Boston University Gain of Function Controversy
Headlines make this seem much worse than it really is- but we probably still should not be doing this!
In the past week, there has been a lot of hubbub around research done at Boston University on the SARS-CoV-2 virus. I first saw the story on twitter, with headlines like this:
Predictably, most people concerned about this issue then fell into their set-out battlelines. If you are concerned about gain of function research, this is further proof of why it can be dangerous and why current safeguards are not enough. If you are concerned about brakes, disincentives, and vilification of important biology research and researchers, this is a classic example of overreaction to necessary and safe science.
While my writing on this blog has been about wisdom, poetry, and song lyrics so far, I am currently working in a BSL-2 lab in pathogen detection, and have experience in infectious disease modeling and biosafety practices, including a certificate in next generation biosecurity. I am motivated to use my career to help prevent future global pandemics, especially those that would be considered a Global Catastrophic Biological Risk (GCBR). I think now is a good time to add my voice into this important debate, to add some context and clarity. I will post a series of posts over the next few weeks on GCBRs more generally, but this post will focus on this specific research and the response to it. Let’s break down some of the important claims.
1. Researchers at Boston University say they have developed a new COVID strain that has an 80% kill rate
This is true- it’s also very, very misleading. First of all, the strain they created has an 80% kill rate in mice. If it kills mice, it might kill humans just as well, right? No. The Washington strain, the originally circulating virus from early 2020 that is often used as the baseline in research, killed 100% of mice in this experiment. The strain they created was based on the Washington strain, so it actually made the virus less lethal in mice. However, it was made by combining the Washington strain with the Omicron variant spike; Omicron causes mild, non-fatal disease in these mice. One way of looking at this experiment is that they slightly decreased the fatality of the Washington strain, but gave it the immune escape and transmissibility capabilities of Omicron; another way of looking at it is they made Omicron much, much more deadly. But again, this was all done in one specific strain of mice that has been specifically created to express human ACE2 receptors, and used to study the effects of the SARS-CoV-2 virus in an animal model.
2. This research was gain of function research
Gain of function is defined many different ways for different purposes, so let’s break this down a little further.
Gain of function- laymen/wikipedia/literal definition:
Yes. The researchers added the Omicron spike protein (the part that attached to cell receptors to gain entry into the cell) to the Washington strain virus backbone, giving the Washington strain the added immune escape and receptor binding capability of Omicron. Or, they added the severe disease function to the already transmissible Omicron variant. Whether you make Omicron deadlier or the original more transmissible, either way, that’s gain of function.
Gain of function- HHS dual research of concern (2014 moratorium)
Legally moot as this no longer applies, but practically, obviously yes. This definition was created before SARS-CoV-2 was known to humans (or probably existed at all), but prevented gain of function research on pandemic-capable pathogens, specifically research that would increase the transmissibility or pathogenicity of SARS-CoV, MERS-CoV, and influenza. To me, it seems a little absurd to say that making SARS-CoV more transmissible in humans is dual use research of concern, but not SARS-CoV-2…that is a little like saying it is bad to light fires if your county is in a red flag fire weather warning, but once there is already a fire somewhere in your county it’s fine. They have since lifted this moratorium, and required more scrutiny to receive NIH funding in this area. The current framework is known as P3CO, and requires that research in enhanced pathogens of pandemic potential (ePPPs) go through a committee review process.
Gain of function: HHS ePPP
Here are the HHS definitions:
A. A potential pandemic pathogen (PPP) is a pathogen that satisfies both of the following: 1. It is likely highly transmissible and likely capable of wide and uncontrollable spread in human populations; and 2. It is likely highly virulent and likely to cause significant morbidity and/or mortality in humans.
B. An enhanced PPP is defined as a PPP resulting from the enhancement of the transmissibility and/or virulence of a pathogen. Enhanced PPPs do not include naturally occurring pathogens that are circulating in or have been recovered from nature, regardless of their pandemic potential.
Either way you slice it, this is ePPP research. It is either taking a pathogen of pandemic potential (Washington strain) and making it more transmissible, or taking a pathogen of pandemic potential (Omicron) and making it more virulent. This strain does not exist in nature. What is disputed is whether this was funded by the NIH and therefore requiring this extra review; see below for that discussion.
3. This research is dangerous
I will do a deeper dive into the potential dangers of gain of function research in a later post. In this specific case, I think this research is dangerous. The NIH framework is set up mostly to prevent nasty pathogens and the knowledge of how to create nasty pathogens out of the hands of people who would want to intentionally use a nasty pathogen to cause harm. This is a good goal, but not really a big risk in this case. The bigger risk here comes from accidental release. Of course, the researchers involved were in a BSL-3 lab, and followed all of the protocols to avoid this- but so did these Taiwanese researchers when one was bitten by a mouse that led to an outbreak of 110 cases. Unfortunately, that case is not one cherry picked example- scrolling through this list might give you the heebie jeebies in time for Halloween. The US moratorium in 2014 was prompted by high profile failures to protect people and pathogens by the CDC, including exposing people to anthrax, sending flu samples contaminated with highly pathogenic avian influenza (case fatality rate in humans over 50%), and finding vials of viable smallpox in a storage room. Humans are fallible, even well intentioned researchers following good protocols- for that reason, we need to not make pathogens that are not worth a small chance of being accidentally let out.
4. This research was funded by the NIH
The NIH did not give a specific grant for this experiment; however, they definitely used funds from four NIH grants, and NIH is looking in to whether this should have been subject to the NIH Grants Policy Statement or met the criteria for review under the HHS Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (HHS P3CO framework). In the preprint paper, they say this:
This work was supported by…National Institutes of Health, NIAID grants R01 AI159945 (to SB and MS) and R37 AI087846 (to MUG), NIH SIG grants S10- OD026983 and SS10-OD030269 (to NAC)
We fulfilled all required regulatory obligations and protocols. Following NIAID’s guidelines and protocols, we did not have an obligation to disclose this research for two reasons. The experiments reported in this manuscript were carried out with funds from Boston University. NIAID funding was acknowledged because it was used to help develop the tools and platforms that were used in this research; they did not fund this research directly. NIH funding was also acknowledged for a shared instrumentation grant that helped support the pathology studies. We believe that funding streams for tools do not require an obligation to report. Secondly, there was no gain of function with this research. If at any point there was evidence that the research was gaining function, under both NIAID and our own protocols we would immediately stop and report.
“Evidence that the research was gaining function” makes this pretty clear that this was not written by the scientists involved or by anyone who understands what gain of function is- the research does not gain function, the pathogens gain functions (like transmissibility or pathogenicity) through the research. With regards to what the specific NIH funding acknowledged, this may be wishful thinking or putting there best legal foot forward, but may not be actually true:
I have not personally looked into what those grants are for specifically. What is clear is that they did use NIH money for at least something warranting a thank you in their paper, and that the NIH is looking into whether the proper procedures were followed. What is also very clear is that if you can skirt around the policy meant to provide extra scrutiny on making pandemic capable pathogens worse by not telling your funder what you will use the equipment for, we need a better system.
Again, BU’s statement ended with:
If at any point there was evidence that the research was gaining function, under both NIAID and our own protocols we would immediately stop and report.
If this was not funded by the NIAID, they would not need to report anything to them- if some billionaire gave them money to do this research, they could legally do it without notifying the NIH. It seems like they are simply denying wrongdoing in a statement written by the lawyers- I will be interested to see the results of the NIH review. There are some pretty glaring loopholes in this system that we can hopefully close thanks to the light shown through them by this incident.
5. This research is useful
This is the claim that is most reliant on personal opinion. We certainly did learn something from this experiment- namely, that the drop off in virulence from the Washington strain to Omicron did not come entirely from the changes in the spike protein. That is good to know! However, some of the claims about this making it easier to make better vaccines or therapeutics are, in my opinion, nonsense. This is creating a strain that does not exist in the world, and testing it in mice that have incredibly different reactions to this virus than humans do. First of all, this virus as it exists in the lab will almost certainly never exist in nature unless it is released from the lab, because evolution takes different paths. Even if we threw off all restrictions and poured money into gain of function research to find the next strain, we wouldn’t. Random mutations can have unexpected consequences, especially when you are studying the virus in a model organism so far away from humans that you have to genetically engineer human ACE2 receptors so they can even be infected by the virus. Secondly, we were able to create amazing vaccines within hours of knowing the genome of the virus- the bottleneck to faster vaccine development is not knowing what to make the vaccine against, it is the testing process to make sure it is safe and efficacious in humans. Creating a virus that does not exist in nature does not help us here, because no one is going to make a vaccine or approve a vaccine trial for a variant that is not spreading in the wild and likely never will. There is important research we need to do to make vaccines better and faster, and poorly thought out barriers to that kind of research, but this is not that.
Ultimately, this research does provide some scientific value, but in my opinion not nearly enough to be done in a BSL-3 lab without any review by the NIH or anyone else. Here is the preprint, where you can read the author’s motivations and discussion of potential benefits for yourself.
Next Friday I will have my normal short form post on a piece of wisdom; I will also start writing more about GCBRs over the next few weeks. My next biosecurity related post will be about minimal trust investigations, Gell-Mann Amnesia, and what we can learn from media storms like this one. Please reach out if there is any specific questions I can answer or things I can clarify in this space.
How dangerous was the Washington strain to humans?