Are the gains from gain-of-function research worth the risks?
Scientists have long argued that gain-of-function research, which can make viruses and other infectious agents more contagious or more deadly, was necessary to develop therapies and vaccines to counter the pathogens in case they were used for biological warfare. As the SARS-CoV-2 origins are being investigated, one prominent theory suggests it had leaked from a biolab that conducted gain-of-function research, causing a global pandemic that claimed nearly 6.9 million lives. Now some question the wisdom of engaging in this type of research, stating that the risks may far outweigh the benefits.
“Gain-of-function research means genetically changing a genome in a way that might enhance the biological function of its genes, such as its transmissibility or the range of hosts it can infect,” says George Church, professor of genetics at Harvard Medical School. This can occur through direct genetic manipulation as well as by encouraging mutations while growing successive generations of micro-organism in culture. “Some of these changes may impact pathogenesis in a way that is hard to anticipate in advance,” Church says.
In the wake of the global pandemic, the pros and cons of gain-of-function research are being fiercely debated. Some scientists say this type of research is vital for preventing future pandemics or for preparing for bioweapon attacks. Others consider it another disaster waiting to happen. The Government Accounting Office issued a report charging that a framework developed by the U.S. Department of Health & Human Services (HHS) provided inadequate oversight of this potentially deadly research. There’s a movement to stop it altogether. In January, the Viral Gain-of-Function Research Moratorium Act (S. 81) was introduced into the Senate to cease awarding federal research funding to institutions doing gain-of-function studies.
While testifying before the House COVID Origins Select Committee on March 8th, Robert Redfield, former director of the U.S. Centers for Disease Control and Prevention, said that COVID-19 may have resulted from an accidental lab leak involving gain-of-function research. Redfield said his conclusion is based upon the “rapid and high infectivity for human-to-human transmission, which then predicts the rapid evolution of new variants.”
“It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen,” said Gerald Parker, associate dean for Global One Health at Texas A&M University.
“In my opinion,” Redfield continues, “the COVID-19 pandemic presents a case study on the potential dangers of such research. While many believe that gain-of-function research is critical to get ahead of viruses by developing vaccines, in this case, I believe that was the exact opposite.” Consequently, Redfield called for a moratorium on gain-of-function research until there is consensus about the value of such risky science.
What constitutes risky?
The Federal Select Agent Program lists 68 specific infectious agents as risky because they are either very contagious or very deadly. In order to work with these 68 agents, scientists must register with the federal government. Meanwhile, research on deadly pathogens that aren’t easily transmitted, or pathogens that are quite contagious but not deadly, can be conducted without such oversight. “If you’re not working with select agents, you’re not required to register the research with the federal government,” says Gerald Parker, associate dean for Global One Health at Texas A&M University. But the 68-item list may not have everything that could possibly become dangerous or be engineered to be dangerous, thus escaping the government’s scrutiny—an issue that new regulations aim to address.
In January 2017, the White House Office of Science and Technology Policy (OSTP) issued additional guidance. It required federal departments and agencies to follow a series of steps when reviewing proposed research that could create, transfer, or use potential pandemic pathogens resulting from the enhancement of a pathogen’s transmissibility or virulence in humans.
In defining risky pathogens, OSTP included viruses that were likely to be highly transmissible and highly virulent, and thus very deadly. The Proposed Biosecurity Oversight Framework for the Future of Science, outlined in 2023, broadened the scope to require federal review of research “that is reasonably anticipated to enhance the transmissibility and/or virulence of any pathogen” likely to pose a threat to public health, health systems or national security. Those types of experiments also include the pathogens’ ability to evade vaccines or therapeutics, or diagnostic detection.
However, Parker says that dangers of generating a pandemic-level germ are tiny. “It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen.” Since gain-of-function guidelines were first issued in 2017, only three such research projects have met those requirements for HHS review. They aimed to study influenza and bird flu. Only two of those projects were funded, according to the NIH Office of Science Policy. For context, NIH funded approximately 11,000 of the 54,000 grant applications it received in 2022.
Guidelines governing gain-of-function research are being strengthened, but Church points out they aren’t ideal yet. “They need to be much clearer about penalties and avoiding positive uses before they would be enforceable.”
What do we gain from gain-of-function research?
The most commonly cited reason to conduct gain-of-function research is for biodefense—the government’s ability to deal with organisms that may pose threats to public health.
In the era of mRNA vaccines, the advance preparedness argument may be even less relevant.
“The need to work with potentially dangerous viruses is central to our preparedness,” Parker says. “It’s essential that we know and understand the basic biology, microbiology, etc. of some of these dangerous pathogens.” That includes increasing our knowledge of the molecular mechanisms by which a virus could become a sustained threat to humans. “Knowing that could help us detect [risks] earlier,” Parker says—and could make it possible to have medical countermeasures, like vaccines and therapeutics, ready.
Most vaccines, however, aren’t affected by this type of research. Essentially, scientists hope they will never need to use it. Moreover, Paul Mango, HSS former deputy chief of staff for policy, and author of the 2022 book Warp Speed, says he believes that in the era of mRNA vaccines, the advance preparedness argument may be even less relevant. “That’s because these vaccines can be developed and produced in less than 12 months, unlike traditional vaccines that require years of development,” he says.
Can better oversight guarantee safety?
Another situation, which Parker calls unnecessarily dangerous, is when regulatory bodies cannot verify that the appropriate biosafety and biosecurity controls are in place.
Gain-of-function studies, Parker points out, are conducted at the basic research level, and they’re performed in high-containment labs. “As long as all the processes, procedures and protocols are followed and there’s appropriate oversight at the institutional and scientific level, it can be conducted safely.”
Globally, there are 69 Biosafety Level 4 (BSL4) labs operating, under construction or being planned, according to recent research from King’s College London and George Mason University for Global BioLabs. Eleven of these 18 high-containment facilities that are planned or under construction are in Asia. Overall, three-quarters of the BSL4 labs are in cities, increasing public health risks if leaks occur.
Researchers say they are confident in the oversight system for BSL4 labs within the U.S. They are less confident in international labs. Global BioLabs’ report concurs. It gives the highest scores for biosafety to industrialized nations, led by France, Australia, Canada, the U.S. and Japan, and the lowest scores to Saudi Arabia, India and some developing African nations. Scores for biosecurity followed similar patterns.
“There are no harmonized international biosafety and biosecurity standards,” Parker notes. That issue has been discussed for at least a decade. Now, in the wake of SARS and the COVID-19 pandemic, scientists and regulators are likely to push for unified oversight standards. “It’s time we got serious about international harmonization of biosafety and biosecurity standards and guidelines,” Parker says. New guidelines are being worked on. The National Science Advisory Board for Biosecurity (NSABB) outlined its proposed recommendations in the document titled Proposed Biosecurity Oversight Framework for the Future of Science.
The debates about whether gain-of-function research is useful or poses unnecessary risks to humanity are likely to rage on for a while. The public too has a voice in this debate and should weigh in by communicating with their representatives in government, or by partaking in educational forums or initiatives offered by universities and other institutions. In the meantime, scientists should focus on improving the research regulations, Parker notes. “We need to continue to look for lessons learned and for gaps in our oversight system,” he says. “That’s what we need to do right now.”
A promising development in science in recent years has been the use technology to optimize something natural. One-upping nature's wisdom isn't easy. In many cases, we haven't - and maybe we can't - figure it out. But today's episode features a fascinating example: using tech to optimize psychedelic mushrooms.
These mushrooms have been used for religious, spiritual and medicinal purposes for thousands of years, but only in the past several decades have scientists brought psychedelics into the lab to enhance them and maximize their therapeutic value.
Today’s podcast guest, Doug Drysdale, is doing important work to lead this effort. Dr. Drysdale is the CEO of a company called Cybin that has figured out how to make psilocybin more potent, so it can be administered in smaller doses without side effects.
The natural form of psilocybin has been studied increasingly in the realm of mental health. Taking doses of these mushrooms appears to help people with anxiety and depression by spurring the development of connections in the brain, an example of neuroplasticity. The process basically shifts the adult brain from being fairly rigid like dried clay into a malleable substance like warm wax - the state of change that's constantly underway in the developing brains of children.
Neuroplasticity in adults seems to unlock some of our default ways of of thinking, the habitual thought patterns that’ve been associated with various mental health problems. Some promising research suggests that psilocybin causes a reset of sorts. It makes way for new, healthier thought patterns.
So what is Dr. Drysdale’s secret weapon to bring even more therapeutic value to psilocybin? It’s a process called deuteration. It focuses on the hydrogen atoms in psilocybin. These atoms are very light and don’t stick very well to carbon, which is another atom in psilocybin. As a result, our bodies can easily breaks down the bonds between the hydrogen and carbon atoms. For many people, that means psilocybin gets cleared from the body too quickly, before it can have a therapeutic benefit.
In deuteration, scientists do something simple but ingenious: they replace the hydrogen atoms with a molecule called deuterium. It’s twice as heavy as hydrogen and forms tighter bonds with the carbon. Because these pairs are so rock-steady, they slow down the rate at which psilocybin is metabolized, so it has more sustained effects on our brains.
Cybin isn’t Dr. Drysdale’s first go around at this - far from it. He has over 30 years of experience in the healthcare sector. During this time he’s raised around $4 billion of both public and private capital, and has been named Ernst and Young Entrepreneur of the Year. Before Cybin, he was the founding CEO of a pharmaceutical company called Alvogen, leading it from inception to around $500 million in revenues, across 35 countries. Dr. Drysdale has also been the head of mergers and acquisitions at Actavis Group, leading 15 corporate acquisitions across three continents.
In this episode, Dr. Drysdale walks us through the promising research of his current company, Cybin, and the different therapies he’s developing for anxiety and depression based not just on psilocybin but another psychedelic compound found in plants called DMT. He explains how they seem to have such powerful effects on the brain, as well as the potential for psychedelics to eventually support other use cases, including helping us strive toward higher levels of well-being. He goes on to discuss his views on mindfulness and lifestyle factors - such as optimal nutrition - that could help bring out hte best in psychedelics.
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Cybin development pipeline
Cybin's promising phase 2 research on depression
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Mets owner Steve Cohen invests in psychedelic therapies
Doug Drysdale, CEO of Cybin
Story by Big Think
It is a mystery why humans manifest vast differences in lifespan, health, and susceptibility to infectious diseases. However, a team of international scientists has revealed that the capacity to resist or recover from infections and inflammation (a trait they call “immune resilience”) is one of the major contributors to these differences.
Immune resilience involves controlling inflammation and preserving or rapidly restoring immune activity at any age, explained Weijing He, a study co-author. He and his colleagues discovered that people with the highest level of immune resilience were more likely to live longer, resist infection and recurrence of skin cancer, and survive COVID and sepsis.
Measuring immune resilience
The researchers measured immune resilience in two ways. The first is based on the relative quantities of two types of immune cells, CD4+ T cells and CD8+ T cells. CD4+ T cells coordinate the immune system’s response to pathogens and are often used to measure immune health (with higher levels typically suggesting a stronger immune system). However, in 2021, the researchers found that a low level of CD8+ T cells (which are responsible for killing damaged or infected cells) is also an important indicator of immune health. In fact, patients with high levels of CD4+ T cells and low levels of CD8+ T cells during SARS-CoV-2 and HIV infection were the least likely to develop severe COVID and AIDS.
Individuals with optimal levels of immune resilience were more likely to live longer.
In the same 2021 study, the researchers identified a second measure of immune resilience that involves two gene expression signatures correlated with an infected person’s risk of death. One of the signatures was linked to a higher risk of death; it includes genes related to inflammation — an essential process for jumpstarting the immune system but one that can cause considerable damage if left unbridled. The other signature was linked to a greater chance of survival; it includes genes related to keeping inflammation in check. These genes help the immune system mount a balanced immune response during infection and taper down the response after the threat is gone. The researchers found that participants who expressed the optimal combination of genes lived longer.
Immune resilience and longevity
The researchers assessed levels of immune resilience in nearly 50,000 participants of different ages and with various types of challenges to their immune systems, including acute infections, chronic diseases, and cancers. Their evaluationdemonstrated that individuals with optimal levels of immune resilience were more likely to live longer, resist HIV and influenza infections, resist recurrence of skin cancer after kidney transplant, survive COVID infection, and survive sepsis.
However, a person’s immune resilience fluctuates all the time. Study participants who had optimal immune resilience before common symptomatic viral infections like a cold or the flu experienced a shift in their gene expression to poor immune resilience within 48 hours of symptom onset. As these people recovered from their infection, many gradually returned to the more favorable gene expression levels they had before. However, nearly 30% who once had optimal immune resilience did not fully regain that survival-associated profile by the end of the cold and flu season, even though they had recovered from their illness.
Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance.
This could suggest that the recovery phase varies among people and diseases. For example, young female sex workers who had many clients and did not use condoms — and thus were repeatedly exposed to sexually transmitted pathogens — had very low immune resilience. However, most of the sex workers who began reducing their exposure to sexually transmitted pathogens by using condoms and decreasing their number of sex partners experienced an improvement in immune resilience over the next 10 years.
Immune resilience and aging
The researchers found that the proportion of people with optimal immune resilience tended to be highest among the young and lowest among the elderly. The researchers suggest that, as people age, they are exposed to increasingly more health conditions (acute infections, chronic diseases, cancers, etc.) which challenge their immune systems to undergo a “respond-and-recover” cycle. During the response phase, CD8+ T cells and inflammatory gene expression increase, and during the recovery phase, they go back down.
However, over a lifetime of repeated challenges, the immune system is slower to recover, altering a person’s immune resilience. Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance despite the many respond-and-recover cycles that their immune systems have faced.
Public health ramifications could be significant. Immune cell and gene expression profile assessments are relatively simple to conduct, and being able to determine a person’s immune resilience can help identify whether someone is at greater risk for developing diseases, how they will respond to treatment, and whether, as well as to what extent, they will recover.