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.”
The Friday Five: Artificial DNA Could Give Cancer the Hook
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
Here are the promising studies covered in this week's Friday Five:
- Artificial DNA gives cancer the hook
- This daily practice could improve relationships
- Can social media handle the truth?
- Injecting a gel could speed up recovery
- A blood pressure medicine for a long healthy life
9 Tips for Online Mental Health Therapy
Telehealth offers a vast improvement in access and convenience to all sorts of medical services, and online therapy for mental health is one of the most promising case studies for telehealth. With many online therapy options available, you can choose whatever works best for you. Yet many people are hesitant about using online therapy. Even if they do give it a try, they often don’t know how to make the most effective use of this treatment modality.
Why do so many feel uncertain about online therapy? A major reason stems from its novelty. Humans are creatures of habit, prone to falling for what behavioral scientists like myself call the status quo bias, a predisposition to stick to traditional practices and behaviors. Many people reject innovative solutions even when they would be helpful. Thus, while teletherapy was available long before the pandemic, and might have fit the needs of many potential clients, relatively few took advantage of this option.
Even when we do try new methodologies, we often don’t do so effectively, because we cling to the same approaches that worked in previous situations. Scientists call this behavior functional fixedness. It’s kind of like the saying about the hammer-nail syndrome: “when you have a hammer, everything looks like a nail.”
These two mental blindspots, the status quo bias and functional fixedness, impact decision making in many areas of life. Fortunately, recent research has shown effective and pragmatic strategies to defeat these dangerous errors in judgment. The nine tips below will help you make the best decisions to get effective online therapy, based on the latest research.
Trust the science of online therapy
Extensive research shows that, for most patients, online therapy offers the same benefits as in-person therapy.
For instance, a 2014 study in the Journal of Affective Disorders reported that online treatment proved just as effective as face-to-face treatment for depression. A 2018 study, published in Journal of Psychological Disorders, found that online cognitive behavioral therapy, or CBT, was just as effective as face-to-face treatment for major depression, panic disorder, social anxiety disorder, and generalized anxiety disorder. And a 2014 study in Behaviour Research and Therapy discovered that online CBT proved effective in treating anxiety disorders, and helped lower costs of treatment.
During the forced teletherapy of COVID, therapists worried that those with serious mental health conditions would be less likely to convert to teletherapy. Yet research published in Counselling Psychology Quarterly has helped to alleviate that concern. It found that those with schizophrenia, bipolar disorder, severe depression, PTSD, and even suicidality converted to teletherapy at about the same rate as those with less severe mental health challenges.
Yet teletherapy may not be for everyone. For example, adolescents had the most varied response to teletherapy, according to a 2020 study in Family Process. Some adapted quickly and easily, while others found it awkward and anxiety-inducing. On the whole, children with trauma respond worse to online therapy, per a 2020 study in Child Abuse & Neglect. The treatment of mental health issues can sometimes require in-person interactions, such as the use of eye movement desensitization and reprocessing to treat post-traumatic stress disorder. And according to a 2020 study from the Journal of Humanistic Psychology, online therapy may not be as effective for those suffering from loneliness.
Leverage the strengths of online therapy
Online therapy is much more accessible than in-person therapy for those with a decent internet connection, webcam, mic, and digital skills. You don’t have to commute to your therapist’s office, wasting money and time. You can take much less medical leave from work, saving you money and hassle with your boss. If you live in a sparsely populated area, online therapy could allow you to access many specialized kinds of therapy that isn’t accessible locally.
Online options are much quicker compared to the long waiting lines for in-person therapy. You also have much more convenient scheduling options. And you won’t have to worry about running into someone you know in the waiting room. Online therapy is easier to conceal from others and reduces stigma. Many patients may feel more comfortable and open to sharing in the privacy and comfort of their own home.
You can use a variety of communication tools suited to your needs at any given time. Video can be used to start a relationship with a therapist and have more intense and nuanced discussions, but can be draining, especially for those with social anxiety. Voice-only may work well for less intense discussions. Email offers a useful option for long-form, well-thought-out messages. Texting is useful for quick, real-time questions, answers, and reinforcement.
Plus, online therapy is often cheaper than in-person therapy. In the midst of COVID, many insurance providers have decided to cover online therapy.
Address the weaknesses
One weakness is the requirement for appropriate technology and skills to engage in online therapy. Another is the difficulty of forming a close therapeutic relationship with your therapist. You won’t be able to communicate non-verbals as fully and the therapist will not be able to read you as well, requiring you to be more deliberate in how you express yourself.
Another important issue is that online therapy is subject to less government oversight compared to the in-person approach, which is regulated in each state, providing a baseline of quality control. As a result, you have to do more research on the providers that offer online therapy to make sure they’re reputable, use only licensed therapists, and have a clear and transparent pay structure.
Be intentional about advocating for yourself
Figure out what kind of goals you want to achieve. Consider how, within the context of your goals, you can leverage the benefits of online therapy while addressing the weaknesses. Write down and commit to achieving your goals. Remember, you need to be your own advocate, especially in the less regulated space of online therapy, so focus on being proactive in achieving your goals.
Develop your Hero’s Journey
Because online therapy can occur at various times of day through videos calls, emails and text, it might feel more open-ended and less organized, which can have advantages and disadvantages. One way you can give it more structure is to ground these interactions in the story of your self-improvement. Our minds perceive the world through narratives. Create a story of how you’ll get from where you are to where you want to go, meaning your goals.
A good template to use is the Hero’s Journey. Start the narrative with where you are, and what caused you to seek therapy. Write about the obstacles you will need to overcome, and the kind of help from a therapist that you’ll need in the process. Then, describe the final end state: how will you be better off after this journey, including what you will have learned.
Especially in online therapy, you need to be on top of things. Too many people let the therapist manage the treatment plan. As you pursue your hero’s journey, another way to organize for success is to take notes on your progress, and reevaluate how you’re doing every month with your therapist.
Identify your ideal mentor
Since it’s more difficult to be confident about the quality of service providers in an online setting, you should identify in advance the traits of your desired therapist. Every Hero’s Journey involves a mentor figure who guides the protagonist through this journey. So who’s your ideal mentor? Write out their top 10 characteristics, from most to least important.
For example, you might want someone who is:
- Empathetic
- Caring
- Good listener
- Logical
- Direct
- Questioning
- Non-judgmental
- Organized
- Curious
- Flexible
That’s my list. Depending on what challenge you’re facing and your personality and preferences, you should make your own. Then, when you are matched with a therapist, evaluate how well they fit your ideal list.
Fail fast
When you first match with a therapist, try to fail fast. That means, instead of focusing on getting treatment, focus on figuring out if the therapist is a good match based on the traits you identified above. That will enable you to move on quickly if they’re not, and it’s very much worth it to figure that out early.
Tell them your goals, your story, and your vision of your ideal mentor. Ask them whether they think they are a match, and what kind of a treatment plan they would suggest based on the information you provided. And observe them yourself in your initial interactions, focusing on whether they’re a good match. Often, you’ll find that your initial vision of your ideal mentor is incomplete, and you’ll learn through doing therapy what kind of a therapist is the best fit for you.
Choose a small but meaningful subgoal to work on first
This small subgoal should be sufficient to be meaningful and impactful for improving your mental health, but not a big stretch for you to achieve. This subgoal should be a tool for you to use to evaluate whether the therapist is indeed a good fit for you. It will also help you evaluate whether the treatment plan makes sense, or whether it needs to be revised.
Know when to wrap things up
As you approach the end of your planned work and you see you’re reaching your goals, talk to the therapist about how to wrap up rather than letting things drag on for too long. You don’t want to become dependent on therapy: it’s meant to be a temporary intervention. Some less scrupulous therapists will insist that therapy should never end and we should all stay in therapy forever, and you want to avoid falling for this line. When you reach your goals, end your therapy, unless you discover a serious new reason to continue it. Still, it may be wise to set up occasional check-ins once every three to six months to make sure you’re staying on the right track.