Leave the bats in their caves: it's time to put an end to gain-of-function research on viruses

Why have scientists spent years exploring remote bat caves, pulling out bats infected with novel coronaviruses, and transporting them (or at least samples of infected tissue) into major cities? If you asked the scientists, they’d explain that their research would help prevent the next pandemic. Instead, they might have caused it.

A newly released set of documents, including a rejected grant proposal, shows that a group of scientists at EcoHealth Alliance, a nonprofit research institute in New York, was pursuing “gain of function” research, together with scientists at China’s Wuhan Institute of Virology, that had the potential to create dangerous new strains of coronaviruses. But before I get to that, let’s consider how we got here.

Eight years ago, I wrote an article warning that “scientists will create a deadly new flu strain, just to prove they can.” Those scientists, who were focused on the influenza virus at the time, were boasting about their ability to create pandemic-type viruses in the lab. Don’t worry, they said, we are very careful and these viruses will never leak out into the real world.

Soon after that, these same scientists–Ron Fouchier of Erasmus University and Yoshihiro Kawaoka of the University of Wisconsin–published a paper proving that they had done just that. I wrote another article, asking:

“Should scientists be artificially mutating viruses so that they have the potential to become a worldwide pandemic?”

I wasn’t the only one questioning the wisdom of pursuing this line of research. Hundreds of scientists formed a consortium, the Cambridge Working Group, opposed to gain-of-function research on influenza and other deadly viruses. In response, the Obama White House formed a commission in 2014 to evaluate the risks and benefits of gain-of-function research in viruses.

At the same time, the US instituted a pause on all research that could “confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals.” That was a good step. (Covid-19, which didn’t exist at that time, is in the SARS family of viruses.)

In early 2017, after all the noise and protests died down, NIH quietly lifted the pause, allowing the research to resume again. Many scientists objected again, including me. I wrote that

“engineering the flu to be more virulent is a terrible idea.... this research is so potentially harmful, and offers such little benefit to society, that I fear that NIH is endangering the trust that Congress places in it.”

This time, though, the NIH dismissed the concerns of scientists like me and all those in the Cambridge Working Group, basically saying “don’t worry, we’ll be careful.” (I also got the sense that NIH didn’t like having outside scientists second-guessing their decisions, but maybe that’s just me.)

Just out of curiosity, let’s look at some of the warnings from the Cambridge Working Group. They pointed out that if things went wrong, gain-of-function research might create a pandemic virus that, if it accidentally escaped, could kill at least 2,000 people per year. At the high end, warned scientists Marc Lipsitch and Thomas Inglesby in a paper published in late 2014, the world might see 1.4 million deaths per year.

Unfortunately, the higher estimate was too low: Covid-19 has now killed over 4.8 million people in 21 months. Of course, we don’t know if gain-of-function research was responsible.

After lifting the pause, NIH quickly restored funding to gain-of-function flu research, in projects such as “Transmissibility of avian influenza viruses in mammals,” which was led by the University of Wisconsin’s Yoshihiro Kawaoka. What’s more unfortunate, though, is that in 2019 the NIH funded another grant, on coronaviruses in bats (which includes SARS-CoV-2, the Covid-19 virus), to a research institute called the EcoHealth Alliance, led by virologist Peter Daszak.

Now, back to that new tranche of documents that I mentioned at the top of this article.

EcoHealth Alliance has received a huge amount of negative attention over the past year and a half, because they work closely with the Wuhan Institute of Virology (WIV), an institute in China where gain-of-function work on coronaviruses was apparently being pursued. WIV is at the center of the “lab leak” hypothesis, which posits that the Covid-19 pandemic begin with an accidental release of viruses from the lab in Wuhan.

So far, we don’t know if WIV had any role in starting the pandemic, but the circumstantial evidence at least makes this credible, as I wrote last year. WIV’s scientists have collected hundreds of infected bats from distant caves and brought them back to Wuhan for study. Some of that work–collecting those viruses–was funded by a grant from NIH to EcoHealth Alliance.

Government officials, particularly the leaders of NIH and NIAID, Francis Collins and Anthony Fauci, have insisted that NIH never funded gain-of-function research on coronaviruses. In May of this year, Collins issued a statement that

“neither NIH nor NIAID have ever approved any grant that would have supported `gain-of-function’ research on coronaviruses that would have increased their transmissibility or lethality for humans.”

I believe this statement is true; however, note the very careful qualification there. NIH isn’t saying that it never funded any GoF work on coronaviruses–because it apparently did, if you look at the NIH grant to EcoHealth Alliance. That grant mentions “in vivo infection experiments” which suggests that they were infecting mice with coronaviruses. So the NIH statement only says the work would not have made coronaviruses more infectious or more lethal in humans. That’s a very narrow statement.

The newly released documents, uncovered and released by a group called DRASTIC, includes a grant proposal from EcoHealth Alliance to the US Department of Defense. This $14M proposal describes gain-of-function research intended to make SARS viruses more virulent, and that might give those viruses the ability to infect mammals. Fortunately, the DoD didn’t fund the work, but EcoHealth Alliance was clearly very interested in this line of research.

The proposal itself describes how EcoHealth would genetically engineer new viruses, taking the spike protein from one bat coronavirus and inserting it into a different one, and then infecting mice to see what happens. For technical reasons, the proposal says that this process is “exempt from dual-use and gain of function concerns.” However, the DoD reviewer who rejected the proposal disagreed, stating that the proposal “does not mention or assess potential risks of Gain of Function (GoF) research” and that it “does potentially involve GoF research.”

But the danger goes beyond gain-of-function research, a point that is often missed. EcoHealth Alliance also proposes to take “a complete inventory of bats and their SARSr-CoVs at our invention test site cave complex in Yunnan, China that harbors bats with high-risk SARSr-CoVs.” (This was written before the Covid-19 pandemic, obviously.) Previous work by EcoHealth Alliance, including work funded by NIH, involved the same strategy: going out into remote caves and collecting bats with “high-risk” coronavirus infections.

What the heck are they doing? Why are scientists going to remote sites and collecting infected animals and then bringing them back into the middle of cities?

The argument was (and is) that research on these viruses will help us to develop better vaccines and better treatments, and to respond to the next pandemic. We’ve been hearing this for years from the influenza scientists doing gain-of-function work.

For years, I’ve been saying that these claims of theoretical future benefits from gain-of-function research are nonsense. For example, in 2014 I wrote that

“to claim that creating super-viruses in the lab will lead to `improved surveillance’ is, frankly, laughable.”

Well, the next pandemic has arrived. Did all of that gain-of-function research help us fight it? No.

All of the gain-of-function research, and all of the efforts to collect high-risk viruses out in the field, did nothing to help us stop the pandemic. It didn’t help us design better vaccines (although the mRNA vaccines are terrific), it didn’t help us develop better treatments, and it didn’t help us with any public health measures.

It’s long past time to put an end to dangerous work that creates novel, incredibly dangerous viruses in the lab. All of the claims of supposed benefits have now been shown to be little more than hand-waving. (I could use a more vulgar term, but I won’t.)

It’s also time to ask, very critically, whether anyone should be venturing out into remote areas to collect animals that are infected with possible pandemic-causing microbes, and bringing those animals back to densely populated areas. Rather than preventing pandemics, these activities are more likely to cause them.

Look, I know that the lab-leak hypothesis is just that: a hypothesis. It might be that the Covid-19 pandemic was caused by a natural event, when a virus from a wild bat infected a human. It might also turn out that the pandemic started with an accidental infection in a lab, possibly in the Wuhan Institute of Virology where thousands of bat viruses were collected and studied. We might never know.

But one thing has clearly changed. We now largely agree that a virus collected in a lab could cause a worldwide pandemic, killing millions of people. We also have evidence, staring us in the face, that many years of gain-of-function research gave us no help in fighting the pandemic.

It’s time to put a permanent end, not just a pause, to any research that makes pathogens more deadly. And while we’re at it, we should re-examine any research that collects viruses or other pathogens from wild animals, asking if that research too might be more likely to harm than to help humankind. From where I’m sitting, the answer is clear.

What do Trump and Yale Medical School have in common? Both were duped about hydroxychloroquine

Hydroxychloroquine, promoted just a few short weeks ago as a cure for COVID-19, is useless.

Actually, it's worse than that. Hydroxychloroquine causes heart arrythmias, which can be fatal. Data from early trials of hydroxychloroquine show that it is killing people, not saving them.

Why, then, are so many people talking about hydroxychloroquine? The answer is a tale of scientific hubris and incompetence bordering on fraud. It's also a tale of how Yale Medical School and the Trump administration both fell for it.

Part 1: the hubris of a French "science star."
Last week, the New York Times ran a lengthy profile of Didier Raoult, a French microbiologist who the Times lauded as a "science star." Raoult vaulted into the public eye in March, when he published a very small study claiming that a combination of hydroxychloroquine, an anti-malarial drug, and the antibiotic azithromycin could cure COVID-19. Claimed Raoult:

"We know how to cure the disease" (Didier Raoult, quoted in the NY Times)

Actually, Raoult's proclamations began earlier, on February 25, when he posted a video on YouTube called "Coronavirus, game over." Not surprisingly, the world took notice. (Note that as the evidence for his so-called treatment evaporated, he re-titled the video "Coronavirus, towards a way out of the crisis.")

Raoult's study was deeply flawed, and it has been taken apart by multiple scientists, so I won't repeat all their points here. A good summary of many of the flaws was written by Elisabeth Bik, first on Twitter and then in a blog article, back in late March. Among other flaws, the study dropped 6 of the 26 patients who were given hydroxychloroquine without explaining why. One of those patients died. “My results always look amazing if I leave out the patients who died,” Bik commented.

Raoult is not happy with Dr. Bik. He recently called her a "witch hunter" on Twitter. This apparently is not unusual for Raoult; the NY Times compares his psychology to that of Napoleon. I wonder what he'll call me after this article appears.

In addition to its serious flaws, the paper was published in a journal whose editor-in-chief, Jean-Marc Rolain, was also a co-author on the paper. Even worse is the fact that, as the journal itself notes, the paper was accepted just one day after being submitted. Clearly, this paper did not undergo careful peer review, and it reeks of extremely sloppy science.

Since then, several larger, better-run studies have either found no benefit for hydroxychloroquine, or found actual harm. To be specific, a study of 368 patients in US Veterans Administration hospitals found that the mortality rate in patients given hydroxychloroquine was 27.8%. Patients who received both hydroxychloroquine and the antibiotic azythromycin had a mortality rate of 22.1%. But patients who did received neither one had a mortality rate of 11.4%.

In other words, giving patients hydroxychloroquine doubled their risk of dying.

One final note about Didier Raoult: he has a truly unbelievable number of scientific publications, over 2,800 according to PubMed. From 2012-2019, he averaged 176 papers per year, or about one paper every two days. Speaking as a scientist, it simply isn't possible that he made any real contribution to the vast majority of these papers. The NY Times explained that Raoult puts his name on every paper published by his institute, which employs hundreds of scientists. Again, speaking as a scientist, this is grossly unethical. No scientist should put his/her name on a paper unless they made a genuine scientific contribution to it. At many universities, Raoult's behavior would be grounds for dismissal.

Part 2: Trump and Yale Medical School fall for it.
As the NY Times reported, and as most of the U.S. knows, Trump began touting the benefits of hydroxychloroquine at a news conference on March 19:

“I think it’s going to be very exciting. I think it could be a game changer and maybe not. And maybe not," Trump said.

Right. Soon after that, the FDA, "under what appears to have been strong pressure from the Trump administration," issued an emergency use authorization for hydroxychloroquine.

Medical experts, including NIAID director Anthony Fauci, quickly injected a note of caution, pointing out that the evidence was very preliminary, and that we needed better studies. Nonetheless, Trump and his political allies ran with the news that a "cure" was available. They were wrong.

Perhaps most disturbing, though, was the behavior of some highly regarded doctors, who also fell for Didier Raoult's hype. One might excuse politicians for being fooled–they don't have the training–but the same excuse doesn't work for a medical expert.

And yet on March 26, Yale Medical School boldly tweeted out its "Treatment algorithm for COVID19," promoted with two megaphone icons:

Attached to the tweet was a graphic of a flowchart, showing that the first steps in their treatment algorithm were hydroxychloroquine and atazanavir. At the time, I replied to their tweet and warned them that there was no good evidence for their recommendations. Their response:

"While there are no FDA approved treatments for COVID19, this protocol is based on available knowledge, personal observations & communications from other institutions. In the absence of firm evidence for best treatments, this is intended as a working document & subject to change."

Well, at least they responded. But in their response, they admit that their protocol is based on anecdotal evidence and little else. This is seriously disappointing, coming as it does from one of the nation's top medical schools. It also displays hubris not that dissimilar from Didier Raoult's.

Now that more evidence has emerged, and we know that hydroxychloroquine doesn't help and probably harms COVID19 patients, has Yale updated its treatment protocol? Well yes: they tweeted out a new algorithm on May 15. Now it says:

"Consider hydroxychloroquine x 5 days with close cardiac monitoring."

This is truly appalling. The only evidence of efficacy was the small, badly-run study promoted by Didier Raoult, which has now been contradicted by much larger, better run studies. We now know that hydroxychloroquine is harmful. Others on Twitter quickly questioned the new Yale recommendation, but it's still there as of this writing.

So there you have it. As of this writing, many so-called experts are still pushing the use of an ineffective, dangerous drug that doesn't help, and may harm, people infected with the SARS-CoV-2 coronavirus. A bogus claim promoted by a self-important, egotistical scientist who published a sloppy study in a journal run by one of his co-authors turned into millions of doses of medication wrongfully prescribed.

And for now, Yale Medical School still hasn't admitted any error. I'm waiting.

[Note: I am an alumnus of Yale University, and I have long been one of its biggest fans. I did not attend medical school there, but their unscientific behavior is nonetheless especially disappointing to me as an alum.]

The first at-home coronavirus test is out, and it's useless

The FDA and a major laboratory testing company, LabCorp, just announced the first FDA-approved at-home test for COVID-19.

The problem is, it's almost useless. Here's why.

1. It's far too expensive, at $119 per test. Only wealthy people will be able to take advantage of this.
2. The kit itself (called the Pixel) is little more than a long Q-tip and saline solution. As the FDA describes it:

"LabCorp’s molecular test permits testing of a sample collected from the patient’s nose using a designated self-collection kit that contains nasal swabs and saline."

Your $119 pays for FedEx shipping both ways and for the actual test, which is done at LabCorp's facility.
3. It's far too slow. You have to apply for the kit, get it authorized by a physician, wait for the kit to arrive, ship it back, and only then will LabCorp run the test. You find out the results online. This sounds like it will take at least 5 days, probably a week. Much faster tests are available already for those who can drive to a testing site.
4. LabCorp doesn't have many of the kits available yet. Their own website, citing "limited quantities," says they will only sell the kits to healthcare workers and first responders for now.
5. For unexplained reasons, the company states that the kits aren't available at all in New York, New Jersey, Maryland, and Rhode Island. As everyone knows by now, New York has more cases than any other state in the country.

I was briefly excited when I saw this announcement. It turns out to describe a low-volume, overpriced test that will likely have little or no impact on the pandemic. We need millions of tests, freely available to everyone, not a small number of expensive tests only available to a few.

Coronavirus: time to panic?

The world is starting to panic over the 2019 coronavirus outbreak. Are we over-reacting?

Here are 3 reasons why we should panic, followed by 4 reasons why we shouldn't.

1. The virus, 2019-nCoV, is completely new to humans, and we don't know exactly how bad it will get. As of 29 February, it has already killed nearly 3,000 people, over 2,700 of them in China. 
2. It appears to be very infectious. Cases are now appearing in people who didn't travel to China, and who didn't have any contact with known cases. Coronavirus illness (newl named COVID-19) has now been reported in over 60 countries, on every continent except Antarctica. No matter where you are, it is probably coming your way.
3. The mortality rate has been reported to be as high as 2%.  The Johns Hopkins University tracking site makes it appear even higher, with 2,933 deaths out of 85,688 cases, which is over 3%. By comparison, the 1918 Influenza pandemic had a mortality rate of around 2-3%, and in that epidemic, the worst in modern history, 30–50 million people died, which was 1.7% of the world's population at the time.  Extrapolating to today's population of 7.7 billion people, a virus that deadly would kill 130 million people.

This seems really bad. So perhaps we are not overreacting.

On the other hand, there are several very good reasons why we should stay calm.

1. The mortality rate is probably much, much less than 2%. The rapid spread of COVID-19 suggests that many more people are infected than those who have confirmed cases. The number of people who have no symptoms or very mild symptoms is likely to be ten times as high as the number of reported cases. (This is only a guess.) That would mean the mortality rate might be only 0.2%, or even lower. We still don't know. (The cruise ship that was quarantined in the Japan had just over 700 cases, and 6 people have died, suggesting a mortality rate of 1%.)
2. The reported mortality rate is dramatically lower in young people. If you are under 30, you can probably relax a bit. However, if you are over 70, the mortality rate is frighteningly high, 8-15%. 
3. 2,933 deaths is a tragedy, but it's a tiny number compared to the annual deaths from the influenza virus, which we have learned to live with. In the U.S. alone, the CDC estimates that 12,000–61,000 people die each year from the flu (the number varies a lot because the virus itself changes from year to year), and 9-45 million people get sick. The worldwide totals are far higher. So in terms of numbers, the world is definitely over-reacting to the new coronavirus.
4. Infectious viruses tended to become milder over time. At least 4 other coronaviruses already circulate among humans, causing little more than mild cold symptoms. It is quite possible that the virus causing COVID-19, nCoV-19, may mutate to become a milder disease as well. RNA viruses mutate extremely rapidly, and from an evolutionary perspective, viruses adapt to their hosts by becoming milder. (My perspective is based in part on my past research on the influenza virus.) From the virus's point of view, it can't spread itself around if the host is too sick.

What can we do? A few things:

1. Panic isn't helpful. Don't panic.
2. In the short term, the best response will be to develop a vaccine. (Dr. Peter Hotez and colleagues at Baylor College of Medicine are already working on one.) We need to dramatically increase government investment in vaccine development. It seems that the U.S. is doing that, although not quickly enough.
3. If you feel sick, stay home.
4. It's probably best to avoid travel to a location where COVID-19 is known to be circulating widely. Right now this list includes China and Iran, but it could grow in the coming weeks.
5. In the longer term, we need to increase rather than cut biomedical research funding. Even if we get a vaccine, we still need actual treatments, not only for COVID-19 but for other viruses. (Most viruses are incurable with current technology.) The recent proposal out of the White House aims to cut NIH funding by 7% and CDC funding by 16%. As anyone following the coronavirus news now realizes, the CDC is responsible for tracking the virus in the U.S. and for coordinating our public health measures to respond to the outbreak.

Finally, I should add a note of caution about the bogus treatments already being hawked by peddlers of pseudoscience. There are multiple websites and Facebook pages, including some anti-vaccine sites, already claiming they know how to treat coronavirus illness. (I won't link to any of them, as I don't want to give them the traffic.) These are complete scams. No one has any treatment that will prevent or cure COVID-19, but if we make the investment, we'll get a treatment one day.

(Note: the WHO has renamed the virus SARS-CoV-2, but The Lancet article that first described its genome calls it nCoV-19.)

Research on artificially engineered flu strains expected to kill 2000 people per year

2,000 deaths expected for each year of research on how to turn avian flu into a more deadly virus. 

That’s the estimate in a new analysis by Harvard University’s Marc Lipsitch, professor and director of the Center for Communicable Disease Dynamics in the Harvard School of Public Health.

I heard Lipsitch present his results at an invitation-only hearing held at the National Academy of Sciences on December 15. The purpose of the two-day meeting, which was organized by the National Science Advisory Board for Biosecurity (NSABB), was to discuss the risks and benefits of “gain of function” research on viruses, especially the influenza virus.

What is gain-of-function (GOF) research? In this context, GOF means experiments designed to give a pathogen new powers, such as the ability to infect new species, or to jump from person to person more easily. Scientists have already conducted GOF experiments on the flu virus, and now they are considering other viruses including SARS and MERS.

What prompted the NSABB hearing was the series of experiments by researchers in the U.S. and the Netherlands designed to transform avian influenza (or “bird flu”) into a human-transmissible virus. These novel, lab-created flu strains have the potential to cause a worldwide pandemic. When virologists Ron Fouchier and Yoshi Kawaoka first published their experiments two years ago, the public, the press, and many members of the scientific community (including me; see here and here) expressed serious alarm. After a brief hiatus, though, the experiments continued. 

In mid-October, the U.S. government announced a “pause” in gain-of-function experiments, which has Fouchier, Kawaoka, and their colleagues very upset.

At the NSABB meeting in December, the vast majority of panelists were influenza researchers defending GOF research, arguing that it could lead to valuable insights about the flu. As a group, they seem to have convinced themselves that everything is fine, and they want to tell the rest of us that there’s nothing to worry about. Prof. Lipsitch (and a couple of other speakers) stood out as a voice of reason. He was one of the very few scientists who took a hard look at the risks and also pointed out alternative, low-risk methods for answering the same scientific questions.

Lipsitch conducted a careful risk analysis (something apparently not even considered by Fouchier and Kawaoka) looking at the chances of a virus escaping a lab, of such a virus causing further infections, the likely number of fatalities, and more. It turns out that the scientific community has excellent data quantifying all the key variables involved, as Lipsitch documented. He and his colleague Tom Inglesby just published these figures, with supporting data, in the journal mBio.

Using conservative estimates, many of them provided by influenza researchers themselves, Lipsitch calculated that for each year of gain-of-function research on pandemic viruses, we can expect at least 2,000 fatalities worldwide. And that’s only the low end: at the other extreme, this estimate rises to 1.4 million fatalities per year.

Lipsitch also described many other ways to study and defeat influenza, all of them with little or no risk, which he’s published in the journal PLoS Medicine. His point is that even if we accept the supposed benefits of GOF research, there are far less risky ways to obtain those same benefits.

One of the most ironic–or outrageous–claims of the pro-GOF scientists is that these experiments will help us predict future pandemic flu strains, and even help us design a vaccine in advance of outbreaks. The irony is that this year, the seasonal flu vaccine is a poor match to the strains that are circulating. This vaccine was chosen only 9 months ago, based on extensive surveillance of circulating flu strains, demonstrating how difficult it is to predict even the regular seasonal flu. As a result, we’re having a very bad flu season this year (aside: it's still worth getting the flu vaccine).

During the discussion at the NSABB meeting, an audience members observed that the claims of Fouchier, Kawaoka, and other pro-GOF scientists is hubris. She pointed out that not only are they claiming that they can predict future outbreaks–which no one has ever done accurately–but that we should invest billions of dollars stockpiling specially-designed vaccines based on their predictions. (This was indeed suggested by one of the presenters.) 

2000 deaths per year. And that’s only the direct risk: what about the risk from publishing these experiments? What happens when we provide instructions on how to build deadly biowarfare agents to anyone with an internet connection? Indeed, “gain of function” research on pandemic pathogens is really biowarfare research, which supposedly ended after the Cold War.

I’m a huge supporter of biomedical research and of NIH in general. NIH research has yielded tremendous benefits to the public health, as I’ve written before. We don’t need to overreact by cutting medical research in general, but we can make the “pause” in gain-of-function research permanent. There are far better things to do with our research funds. If you want to register your concerns, write to the NSABB at nsabb@od.nih.gov and tell them to recommend a permanent halt to gain-of-function research on pathogenic viruses.