T he computer scientist whom Presi- presidentially appointed oversight body.
ments and piece them back together. dent Donald Trump picked last His 5-year stint has given him an insider’s
month as the next director of the look at the $8 billion agency, and a chance
Calvignac-Spencer’s team drew up a new National Science Foundation (NSF) to work with Trump’s science adviser,
phylogenetic tree using the 1912 genome has followed the path taken by an Kelvin Droegemeier, who served on NSB to-
as well as a new one from 1960, pieced to- untold number of foreign-born re- gether with Panchanathan for 2 years.
gether from a sample in another collection, searchers by seeking greater opportunities
and other available genomes. The result- in the United States. If the Senate confirms Droegemeier, who hailed the president’s
ing tree suggests the disease could have him, as seems likely, 58-year-old, India-born 19 December 2019 announcement of the
jumped to humans as early as 345 B.C.E.— Sethuraman Panchanathan will become pending nomination as “a win for science
right around the time human populations not only the second NSF director of Asian in the Trump administration,” has strength-
reached the critical size. American descent, but a living embodiment ened ties between NSB and the White House
of how the international flow of talent has Office of Science and Technology Policy since
The earlier date for measles’ emergence helped fuel U.S. leadership in global science. becoming OSTP director in January 2019.
also reflects the models that the team used Some observers credit Droegemeier with not
to analyze the viral sequences. When draw- Panchanathan, who goes by “Panch,” is only championing Panchanathan for the NSF
ing up a family tree using differences in ge- executive vice president for research and post, but also persuading the White House
nomes, researchers must estimate the speed chief innovation officer at Arizona State to queue up a new director before France
at which viral genomes diverge. In the past, University (ASU) where he has worked Córdova finishes her 6-year term in March.
their estimates were often too high, because since 1997. A former chair of its computer
some deleterious mutations tend to disap- science and engineering department, he Panchanathan’s interests dovetail with
pear over time. The new model accounts founded the university’s school of comput- NSF priorities, says Kambhampati, who at-
for this effect, called purifying selection. It ing and informatics and created and leads tended the same prestigious school, the In-
pushes back the divergence of measles and its center for cognitive ubiquitous comput- dian Institute of Technology (IIT), Madras,
rinderpest even without including the 1912 ing, a technology that uses artificial intel- that launched Panchanathan’s career. “He’s
genome. But the genome strengthens the ligence and machine learning to help those very strong on interdisciplinary and use-
new timeline, Calvignac-Spencer says. with disabilities. inspired basic research, as well as entrepre-
neurship and partnerships with industry.”
The researchers can’t rule out that the “His star has kept rising,” says Subbarao
measles virus first circulated in humans Kambhampati, an ASU computer scientist Curiously, Panchanathan will be the sec-
and then jumped to cattle, but that seems and a longtime colleague and friend. “I ond IIT Madras alum to lead NSF; fellow
unlikely, says Albert Osterhaus of the Uni- think he’s got three or four jobs. But he has alum Subra Suresh, a materials scientist,
versity of Veterinary Medicine in Hanover, a crazy amount of energy, and he seems to directed the agency for 2.5 years during
Germany. For one, ungulate herds probably like going full speed all the time.” the first term of former President Barack
reached the critical population size long be- Obama. Suresh, who is 5 years older than
fore humans did. And the closest relative of
the two viruses, which is even older, causes
peste des petits ruminants, a sheep and
goat disease that probably crossed to cattle
more easily than to humans.

Similar studies have suggested that HIV
and other pathogens also took off in the
wake of major changes in the human popu-
lation structure, Worobey says. “It seems
like changes in human ecology really did
coincide with the successful emergence of
these viruses.”

The ability to fish viral RNA out of very
old samples has renewed interest in the
Virchow collection, says Thomas Schnalke,
head of the museum. “It came as a kind of
revolution for us that researchers are com-
ing and saying: ‘Your samples are interest-
ing for us again.’” Calvignac-Spencer has
already labeled additional specimens he’d
like to study with orange stickers. “It’s a
treasure trove,” he says. “A window to the
past that we can open now.” j

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Sethuraman Panchanathan’s research has focused on U.S. BUDGET
building technologies to help those with disabilities.
Congress again rejects Trump
Panchanathan, attended IIT Madras in the cuts, smiles on science agencies
mid-1970s, and he says its graduates—who
are drawn from the most scientifically pre- 2020 spending bill increases research budgets, but next
cocious of the country’s vast pool of young year will be tougher as lawmakers will have less to spend
people—“have done very well” in life.
CREDITS: (GRAPHIC) D. MALAKOFF/SCIENCE; (DATA) U.S. CONGRESS/WHITE HOUSE OFFICE OF MANAGEMENT AND BUDGET By Jeffrey Mervis Survey that the Trump administration had
Open borders fostered his own career, targeted. And the bill includes the first fed-
Percentage change says Suresh, who left NSF in 2013 to become L ast summer, U.S. congressional lead- eral funding for gun violence research in
president of Carnegie Mellon University, ers and the White House agreed to decades and language urging reductions in
and is now president of Nanyang Techno- raise federal spending over the next the use of animals in research.
logical University. Leading NSF could put 2 years by $125 billion above pro-
Panchanathan on a similar leadership tra- jected levels. The deal effectively However, this year’s totals for research
jectory. In 2017, he was runner-up to become removed the threat of large cuts to may be a high-water mark for Trump’s
president of the University of Arizona, and research agencies that President Donald 4-year term. Unless the White House and
Kambhampati says he has been considered Trump had proposed in his 2020 budget Democrats take the unlikely step of reopen-
for other top academic positions. “Panch request. But those agencies didn’t learn ing the budget deal, Congress will have just
enjoys playing a leadership role within the precisely how much money they would get $5 billion to add to agency budgets in 2021,
scientific community,” Kambhampati says. until late last month, when Trump signed far less than the $44 billion extra it was
“He tends to have a big vision on issues.” a $1.37 trillion spending bill for the 2020 able to hand out this year. (The July 2019
fiscal year, which ends on 30 September. agreement erased draconian cuts sched-
Panchanathan declined to comment on his uled to go into effect in 2021.) So any ma-
nomination. But in October 2019, he got the In the short term, the news is good. Once jor spending increases next year will have
chance to appear on a national policy stage, again, the National Institutes of Health to come at the expense of cuts elsewhere.
testifying at a Senate hearing on “ensuring (NIH) did the best, with Congress overrid-
America’s economic and strategic leader- ing Trump’s proposed $5 billion cut and The bad news came early for the National
ship” through research and innovation. handing the agency a fifth straight annual Science Foundation (NSF), which received
increase of at least $2 billion. Science pro- a second straight year of modest growth.
Senators spared Panchanathan when grams at the Department of Energy and The agency was already under siege from
they pressed a panel of top scientists on NASA made a similar rebound from a pro- Trump, who wanted to cut its $8 billion
the sensitive issue of combating threats to posed double-digit cut to a healthy increase, budget by 12%. Legislators had fought back:
U.S. research from foreign influences. But and DOE’s Advanced Research Projects A spending bill passed by the House of Rep-
he weighed in when they asked about ways Agency-Energy escaped a proposed termi- resentatives in June 2019 would have grown
to eliminate gender discrimination and nation and instead will grow by a robust NSF’s budget by $565 million, and in Oc-
remove barriers to entry for those groups 16%. Congress also strengthened climate tober the Senate voted for a bump of $242
underrepresented in science. and environmental research programs at million. But rather than splitting the differ-
the National Oceanic and Atmospheric ence, Congress ended up giving NSF only a
He cited a program at ASU that has at- Administration and the U.S. Geological $205 million increase, less than both marks
tracted more undergraduate women into and only 2.5% above last year.
the mostly male discipline of engineering
by showing how it relates to the social sci- Reversal of fortune
ences, where women are often a majority.
The social sciences also play an important Congress not only rejected deep budget cuts to major science agencies proposed by President Donald Trump
role in his research. But he refused to of- for 2020, but also provided sometimes hefty increases in a final spending deal.
fer legislators a silver bullet for creating a
more diverse scientific workforce. Under- Trump request versus 2019 2020 1nal appropriations ($ increase)
represented groups “need more role mod-
els,” he said. “And culture change is hard.” 10

Even those who don’t know him well ($2.6 billion) ($410 million) ($230 million) ($205 million)
expect him to be a good fit for NSF. “He’s
got all the right qualifications,” says Arden 5
Bement, an emeritus professor at Purdue
University who was nominated by former 0
President George W. Bush and preceded
Suresh as NSF director. “And I think he’ll be –5
a good partner with Kelvin. ... There’s going –10
to be a lot of uncertainty in the next year or
so,” Bement adds, drily, “and having those –15
two hands at the helm should help science
to stay on course.” –20 DOE NASA NSF
NIH science science
Córdova, nominated by Obama to head
NSF, says she’s “thrilled with Panch’s nom-
ination.” She deflected a question about
her plans after leaving the agency, saying,
“The most important thing for me is to
finish strong.” j

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Competition with other programs about $480 million per year on research PUBLIC HEALTH

funded within the same pot of money, to- comparing the benefits of medical treat- Global polio
eradication
gether with a cut to that pot that came late ments. Congress created PCORI under the falters in the
final stretch
in the process, is a major reason. Fund- 2010 Affordable Care Act, and patient ad-
Vaccine-derived outbreaks
ing for the Executive Branch is spread vocacy and research organizations success- may force a change in
“endgame” strategy
across 12 appropriations subcommittees. fully pushed for PCORI’s renewal (Science,
By Leslie Roberts
The Commerce, Justice, and Science (CJS) 6 December 2019, p. 1179). Congress also
T he “endgame” in the decadeslong
panel funds NSF, as well as NASA and the gave the institute more leeway to consider campaign to eradicate polio suffered
major setbacks in 2019. While the ef-
Commerce and Justice departments. costs in assessing competing treatments. fort lost ground in Afghanistan and
Pakistan, which recorded 116 cases of
Senator Richard Shelby (R–AL), chair- The bill also marks a turning point in wild polio—four times the number in
2018—an especially alarming situation de-
man of both the Senate’s CJS panel and the the long-running debate over federal fund- veloped in Africa. In 12 countries, 196 chil-
dren were paralyzed not by the wild virus,
full committee, had already committed to ing for research on gun violence. NIH and but by a strain derived from a live vaccine
that has regained its virulence and ability to
giving the Commerce Department’s Cen- the Centers for Disease Control and Pre- spread. Fighting these flare-ups will mean
difficult decisions in the coming year.
sus Bureau the additional $3.5 billion it vention will split $25 million, ending a 24-
The culprit in Africa is vaccine-derived
needed to conduct the 2020 census. Shelby year drought for awards dedicated to such polio virus type 2, and the fear is that it
will jump continents and reseed outbreaks
is also a big supporter of NASA, which research. Congress also ordered the direc- across the globe. A brand new vaccine is
now being rushed through development to
spends billions of dollars in his home state tors of NIH and CDC to report to Congress quash type 2 outbreaks. Mass production
has already begun, even though the vaccine
of Alabama. That huge economic impact within 30 days on how it plans to support is still in clinical trials; it could be rolled
out for emergency use as early as mid-2020.
translates into a vocal constituency. “ideologically and politically unbiased re- At the same time, the Global Polio Eradica-
tion Initiative (GPEI) is debating whether to
In contrast, although NSF enjoys broad search projects.” Scientists “spent so many combat the resurgent virus by re-enlisting a
triple-whammy vaccine pulled from global
support among legislators, the agency “is years wondering whether we could even do use in 2016. That would be a controversial
move, setting back the initiative several
everyone’s second choice” this research. This is a clear years, as well as a potential public relations
disaster—an admission that the carefully
when it comes to spending signal that not only can we crafted endgame strategy has failed.
do it, but they want us to do
“An increase forpriorities, says Joel Widder, “All options are on the table,” says viro-
logist Mark Pallansch of the U.S. Centers
whose Federal Science Part- NSF that is it,” says Charles Branas, a for Disease Control and Prevention, one
ners lobbies for universities above inflation is firearm violence epidemio- of the five partner organizations in GPEI.
and research institutions. logist at Columbia University. “We are clearly in the most serious situation
we have been in with the program,” adds
So, after a 6-month nego- a good thing and Other provisions go be- Roland Sutter, who recently stepped down
tiation between House and yond spending. At the urging as the director of polio research at the
World Health Organization (WHO).
Senate negotiators left the we should be of animal rights advocates,
CJS panels with less money thankful for it …” Congress ordered the Depart- The heart of the problem is the live oral
than either had planned for, ment of Veterans Affairs to polio vaccine (OPV), the workhorse of the
NSF lost out. Joel Parriot, devise a plan to reduce or end eradication program—the only polio vac-
American Astronomical Society dog, cat, and primate testing
Research advocates say by 2025. Similarly, it directed
it’s not such a bad deal.

“An increase for NSF that the Food and Drug Adminis-

is above inflation is a good thing and we tration to develop a strategy and timeline for

should be thankful for it given all the phasing out tests that involve primates and

other CJS pressures,” says Joel Parriott of retiring its research monkeys, and NIH to tell

the American Astronomical Society. “And Congress how it is moving to reduce the use

compared to the president’s request, this of primates in research.

is crazy good.” The budget also appears to settle, for

One big winner within NSF’s new bud- now, a debate over whether the United

get are institutions planning new or up- States should remain fully engaged in

graded “midscale research infrastructure,” ITER, the giant international experimen-

such as small telescopes or communica- tal fusion reactor under construction near

tions networks, that cost from $6 million Cadarache in France. Some legislators have

to $70 million. Scientists say NSF funding wanted DOE to withdraw from the project

has failed to keep up with the demand for because of cost overruns and delays, and

these types of tools. Congress had scaled back U.S. contribu-

For the first time in decades, NSF this year tions. But lawmakers approved an 83% in-

requested $30 million for midscale projects crease, to $242 million in 2020, including

in its research account, as well as $45 million $85 million in cash and $157 million for

in an account normally used to build more manufacturing parts. That funding essen-

costly facilities. Congress liked the idea so tially puts the U.S. contribution back on

much that it upped the amount in the large the track DOE envisioned in 2017.

facilities account to $65 million, bringing the The new year means a new budget cycle.

total for midscale projects to $95 million. Trump will deliver his State of the Union

Lawmakers used the appropriations address to Congress on 4 February and

process to settle some policy matters. For shortly after deliver his 2021 spending plan

instance, the final bill renews, for 10 years, to Congress, which will then have its say. j

a government-created nonprofit organiza-

tion called the Patient-Centered Outcomes With reporting by Adrian Cho, David Grimm,

Research Institute (PCORI), which spends Jocelyn Kaiser, and Meredith Wadman.

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Polio vaccinators in northwestern Nigeria, where the live-virus vaccine itself is causing new infections. still be a big benefit,” Wenger says, but the
program is hoping for more.
PHOTO: PIUS UTOMI EKPEI/AFP/GETTY IMAGES cine powerful enough to stop viral circu- drop if supplies run critically low, despite
lation. Given as two drops into a child’s what it calls “a relatively weak level of evi- Sutter worries GPEI is “putting all of its
mouth, OPV for decades contained a mix dence” that the smaller dose is as effective.) eggs into the nOPV basket.” The novel vac-
of three weakened polio viruses, one for Meanwhile, the risk of explosive outbreaks cine could quickly lose its genetic stability
each of the three wild serotypes that have around the globe is ratcheting up, because if it exchanges key chunks of DNA with re-
long plagued humanity. All three serotypes millions of children born since the switch lated viruses, he says. But how often these
in the vaccine have the potential to revert have little or no immunity to type 2 virus. critical “recombination events” occur won’t
to more dangerous versions; that’s why the be known until the vaccine is used in larger
endgame strategy calls for deploying OPV WHO’s Michel Zaffran, who leads GPEI, populations. GPEI’s Independent Monitor-
in massive campaigns to eradicate the wild says there’s room to make better use of ing Board noted recently that the program is
virus, then ending its use entirely. mOPV2 by detecting outbreaks sooner, get- “rather starry-eyed” about nOPV2’s prospects.
ting money and vaccines to countries ear-
Wild serotype 2 was last sighted in 1999, lier, and reaching more children. “There are If novel OPV2 doesn’t work or vaccine-
so in 2016, as a first step in the endgame, things we can do even without a new tool,” derived outbreaks spiral out of control
all 155 countries using OPV replaced the agrees Jay Wenger of the Bill & Melinda before it is ready, the program might have
trivalent version with a bivalent one, lack- Gates Foundation, a partner in GPEI. little choice but to resurrect trivalent live
ing the type 2 component. Announced with vaccine, which would reintroduce immu-
great fanfare, “the switch” was billed as the But hopes are pinned on a novel OPV nity against type 2 in young children while
biggest vaccine rollout ever. Some type 2 (called nOPV2) that doesn’t revert so eas- maintaining protection against serotypes 1
outbreaks would inevitably occur for sev- ily. A Gates-funded research consortium and 3. The vaccine might be used in cam-
eral years, GPEI realized, but those would is developing two candidates, each with paigns across Africa, reintroduced into rou-
be fought, somewhat paradoxically, by rush- changes at multiple nucleotides to increase tine immunization, or both.
ing in essentially the same vaccine that genetic stability. Small phase I clinical tri-
gave rise to them in the first place: a live, als suggested both trigger an immune re- The program is now struggling to de-
monovalent vaccine targeted against type sponse and are safe and unlikely to regain fine the “triggers” that would warrant this
2 (mOPV2). If used in well-run campaigns, virulence. Phase II studies are underway in move. Is it reestablishment of type 2 across
and only in outbreak regions, mOPV2 could Belgium and Panama, but GPEI has already Africa? In Asia? The failure of nOPV2? The
stop outbreaks without seeding new ones, started to manufacture one candidate and depletion of the mOPV2 emergency stock-
models suggested. hopes to have at least 100 million doses pile? “It is actually a hard question. … It’s a
available this summer. GPEI is also push- public health judgment call,” Wenger says.
It often has not turned out that way. In- ing for an Emergency Use Listing, a never- “People have different ideas on timing and
stead of fading away, the number of type 2 before-used WHO mechanism that would triggers,” Zaffran adds. But officials need
outbreaks in Africa almost tripled from enable the program to deploy the vaccine to decide soon whether to ramp up pro-
2018 to 2019. Most of today’s outbreaks stem while it collects more data. duction of OPV3 again, which could take
from mOPV2 responses to previous ones, several years.
and GPEI is burning through its emergency It’s a risky strategy. The vaccine could
stockpile of mOPV2 faster than it can be re- fail or be delayed, and it won’t solve all the Some experts fervently hope to avoid
plenished. (Based on a small study in Mo- problems. It won’t be better at stopping reintroduction of the trivalent vaccine.
zambique, a WHO advisory panel recently outbreaks, just less likely to seed new ones. “It would be an enormous blow to the po-
recommended halving the dose to one How much less likely remains to be seen. lio program and to international public
“Even if it is just 100 times safer, that will health,” says Nicholas Grassly, a modeler
and epidemiologist at Imperial College
London. Sutter, on the other hand, favors
reintroduction sooner rather than later.
Trivalent OPV “is the only thing we know
has eradicated type 2 in the past and prob-
ably could eradicate it again,” he says. But
he agrees it would be a hard decision to
communicate, given the huge global ef-
fort that went into persuading countries to
switch to the bivalent vaccine in the first
place. “How do we explain to the world
that we have to go backward, not forward?”
Sutter asks.

There’s a bigger issue, too. No vaccine
can stop polio if it doesn’t get into children’s
mouths, program leaders and their advisers
caution—and that has been a long-standing
problem anywhere the virus, vaccine-derived
or wild, still circulates. The polio eradica-
tion program has been struggling with
complacency, fatigue, resistance, and poor
planning—all human issues that technology
can’t fix. j

Leslie Roberts is a journalist in Washington, D.C.

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N EEWWSS

FEATURES

FIGHTING

WORDS

Virologist Roberto Burioni
has become a celebrity
in Italy by sparring with
vaccine skeptics

By Douglas Starr

I n May 2016, Roberto Burioni, a viro- sage simple: “The Earth is round, gasoline is journalist Alessandro Milan called Burioni’s PHOTO: TANIA/CONTRASTO/REDUX
logist at Vita-Salute San Raffaele flammable, and vaccines are safe and effec- rebuttal to Red Ronnie “the 13 most beauti-
University in Milan, Italy, was asked tive,” he said. “All the rest are dangerous lies.” ful words heard on TV in the last year.”
to appear on a popular TV talk show
to face off against two opponents of “It went off like a bomb,” Burioni recalls. So began the unlikely media career of
vaccines—a former DJ, Red Ronnie, Emails from viewers poured into the show, Roberto Burioni. In just a few years, he
and an actress and TV personality, with some questioning how the publicly has gone from being a respected but little-
Eleonora Brigliadori. The host gave funded TV network hosting it could allow known professor to a major media person-
most of the air time to the Italian such ill-informed personalities to speak ality and an internet savvy advocate for
celebrities. Then, with just a few minutes about medicine. Burioni took up the theme science. In a country where the government
left, he turned to Burioni. on his Facebook page, asking how one has sometimes promoted dubious medi-
branch of government could broadcast lies cine, such as unproven stem cell therapies,
Burioni realized he didn’t have time to about vaccines while its health agency pro- Burioni has become an outspoken advocate
make the usual arguments about statistics moted immunization. More than 5 million for scientific evidence on vaccines and other
and scientific uncertainty, so he kept his mes- people responded to his comments. Radio medical topics, and a harsh critic of pseudo-

16 3 JANUARY 2020 • VOL 367 ISSUE 6473 sciencemag.org SCIENCE

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Roberto Burioni had never appeared on TV before more from disease cures than from vaccines,” than $200,000 from the government, on the
a 2016 appearance catapulted him to fame. he declared. “So if you don’t vaccinate your grounds that the measles vaccine distrib-
children, the pharmaceutical multinationals uted by the national health service caused
science. Nearly 480,000 people now follow will be sincerely grateful to you.” his condition. News of the decision spread
him on Facebook—an impressive number in on the internet like a contagion, igniting
a country of 60 million. A web page he and That post and others hit a nerve. Within false beliefs and conspiracy theories. “The
colleagues established to provide general weeks his social media followers grew from year 2012 was identified as the breaking
health information gets more than 100,000 about 100 to six digits. A voice like Burioni’s— point in the public’s confidence in vaccina-
visitors per month. that of an expert who sees no reason to tion in Italy,” researchers at the University
mince words or suffer fools—was evidently of Pisa wrote in a study of the web’s effect
Burioni, with his shock of graying hair, what many Italians were looking for. on vaccinations. An appeals court reversed
peaked eyebrows, and ironic smile, appears that judge’s decision in 2015, but the dam-
often on TV and at public events. His four As in many Western nations, concern age was done.
recent science books for popular audiences about vaccines had surged in Italy in the late
have become best sellers. The Italian edi- Antivaccination sentiment infected not
tion of Forbes magazine named him one of “He’s the one scientist only the courts, but also entertainment and
Italy’s top five internet game changers, and who stood up and politics. In the late 1990s, for example, a
a former health minister nominated him for comedian named Beppe Grillo had become
Italy’s gold medal in public health. said,‘This is bullshit.’” famous in Italy for denouncing vaccination.
Ten years ago, he co-founded the Five Star
Internet prominence brings trolls, and Guido Silvestri, Emory University Movement, a libertarian political party that
Burioni has been forced to worry about became a dominant member of Italy’s ruling
security. Some respected health research- 1990s after U.K. doctor Andrew Wakefield coalition and embraced antiscience positions.
ers and journalists have also been critical, published his now notorious study in The
saying his blunt, even abrasive manner Lancet linking autism to the measles, Vaccination rates, which had been climb-
inflames an already polarized conflict. But mumps, and rubella (MMR) vaccine. The ing since the 1990s, started to slide. Uptake
many public health experts credit him with study was later shown to be fraudulent, and of the MMR vaccine declined from a peak
changing Italy’s debate about vaccination Wakefield lost his medical license. But that of nearly 94% in 2010 to just over 85% in
and elevating the profile of science there. didn’t stop him from continuing to prosely- 2015—one of the lowest rates in Europe,
tize against vaccines or prevent vaccine op- and well below the 95% needed for herd
“I think he’s had a major impact on the ponents from embracing his study. immunity. Almost in lockstep, the nation’s
public’s understanding on the topic of vac- measles rate climbed to the second highest
cinations and science in general,” says Pier The Italian government insisted vaccines in Europe, after Romania’s.
Luigi Lopalco, who studies epidemiology were safe, but a series of medical scandals
and public health at the University of Pisa. had damaged its credibility. The most re- THAT WAS THE SITUATION Burioni waded
“He’s re-established the right of scientists to cent involved an experimental treatment into when he made his appearance on Ital-
speak directly to the people without having called Stamina therapy, developed by an ian TV. He’d never been on TV before, and
a DJ or actor intervene.” entrepreneur who claimed to be able to re- when the network called he assumed he’d
generate nerves from stem cells and cure be speaking to other medical experts. He
BURIONI MIGHT seem an unlikely media per- conditions such as Parkinson’s disease and was shocked to find that he’d be sharing the
sonality. He followed a rigorous academic muscular dystrophy. The inventor, Davide broadcast with two people who knew noth-
track: a medical degree in Rome; a Ph.D. Vannoni, received huge fees from desper- ing about vaccines. Hence his curt reply,
in microbiology in Geneva, and several ate patients, despite having produced no and the public’s enthusiastic response.
years of postdoctoral research at the U.S. clinical studies or peer-reviewed papers.
Centers for Disease Control and Preven- Scientist denounced the treatment, and the As he saw it, a door had opened and he
tion, the University of Pennsylvania, the Italian Medicines Agency ruled it unsafe. had to walk through it. The public seemed
University of California, San Diego, and But the Italian Senate, bowing to public hungry for straight talk from an expert,
the Scripps Research Institute. As a profes- opinion, permitted doctors and hospitals to and he obliged. “I realized that the lan-
sor in Milan, he develops monoclonal anti- administer it and funded a nearly $4 mil- guage of social media needs to be differ-
body therapies for herpes, hepatitis C, and lion clinical trial that was never completed. ent than the language used in conferences,
other viral diseases—work that has led to with colleagues or even with patients,” he
30 international patents. Stamina therapy was finally outlawed says, “so I tried to use not a single diffi-
in 2014, and Vannoni received a 22-month cult word.” He turned instead to concrete,
He made his first foray into social media suspended sentence for fraud. (He died in nonmedical metaphors in his Facebook
in 2015, when a friend who had created a December 2019.) Later, it was revealed that and Twitter postings. “Does an aircraft en-
Facebook group for mothers asked him to Italy’s current prime minister, attorney gineer take a vote among the passengers
write an explainer about vaccines. Burioni, Giuseppe Conte, won a court case in 2013 as to how many wheels to put on an air-
already irked by Italy’s growing antivaccine that allowed Stamina therapy to be given plane?” he asked. “No—the engineer is the
movement, agreed. “I felt it was my duty to to a girl suffering from an incurable neuro- expert, he’s trained for this job, and it’s his
do something as a doctor and a professor logical condition. The child later died. job to decide.”
and as a father of an 8-year-old daughter.” He
worried that the push to resist vaccinations Courts in Italy have compounded the When one of the largest publishers in It-
could put her and her classmates at risk. problem. Local judges often lack scientific aly asked him to write a book on vaccines,
He posted a five-point rebuttal of popular expertise and are allowed pick their own Burioni cranked it out in 4 months. A night
vaccine misconceptions and conspiracy the- consultants on technical matters. In one owl, he wrote after his wife and daughter
ories—including the notion that drug compa- egregious case in 2012, a judge in Rimini went to bed. “I never realized that I was good
nies promote vaccination in order to increase relied on Wakefield’s discredited research at writing,” he says. “Here I was at 54 years
profits. “Pharmaceutical houses earn much to award the family of an autistic boy more old; how would you say it—a late bloomer?”

SCIENCE sciencemag.org 3 JANUARY 2020 • VOL 367 ISSUE 6473 17

Published by AAAS

A 2017 law requiring childhood vaccinations triggered protests and threats in Italy. In the Senate, Roberto The result, Vaccines are not an Opinion: PHOTOS: (TOP TO BOTTOM) AUGUSTO CASASOLI/A3/CONTRASTO/REDUX; STEFANO MONTESI/CORBIS VIA GETTY IMAGES
Burioni’s allies displayed a doctored photo that circulated online, showing his face grafted onto an image of Vaccinations Explained to Those Who Really
Aldo Moro, an Italian prime minister murdered in 1978. In Rome, opponents of the law flooded the streets. Don’t Want to Understand, was a novelty in
a country where scientists rarely communi-
18 3 JANUARY 2020 • VOL 367 ISSUE 6473 cate in colloquial language. In it, Burioni ex-
plains how vaccines work, traces the history
of vaccination and of vaccine denialism,
and dismantles the denialists’ arguments.
He brings up tragic case histories of people
who died young for want of a vaccine and
skewers prominent vaccine opponents,
such as Jenny McCarthy, who declared on
Oprah that she learned her biology “from
the university of Google.” He hammers on
the theme that you can’t substitute opinion
for facts. The book’s popularity made him a
fixture on radio and TV. “The speed of light
can’t be decided by a show of hands,” he’d
say in talk show appearances.

In his later bestsellers, Burioni widened
his case against pseudoscience in Italy. “We
are a country forever wobbling between sci-
ence and superstition,” he says. He railed
against judges who ruled that unproven
treatments such as Stamina therapy had to
be given to patients who requested them,
often in publicly funded hospitals. He also
criticized the Italian public health system
for reimbursing patients for homeopathy—
pseudoscientific medical treatments that
use an extremely dilute concentration of a
substance that causes symptoms similar to
those of the disease.

Burioni says he wants to promote a respect
for expertise. “I know something about vac-
cines, viruses, and bacteria because I have
been studying them for a lifetime,” he writes
in Conspiracy of Dunces: Why Science Can’t
be Democratic, his second book. “But I have
no idea how to bake a cake or wire a lamp, so
I go to a bakery or call an electrician.”

Trouble begins, he says, when electri-
cians, bakers, and other nonscientists feel
qualified to weigh in on vaccination. The
internet abets the problem, he says: Un-
filtered by editors, it levels the playing field
between experts and “dunces.” A mass me-
dia committed to presenting both sides of
every issue makes things worse. “I can’t sup-
port a world in which lies are given the same
dignity as the truth,” he heatedly remarked
on an interview show. “Enough already!
Enough!” The audience burst into applause.

Burioni’s books, postings, and media
presence have made him a celebrity sci-
entist in Italy akin to, say, Neil deGrasse
Tyson in the United States. Hardly a week
goes by without him appearing on TV
or in a glamour shot in a newspaper or
magazine. At a recent conference in Milan
about future technologies, the audience—
including many influential business leaders—
swarmed him after his talk, asking for advice
and autographs.

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NEWS | FEATURES

“I feel a bit embarrassed by it all,” Burioni their children. That’s why scientists have bring up a list of antivaccination groups

says, seeming not at all embarrassed but examined vaccines with such care, she tells among top results. Now, the first hits in-

very much amused. (In fact he seems to rel- viewers. “People are much more educated clude Burioni’s websites and the vaccine

ish the publicity, having recently appeared than they used to be,” she says. “They want information sites created by the World

on an Italian comedy show in a version of to understand what we are doing to their Health Organization and Italy’s health au-

Name That Tune.) He’s proud that despite children. So you cannot approach them in a thorities. Similarly, radio and TV shows

all the media appearances he hasn’t missed paternalistic way.” have become more likely to book scientists

giving a lecture and continues to work full- Others appreciate Burioni’s no-holds- instead of actors and DJs to discuss vac-

speed in his lab. barred style. “I know he likes to make jokes cination, according to Lopalco and others

Yet it hasn’t all been fun. His time for fam- that sometimes can be seen as abrasive,” who monitor the media.

ily and leisure has suffered. More disturb- says Guido Silvestri, a longtime friend and a Recently, Burioni expanded his cam-

ing, at one point police had to stand watch pathologist at Emory University. “But what paign for science. In late 2018, he and half

over his house after someone threatened his kind of debate can you have with someone a dozen colleagues created Medical Facts,

daughter online—one of many death threats. who says that vaccines are a conspiracy to a web portal that posts news, advice, and

In 2018, Burioni and his family were vaca- kill children? He’s the one scientist who comments on a variety of health issues.

tioning at the beach town of Rimini when a stood up and said, ‘This is bullshit.’” In January 2019, he and Silvestri posted

vaccine opponent caught sight of him and a manifesto called “The Pact for Science,”

posted on the web. Within minutes an on- THINGS ARE IMPROVING. In the summer of supporting research and education and

line posse had weighed in with suggestions 2017, after the nadir in vaccination rates calling for the use of objective science in

on how to harass him; on the advice of police and the spike in preventable disease, the government decisions. It has attracted

he and his family went elsewhere.

He’s also been the subject of

CREDITS: (GRAPHIC) N. DESAI/SCIENCE; (DATA) EPICENTRO; F. D’ANCONA ET AL., EURO SURVEILL. 24(26), (2019); INTEGRATED SURVEILLANCE OF MEASLES AND RUBELLA IN ITALY, 55, (2019) more substantive criticism for Setback and recovery
his “Burioni blasts”—devastating
replies to even the mildest op- After rising for years, measles vaccination rates in Italy fell until 2015 because of unfounded safety concerns, abetted by some
position. When a Facebook fol- government and court actions; measles cases spiked. Public education and a 2017 law have boosted rates since then.

lower said he was trying to figure 100 %
out the vaccine issue in his own

head, Burioni replied, “When Vaccination rate

you go on social media you can 90
be reasonably sure that the inte-

rior of that head is as empty as a

tire tube.” He’s also been known 80

to ban even mild critics from

his Facebook page and discount 70
the work of science journalists

on the vaccine issue. “This is not 0
what you would call public out-

reach,” says Sergio Pistoi, a science Number of cases 10000
writer and molecular biologist

in Tuscany. 5000
Burioni’s broadsides polarize

and oversimplify a complicated

discussion, adds Fabio Turone, 0 2005 2010 2015 2018
a science writer and director of 2000

the Center for Ethics in Science

and Journalism. Fewer than 1% of Italians government passed a law that set up pub- thousands of signatures from people as

are hard-core vaccine deniers, he says; but lic education programs and requires all diverse as the head of the left-leaning

about 15% are “vaccine hesitant” because schoolchildren to get 10 essential vaccina- democratic party and Grillo himself, one

they have concerns about vaccines or find tions before kindergarten. Even though the of Italy’s original vaccine deniers. In June

them hard to get. (In Italy, doctors at the law is loosely enforced, it’s working. Vacci- 2019, Burioni and colleagues created a

public health service—not the child’s pe- nation rates have rebounded, according to group related to the pact that will advocate

diatrician—administer vaccinations, and Italy’s National Institute of Health. After for science and help local judges gather

some health service centers closed after bottoming out at 85.3% in 2015, measles better information when adjudicating

the budget crash of 2008.) Such people are vaccination has risen to 94.1%, within strik- cases involving science and health.

best reached by persuasion, not mockery, ing distance of the 95% needed to prevent “The world has changed,” Burioni says,

Turone says. outbreaks when single cases pop up. The acknowledging both the good and “cata-

Roberta Villa, a journalist and doctor, law has proved so effective that France and strophic” effects of social media. “Science

calls for a more empathetic approach. Her Germany passed similar laws in 2019. needs to find a new voice—not the lan-

YouTube videos show her sitting at her Burioni and others don’t claim he is re- guage of scientific congresses, but a lan-

kitchen table, a cup of coffee in hand and sponsible for the turnaround, but public guage that’s understandable, passionate,

a drawing of Snoopy in the background, ex- health researchers say the “Burioni effect” and convincing.” j

plaining that as a mother of six she under- has altered public discourse. Four years

stands that all parents want to protect ago, googling “vaccines” in Italy would Douglas Starr is a journalist in Boston.

SCIENCE sciencemag.org 3 JANUARY 2020 • VOL 367 ISSUE 6473 19

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INSIGHTS BOOKS et al.

SCIENCE FICTION PHOTO: COURTESY OF THE RALPH MCQUARRIE ARCHIVES

20 3 JANUARY 2020 • VOL 367 ISSUE 6473 Asimov at 100

From epic space operas
to rules for robots, the
prolific author’s literary
legacy endures

By James Gunn

G ertrude Blugerman once asked of
her husband, Isaac Asimov, “What
will you say at the end of your life if
you have written one hundred books
but have missed living?” “Only one
hundred?” he replied. Asimov wrote
of this incident in Opus 100, his hundredth
book, published in 1969. He would write or
edit more than 500 books in his lifetime.

Asimov was brought to the United States
at the age of 3 from Petrovichi, a small town
in the still relatively new Soviet Union. His
birthday—2 January 1920—was one settled
on by his parents. (Records in Petrovichi
were unreliable, and he may have been
born as early as November 1919.) The fam-
ily settled in Brooklyn, New York, where his
father opened a candy store that also sold
newspapers and magazines. It was an en-
terprise in which all members of the family
participated. Perhaps not surprisingly, Isaac
was drawn to the magazines, particularly the
colorful science fiction publications.

Asimov was a gifted student with a capa-
cious memory who moved easily through
grade school and high school. In the first of
his autobiographies (he published two com-
prehensive volumes and, later, two supple-
mental tomes), he recounted how he would
acquire his textbooks for the semester, read
them on his walk home, and never open
them again. When I interviewed him for
the book I wrote about his life and work (1),
I asked if he ever forgot anything, and he said
that once he had been reciting the second
verse of the U.S. national anthem and, for a
moment, could not think of how it started.

Asimov attended Seth Low Junior College,
a branch of Columbia University in Brooklyn,
graduating in 1939 from Columbia when
Seth Low closed in 1938. He majored in
chemistry after discovering in his freshman
year that to major in zoology, one would be
required to dissect cats.

This pensive android appeared on the cover
of Asimov’s 1990 collection Robot Visions.

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The year 1939 was also when Asimov’s mentioned Opus 100—and was, it turned should appear one night in a thousand years,

first science fiction story was published in out, only just getting started. Soon his books, how would men believe and adore; and

the magazine Astounding Science Fiction. written on topics ranging from the Bible to preserve for many generations the remem-

The sale of his stories paid for his college the human body, began appearing as often brance of the city of God which had been

expenses, including the master’s degree he as monthly, leading Harvard paleontologist shown! But every night come out these en-

would later earn in chemistry. (He was re- George C. Simpson to call him “one of our voys of beauty, and light the universe with

jected twice for medical school but would go natural wonders and national resources” (1). their admonishing smile.” And in an article

on to earn his doctorate, again in chemistry.) Asimov was a popular public speaker in Isaac Asimov’s Science Fiction Magazine

In 1942, Asimov began research as a chem- and a regular participant in science fiction (3), Asimov credited my words with helping

ist at the Philadelphia Navy Yard. Meanwhile, conventions, where, despite having earned him overcome his fears about writing a se-

he continued to sell stories but considered a formidable reputation as one of the “big quel to the Foundation trilogy. The resulting

himself a third-rate writer until his nov- three” science fiction authors of the era, he series (4) brought the Foundation trilogy and

elette “Nightfall” received a cover story in remained approachable. He participated his robot novels together into a single future

Astounding Science Fiction in 1941. The fol- in a variety of social organizations, includ- history and became his first bestseller.

lowing year, the first story of his Foundation ing Mensa; the Humanist Society (of which A case can be made that, like H. G. Wells,

series was published. During this period, he he was named the honorary president); the Asimov came along at the right time. (Wells

began the first of his robot stories, which Baker Street Irregulars, a society dedicated once commented that he made his writing

were published together in 1950 as I, Robot. to the appreciation of Sherlock Holmes; and debut in the 1890s, when the public was

In September 1945, Asimov was drafted the Trap-Door Spiders, a luncheon group looking for new writers.) But Asimov also

into the U.S. Army and served for 6 months that served as the inspiration for the fic- had a restless and productive mind. His

before being honorably discharged. He re- tional Black Widowers club in a series of early experience of reading, and then writ-

turned to Columbia, where he earned his mystery stories and novels he wrote. ing, science fiction gave his popular science

doctoral degree in 1948 before accept- writing a rare narrative model, while

ing his first (and only) academic ap- his fiction similarly benefited from his

pointment at Boston University. scientific training.

Science fiction received a boost from Some of Asimov’s critics complained

World War II. The number of magazines that his writing lacked style. He re-

publishing it increased in the aftermath sponded by asserting that he had a

of the war, and book publishers soon fol- style: clarity. But it also was true that

lowed. The subsequent Space Age and he was able to adopt new methods, par-

concerns evoked by Sputnik also led to ticularly in his later works.

publishing opportunities in the realm Asimov’s fiction was based on the

of science popularization. Asimov’s en- presumption that humanity would

gagement with the latter genre began solve its problems by thinking coolly

with a 1953 biology text coauthored with and logically. In his nonfiction writ-

two other faculty members. This would ing, he often grappled with the messier

be the beginning of a series for which realities of human nature. There are

the earnings—together with those of his no records of how many minds he in-

science fiction and other writing—soon fluenced with the latter, but his abil-

exceeded his university salary. Asimov brought drama and narrative to his nonfiction science ity to communicate difficult scientific

When Asimov was reprimanded for writing and often grounded his fiction in real scientific principles. ideas in simple language has not been

failing to conduct any research, he re- equaled since.

plied that he considered his writing his re- Kurt Vonnegut is reported to have once Asimov once told a friend that if he had a

search. Shortly afterward, he was terminated. asked Asimov how it felt to be the man who hang-up, it was his desire to write, saying that

He had previously been promoted to the rank knows everything, to which Asimov is said he wanted to die with his nose stuck between

of associate professor with tenure, and after a to have replied that he only knew how it felt two typewriter keys. It did not happen that

2-year battle it was determined that he would to have the reputation of omniscience. On way. His second wife and widow, Janet, con-

be allowed to stay on. He chose instead to another occasion, an editor reportedly en- firmed after his death that Asimov had con-

leave to focus on his writing. couraged Asimov to write an autobiography. tracted AIDS from a blood transfusion during

By the time I filmed him for my literature “But I’ve never done anything,” he protested. open-heart surgery a decade before. He had

PHOTO: MONDADORI PORTFOLIO/CONTRIBUTOR/GETTY IMAGES of science fiction film series in 1972, Asimov He returned a year later with a thick manu- been persuaded by his doctors to keep this

was living in a high-rise off of Central Park script. When the editor failed to protest its information confidential, because of concerns

and was in the middle of divorcing his first length, Asimov left and returned with an- that it would deter people from undergoing

wife. “Science fiction writers and readers other manuscript, just as thick. “What would necessary surgery. He died from complica-

didn’t put a man on the moon,” he reflected you have written if you had done anything?” tions of the disease in 1992 at the age of 72.

during our interview, “but they created a cli- the editor is said to have replied. But his legacy, and his books, remain. j

mate of opinion in which the goal of putting Although he claimed no false modesty— REFERENCES AND NOTES
a man on the moon became acceptable.” “nor true modesty either” (2)—he insisted on
acknowledging the role of others in his suc- 1. J. E. Gunn, Isaac Asimov: The Foundations of Science
Asimov had, by this time, already pub- cess. He credited editor John W. Campbell Fiction (Oxford Univ. Press, 1982).
lished his hundredth book—the previously with the invention of the three laws of robot-
ics and with introducing him to the Ralph 2. J. E. Gunn, Alternate Worlds: The Illustrated History of
The reviewer is the founder of the Gunn Center for the Study Waldo Emerson quotation that inspired Science Fiction (A & WVisual Library, 1975).
of Science Fiction, University of Kansas, Lawrence, KS 66045, Asimov to write “Nightfall”: “If the stars
USA. Email: [email protected] 3. I.Asimov,“The story behind the‘Foundation’,”Isaac
Asimov’s Science Fiction Magazine, December 1982.

4. I.Asimov, Foundation’s Edge (Doubleday, 1982).

10.1126/science.aba0303

SCIENCE sciencemag.org 3 JANUARY 2020 • VOL 367 ISSUE 6473 21

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INSIGHTS

PERSPECTIVES

INFECTIOUS DISEASE

Uncovering the ART of antimalarial resistance

A key mechanism of resistance to the antimalarial drug artemisinin is identified

By Danushka Marapana and Alan F. Cowman However, the initial identification of ART this carboxyl-terminal Kelch-repeat region.

resistance in western Cambodia in 2008 Directed mutagenesis studies of both ART-

T he identification of artemisinin (ART) followed by rapid spread throughout the naïve strains and clinical isolates have
in 1971 allowed treatment of malaria Greater Mekong Subregion of Southeast confirmed the causal role of PfKelch13 in
resistant to chloroquine, the prevail- Asia forewarned of a major issue for the mediating ART resistance (7, 8). Multiple
ing drug at the time, and provided malaria elimination agenda in that re- hypotheses implicate PfKelch13 as a re-
hope for a malaria-free world (1). To- gion (3). Additionally, the potential spread sponder to downstream effects of ART

day, malaria control efforts have been of ART resistance to sub-Saharan Africa activation, especially in up-regulation of

very successful, with 32% fewer deaths over would make elimination programs even pathways involved in the cellular stress

the past 8 years (2). However, the emergence more challenging. response and reduced protein translation

of resistance to ART and other antimalari- ART resistance manifests as enhanced in the presence of ART-induced stress (9–

als threatens to become a major problem in survival and delayed clearance of young 11). However, the possibility of PfKelch13

the continuing program to eliminate and ring-stage parasites after a concen- acting upstream as a conduit for ART ac-

eventually eradicate malaria (3). ART com- trated exposure to ART or its derivatives. tivation was not investigated prior to the

bination therapies (ACTs) are the Birnbaum et al. study.

current gold standard for the treat- Birnbaum et al. found that

ment and control of malaria, and Gateway for activation PfKelch13 and its interacting pro-
how parasites that cause malaria teins are localized in vesicles close
in humans mediate this resistance Malaria parasites ingest hemoglobin to produce heme from the to cytostomes, which are erythro-
is of intense interest for preventing host red blood cell using cytostomes. The interaction of heme in the cyte-cytosol containing structures
parasite food vacuole with artemisinin (ART) causes activation of

the spread of drug resistance. On the drug and parasite killing. PfKelch13-containing vesicles regulate produced by the parasite. They

page 51 of this issue, Birnbaum et the uptake of hemoglobin by Plasmodium falciparum and thereby discovered that proteins in this

al. (4) answer this critical question affect the amount of ART activation through reduced heme availability. PfKelch13 compartment are re-

by identifying the molecular mecha- quired for the endocytic uptake of

nism of ART resistance in the most hemoglobin; however, PfKelch13 it-

lethal human malaria parasite, Plas- Cytostome self is essential for this process only

modium falciparum. in the young ring-stage parasites.

As malaria parasites infect and PfKelch13 By investigating the link between
grow within human erythrocytes vesicles PfKelch13, hemoglobin uptake, and

(red blood cells), they actively en- ART ART activation, Birnbaum et al.
gulf and digest host hemoglobin Heme found that PfKelch13-inactivated
in a dedicated parasite-derived parasites and those carrying ART

food vacuole (see the figure). Hemoglobin resistance–conferring Pfkelch13

Hemoglobin is broken down into Red blood Food Nucleus mutations display depleted con-
amino acids, which are used for the cell vacuole centrations of the protein. These
synthesis of parasite proteins, and PfKelch13-depleted parasites ex-
iron-bound heme, which is gradu- Plasmodium Endoplasmic hibit decreased hemoglobin uptake
ally detoxified within hemozoin falciparum reticulum as well as enhanced ring-stage sur-
crystals. Heme binding results in parasite vival during high-dose ART treat-

cleavage of the endoperoxide bond ment. Thus, PfKelch13 is a facilita-

of ART, enabling drug activation. Active Molecular genotyping of ART-resistant par- tor of ART activation, and Birnbaum et al.

ART produces free radicals and reactive asites uncovered single nonsynonymous propose an elegant model to merge a large

oxygen species that attack protein and mutations in a P. falciparum–specific gene body of prior research into a comprehen-

lipid molecules of the developing para- called Pfkelch13 (6). The PfKelch13 protein sive pathway of ART resistance.

site. ART treatment of intraerythrocytic contains three main functional regions: a In this model, mutations in the Kelch

Plasmodium parasites results in rapid kill- parasite-specific localization sequence, a propeller domains of PfKelch13 impair the GRAPHIC: KELLIE HOLOSKI/SCIENCE

ing of all life cycle stages, including the BTB/POZ domain that typically facilitates ability of parasites to endocytose hemoglo-

young “ring” stage of infection, which is ubiquitin-mediated degradation, and a bin during the young ring stage of infection.

resistant to most antimalarial drugs (5). carboxyl-terminal Kelch propeller repeat Consequently, hemoglobin degradation is

region that is predicted to function as a reduced, and less heme becomes available

Department of Medical Biology, Faculty of Medicine, scaffold for protein-protein interactions for ART activation. Hemoglobin catabolism
Dentistry and Health Sciences, University of Melbourne, (6). Nearly all clinically relevant ART- also provides the parasite with a source of
Parkville, VIC 3052, Australia. Email: [email protected] resistance mutations are localized within amino acids for protein synthesis. Therefore,

22 3 JANUARY 2020 • VOL 367 ISSUE 6473 sciencemag.org SCIENCE

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it seems that resistance to ART carries a bio- PHYSICS
logical trade-off for the parasite: It grows at
a slower rate owing to the decreased avail- Majorana fermions go for a ride
ability of amino acids for protein translation.
Therefore, the unfolded protein response, Evidence for propagating Majorana quasiparticles
which alleviates cellular stress caused by is found in a topological superconductor
accumulation of unfolded and misfolded
proteins, is up-regulated in parasites in an By Sumanta Tewari1 and Tudor D. Stanescu2 scribe the “regular” particles (for example,
attempt to withstand the toxic effects of re- electrons and neutrons), whereas the nega-
active ART metabolites (10, 11). E nrico Fermi described Ettore Ma- tive-energy solutions—initially regarded by
jorana as having the mind of a ge- even Dirac as unphysical—are now known
How does PfKelch13 function in he- nius. The Majorana fermion, born to describe their so-called “antiparticles”
moglobin endocytosis? A likely scenario as a testimony to the truthfulness of (for example, positrons for electrons and
is that the cysteine-containing Kelch do- mathematical aesthetics, has recently antineutrons for neutrons). For every quan-
mains, which allow protein-protein inter- returned to the center stage of mod- tum mechanical particle that obeys the
actions, function as a molecular scaffold ern physics. These are particles that are Dirac equation, there are subatomic anti-
to engage PfKelch13 partner proteins to also their own antiparticles. For decades, particles with physical properties that are
facilitate hemoglobin transport. Inhibitors Majorana’s theory was considered a math- identical in some respects to those of the
against eukaryotic Kelch proteins disrupt ematical curiosity that has little to do with corresponding particle (for example, the
protein-protein interactions by chemi- reality. However, they have now become same mass) and exactly opposite in some
cally modifying the Kelch cysteine residues the key concept associated with certain others (for example, baryon numbers and
(12). This could be an avenue to disrupt types of quasiparticles in condensed-mat- opposite electric charges). Thus, the nega-
PfKelch13-mediated hemoglobin digestion ter systems (1). In the condensed-matter tively charged electron has an antielec-
and nutrient uptake by the parasite. A rela- context, they are not fundamental particles tron called a positron that is the positively
tively unexplored facet of PfKelch13 is the like electrons or neutrinos but emerging charged counterpart with equal mass. The
BTB/POZ domain (6). In other eukaryotes, excitations that we term quasiparticles. On neutron and the antineutron have the same
this domain forms a Cullin-3–E3 ubiquitin page 104 of this issue, Wang et al. (2) pro- mass but opposite baryon numbers.
ligase complex and promotes the protea- vide strong evidence for the observation of
somal degradation of multiple protein sub- Majorana quasiparticles in an iron-based In the late 1930s, Ettore Majorana showed
strates (13). However, P. falciparum does superconductor, FeSe Te . that the Dirac equation accepts a class of so-
not appear to encode a canonical homolog lutions that describes particles that are iden-
of Cullin-3, and because PfKelch13 itself x 1–x tical in every respect to their antiparticles.
is localized within a distinct subcompart- The original candidates for Majorana fermi-
ment in the parasite cytoplasm (14), it will The concept of Majorana fermions has its ons—neutrons and neutrinos—appeared to
be interesting to identify how PfKelch13 roots in a celebrated equation discovered in have distinct antiparticles. For neutrinos,
ubiquitinates proteins. the late 1920s by physicist Paul Dirac. The the jury is still out, but the concept of Ma-
Dirac equation seamlessly brings together jorana fermions has become central to de-
Pfkelch13 mutation is not the only mech- quantum mechanics and the special theory velopments in supersymmetry, dark matter,
anism of ART resistance, because parasites of relativity and provides the quantum me- and, most recently, certain types of emerg-
that display an increased ring-stage sur- chanical description of spin-half fermions, ing quasiparticles in condensed-matter sys-
vival phenotype but lack Pfkelch13 muta- such as electrons, protons, and neutrons. tems. In condensed-matter systems, they
tions have been reported (15). It would be The equation has the property that if a solu- can emerge in a special class of supercon-
intriguing to investigate whether these tion exists with an energy +E, –E is also a
parasites also show defects in hemoglobin solution. The positive-energy solutions de-
uptake. In addition to ART, ACTs include a
partner drug that typically targets the he- Inferring Majorana modes
moglobin digestion mechanism of the par-
asite. Future formulations of ACTs might Indirect observations support the existence of propagating Majorana quasiparticles (QPs) in the presence
be more effective by using partner drugs of surface topological superconducting states (blue) emerging from the bulk states (red).
targeting other biochemical pathways. j
Surface Domain wall
REFERENCES AND NOTES
G
1. Y.Tu, Nat. Med. 17, 1217 (2011). X
2. “World malaria report 2018”(World Health
Z
Organization, 2018); www.who.int/malaria/
publications/world-malaria-report-2018/en/. G
3. A. M. Dondorp et al., N. Engl.J. Med. 361, 455 (2009). X
4. J. Birnbaum et al., Science 367, 51 (2020). Bulk
5. C. L. Hartwig et al., Biochem. Pharmacol. 77, 322 (2009).
GRAPHIC: C. BICKEL/SCIENCE 6. F.Ariey et al., Nature 505, 50 (2014). Setting the stage Defning the directions XGX XGX
7. J. Straimer et al., Science 347, 428 (2015). The iron-based The reciprocal lattice Topological surface Majorana QPs
8. M. Ghorbal et al., Nat. Biotechnol. 32, 819 (2014). topological superconduc- points of the bulk states Along the domain wall, a
9. C. Dogovski et al., PLOS Biol. 13, e1002132 (2015). tor has a domain wall (X, G, Z) and surface In the bulk, valence and linear set of allowed low-
10. S. Mok et al., Science 347, 431 (2015). (black line) separating states (X, G) are shown. conducting bands (red) do energy states (orange)
11. P.J. Shaw et al., BMC Genomics 16, 830 (2015). two regions shifted by not touch. Surface valence would connect the gapped
12. A. Cuadrado et al., Nat. Rev. Drug Discov. 18, 295 (2019). one-half of a unit cell. and conduction bands bands of the topological
13. L. Pintard,A.Willems, M. Peter, EMBO J. 23, 1681 (2004). (blue) touch at one point. superconductor.
14. J. Birnbaum et al., Nat. Methods 14, 450 (2017).
15. A. Mukherjee et al., Malar.J. 16, 195 (2017).

10.1126/science.aba0445

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INSIGHTS | PERSPECTIVES

ductors called topological superconductors tified topological superconducting surface DEVELOPMENTAL BIOLOGY

as either quasiparticles localized at certain states with high-resolution angle-resolved Building a
carnivorous trap
types of defects, such as vortices, or as de- photoemission spectroscopy (9) and ob-
Experiments and
localized quasiparticles propagating along served sharp zero-bias peaks inside vortex computations reveal
developmental origins of
the boundaries or the walls between differ- cores (10). The authors’ scanning tunnel- cup-shaped leaves

ent domains of superconductivity (see the ing microscopy studies show a flat (bias- By Derek E. Moulton and Alain Goriely

figure). In condensed-matter physics, the independent) differential conductance V ariation, according to evolutionary bi-
ologist Stephen Jay Gould, is “nature’s
Majorana quasiparticles are predicted to along the domain wall. This signature is only irreducible essence” (1). The vari-
ation and diversity of shapes in nature
obey fundamentally new particle statistics the hallmark of the linearly dispersing Ma- is a central focus of both evolutionary
and developmental biologists. Uni-
that generalize from the Fermi-Dirac statis- jorana quasiparticles propagating along a fied under the unlikely roof of “evolutionary
developmental biology,” the ultimate goal of
tics governing identical particles with half- one-dimensional defect. The spatial distri- these scientists is to understand how varia-
tion arises both through natural selection (on
integer spin. Experimental observations of bution of domain wall states as a function geological time scales) and during develop-
ment (on embryological time scales). On page
sharp tunneling conductance peaks that of energy is also consistent with the evo- 91 of this issue, Whitewoods et al. (2) present
a fascinating example of evolutionary devel-
are consistent with the presence of Majo- lution expected from the Majorana quasi- opmental biology in a carnivorous plant.

rana quasiparticles in semiconductor-su- particle being localized along the domain The herbarium of our early school years
taught us that leaves come in many different
perconductor heterostructures (3–5) and wall at zero energy to become delocalized sizes, shapes, and textures that have evolved
by subtle gene rearrangements to solve vari-
ferromagnetic atomic chains deposited on as its energy approaches the gap edge. ous packing and arrangement problems (3).
Whereas many leaves are nearly flat, so as
superconductors (6) have been reported The authors also show a robust zero bias to present their best face to the Sun, others
have been sculpted by evolution to function
in the past few years, although definitive anomaly observed in vortex cores below as mechanical devices; ropes, springs, spikes,
claws, spears, hooks, catapults, and traps are
evidence is still lacking (7). These observa- the superconducting transition tempera- the medieval weapons that plants use in their
daily struggle with the environment. Perhaps
tions have only been on static quasipar- ture T , which is a signature of companion most intriguing are carnivorous traps, the re-
c venge of the plant kingdom and one of the
lesser-known interests of Darwin (4).
ticles, otherwise called localized or bound Majorana quasiparticles localized at vortex
The humped bladderwort (Utricularia
states. By contrast, evidence for Majorana cores consistent with previous studies (10). gibba), is an inconspicuous, easy-to-grow
aquatic plant found on all inhabited con-
quasiparticles that propa- “Experimental The experiments from tinents. Yet, it has developed a nearly
gate along the boundaries observations… Wang et al. provide a com- spherical cage and a sophisticated release
or walls between different pelling case for topological mechanism that can swallow an unsuspect-
domains in superconductors superconductivity and propa- ing crustacean in a few milliseconds (5).
How can a leaf develop into such an elegant
has not been observed. are consistent gating Majorana quasipar- and complicated structure?
The challenge associated ticles in a class of iron-based
With its small genome, the bladderwort
with the experimental dem- with the presence superconductors. This system turns out to be an excellent model system. In
onstration of Majorana qua- of Majorana is attractive because the ob- these plants, the same branch supports both
siparticles stems, essentially, servations and theory sug- needle-like leaves and bladder-shaped traps

from the complexity of the gest Majorana behavior occur Oxford Centre for Industrial and Applied Mathematics
in a single material, without (OCIAM), Mathematical Institute, University of Oxford,
quasiparticles…”proposed host systems. These Oxford OX2 6GG, UK. Email: [email protected]

systems are multicomponent a heterostructure. The find-

heterostructures (3–6) predicted to behave ings open a new chapter in the field of

as topological superconductors under con- iron-based superconductors and represent

trolled external conditions. By contrast, a large step in the quest for Majorana fer-

Wang et al. exploit a key advantage of the mions in condensed-matter systems. For

iron-based superconductor FeSe Te in practical applications, Majorana systems
x 1–x

that it consists of a single material that sup- in condensed-matter physics are attractive

ports all the key ingredients necessary for for quantum computing because their fun-

Majorana physics. This requires a nontrivial damentally new particle statistics may be

electronic band structure, superconductiv- useful for the development of fault-tolerant

ity, and special types of domain walls that topological quantum computation (11, 12).

can support propagating Majorana qua- This makes these iron-based systems im-

siparticles. The surface of this system is a portant both for fundamental science and

topological superconductor with a special quantum technology. j

band structure, based on an argument put REFERENCES AND NOTES
forward by Fu and Kane (8). A domain wall
separating regions of the crystalline lattice 1. N. Read, D. Green, Phys. Rev. B 61, 10267 (2000).
shifted by half a unit-cell should support a 2. Z. Wang et al., Science 367, 104 (2020).
pair of counterpropagating Majorana quasi- 3. J. D. Sau, R. M. Lutchyn, S. Tewari, S. Das Sarma, Phys.

Rev. Lett. 104, 040502 (2010).

particles identifiable with a linear energy- 4. V. Mourik et al., Science 336, 1003 (2012).
momentum dispersion relation (8). 5. H. Zhang et al., Nature 556, 74 (2018).
6. S. Nadj-Perge et al., Science 346, 602 (2014).
Wang et al. used a combination of pre- 7. C. Moore, C. Zeng, T. D. Stanescu, S. Tewari, Phys. Rev. B
vious studies and experimental and theo-
98, 155314 (2018).

retical evidence to show that this scenario 8. L. Fu, C. L. Kane, Phys. Rev. Lett. 100, 096407 (2008).
exists for FeSe Te . Previous studies iden- 9. P. Zhang et al., Science 360, 182 (2018).
10. D. Wang et al., Science 362, 333 (2018).
x 1–x

11. A. Kitaev, Phys. Uspekhi 44, 131 (2001).

1Department of Physics and Astronomy, Clemson 12. C. Nayak, S. H. Simon, A. Stern, M. Freedman, S. Das
University, Clemson, SC 29634, USA. 2Department Sarma, Rev. Mod. Phys. 80, 1083 (2008).
of Physics and Astronomy, West Virginia University,
Morgantown, WV 26506, USA. Email: [email protected] 10.1126/science.aaz6961

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(see the figure). Both structures develop from by inducing expression of one of the genes in tion of cell division? The new model demon-
the same initial dome-shaped organ primor- an abnormal position on a leaflet. strates a logical sequence of differential gene
dia. The selection of one shape or the other expression preceding growth polarity, which
occurs through the physical translation of a Having established relevant gene expres- precedes cell-division orientation.
delicate variation in differential gene expres- sion profiles, Whitewoods et al. turned to
sion and morphogen production, which can a computational model for leaf morpho- By showing that spherical traps, conical
be probed experimentally and theoretically genesis. Most computational work in plant needles, and flat leaves all can be generated
through computational modeling. biology tends to model morphology by track- from the same initial tissue shape through
ing cell growth and division (7). One of the small shifts in gene expression and growth
During its development, the leaf must singular features of the authors’ research differentials inspired by morphogen distribu-
solve a problem in geometry. There is a fun- was their study of growth deformations at tion, the new study opens exciting lines of re-
damental difference between a flat sheet the tissue level. In their model, each point search. For example, can these polarity fields
and a sphere, a fact that can be appreciated in the budding organ—treated as a three- be explicitly identified by measurements of
by trying to flatten an orange peel. The two dimensional continuum—was given differ- gene expression at the cellular level? How
states are geometrically incompatible, so ent growth rates in each of three selected are the polarity fields influenced by chemi-
transforming one into the other involves directions. These directions are linked to a cal and mechanical stimuli (12)? And how
either stretching or cutting. Because the in- polarity field obtained by the diffusion of a exactly does the developmental process form
a functioning trap? The trap mechanism in-
Bladderwort beginnings volves the slow build-up and rapid release of
mechanical energy (13), which is intimately
During development of the humped bladderwort, the same initial primordia (arrow) on a single branch linked to morphological changes during de-
can be transformed into either needle-like leaves (left, top circle) or carnivorous traps (left, bottom circle). velopment (14), but the connection has not
The key to shaping an organ is differential gene expression, which creates differential growth that is either yet been explored.
heterogeneous or anisotropic.
More broadly, Whitewoods et al. offer key
Primordia insights into the competing pressures that
ultimately shape every living thing. Develop-
Varied rates ment is inherently a physical process and is
of growth in thus the end result of physical forces subtly
diferent manipulated by genetic clues. To understand
parts of the such a process requires analysis across mul-
organ tiple scales as well as the integrated tools of
mechanics, mathematics, and biology (15).
Heterogeneous growth However, this multidisciplinary approach
tells only half the story of evolutionary de-
Entrance Varied rates velopmental biology. On the species scale,
of growth in evolution is driven by forces that enable one
Trap diferent organism to successfully reproduce while
door directions another dies out. To properly connect evolu-
tionary and embryonic forces across vastly
Anisotropic growth different scales is to understand the very
nature of variation: “the hard reality” (1). j
GRAPHIC: N. DESAI/SCIENCE tegrity of the leaf is preserved through de- morphogen. Their model is an adaptation of
velopment, the incompatible morphological the theory of morphoelasticity (8), which al- REFERENCES AND NOTES
change from dome to needle or trap can oc- lows for continuous changes resulting from
cur only through differential growth that can both mechanics and growth. This theory has 1. S.J. Gould, Discover 6, 40 (1985).
be either anisotropic (varied rates of growth been used successfully in animal morpho- 2. C. D.Whitewoods et al., 367, 91 (2020).
in different directions) or heterogeneous genesis to describe the formation of a wide 3. D. Kierzkowski et al., Cell 177, 1405 (2019).
(varied rates of growth in different parts of range of structures, from folds in the brain 4. C. Darwin, Q.J. Microsc. Sci. 1874, 185 (1874).
the organ). For example, a small sphere of to seashell architecture (9, 10). 5. O. Berg, M. D. Brown, M.J. Schwaner, M. R. Hall, U.
material may be deformed into an ellipsoid
or with a bulge on one side (see the figure). Notably, by simply varying the growth K. Müller, J. Exp.Zool.A Ecol. Integr. Physiol. 333, 29
rates, the computational model showed how (2020).
The challenge, then, is to decipher the ge- the same dome can develop into either a 6. E. E. Kuchen et al., Annu. Rev. Plant Biol. 62, 365 (2012).
netic underpinnings of the necessary growth needle-like cone or a planar leaf shape. By 7. P. Prusinkiewicz,A. Runions, New Phytol. 193, 549
differentials. Much is known about the effects making these growth rates nonuniform in (2012).
of particular genes on the shape of leaves (6). space, Whitewoods et al. further demon- 8. A. Goriely,“The Mathematics and Mechanics of
In developing leaves, key genes are expressed strated a simple mechanism for generating Biological Growth”(Springer, 2017).
differentially in zones on the adaxial (upper) cup-shaped traps and other features, such as 9. D.Ambrosi et al., J. R. Soc. Interface 16, 20190233
versus abaxial (lower) surfaces. Whitewoods the ridges found in a related cousin, Sarrace- (2019).
et al. revealed that these same genes are ex- nia purpurea (11). The model also provided 10. D. E. Moulton, A. Goriely, R. Chirat, Proc. Natl.Acad. Sci.
pressed differently in leaflets that form traps some insight into a chicken-and-egg prob- U.S.A. 10.1073/pnas.1916520116 (2019).
versus ones that form needle-like leaves. This lem in development: Does the orientation of 11. K. Fukushima et al., Nat. Commun. 6, 6450 (2015).
crucial observation was confirmed by show- cell division generate growth anisotropy, or 12. O. Hamant et al., Science 322, 1650 (2008).
ing that trap development can be inhibited does growth anisotropy generate the orienta- 13. O. Berg, K. Singh, M. R. Hall, M.J. Schwaner, U. K. Müller,
Integr. Comp. Biol. 2019, icz144 (2019).
14. H. Hofhuis et al., Cell 166, 222 (2016).
15. V. Mirabet, P. Das,A. Boudaoud, O. Hamant, Annu. Rev.
Plant Biol. 62, 365 (2011).

ACKNOWLEDGMENTS

A.G. is supported by the Engineering and Physical Sciences
Research Council, grant EP/R020205/1.

10.1126/science.aba3797

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INSIGHTS | PERSPECTIVES

FLUORESCENT PROTEINS in the transition state, the P-ring and I-ring
are nearly perpendicular (9). This geometry
Electrostatics affect the glow reduces the amount of p-p orbital overlap
between the P-ring and I-ring, which re-
Chromophore twisting is probed with unnatural amino acids sults in negative charge flowing back from
the I-ring to the P-ring. Alternatively, in
By Cheng Hu1, Xiaohong Liu2, Jiangyun Wang2 light produces the nonprotonated nonfluo- the S1 state, the P-ring can rotate to reach
rescent trans form. This switching enables another fluorescence off-state 2, and this
T he chromophores of fluorescent pro- applications in super-resolution imaging process causes more negative charge flows
teins (FPs) form through self-cata- (4) and optogenetics (5). In this protein, the from the P-ring to the I-ring. Electron-
lyzed posttranslational modifications chromophore is formed from Cys62, Tyr63, donating group substitution on Tyr63 can
(1). In the original green FP (GFP) and Gly64. Investigation of the contribution lower the excited-state barrier for P-bond
isolated from the jellyfish Aequorea of the electrostatics to FQY requires fine- rotation and decreases FQY.
victoria, Ser65, Tyr66, and Gly67 resi- tuning electrostatic parameters in the com-
dues form the 4-(p-hydroxybenzylidene)- plex protein environment. Genetic code ex- Romei et al. show that the electric field
5-imidazolinone (HBI) chromophore that pansion (6) allows unnatural amino acids exerted by the chromophore’s environment
contains a phenolate ring (P-ring), an im- (UAAs) to be introduced into FPs. Yu et al. can either promote or hinder charge trans-
idazoline ring (I-ring), and a monomethine (7) and others established methods for the fer, and thereby could effectively control
bridge (1). The protein cage excludes wa- genetic incorporation of large numbers of the choice of bond rotation and isomeri-
ter that can quench fluorescence, but also Tyr analogs to modify the chromophore. zation pathway after photoexcitation. For
enhances the fluorescence quantum yield optogenetic applications, photoinduced
(FQY) by restricting bond-twisting photo- Upon photon absorption, the chromo- rotation around a specific bond of the FP
phore enters the S1 state, in which negative chromophore or a retinal chromophore
triggers a distinct conformational change
Excited-state outcomes of the protein, which results in specific
kinase activation (5) or ion conductance
Romei et al. used genetic code expansion of a Tyr residue to change the H atom (denoted X) of a protein (10). Engineering the electrostatic and ste-
chromophore to groups that withdraw electrons (such as Cl) or donate electrons (such as OCH3) to explore the ric environment of the chromophore by
effects of electrostatics on fluorescence (R1 and R2 are contacts to the protein). introducing charged, hydrogen-bonding,
or unnatural amino acids in the protein
Carbon Hydrogen Nitrogen Oxygen R group X group scaffold could lead to more precise control
of chromophore twisting and downstream
Electron fow e– Electron fow e– e– Electron fow signaling pathways, or create photoswitch-
able FPs with higher total photon number
Rotation X Rotation and faster on-off state switching for super-
resolution imaging (4).
P-bond I-bond
rotation rotation Recent advances in time-resolved serial
R2 femtosecond crystallography with x-ray
U I-ring free electron lasers (XFELs) have visual-
P-ring I-ring R1 ized bond-rotation events in proteins (9).
P-ring I-ring P-ring Transient absorption spectroscopy could
probe how genetically encoded UAAs influ-
To of-state 2 On state (cis) To of-state 1 (trans) ence the I-bond rotation and P-bond rota-
Rotation around the P-ring Photoexcitation creates the cis Crossing the bond-rotation tion pathways. These insights could in turn
leads to an of-state and moves fuorescent S1 state. Charge fows barrier creates the trans of-state. inform new mutagenesis efforts to develop
more charge to the I-ring. from the P-ring to the I-ring. Charge fows back to the P-ring. improved FPs. j

isomerization of the HBI chromophore. charge flows from the P-ring to the I-ring REFERENCES AND NOTES GRAPHIC: A. KITTERMAN/SCIENCE
However, the protein could also improve (see the figure). Romei et al. found that
FQY through electrostatic effects. As re- replacing Tyr63 with analogs bearing an 1. A.Acharya et al., Chem. Rev. 117, 758 (2017).
ported on page 76 of this issue, Romei et al. electron-withdrawing group required more 2. M. G. Romei, C.-Y. Lin, I. I. Mathews, S. G. Boxer, Science
(2) studied the effect of introducing groups energy to transfer the electron, which blue-
that donate or withdraw chromophore shifted the absorption maximum, and sub- 367, 76 (2020).
electrons on the FQY of the photoswitch- stitution with an electron-donating group 3. A. C. Stiel et al., Biochem.J. 402, 35 (2007).
able FP Dronpa2 (3). red-shifted the absorption maximum. Both 4. Z. Fu et al., Nat. Methods 10.1038/s41592-019-0613-6
substitutions decreased FQY and likely low-
Mutations of residues near the chromo- ered the energy barrier for bond rotation. (2019).
phore can fine-tune the bond-rotation en- 5. X.X.Zhou, L.Z. Fan, P. Li, K. Shen, M.Z. Lin, Science 355,
ergy barrier to create photoswitchable vari- The next challenge was to decipher the
ants. In Dronpa2, green light produces the mechanism of how bond twisting is modu- 836 (2017).
protonated fluorescent cis form, and blue lated by electrostatics (8). In the transfor- 6. J.W. Chin, Nature 550, 53 (2017).
mation from the S1 state to the fluorescence 7. Y.Yu,X. Liu,J.Wang, Acc. Chem. Res. 52, 557 (2019).
1Institute of Synthetic Biology, Shenzhen Institutes of off-state 1, a cis-trans isomerization of the 8. C.Y. Lin,J. Both, K. Do, S. G. Boxer, Proc. Natl.Acad. Sci.
Advanced Technology, Chinese Academy of Sciences, double bond connecting the P-ring and
Shenzhen, China. 2Institute of Biophysics, Chinese I-ring is required. Previous studies of the U.S.A. 114, E2146 (2017).
Academy of Sciences, Chaoyang District, Beijing, China. photoswitchable FP rsEGFP2 showed that 9. N. Coquelle et al., Nat. Chem. 10, 31 (2018).
Email: [email protected] 10. K. K.Yang,Z.Wu, F. H.Arnold, Nat. Methods 16, 687

(2019).

ACKNOWLEDGMENTS

Supported by the National Science Foundation of China
(21750003, 21837005, 21890743, and U1632133) and the
Chinese Academy of Sciences (QYZDB-SSW-SMC032).

10.1126/science.aba0571

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Research is needed to understand the
projected increase in cancer incidence
and mortality in sub-Saharan Africa.

GLOBAL HEALTH in the tumor suppressor gene TP53, muta-
tions in GATA binding protein 3 (GATA3),
Cancer in sub-Saharan Africa and greater genomic mutational burden (in-
dicating aggressive biology), compared with
Knowledge of cancer in Africa brings needed breast tumors from African Americans or
diversity to improve health worldwide Caucasians (4). This suggests different tumor
etiologies by race or geography, perhaps re-
PHOTO: STRINGER/REUTERS/NEWSCOM By Timothy R. Rebbeck in SSA launched the research that identified flecting particular environmental exposures
Epstein-Barr virus as the causal agent of to carcinogens, and may provide knowledge
C ancer is an increasing global pub- Burkitt's lymphoma (2), thus providing some about the spectrum of breast cancer molec-
lic health burden. This is especially of the earliest knowledge about the infectious ular phenotypes that may be composed of
the case in sub-Saharan Africa (SSA); and molecular etiology of cancer. Similarly, distinct molecular subtypes and represent
high rates of cancer—particularly of the high prevalence of HIV infection and the different frequencies of known subtypes in
the prostate, breast, and cervix—char- attendant large number of HIV-associated non-Africans. Knowledge of these differences
acterize cancer in most countries in cancers in SSA have enabled research that can lead to optimized monitoring and treat-
SSA. The number of these cancers in SSA is has led to understanding of the causes and ment across all populations.
predicted to more than double in the next treatment of cancers exacerbated by HIV
20 years (1). Both the explanations for these infection, including cervical cancer, Kaposi's Early age at diagnosis is a hallmark of
increasing rates and the solutions to address sarcoma, and non-Hodgkin's lymphoma (3). cancer in SSA, which has been proposed to
this cancer epidemic require SSA-specific reflect a higher rate of hereditary cancer in
data and approaches. The histopathologic Patients with cancer in SSA are often di- SSA. This is supported by the observation
and demographic features of these tumors agnosed when their disease is in advanced that although 29% of SSA women and 33% of
differ from those in high-income countries stages. This is in part a consequence of inad- Caucasian women are between ages 25 and
(HICs). Basic knowledge of the epidemiology, equate resources for cancer prevention and 49, 58% of SSA women are diagnosed with
clinical features, and molecular characteris- early detection. Delayed diagnosis coupled breast cancer before they are 50 years old,
tics of cancers in SSA is needed to build pre- with inadequate treatment options is a ma- compared with 21% of Caucasian women (5).
vention and treatment tools that will address jor reason for the continent’s cancer mortal- Breast tumors in SSA Black cases are twice as
the future cancer burden. The distinct dis- ity rates, which are 1.5- to 4-fold higher than likely as SSA Caucasian cases to be the triple-
tribution and determinants of cancer in SSA in HICs for leading cancers (1). Studies that negative subtype, meaning that the estrogen,
provide an opportunity to generate knowl- focus on features of late-stage and aggressive progesterone, and HER2 receptors are not
edge about cancer risk factors, genomics, and disease will be required to better understand expressed by the breast cancer cells, making
opportunities for prevention and treatment how to manage such disease states. This re- them highly aggressive and difficult to treat
globally, not only in Africa. search is required to develop and implement (6). These molecular features are hallmarks
early detection and treatment modalities that of hereditary cancers; genetic testing for
The most frequent cancers in African coun- can be implemented in low-resource settings pathogenic sequence variants in the tumor
tries include prostate, lung, liver, leukemia, such as SSA, where availability of laboratory suppressor genes breast cancer 1 (BRCA1)
non-Hodgkin’s lymphoma, and Kaposi's sar- or imaging technologies is limited. and BRCA2 in a series of Nigerian breast can-
coma in men and breast and cervical cancer cer cases suggested that the rate of cancers
in women (see the figure). Distinct risk fac- Although molecular and other biologi- in women with BRCA1 or BRCA2 germline
tors in SSA contribute to the understanding cal data that address cancer etiology and pathogenic sequence variants is higher than
of cancer etiology in ways that may not be as progression in SSA are limited, emerging in Caucasian populations (7). Although large
easily studied in HICs. For example, the ob- evidence suggests that distinct tumor histo- population studies of hereditary cancer in
servation of high rates of Burkitt's lymphoma pathology, tumor subtypes, and molecular SSA do not yet exist, BRCA1 and BRCA2 mu-
signatures exist in SSA. For example, Nige- tations of SSA origin are also found in Afri-
Dana-Farber Cancer Institute and Harvard T. H. Chan rian breast cancer cases were defined by in- can Americans, and the type of mutations in
School of Public Health, Boston, MA, USA. creased mutational signature associated with BRCA1 and BRCA2 differs between SSA and
Email: [email protected] deficiency of the homologous recombination non-SSA populations (8).
DNA repair pathway, pervasive mutations
Generation of knowledge about cancer in
SSA will lead to both improved cancer pre-
vention and treatment. Protocols and net-
works are being formed to study cancer in
SSA patients and translate this knowledge to
health care in SSA (9). These protocols may
begin with those used in HICs but must be op-
timized to low-resource settings, which have
limited access to equipment, trained person-
nel, and therapies. Although the availability
of basic research infrastructure is more lim-
ited in SSA than in HICs, there are numerous
basic science and translational research insti-
tutes in SSA, including those that can address

SCIENCE sciencemag.org 3 JANUARY 2020 • VOL 367 ISSUE 6473 27

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INSIGHTS | PERSPECTIVES

cancer genomics and molecular biology. tions been included in the original study co- (12). Selection against a prostate cancer sus-

Pan-African initiatives, such as the Human hort. Similarly, it has been observed that use ceptibility locus on chromosome 2q37 has led

Heredity and Health in Africa (H3Africa) ini- of artificial intelligence and other “big data” to lower frequencies of this risk allele in Cau-

tiative, have developed common protocols, approaches in diagnostic and therapeutic casians and higher frequencies in Africans

data systems, and collaborative networks applications will be suboptimal if these ap- and African Americans (12). KhoeSan (an in-

that are developing the infrastructure and proaches are trained and validated in nondi- digenous southern African people) ethnicity

resources required to address cancer needs verse populations. has also been associated with prostate cancer

in SSA. Africa-based organizations that foster A limited scope of population data may risk (13). These data from African popula-

cancer research, translation, infrastructure, perpetuate or exacerbate existing biases in tions may help elucidate the causes of cancer

and training also exist, including the African the information needed to generate effec- disparities, particularly in African Americans.

Academy of Sciences and the African Organi- tive clinical and public health interventions Diagnostic, monitoring, and treatment

zation for Research and Training in Cancer. (11). Thus, it is not only the underrepresented technologies developed out of necessity in

The World Economic Forum has initiated a population that will benefit from increased low-resource settings provide an opportunity

for cost-efficient and accessible

technologies that can be imple-

Cancer in Africa compared with high-income countries mented in HICs. In particular,
development of point-of-care
The occurrence of the common types of cancer in sub-Saharan Africa (SSA) differs from that in high-income countries (HICs). The technologies that provide rapid
newly diagnosed cancer cases in 2018, as a percentage of the total population, are shown for SSA versus HICs. It is estimated that and accurate cancer diagnosis
incidence of the most common cancers will approximately double between 2018 and 2040 in SSA. Data were obtained from (15). or treatment in SSA could be ap-

Bladder Breast Cervix Uterus Esophagus Kaposi’s Liver plied in community settings to
sarcoma address disparities in access to

Female SSA 31.42.%2% 25.8% 23.3% 2.1% 2.3% cancer services in HICs. When
2.4% 2.8% technologies, including data-

Female HICs 2.1% 24.5% 2.1% 5.2% 0.6% <0.1% 1.5% derived models of risk or prog-

nosis, are not developed so that

Male SSA 2.9% 4.2% 6.2% 7.2% they can be applied in diverse
Male HICs 6.0% 1.8% 0.1% 2.9% settings and populations, health
disparities can be created or

Lung Non-Hodgkin's Ovary Pancreas Prostate Stomach Thyroid increased (14). Development of
lymphoma technologies that can be used
in SSA could provide knowledge

Female SSA 1.6% 3.1% 3.4% 1.1% 2.4% 1.9% about optimal implementation
3.1% 2.7% 3.2% of these technologies world-
Female HICs 9.5%
2.9% 4.7% wide. Advances in science and

Male SSA 4.6% 5.6% 1.8% 21.5% technology and the concomitant
4.1% 0.9% increase in capacity for health

Male HICs 12.0% 3.2% 2.8% 18.9% 4.5% 1.2% improvements will increase di-
versity as a means to remove

bias from cancer genomics stud-

“Leapfrogging with Precision Medicine” ini- research representation but all populations. ies and improve the quality of cancer pre-

tiative that will advance the use of genetics There is growing evidence that genetic risk vention and treatment globally. j

and genomics in cancer prevention and treat- prediction models developed in Cauca-

ment. These and many other institutions and sian populations may not be appropriate in REFERENCES AND NOTES

activities have the potential to develop the African-descent populations. These results 1. D. Parkin et al., Eds., Cancer in Sub-Saharan Africa (IARC
knowledge and sustainable resources needed suggest that ancestry-specific models may Scientific Publication no. 167, IARC, 2018).
to address the cancer burden in SSA. be required to optimally predict cancer
2. D. Burkitt, Br.J. Surg. 46, 218 (1958).
3. L. Chinula et al., Curr. Opin. HIVAIDS 12, 89 (2017).

In addition to benefiting the treatment of risk. Such models may use genetic variants 4. J.J. Pitt et al., Nat. Commun. 9, 4181 (2018).
cancer patients in SSA, the knowledge gained defined from the discovery of relevant race- 5. Population Division, United Nations Department of
from research on the continent will be inform- specific disease-associated variants and/or
ative for cancer globally. Evidence suggests use ancestry-specific genomic markers to de- Economic and Social Affairs, 2019 Revision of World
that diversity in study populations will im- fine ancestry rather than self-identified race Population Prospects; https://population.un.org/wpp.
prove the ability to generate and generalize or ethnicity. 6. V.A. McCormack et al., Breast Cancer Res. 15, R84
(2013).
7. Y.Zheng et al., J. Clin. Oncol. 36, 2820 (2018).
8. T. R. Rebbeck et al., Hum. Mutat. 39, 593 (2018).

knowledge that can be applied to cancer and Because of the underlying genetic and ge- 9. C.Andrews et al., J. Glob. Oncol. 4, 1 (2018). GRAPHIC: X. LIU/SCIENCE
other diseases. For example, rare mutations nomic relationships between Africans and 10. A. K. Manrai et al., N. Engl.J. Med. 375, 655 (2016).
judged to be pathogenic on the basis of Cau- members of the African diaspora (primarily 11. G. Kuhnen,A. Rebhan (2019); www.advisory.com/
casian mutation frequency data were later in North America and Europe), knowledge
found to occur commonly in African Ameri- gained from research in SSA can be used to daily-briefing/2019/02/04/ai.
can populations (10). Knowledge of mutation address health disparities that are prevalent 12. J. Lachance et al., Cancer Res. 78, 2432 (2018).
frequency subsequently led to the opposite in members of the African diaspora. West 13. D. C. Petersen et al., BMC Med. Genomics 12, 82 (2019).
14. D.Weiss et al., PLOS ONE 13, e0195447 (2018).
15. The Global Cancer Observatory; https://gco.iarc.fr.

conclusion that these variants were non- African genomic ancestry (the ancestral ori- ACKNOWLEDGMENTS
pathogenic. This misclassification of patho- gin of most African Americans) has been re-
genicity led to molecular misdiagnoses that ported to confer the highest genomic risk for The author is supported by National Institutes of Health grant
U01-CA184734.

could have been avoided had diverse popula- prostate cancer of any population worldwide 10.1126/science.aay4743

28 3 JANUARY 2020 • VOL 367 ISSUE 6473 sciencemag.org SCIENCE

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CELL BIOLOGY

Gene expression regulated by RNA stability

The factor responsible for autoregulation of tubulin RNA stability is identified

By Ofer Shoshani and Don W. Cleveland mosomes. By inactivating both maternal and tion that the tubulin concentration directly
paternal copies of the gene encoding TTC5, participates in the ribosomal complex with
O ne of the first discoveries of gene Lin et al. demonstrate that tubulin autoregu- TTC5 and the MREI peptide. Instead, the
expression mediated by controlling lation is essential for maintaining faithful findings of Lin et al. support a counterintui-
messenger RNA (mRNA) stability is chromosome segregation, with a modest in- tive model in which cells ordinarily contain a
autoregulation of tubulin synthesis. crease in chromosome segregation errors in cytosolic factor that prevents TTC5 binding
In this regulatory process, the con- the absence of TTC5. Errors in chromosome to MREI-ribosome complexes and that this
centration of tubulin subunits modu- inheritance are key drivers of tumorigenesis, inhibitor is inactivated when the tubulin di-
lates the stability of the mRNAs from which so maintenance of the genome is important mer concentration increases (see the figure).
they are translated (1, 2). In the 1980s it was (10). However, Lin et al. have determined
found that only translated tubulin mRNAs that cells with inactivated tubulin autoregu- The study of Lin et al. is a major step in
are autoregulated (3) and that translation lation are viable and can continue to survive deciphering a regulatory pathway for con-
had to continue through at least 41 amino and duplicate. This is unexpected because trolling expression of an important cellular
acids (4). This is enough for the nascent tu- disruption of autoregulation would be pre- product (tubulin) through cotranslationally
bulin polypeptide to emerge from the ribo- dicted to yield runaway tubulin synthesis, mediated mRNA instability. It should be
some (5). Later work established that when which in turn should have severely disrupted noted, however, that important steps in the
the tubulin subunit pool is high, the first microtubule assembly dynamics and func- autoregulatory pathway remain unidentified,
four amino acids (Met-Arg-Glu-Ile, MREI) tion. Perhaps additional factors are involved, including (i) the factor that inhibits TTC5
emerging during nascent tubulin translation the activities of which might compensate, to binding activity when tubulin levels are nor-
serve as a regulatory tag. Recognition of this some extent, for the lack of TTC5 activity. mal, (ii) the newly proposed autoregulatory
tag promoted the degradation of the trans- signal generated by an increased pool of tu-
lating tubulin mRNA (4, 6–8). More than 30 The new work also casts doubt on the no- bulin subunits, (iii) the nuclease(s) that medi-
years later, on page 100 of this issue, Lin et ate tubulin mRNA degradation, and (iv) the
al. (9) identify tetratricopeptide repeat pro- Autoregulation of tubulin RNA activation of those nucleases once TTC5 rec-
tein 5 (TTC5) as the regulator that binds to ognizes the nascent tubulin peptide.
nascent tubulin polypeptides. Tubulin messenger RNA (mRNA) instability is mediated
by cotranslational binding of tetratricopeptide repeat This may only be the tip of the iceberg for
With the exception of a high-resolution protein 5 (TTC5) to the tubulin amino-terminal cotranslational control of gene expression.
confirmation that an elevated pool of tu- tetrapeptide MREI and activation of one or more Work in yeast suggests that mRNA decay
bulin subunits selectively represses tubulin ribosome-associated nucleases. through cotranslational regulation is wide-
synthesis (8), no progress toward under- spread (11) and that it involves a 59-to-39
standing the autoregulation of tubulin ex- a/b-tubulin I ER Unknown RNA exoribonuclease 1 (xrn1) (12). The TTC5
pression was made since 1988. The most concentration TTC5 structure bound to a ribosome, as beautifully
attractive model for how the pool size of inhibitor determined by Lin et al., provides clues that
tubulin subunits could trigger rapid mRNA might allow the identification of additional
degradation to suppress new tubulin syn- NORMAL Transfer TTC5 regulators (perhaps containing the same tet-
thesis was that it was the tubulin a/b dimer, RNA AAA ratricopeptide repeats found in TTC5) that
the unit that assembles into microtubules, Ribosome can bind the ribosome exit tunnel and simul-
that cotranslationally bound to the MREI 5' Tubulin mRNA taneously recognize targets encoded by dif-
tetrapeptide. Lin et al. disprove this model. ferent mRNAs. j
They use mass spectrometry and in vitro Tubulin autoregulation activated
translation of an mRNA encoding the first REFERENCES AND NOTES
94 amino acids of b-tubulin to identify HIGH Unknown
TTC5 as the protein that recognizes the na- TTC5 inhibitor 1. T.J.Yen, D.A. Gay,J. S. Pachter, D.W. Cleveland, Mol. Cell.
scent b-tubulin MREI tetrapeptide in com- is inactivated Biol. 8, 1224 (1988).
plex with the large ribosomal subunit.
GRAPHIC: V. ALTOUNIAN/SCIENCE Nuclease 2. D.W. Cleveland, M.A. Lopata, P. Sherline, M.W.
a- and b-tubulin form a heterodimer that Kirschner, Cell 25, 537 (1981).
serves as the building block for microtubule 5'
polymers, the tracks along which cargoes 3. D.W. Cleveland, M. F. Pittenger,J. R. Feramisco, Nature
are moved by dynein and kinesin family mo- Tubulin 305, 738 (1983).
tors. During cell duplication, microtubule- mRNA degraded
directed trafficking is essential for delivery to 4. D.A. Gay,T.J.Yen,J.T. Lau, D.W. Cleveland, Cell 50, 671
each daughter cell of a complete set of chro- (1987).

Ludwig Institute for Cancer Research and Department of 5. J. S. Pachter,T.J.Yen, D.W. Cleveland, Cell 51, 283 (1987).
Cellular and Molecular Medicine, University of California, San 6. T.J.Yen, P. S. Machlin, D.W. Cleveland, Nature 334, 580
Diego, La Jolla, CA 92093, USA. Email: [email protected]
(1988).
7. A.Yonath, K. R. Leonard, H. G.Wittmann, Science 236,

813 (1987).
8. I. Gasic, S.A. Boswell,T.J. Mitchison, PLOS Biol. 17,

e3000225 (2019).
9. Z. Lin et al., Science 367, 100 (2020).
10. U. Ben-David,A.Amon, Nat. Rev. Genet. 21, 44 (2020).
11. V. Pelechano,W.Wei, L. M. Steinmetz, Cell 161, 1400

(2015).
12. W. Hu,T.J. Sweet, S. Chamnongpol, K. E. Baker,J. Coller,

Nature 461, 225 (2009).

10.1126/science.aba0713

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INSIGHTS

POLICY FORUM cama Desert, destroying fragile ecosystems,
and converting meadows and lagoons into
ENERGY salt flats. The extraction, crushing, refining,
and processing of cadmium, a by-product of
Sustainable minerals and zinc mining, into compounds for recharge-
metals for a low-carbon future able nickel cadmium batteries and thin-film
photovoltaic modules that use cadmium tel-
Policy coordination is needed for global supply chains luride (CdTe) or cadmium sulfide semicon-
ductors can pose risks such as groundwater
By Benjamin K. Sovacool1, Saleem H. Ali2,3,4, more than 7100 GW (3). The materials and or food contamination or worker exposure to
Morgan Bazilian5, Ben Radley6, Benoit metals demanded by a low-carbon economy hazardous chemicals, especially in the supply
Nemery7, Julia Okatz8, Dustin Mulvaney9 will be immense (4). One recent assessment chains where elemental cadmium exposures
concluded that expected demand for 14 are greatest. REEs, such as neodymium and
C limate change mitigation will cre- metals—such as copper, cobalt, nickel, and the less common dysprosium, are needed for
ate new natural resource and supply lithium—central to the manufacturing of magnets in electric generators in wind tur-
chain opportunities and dilemmas, renewable energy, EV, fuel cell, and storage bines and motors in EVs, control rods for nu-
because substantial amounts of raw technologies will grow substantially in the clear reactors, and the fluid catalysts for shale
materials will be required to build next few decades (5). Another study projected gas fracking. But REE extraction in China has
new low-carbon energy devices and increases in demand for materials between resulted in chemical pollution from ammo-
infrastructure (1). However, despite attempts 2015 and 2060 of 87,000% for EV batteries, nium sulfate and ammonium chloride and
at improved governance and better corpo- 1000% for wind power, and 3000% for solar tailings pollution that now threaten rural
rate management, procurement of many cells and photovoltaics (6). Although they are groundwater aquifers as well as rivers and
mineral and metal resources occurs in areas only projections and subject to uncertainty, streams. Several metals for green technolo-
generally acknowledged for mismanage- the World Bank put it concisely that “the gies are found as “companions” to other ores
ment, remains environmentally capricious, clean energy transition will be significantly with differential value and unsustainable
and, in some cases, is a source of conflict mineral intensive” (7) (see the figure). supply chains (9).
at the sites of resource extraction (2). These
extractive and smelting industries have thus Many of the minerals and metals needed POLICY RECOMMENDATIONS
left a legacy in many parts of the world of for low-carbon technologies are considered With these sobering social and environmental
environmental degradation, adverse impacts “critical raw materials” or “technologically aspects of current mineral extraction in mind,
to public health, marginalized communities critical elements,” terms meant to capture we suggest four policy recommendations.
and workers, and biodiversity damage. We the fact that they are not only of strategic or
identify key sustainability challenges with economic importance but also at higher risk Diversify mining enterprises for local
practices used in industries that will supply of supply shortage or price volatility (8). But ownership and livelihood dividends
the metals and minerals—including cobalt, their mining can produce grave social risks. Although large-scale mining is often eco-
copper, lithium, cadmium, and rare earth A majority of the world’s cobalt, used in the nomically efficient, it has limited employ-
elements (REEs)—needed for technologies most common battery chemistries for EVs ment potential, only set to worsen with the
such as solar photovoltaics, batteries, elec- and stationary electricity storage, is mined recent arrival of fully automated mines. Min-
tric vehicle (EV) motors, wind turbines, fuel in the Democratic Republic of Congo (DRC) ing can concentrate occupational hazards as
cells, and nuclear reactors. We then propose (see the map), a country struggling to recover well as environmental risk, as demonstrated
four holistic recommendations to make min- from years of armed conflict. There, women most severely by tailings pond disasters and
ing and metal processing more sustainable and sometimes children often work in or mining wastewater contamination. Even
and just and to make the mining and extrac- around mines for less pay or status than their where there is relative political stability and
tive industries more efficient and resilient. male and adult counterparts, without basic stricter regulatory regimes in place, there
safety equipment (see the photo). Owing to a can still be serious environmental failures, as
Between 2015 and 2050, the global EV lack of preventative strategies and measures exemplified by the recent global rise in dam
stock needs to jump from 1.2 million light- such as drilling with water and proper ex- failures at settling ponds for mine tailings.
duty passenger cars to 965 million passenger haust ventilation, many cobalt miners have The level of distrust of extractive industries
cars, battery storage capacity needs to climb extremely high levels of toxic metals in their has even led to countrywide moratoria on all
from 0.5 gigawatt-hour (GWh) to 12,380 body and are at risk of developing respiratory new mining projects, such as in El Salvador
GWh, and the amount of installed solar pho- illness, heart disease, or cancer. and the Philippines.
tovoltaic capacity must rise from 223 GW to
In addition, mining frequently results in Traditional labor-intensive mechanisms of
1University of Sussex, Brighton, UK. 2University of severe environmental impacts and commu- mining that are possible to undertake with
Delaware, Newark, DE, USA. 3University of Queensland, nity dislocation. Moreover, metal produc- less mechanization and without major capital
Brisbane, Queensland, Australia. 4United Nations tion itself is energy intensive and difficult to investments are called artisanal and small-
International Resource Panel, United Nations Environment decarbonize. Mining for copper, needed for scale mining (ASM). Although ASM is not
Programme, Nairobi, Kenya. 5Colorado School of Mines, electric wires and circuits and thin-film solar immune from poor governance or environ-
Golden, CO, USA. 6London School of Economics, London, cells, and mining for lithium, used in batter- mental harm, it provides livelihood potential
UK. 7Katholieke Universiteit Leuven, Leuven, Belgium. ies, has been criticized in Chile for depleting for at least 40 million people worldwide, with
8SYSTEMIQ Ltd., London, UK. 9San José State University, local groundwater resources across the Ata- an additional three to five times more people
San José, CA, USA. Email: [email protected] indirectly supported by the sector (10). It is
also usually more strongly embedded in local
and national economies than foreign-owned,
large-scale mining, with a greater level of

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value retained and distributed within the ability to increase productivity and mecha- committed to “responsible sourcing” of raw
country. Diversifying mineral supply chains nize production, even in hostile regulatory materials for batteries.
to allow for greater coexistence of small- and and governance environments. More space
large-scale operations is needed. Yet, efforts for and support to ASM to pursue this trajec- Traceability schemes, however, may be im-
to incorporate artisanal miners into the for- tory would enhance its capacity to meet the possible to fully enforce in practice and could,
mal economy have often resulted in a scar- increased demand for minerals required in in the extreme, merely become an exercise in
city of permits awarded, exorbitant costs for the move toward a low-carbon future. One public relations rather than improved gover-
miners to legalize their operations, and ex- place to begin is with the redistribution of nance and outcomes for miners. In the east-
tremely lengthy and bureaucratic processes dormant mining concessions previously ern DRC, for example, cassiterite, the mineral
for registration. granted to (but unused by) mining compa- that tin is extracted from, is exported through
nies so that local ASM operators can legally a traceability system yet can nonetheless have
Development donors need to focus on work in these locations, as has been taking contributed to conflict financing or labor and
bottom-up formalization efforts rather than place recently in Tanzania. human rights abuses while simultaneously
merely facilitating government efforts to bet- introducing heavy financial costs onto local
workers for the right to participate in the sys-
A creuseur, or digger, descends into a Congolese copper and cobalt mine in Kawama. Wages are low, and working tem (11). Nonetheless, traceability is not with-
conditions are dangerous, often with no safety equipment or structural support for the tunnels. out promise, and examples from Blockchain
technology show how the use of artificial in-
PHOTO: MICHAEL ROBINSON CHAVEZ/THE WASHINGTON POST VIA GETTY IMAGES ter regulate the sector for increased tax rev- Acknowledge the limits of traceability telligence algorithms for data processing has
enues. There needs to be a focus on policies A great deal of attention has focused on fos- the potential for greater assurance but ulti-
that recognize its livelihood potential in areas tering transparency and accountability of mately relies on the accuracy of data being
of extreme poverty. Moreover, formalization mineral mining by means of voluntary trace- fed into the supply chain.
of the sector should focus on creating stron- ability or even “ethical minerals” schemes.
ger, more accountable arrangements to drive International groups, including Amnesty Transparency of supply chains is a means
greater value of resource revenues down the International, the United Nations, and the to an end and will only be effective if con-
supply chain to ASM miners to ensure better Organisation for Economic Co-operation sumers or regulators start to differentiate
environmental and safety mechanisms and and Development, have all called on mining between products being provided. There are
expand their access to markets. The recent companies to ensure that supply chains are effective lessons on traceability and transpar-
decision of the London Metals Exchange to not sourced from mines that involve illegal ency arising from the Kimberley Process for
have a policy of “nondiscrimination” toward labor and/or child labor. In concert, Eur- conflict diamonds; the Extractive Industries
ASM is a positive sign in this regard. Certain asian Resources Group (ERG) launched their Transparency Initiative for oil, gas, and min-
industry actors have demonstrated a com- Clean Cobalt Framework in 2018, First Cobalt eral resources; and the Fairmined Standard
mitment to, and the benefits of, this type has their Responsible Cobalt Initiative, RCS for gold that could be applied to the mineral
of approach, such as Fairphone’s sourcing Global has its Better Cobalt program, Am- supply chains needed for decarbonization.
of the mineral columbite-tantalite (coltan) nesty International is working on an Ethical Paramount among these is an acknowledg-
used in mobile phones. At the level of gov- Battery framework, and the World Economic ment that traceability schemes offer a largely
ernment policy, ASM has demonstrated its Forum launched a Global Battery Alliance technical solution to profoundly political
problems and that these political issues can-
not be circumvented or ignored if meaningful
solutions for workers are to be found. Trace-
ability schemes ultimately will have value if
the market and consumers trust their au-
thenticity and there are few potential oppor-
tunities for leakage in the system.

Explore new resource streams
Although primary emphasis must be placed
on resource efficiency (higher output or us-
age of product per unit of resource input)
and recycling, there will likely be a need
for primary resource extraction as well
owing to clean-energy infrastructure de-
mand. New resource streams—including
metal availability in seawater (desalina-
tion) and groundwater (geothermal brines),
material substitution or material intensity
reductions, and materials recovery and
recycling—also hold promise for diversify-
ing supply chains, as long as they maintain
environmental sustainability and protect
worker safety.

Although mining in terrestrial areas is
likely to continue to meet the demands of
low-carbon technologies in the nearer term,
we need to carefully consider mineral sources
beneath the oceans in the longer term. The

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INSIGHTS | POLICY FORUM

International Seabed Authority, set up under initially but can become more challenging the end of their useful life and encourages
the United Nations (UN) Convention on the to procure over time. Moreover, substitution durability, extended product lifetimes, and
Law of the Sea, is in the process of issuing may be limited to particular innovations or designs that are easy to reuse, repair, or re-
regulations related to oceanic mineral extrac- niches. Alternatives to lithium-ion batteries, cover materials from. A successful EPR pro-
tion. This process is a rare opportunity to be such as sodium-ion batteries, are becoming gram known as PV Cycle has been in place in
proactive in setting forth science-based envi- more practical and feasible. But finding sub- Europe for photovoltaics for about a decade
ronmental safeguards for mineral extraction. stitutes for metals like platinum group met- and has helped drive a new market in used
For metals such as cobalt and nickel, ocean als in key technologies such as fuel cells has photovoltaics that has seen 30,000 metric
minerals hold important prospects on the become increasingly difficult, and reserves tons of material recycled. To date, EPR has
continental shelf within states’ exclusive eco- are dwindling. mainly shaped collection, recycling, and
nomic zones as well as the outer continental waste management to ensure safe and re-
shelf regions. Within international waters, Recycling and better resource efficiency sponsible disposal of specific classes of prod-
metallic nodules found in the vast Clarion- can play a part at extending and enhancing ucts like e-waste, paint, and pharmaceuticals,
Clipperton Zone of the Pacific as well as in the lifetimes of products and also stretch- but, in concept, it is also meant to help drive
cobalt and tellurium crusts, which are found ing out mineral reserves. Closed-loop sup- more sustainable design as well as options
in seamounts worldwide, provide some of the ply chains based on circular economy ideas for reuse and repair. There is evidence of
richest deposits of metals for green technolo- in addition to advancements in metallurgy, EPR’s influence on green design in the global
gies. Difficult extraction and declining re- reverse logistics, waste separation, materi- solar industry. For example, thin-film manu-
als science, waste processing, and advanced facturer First Solar screens new materials to
ensure that they will not negatively influence
Growth in mineral needs for low-carbon energy technology their recycling process, through which they
currently recover 90% of their CdTe semicon-
Mineral Production Demand ductor material and 90% of their glass. To
(kilo–metric tons) more easily recycle the plastics and copper
Lithium 965% from photovoltaics, some manufacturers are
2017 2050 seeking out halogen-free components.

43 415 Space mining, although potentially use-
ful for developing lunar and planetary bases
Cobalt 585% 110 644 farther into the future, has less potential for
meeting the demand for minerals for imme-
Graphite 383% 1200 4590 diate decarbonization on Earth. A possible
exception to this may be platinum group
Indium 241% 0.72 1.73 metals from asteroids, but here, too, the time
frame and quantity of production would pre-
Vanadium 173% 80 138 clude its use in meeting immediate technol-
ogy needs for climate mitigation.
Nickel 108% 2100 2268
Silver 60% Incorporate minerals into climate
25 15 and energy planning
Given the centrality of minerals and metals
Neodymium 37% 23 8 to the future diffusion of low-carbon technol-
ogies, materials security should be actively
Molybdenum 11% 290 33 incorporated into formal climate planning.
This could be connected to ongoing planning
Aluminum 9% 60,000 5583 as part of the nationally determined contri-
butions (NDCs) under the Paris Accord, the
Copper 7% 19,700 1378 European Commission’s National Energy
and Climate Plans (NECPs), or even energy
( )Percentage = policy-making at the national scale. Climate
Manganese 4% 2050 demand 16,000 694 planners could begin by mapping out their
2017 production NDC contributions alongside a list of “criti-
cal minerals” for energy security (see supple-
0 100% mentary materials).

All production and demand data refect annual values. 2017 data re.ect annual production for all uses. 2050 data re.ect estimated demand for only Although care must be taken to ensure
low-carbon energy technology uses. Data from (7). that the NDC process does not become too
broad or research intensive, we believe the
serves of some terrestrial minerals, as well as recycling can all enhance the longevity and NDCs are the most tangible international GRAPHIC: X. LU/SCIENCE
social resistance against terrestrial mining, continual reuse of minerals and metals. Re- policy consensus mechanism on this mat-
may lead to oceanic mineral reserves becom- searchers at the U.S. National Renewable En- ter. The NDCs can incorporate some of the
ing more plausible sources. Minerals near ergy Laboratory estimate that 65% of the U.S. mineral sourcing challenges through ef-
hydrothermal vents are in more pristine and domestic cobalt demand in 2040 could be forts at resource efficiency. The Group of
distinctive ecosystems and should likely re- supplied by end-of-life lithium-ion batteries, Seven (G7) has taken on this linkage, and
main off-limits for mineral extraction for the provided a robust take-back and recycling in- policies to motivate resource efficiency can
foreseeable future. frastructure is in place. be a means of keeping track of material

Technological substitution can play an im- Extended producer responsibility (EPR)
portant role as well. Copper offers an illustra- is a framework that stipulates that produc-
tive example. Higher copper prices in recent ers are responsible for the entire lifespan of
years have incentivized replacement in new a product, including at the end of its useful-
applications in the automotive industry, such ness. EPR would, in particular, shift respon-
as wire harnesses and replacing copper with sibility for collecting the valuable resource
aluminum winding in motors. However, sub- streams and materials inside used electron-
stitution to other primary metals or even syn- ics from users or waste managers to the com-
thetics could merely shift resource demand to panies that produce the devices. EPR holds
another material that may be more abundant producers responsible for their products at

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and mineral supply chains. For example, a Countries accounting for the largest share of critical raw materials
materials assessment for particular infra-
structure options for climate change miti- Russia
gation or adaptation could be included in 46% Palladium
cost-benefit analyses. Recent work has sug-
gested that the social acceptability of ty- China
ing resource-efficient products to climate
change mitigation efforts is strong (12). France 87% Antimony
43% Hafnium
Having each country create a list of criti- USA 44% Baryte
cal minerals within its NDC process and 90% Beryllium DRC
show possible trade-offs and shortfalls 73% Helium 64% Cobalt 82% Bismuth
could lead to several benefits. More efforts
on national critical material analysis could Brazil South Africa 64% Fluorspar
result in improved mapping of mineral 90% Niobium 85% Iridium
supply chains, for which there is already 70% Platinum 73% Gallium
a notable gap across many developing 83% Rhodium
countries and regions. The analytical ef- 93% Ruthenium 67% Germanium
forts would enhance our understanding of
supply constraints and demand patterns, Thailand 57% Indium
which in turn could lead to a better un-
derstanding of future prices and drivers, 32% Natural rubber 87% Magnesium
especially those beyond the control of gov- 69% Natural graphite
ernments and policy as agents of change.
The process of mapping mineral demands Rwanda 44% Phosphate rock
for NDCs, NECPs, and national energy
policies could lead to new linkages and 31% Tantalum 38% Phosphorus
networks and a raising of awareness, con- 66% Scandium
necting the traditional minerals and met-
als community to other research and social 61% Silicon metal
communities, especially in climate policy
and energy studies. In this way, climate 84% Tungsten
mitigation could be twinned with minerals
security and industrial strategy as a way to 53% Vanadium
meet broad sets of goals (environmental,
political, and economic) in one stroke. 95% LREEs

AN ETHICAL CONUNDRUM 95% HREEs
Mineral and metal supplies are geologi-
cally determined, yet socially mediated. DRC, Democratic Republic of Congo; LREEs, light rare earth elements; HREEs, heavy rare earth elements. Figure modifed from European
Even if supplies are enhanced through co- Commission, "Third list of critical raw materials for the EU of 2017" (European Commission, 2017); https://ec.europa.eu/growth/sectors/
products of other industries, new resource raw-materials/specifc-interest/critical_en.
streams, and considerable expansion of re-
GRAPHIC: ADAPTED FROM EUROPEAN UNION/CC-BY BY X. LU/SCIENCE cycling and increased recovery rates, there Consideration should also be given to REFERENCES AND NOTES
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supply chains (13). This is exacerbated by positive development footprint while also 1. Intergovernmental Panel on Climate Change (IPCC),
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the minor metals. Hence, trade policy will impacts (14). Utilizing tools such as the Re- Eds. (IPCC Special Report, IPCC, 2018); www.ipcc.ch/
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the supply chain. For example, although may be treaty fatigue among policy-makers, 3. International Renewable Energy Agency (IRENA),
the U.S. government strategy for mineral an intertreaty protocol on mineral supply “Global energy transformation: A roadmap to 2050”
supply security released in June 2019 high- chains to ensure that the goals of existing (IRENA,Abu Dhabi, 2018).
lights the importance of trade with allies treaties are met could enhance effective gov-
and partners, it does not consider where ernance. Conversations in this vein should 4. International Resource Panel,“Global resources outlook
it is most ecologically efficient to source be attempted among the parties to the UN 2019: Natural resources for the future we want”(United
minerals. Pursuing decarbonization si- Framework Convention on Climate Change, Nations Environment Programme, Nairobi, 2019); www.
multaneously with principles of a circular through the UN Environment Assembly, as resourcepanel.org/reports/global-resources-outlook.
economy, coupled with increased market well as more focused mechanisms such as
transparency mechanisms and full life- the U.S. government’s recently launched 5. E. Dominish, N. Florin, S.Teske,“Responsible miner-
cycle reporting, could yield important so- Energy Resource Governance Initiative, the als sourcing for renewable energy”(Institute for
cial and environmental benefits. World Bank’s Climate-Smart Mining Facil- Sustainable Futures, University of Technology, Sydney,
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and Technology for Raw Materials.
6. A. Månberger, B. Stenqvist, Energy Policy 119, 226
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table, it is high time we realize that the ele- 7. World Bank,“Climate-smart mining: Minerals for
ments, and the minerals in which they are climate action”(World Bank, 2018); www.world-
embedded, are essential to our attainment bank.org/en/topic/extractiveindustries/brief/
of low-carbon goals. There is an ethical co- climate-smart-mining-minerals-for-climate-action.
nundrum to addressing climate change only
by aggravating other social and ecological 8. European Commission,“Communication from the
problems related to unsustainable mineral Commission to the European Parliament, the Council,
and metal supply chains. But done sustain- the European Economic and Social Committee, and the
ably, an impending mining boom could help Committee of the Regions on the 2017 list of critical
lift communities out of poverty, accelerate raw materials for the EU”(COM/2017/490, European
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and further the realization of energy and
climate targets. Which direction it takes 9. N.T. Nassar,T. E. Graedel, E. M. Harper, Sci.Adv. 1,
will depend considerably on how metal and e1400180 (2015).
mineral supply chains are governed over
the next few critical years. j 10. World Bank,“2019 state of the artisanal and small-scale
mining sector”(World Bank,Washington, DC, 2019).

11. B. Radley, C.Vogel, Extr. Ind. Soc. 2, 406 (2015).
12. C. E. Cherry, K. Scott,J. Barrett, N. F. Pidgeon, Nat. Clim.

Chang. 8, 1007 (2018).
13. S. H.Ali et al., Nature 543, 367 (2017).
14. L.J. Sonter, S. H.Ali,J. E. M.Watson, Proc. R. Soc. London

Ser. B 285, 20181926 (2018).

ACKNOWLEDGMENTS

This project received funding from the European Union’s
Horizon 2020 research and innovation program under
grant agreement no. 730403“Innovation pathways,
strategies and policies for the low-carbon transition in
Europe (INNOPATHS).”The content of this deliverable
does not reflect the official opinion of the European Union.
Responsibility for the information and views expressed herein
lies entirely with the author(s).

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/367/6473/30/suppl/DC1

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Although this serves as important experi-
ence, students with disabilities may find it
prohibitively challenging to work so many
consecutive hours. A reduction in required
on-call hours would allow students with
and without disabilities to thrive in their
training. Students pursuing specialties
with extended-call commitments could
elect to gain this exposure.

Cody Lo
Faculty of Medicine, University of British Columbia,
Vancouver, BC V6T 1Z2, Canada. Twitter: @cody_lo

LETTERS Despite being the most popular event at
scientific conferences, poster sessions are
NEXTGEN VOICES probably the least accessible. As someone
who struggles with low vision, I find poster
Making science accessible sessions frustrating. Most posters have
unreadable fonts, unclear images, and
To mark the 30th anniversary of the Americans with Disabilities Act, poor color contrast. Conference organiz-
we asked young scientists this question: What one thing would you ers should encourage poster presenters to
change about the training or careers in your field to improve make a 2-minute video summary of their
accessibility for people with visible and/or invisible disabilities? work. The video and the presenter’s con-
A selection of their responses is below. Follow NextGen Voices on tact information could then be accessed by
Twitter with hashtag #NextGenSci. Read previous NextGen Voices survey scanning a QR code. These QR codes would
results at https://science.sciencemag.org/collection/nextgen-voices. help build camaraderie among research-
ers; unlike business cards, conference
Provide logistical support discussions. Alternatively, written sum- goers would have details of the presenters ILLUSTRATION: ROBERT NEUBECKER
maries prepared beforehand should together with their presentations.
Because I have dyslexia, I use read-out- accompany visual and oral presentations.
loud software, but it is not well suited to This would allow learners to read the Edmond Sanganyado
journal articles with citations. Listening material as explained by the professor, Provincial Key Laboratory of Marine Biotechnology,
to citations makes keeping track of the rather than a textbook, multiple times for Shantou University, Shantou, Guangdong, 515063,
paper difficult and can add hours of stronger comprehension. China. Twitter: @ESanganyado
reading time. Some expensive software Juliet Tegan Johnston
allows you to select what to read, but it In physical anthropology, the majority of
can take days to mark the citations and is Department of Civil, Environmental, and Geo- assessments of ancestry, sex, and age of
impractical when reading many journal Engineering, University of Minnesota, Minneapolis, a skeleton are based on morphological
articles. A tool that allows the listener to MN 55455, USA. Twitter: @queermsfrizzle features. However, only a limited number
skip the citations would help. of models are provided to demonstrate the
Kristen Tuosto Wet labs are designed for people with no differences. The inclusion of 3D models
physical challenges. Many of us who could with differing variations of features would
Center for the Advanced Study of Human contribute to science have difficulties not be helpful to every student, not just the
Paleobiology, The George Washington University, with the techniques or knowledge but ones who are differently abled. I believe it
Washington, DC 20052, USA. rather with the need to spend hours sitting would bridge the divide between recently
Email: [email protected] on a lab stool. Adjustable benches and graduated students and experienced practi-
equipment would improve accessibility and tioners, allowing for greater mentorship of
Movies have subtitles for a reason. People the wet lab experience for all scientists. other technical aspects of the work.
might be hearing impaired or easily dis- Carol Connolly
tracted, have trouble deciphering accents, Kristy A. Winter
or understand written information better. Dublin 18, Ireland. College of Humanities, Arts, and Social
Speech-to-text technology, which enables Email: [email protected] Sciences, Flinders University, Bedford Park, SA
instructors to instantly provide written 5042, Australia. Twitter: @Winterhiccup
versions of their lecture materials, should Many fields of medicine require physicians
be used in real time during classroom to work on call for more than 24 hours. Having a disability can be very expensive.
In addition to costs such as out-of-pocket
fees for therapy, people with mobility
impairments may pay more for rent, as
accessible apartments tend to be more
expensive, or more for food because of
specific dietary needs. These higher costs
contribute to a higher risk of poverty
for people with disabilities. Therefore,
increasing pay for Ph.D. students would
make it more likely that students with
a disability—as well as students from

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INSIGHTS

ILLUSTRATION: ROBERT NEUBECKER disadvantaged backgrounds—could pursue for a job when you have a disability. Will allow all graduate students the opportunity
a scientific career. department leaders be willing to make to develop a better work-life balance and
Tanja Roembke accommodations, and will they worry that become more productive scientists.
hiring me will affect productivity? Academia
Institute of Psychology, RWTH Aachen University, needs to avoid direct comparison between Ashley B. Heim
Aachen, NRW 52062, Germany. researchers with and without disabilities. School of Biological Sciences, University of
Email: [email protected] The academic paths of researchers with Northern Colorado, Greeley, CO 80639, USA.
disabilities may differ, for example, because Email: [email protected]
Much of the scientific work in the field of of prolonged stays in hospitals or numerous
chemistry depends on colors. For those who surgeries and rehabilitations. However, these The shame and stigma of disabilities
are color blind, the use of techniques such as “hardships” make us better researchers: caused by depression and post-traumatic
acid-base titrations or spectroscopy presents They push us to develop excellent organi- stress disorder prevent the people who have
a challenge. Technology could help. If an app zational skills, creativity, stress resilience, them from asking for help. Breaking this
could analyze a smartphone camera photo emotional intelligence, and grit. Students in barrier would be easier if colleagues and
and correct different types of color blindness STEM fields need role models in the form of especially principal investigators and group
by converting the colors into decipherable lecturers or professors with disabilities. They leaders were trained to identify the signs and
patterns, it could be used not only in the lab need to see that it can be done and that reach out to ensure their support. Building
but also to convert figures in textbooks and universities and departments are inclusive the basic bridge of trust and safety is the
papers into more accessible images. in reality and not only on paper. most important first step in accessing people
Wagner Eduardo Richter Aleksandra Kosanic with hidden disabilities. Supervisors should
be trained to create and communicate a
Department of Chemical Engineering, Ecology Team, Department of Biology, safe, kind environment and to access further
Technological Federal University–Paraná, Paraná, University of Konstanz, D 78457 Konstanz, resources for help.
Brazil. Email: [email protected] Germany. Twitter: @SashaKosanic
Pragya Srivastava
Hearing impairment affects a sizeable In my field of astronaut training and Department of Bioengineering, University
minority of world inhabitants. To better operations, it is clear that humans some- of Pennsylvania, Philadelphia, PA 19104, USA.
welcome all scientists, we must incorporate times need equipment to thrive in their Twitter: @Prags0211
sign-language translation and closed- environment. Just as an astronaut needs
captioning services in scientific meetings specialized technology to survive in space Facilitating accessible learning spaces for
and conferences. Computer technologies and a diver needs scuba gear to survive students with invisible disabilities poses
are advancing, and machine translation in water, people with disabilities benefit unique challenges, since neither student nor
services are now available at a fraction of from access to the right tools. Technology, instructor is initially aware of the other’s
their former cost. This simple modification whether a brain-controlled exoskeleton, condition. Moreover, some invisible diagno-
could have a lasting impact on the progres- artificial limbs, or a computer-generated ses, such as autism spectrum disorder (ASD),
sion of science through inclusion. voice, allows us to overcome environmental carry a degree of social stigma. If they feel
Kyle J. Isaacson challenges and transform into super- comfortable doing so, I believe it would be
humans. If more people understood this valuable for course instructors and graduate
Department of Biomedical Engineering, University concept, more individuals with disabilities mentors affected by ASD to acknowledge
of Utah, Salt Lake City, UT 84112, USA. would be involved in scientific fields. this fact to their students. This would make
Twitter: @kjisaacson Loredana Bessone it easier for students to open up about their
own invisible challenges and reduce both
Foster inclusive community European Space Agency, Cologne, NRW 51147, perceived and actual stigmatization.
Germany. Twitter: @esa_caves
When onboarding a new member, the P. William Hughes
research group leader should affirm the In graduate school, mental health is often Department of Ecology, Environment, and Plant
entire group’s commitment to accommo- put on the back burner. Encouraging Sciences, Stockholm University, Stockholm, 10691,
dating anyone with a disability. Affirming more discussions about and providing Sweden. Twitter: @pwilliamhughes
this commitment to every new member more institutional support for mental
ensures people with invisible disabilities health would foster a more welcoming We need to change the narrative to value
are not unintentionally ignored, empow- and accepting environment. It would also the experience of overcoming adversity
ers people with a disability to disclose rather than viewing those who have over-
information and request accommodations, come challenges as inferior or damaged. I’d
and sets clear expectations for those with- love to see a seminar series where estab-
out disabilities to make accommodation lished principal investigators could openly
requests a priority. Having this conversa- discuss the challenges they faced and
tion during onboarding also helps form how they overcame those challenges. This
a community that is supportive of people would increase representation and a sense
with disabilities and in turn benefits from of belonging among people with invisible
their unique perspectives. disabilities who might not otherwise know
Michael Raitor who else is out there. It would also reduce
stereotyping from able scientists.
Department of Mechanical Engineering,
Stanford University, Stanford, CA 94305, USA. Caitlin M. Aamodt
Email: [email protected] Neuroscience Interdepartmental PhD Program,
University of California, Los Angeles, Los Angeles,
As a researcher with cerebral palsy, I know CA 90025-4816, USA. Twitter: @CaitlinAamodt
first-hand the fear that comes with applying
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RESEARCH

IN SCIENCE JOURNALS

Edited by Michael Funk

NEUROSCIENCE Light micrograph
showing cortical
Human dendrites are special
neurons with
A special developmental program in the human brain drives branching dendrites
the disproportionate thickening of cortical layer 2/3. This
suggests that the expansion of layer 2/3, along with its somatodendritic recordings revealed previously unknown classes
numerous neurons and their large dendrites, may contribute of action potentials in the dendrites of these neurons, which
to what makes us human. Gidon et al. thus investigated the make their activity far more complex than has been previously
dendritic physiology of layer 2/3 pyramidal neurons in slices taken thought. These action potentials allow single neurons to solve two
from surgically resected brain tissue in epilepsy patients. Dual long-standing computational problems in neuroscience that were
considered to require multilayer neural networks. —PRS
Science, this issue p. 83

MULTIPLEX GENOMICS capture gene expression profiles provides a key insight into the the knot as the two strands are PHOTO: CNRI/SCIENCE SOURCE
from thousands of experimental twin-forming process, which pulled apart. The authors show
Single-cell chemical conditions in a single experiment. might be exploited for develop- why some common knots slip
transcriptomics —LMZ ing nanoparticles suitable for a easily and untie, whereas others
variety of applications. —BG hold tight. —MSL
Single-cell transcriptomic Science, this issue p. 45
technologies have emerged as Science, this issue p. 40 Science, this issue p. 71
powerful tools to explore cellular N A N O PA R T I C L E S
heterogeneity at the resolution APPLIED PHYSICS OPTICS
of individual cells. Srivatsan Finding the fivefold path
et al. now add another layer of It’s knot what you know Miniaturizing particle
information and complexity by Crystals formed in nature or accelerators
combining single-cell transcrip- synthesized in a lab can have Why is it that some knots seem
tomics with oligo hashing and domains with different orienta- to hold tight while others readily Particle accelerators are usually
small molecule screening in a tions that are called twins. Having slip apart? Patil et al. develop a associated with large national
method called sci-Plex. Because five of these domains is relatively theoretical analysis of the stabil- facilities. Because photons
screening many chemical com- common, but how these fivefold ity of knots and find links between are able to impart momentum
pounds requires the ability to twins form is still a mystery. Song topological parameters (twist to electrons, there are also
profile many cells, and because et al. combined in situ trans- charge, crossing numbers, hand- efforts to develop laser-based
screens perturb cells in many mission electron microscope edness) and mechanical stability. particle accelerators. Sapra
different ways, the authors observations with simulations The theory is confirmed using et al. developed an integrated
demonstrate the effects of 188 to find two different pathways simulations and experiments particle accelerator using pho-
compounds in three cancer for forming fivefold twins in on color-changing fibers that tonic inverse design methods to
lines. The sci-Plex method can gold, platinum, and palladium optically show localized stress optimize the interaction between
nanoparticles. This combination differences in different parts of

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the light and the electrons. They or changes in cis-regulatory IN OTHER JOURNAL S Edited by Caroline Ash
show that an additional kick of sequences? Britton et al. exam- and Jesse Smith
around 0.9 kilo–electron volts ine the Mata2 protein in a
(keV) can be given to a bunch Saccharomycotina clade of Artist’s conception
of 80-keV electrons along just fungi. They show that a newly of a Snowball Earth
30 micrometers of a specially evolved transcription circuit
designed channel. Such miniatur- involving repression of the almost entirely
ized dielectric laser accelerators a-specific genes by the ancient covered by ice
could open up particle physics to homeodomain protein Mata2
PHOTO (FROM LEFT): SURADECH KONGKIATPAIBOON/ALAMY STOCK PHOTO; CHRIS BUTLER/SCIENCE SOURCE a number of scientific disciplines. occurred in two stages sepa- SNOWBALL EARTH
—ISO rated by millions of years. In the
first stage, Mata2 acquired Beating the freeze
Science, this issue p. 79 several coding changes followed
by changes in cis-regulatory D espite multiple episodes during the Cryogenian period
ARCHAEOLOGY sequences. This clade-specific in which the planet was mostly covered in ice for millions
requirement explains how the of years—essentially shutting down air–sea exchange
Middle Stone Age cooking coding changes of Mata2 were and causing widespread ocean anoxia—marine aerobic
in place long before the new eukaryotes somehow survived those Snowball Earth
Early evidence of cooked starchy a-specific gene repression circuit conditions. How did they do it? Lechte et al. show that oxygen-
plant food is sparse, yet the con- arose. —BAP ated glacial meltwater was supplied to the oceans near ice
sumption of starchy roots is likely sheet grounding lines, offering a lifeline to microbial communi-
to have been a key innovation Science, this issue p. 96 ties there. This process may have created glaciomarine oxygen
in the human diet. Wadley et al. oases that were critical to the survival and evolution of those
report the identification of whole, PARASITIC INFECTIONS organisms during episodes of extreme glaciation. —HJS
charred rhizomes of plants of the
genus Hypoxis from Border Cave, Parasite perturbation Proc. Natl. Acad. Sci. U.S.A. 116, 25478 (2019).
South Africa, dated up to 170,000 of immunity
years ago. These archaeobotani- T CELL SIGNALING the targeting of either alone, but
cal remains represent the earliest Helminths—a broad grouping how they functionally cross-talk
direct evidence for the cooking of of parasitic worms—infect bil- Checkpoint cross-talk is not well defined. Zhao et al.
underground storage organs. The lions of people and are known report that PD-L1 (the main
edible Hypoxis rhizomes appear to modulate host immune Immunotherapy using antibod- ligand of PD-1) and CD80 (shared
to have been cooked and con- responses to promote their own ies that block the programmed ligand for CTLA-4 and the central
sumed in the cave by the Middle survival. De Ruiter et al. used cell death (ligand) 1 [PD-(L)1] costimulatory receptor CD28),
Stone Age humans at the site. mass cytometry to determine or cytotoxic T lymphocyte– heterodimerize in cis. Using their
Hypoxis has a wide geographi- which immune cells are affected associated protein 4 (CTLA-4) model system, the authors found
cal distribution, suggesting that by helminth infection. They immune checkpoint pathways the PD-L1:CD80 cis complexes
the rhizomes could have been a analyzed samples from rural has resulted in impressive to be defective in binding either
ready and reliable carbohydrate Indonesians before and after responses for some cancer PD-1 or CTLA-4, but the abil-
source for Homo sapiens in deworming treatment. These patients. Combined inhibition ity of CD80 to activate CD28
Africa, perhaps facilitating the were compared to samples of both pathways has generally appeared to be fully preserved.
mobility of human populations. from Europeans and urban delivered better responses than
—AMS Indonesians, neither of which
had been exposed to helminths.
Science, this issue p. 87 Helminths expanded specific
type 2 and regulatory immune
EVOLUTIONARY BIOLOGY cells, and many immune altera-
tions reverted upon deworming.
Generating a new These details on host–pathogen
transcriptional network interaction could inform future
targeted therapies. —LP
Organismal novelties result
from changes in transcriptional Sci. Transl. Med. 12,
circuits. But what comes first, eaaw3703 (2020).
changes in regulatory protein
Modern example of storage organs
from a species of the Hypoxis genus,

which includes the African potato

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RESEARCH | IN OTHER JOURNALS

METALS IN BIOLOGY

Copper on the half shell

O ysters, like many marine mollusks, have
a complex life cycle that requires changes
in their body and biochemistry. Weng et al.
examined how the abundance and distribu-
tion of copper, a trace element essential for
metabolism, changes in larval and juvenile oysters
as they develop. Using a combination of imag-
ing techniques, they see copper accumulation in
certain organs during developmental transitions,
especially in the cells’ mitochondria. Both cell
proliferation and programmed cell death involve
biochemical processes linked to mitochondrial
copper concentrations. Understanding metal
ion distributions may offer insights valuable for
conservation and cultivation. —MAF

Environ. Sci.Technol. 53, 14724 (2019).

Oysters have a particularly critical need for the trace element
copper during their late pelagic larval stage (pictured).

The interaction of checkpoint the lines and edges converge on and inactivate perforin. —SMH that selective transplantation of PHOTO: STEPHANIE ALEXANDER, UNIVERSITY OF MARYLAND CENTER FOR ENVIRONMENTAL SCIENCE HORN POINT OYSTER HATCHERY
pathways might allow opportuni- her mental model of a scene, thus Nat. Commun. 10, 5396 (2019). extinct taxa could aid a healthy
ties to improve therapy. —PNK providing a window into her visual microbiota to recover after anti-
cortex. —PRS M I C R O B I O TA biotics exposure. —CA
Immunity 51, 1059 (2019).
J. Neurosci. 39, 9410 (2019). Postantibiotic recovery Cell Host Microbe 26, 650 (2019).
NEUROSCIENCE
CELL BIOLOGY Antibiotic consumption by PHYSICS
Filling a blank canvas humans is ubiquitous. Although
Kill, but don’t be killed they are lifesaving and valuable Tailoring electronic
Natural scenes can be decoded in medicines, antibiotics can harm properties
the brain in the early visual cortex. Cytotoxic T lymphocytes (CTLs) resident mutualistic micro-
Decoding is a product of planned recognize and destroy infected organisms in unpredictable ways The layered material a-RuCl
output (feedforward) corrected or malignant cells. CTLs secrete leading to physiological damage. 3
by experience (feedback). Morgan the pore-forming protein per- Ng et al. systematically explored
et al. occluded one quadrant of forin into the immune synapse, the long-term effects of antibi- has piqued the interest of physi-
the visual field of human partici- where perforin disrupts the otic treatment on transplanted cists as a potential platform for
pants and then presented them target cell plasma membrane human microbiota in mice. The the so-called Kitaev model—a
with images of landscape scenes. and initiates cell death pathways. alpha-diversity of Bacteroides type of quantum spin liquid
Responses in the visual cortex Paradoxically, the secreted spp. suffered mass extinction that hosts exotic excitations.
(areas V1 and V2) were measured perforin only damages the by streptomycin within hours of However, in addition to the
for each person by functional target cell, leaving the producer treatment, whereas Firmicutes magnetic interactions of the
magnetic resonance imaging. lymphocytes unscathed and were more resilient. Such taxa- Kitaev model, a-RuCl3 also hosts
Even in the occluded region, able to attack another target cell. specific selection depended on non-Kitaev interactions. Biswas
information about the scene was What protects the lymphocyte the antibiotic used, influenced et al. investigated theoretically
being decoded. To access what is unclear. Using a variety of the recovered community com- whether a heterostructure
the brain had modeled for the approaches, Rudd-Schmidt et position, and affected resilience consisting of a a-RuCl3 mono-
occluded region, participants al. found that two distinct but to subsequent treatments. layer on top of graphene would
were asked to complete the image coordinated mechanisms were Diet was an important variable: be a better approximation of
by line drawings on an electronic deployed by CTLs to protect Without microbiota-accessible the Kitaev model. Using ab initio
drawing tablet. The drawings were themselves. Both mechanisms fiber in the diet, mucus graz- calculations, the researchers
shown to all participants, who depended on the dynamic regu- ers predominated, which may found that the a-RuCl3 layer
scored how well the “averaged” lation of plasma membrane lipid facilitate the activity of patho- would experience strain and
drawing for each scene matched composition and topology. High gens, such as Acinetobacter become doped by graphene
the complete image. Mental membrane lipid order made muciniphila. Recolonization from electrons. The strain would
models at the first visual cortical the CTL presynaptic membrane untreated cage mates was also make the Kitaev interactions
stage were predicted by the line refractory to perforin binding. vital for healthy reestablishment more dominant, and the doping
drawings. So, faced with a blank Furthermore, phosphatidyl- of the microbiota, especially may provide a route towards
canvas, an artist may be using serine, exposed on the killer cell of Bacteroidetes. It is possible p-wave superconductivity in this
cortical feedback processing until membrane, appeared to bind system. —JS

Phys. Rev. Lett. 123, 237201 (2019).

38 3 JANUARY 2020 • VOL 367 ISSUE 6473 sciencemag.org SCIENCE

Published by AAAS

RESEARCH

ALSO IN SCIENCE JOURNALS
Edited by Michael Funk

NEUROSCIENCE MALARIA associated with condensed mat- PLANT SCIENCE
ter systems. —ISO
The neural substrate An artemisinin resistance Subtle origin for
of memory mechanism Science, this issue p. 59 complex shapes

The ability to form memory is Species of the malaria parasite TOPOLOGICAL MATTER The cup-shaped leaves of
an essential trait that allows Plasmodium live in red blood carnivorous plants have evolved
learning and the accumula- cells and possess a highly Looking for chiral multiple times from ancestors
tion of knowledge. But what is conserved gene called kelch13. Majoranas with flat leaves. Studying devel-
a memory? There has been a Single point mutations in this opment of the carnivorous trap
long history of searching for the gene are associated with resis- Chiral Majorana modes have been in the humped bladderwort,
neuronal substrate that forms tance to the frontline artemisinin predicted to exist in heterostruc- Utricularia gibba, Whitewoods
memory in the brain, and the drugs. Birnbaum et al. found that tures consisting of a quantum et al. identified genes similar to
emerging view is that ensembles Kelch13 and associated proteins anomalous Hall insulator and a those expressed in surfaces of
of engram cells explain how comprise an endocytic compart- superconductor. Kayyalha et al. flat leaves (see the Perspective
memories are formed and ment associated with feeding fabricated more than 30 such by Moulton and Goriely).
retrieved. In a Review, Josselyn on host erythrocytes (see the samples and used transport Ectopic expression and compu-
and Tonegawa discuss the Perspective by Marapana and measurements to look for signa- tational modeling reveals how
evidence for engram cells as a Cowman). Hot targets for arte- tures of the Majorana modes. The slight shifts in gene expression
substrate of memory, particu- misinin research also occur in data indicated that the transport domains make the difference
larly in rodents; what we have this compartment, including the signatures previously thought between a flat leaf and a convo-
learned so far about the features proteins UBP1, AP-2m, and the to be associated with Majorana luted trap structure. Flexibility
of memory, including memory parasite homolog of the endocy- physics could, in their samples, be in growth rates in orthogonal
formation, retrieval over time, tosis protein Eps15. Inactivation explained using a more mundane polarity fields allows for diver-
and loss; and future directions of Kelch13 compartment mechanism. —JS sity in shapes formed through
to understand how memory proteins revealed that these development. —PJH
becomes knowledge. —GKA are required for endocytosis of Science, this issue p. 64
host hemoglobin. Artemisinins Science, this issue p. 91;
Science, this issue p. 39 are activated by hemoglobin TOPOLOGICAL MATTER see also p. 24
degradation products, so these
GLOBAL HEALTH mutations render the parasite A possible propagating TUBULIN
resistant to these drugs to differ- Majorana
Cancer in diverse ent extents. —CA Mechanism of tubulin
populations Majorana states in solid-state autoregulation
Science, this issue p. 51; systems may one day form a
Much of what is known about see also p. 22 basis for topological quantum Cells tightly control the abun-
the signature genetic altera- computing. Most of the candi- dance of key housekeeping
tions and clinical features of TOPOLOGICAL OPTICS dates identified so far have been factors, such as ribosomes and
cancer comes from studying Majorana bound states, but chaperones, to maintain them
Caucasian patients in high- Optically contorting into theorists have predicted that at optimal levels needed for
income countries. However, this new dimensions propagating Majorana states may homeostasis. Most abundance
does not reflect the diversity of exist as well. Wang et al. looked control mechanisms involve
heritage in most societies and Creating synthetic dimensions for such a state on the surface feedback regulation of mRNA
therefore does not allow patients has generated interest in many of the material FeSe0.45Te0.55 transcription, but others, such as
to be diagnosed and treated branches of science, ranging (see the Perspective by Tewari tubulins, are regulated by highly
effectively. In a Perspective, from ultracold atomic physics and Stanescu). Using scanning specific mRNA degradation. Lin
Rebbeck discusses the emerging to photonics. The ability to do tunneling spectroscopy, the et al. found that tetratricopep-
evidence that cancers in patients so provides a versatile platform researchers measured a flat, tide protein 5 (TTC5) binds to
in sub-Saharan Africa are clini- for realizing effective gauge bias-independent density of nascent alpha and beta tubulins
cally and molecularly distinct. potentials and novel topological states along a particular type of on translating ribosomes to
Understanding these differences physics that might be difficult domain wall, which was consis- trigger degradation of their
should improve treatment of or impossible to realize in real tent with a theoretical prediction associated mRNAs when excess
patients in sub-Saharan Africa as systems. Dutt et al. show that a for a propagating Majorana tubulin is present (see the
well as the diaspora. Assessment structured optical ring cavity can state in this material. Although Perspective by Shoshani and
of the diversity of genetic sustain more than one synthetic topologically trivial origins of this Cleveland). In the absence of
alterations can also improve how dimension. Under modulation, finding are difficult to completely TTC5-mediated tubulin autoreg-
cancer is diagnosed and classi- coupling the different degrees of rule out, the work is likely to ulation, cells display error-prone
fied in all populations. —GKA freedom within the resonator is stimulate interest in iron-based chromosome segregation, a
used synthesize two additional superconductors as hosts of process critically dependent on
Science, this issue p. 27 dimensions. The authors are Majorana states. —JS tubulin concentration. —SMH
then able to emulate many com-
plex physical phenomena usually Science, this issue p. 104; Science, this issue p. 100;
see also p. 23 see also p. 29

38-B 3 JANUARY 2020 • VOL 367 ISSUE 6473 sciencemag.org SCIENCE

Published by AAAS

FLUORESCENT PROTEINS stemming from the inhomoge- RESEARCH
neity of the chemical doping 3 JANUARY 2020 • VOL 367 ISSUE 6473 38-C
Electrostatics guide process. In particular, the size of
chromophore twist the spectroscopic gap can vary
widely across a single sample.
Photoisomerization—the Massee et al. used the tip of a
twisting of bonds in a molecule scanning tunneling microscope
in response to absorption of to manipulate atoms on the
light—is exploited in biology to surface of a member of the
sense light and can influence Bi2Sr2CaCu2O8+x cuprate family.
the photophysical properties Moving bismuth atoms up or
of fluorescent proteins used in down caused adjacent atoms to
imaging applications. Romei et shift laterally, leading to revers-
al. studied this behavior by intro- ible local changes in the size of
ducing unnatural amino acids the gap. It is expected that the
into the photoswitchable green technique can be used to probe
fluorescent protein Dronpa2, the influence of the local lattice
thus systematically altering the on the electronic states of other
electronic properties of the chro- correlated materials. —JS
mophore (see the Perspective
by Hu et al.). Crystal structures Science, this issue p. 68
and spectroscopic analyses of a
series of these variants support a
model in which the electrostatic
interactions between the chro-
mophore and its environment
influence the barrier heights for
twisting around different bonds
during photoisomerization. These
insights may guide future design
of photoswitchable proteins with
desired properties. —MAF

Science, this issue p. 76;

see also p. 26

CANCER

A movement orchestrated
by DNA damage

Doxorubicin is a commonly used
therapeutic that kills cancer
cells by inducing genotoxic
stress. Harvey et al. found
that treatment of cancer cells
with clinically relevant doses
of doxorubicin promoted the
phosphorylation of the transla-
tion factor eIF2a, which, rather
than inhibiting protein syn-
thesis as might be expected,
led to increased migration.
Inhibiting eIF2a phosphoryla-
tion with a U.S. Food and Drug
Administration–approved drug
restricted doxorubicin-induced
cell migration. —WW

Sci. Signal. 12, eaaw6763 (2019).

SUPERCONDUCTIVITY

Manipulating the gap

Cuprate superconductors
typically have a large amount
of spatial inhomogeneity, partly

SCIENCE sciencemag.org

Published by AAAS

RESEARCH

◥ memory consolidation and retrieval processes.
Third, it is now possible to artificially manip-
REVIEW SUMMARY

ulate memory encoding and retrieval processes

NEUROSCIENCE to generate false memories, or even create a

Memory engrams: Recalling the past and memory in mice without any natural sensory
imagining the future
experience (implantation

◥

ON OUR WEBSITE of a memory for an expe-

Read the full article rience that did not occur).
Fourth, “silent” engrams
at http://dx.doi.

Sheena A. Josselyn* and Susumu Tonegawa* org/10.1126/ were discovered in amne-
science.aaw4325 sic mice; artificial reac-
tivation of silent engrams
..................................................

BACKGROUND: The idea that memory is stored There are several recent advances in engram induces memory retrieval, whereas natural

as enduring changes in the brain dates back research. First, eligible neurons within a given cues cannot. Endogenous engram silencing

at least to the time of Plato and Aristotle (circa brain region were shown to compete for al- may contribute to the change in memory over

350 BCE), but its scientific articulation emerged location to an engram, and relative neuronal time (e.g., systems memory consolidation) or

in the 20th century when Richard Semon excitability determines the outcome of this in different circumstances (e.g., fear memory

introduced the term “engram” to describe the competition. Excitability-based competition extinction). These findings suggest that once

neural substrate for storing and recalling also guides the organization of multiple en- formed, an engram may exist in different

memories. Essentially, Semon pro- states (from silent to active) on the

posed that an experience activates a basis of their retrievability. Although

population of neurons that undergo initial engram studies focused on sin-

persistent chemical and/or physical gle brain regions, an emerging concept

changes to become an engram. Sub- is that a given memory is supported

sequent reactivation of the engram by an engram complex, composed of

by cues available at the time of the functionally connected engram cell

experience induces memory retrieval. ensembles dispersed across multiple

After Karl Lashley failed to find the brain regions, with each ensemble

engram in a rat brain, studies attempt- supporting a component of the overall

ing to localize an engram were largely memory.

abandoned. Spurred by Donald O. Hebb’s

theory that augmented synaptic strength OUTLOOK: The ability to identify and

and neuronal connectivity are critical manipulate engram cells and brain-

for memory formation, many research- wide engram complexes has intro-

ers showed that enhanced synaptic duced an exciting new era of memory

strength was correlated with memory. research. The findings from many labs

Nonetheless, the causal relationship are beginning to define an engram as

between these enduring changes in the basic unit of memory. However,

synaptic connectivity with a specific, many questions remain. In the short

behaviorally identifiable memory at term, it is critical to characterize how

the level of the cell ensemble (an en- information is stored in an engram,

gram) awaited further advances in including how engram architecture

CREDIT: ADAPTED FROM T. J. RYAN ET AL., SCIENCE 348, 1007 (2015). experimental technologies. An engram cell alongside a nonengram cell. Within the hippocam- affects memory quality, strength, and
pus, dentate gyrus cells were filled with biocytin (white) to examine precision; how multiple engrams in-
ADVANCES: The resurgence in research morphology. Engram cells active during context fear conditioning were teract; how engrams change over time;
examining engrams may be linked engineered to express the red fluorescent protein mCherry, which and the role of engram silencing in
to two complementary studies that appears pink owing to overlap with biocytin signals. Axons of the these processes. The long-term goal
applied intervention strategies to tar- perforant path (green) express the excitatory opsin channelrhodopsin 2 of engram research is to leverage the
get individual neurons in an engram and a fluorescent marker (enhanced yellow fluorescent protein). The fundamental findings from rodent en-
supporting a specific memory in mice. upper blade of the dentate gyrus granule cell layer is revealed by the gram studies to understand how infor-
One study showed that ablating the nuclear stain 4′,6-diamidino-2-phenylindole (DAPI, blue). mation is acquired, stored, and used in
subset of lateral amygdala neurons humans and facilitate the treatment of

allocated to a putative engram dis- human memory, or other information-

rupted subsequent memory retrieval (loss grams in the brain and determines how these processing, disorders. The development of

of function). The second study showed that engrams interact. Second, research examin- low- to noninvasive technology may enable

artificially reactivating a subset of hippocam- ing the nature of the off-line, enduring changes ▪new human therapies based on the growing
pal dentate gyrus neurons that were active in engram cells (neurons that are critical com-
during a fearful experience (and, therefore, ponents of an engram) found increased synap- knowledge of engrams in rodents.

part of a putative engram) induced memory tic strength and spine density in these neurons

retrieval in the absence of external retrieval as well as preferential connectivity to other

cues (gain of function). Subsequent findings downstream engram cells. Therefore, both The list of author affiliations is available in the full article online.
from many labs used similar strategies to increased intrinsic excitability and synaptic *Corresponding author. Email: [email protected]
identify engrams in other brain regions sup- plasticity work hand in hand to form engrams, (S.A.J.); [email protected] (S.T.)
porting different types of memory. and these mechanisms are also implicated in Cite this article as S. A. Josselyn and S. Tonegawa, Science
367, eaaw4325 (2020). DOI: 10.1126/science.aaw4325

Josselyn et al., Science 367, 39 (2020) 3 January 2020 1 of 1

RESEARCH

◥ veloped a cell assembly theory (similar to
Semon’s engram complex) (15). Hebb hypothe-
REVIEW sized that a cell assembly is formed between
reciprocally interconnected cells that are sim-
NEUROSCIENCE ultaneously active during an experience. Suffi-
cient activity within the cell assembly induces
Memory engrams: Recalling the past and growth and/or metabolic changes that strength-
imagining the future en the connections between these cells [a con-
cept distilled in the phrase “neurons that fire
Sheena A. Josselyn1,2,3,4,5* and Susumu Tonegawa6,7* together, wire together” (16)]. These synap-
tic and metabolic changes (perhaps including
In 1904, Richard Semon introduced the term “engram” to describe the neural substrate for storing memories. changes in intrinsic neuronal excitability) have
An experience, Semon proposed, activates a subset of cells that undergo off-line, persistent chemical implications for the function of a cell assem-
and/or physical changes to become an engram. Subsequent reactivation of this engram induces memory bly. For instance, reactivation of only a frac-
retrieval. Although Semon’s contributions were largely ignored in his lifetime, new technologies that tion of assembly cells was hypothesized to
allow researchers to image and manipulate the brain at the level of individual neurons has reinvigorated produce reactivation of the entire assembly
engram research. We review recent progress in studying engrams, including an evaluation of evidence for (15) [a process similar to pattern completion
the existence of engrams, the importance of intrinsic excitability and synaptic plasticity in engrams, and the (17–19)]. By contrast, destruction of a fraction
lifetime of an engram. Together, these findings are beginning to define an engram as the basic unit of memory. of assembly cells would not necessarily produce
catastrophic failure of the entire represent-
M emory is the ability to use the past in change in some aspect of brain state but was ation (but rather gracefully degrade the rep-
service of the present or future (1, 2). suitably cautious when asked to speculate on resentation). Interestingly, Semon also proposed
Memory is central to our everyday lives the precise neural mechanisms underlying an similar types of properties for an engram (5).
and defines who we are. Without it, engram, “To follow this into the molecular
field seems to me…a hopeless undertaking at Together, these (and other) scientists helped
we are condemned to an eternal pre- the present stage of our knowledge and for my define and describe an engram. However, there
sent. That memory persists after an experience part, I renounce the task” (7, p. 154). was a paucity of studies examining the biol-
ogical basis of engrams. More than 100 years
suggests that an internal representation of A few years later, though, Karl Lashley, a ago, Semon wrote that to examine the neuro-
this experience is stored in the brain and that geneticist turned psychologist, took up this biological basis of an engram represented a
challenge by systematically attempting to lo- “hopeless undertaking.” This may no longer be
later this representation can be reconstructed calize an engram in a mammalian brain (12–14). true. Recent excitement surrounding engram
In a typical study, Lashley trained rats over research may stem directly from the develop-
and used. In 1904, Richard Semon, an evolu- many days to solve a maze by running a dis- ment of new tools allowing cell ensembles to
tionary zoologist turned memory theorist, in- tinct route to collect a reward. Hypothesizing be imaged and manipulated at the level of the
troduced the term “engram” to describe such that some critical component of the engram individual cell. We begin by briefly reviewing
memory representations (3, 4). Semon defined supporting this maze-route memory is local- the neurobiological evidence supporting the
an engram as “…the enduring though primar- ized in the cortex, Lashley removed cortical existence of engrams in the rodent brain and
ily latent modifications in the irritable sub- tissue of varying sizes from varying locations our collective ability to not only find but also
stance produced by a stimulus…” (5, p. 12; 6). and then tested the rats’ memory for the maze manipulate engrams to better understand
He postulated a fundamental “law of engra- route. Although the amount of cortical tissue memory. Then, we discuss the current state of
phy” in which “all simultaneous excitations… removed correlated with overall memory im- engram research by examining the results of
form a connected simultaneous complex of pairment, the location of the lesion did not. explicit engram studies and previous memory
After more than 30 years of searching, Lashley and plasticity findings from an engram point of
excitations which, as such, act engraphically, failed to find an engram, declaring it “elusive.” view. Guided by Semon, we define an engram
that is to say leaves behind it a connected, as an enduring off-line representation of a past
and to that extent, unified engram-complex” The next leap in engram-related research experience (Box 1). It is important to note that
(7, p. 159–160). An engram, therefore, is rough- came when Donald O. Hebb, a psychologist, an engram is not yet a memory but rather pro-
ly equivalent to a “memory trace.” memory theorist, and student of Lashley, de- vides the necessary physical conditions for a

Semon’s innovative ideas were largely over-
looked or dismissed during his lifetime. How-
ever, his theories foreshadowed many prominent
contemporary memory concepts (8–11). Semon
defined an engram as an off-line, physical

1Program in Neurosciences & Mental Health, Hospital for Box 1. Engram definitions.

Sick Children, Toronto, Ontario M5G 1X8, Canada. An “engram” refers to the enduring offline physical and/or chemical changes that were elicited by
2Department of Psychology, University of Toronto, Toronto, learning and underlie the newly formed memory associations.
Ontario M5S 3G3, Canada. 3Department of Physiology,
“Engram cells” are populations of cells that constitute critical cellular components of a given
University of Toronto, Toronto, Ontario M5G 1X8, Canada. engram. These cells may (or may not) also be critical components of engrams supporting other
4Institute of Medical Sciences, University of Toronto, memories. Engram cells are (i) activated by a learning experience, (ii) physically or chemically modified
Toronto, Ontario M5S 1A8, Canada. 5Brain, Mind & by the learning experience, and (iii) reactivated by subsequent presentation of the stimuli present at
the learning experience (or some portion thereof), resulting in memory retrieval.
Consciousness Program, Canadian Institute for Advanced
An “engram cell ensemble” refers to the collection of engram cells localized within a brain region.
Research (CIFAR), Toronto, Ontario M5G 1M1, Canada. Engram cell ensembles in each brain region are connected, forming an “engram complex,” which is the
6RIKEN-MIT Laboratory for Neural Circuit Genetics at the entire brainwide engram supporting a memory that is stored in sets of engram cell ensembles in
different brain regions connected via an engram cell pathway.
Picower Institute for Learning and Memory, Department of

Biology and Department of Brain and Cognitive Sciences,

Massachusetts Institute of Technology, Cambridge, MA 02139,
USA. 7Howard Hughes Medical Institute, Massachusetts

Institute of Technology, Cambridge, MA 02139, USA.

*Corresponding author. Email: [email protected]

(S.A.J.); [email protected] (S.T.)

Josselyn et al., Science 367, eaaw4325 (2020) 3 January 2020 1 of 14

RESEARCH | REVIEW

memory to emerge (20). Memories are re- semble, Mayford and colleagues (41) tagged neurons after training (58). Ablating CREB-
trieved when appropriate retrieval cues success- neurons active during auditory fear condition- overexpressing neurons disrupted freezing to
fully reactivate an engram in a process Semon ing. In this commonly used memory task, an subsequent tone presentation, as if the mem-
dubbed “ecphory.” initially innocuous tone (a conditioned stimu- ory was erased (Fig. 1). Importantly, mice were
lus) is paired with an aversive footshock (an capable of learning a new fear conditioning
Experimental strategies to evaluate engrams unconditioned stimulus) in a conditioning task (showing overall LA function was not
context. When subsequently reexposed to the compromised), and ablating a similar number
To evaluate the existence of engrams, we adapt tone or conditioning context, rodents freeze of non–CREB-overexpressing cells (nonengram
the criteria and experimental strategies dis- (the active, learned conditioned response), cells) did not disrupt memory (showing speci-
cussed by Morris and colleagues (21, 22) in showing memory of the training experience ficity of the memory disruption at the cellular
their landmark papers evaluating the impor- (44). In this experiment, mice were replaced in level).
tance of synaptic plasticity in memory. Spe- the conditioning context 3 days after training,
cifically, we discuss evidence from four types and active neurons were marked with zif268 Subsequent studies using diverse methods to
of studies. First, observational studies sup- immunohistochemistry. Consistent with the permanently or reversibly inactivate allocated
porting the existence of engrams in the rodent existence of an engram supporting this con- or tagged neurons across several brain areas
brain should show that the same (or overlap- ditioned fear memory, the overlap of neurons hypothesized to be part of an engram, in many
ping) cell populations are activated both by an active during training (tagged) and testing memory tasks, produced comparable results
experience and by retrieval of that experience (zif268+) in the basal amygdala nucleus ex- (40, 48, 53, 63, 66, 67). Together, these findings
and that, furthermore, learning should induce ceeded chance (~11% total cells) (41). suggest that neurons active during an expe-
long-lasting cellular and/or synaptic modifica- rience become engram cells that are indispens-
tions in these cells. Second, loss-of-function Similar results, using different tagging meth- able (or somehow necessary) for successful
studies should show that impairing engram ods, across multiple brain regions [including subsequent memory expression.
cell function after an experience impairs sub- dorsal hippocampus (40, 45–55), amygdala
sequent memory retrieval. Third, gain-of- (41, 45, 49, 51, 55, 56), and cortex (42, 45, 55, 57)] Why were these loss-of-function studies per-
function studies should show that artificially were reported for a variety of different mem- haps successful in “finding an engram” when
activating engram cells induces memory ret- ory tasks (including contextual fear condition- Lashley was not? First, Lashley may have used
rieval, in the absence of any natural sensory ing, auditory fear conditioning, and novel an inappropriate behavioral test to probe an
retrieval cues. Fourth, mimicry studies should object exploration). Control studies revealed engram. The well-learned maze task Lashley
artificially introduce an engram of an experi- that tagged cells were only reactivated by the typically used could be solved using different
ence that never happened into the brain and corresponding conditioned stimulus and not strategies and, therefore, may have been in-
show that rodents use the information of an by stimuli unrelated to the training experience sensitive to damaging a distinct brain region.
artificial engram to guide behavior. (45). Although most observational studies did Second, Lashley may have targeted the wrong
not address directly the enduring, learning- brain region for this type of spatial memory
Memory traces, or at least physiological cor- induced changes hypothesized by Semon, over- task (68).
relates of memory, have been examined in in- all, these results (and their notable consistency
vertebrate species, such as flies (23–27), octopus across methods, tasks, and labs) provide broad Gain-of-function studies
(28, 29), Aplysia sea slugs (30, 31), honey bee support for the existence of engrams. How-
(32), and Hermissenda sea slugs (33). More- ever, causal studies are necessary to show that Gain-of-function studies attempt to induce
over, pioneering studies in mammals (34–36) these reactivated putative engram cells indeed memory retrieval in the absence of natural
greatly informed our current understanding of function as part of the internal representation retrieval cues by artificially reactivating en-
the neural basis of memory but did not ex- of an experience. gram cells. Tonegawa and colleagues (69)
amine memory at the cell ensemble level. The provided the first gain-of-function evidence
discussion here is limited primarily to rodent Loss-of-function studies for the existence of an engram. Hippocampal
experiments examining memory of an explicit dentate gyrus (DG) neurons active during con-
experience that probe memory at the level of Loss-of-function studies attempt to “capture” textual fear conditioning (in which a context
an engram. engram cells and specifically disrupt their func- was paired with a footshock) were tagged (41)
tion before a memory test. Josselyn and col- to express the excitatory opsin channelrhodop-
Observational studies leagues (58) performed the first loss-of-function sin 2 (ChR2) (70). When tested in a nontraining
memory study at the level of a cell ensemble. context, mice did not freeze. However, photo-
Typically, observational studies take advantage An allocation strategy was used to capture stimulation of tagged engram cells was suffi-
of immediate early genes (IEGs) such as c-Fos, putative engram cells in the amygdala lateral cient to induce freezing, the learning-specific
Arc (activity-regulated cytoskeleton-associated nucleus (LA) supporting an auditory fear con- conditioned response (44), even though mice
protein), or Zif268 (zinc finger protein 225) ditioned memory in mice. That is, a small, had never been shocked in this nontraining
(37–39) to visualize active neurons. Cells active random population of LA neurons was biased context (Fig. 2). Importantly, light-induced
during a memory test are marked using IEG for inclusion (or allocation) into a putative en- freezing was not due to activation of pre-
immunohistochemistry, whereas cells active gram using a neurotropic virus expressing wired learning-independent neural circuits or
during a training experience are “tagged” CREB (Ca++/cyclic AMP–responsive element- a simple reflex response, because similar photo-
through the use of temporally inducible IEG binding protein). CREB is a transcription fac- stimulation of tagged DG neurons failed to
promoters that drive the expression of more tor that increases both neuronal excitability induce freezing if downstream CA1 neurons
enduring fluorescent (or other) reporter pro- (59–64) and dendritic spine density (60, 65). were silenced during training (thereby prevent-
teins (40–43). Above-chance overlap between Therefore, neurons infected with this CREB ing learning) (71).
these two cell populations (“active during train- vector were hypothesized to be biased for in-
ing” and “active during test”) within a brain clusion into an engram. A virus expressing Artificial optogenetic or chemogenetic (72, 73)
region (or throughout the brain) is suggestive both CREB (to allocate neurons) and an indu- reactivation of tagged or allocated engram cells
of an engram. cible construct that produces cell-autonomous across several brain regions similarly induced
ablation was used to specifically kill allocated memory expression without external sensory
In an initial observational study designed to retrieval cues in a variety of tasks (42, 53, 74–81).
examine a memory at the level of a cell en- Therefore, artificial engram cell reactivation

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Fig. 1. Engram loss-of-function studies disrupt subsequent memory during the fear memory test (green filled circles), suggesting that allocated
retrieval. (A) Ablating allocated neurons. Lateral amygdala principal (excitatory) neurons are preferentially recruited to an engram supporting this conditioned
neurons were experimentally allocated to an engram (blue circles) by means of fear memory. Specifically ablating experimentally allocated neurons (red circles)
overexpression of the transcription factor CREB (122). Mice received auditory before a second memory test disrupts memory retrieval. (B) Ablating a similar
fear conditioning during which a tone (conditioned stimulus) was paired with a number of random, nonallocated neurons does not disrupt memory retrieval.
footshock (unconditioned stimulus). The majority of allocated neurons are active [Images: Adapted from (122)].

serves as a sufficient retrieval cue to “reawaken” been shocked in this context. That is, mice brain as mice explored a new context (context A).
a dormant engram to induce memory expres- retrieved an artificial memory. Mice also froze Chemogenetically reactivating these neurons
sion, similar to Semon’s original definition of in context B (showing natural memory retriev- while mice were fear conditioned in context
ecphory [“the influences which awaken the al), but not in a third distinct context (context B produced a “hybrid or synthetic” context
mnemic trace or engram out of its latent state C), indicating freezing was a context-specific, representation that was not retrievable by
into one of manifested activity” (5, p. 12)]. and not a generalized, response (46). Both either context alone [unlike (46), above]. How-
memories produced by “natural” and “arti- ever, mice froze in a test session that more
Mimicry experiments ficial” means could only be retrieved by their closely matched the training conditions (place-
respective conditioned stimuli, indicating both ment in context B while chemogenetically ac-
During natural memory retrieval, the sensory memories retained their identities. Similar tivating context A engram cells), suggesting
conditioned stimulus (e.g., the training con- to a compound conditioned stimulus in which that this hybrid memory incorporated both
text) is thought to reactivate engram cells to both a tone and light predict footshock, the natural and artificial cues. Differences in the
induce memory retrieval. The first gain-of- strength of the natural and artificial mem- spatial and temporal properties of artificial
function study (69) was designed to mimic ories were roughly 50% of a single “normally engram reactivation (more acute optogenetic
this retrieval process by directly reactivating induced” memory, suggesting cue competi- activation of localized tagged DG neurons
engram cells by means of optogenetic stimu- tion between the natural and artificial condi- versus longer-term chemogenetic activation of
lation, thus circumventing the need for the tioned stimuli [as originally described by (82)]. nonlocalized tagged neurons across the brain)
conditioned stimulus. That is, artificial stim- Therefore, when a biologically important event may account for the discrepant outcomes of
ulation replaced the natural conditioned stim- (e.g., footshock) occurs while an animal is these two artificial conditioned stimuli studies.
ulus to induce memory retrieval. Optogenetic retrieving a previously formed but perhaps
stimulation of engram cells has also been used unrelated memory, the two stimuli can be as- Neurons active during presentation of an
to artificially retrieve a previously experienced sociated to form a new but false episodic mem- unconditioned stimulus have also been tagged
sensory stimulus during the formation of a ory. An analogous mechanism may underlie and artificially reactivated (85). Neuronal en-
new memory. For instance, DG neurons ac- human false memories, except that in humans, sembles active during context exploration (the
tive during exploration of a new context (con- the previously acquired memory would be re- conditioned stimulus) and footshock (the un-
text A) were photostimulated when mice later trieved by natural processes (83). conditioned stimulus) were tagged separately
received footshocks in a different context (con- in the CA1 subfield of the hippocampus and
text B). During a memory test, mice replaced Mayford and colleagues (84) used a similar the basolateral complex of the amygdala, re-
in context A froze, even though they had never approach but tagged active neurons across the spectively. Synchronous optogenetic activation

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AB473 nm of these ensembles while mice were in the
homecage was sufficient to induce a false mem-
CD Freezing (%) ory; mice froze in the tagged (but nonshocked)
context, as if the conditioned stimulus and
40 unconditioned stimulus had been paired.
30
20 Finally, a recent study investigated whether
10 a memory could be implanted through artifi-
cial means in the total absence of natural
0 stimuli (either conditioned stimulus or uncon-
ditioned stimulus). To be a true memory im-
Off On Off On plantation, such an experiment should satisfy
E several criteria (86). First, the “learning expe-
rience” should occur entirely within the brain
Fig. 2. Gain-of-function method for engram identification and distributed engram ensembles. through, for example, direct stimulation of pu-
(A) A c-fos–tTA transgenic mouse is injected with AAV9-TRE-ChR2-mCherry (allowing active neurons tative conditioned-stimulus and unconditioned-
in the absence of doxycycline to express the excitatory opsin ChR2) and implanted with an optical fiber stimulus neural pathways. Second, the presence
to target blue light to activate ChR2-expressing neurons in the DG. (B) Basic experimental scheme. Mice of the implanted memory should be probed
are habituated to context A with light stimulation while on doxycycline for 5 days and are then taken off through presentation of a “real” external re-
doxycycline for 2 days (to open the tagging window) and exposed to contextual fear conditioning (CFC) in trieval cue (not just the internal neural cue).
context B. Mice are put back on doxycycline (to close the tagging window) and tested for 5 days in context A Finally, behavioral manifestation of this mem-
with light stimulation. (C) Representative image showing the expression of ChR2-mCherry–positive (red) ory should reflect the predicted memory con-
engram cells in a mouse that was taken off doxycycline for 2 days and underwent CFC training. [Image credit: tent and be retrieved only by the “trained”
X. Liu and S. Ramirez (Tonegawa lab)] (D) Mice expressing ChR2 in engram cells from CFC in context B (red) conditioned stimulus (not to similar cues).
show greater freezing during test light-on epochs in context A than a control group expressing mCherry only. In this study, optogenetic stimulation of a
Error bars indicate standard error of the mean. [Graph: Adapted from Liu et al. (69)] (E) A part of the engram genetically specific olfactory glomerulus (the
cell ensemble complex for contextual fear memory. It is generally thought that the engram for a specific conditioned stimulus) was paired with opto-
memory is distributed in more than one brain region. For instance, for contextual fear memory, the engram genetic stimulation of either appetitive or
cell ensemble in the entorhinal cortex layer II (EC-II) as well as hippocampal subfields [DG, CA3, CA2, CA1, aversive neural pathways (the unconditioned
and subiculum (Sub)] may represent context, whereas amygdala engram cell ensembles represent fear stimuli) (86). After this entirely intracranial
information. These engram cell ensembles are functionally connected to form an engram cell ensemble conditioning, mice showed either an attrac-
complex. Thus, a concept has emerged that a specific pattern of cellular connectivity within an engram cell tion or aversion, respectively, to the real odor
ensemble complex serves as the substrate for a specific memory. US, unconditioned stimulus; LA, lateral that activated this olfactory glomerulus. In
nucleus of the amygdala; BLA, basolateral nucleus of the amygdala; CS, conditioned stimulus. short, a memory was made in the absence of
experience. These results satisfy the mimicry
criterion of experimental evidence outlined
by Martin and colleagues (21, 22) and, as such,
provide another line of persuasive evidence for
the existence of engrams.

Understanding memory through engrams
The “enduring changes” of an engram

The ability to label in vivo engram cells sup-
porting a specific memory provided an op-
portunity to investigate the nature of the
“enduring changes” proposed by Semon. Guided
by Hebb’s influential theory on the critical
importance of synaptic plasticity (the increase
in synaptic strength between neurons) in mem-
ory [e.g., (21, 22)], Tonegawa and colleagues
showed that learning augmented synaptic
strength, specifically in engram cells. First, 1 day
after training, hippocampal DG granule en-
gram cells tagged during contextual fear con-
ditioning showed greater synaptic strength
[higher AMPA/NMDA ratio, which is a means
of assessing basal strength of excitatory synap-
ses by examining the relative expression of
amino-3-hydroxy-5-methyl-4-isoxazole pro-
pionic acid receptor (AMPAR)–mediated sy-
naptic currents to N-methyl-D-aspartate receptor
(NMDAR)–mediated synaptic currents of a
population of stimulated synapses (87)] and
increased spine density at entorhinal cortex
junctions than nonengram DG cells (71).

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Second, compared to nonengram CA3 cells, to examine overlap between neurons active at wave ripples), tending to co-occur with rhythmic
downstream CA3 engram cells were more contextual fear training and testing, Luo and firing of cortical neurons (termed spindles)
functionally connected with upstream DG en- colleagues (42) showed that retrieval of a re- (114). Disrupting either sharp-wave ripple–
gram cells (71). Moreover, Kaang and colleagues mote (14 day) contextual fear memory engaged spindle coupling (115, 116) or sharp-wave ripple–
showed that the number and sizes of spines more neurons in prelimbic cortex than retrieval associated replay of hippocampal place cells
on CA1 engram cells tagged during contex- of a recent (1 day) memory, suggesting that (104, 105, 117, 118) impairs memory recall. The
tual fear conditioning receiving input from an engram changes over time [consistent with precise role of these rhythmic oscillations with
CA3 engram cells was greater than on non- the findings of (100)]. Finally, a preliminary respect to engram cells is unclear. Sharp-wave
engram CA1 cells. This enhanced interregional study (99) mapped candidate engram ensem- ripples promote synaptic depression of CA1
connectivity between CA3 and CA1 engram bles representing a contextual fear condition- hippocampal neurons (119, 120). A recent study
cells correlated with memory strength and ing memory in 409 brain regions in mice. suggests that CA1 engram cells tagged during
occluded long-term potentiation (LTP), sug- Roy and colleagues tagged cells active at train- context exploration are more likely than non-
gesting a previous LTP-like phenomenon endo- ing and those active at recall throughout the engram neurons to participate in sharp-wave
genously occurred (88). Similarly, LA engram brain in the same mouse using a CLARITY- ripple events, perhaps allowing these engram
cells tagged during auditory fear conditioning like tissue-clearing technique (101) dubbed cells to escape this SWS-induced synaptic de-
showed enhanced synaptic connectivity with SHIELD (stabilization under harsh conditions pression (120). In this way, postencoding re-
presynaptic neurons (56, 89). Finally, shrink- via intramolecular epoxide linkages to prevent activation of engram cells during oscillatory
ing potentiated synapses in primary motor degradation) (102), thereby permitting the en- rhythms may help refine an engram by de-
cortex (M1) engram cells supporting a motor tire intact brain to be imaged at once. From creasing irrelevant “noise” of nonengram neu-
memory disrupted subsequent performance this activation data, these researchers devel- ronal activity during memory consolidation.
of this, and not a similar, motor memory (90). oped an “engram index” (defined as the degree
Together, these studies are beginning to inte- to which cells in a given brain region were Lifetime of an engram
grate previous research on synaptic plasticity active at memory encoding and retrieval) Birth of an engram
with engrams and suggest preferential en- that allowed the rank ordering of different
gram cell–to–engram cell connectivity is a crit- brain regions. Using optogenetic and chemo- Josselyn, Silva, and colleagues discovered that
ical part of the enduring changes to an engram genetic methods to interrogate the effects of during engram formation, eligible neurons
generated by learning. Overall these findings artificially activating regions with a high en- in a given brain region compete against each
suggest an update of Hebb’s axiom: Engram gram index, this study showed many of these other for allocation (or recruitment) to an en-
cells that fire together, wire together. engram ensembles are functionally connected gram. Neurons with relatively increased intrin-
and activated simultaneously by an experience. sic excitability win this allocation competition
Distributed engram ensembles These findings suggest that an experience is to become engram cells (58, 63, 66, 76, 77, 121–126)
represented in specifically connected multiple (Fig. 3). Competitive excitability-based alloca-
Although one specific brain region is often ex- engram ensembles distributed across multiple tion to an engram occurs in other brain re-
amined in engram studies, it is generally ap- brain regions and provide experimental sup- gions and supports different types of memories
preciated that an engram supporting a specific port for Semon’s “unified engram complex” [e.g., dorsal CA1 region of hippocampus (91–93)
experience may be widely distributed through- hypothesis. and prefrontal cortex (126) (for a contextual
out the brain. Engram cell ensembles in dif- fear memory), insular cortex (127) (conditioned
ferent brain regions may support distinct Engrams, place cells, and sleep taste-aversion memory), and retrosplenial cor-
aspects of an experience. For instance, in tex (128) (spatial memory)].
contextual fear memory, hippocampal (DG, Location-specific firing of CA1 place cells is
CA3, and CA1) engram cell ensembles may well established (103). Stable place cells may In addition to aversive memories, LA neu-
represent the context (40, 48, 91–93), whereas be important in engrams supporting spatial rons experimentally made more excitable during
amygdala engram cell ensembles may repre- or contextual memories (104–106). Recently, training were also preferentially allocated to
sent valence information (69, 71, 75), and cor- McHugh and colleagues (107) contrasted the an engram supporting a cocaine-cue reward-
tical engram cell ensembles may represent roles of CA1 place cells and engram cells in ing memory (66). Similarly, increasing the ex-
distinct sensory information (79, 94–96). memory. While mice explored a new context, citability of a small, random portion of piriform
engram cells were tagged and place cells iden- cortex principal neurons resulted in their allo-
Several studies have examined potential tified using tetrode recordings. Most tagged cation to an engram supporting either a re-
engram cell ensembles supporting contextual engram cells were also place cells, but the warding or an aversive olfactory memory,
fear memories across the brain (42, 97–99). majority of place cells were not tagged. Non- depending on the nature of the training ex-
For instance, Frankland and colleagues com- tagged place cells behaved like traditional perience (129). Excitability-based neuronal allo-
pared the brainwide (84 brain regions) dis- place cells (stable in the same context but re- cation is predicted by computational modeling
tribution of active cells after retrieval of recent mapping in a new context). By contrast, tagged (130–132), occurs endogenously (56, 89), and is
(1 day after training) versus remote (36 days place cells fired in a context-specific manner, consistent with previous research implicating
after training) contextual fear memory. On albeit with imprecise spatial information, and intrinsic excitability in the formation of inver-
the basis of coactivation, graph theory was were not active (did not remap) in a new con- tebrate memory traces (33, 133–135). Together,
used to construct functional connectome “mem- text. Therefore, engram cells may provide gen- these findings suggest that in some brain re-
ory maps” (97) and identify hub-like regions eral contextual information, with nontagged gions, at any given time, a small portion of
hypothesized to play privileged roles in mem- place cells providing precise spatial information. eligible neurons are “primed” to become part
ory retrieval. Subsequent chemogenetic in- of an engram (should an experience occur),
hibition confirmed that these identified hub Postencoding reactivation or replay of hip- regardless of experience valence.
regions were necessary for subsequent mem- pocampal place cell firing, especially during
ory retrieval (98). Using a combination of slow-wave sleep (SWS) (108, 109), is thought Although stable place cells and engram cells
engram tagging technology [targeted recom- to be important for memory consolidation in dorsal CA1 of the hippocampus differ (107),
bination in active populations 2 (TRAP2) trans- (110–113). During SWS, hippocampal neurons some mechanisms underlying their formation
genic mice] and IEG immunohistochemistry fire in an oscillatory rhythm (termed sharp- may be shared. In a given environment, only
a small subset of CA1 neurons are place cells,

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Fig. 3. Neuronal allocation to an engram. Eligible neurons compete for allocation to an engram size (89, 122) [for review, see (146)]. Rather, a
supporting a memory, and neurons with increased relative excitability at the time of training “win” stronger memory engages a greater number
this competition for allocation. (A) Neurons that were endogenously more excitable than their of synapses between engram cells (88).
neighbors at the time of training or were experimentally manipulated to become relatively more excitable
(blue circles) are preferentially allocated to an engram (green filled circles). Subsequent disruption Several lines of evidence suggest that one
of these allocated or engram neurons disrupts memory retrieval (top right), whereas artificial mechanism constraining engram size involves
reactivation of these neurons elicits memory retrieval in the absence of normal sensory retrieval inhibitory neurons. Thus, inhibiting parvalbumin-
cues (bottom right). (B) Neurons with relatively decreased excitability at the time of training (either containing interneurons in the basolateral
endogenously or through experimental manipulation) (purple circles) are preferentially excluded amygdala complex increased the size of an
from the engram (green filled circles). Subsequent disruption of nonallocated or nonengram neurons engram in the LA supporting an auditory
does not impact memory retrieval. fear memory through a process involving di-
synaptic inhibition (145), in which an excitatory
because the majority of CA1 neurons are silent persist. Both allocation and selective stabiliza- neuron inhibits another excitatory neuron via
(136). Those neurons with relatively higher ex- tion resonate with the conceptual framework an intervening inhibitory neuron. Moreover,
citability immediately before placement in a of Darwinian competition. inhibiting somatostatin-containing interneu-
novel environment are more likely to become rons increased the size of a DG contextual fear
place cells in that environment (137–139), and Observational and tagging experimental stud- memory engram through a lateral-inhibition
experimentally increasing the excitability of ies agree with computational theories [e.g., like process (147). The importance of inhibitory
an initially silent cell biased this cell toward (144)] that an engram is sparsely encoded. neurons in engrams has also been highlighted
becoming a place cell (140, 141). That is, not all neurons within a given brain in human studies. For instance, evidence sug-
region become an engram cell supporting a gests that in the cortex, associative memories are
It is interesting to note the similarities be- particular memory. The size of an engram represented in excitatory engrams and matched
tween data from current allocation studies and within a given brain region (that is, the num- (equal and opposite) inhibitory engrams. Mem-
the long-standing idea of selective stabilization ber of engram cells) is stable and invariant to ories are expressed upon disinhibition of the
(142, 143). Selective stabilization proposes memory strength. For instance, the size of an excitatory engram (148–150). Further explora-
that multiple prerepresentations are endog- LA engram (number of LA engram cells) is tion of excitatory-inhibitory balance in engram
enously generated in the brain and only one or similar for an auditory fear conditioned mem- formation, storage, and retrieval is necessary
a few that fit the situation are selected at any ory and a cocaine-cue memory (66, 122, 145), to understand how these opposing forces in-
given point of time to control behavior and/or and memory strength does not affect engram teract to support memory function.

Silent engrams in memory loss

Engrams may become damaged, such that a
memory becomes forever unavailable. How-
ever, engrams may also be temporarily inac-
cessible, such that the engram still exists but
cannot be retrieved by natural means. Silent
engrams, engrams that cannot be retrieved
by natural retrieval cues but can be retrieved
with direct optogenetic stimulation, were first
revealed in an experiment in which the pro-
tein synthesis inhibitor, anisomycin, was ad-
ministered immediately after contextual fear
conditioning in mice (71). Inhibiting protein
synthesis before or immediately after an ex-
perience is known to induce amnesia (151, 152)
and block cellular consolidation (153–155). Cel-
lular consolidation refers to the relatively fast
process of memory stabilization thought to
involve the expression of genes necessary to
strengthen synapses. By contrast, systems con-
solidation (discussed below) refers to the slower,
time-dependent reorganization of memories
over distributed brain circuits (156–159).

In this study, mice administered anisomy-
cin immediately after training showed little
freezing when replaced in the training con-
text 1 day later (71). Therefore, as expected,
disrupting protein synthesis induced retro-
grade amnesia by blocking cellular consolid-
ation. However, optogenetic reactivation of DG
engram neurons tagged during contextual fear
training was sufficient for memory recovery,
even 8 days after training (Fig. 4). These re-
sults indicate that the engram was formed and
persisted for several days but that this engram

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Non engram cell Silent engram cell Reactivated silent engram cell Active engram cell Reactivated active engram cell variant of an auditory fear conditioning task
in which the tone conditioned stimulus was
A Active Engram Silent Engram replaced by optogenetic activation of LA axon
terminals from neurons originating in the
In amnesia and early Alzheimer’s disease Natural recall Natural recall Artificial recall medial geniculate nucleus and auditory cor-
Context A Context A (ChR2 + blue laser) tex. Immediately after conditioning, long-term
depression (LTD)–like optogenetic stimula-
Context B tion was administered. LTD is thought to
weaken synaptic efficacy and decrease spine
Spine density Spine density Spine density density (162–165). Consistent with the inter-
HIGH LOW LOW pretation that LTD-like stimulation silenced
the engram, this opto-LTD stimulation im-
Freezing No Freezing Freezing paired subsequent memory recall. However,
Recent natural recall Remote natural recall LTP-like optogenetic stimulation allowed the
B Basal level memory to be retrieved (consistent with the
interpretation that the engram was “unsi-
Hippocampus CFC Dematuration lenced”). Again, subsequent LTD-like opto-
Dox(-) genetic stimulation silenced this memory,
whereas LTP-like optogenetic stimulation al-
During Systems Consolidation Spine density: HIGH Spine density: LOW lowed recovery of this memory.

mPFC CFC Maturation These findings raise the question of whether
Dox(-) engrams (and the memories they support) in
other amnesic conditions are truly “lost” or are
No Freezing Spine density: LOW Spine density: HIGH simply inaccessible such that they cannot be
Freezing Freezing retrieved under natural conditions. Silent en-
grams were reactivated by artificially stim-
Fig. 4. Active and silent engram cells in amnesia and during memory systems consolidation. ulating engram cells in amnestic mice used to
(A) Active engram cells have higher spine density and are activated in the conditioned context A to study the early stages of Alzheimer’s disease
produce the conditioned response, freezing. Silent engram cells generated in amnesia and in a mouse designed (AD) (166, 167). These transgenic mice [APP/
to model early Alzheimer’s disease show lower spine density and cannot be activated in the conditioned PS1 mice containing human transgenes with
context A to produce a conditioned response but can be activated by blue light in an unconditioned context B if the familial AD mutation in both amyloid pre-
they were tagged with ChR2 during encoding. (B) During memory systems consolidation, active engram cursor protein (APP) and presenilin 1 (PSEN1)]
cells with high spine density are formed in the hippocampus during contextual fear conditioning and for several showed contextual fear memory deficits (166).
days, the conditioned context can evoke a conditioned response. However, by two weeks (remote recall), However, optogenetic reactivation of ChR2-
these hippocampal engram cells demature to become silent, with reduced spine density. In the mPFC, engram labeled DG engram cells induced robust freez-
cells are formed during CFC but are silent with low spine density. During the following 2 weeks, these mPFC ing comparable to control mice (166). Consistent
silent engram cells acquire higher spine density and become active engram cells. with other examples of silent engram cells,
DG engram cells in these mice used to study
could not be retrieved by natural means. Silent structural plasticity within engram cells. Con- AD showed decreased spine density. However,
DG engram cells showed weaker physiological sistent with this, genetic restoration of spine LTP-like optogenetic stimulation at entorhinal
(increased synaptic strength) and structural density [targeted overexpression of p-21 acti- cortex engram cell inputs onto DG engram
(increased dendritic spine density) alterations vated kinase (PAK 1)] also allowed a silent en- cells restored not only spine density in DG en-
than normal engram cells (in control mice), gram to be reactivated and memory expressed gram cells but also the ability of natural re-
suggesting that a silent engram may be the by natural retrieval cues (160). trieval cues to elicit memory retrieval (thereby
result of disrupting the synaptic strengthening unsilencing the engram) (166). These findings
normally induced by training. That optoge- The idea that engrams may be silenced by in mice are consistent with reports that mem-
netic activation of DG engram cells was able disrupting synaptic efficacy and spine den- ory retrieval in people with early-stage AD
to induce memory retrieval suggests that di- sity and reawakened by enhancing synaptic may be enhanced by particular retrieval cues
rect optogenetic activation was able to cir- plasticity is consistent with findings from a (168, 169). Therefore, under certain conditions,
cumvent this requirement for synaptic and nonengram study examining auditory fear a previously inaccessible memory may be re-
conditioning (161). Rats were trained in a trieved in human AD, consistent with the in-
terpretation that some engrams in early-AD
brains may be silent rather than lost.

Apart from clinical implications, the finding
of silent engrams is relevant to discussions
on the role of protein synthesis–dependent
cellular consolidation in terms of memory stor-
age versus retrieval. There has been persistent
debate on this issue (170–173). The majority
of neuroscientists examining cellular memory
consolidation may favor the view that disrupt-
ing protein synthesis disrupts memory storage.
However, in many amnesia experiments, mem-
ory storage is conflated with memory retrieval.

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The finding that optogenetically stimulating a LA neurons, that is, the reversal of synaptic DG neurons active during training remains an
silent engram in an otherwise amnestic mouse, potentiation induced by fear conditioning open question (40, 51).
even 1 week after training, induces memory re- (179, 180). Moreover, after fear conditioning,
trieval challenges the view that protein synthesis– LTD-like electrical stimulation of external cap- Finally, a recent study examined fear ex-
dependent cellular consolidation is important sule inputs to the LA induces synaptic depot- tinction engrams in the amygdala and found
for memory storage. Instead, these findings entiation and decreases fear behavior (181), that extinction engram cells were formed
suggest that the role of cellular consolidation resembling both extinction and engram silenc- in a genetically distinct and “reward-responsive”
is to enhance subsequent retrievability of an ing. Finally, shortly after extinction training, subpopulation of basal amygdala neurons.
engram, consistent with the idea of engram the chemogenetic artificial activation of cells These fear extinction engram cells suppressed
“retrieval handles” that are established after tagged brainwide during context fear training the fear engram neurons that were also present
memory formation and may be remodeled (the putative fear engram) was reported to in- in basal amygdala and, furthermore, induced
after memory retrieval (1). Importantly, silent crease freezing levels (182), suggesting that the appetitive behavior when optogenetically stim-
engrams are consistent with the pioneering original fear engram was silenced during ex- ulated (195). These findings in mice are con-
cognitive psychologist Endel Tulving’s (174) tinction. The similarities between engram sistent with the results of a recent study in
conceptual distinction between memory avail- silencing and extinction are consistent with fruit flies (26) and highlight the similarities
ability and accessibility, in which memory fail- theoretical views that during extinction, the between fear extinction and reward processes
ure may reflect the absence of the information conditioned stimulus–unconditioned stimulus across species. Moreover, these results are
or difficulties accessing the information [see contingency is “unlearned” (183, 184). consistent with the general idea of competi-
(175) for review]. tion between memory traces in the control
However, other accounts stress that extinc- of behavior.
Silent engrams in normal memory tion does not reflect unlearning the original
association (perhaps by silencing the original Silent engrams and time
Memory may change with time and circum- engram) but rather reflects learning a new
stance. Might these changes in memory be “conditioned stimulus–no unconditioned stim- The representation of a memory in the brain
mediated by endogenous engram silencing? ulus” association (185, 186) with a correspond- may change with time. For instance, dorsal
This was explored in a social discrimination ing new extinction engram. That the original hippocampal lesions in rodents disrupt ex-
task in which mice interact more with a new, memory is not “erased” by extinction is sug- pression of contextual fear memories in the
rather than a familiar, mouse. This social dis- gested by findings that after extinction train- days, but not weeks after training (196–198).
crimination memory lasts roughly an hour ing, the conditioned response may return if At more remote times, cortical areas, includ-
after exposure to a familiar mouse (the train- the conditioned stimulus is presented (i) in a ing anterior cingulate cortex or medial pre-
ing experience) and is absent 24 hours after new nonextinction context (renewal), (ii) after frontal cortex (mPFC), become preferentially
training (176). The dorsal CA2 to ventral CA1 a stressor (reinstatement), or (iii) after the pas- engaged (100). The time-dependent reorgan-
(vCA1) hippocampal circuit plays a pivotal role sage of time (spontaneous recovery) (187–192). ization of memory reflects systems consoli-
in social discrimination (177), with a vCA1 en- A recent study concluded that contextual fear dation, a process that typically refers to initially
gram representing the familiar mouse (178). extinction may be supported by a novel fear hippocampal-based episodic-like memories
Consistent with the time course of social dis- extinction engram in the DG that is distinct (158, 159). Systems consolidation was recently
crimination memory, the familiar mouse en- from and suppresses the contextual fear DG examined at the level of the engram in the
gram in vCA1 becomes silent an hour after engram with a time course that corresponds hippocampus and mPFC, where findings in-
training. However, artificially reactivating this to the emergence of spontaneous recovery dicate time-dependent silencing of active en-
engram 24 hours after training (when the (53). In this experiment, spontaneous recovery grams and conversions of silent engrams to
social discrimination memory normally has was observed remotely (29 days), but not re- active engrams (51, 199). During contextual
dissipated) reinstates social discrimination cently (6 days), after extinction training. More- fear conditioning, active mPFC neurons were
memory, as if the trained-but-forgotten famil- over, the original fear engram was reactivated labeled to express ChR2. When placed in the
iar mouse is being remembered. Besides arti- at the remote, but not recent, memory test conditioning context, mice showed robust
ficial engram reactivation, the accessibility after extinction training. The opposite pat- freezing when tested either 2 days or 13 days
of vCA1 engram (and social discrimination tern of results was observed for active cells after training. However, the engram ensemble
memory) is prolonged by interventions such tagged after extinction training (the presumed components supporting memory retrieval
as group housing. These findings provide a fear extinction engram). Interestingly, artifi- differed with test time. Tagged mPFC neurons
hint that engram silencing may be one way in cial reactivation of the fear extinction engram were reactivated 13 days, but not 2 days, after
which the brain normally regulates mnemonic prevented spontaneous recovery of the origi- training, suggesting that the mPFC engram
processes. nal fear memory, even at remote times. These was silent shortly after training but active after
results suggest that the original fear engram longer delays. DG engram cells showed an
Additional evidence comes from memory ex- and the extinction engram compete for con- opposite pattern; DG engram cells were reac-
tinction studies. After conditioning, repeated trol over behavior; the extinction engram first tivated shortly after training but silenced more
presentation of the conditioned stimuli alone suppressed or silenced the original fear engram, remotely. Similar to other instances of silent
(in the absence of the unconditioned stimulus) but, with time, the fear extinction engram was engrams discussed above, the mPFC engram
produces a gradual decrease of the condi- itself silenced. Conversely, activation of a re- cells shortly after training and the DG engram
tioned response (82)—a phenomenon called mote DG contextual fear engram (labeled cells at longer delays after training showed re-
extinction. Therefore, after extinction training, 25 days after contextual fear conditioning) duced spine density, and, furthermore, opto-
the ability of the conditioned stimulus to in- itself may also be important for subsequent genetic activation of these silent engrams was
duce memory retrieval is diminished, an out- fear memory extinction (52), perhaps sim- sufficient to induce memory retrieval. Inter-
come that is similar phenomenologically to ilar to a process referred to as reconsolidation- estingly, posttraining tetanus toxin–induced
engram silencing. Might engram silencing ac- updating (193, 194). However, the extent to inhibition of the input from DG engram cells
count for extinction? Consistent with this which DG neurons that were activated 25 days to mPFC engram cells blocked the maturation
general idea, some auditory fear extinction after contextual fear conditioning overlap with of the silent mPFC engram cells to an accessible
protocols induce synaptic depotentiation of state, suggesting coordinated network function

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RESEARCH | REVIEW

between different engram ensemble components autophagy made the engram unavailable rather ilar memories (two fear memories or two
is important in systems consolidation. than simply inaccessible. contextual memories), two aversive, but oth-
erwise dissimilar memories (a conditioned
Memories may also become less precise and From engrams to knowledge fear and a conditioned taste aversion mem-
more generalized with time (200–202). Ac- ory), were integrated by repeated coretrieval
cording to memory transformation theory, Thus far, we have discussed engrams support- of these memories (220). Overall, these data
changes in the nature and quality of memories ing a single memory. Of course, animals (in- from rodent experiments agree with results
correspond to changes in neural representa- cluding humans) learn and remember many from human memory experiments showing
tions, with hippocampal-dependent context- things. Some of these experiences may be best that the representations of memories for events
specific detailed memories transforming into remembered as distinct episodes, rich with epi- experienced close in time or with related con-
gist-like schematic memories represented in sodic details (207–209). However, in other cir- tent overlap may be integrated or linked, thus
cortical structures over time (201, 203, 204). cumstances, it may be advantageous to link enabling generalization and flexible use of this
The neural processes governing remote mem- related experiences, thereby creating a gen- shared information [e.g., (212, 221–224)].
ory generalization at the engram level suggest eral concept or principle (210–214). This raises
that the availability of the DG engram is crit- the question of how engrams representing Memory retrieval also transiently reactivates
ical for memory specificity (205). In this experi- different experiences interact. The mecha- engram cells (89, 215, 219). This increase in
ment, shortly after contextual fear conditioning nisms governing neuronal allocation to an excitability both enhances the precision and
(1 day), mice froze in the training context only, engram supporting a single experience also efficiency of memory retrieval (219) and opens
whereas at more remote time points (16 days serve to either coallocate neurons to overlap- a new “coallocation window” (215), perhaps
after training), mice also froze in a nonshocked ping engrams (thereby linking experiences) explaining how new information is integrated
context. This finding is consistent with previous or disallocate neurons to nonoverlapping en- into preexisting knowledge.
reports of contextual fear memory generalizing grams (thereby disambiguating experiences)
over time (51, 201). At the recent, but not re- (121, 215–217) (Fig. 5). In this way, relative Conclusions and perspectives
mote, time, DG engram cells showed greater neuronal excitability is critical not only for
connectivity to parvalbumin-expressing CA3 initial engram formation but also in organiz- Overall, these studies provide persuasive evi-
basket cells (thereby inhibiting CA3 pyramidal ing different memory representations across dence for the existence of engrams in rodent
neurons through feedforward inhibition) than the brain. brains. We agree with Endel Tulving who
nonengram DG cells, suggesting that greater stated “As a scientist I am compelled to the
feedforward inhibition in DG-CA3 circuits helps Neurons that are relatively more excitable conclusion—not postulation, not assumption,
maintain memory precision. Interestingly, opto- than their neighbors at the time of an exper- but conclusion—that there must exist certain
genetic activation of DG engram cells 10 days ience are more likely to be allocated to the physical-chemical changes in the nervous tissue
after training did not induce memory retrieval engram supporting the memory of that ex- that correspond to the storage of informa-
(suggesting that this engram had become un- perience (121). Increased excitability in engram tion, or to the engram, changes that constitute
available), except if feedforward inhibition of cells is also maintained for several hours after the necessary conditions of remembering. (The
CA3 pyramidal neurons was genetically en- an experience (215, 218, 219). Therefore, if a alternative stance, that it may be possible for
hanced. Moreover, mice with genetically en- related experience occurs in this time win- any behavior or any thought to occur indepen-
hanced feedforward inhibition also showed dow, these same (or overlapping) engram dently of physical changes in the nervous sys-
precise memory, even when tested at more cells are more excitable than their neighbors tem, as all your good readers know, is sheer
remote times. Together, these data suggest that and thus coallocated to the engram support- mysticism)” (225). The findings from many labs
enhanced feedforward inhibition onto CA3 ing the memory of the second experience. using different methods to examine many types
neurons maintains DG engram cell availability Because the memories of the two experiences of memory converge to support the idea that
and delays the loss of context specificity asso- are coallocated to overlapping engram cells, complex information may not be represented
ciated with remote memories. these two memories become linked (or inte- in single cells [e.g., a “grandmother cell”
grated); thinking of one experience automat- (226, 227)]; instead, these findings suggest
These findings suggest that engram silenc- ically makes one think of the second. For that the basic unit of computation in the brain
ing may represent a continuum of a natural example, LA neurons allocated to one fear is an engram (228, 229).
state of an engram. That is, an engram may be memory were coallocated to a second fear
(i) unavailable (neither natural conditioned memory if the second event occurred minutes To understand a complex, multilayered sys-
stimuli nor artificial reactivation induces to hours (30 min to 6 hours), but not 24 hours, tem such as the brain, it is crucial to causally
memory expression), (ii) silenced (only arti- after the first (215). This linking occurred even link a process or phenomenon occurring at a
ficial reactivation is sufficient to induce mem- if the conditioned stimuli used in the two lower level of complexity to those at higher
ory expression), (iii) dormant or latent, as training sessions were of different modalities levels. Traditionally, such studies have been
initially named by Semon (natural condi- (e.g., a light and a tone or a context and a carried out using interventions such as tissue
tioned stimuli may induce memory retriev- tone). Similarly, coallocation of CA1 engram lesion or pharmacological disruption. Many
al), or (iv) active (currently being retrieved). cells supporting memories of two distinct of the studies discussed in this review took
Different processes may mediate these distinct contexts was observed if exposure to the con- advantage of state-of-the-art intervention
engram states. For example, similar to silenc- texts was separated by a short time interval techniques and their combinations, includ-
ing a DG engram, posttraining anisomycin (216). Behaviorally extinguishing one memory ing temporally inducible targeted transgenics
administration silenced an LA engram sup- produced extinction for the second mem- and optogenetics, that may generally per-
porting an auditory fear memory (79). How- ory, even though the second memory was mit the identification of more precise cause-
ever, if in addition to anisomycin, a peptide not behaviorally extinguished, indicating that consequence relationships. Nevertheless, even
to induce autophagy (a mechanism of pro- the two memories were functionally linked advanced interventions inevitably artificially
tein degradation) was administered after (215). Coallocated memories may maintain manipulate the brain and therefore provide in-
training, then optogenetic reactivation of in- their distinct identity by engaging specific formation as to what an engram can do, but not
puts to the LA was no longer sufficient to in- synapses within shared engram cells (79). necessarily what it does do (physiologically).
duce memory retrieval (206), suggesting that Moreover, in addition to integrating two sim- This point has been articulated in several other
reviews on memory research [e.g., (230)].

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RESEARCH | REVIEW

Fig. 5. Neuronal allocation and memory linking. Neurons with increased excitability at the time of event signed to study the memory deficits of AD
1 (blue) are allocated to the engram supporting this memory (blue filled circles outlined in orange). hint at the extraordinary translational po-
These allocated engram neurons remain more excitable than their neighbors for several hours after event 1. If tential of this line of research.
a similar event 2 (green) occurs during this time, neurons allocated to the engram supporting event 1 are
more excitable and, therefore, also allocated to the engram supporting event 2 (blue and green filled circles Some additional general themes emerge
outlined in orange). In this way, neurons are coallocated to events 1 and 2. By virtue of coallocation, these from the results of engram studies. The first
two memories become linked. After some time, neurons allocated to the engram supporting event 1 become theme is that findings from engram studies
less excitable than their neighbors (“refractory”), and if event 2 occurs in this time window, a new population are reminiscent of reconsolidation studies.
of more excitable neurons wins the competition for allocation to the engram supporting event 2. This Upon retrieval, a memory may enter a labile
disallocation allows the two memories to be remembered separately. Circles with red dashed outlines represent and modifiable state that lasts for several
less excitable neurons. hours. The process of restabilizing this mem-
ory is referred to as reconsolidation. Although
However, the results of these intervention memory, memory systems consolidation, and reconsolidation has a longer history (234), the
studies provide direction as to which processes perhaps fear extinction training) silences en- modern reawakening of this phenomenon
we should focus our efforts to understand how grams such that they can no longer be ac- stems from a finding by Nader, LeDoux, and
the brain actually forms and retrieves mem- cessed by normal sensory cues. However, these Schafe (235). At the time that this ground-
ory. Furthermore, the high specificity of the studies show that silent engrams still exist in breaking study was conducted, the general
state-of-the-art intervention methods, spanning the brain and that the information they rep- thinking was that memories become stabi-
from the molecular level up to the behavioral resent may not be forever lost. The pioneering lized in a process of cellular consolidation that
level, have already revealed mechanisms that psychologist and behaviorist Edward Tolman occurs once, shortly after a learning experi-
would have been difficult to study using other (231) advanced the concept of latent learning ence. However, Nader, LeDoux, and Schafe
techniques. For instance, these artificial inter- and latent memory: learning that occurs with- challenged this view by showing that memory
vention studies allowed the field to identify out reinforcement, the memory of which is not retrieval opens a several-hour “reconsolidation
the silent state of an engram and the mech- revealed or expressed until the need or mo- window” during which different interventions
anism underlying memory allocation. tivation for the acquired knowledge arises may weaken or strengthen the original mem-
(232, 233). It would be interesting to deter- ory. For instance, disrupting protein synthesis
More than 100 years ago, Semon put forth a mine whether at least some latent memories during the reconsolidation window of a condi-
law of engraphy. Combining these theoretical are based on silent engrams and, if so, use the tioned fear memory produced apparent am-
ideas with the new tools that allow researchers conversion of silent engram to active engram as nesia for this memory. This result was replicated
to image and manipulate engrams at the level a means of identifying and characterizing the and generalized to several types of memory
of cell ensembles facilitated many important brain circuits mediating the relevant motivation. (156, 236, 237). There are many similarities
insights into memory function. For instance, between this reconsolidation blockade and
evidence indicates that both increased intrin- A continuum of engram accessibility states engram silencing. For instance, reconsolidation
sic excitability and synaptic plasticity work may exist. Engrams may be entirely unavail- blockade is only observed when a memory is
hand in hand to form engrams and that these able and not retrievable, even through artifi- being actively retrieved, because administer-
processes may also be important in memory cial means (the memory would be forgotten). ing anisomycin (or another similar interven-
linking, memory retrieval, and memory con- Or, engrams may be silenced such that mem- tion) in the absence of memory reactivation
solidation. Interestingly, disrupting synaptic ories may be retrieved by artificially reactivat- does not impair its subsequent retrieval. Viewed
plasticity in engram cells either by disease ing engram cells. The processes that silence or from an “engram conceptual framework,” re-
processes (as in mice used to study AD) or erase an engram, as well as strategies for un- trieval of a specific memory would activate the
amnestic drugs (such as protein synthesis in- silencing engrams, are a subject for further underlying engram, and disrupting protein syn-
hibitors) or during some natural behaviors investigation. That it was possible to arti- thesis shortly after this activation might silence
(housing condition in social discrimination ficially reactivate silent engrams in mice de- this engram. The function of reconsolidation
may be to update a memory (1, 211, 238–240).
That the reconsolidation window is not unlike
the coallocation window suggests that these
two processes might be similar ways of ex-
plaining the same (or similar) phenomenon
at different levels of analysis.

A second emerging theme is that of com-
petition. Allocation to an engram involves
competition between eligible neurons within
a given brain region at the time of memory
encoding. Competition represents a funda-
mental property of many biological systems
and has been previously shown to be im-
portant in other mnemonic phenomena. For
instance, memory traces may compete for con-
trol of behavior at the time of retrieval (241).
In addition, human studies reveal that mem-
ories may compete if they are linked to a
common retrieval cue. Retrieval of a target
memory may lead to retrieval-induced for-
getting of currently irrelevant competing mem-
ories (242).

Josselyn et al., Science 367, eaaw4325 (2020) 3 January 2020 10 of 14