Day 475: Back to the Lab

The Commonwealth will be following the CDC's guidance to (mostly) return to normal on May 29th. The masking will continue on public transit and rideshares, and in hospitals, care facilities, and schools (of all places). Surprisingly, even Somerville, famed overreactionary city, is going along with the plan. (Yes, they announced it via Twitter.) Massachusetts cases were up a twelfth of a percentage point today.

With the craziness waning, theories are turning to where it all went wrong. Science writer Nicolas Wade wrote up the born-in-a-lab story on Medium this month, complaining that scientists are afraid to risk grants to investigate it and the press has ignored the theory.

“When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus,” said David Baltimore, an eminent virologist and former president of CalTech. “These features make a powerful challenge to the idea of a natural origin for SARS2,” he said.

Then Science published a letter of doubt about the origins of SARS-CoV-2.

We must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data. A proper investigation should be transparent, objective, data-driven, inclusive of broad expertise, subject to independent oversight, and responsibly managed to minimize the impact of conflicts of interest.

The New York Times put their finger in the wind and finally decided it was newsworthy, though they still take the side of a natural origin.

P.S. David Cole derides the purely human transmission angle, though with a sketchy argument that would also prove the discredited wet market origin theory.

Day 128: Stabbed in the Back by the Spike Protein

The world is at seven million cases with 406,000 deaths and about 3.5 million recovered. The US has reached two million cases with 112,000 deaths. While India has legitimately surpassed Italy to reach #6, it is still well in the lee of #4 Spain despite the usual rash of reports to the contrary. The UK, however, is looking to move up from #5 momentarily. Massachusetts cases are up 0.3% on the eve of Phase 2 of the state's reopening plan.

On the made-in-a-lab front, Forbes has published a Norwegian scientist's claims that SARS-CoV-2 was so made in a lab, and the Quarterly Review of Biophysics has accepted the article behind his claims, A Candidate Vaccine for Covid-19 (SARS-CoV-2) Developed from Analysis of its General Method of Action for Infectivity. Although the paper is nominally about their vaccine (Biovacc-19), the authors' approach relies upon their view of the virus as genetically engineered:

Although no other Covid-19 vaccine design programme appears to follow this methodology, we believe, from experience, that successful vaccine design logically starts with a thorough understanding of the aetiology of the target virus which appears in this case to be quite singular. In consequence of our researches and therefore unlike conventionally developed vaccines, Biovacc-19's Method of Operation is solely upon non human-like (NHL) epitopes which are 21.6% of the composition of this coronavirus's Spike protein.

Interestingly, their approach was honed not on the dark web of COVID conspiracy theories, but in the trenches of HIV vaccine development:

It is thirty six years since the world was promised an HIV vaccine that would be ready in eighteen months. We correctly predicted the failure of all three major HIV/AIDS vaccines over those years, and specifically the danger of poor immune responses to conserved human-like domains and antibody- enhanced infectivity to high mutating domains. Earlier this year, the latest South African trial was terminated due to futility in preventing HIV transmission (UNAIDS, 2020). From our past HIV experience, we therefore observe that in the present context, any vaccine design based on the whole Spike protein of SARS-CoV-2 may not be immunogenic due its high human similarity compared to a vaccine with specifically selected NHL epitopes, such as Biovacc-19 does - and is.

Covid-19 candidate vaccines designed without appreciating these problems may run similar risks to those experienced with HIV vaccines that failed to show protection. The possibility of inducing autoimmune responses or antibody-dependent enhancements, needs to be carefully guarded against because there is published evidence that an HIV candidate vaccine has actually enhanced infectivity (Duerr et al., 2012): "Vaccinations were halted; participants were unblinded. In post hoc analyses, more HIV infections occurred in vaccinees vs placebo recipients in men who had Ad5-neutralizing antibodies and/or were uncircumcised. Follow-up was extended to assess relative risk of HIV acquisition in vaccinees vs placebo recipients over time”. Such antibody-dependent enhancement (ADE) has been observed for coronaviruses in animal models, allowing them to enter cells expressing Fc𝛾R.

For specific accusations against the US and China for their gain-of-function viral research, you have to go back to the Forbes article. (This is left as an exercise for the reader.)

The PlagueBlog files contain another recent discussion of the stabby alien spike protein of SARS-CoV-19, the preprint The emergence of SARS-CoV-2 by an unusual genome reconstitution at Research Square. The authors found an unusual 7-amino-acid (7aa) sequence within the spike protein that they felt was unnatural, but instead of making accusations in Forbes they BLASTed it a lot until they found a matching sequence in Plasmodium malariae, the malaria parasite.

Crazier than made-in-a-lab though that may sound, the authors take it seriously. They conclude with some interesting speculation about using malaria drugs against COVID-19, and note yet another pattern distinguishing hard-hit Western countries with those places that are getting off easier: malaria prevalence.

Day 123: Made in a Lab

In a fortunate moment of insomnia, one of PlagueBlog's vast team of reporters spotted a 338-page preprint on Reddit about how SARS-CoV-2 was engineered in a lab. The reporter was only a few pages into this fascinating read when the moderators found it and scrubbed it from Reddit—but not from viXra.org, an unmoderated preprint server set up to avoid censorship at arXiv.org. The paper, by graduate student Murat Seyran, is titled Host Change -Tropism [sic] Pattern of Human Coronaviruses Suggesting the Engineered Nature of Severe Acute Respiratory Syndrome Coronavirus 2.

Most of the 338 pages are the supplementary materials, including some nice tables comparing various coronavirus sequences, plus 7 less approachable sets of sequence alignment results that don't really fit the page format. The text itself is quite readable at only 15 pages, and nicely summarizes the seven known human coronaviruses and the (ongoing) changes from their animal sources that make them infective in humans. It's worth a read just for that, even if you're uninterested in the question of whether SARS-CoV-2 was bioengineered.

So what is suspicious about SARS-CoV-2? One issue is a change that didn't happen that normally does during coronavirus adaptation to humans:

[The] N-terminal domain (NTD) of CoVs Spike (S) Protein contains a specific glycan-binding region as the first contact area with the new host. Specific glycan-binding immune receptors e.g. C-type lectins recognize NTD of S Protein of CoV and exterminate the virus before its adaptation. [...] Strikingly, SARS-CoV-2 does not have a single amino acid (aa.) alteration or deletion on its glycan-binding region NTD of its S Protein compares to its parent virus BatCoV RaTG13. The flat and unsunken surface of SARS-CoV-2 NTD S Protein conflicting with the general adaptation and survival pattern of all CoVs.

And that's only the first difference of three. The second is that a "template-switching" model of coronavirus replication restricts mutations to certain sites. ("CoVs pause their replication on certain domains and have recombinations on these specific sites.") However, the second major mutation of SARS-CoV-2 involving the virus' use of host cell furin protease is not at one of these sites, and that suspiciously altered site continues to stubbornly not mutate in the wild:

However, other betacoronavirus lineage B members and the clinical strains of SARS-CoV-2 do not have any alterations on S Protein S1/S2 suggesting SARS-CoV-2 obtained this trait with a one-time unique event.

The third suspicious trait is similar; coronaviruses generally continue to adapt to the host in certain positive selection sites, including the receptor binding domain (RBD).

However, despite millions of SARS-CoV-2 infections, RBD has not indicated a single high-frequency aa. substitution suggesting the too-perfect angiotensin-converting enzyme 2 (ACE2) binding that was gained with a one-time alteration. Unlike the RBDs of other CoVs, SARS-CoV-2 RBD is not a positive selection site.

Besides the purely biological arguments, the author has some other evidence to bring to bear for bioengineering. Firstly, engineering coronaviruses was all the rage before a US moratorium on such research, and, possibly, afterwards. Secondly, coronaviruses are postulated to spread to humans through bat and camel droppings polluting the water supply, but China's bat diversity is relatively low and its water supply relatively safe from such issues.

The author concludes with a series of rhetorical questions reflecting what has come before:

The engineered origin of the SARS-CoV-2 was mainly rejected (Andersen 2020) the question is how SARS-CoV-2 survived the immunity of pangolins or humans during the very first interaction with its flat easy-target sialic acid-binding domain? SARS-CoV-2 indicate the low frequency of mutations on its RBD and how the virus obtained such effective RBD compositions without destroyed by pangolin or human immunity due to its easy target sialic acid-binding domain? Why only the RBD had mutations meanwhile the rest of the genome was almost unaltered? Betacoronavirus lineage B CoVs including SARS-CoV S Protein does not have a pattern of recombination on S1/S2 region how SARS-CoV-2 obtained that ability and how we do not see any further recombinations in the clinic SARS-CoV-2 strains? SARS-CoV-2 clinic strains do not have any high-frequency mutations on NTD and RBD how the virus obtained such perfect and precise host cell membrane interaction capacity, unlike SARS-CoV, perished due to its failed adaptation? Why we have not seen any pandemic caused by CoVs before? Why these pandemics did not emerge in places where people rely on water sources shared with bats or bats consumed as bushmeat? In summary, if SARS-CoV-2 is not an engineered Bat CoVs RaTG13, its unnatural host tropism pattern and pandemic potential compare to other human pathogenic CoVs raising those questions.

It's interesting that the author is suspicious of SARS-CoV-2 despite accepting the bat coronavirus BatCoV RaTG13 as its natural ancestor, because other made-in-a-lab theories are equally, if not more, suspicious of RaTG13 itself.

If you follow the conspiracy theories, you have probably heard of "batwoman" Zhengli Shi, a researcher from the Wuhan Institute of Virology who allegedly discovered RatG13 in 2013, although the sequence was not published until this January as part of a COVID-19 paper and (so the conspiracy theory goes) the samples may not be extant, if they ever were. (The alternative hypothesis is that the sequence was invented as a missing link to conceal the engineered nature of SARS-CoV-2.) Instead, the postulated ancestors of SARS-CoV-2 are BatCoV ZC45 and BatCoV ZXC21, plus Zhengli Shi. The similarities are explained at both the link above and in the related blog post.

If you're interested in more mainstream reporting on viral origins, ArsTechnica investigates a two-species origin theory, in which a pangolin takes on the role of Zhengli Shi. The source paper is here, with plenty of analysis of BatCoVs RaTG13, ZC45 and ZXC21, plus some PanCoVs.

PlagueBlog does not endorse any particular origin theory for SARS-CoV-2.

P.S. Massachusetts cases are up 0.36% today (probable cases included).

On the tin-pot mayors vs. state and federal constitutions front, a New Hampshire resident is suing the city of Nashua in Hillsborough County Superior Court South over face mask requirements exceeding those of the state.

In the lawsuit, Fojo argues that the city has failed to explain why its health officials are not heeding the guidance of the World Health Organization.

"The ordinance’s justification that 'slowing the spread' of the coronavirus is somehow still a societal objective also ignores the fact that the entire state of New Hampshire has been wildly successful at 'flattening the curve' since it never came close to reaching the capacity of its health care system," the complaint states.

The Bubonic Plague of Justinian

In The Guardian and elsewhere: a new journal article in the Lancet identifies the sixth-century Plague of Justinian as Yersinia pestis.

Professor Edward Holmes, from the University of Sydney, was one of the authors of the study, and said it was the oldest pathogen ever sequenced.
"This is the first complete genome from one of the most significant disease events in human history," he said.
The results showed the strains from the plague victims were distinct from those involved in the Black Death, the later pandemic which killed an estimated 60% of the European population.
The Justinianic strains appear to be an evolutionary “dead end” when compared with modern strains, and most likely originated from Asia and then spread to Europe along trade routes such as the Silk Road.

Plague and Hemochromatosis

I tweeted this a few days back, but today everyone decided to tell me about it. So here's the latest story about the scientist with undiagnosed hemochromatosis who died of the attenuated plague virus he was working with, a year and a half ago now.

Casadaban was conducting laboratory research on the bacterium that causes the plague when he became sick. The germ was genetically weakened and considered harmless to humans. It was considered so safe, Casadaban’s work with the live plague bacteria wasn’t noted when he fell ill, according to the CDC. A professor at the university for 30 years, by all accounts he had followed the proper safety protocols, the report said.
[...] An autopsy found the researcher had a medical condition called hemochromatosis, which causes an excessive buildup of iron in the body, according to the CDC report. The disorder affects about 1 in 400 people and goes unnoticed in about half of patients.
Casadaban’s illness is important because of the way the plague bacterium had been weakened. Yersinia pestis needs iron to survive. Normally it gets this iron by stealing it from a host’s body with proteins that bind to it and help break it down. To make the bacterium harmless, scientists genetically stripped it of the proteins needed to consume iron.

It seems hemochromatosis may not be the protection against Yersinia pestis its been made out to be.

BU's Leaky Biolabs

Via ProMED-mail: the Boston Globe reports on another BU researcher who accidentally brought his work home with him.

The genetic tests, conducted at the state laboratory in Jamaica Plain, compared a blood sample from the researcher with bacterial matter recovered from the lab where he was working on BU’s South End campus. “The bottom line,’’ said Dr. Anita Barry, top disease tracker at the Boston Public Health Commission, “is they matched.’’
The analysis erased any doubt about what caused the researcher to become sick last month and intensified investigations into precisely how he was exposed to a germ known as Neisseria meningitidis, which can cause meningitis.
The city’s biological lab safety division will review safety procedures in BU’s medical labs, to ensure that the school is doing everything possible to minimize researchers’ exposure to pathogens, Barry said.

I thought they did that last time.

PlagueBlog recommends moving to the suburbs before the new BU biolab opens downtown. And by "suburbs" I mean Maine.

Refrigerate After Opening

Via twitter: Wired reports on a company that's making beer from Eocene yeast recovered from amber.

Lambert and Cano had toyed with the idea for 12 years. Before Ambergene went under, the company made a batch on a lark. "We called it Jurassic Amber Ale or T-Rex Lager or something, and it was pretty good," Cano says. It was served at his daughter's wedding, and they even sent some to the Jurassic Park 2 cast party. That experiment had Cano and Lambert itching to release a beverage commercially. But they wanted it to be something respectable.

Needless to say, PlagueBlog recommends against eating anything that's over 40 million years old. In fact, only under the most extraordinary circumstances should you eat anything over 4 years old.

Anthrax Redux

Via ProMED-mail: The New York Times reports on the life and spores of the late Dr. Bruce Edwards Ivins.

Focused for years on the wrong man, the bureau missed ample clues that Dr. Ivins deserved a closer look. Only after a change of leadership nearly five years after the attacks did the bureau more fully look into Dr. Ivins’s activities. That delay, and his death, may have put a more definitive outcome out of reach.
Brad Garrett, a respected F.B.I. veteran who helped early in the case before his retirement, said logic and evidence point to Dr. Ivins as the most likely perpetrator.
“Does that absolutely prove he did it? No,” Mr. Garrett said. With no confession and no trial, he said, “you’re going to be left not getting over the top of the mountain.”

And doubts will persist:

In November, four of Dr. Ivins’s closest co-workers wrote a glowing obituary of their “valued collaborator” for Microbe, the leading microbiology journal. It did not mention the anthrax accusations and was a singular protest by the four scientists against the F.B.I.’s conclusion.
“His colleagues and friends will remember him not only for his dedication to his work,” the obituary said, “but also for his humor, curiosity and great generosity.”

Magic Finger Powder

Via plime: the BBC reports on an Ohio man who allegedly regrew a severed fingertip using his brother's experimental extra-cellular matrix.

"There are all sorts of signals in the body," explains Dr Badylak.
"We have got signals that are good for forming scar, and others that are good for regenerating tissues.
"One way to think about these matrices is that we have taken out many of the stimuli for scar tissue formation and left those signals that were always there anyway for constructive remodelling."
In other words when the extra cellular matrix is put on a wound, scientists believe it stimulates cells in the tissue to grow rather than scar.

Good Filoviruses Make Good Neighbors

Via Universal Hub: the Boston Globe reports on the NIH's Draft Supplementary Risk Assessments And Site Suitability Analyses for the National Emerging Infectious Diseases Laboratory Boston University. In short, there's no reason Boston University shouldn't build a new lab in the South End to play with Ebola:

Researchers at the State University of New York at Buffalo compared what would happen if germs migrated from the lab into its South End neighborhood with what might happen if the lab had instead been built on more secluded property owned by BU in Tyngsborough or Peterborough, N.H.
The report concludes that even if an accident happened in the lab "under realistic conditions, infectious diseases would not occur in the communities as a result." The study also concludes that "there was no difference in simulated disease transmission among the urban, suburban, or rural communities."

Nature Finds a Way

Eye on DNA reports on a mule who gave birth to a...mulette?

If a horse breeds with a donkey, they end up with sterile offspring that have 63 chrosomes - 32 chromsomes from the horse parent and 31 from from the donkey parent. Horse-donkey offspring aka mules are sterile because their odd number of chromosomes makes it technically difficult for chromosomes to pair up properly during the process of meiosis (cell divison of sperm and eggs). This should mean that mules cannot reproduce.
A female mule in Colorado has beaten insurmountable odds and given birth to a foal.

CDC Closes Texas A&M's Biodefense Lab

Via ProMED-mail: CIDRAP reports that the CDC has shut down Texas A&M's biodefense research lab for failure to report accidents.

In April, the Sunshine Project reported that a Texas A&M researcher had been infected with Brucella after a February 2006 aerosol chamber mishap and that the school did not immediately notify the CDC as required by federal law. Five days ago, the watchdog group reported that the exposure of three other Texas A&M workers to C burnetti, which causes Q fever, was confirmed in April 2006 but also was not reported to the CDC.

The CDC noted other concerns as well:

In the Jun 30 letter, the CDC outlined the concerns it has about the lab, which include the adequacy of biosafety plans, security of the facility from unauthorized visitors, occupational safety protocols, authorization from the CDC to work with certain agents, and compliance with federal select agent regulations.

Playing with the Spanish Flu

Nature has a Web focus on the 1918 flu virus. For a free account of the latest on Frankenstein's reconstituted flu virus, see this press release from the University of Wisconsin-Madison:

By infecting monkeys with the virus, the team was able to show that the 1918 virus prompted a deadly respiratory infection that echoed historical accounts of how the disease claimed its victims.

Shocking! But wait, there's more:

Importantly, the new work shows that infection with the virus prompted an immune response that seems to derail the body's typical reaction to viral infection and instead unleashes an attack by the immune system on the lungs. As immune cells attack the respiratory system, the lungs fill with fluid and victims, in essence, drown.

Somehow I doubt anyone spent the last 90 years believing that the victims were drowning in liquid flu virus. But on a more optimistic note,

The same excessive immune reaction is characteristic of the deadly complications of H5N1 avian influenza, the strain of bird flu present in Asia and which has claimed nearly 150 human lives, but has not yet shown a capacity to spread easily among people.
"What we see with the 1918 virus in infected monkeys is also what we see with H5N1 viruses," Kawaoka says, suggesting that the ability to modulate immune response may be a shared feature of the most virulent influenza viruses.

At least these guys are playing with Frankenstein's Flu at biosafety level 4 this time:

In the new study, conducted in a high-level biosafety laboratory (BSL 4) at the Public Health Agency of Canada's National Microbiology Laboratory, seven primates were infected with the reconstructed 1918 virus. Clinical signs of disease were apparent within 24 hours of infection, and within eight days, euthanization was necessary. The rapid course of the disease mirrors how quickly the disease ran its course in its human victims in 1918.

Not in My Front Yard

Here in Boston, Maura Hennigan is running for mayor. She is against the construction of a biosafety level four lab in the city of Boston:

Over 150 scientists, including two Nobel laureates from Harvard have openly opposed the Biolab by sending a letter to Tom Menino. These 150 scientists, physicians, public health specialist, and academics oppose the Biolab being built in a densely populated urban area; there are 50,000 people within one mile and more than one million people within 10 miles of the proposed site.

The election is Tuesday, November 8th.

The Plague Mice

ABC News reports that at least three mice infected with Yersinia pestis have been missing from the Public Health Research Institute in Newark, NJ for at least two weeks. The FBI Joint Terror Task Force and the CDC are investigating.

"We're satisfied that there is no public safety risk, and there doesn't seem to be any nexus to criminal activity or terrorism," he added.
Nevertheless, federal authorities, including the FBI, have criticized the lab for lax procedures that resulted in a potential public health menace.
"This is the black death," said Richard Ebright, a microbiologist at Rutgers University. "This is the disease that killed a quarter of Europe's population."

From the Yes This IS Your Grandfather's Influenza department...

CNN reports on the unwise distribution of 1957's Asian flu (A, H2N2) to 4,000 laboratories worldwide for testing.

The samples, part of a package of pathogens sent to laboratories to test their ability to identify them, were last seen in nature in the United States in 1968, Gerberding said. Anyone born since then would presumably have no immunity to the virus, she said.
Gerberding said authorities were still trying to determine how many laboratories got the samples of the virus, called Influenza A H2N2.

Thanks to an unnamed source, who also mentioned The Unsung Vaccinologist:

Joining Merck in 1957, he mobilized the production of 20 million doses of flu vaccine, protecting the country from one of the last great flu pandemics.

Cryogenic Bacteria

The Environment News Service reports on frozen microbes: they weren't infectious, but bacteria unearthed from the Alaskan tundra five years ago came to life in the lab after 32,000 years at -4° Celsius. It's taken the past five years to prove that it's a new species.

Commenters at Slashdot note that bacteria have been revived after 25 million years.

Tularemia (Lab Exposure)

The dirty bomb scare here in Boston is distracting from another bit of terrorism-related news: three researchers at BU were infected with tularemia in, apparently, at least two separate lab accidents. The cases, which have been attributed to violations of safety procedures, were discovered by November but were concealed from the public during hearings about BU's planned high-security bioterrorism research lab.

These are not the people I want juggling vials of smallpox in South Boston.

The Spanish Flu Gene

Those Spanish Flu revivalists have sent some results to Nature. They've been killing mice with their Frankenstein Flu. This New York Times article goes into more detail about the deadly hemagglutinin (HA) gene the researchers now suspect caused the extraordinary virulence of the 1918-1919 epidemic.

Even more disturbing than the resurrection itself, the researchers have decided that the virus behind the worst epidemic of all time (20-50 million people dead in the space of a year) no longer requires a Biosafety Level 4 containment; they'll just make do with the Level 3 facilities at the University of Washington.

PlagueBlog recommends against travel to Washington State this winter.

Resurrecting the Spanish Flu

The Simon criticizes efforts to resurrect the Spanish Flu from cadavers at the University of Washington. Thanks to Fludemic for the link.