Gain-of-function research on viruses justifies itself with a scientific error

We still don’t know where Covid-19 started, although we’re pretty sure it started in or near the city of Wuhan, China. The leading theories are that it started either in the Huanan Wholesale Seafood Market (in Wuhan), a live animal food market, or in the Wuhan Institute of Virology (WIV), a large virus research center in another part of the city.

We might never know, because we’d need access to all of the viruses being studied at WIV in late 2019, and those viruses might not even exist any longer.

I’ve been on the fence about this question since the pandemic started (as I wrote here and here and here), in part because we just don’t have enough data. However, I’m now starting to lean more strongly towards the hypothesis that the Covid-19 virus started in the Wuhan Institute of Virology. I just listened to the interview that Sam Harris did with science journalist Matt Ridley and biologist Alina Chan, who together wrote an entire book on the origins of Covid-19, and the evidence they compiled is compelling.

Let’s look at a few key points.

First, the virus itself, SARS-CoV-2, almost certainly originated in bats, and those bats almost certainly came from caves in southern China, over 1000 kilometers away from Wuhan. The bats didn’t get to Wuhan on their own.

So either someone transported bats to the Huanan Seafood Market, or they transported viruses from the bats to WIV. These are our choices.

Second, WIV was doing research on coronaviruses for years. Their scientists traveled regularly to caves in southern China to find novel viruses, and they’ve acknowledged that WIV’s labs had bat viruses, including viruses related to SARS-CoV-2, before the pandemic began.

Third–and this point is under some dispute–many scientists have argued that the virus was a naturally-occurring one. However, this doesn’t make it more likely that the virus originated in the seafood market. It’s just as likely that a scientist or technician working at WIV was accidentally infected, and then went home (maybe stopping by the seafood market on the way) and started a worldwide pandemic.

Fourth, it’s hard to believe that it’s merely a coincidence that one of the top virology labs in China just happened to be located in the city where the pandemic began. WIV was not only the foremost lab in China doing work on SARS-like viruses, but they also claimed previously that they intended to do gain-of-function work to make these viruses more pathogenic.

This startling fact emerged when a 2018 grant proposal by EcoHealth Alliance, a US-based nonprofit that was working with WIV, was leaked to the press in 2021. Even though that proposal was never funded, the text 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.

But wait, some will say: we now have peer-reviewed studies pointing to the seafood market as the epicenter of the pandemic. (I wrote about those studies back in March 2022.) However, as Alina Chan and Matt Ridley explained to Sam Harris (and in their book), the Chinese authorities in early 2020 focused all their attention on the seafood market, to the exclusion of anywhere else. They collected loads of samples from people who had been in or near the market, and very little from anywhere else. Thus we seem to have a classic case of confirmation bias: when you only look at the place where you’re convinced the virus originated, and you find some evidence, then you stop looking. We simply don’t know if the virus was anywhere else.

Now, to the main topic for today: the scientific error used to justify gain-of-function research on dangerous viruses, the error that might have led to the Covid-19 pandemic. Let me explain.

Why, one might ask, were scientists from the Wuhan Institute of Virology going out into the wild, to places where humans would not otherwise go, and bringing back deadly viruses?

This doesn’t just happen in China. The US is funding a large effort to do exactly the same thing: through a program called DEEP VZN (”deep vision,” get it?), USAID is funding scientists in the US and in Africa, Asia, and Latin America to venture into unpopulated areas of the jungle, and to find animals carrying viruses that might infect humans. They’re hoping (!) to discover 8,000 to 12,000 new viruses, and they’re particularly interested in viruses that could cause the next pandemic.

Why does anyone do this? Virus hunters believe that through these efforts, they can predict which of these viruses are destined to become the next pandemic. Furthermore, the argument goes, through gain-of-function research, virologists will be able to determine just what the new pandemic strains will look like. Then, armed with this knowledge, they can convince governments and private companies to design, manufacture, and stockpile vaccines against these viruses. This way (the argument goes) when the pandemic emerges, we’ll be ready.

At the center of this scientific strategy is an obvious error about evolution.

I’ll have to get a bit technical to explain here, so bear with me: the genome of the SARS-CoV-2 virus contains about 30,000 bases of RNA. The key protein that lets it infect human cells is called the Spike protein, which is about 1300 amino acids long and is encoded by about 3900 RNA bases. RNA has an alphabet of 4 letters (A, C, G, and U), which means that each of those positions can mutate into one of the other 3 letters. So we have almost 12,000 possible mutations that affect just one base in the Spike protein.

But 2 or more mutations can happen at once, quite easily, and this too could make the virus more infectious. How many combinations of 2 positions and 3 mutations are possible? Well, about 650,000,000.

And these aren’t the only mutations that might create a pandemic virus. So we’re supposed to believe that:

1. gain-of-function experiments in the lab will create precisely the same mutations that would happen in the wild, and
2. virologists can then predict, based on their experiments, that a virus is likely to cause a pandemic, and
3. this evidence is so convincing that governments will manufacture and stockpile vaccines based on these experiments, and
4. that this in turn will allow us to prevent the next pandemic.

Yeah, right. The evolutionary mistake is in the first point above, by the way.

Something happened in Wuhan. You might think that virologists, upon hearing about the gain-of-function research at WIV, would pause and think, oh no, we hope our colleagues’ research didn’t cause the pandemic! But instead, they closed ranks and doubled down.

In case you think I’m exaggerating, consider this: just a month ago, 156 virologists co-authored an article in the Journal of Virology that declared:

“gain-of-function research-of-concern can very clearly advance pandemic preparedness and the development of vaccines and antivirals. These tangible benefits often far outweigh the theoretical risks posed by modified viruses.”

In case that wasn’t clear enough, they assert twice more in the article that gain-of-function research will help us prepare for pandemics.

Virologists have been making this argument for years, and yet their experiments had no benefit at all–none, zero, zip–when we were finally faced with a true pandemic. Why should we believe this claim now?

Instead, it’s possible that gain-of-function research, along with the search for novel viruses in the wild, might have accidentally caused the pandemic.

Let me conclude by emphasizing that the vast majority of research on viruses and infectious diseases is incredibly important. Vaccines, antibiotics, antivirals, and other treatments have saved millions of lives, and the scientists doing this work should be applauded. Shutting down dangerous gain-of-function research–by which I mean research designed to take a virus or bacterium and make it more deadly in humans or in other animals–would only affect a tiny percentage of virologists worldwide. Let’s tell them to stop. If they can’t find something better to do, other scientists can.

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.

Why the "Lab Leak" Hypothesis Doesn’t Mean the COVID-19 Virus was Engineered

The “lab leak” hypothesis about the origin of Covid-19 has been getting a lot of attention lately, and deservedly so. This is the idea that the SARS-CoV-2 virus accidentally escaped from a laboratory in Wuhan, China, that conducts research on coronaviruses. Just a few weeks ago, a group of highly respected virologists and epidemiologists published a letter in the journal Science calling for a more thorough investigation, stating that the lab leak hypothesis was not taken seriously enough in earlier investigations.

The coincidence of having a major virus research facility, the Wuhan Institute of Virology (WIV), just a short distance from the live animal food market that was originally believed to be the source of the outbreak is too great to ignore. Even more curious is that WIV was actively doing research on coronaviruses in bats, including the bats that carry a strain of SARS-CoV-2 that is the closest known relative to the Covid-19 virus itself.

From the beginning of the outbreak, attention was focused on WIV, and various conspiracy theorists suggested, without any evidence, that the Covid-19 virus was either intentionally engineered, intentionally released, or both. Let me just say right off the bat that I don’t believe either of those claims.

However, I do think the lab leak hypothesis is credible, and it’s also possible that “gain of function” research (more about this below) might be responsible.

In arguing against (unsupported) claims that the Chinese released the virus on purpose, a group of virologists published a paper very early in the pandemic, in March 2020, which looked at the genome sequence of the virus and concluded that “SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.” Other studies since then have come to similar conclusions: the virus is very similar to naturally-occurring coronaviruses, and it is possible that it simply evolved naturally in the wild, probably in bats.

Even so, the lab leak hypothesis remains highly credible, regardless of whether or not the virus was genetically engineered. Here’s why. First, we know that lab accidents can happen and viruses can escape, even if these accidents are rare. We also know that the Wuhan Institute of Virology had thousands of viruses, including coronaviruses, in its facility. And despite claims that viruses couldn’t possibly have escaped accidentally, a 2017 Nature article describing the then-new Wuhan Institute reported, perhaps prophetically, that “worries surround the [Wuhan Institute of Virology], too. The SARS virus has escaped from high-level containment facilities in Beijing multiple times.”

The secrecy of the Chinese government, which has not yet allowed independent, outside scientists full access to WIV to investigate, hasn’t helped matters. We need to know if any viruses in WIV are similar to the Covid-19 virus, and at this point we can’t trust the Chinese government’s assurances on this question. Of course, even if they allow outsiders to investigate now, we cannot know that they have preserved all the viruses that were present in the lab in the winter of 2019-2020.

Now let’s talk about gain-of-function research. Gain of function, or GoF, refers to research that tries to make viruses or bacteria more harmful, by making them more infectious. This seems crazy, right? And yet it’s been going on for years, despite the efforts of many scientists to stop it. In the past, GoF research focused on the influenza virus, and in particular on a small number of scientists (highly irresponsible ones, in my view) who were trying to give avian influenza–bird flu–the ability to jump from birds into humans. I wrote about this in 2013, and in 2017, and again in 2019, each time calling on the US government to stop funding this extremely dangerous work. The NIH did put a “pause” on gain-of-function research for a few years, but the work resumed in 2019.

Now, let me explain why GoF research does not require artificially engineering a virus. Viruses mutate very rapidly all by themselves, and RNA viruses like influenza and SARS-CoV-2 mutate even more rapidly than DNA viruses. So a GoF experiment doesn’t need to engineer a virus to make it more infectious: instead, scientists can simply grow a few trillion viral particles, which is easy, and design experiments to select the ones that are more infectious. For example, some GoF research on bird flu simply sprays an aerosol mixture of viruses into a ferret’s nose (influenza research often uses ferrets, since you can’t ethically do this with people), and waits to see if the ferret comes down with the flu. If it does (and this has been done, successfully), the strain that succeeds now has a new function, because it can infect mammals. The viruses that are artificially selected (as opposed to natural selection) in these experiments will appear completely natural; no genetic engineering required.

We know that WIV was conducting gain-of-function experiments, and we know that its work included coronaviruses. Was the Wuhan Institute of Virology running GoF experiments on SARS-CoV-2 viruses from bats? Possibly. And if it was, these experiments could easily have produced a strain that infected humans. If a lab employee was accidentally infected with such a strain, that could have started the pandemic. And even if SARS-CoV-2 wasn’t the subject of GoF experiments, a naturally-occurring strain being studied at WIV could still have infected one of their scientists and thereby leaked out into the population.

I’m not saying that any of these events is likely. I am, however, agreeing with the scientists who, in their recent letter to Science, called for a deeper investigation into the cause of the Covid-19 pandemic.

Finally, let me echo a sentiment they expressed in their letter, which is best said by simply quoting them: “in this time of unfortunate anti-Asian sentiment in some countries, we note that at the beginning of the pandemic, it was Chinese doctors, scientists, journalists, and citizens who shared with the world crucial information about the spread of the virus—often at great personal cost.” Rather than seeking to cast blame, we need to uncover the origin of the Covid-19 pandemic, and any behaviors that led to it, as a means to help all societies prevent future pandemics. 

Are you "vaccine hesitant"? You may be in a cult

Edward Jenner, who pioneered vaccination, and two colleagues
 (right) seeing off three anti-vaccination opponents, with the dead
lying at their feet (1808). I Cruikshank/Wellcome Images/Wikimedia
Commons, CC BY-SA

The World Health Organization recently declared that "vaccine hesitancy," as they called it, was one of the top 10 threats to global health. That's right: it was up there with air pollution, climate change, influenza, Ebola, and other threats.

For the WHO, "vaccine hesitancy" is a polite phrase designed to engage the public and highlight how serious the problem is, without angering those who are guilty of it. I'm not going to be quite so polite here: "vaccine hesitant" means anti-vax. The anti-vax movement, which aggressively spreads fear and misinformation about vaccines, has become a major, worldwide threat.

It also resembles a cult, as I'll explain.

The most recent anti-vax nonsense centers on the new coronavirus that originated in China, and that has led the Chinese government to impose a massive quarantine affecting millions of people. This is a genuine public health crisis, and it has nothing to do with vaccines. Nonetheless, some anti-vaxxers are claiming, without evidence, that the new virus originated from a failed effort to create a coronavirus vaccine. I don't have time to get into that here, but Orac has a lengthy, detailed takedown of that bogus claim.

"Vaccine hesitancy" sometimes refers to parents who are just learning about vaccines for the first time, and who rely on the Internet to search for information. Unfortunately, these new parents are likely to be flooded with anti-vax messages, especially on Facebook. (In recent years, Google has taken steps to lower the priority of anti-vax sites, which has improved things considerably. Sites such as healthychildren.org now appear near the top of searches for "vaccine safety.") It's entirely reasonable to ask your doctor about the benefits and risks of vaccines.

But the answers that parents hear should be clear: vaccines work. As physician ZDoggMD (a pseudonym, obviously) explains in this video:

"Anti-vaccine sentiment is a poisonous scourge.... There's no debate about vaccines. Let's get over that nonsense that the media and celebrities have created, okay? There is nobody in the medical community of any actual reputation who believes that there are two sides to this."

The problem is that anti-vaxxers are continuously creating new websites, Facebook groups, and even movies to spread misinformation about vaccines, particularly the long-debunked claim that vaccines cause autism.

Why do I suggest that anti-vaxxers resemble a cult? Because they have several of the key features of cults, such as:

1. Members of the cult have special insights that outsiders cannot comprehend. With anti-vaxxers, this means they are completely convinced that they know that vaccines cause harm, despite mountains of evidence to the contrary.
2. The group and its leaders are the exclusive means of knowing "truth" or receiving validation, and no other process of discovery is credible. The anti-vax movement has had several prominent leaders, whose followers flock to their speeches and events. These include Andrew Wakefield, the disgraced former doctor who lost his medical license after it was revealed that he had committed fraud. His followers, though, either don't know or ignore his fraudulent past, and regard him as a hero. He makes a living from his books, a movie, and speaking fees, all based on spreading fear about vaccines. An even more prominent anti-vax leader is Robert Kennedy, Jr., who also sells books and gives speeches proclaiming the harms of vaccines. Thanks to his famous name, and despite the fact that he has no medical or scientific training, some people believe him.
3. Unreasonable fear about the outside world, such as impending catastrophe, evil conspiracies and persecutions. Conspiracy theories are the core of many anti-vax arguments. The most common version holds that the "medical establishment" (whoever that is) are hiding the dangers of vaccines so that they can make money. This is utter nonsense. All of doctors I know in the infectious disease community are motivated by a wish to cure disease. In any case, most doctors make little or no money from the vaccines they administer.
4. No meaningful financial disclosure regarding budget or expenses. Some anti-vaxxers profit handsomely by selling bogus, ineffective supplements as alternatives to vaccines. (I'm looking at you, Joe Mercola.) Because supplements are largely unregulated, they get away with it. They'd prefer you to think they're "just in it for the children."

I've no doubt that anti-vaxxers like Wakefield, Kennedy, and others would deny that they are conspiracy theorists, because that's how conspiracy theorists operate. If you question them (they argue), you must be part of the conspiracy. By their own reasoning, they can never be wrong.

So if you encounter someone, either on the sidelines at your kid's soccer game, on Facebook, or elsewhere, who is spreading claims that vaccines are harmful, pause for a minute and ask: what is the source of this information? Is it coming from someone who is profiting from this fear-mongering? There's a good chance the answer is yes.

It's ironic that when the world is faced with a true health emergency, such as the Ebola virus or the Wuhan coronavirus, the first thing that public health experts start to work on is a new vaccine. That's because vaccines provide our best protection against infections. We now have effective vaccines for 16 diseases that used to harm and even kill children in large numbers around the world. We've eliminated smallpox worldwide, and we've nearly eliminated polio, thanks to vaccines. Their very effectiveness is what has allowed the anti-vax message to take hold: many people are no longer frightened of dying from infectious diseases.

We're still a long way from conquering infections, but there's no reason for the world to slip back in time to an era when large numbers of people died from preventable infections. Vaccines work, if we'll let them.