The NEW ENGLA ND JOURNAL of MEDICINEPerspective
June 22, 2023

The Origins of Covid-19 — Why It Matters(and Why It Doesn’t)
Lawrence O. Gostin, J.D., and Gigi K. Gronvall, Ph.D.​​The Origins of Covid-19

W

hen health emergencies arise, scientists
seek to discover the cause — such as
how a pathogen emerged and spread— because this knowledge can enhance our understanding of risks and strategies
for prevention, preparedness, andmitigation. Yet well into thefourth year of the Covid-19 pandemic, intense political and scientific debates about its origins
continue. The two major hypotheses are a natural zoonotic spillover, most likely occurring at theHuanan Seafood Wholesale Market, and a laboratory leak fromthe Wuhan Institute of Virology(WIV). It is worth examining theefforts to discover the origins ofSARS-CoV-2, the political obstacles, and what the evidence tells
us. This evidence can help clarify
the virus’s evolutionary path. But
regardless of the origins of thevirus, there are steps the global
community can take to reduce
future pandemic threats.
The origins story dates backto December 31, 2019, when theWorld Health Organization (WHO)learned of a cluster of cases ofpneumonia of unknown cause inWuhan (see timeline). Wuhan authorities closed the Huanan market the next day, rendering live
animals unavailable for testing.
China publicly shared the SARSCoV-2 genetic sequence on January 10, 2020. It was not until
weeks after the WHO declared
Covid-19 a Public Health Emergency of International Concern
on January 30 that the WHO–n engl j med 388;25

nejm.org

China Joint Mission visited Beijing and Wuhan (February 16 toFebruary 24).
The joint WHO–China technical report published in March
2021 rated a zoonotic spillover asa “likely to very likely” source ofthe virus, cold food–chain products as “possible,” and a laboratory
incident as “extremely unlikely.”1
The WHO director-general immediately repudiated the report’s
findings, believing it was premature to rule out a possible laboratory incident. An open letter published in Science on May 14, 2021,
credited the laboratory theory,calling for open access to laboratory records and science-based
studies.2 On October 13, 2021,
the WHO director-general established the Scientific Advisory
Group for the Origins of Novel
Pathogens (SAGO). China officially rejected the WHO’s plan

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May 26, 2021

NATIONAL

Actions taken by the U.S. government and agencies

June 9, 2022

Office of the Directorof National Intelligence
releases a declassified
assessment on theorigins of Covid-19

October 29, 2021

2022

WHO establishes SAGO

October 13, 2021

March 16, 2023

January 25, 2023

2023

In Science, 2 studies provide
evidence that SARS-CoV-2 most
likely emerged through multiple
zoonotic transmissions atHuanan Seafood Wholesale
MarketJuly 26, 2022

Virologists announce they havelocated SARS-CoV-2 data associated with positive samplescollected at Huanan Seafood
Wholesale Market, pointing
to a raccoon dog origin

President Biden signs the COVID-19
Origin Act of 2023, declassifying nationalintelligence on SARS-CoV-2 origins

March 20, 2023

First congressional hearing of SelectSubcommittee on the Coronavirus
Pandemic

March 8, 2023

FBI director states that the Bureau
assesses SARS-CoV-2 as most likely originating from a laboratory incident

March 1, 2023

The Wall Street Journal reports that the Department of Energy concludes SARS-CoV-2 mostlikely originated from a laboratory incident

February 26, 2023Department of Health and Human
Services Inspector General issues reportconcluding that National Institute ofAllergy and Infectious Diseases failed toadequately oversee an EcoHealthAlliance grant for research into batviruses at Wuhan Institute of Virology

SAGO releases preliminary
report recommending further
study on both hypotheses
for SARS-CoV-2 origins

Actions taken by the government of the People’s Republic of China

Actions taken by international health agencies

Scientific milestones related to Covid-19 origins

President Biden orders intelligence agencies to conduct a90-day review of evidence onSARS-CoV-2 origins

2021

In Science, 17 scientists
call for a transparent
investigation into
SARS-CoV-2 origins,
including a fullinvestigation oflaboratory incident
hypothesis

May 14, 2021

WHO–China technical report evaluates
introduction through an intermediate
animal as likely or very likely and alaboratory incident as extremelyunlikely. WHO director-general calls
for further investigation of laboratory
incident hypothesis

March 30, 2021

Key Events in the Effort to Determine the Origins of the Covid-19 Pandemic.
FBI denotes Federal Bureau of Investigation, SAGO Scientific Advisory Group for the Origins of Novel Pathogens, and WHO World Health Organization.

Cases of pneumonia
of unknown cause inWuhan, China,
reported to WHO

December 31, 2019

Chinese scientists publicly
share the SARS-CoV-2
genetic sequence

January 10, 2020

Chinese authorities close
Huanan Seafood Wholesale
Market for sanitation anddisinfection

January 1, 2020

2020

World Health Assembly adopts
resolution requesting the WHO
director-general work with the World
Organization for Animal Health, theFood and Agriculture Organization of theUnited Nations, and member nations toidentify SARS-CoV-2 origins

May 19, 2020WHO–China team conducts
joint on-the-ground investigation of Huanan Seafood
Wholesale Market

January 14–February 10, 2021

WHO–China Joint Missionvisits Beijing and WuhanFebruary 16–24, 2020

WHO declares Covid-19
a Public Health
Emergency ofInternational ConcernJanuary 30, 2020

INTERNATIONALPERS PE C T IV E
The Origins of Covid-19

The Origins of Covid-19

PE R S PE C T IV E

for a second phase of investigation of origins. The SAGO’s preliminary report warned that Chinawas withholding key data.
Recently, a team of international experts announced that theyhad identified data on SARSCoV-2–positive environmental samples collected from the Huanan
market in January 2020, which
China had withheld from thepublic domain for 3 years. Chinese scientists had uploaded thedata to GISAID (the Global Initiative on Sharing All Influenza
Data) but then removed them. In
response to pressure from theWHO, China restored those datato GISAID.
Determining the origins ofSARS-CoV-2 should be strictly ascientific matter, but it has become embroiled in politics. InMarch 2020, the Chinese Ministry of Foreign Affairs alleged,without evidence, that U.S. Army
personnel had introduced SARSCoV-2 during a visit to Wuhan,
prompting President Donald
Trump to claim that the virus
originated at the WIV. Accusing
the director-general of siding withChina, Trump notified the United Nations that the United States
intended to withdraw from theWHO. Although President Joe
Biden later reversed that decision,
the origins controversy has continued. On May 26, 2021, Bidenordered U.S. intelligence agencies to review the competing origins hypotheses. The Office ofthe Director of National Intelligence released the “DeclassifiedAssessment on COVID-19 Origins,”
finding that the evidence to support either of the two plausible
theories was inconclusive and acknowledging that China’s cooperation was necessary for reaching any conclusive assessment.3
Origins politics heated up ear-ly this year. On January 25, 2023,
the Office of the Inspector General of the Department of Healthand Human Services concluded
that the National Institute ofAllergy and Infectious Diseases
had failed to adequately oversee agrant to the EcoHealth Alliancefor research into bat viruses atthe WIV.4 A month later, theDepartment of Energy, which oversees a network of 17 U.S. laboratories, concluded with “low confidence” that SARS-CoV-2 most
likely arose from a laboratory incident. The Federal Bureau of Investigation said it favored thelaboratory theory with “moderate” confidence. Four other agencies, along with a national intelligence panel, still judge thatSARS-CoV-2 emerged from natural zoonotic spillover, while tworemain undecided. All U.S. intelligence agencies rejected the allegation that participants in a clandestine Chinese biologic weapons
program intentionally developed
SARS-CoV-2. Yet a report issued
in mid-December 2022 by Republican members of the House ofRepresentatives still credited thattheory. On March 20, 2023, Bidensigned a bill declassifying documents about Covid-19’s origins, and Congress commenced
hearings.
Of the three possibilities —natural, accidental, or deliberate— the most scientific evidence
yet identified supports naturalemergence. More than half of theearliest Covid-19 cases were connected to the Huanan market,
and epidemiologic mapping revealed that the concentration ofcases was centered there. In January 2020, Chinese officials
cleared the market without testing live animals, but positive environmental samples, including
those from an animal cage and an engl j med 388;25

nejm.orghair-and-feather–removal machine,
indicated the presence of both
SARS-CoV-2 and Covid-susceptible animals.5 Recently released
findings included raccoon dog
DNA, pointing to a possible
SARS-CoV-2 progenitor. Samples
from early cases in humans also
contained two different SARSCoV-2 lineages. Although only
one lineage spread globally, theexistence of multiple lineages
suggests that a SARS-CoV-2 epidemic in animals may have led
to multiple spillover events.
Proponents of the accidentallaboratory leak theory stress thegeographic location of the WIV
in the city where the pandemic
began. They point to the presence of the bat coronavirus
RaTG13 strain at the laboratory,
arguing that genetic manipulations such as gain-of-function(GOF) research may have produced SARS-CoV-2. Most scientists refute this theory because
there is considerable evolutionary
distance between the two viruses. However, the possibility thatthe laboratory held a different
progenitor strain to SARS-CoV-2
that led to a laboratory leak cannot be unequivocally ruled out.
China’s obfuscation may meanthat we will never have certainty
about the origins of the greatest
pandemic in more than a century. After all the world has suffered in loss of life, economic
hardship, and exacerbated healthdisparities, there is intrinsic value in knowing the cause. An objectively determined body of scientific facts cannot fully defuse
the political rhetoric surrounding
the origins investigation, but thesearch must continue. The newly
released genetic data may reveal
whether specific animals wereinfected and offer information
about where they came from,

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The Origins of Covid-19

PERS PE C T IV E

opening new possibilities to investigate, which may also improve
attribution techniques for investigating future outbreaks. Irrespective of Covid’s origins, futureoutbreaks could result from deliberate, accidental, or naturalcauses, and improving our ability
to understand and prove theories
will be critical. We propose threeimportant steps for fortifying
pandemic preparedness.
First, preventing spillovers byusing a One Health strategy linking animal, human, and environmental health is vital. Some 60%
of outbreaks of diseases previously unseen in humans arise
from natural zoonoses. Humanand animal populations could be
separated more effectively withstricter regulation of wet markets and enforcement of laws
prohibiting wildlife trade. Landmanagement efforts such as halting deforestation would benefit
the environment while creatinga buffer between wildlife andhumans. Widespread
An audio interview
use of sustainablewith Lawrence
and humane farmGostin is available
ing practices would
at NEJM.org
eliminate overcrowding of domesticated animals
and curtail prophylactic antimicrobial use — with added benefits in preventing antimicrobialresistance.
Second, it is important to fortify laboratory safety to reduce
the risks of unintentional releaseof a dangerous pathogen. Regulatory requirements should in-2308

clude site-specific and activityspecific risk assessments to
identify and mitigate risks; core
protocols for infection prevention and control; and training forproper use of, and access to, personal protective equipment. International standards exist for bio­risk management, which should
be broadly adopted.
Third, GOF research designed
to elucidate the transmissibility
or pathogenicity traits of pathogens should be appropriately overseen to reduce risks while allowing important research and vaccine
development to continue. Such
research may result in the crea­tion of microbes with enhanced
pandemic potential, which could
be released unintentionally or intentionally. However, there is nointernational agreement about
which research activities are problematic or how to reduce risks.
On January 27, 2023, the U.S. National Science Advisory Board for
Biosecurity issued a more rigorous framework for oversight ofresearch, which prominent virologists criticized as overbroad andinhibitory to U.S. vaccine development. Since GOF research isconducted in laboratories globally, an international framework isneeded.
Since the pandemic’s earliest
days, controversy has swirled
about how it began. Origins investigations are scientific endeavors, but we need to plan ahead
so that scientists get rapid accessto key geographic sites, open sci-n engl j med 388;25

nejm.org

entific exchange, and full transparency. Though such investigations proceed more slowly than
the news cycle, these steps are
the keys to unlocking the mystery surrounding Covid-19 andpreparing the world for the future outbreaks that are certain tooccur.
Disclosure forms provided by the authors
are available at NEJM.org.
From the O’Neill Institute for National andGlobal Health Law, Georgetown University
Law Center, Washington, DC (L.O.G.); andthe Johns Hopkins Center for Health Security, Baltimore (G.K.G.).
This article was published on June 7, 2023,
at NEJM.org.
1. World Health Organization. WHO-con-vened global study of origins of SARS-CoV-2:
China part. March 30, 2021 (https://www​.­who​.­i nt/​­publications/​­i/​­item/​­who​-­convened​-­global​-­study​-­of​-­origins​-­of​-­sars​-­cov​-­2​-­china​-­part).
2. Bloom JD, Chan YA, Baric RS, et al. Investigate the origins of COVID-19. Science
2021;​372:​694.
3. Office of the Director of National Intelligence. Declassified assessment on
COVID-19 origins. October 29, 2021 (https://www​.­d ni​.­gov/​­i ndex​.­php/​­newsroom/​­reports​-­publications/​­reports​-­publications​-­2021/​­item/​­2263​-­declassified​-­a ssessment​-­on​-­covid​-­19​-­origins).
4. Office of the Inspector General. The National Institutes of Health and EcoHealthAlliance did not effectively monitor awards
and subawards, resulting in missed opportunities to oversee research and other deficiencies. Washington, D.C.:​Department ofHealth and Human Services, January 2023
(https://oig​.­h hs​.­gov/​­oas/​­reports/​­region5/​­52100025​.­pdf).
5. Worobey M, Levy JI, Malpica Serrano L,et al. The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of
the COVID-19 pandemic. Science 2022;​377:​951-9.
DOI: 10.1056/NEJMp2305081
Copyright © 2023 Massachusetts Medical Society.
The Origins of Covid-19

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