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744 14 AUGUST 2020 • VOL 369 ISSUE 6505 sciencemag.org SCIENCE

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14 AUGUST 2020 • VOLUME 369 • ISSUE 6505

CONTENTS

INSIGHTS

POLICY FORUM

766 Distorting science,
putting water at risk
A recent rule is inconsistent with science
and will compromise the integrity
of U.S. waters By S. M. P. Sullivan et al.

PERSPECTIVES

769 Can playing together help
us live together?
A field experiment in Iraq shows that
having Muslim teammates reduced
Christian soccer players’ prejudice
By E. L. Paluck and C. S. Clark

REPORT p. 866

770 Marine food webs destabilized
A combination of warming and

acidification threaten marine biomass

and productivity By S. L. Chown

REPORT p. 829

771 An early start to Huntington’s disease
The huntingtin gene mutation interferes

with neurogenesis in human fetal cortex

By M. DiFiglia

RESEARCH ARTICLE p. 787

773 Designing a wider superelastic window
Adding chromium to an iron alloy enables

shape recovery over a wide temperature range

By P. La Roca and M. Sade

REPORT p. 855

774 The importins of pain
A nuclear protein importer modulates gene

expression to control the persistence of

neuropathic pain By M. S. Yousuf and T. J. Price

REPORT p. 842

775 A coexistence that CuO2
planes can see
Antiferromagnetism and superconductivity

are not at odds in a quintuple-layer cuprate

By I. Vishik

REPORT p. 833

777 Michael Soulé (1936–2020)
Founder of conservation biology

By D. W. Inouye and P. R. Ehrlich

756

NEWS

IN BRIEF

750 News at a glance

IN DEPTH

752 Antibodies may curb pandemic
before vaccines
Now in efficacy trials, monoclonal antibodies
promise to both prevent and treat disease
By J. Cohen

753 For science in Latin America,
‘a fascinating challenge’
Pandemic shows benefits of investments in
research but also poses grave threats
By R. Pérez Ortega and L. Wessel

755 Looking for the light in Haiti
For physician Marie Marcelle Deschamps,
COVID-19 is just the latest challenge By R. Bazell

756 Africa’s pandemic puzzle: why so
few cases and deaths?
Antibody surveys tell a different story than
official tolls By L. Nordling

757 Fed-up archaeologists aim to fix field
schools’ party culture
Drinking and harassment spur experiments,
including local projects and student stipends,
for core training course By L. Wade

758 Don’t crush that ant—it could
plant a wildflower
New findings show how ants choose and

protect the seeds they disperse

By E. Pennisi

FEATURES

760 Lucky strike
Last year, an unusual meteorite crashed in a

Costa Rican rainforest. Rich in the building

blocks of life, it has captivated collectors and

researchers By J. Sokol

Published by AAAS

Page 74

of its C15–C16 olefin. Wolff–Kishner reduction
delivered 44, which has the appropriate func-
tionalities to be converted to the diterpenoid
alkaloid cochleareine (6).

Chemoenzymatic synthesis of
the mitrephorones

Intermediate 40 could be used to divergently
prepare mitrephorones A, B, and C (7, 49, 8)
(Fig. 5C). In accord with its structural sim-
ilarity to 9 or 13, C2 oxidation of 40 with
BM3 MERO1 M177A proceeded very effici-
ently. At high enough enzyme-to-substrate
ratio, this process also led to iterative oxidation
to install a ketone moiety at C2. Enzymatic
oxidation with PtmO6, followed by PDC
oxidation, furnished diketone 45. As is the
case with fujenoic acid (27), PtmO6 was ca-
pable of installing C6-OH on 45. Intermediate
46 proved to be unstable, requiring rapid
methylation of the C19 acid and mild oxida-
tion at C6. Thus, the synthesis of mitrephor-
one C (8) was completed by methylation of
the C19 acid with CH2N2 and by further oxi-
dation at C6 with DMP, followed by keto-enol
tautomerization.
Synthesis of mitrephorone B (49) from 40

commenced by C7 enzymatic oxidation with
PtmO6. Initial attempts focused on the dehy-
dration of the C7-OH to the corresponding
olefin, followed by a ruthenium-catalyzed di-
rect oxidation (31) to install the C6–C7 dione
moiety. However, this sequence was found to
be low yielding and accompanied by forma-
tion of side-products, even at low conversion.
Moreover, this sequence provided no desired
product at all when the C2 carbon exists in the
ketone oxidation state (for the mitrephorone
C series). As a workaround, 40 was oxidized
to the corresponding ketone (48), enzymat-
ically hydroxylated at C6 with PtmO6, and
then methylated and oxidized with PDC. Al-
though this route led to one more step than the
dehydration and oxidation sequence, it pro-
vided a superior overall yield. According to
Magauer’s report (32), conversion of 49 to
mitrephorone A (7) could be achieved through
the use of electrochemical oxidation or White-
Chen catalyst. We found serendipitously that
49 is capable of undergoing a slow autoxi-
dation to form 7 (45% yield after 7 days or
65% yield after 14 days). Such autoxidation did
not take place with 8, suggesting that distal
substituents are capable of modulating the
reactivity of the diosphenol motif of 49. This
discovery allowed us to divergently prepare
the entire known family members of the mi-
trephorones from 40. The use of enzymatic
oxidations with PtmO5-RhFRed, PtmO6, and
BM3 MERO1 M177A proved to be highly en-
abling, as all three members of the family could
be prepared in less than 10 steps, a marked

improvement over previous routes to the
mitrephorones (32, 33).

Conclusion

Using this chemoenzymatic strategy, we pre-
pared nine highly oxidized ent-kaurane and
ent-trachylobane natural products in less than
10 steps each. Central to this strategy is the use
of three selective and scalable biocatalytic pro-
cesses that are able to hydroxylate the A, B,
and C rings of the parent carbocyclic struc-
tures with site selectivity and functional group
compatibility unmatched by any known small-
molecule reagents or catalysts. Leveraging the
newly introduced hydroxyl groups in a series
of carbocationic rearrangements enables rapid
traversal of the diterpene landscape span-
ning the ent-kaurane, ent-atisane, and ent-
trachylobane families. By virtue of the substrate
promiscuity of the enzymes, the biocatalytic
oxidations can also be carefully permuted
and used in conjunction with chemical C–H
oxidations in multistep synthetic sequences
for streamlined access to complex natural
products with minimal functional group in-
terconversions and protecting group manip-
ulations (34). The marriage of chemical and
enzymatic C–H oxidations, in particular, con-
stitutes a powerful means to streamline ac-
cess to highly oxidized terpenes and avoids
circuitous oxidative transformations, which
are at times necessary in the “two-phase”
strategy for terpene synthesis (35) owing to
the exclusive use of small-molecule reagents
or catalysts. The strategy outlined here not
only opens the door for rapid access to a wide
array of ent-kauranes, ent-atisanes, and ent-
trachylobanes but also provides a blueprint
for combining emerging synthetic paradigms
with biocatalysis in the preparation of pri-
vileged molecular scaffolds. Generalization
of this hybrid oxidative approach to other
complex terpene families can be readily en-
visioned by way of identifying and profiling
new oxygenases for site-selective modifications
of building blocks (36) or late-stage function-
alization (37). Finally, continued advancement
in enzyme engineering strategies (38) and
the development of new-to-nature transforma-
tions (39) will further expand the pool of
reactions available for use and ultimately
encourage broader adoption of this strategy
in multistep synthesis.

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ACKNOWLEDGMENTS

We thank P. S. Baran, R. A. Shenvi, T. J. Maimone, and K. M. Engle
for useful discussions. Funding: This work is supported, in part,
by the National Institutes of Health Grant GM134954 (B.S.),
GM128895 (H.R.), and GM124461 (J.D.R.). Author contributions:
X.Z. and H.R. conceived of the work. X.Z., E.K.-S., L.-B.D.,
L.-C.Y., and J.D.R. designed and executed experiments. B.S.
and H.R. provided insight and direction for experimental design.
Competing interests: PtmO3, PtmO5, and PtmO6 are gene
products of the platensimycin and platencin biosynthetic gene
cluster included in U.S. patent no. 8,652,838, for which B.S. is a
patent holder. Data and materials availability: All data are
available in the main text or the supplementary materials.

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/369/6505/799/suppl/DC1
Materials and Methods
Figs. S1 to S7
Tables S1 to S19
References (40–59)
MDAR Reproducibility Checklist
Spectral Data

20 March 2020; accepted 19 June 2020
10.1126/science.abb8271

Zhang et al., Science 369, 799–806 (2020) 14 August 2020 7 of 7

RESEARCH | RESEARCH ARTICLE

Page 75

CORONAVIRUS

DNA vaccine protection against SARS-CoV-2 in
rhesus macaques
Jingyou Yu1*, Lisa H. Tostanoski1*, Lauren Peter1*, Noe B. Mercado1*, Katherine McMahan1*,
Shant H. Mahrokhian1*, Joseph P. Nkolola1*, Jinyan Liu1*, Zhenfeng Li1*, Abishek Chandrashekar1*,
David R. Martinez2, Carolin Loos3, Caroline Atyeo3, Stephanie Fischinger3, John S. Burke3,
Matthew D. Slein3, Yuezhou Chen4, Adam Zuiani4, Felipe J. N. Lelis4, Meghan Travers4,
Shaghayegh Habibi4, Laurent Pessaint5, Alex Van Ry5, Kelvin Blade5, Renita Brown5, Anthony Cook5,
Brad Finneyfrock5, Alan Dodson5, Elyse Teow5, Jason Velasco5, Roland Zahn6, Frank Wegmann6,
Esther A. Bondzie1, Gabriel Dagotto1, Makda S. Gebre1, Xuan He1, Catherine Jacob-Dolan1,
Marinela Kirilova1, Nicole Kordana1, Zijin Lin1, Lori F. Maxfield1, Felix Nampanya1,
Ramya Nityanandam1, John D. Ventura1, Huahua Wan1, Yongfei Cai7, Bing Chen7,8,
Aaron G. Schmidt3,8, Duane R. Wesemann4,8, Ralph S. Baric2, Galit Alter3,8, Hanne Andersen5,
Mark G. Lewis5, Dan H. Barouch1,3,8†

The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical
priority. In this study, we developed a series of DNA vaccine candidates expressing different forms
of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated
animals developed humoral and cellular immune responses, including neutralizing antibody titers at
levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2.
After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the
full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in
bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham
controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting
an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2
in nonhuman primates.

T
he coronavirus disease 2019 (COVID-19)
pandemic has made the development of
a safe, effective, and deployable vaccine
to protect against infection with severe
acute respiratory syndrome coronavirus 2

(SARS-CoV-2) a critical global priority (1–8).
Our current understanding of immune cor-
relates of protection against SARS-CoV-2
is limited but will be essential to enable the
development of SARS-CoV-2 vaccines and

other immunotherapeutic interventions. To
facilitate the preclinical evaluation of vaccine
candidates, we recently developed a rhesus
macaque model of SARS-CoV-2 infection
(9). In the present study, we constructed a set
of prototype DNA vaccines expressing various
forms of the SARS-CoV-2 spike (S) protein
and assessed their immunogenicity and pro-
tective efficacy against SARS-CoV-2 viral chal-
lenge in rhesus macaques.

Construction and immunogenicity of DNA
vaccine candidates

We produced a series of prototype DNA vac-
cines expressing six variants of the SARS-CoV-2
S protein: (i) full length (S), (ii) deletion of the
cytoplasmic tail (S.dCT) (10), (iii) deletion of
the transmembrane domain and cytoplasmic
tail reflecting the soluble ectodomain (S.dTM)
(10), (iv) S1 domain with a foldon trimerization
tag (S1), (v) receptor-binding domain with a
foldon trimerization tag (RBD), and (vi) a
prefusion-stabilized soluble ectodomain with
deletion of the furin cleavage site, two proline
mutations, and a foldon trimerization tag
(S.dTM.PP) (11–13) (Fig. 1A). Western blot
analyses confirmed expression in cell lysates
for all constructs and in culture supernatants
for the soluble S.dTM and S.dTM.PP constructs
(Fig. 1, B and C). Proteolytic cleavage of the
secreted protein was noted for S.dTM but not
S.dTM.PP, presumably as a result of mutation
of the furin cleavage site in S.dTM.PP.
We immunized 35 adult rhesus macaques

(6 to 12 years old) with DNA vaccines in the
following groups: S (N = 4), S.dCT (N = 4),
S.dTM (N = 4), S1 (N = 4), RBD (N = 4), S.dTM.

RESEARCH

Yu et al., Science 369, 806–811 (2020) 14 August 2020 1 of 6

1Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 2Department of Epidemiology, University of North Carolina at Chapel Hill,
Chapel Hill, NC 27599, USA. 3Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. 4Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 5Bioqual, Rockville, MD
20852, USA. 6Janssen Vaccines & Prevention BV, Leiden, Netherlands. 7Children’s Hospital, Boston, MA 02115, USA. 8Massachusetts Consortium on Pathogen Readiness, Boston, MA 02215, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: [email protected]

Fig. 1. Construction of candidate DNA vaccines against SARS-
CoV-2. (A) Six DNA vaccines were produced expressing different
SARS-CoV-2 spike (S) variants: (i) full length (S), (ii) deletion of the
cytoplasmic tail (S.dCT), (iii) deletion of the transmembrane (TM)
domain and cytoplasmic tail (CT) reflecting the soluble
ectodomain (S.dTM), (iv) S1 domain with a foldon trimerization
tag (S1), (v) receptor-binding domain with a foldon trimerization tag
(RBD), and (vi) prefusion-stabilized soluble ectodomain with deletion
of the furin cleavage site, two proline mutations, and a foldon
trimerization tag (S.dTM.PP). Open squares depict foldon
trimerization tags; red lines depict proline mutations.
(B) Western blot analyses for expression from DNA vaccines
encoding S (lane 1), S.dCT (lane 2), S.dTM (lane 3), and S.dTM.
PP (lane 4) in cell lysates and culture supernatants using an
anti-SARS polyclonal antibody (BEI Resources). (C) Western blot
analyses for expression from DNA vaccines encoding S1 (lane 1)
and RBD (lane 2) in cell lysates using an anti–SARS-CoV-2 RBD
polyclonal antibody (Sino Biological).

Page 148

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H
angzhou Innovation Research Institute, Beihang University

is a new high-level research institute jointly established

by Beihang University, Zhejiang Province, Hangzhou City

and Binjiang District. With the mission of “building a world-

class technological innovation platform and innovative talent

training platform in the field of information”, and focusing on

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and health, cognitive science and new materials, Hangzhou In-

novation Research Institute actively explores new mechanisms

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The institute has been included inHangzhou “Prestigious Schools,

Universities, and Institutes” project, and has also been awarded the

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I. Open Positions

1. Principal Investigator

2. Senior research scientist, Senior Associate re-

search scientist

II. Research Areas

Computer science and technology, instrumentation

science and technology, optical engineering, elec-

tronic science and technology, control science and

engineering, material science and engineering, infor-

mation and communication engineering, mechanical

engineering, physics, mathematics, medical imaging

and other relatedmajors.

III. How to Apply

This announcement is long-term effective. For de-

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Please send your resume to [email protected]

(email: “intended position + name”)

Contact: Ms. Tian, Mr. Shi

TEL: +86-571-85367559 19957890995

Email: [email protected]

HANGZHOU INNOVATION

RESEARCH INSTITUTE,

BEIHANG UNIVERSITY

Job Vacancies in China's Universities and Institutes

Please visitwww.acabridge.edu.cn

Contact [email protected]
Scantocheckthesessions

2020 Global Online Job Fair (www.edu.cn/cv)

September 25, High-level Global Talents Recruitment

00:30-14:30 GMT (08:30-22:30 Beijing time)

October 16, High-level Global Talents Recruitment

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Qualification for Applicants

Global scholars, Doctor and Post-doctor, Doctoral Candidates

Key Disciplines

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Technology, Chemistry, Agriculture, Fisheries and Food Science, Law, Life

sciences, Mathematics, Medicine, Physics and Engineering, Psychology

Participating Universities

Beijing Jiaotong University, Harbin Engineering University, Hebei Univer-

sity of Technology, Zhengzhou University, National University of Defense

Technology, Northeastern University(continuously updating)

EVEN SEPARATED BY MOUNTAINS AND RIVERS, WE HAVE OUR BLOOD TIGHTLY CONNECTED

The Coronavirus pandemic has forcedmany of us to consider diferent ways of working and communicating. Chinese univer-

sities and colleges are now holding online job fairs to help overseas scholars explore career options in China.

Page 149

Two decades earlier, I had left my

postdoc—and research—when my

husband landed a tenure-track

job at a small liberal arts college

in a different state. A few years

after our move, I was thrilled

when an opportunity arose for

me to teach at the college. When

people asked whether I missed re-

search, my pat response was that

I was happy with my job. But that

wasn’t the full truth. I always felt

an unpleasant pit in my stomach

while celebrating my husband’s

grants and publication successes,

sad that I couldn’t claim the same

achievements. And twinges of re-

gret gnawed at me when students

in my classes asked whether they

could join my research lab and I

had to tell them no—I didn’t do

research anymore.

A few years ago, those twinges

grew stronger when a pair of tal-

ented students wanted to continue work they had started

as an independent research project in one of my lab classes.

I would have loved to work with these motivated students

after the semester ended. Maybe it was time to explore

whether that was possible.

I had always claimed I didn’t have a research program

because I wasn’t a tenure-track professor, but was that re-

ally the barrier? Was it just easier to blame my status than

to try to get a lab up and running? Was fear of failure

holding me back?

Over the following months, the risks of not starting up

research—boredom, depression, regret—began to outweigh

the risk of trying and failing. I decided to give it a go.

When I reached out to the chair of the department,

he said he would support my plan as long as I was men-

toring students. Colleagues offered to share equipment,

expertise, and space. I had enough money in a college-

provided development fund to buy a few reagents. As for a

research question, while teaching in the introductory lab

I had learned that the worm Lumbriculus variegatus was

inexpensive to work with, and it

offered plenty of interesting ave-

nues for investigation. I was ready

to go.

In June of 2019, I nervously

started to mentor my first group of

research students, worried that my

skills would be rusty or, worse, obso-

lete. Indeed, some bread-and-butter

techniques from my past were no

longer relevant. But I found that

the core process of scientific in-

quiry—asking questions, designing

experiments, interpreting data—

hadn’t changed. And my trouble-

shooting skills quickly kicked in.

Our first western blot looked like a

Rorschach test, but after weeks of

fine-tuning, we had an interpreta-

ble blot—reason for a minor cele-

bration. By the end of the summer,

we had generated enough data to

put together a poster to present at

a conference in January. I left that

meeting feeling optimistic and energized about the future,

wondering why I had waited so long to return to research.

Just 3 months after the conference my research was

interrupted again—frustrating, to say the least. But despite

the COVID-19 restrictions, I have found ways to carry on. I

am currently collaborating remotely with a student who was

slated for full-time lab research this summer. We hatched a

plan: He designs experiments, and I do the hands-on work.

From there, he interprets the data and plans the next steps.

It’s not ideal, but we are making progress.

Even in normal circumstances, research is hard. This

summer, our results have been confusing, and at times I

have felt like throwing in the towel. But I remember how

much I enjoyed the summer of 2019, and that I chose this

path. If I could overcome my fears and return to research

after a 22-year break, I won’t let a slowdown stop me now. j

Kathy Gillen is an assistant professor of biology at Kenyon College

in Gambier, Ohio. Do you have an interesting career story to share?

Send it to [email protected]

“If I could … return to research
after a 22-year break, I won’t let

a slowdown stop me now.”

Interrupted—again

T
he two emails arrived the same early April day. One informed me that I had secured a $3000 grant.

Although the dollar value was small, it was a big step toward restarting my research career after

a 22-year hiatus. The second email announced that my college had canceled in-person student

research for the coming summer because of COVID-19. My newly relaunched research program

had abruptly crashed back to Earth.

By Kathy Gillen

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874 14 AUGUST 2020 • VOL 369 ISSUE 6505 sciencemag.org SCIENCE

WO R K I N G L I F E

Published by AAAS

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