Before Covid, We Are Already Doing Gain-of-Function Research. But Why?


Examples of potential pandemic pathogens (PPP) include the influenza virus, SARS, and MERS — pathogens that may evolve into a pandemic. Gain-of-function (GOF) experiments, therefore, aim to emulate the evolution of a pathogen — such as in gaining virulence, infectivity, or transmissibility — to study what potential outbreaks or pandemics might look like. But is it wise to perform such GOF research?

How GOF experiments are done

GOF research can be done with two methods — site-directed mutagenesis and serial passaging.

Site-directed mutagenesis makes intentional changes in specific locations of a gene sequence. In essence, this genetic engineering technique artificially induces mutations in an organism.

Passaging means infecting cells or animals with a new microbe to accelerate natural evolution and adaptation in a new environment. Passaging is often done in iterations — serial passage — to gradually modify a specific microbial function. As serial passaging mimics natural evolution in a new environment, it does not count as genetic engineering.

History of GOF research in brief

In 2011, the National Science Advisory Board for Biosecurity (NSABB) halted the publication of two GOF studies involving the H5N1 influenza virus, which were the most controversial research ever done at that time.

Two separate research groups in the Netherlands and U.S. induced mutations in the H5N1 influenza virus genome and then passaged it in ferrets for multiple iterations to achieve airborne spread. Such GOF research warns that H5N1 influenza, which does not spread among humans, could evolve an aerosol transmission ability in mammals. “And thus pose a risk of becoming pandemic in humans,” concluded one of the studies.

“Scientists believe it’s likely that the pathogen, if it emerged in nature or were released, would trigger an influenza pandemic, quite possibly with many millions of deaths,” Science reported. “[It’s] probably one of the most dangerous viruses you can make.” Further, the methods sections of those studies might give potential terrorists the blueprint to create bioweapons.

After intense debate, however, the NSABB reasoned that the benefits outweighed the risks. Both studies were ultimately published in 2012 in Science and Nature.

As long as such GOF experiments are done safely, then all are fine. However, records of lab accidents, even in the most advanced government laboratories, have raised more concerns about the continuation of GOF research. There are three examples in 2014 in the U.S. alone:

  1. In the Centers for Disease Control and Prevention (CDC) Anthrax lab incident, workers handled a live Anthrax bacterium that was thought to be dead because scientists did not inactivate the bacteria properly before leaving the lab. About 70 workers possibly exposed to Anthrax were treated with antibiotics and vaccinations, and nobody fell ill.
  2. In the CDC influenza lab incident, the shipment of a harmless H9N2 influenza strain to the USDA poultry lab was contaminated with a dangerous H5N1 influenza strain, although nobody got sick.
  3. In the National Institutes of Health (NIH) smallpox lab incident, six vials of the lethal variola virus were found in the FDA laboratory for low-risk research at the NIH. The vials might have been there since the 1960s and were immediately transferred to the CDC-registered containment laboratory in Bethesda before any disaster happens.

As a result, over 200 researchers signed the “Cambridge Working Group Consensus Statement on the Creation of Potential Pandemic Pathogens (PPPs)” in 2014 which pleads for the cessation of GOF experiments. This statement persuaded U.S. President Barack Obama and the NIH to stop funding GOF research on PPP in 2014.

After a few years of revising research policies, the NIH announced in December 2017 that GOF studies are allowed to continue if it gets approved by the review board of the Department of Health and Human Services (HHS), which also now supervises GOF experiments as they proceed.

How does the HHS decide whether to approve a GOF study or not? 

“The first question is: how likely is the research to result in benefits and how great would these benefits be, and how likely is the research to result in harm, and how great would these harms be?” Professor Michael Selgelid, director of the Centre for Human Bioethics at Monash University and the WHO Collaborating Centre for Bioethics, explained in 2018.

“But risk-benefit assessment is not an exact science, nor is it perfectly objective — a lot of the time, it is going to be very difficult to say what constitutes a situation where the benefits outweigh the risks,” the professor continued.

Regardless, the scientific community has settled on the consensus that certain GOF research is worth investigating as they bring value that offsets potential risks. So, what are the risks and benefits of such research?

Risks of GOF Research

Microbes can leak from labs. Over 1100 cases of unintended leakage of microbes or toxins with potential public health risks happened between 2008 to 2012. 

“More than 200 incidents of loss or release of bioweapons agents from U.S. laboratories are reported each year,” said Richard Ebright, a professor at Rutgers University and head of the Waksman Institute of Microbiology, who also testified before Congress about the CDC’s lab accidents in 2014.

Other well-known lab escapes of pathogens include the H1N1 swine flu in 1977, smallpox in the 1970s, Venezuelan equine encephalitis in 1995, SARS (six separate incidents) after the 2003 epidemic, foot, and mouth disease in 2007, and possibly Covid-19.

Accidental escapes of pathogens belong to the biosafety category. The biosecurity side, in contrast, concerns the risk of bioterrorism acts that exploit the knowledge or material gained from GOF research. While the risks of lab accidents can be predicted with historical records and minimized with proper facilities and safety measures, it is not the case for bioterrorism.

“Biosecurity estimates are difficult, because they involve a calculation of the risk of deliberate nefarious action, and such information is simply not always available,” said a 2014 research review of Arturo Casadevall, a distinguished professor at the Johns Hopkins Bloomberg School of Public Health and Medicine. “In fact, these assessments are so difficult that we have called for the formation of a national board to handle questions related to dual-use research of concern,” which means research that has both beneficial and malicious applications.

Benefits of GOF research

GOF research could determine which viral gene or protein is responsible for a specific function. It answers if “a particular set of genetic changes [is] sufficient to create a particular phenotype…?” stated a 2018 research review by Marc Lipsitch, a professor of epidemiology and director of the Center for Communicable Disease Dynamics at the Harvard T.H. Chan School of Public Health. “This question can be answered only by a GOF experiment because if one does not create the phenotype, one cannot measure it.”

(Phenotype refers to a particular trait of an organism, such as virulence.)

“GOF-type experiments are of particular epistemological value because they directly imply causality,” agreed Prof. Casadevall et al. “The power of GOF experiments is that they are a highly efficient, reliable, and effective tool that can identify certain phenotypes that often cannot be identified by using other scientific approaches.”

Early disease control actions such as animal culling or designs of vaccines or antimicrobials can, thus, be catered to those sets of genes or proteins (or phenotype) that pose a threat to humans. “Gain-of-function experiments allow us to understand how pandemic viruses evolve so that we can make predictions, develop countermeasures, and do disease surveillance,” Carrie Wolinetz, a director of the NIH Office of Science Policy, explained.

In fact, GOF research assists in the preparation of seasonal flu vaccines. “Selection of viruses chosen for CVV [candidate vaccine virus] generation, pilot lot production, and, ultimately, inclusion in the national or global stockpiles are often made with consideration of GOF mutations identified during molecular risk assessment so that viruses with the greatest pandemic potential are selected,” scientists at the WHO Collaborating Center for Influenza Research detailed. “Information garnered from basic influenza virus research, including GOF studies, has benefited public health and the vaccine production process in numerous ways.”

To close

Gain-of-function (GOF) research, especially on potential pandemic pathogens (PPP), sparked controversies in 2011 and faced suspension from 2014 to 2017. However, the risk-benefit analyses by health authorities underscored that GOF research still brings more value than its probable risks. As Prof. Casadevall and others concluded, “Think about both risks and benefits, take obvious precautions, and then make the prudent choice. With enhanced biosafety protocols and improvements in the public health response, we should not ban GOF research but monitor it.”

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