Latest / U.S. Right to Know articles / Before COVID, an NIH lab chief proposed making a SARS-like bat virus more infectious

Transcript

Before COVID, an NIH lab chief proposed making a SARS-like bat virus more infectious · U.S. Right to Know articles

0:09
Written by Lewis Campbell. On a Sunday morning in October 2019, the
0:15
chief of the Virus Ecology Unit at the National Institutes of Health's
0:19
Rocky Mountain Laboratories emailed a postdoctoral scientist in his lab with an
0:23
idea. You should be able to make S with a more broader
0:27
cleavage signature, like furin-like, to enhance infectivity. Vincent Munster Vincent Munster
0:33
and his postdoc, Michael Letko, had spent that year building a system
0:37
to rapidly test whether dozens of SARS-related bait coronaviruses could infect humans
0:42
and cells. That week, Munster read a new preprint from prominent virologists,
0:47
Vinet Menashery and Ralph Berrick's lab groups, showing That the protease trypsin
0:51
could unlock entry for certain traphiruses that otherwise would not infect human
0:56
cells. Lekko had forwarded him the paper two days earlier with the
1:00
note Seems like more groups will be converging on this idea soon.
1:05
You should be able to make S with a more broader cleavage
1:07
signature like Furin like to enhance infectivity. Munster wrote back on October
1:12
6, 2019. You can include a motif like this RXKRR. Might be
1:17
cool to get some synthesized. In virology parlance, S is the coronavirus
1:23
spike protein, which allows the virus to latch onto the cells it
1:26
infects, and RXKRR is a furin cleavage site motif, which can make
1:30
viruses better able to infects, cells and spread. Munster was suggesting that
1:34
his postdoc engineer a furin site into a coronavirus spike protein to
1:39
make it more infectious. Eleven weeks later, a coronavirus carrying a similar
1:44
furin cleavage site emerged in Wuhan, China, spawning the COVID-19 pandemic. It
1:49
remains the only known SARB-Covirus, the SARS-related group of coronaviruses, that Munster
1:54
and Letco were the screening to have one. The email exchange has
1:59
never been made public before. It appears in a 270-page batch of
2:03
records recently released by NIH to US Right to Know in response
2:07
to a request made under the Freedom of Information Act. The request
2:12
sought specific correspondence from Munster's lab in Hamilton, Montana, from March 2019
2:17
through January 22, 2020. The date when his group published one of
2:22
the first papers showing that the new coronavirus used a human cell
2:26
receptor called ACE2 as a doorway into cells. Two new threads run
2:31
through the records. Weeks before the pandemic began, a senior SNIH virologist
2:36
proposed in writing to build into a SARS like spiky protein, the
2:40
feature that would become the central argument for COVID nineteen's laboratory origin
2:44
a furin cleavage site. And through the same year, his lab was
2:49
asking virus hunters for unpublished bat coronavirus spike sequences, and getting them,
2:54
including from researchers in the U.S.-funded consortium called PREDICT, whose New York-based
2:59
lead partner, Eco HealthAsscience, had a long-standing collaboration with the Wuhan Institute
3:05
of Virology to collect and study SARS-related viruses. Each goes to a
3:10
different key point in The origins debate. The Furin cleavage site is
3:14
the single genetic feature most cited in the arguments that SARS-CoV-2 did
3:18
not arise entirely in nature. Unpublished sequences are the other. Because the
3:24
pandemic virus matches nothing in the published scientific literature, most laboratory origin
3:29
scenarios depend on some lab having held a virus the rest of
3:33
the world had never seen. Nothing in the records shows that Letco
3:37
followed through on Munster's suggestion to insert a furin cleavage site in
3:41
a SARS spike protein, however. In fact, the furin cleavage site found
3:45
in SARS-CoV-2 differs from the motif or short sequence of amino acids
3:50
that Munster suggested. Nor do the documents indicate that Rocky Mountain Labs
3:55
possessed SARS-CoV-2 or a close relative, or that either Munster or Letgo
4:00
directly communicated with researchers in Wuhan while working on their project. Their
4:04
research also used synthetic gene fragments, not live viruses, employing particles that
4:09
cannot replicate or spread. Such work generally poses lower biosafety risks. The
4:15
two then unpublished Bat Virus spike sequences obtained from Predict, one from
4:20
Malaysia, and one from Uganda and Rwanda, are also too distantly related
4:24
to SARS-CoV-2 to have given rise to it. Letko, who is now
4:28
an associate professor at Washington State University, declined to comment for this
4:33
story, saying in an email, why you will write what you write,
4:37
regardless of the truth or what I have to say. Munster did
4:41
not respond to requests for comment. He was indicted earlier this year
4:44
for bringing AIMPOC specimens into the U.S. Without proper documentation and giving
4:49
false statements to law enforcement officials as part of unrelated NIH research.
4:54
He has pleaded not guilty. The NIH press office also declined to
4:59
answer questions as about why the agency had not previously told the
5:02
public that its scientists had solicited and obtained unpublished SARS-like coronavirus spike
5:08
sequences, or proposed inserting a
5:10
furin cleavage site into a SARS-like spike before the pandemic. Converging on
5:16
the idea. Munster's suggestion to add a fern cleavage site is the
5:20
second known instance of scientists proposing to insert this distinguishing feature into
5:25
a SARS or SARS-like spike within roughly two years before COVID-19 emerged.
5:31
In 2018, Eco Health Alliance, Barracks Lab, and researchers at the Wuhan
5:36
Institute of Virology had proposed the same kind of modification to the
5:40
Defense Advanced Research Projects Agency, DARPA, in work that would have used
5:44
live, replicating viruses. Their application, known as the DEFUSE proposal, was denied.
5:51
The concept is notable because the furin cleavage site that helped the
5:55
virus cause the pandemic has become central to the debate over the
5:58
pandemic's origins. Some proponents of a laboratory origin view diffuse as a
6:04
blueprint for creating SARS-CoV-2, while prominent supporters of a natural origin have
6:09
argued that deliberately engineering such a feature would have been unlikely and
6:13
unnecessarily cumbersome. Munster's email gives the lab origin supporters another example of
6:19
such a FurinSight proposal. What this shows is that different groups of
6:23
virologists were converging on the idea of inserting cleavage sites in the
6:27
spikes of potentially dangerous coronaviruses. Alina Chan, molecular biologist, The revelation
6:34
about Munster's lab seeking unpublished sequences speaks to a different issue in
6:39
the COVID's origins debate. Because SARS-CoV-2 descends from no virus previously described
6:45
in the scientific literature, any scenario in which it was engineered requires
6:50
assuming that some laboratory held SARS-related sequences that had never been made
6:54
public. A twenty twenty one review of SARS CoV II in Cell,
6:59
by twenty one scientists, called that implausible. There is no rational experimental
7:03
reason why a new genetic system would be developed using an unknown
7:07
and unpublished virus, they wrote. But the records show a U.S. Government
7:12
laboratory doing just two years earlier. Letko's platform was a new genetic
7:17
system, and he sought unpublished sequences precisely because the were unpublished. Sharing
7:22
them, he wrote in April 2019, will surely increase the impact of
7:27
our story by providing a proof of principle with unpublished sequences. Researchers
7:32
in the U.S. Funded virus hunting program supplied two within eight weeks.
7:37
One of the researchers, Simon Anthony, was also an author of the
7:40
Cell Review. Alina Chan, a molecular biologist who has advocated for a
7:45
thorough investigation of laboratory origin scenarios, recently reviewed the Munster Let Go
7:50
email records at the request of U.S. Right to Know. What this
7:55
shows is that different groups of virologists were converging on the idea
7:58
of inserting cleavage sites in the spikes of potentially dangerous coronaviruses, she
8:04
said. Assuming a lab origin of COVID-19, if a lab in Wuhan
8:09
hadn't caused the pandemic, it's plausible that a lab in the US
8:12
would have eventually followed the same path. Selecting sequences. Munster's emailed
8:18
proposal didn't come out of the blue. He and Letko were in
8:21
the middle of a year-long research project that the newly released records
8:25
document from its start. Seven months earlier, in March 2019, Munster and
8:30
Letco set out to answer a question: Of the hundreds of SARS-related
8:34
coronaviruses in research databases worldwide, which ones could infect people? Lecco
8:41
built a workaround that he and Munster described as a rapid and
8:44
scalable platform, according to the records. Rather than build each virus individually,
8:49
they took only the receptor binding domain, the fragment of the spike
8:53
that grips onto them's host cells receptor, and spliced it into a
8:57
SARS-CoV spike backbone. They then loaded these chimeric spikes onto harmless reporter
9:02
particles and used them to infect cells, expressing HACE 2, the receptor
9:07
SARS-CoV uses to enter the human airway. A glow from the bioluminescent
9:11
enzymes luciferase indicated successful cell entry. With Letko's method, what typically had
9:17
taken months to test now took about three weeks. We are seeking
9:21
additional unpublished lineage B beta coronavirus sequences. The limiting ingredient to test
9:27
their method was the spike sequences. Letko had exhausted Thusser's like sequences
9:32
already published. So he and Munster started looking for others that hadn't
9:36
been, the records show. On March 8, 2019, Munster emailed EcoHealth
9:42
Alliance President Peter Daschak, Vice President Kevin Olivall, and Columbia University virologist
9:48
Simon Anthony, attaching a confidential abstract with a chart and figures illustrating
9:53
their project. While we have now tested all of the variation currently
9:58
published for lineage B-beta coronaviruses for their ability to enter primate cells,
10:03
we are seeking additional unpublished lineage B-beta coronavirus sequences to test in
10:08
our platform, Munster wrote. He asked them not to circulate the attachment,
10:13
because the work was still unpublished and quite competitive. Of the three
10:18
recipients, only Anthony, then one of the core leaders on PREDICT appears
10:22
in the released correspondence. He replied later that evening, Hey! Looks super
10:27
cool. Two months of negotiation followed, the emails show. On April fifth,
10:32
Lecco thanked Anthony for agreeing to share betaconavirus lineage B spike sequences
10:38
with us, adding that unpublished material will surely increase the impact of
10:42
our story. On May 2, Anthony reported back from a Predict meeting
10:46
in Vancouver, British Columbia. His team had detected around five or six
10:51
novel two billion viruses, he wrote, but had only managed to get
10:55
spikes for two of them so far. Because neither had been published,
10:59
Letco's paper would be the first report of these viruses in the
11:02
literatures. So long as he credited Predict and its partners as co-authors,
11:07
Anthony said. Letko agreed. Two days later Anthony sent the sequences. He
11:12
identified the as PredictCov fifty one, isolate PDF zero six six six
11:16
six six six six three from Malaysia, which Anthony described as super
11:19
divergent, could be really interesting, and PredictCov forty three from Uganda and
11:24
Rwanda. Absolutely stellar, Munster replied. We'll keep you posted on the results.
11:30
Anthony was generally correct. A small fragment of the Malaysian virus had
11:34
been deposited in GenBank, the NIH's public sequence database, in 2016 and
11:40
referenced the following year in a survey paper Anthony co-authored with Dashak
11:45
and others. But neither its full spike sequence nor its complete genome
11:49
was public. Nothing at all was public about then African virus. In
11:53
neither case could anyone outside Predict obtain the spike sequence, the part
11:58
that determines whether a virus can enter human cells, and the only
12:01
part LETCO's platform could use. A step further. Five months later, after
12:08
reading the new preprint about Tripson, Munster proposed taking Letco's project a
12:12
step further. For a coronavirus to infect a host cell, binding the
12:17
receptor is only the first step. The spike must then be cut
12:20
open by one of the host's own enzymes before the virus can
12:24
fuse with the cell and get inside. These enzymes that cut protein
12:27
apart are called proteases, and each one targets different spots. The protease,
12:32
a spike, is built for largely determines what tissues it can infect.
12:37
SARS-CoV depends on proteases that are not available everywhere in the body.
12:41
Furin, however, is expressed in the most tissues. The menakshree Barrick preprint
12:47
that sparked Munster's idea had shown that adding trypsin from the outside
12:51
could unlock entry into human cells for coronaviruses that otherwise couldn't infect
12:56
them. Trypsin is a far less selective protease, cutting a protein after
13:00
common amino acids rather than requiring a particular short sequence or motif.
13:06
What Munster proposed to let go, engineering a furincite into the spike
13:10
itself, would let The virus cut itself open. Instead of waiting for
13:14
an outside enzyme to do the job, a furincite could clear the
13:17
hurdle in one step to enhance infectivity, as Munster wrote. The idea
13:22
had been proposed before. EcoHealth Alliance submitted the diffused proposal to DARPA.
13:28
Under a program called Preventing Emerging Pathogenic Threats, or Pre-MPT. Its key
13:33
partners included Barracks Laboratory at the University of North Carolina Rand Zhengli
13:37
Shi, the leading coronavirologist at the Wuhan Lab. The proposal aimed to
13:42
introduce human-specific proteolytic cleavage sites, including furin sites, into SARS-related bat
13:48
coronavirus spikes to evaluate and enhance their ability to infect human cells.
13:53
DARPA declined to fund it, faulting the proposal over the risks of
13:57
gain-of-function research. Munster was not named on the proposal submitted to DARPA,
14:03
but according to official congressional correspondence, he had been part of the
14:07
DEFUSE team two months earlier. In April 2024, Senator Rand Paul, then
14:13
ranking member of the Senate Homeland Security and Governmental Affairs Committee, wrote
14:18
to the Department of Health and Human Services and DARPA saying he
14:21
had obtained documents showing that Vincent Munster of NIID's Rocky Mountain Laboratory
14:27
was listed as a partner in the diffuse proposal presented at the
14:31
Pre-P Proposers Day. A January 2018 DARPA event, at which DASAC pitched
14:36
the project to representatives of at least 15 federal agencies. Rocky Mountain
14:42
Laboratories, Paul wrote, was at one point listed as a partner alongside
14:45
the Wuhan Institute of Virology, UNC, Columbia University, Lipkin Lab, and Duke
14:51
Nuss. A disclosure Paul said appeared to contradict former National Institute of
14:55
Allergy and Infectious Diseases director Anthony Fauci's testimony to Congress that NIH
15:01
knew nothing of DEFUSE By the time the proposal reached DARPA that
15:05
March, Munster and his lab were off it. The final list of
15:08
partners included EcoHealth, the WIVE, UNC, DukeNuss, the USGS National Wildlife Health
15:14
Center, and Palo Alto Research Center. Paul demanded from HHS records of
15:19
all communications between Vincent Munster and any individual from EcoHealth Alliance, Wuhan
15:24
Institute of Virology, University of North Carolina, Columbia University, or Duke Nuss.
15:30
Paul has not released his underlying documents, and neither HHS nor DARPA
15:34
has publicly answered his requests. The newly released NIH records show that
15:39
about a year after Diffuse was submitted, Munster asked EcoHealth for unpublished
15:44
SARB-Covirus sequences, that he received them from a virologist at Columbia's Center
15:49
for Infection and Immunity, the Center Ian Lipkin, directs, and that, in
15:54
October 2019, he proposed building a spike with a furin-like cleavage site
15:58
to enhance infectivity. Stephen E. Masseys, a professor of bioinformatics at the
16:03
University of Puerto Rico, and a researcher with Drastic, the independent group
16:08
that first published the diffuse proposal, called Munster's Suggestion Significant, saying it
16:13
shows the Furin Site idea was circulating outside the EHA Viv Wangxi
16:18
group, a reference to EcoHealth Alliance, the Wuhan Institute of Virology, and
16:23
the University of North Carolina. Munster's email does not mention diffuse. His
16:28
idea appears instead as a reaction to the Menaxribaric preprint, framed as
16:32
a potential next experiment for his and Letco's work. And the motif
16:37
he proposed is not the one found in the pandemic virus that
16:39
emerged less than three months later. SARS-CoV-2's site has alanine, where Munster's
16:45
pattern called for lysine or arginine. A suboptimal site. That difference is
16:51
key. The furin site in SARS-CoV-2 substantially improves the virus's ability to
16:56
enter human airway cells and is widely regarded as a major contributor
17:00
to its transmissibility. Its absence from every other sarbocovirus found in nature
17:05
is also one of the observations lab origin proponents cite most often.
17:10
The 2021 Review in Cell also directly addressed whether the site could
17:14
have been engineered. Its authors, including Christian Anderson, Robert Gary, and Simon,
17:19
argued that the site's own sequence weighs against a lab design. SARS-CoV-2's
17:23
motif, R R A R, does not match its canonical form, RXR
17:28
slash KR, they wrote, and is suboptimal compared with those of other
17:32
human coronaviruses. There is no logical reason why an engineered virus would
17:37
utilize such a suboptimal furin cleavage site, which would entail such an
17:41
unusual and needlessly complex feat of genetic engineering, the paper stated. The
17:46
only prior work inserting a furin site at that position in a
17:50
SARS-CoV spike, they noted, had used an optimal sequence in a pseudotype
17:54
system. Massey disputes that framing. He said excessively efficient cleavage can destabilize
18:00
the spike and reduce the virus's ability to enter cells, so, a
18:04
site that looks suboptimal on paper may not be suboptimal for the
18:07
virus. The newly released records show Munster reasoning along Salon's author's lines
18:13
nearly two years before their review appeared. The motif he proposed matches
18:18
the canonical form they describe, not the one they pandemic virus carries,
18:22
and his lab ran a pseudotype system of the kind they cite.
18:27
Read one way. The email corroborates their logic. That a scientist contemplating
18:31
a furance like site reached for the textbook motif, and SARS-CoV-2 does
18:36
not have it. Read another way, it establishes something the review did
18:40
not address. By October twenty nineteen, the idea of adding such a
18:44
furin cleavage site to a SARS related spike to enhance infectivity was
18:48
circulating not only in an unfunded DARPA proposal, but also inside an
18:52
NIH laboratory. What was published? When Chinese scientists ultimately
18:58
posted the genetic sequence of the novel coronavirus spreading in Wuhan on
19:02
January 10, 2020, Letko. And Munster had everything they needed to test
19:07
it in their system. Allowing the scientific community to gain critical information
19:12
on virus tropis in almost real time with the outbreak cover letter
19:17
to Nature. The platform did not require a live virus, only the
19:21
sequence of the small piece of the spike that latches onto a
19:24
human cell. Within hours of the sequence going up, Neilche van Dormelen,
19:29
another scientist in Munster's lab, pasted it into an email to Letko
19:33
and Munster. Letko's expected results by January 26 or 27. They came
19:39
back ahead of schedule. On January 21, Munster decided where to send
19:43
the final manuscript showing their research. Nature it is, he wrote to
19:47
Letko. Let's sick, do two authors and speed this up. The paper
19:52
went out that afternoon to Nature and to the preprint server BioArch
19:55
Civ. Only twelve days had passed since the sequence appeared online. The
20:00
lab made the new method's speed its selling point. Their method reduces
20:05
the time from the sequence being published to having re-il in vitro
20:08
data to under 12 days. The cover letter told Nature's editors, allowing
20:13
the scientific community to gain critical information on virus tropism in almost
20:18
real time with the outbreak. The work drew notice at the top
20:21
of NIID. First data from my lab confirming ACE2 as the receptor
20:26
for 2019 Cov, Munster emailed an NIID coronavirus response list that afternoon.
20:31
Greg Fokers, the chief of staff to the NIID Director Anthony Fauci,
20:36
replied, When this hits Bioorxif might be worth a tweet. The paper
20:41
that was submitted gives no sign that Letco took up Munster's suggestion
20:45
to engineer a cleavage site into a spike, but it does show
20:48
that the scientists used The protease trypsin rather than the furin Munster
20:53
had proposed. The paper's second figure is titled, Trypsin Enhances Lineage B
20:58
entry in various cell lines. It reports that bat coronavirus spusks that
21:03
could not get into human, primate, or pig cells on their own
21:06
did get in once the particles were bathed in the enzyme. The
21:10
Trips and Experiments appear nowhere in the project, before Munster and Letco's
21:14
October exchange about the Menachery Barrack preprint. They are also absent from
21:19
the abstract that Munster previously circulated in the spring. The published paper
21:24
cites the Menachery Barrack preprint that sparked their exchange conversation. Neither of
21:29
the sequences that Anthony sent in May 2019 appears in the paper,
21:33
and neither he nor PREDICT are acknowledged. The only trace of Predict
21:38
in the 18-page manuscript is a footnote citation. The panel of viruses
21:42
the paper did report testing consisted of 29 receptor-binding domains obtained from
21:48
a public database administered by the NIH. One of the two viruses
21:53
resurfaced a year later, when Columbia's Center for Infection and Immunity deposited
21:58
its complete genome in Genbank on july sixth, twenty twenty five and
22:02
a half months after the preprint that was to have carried it.
22:06
In February 2021, the bat coronavirus from Uganda and Rwanda also appeared
22:11
in the journal Virus Evolution, in a study of how SARS-related viruses
22:15
acquired the ability to use the human ACE-2 receptor. Lecko was second
22:20
author, Munster was listed near the end, Anthony was the senior author,
22:24
and the Ugandan and Rwandan field scientists and Predict leadership were included
22:28
as co-authors. As Anthony had said in 2019 would be required. Run
22:33
through Lecco's platform, the virus could not enter human cells through ACE
22:38
2 at all. The Malaysian virus, which Anthony had called the more
22:42
interesting of the two, has never appeared in a published study. Nothing
22:46
in the records says why. Anthony, now a professor at the University
22:50
of California, Davis, did not respond to requests for comment. On May
22:55
24, 2021, two years after he emailed the virus's spike sequence to
23:00
the Montana lab, Colombia deposited its complete genome in Gen Bank on
23:04
behalf of the Predic Consortium, crediting Malaysia's Sabah Wildlife Department and EcoHealth
23:10
Alliance.