What Is Gain of Function Research and Why Is It Done?

Gain-of-function research involves modifying organisms, like viruses or bacteria, to enhance their existing attributes or grant them new ones. The process is like tuning a car engine to increase its speed, where the goal is to augment a specific function for observation. This research is not limited to making organisms more dangerous; that is rarely the objective. Instead, it is a method used to investigate the relationship between an organism’s genetic code and its functional capabilities. By altering these functions, scientists can study processes that occur too slowly in nature, providing insights into evolution and disease.

The Purpose of Gain of Function Research

The primary motivation for gain-of-function (GoF) research is to understand how pathogens evolve and cause disease to protect public health. By studying how a virus might change, scientists can predict future threats and develop countermeasures, such as antiviral drugs and vaccines, before a dangerous new strain emerges. For example, GoF studies contributed to vaccines for diseases like yellow fever and the Johnson & Johnson COVID-19 vaccine.

A significant application is pandemic preparedness. Scientists can identify genetic mutations that might allow an animal virus to infect humans, as was done with the H5N1 influenza virus to understand how it could spread among mammals. This knowledge helps public health officials assess risks from new animal viruses and prioritize interventions.

GoF research also aids in developing therapeutic treatments. Understanding what makes a pathogen more virulent or transmissible helps researchers identify targets for new drugs. For instance, pre-pandemic studies on coronavirus spike proteins were later applied to the rapid development of vaccines, enabling a quicker response to new variants.

The research extends beyond virology, contributing to medicine and agriculture. Associated techniques have been used to develop therapies for cancer and cystic fibrosis, produce insulin, and improve crop resilience and yield.

The Scientific Process

Two common methods in GoF research are directed evolution and genetic engineering. These approaches allow scientists to accelerate the natural process of mutation to study how organisms adapt and change.

Directed evolution encourages an organism to evolve under controlled conditions. One method is serial passaging, where a virus is repeatedly introduced to new cell cultures or hosts. With each passage, natural selection favors mutations that make it better adapted to the new environment. This process mimics natural evolution on a much faster timescale.

Genetic engineering involves the direct manipulation of an organism’s genetic material. Using tools like CRISPR, scientists can make precise changes to the DNA or RNA of a virus to investigate the function of specific genes. For example, altering a single nucleotide can reveal how it affects a virus’s ability to replicate or infect a host. This targeted approach helps confirm predictions from genomic research.

Safety and Oversight

Strict safety protocols and oversight manage the risks of gain-of-function research. A multi-layered system of regulations at institutional and governmental levels protects laboratory workers and prevents the accidental release of modified organisms.

A component of this safety framework is the use of Biosafety Levels (BSLs), which are containment principles for labs working with biological agents. The levels range from BSL-1, for agents not known to cause disease, to BSL-4, for dangerous agents posing a high risk of aerosol-transmitted infections with no available treatments. Each level requires increasingly stringent safety measures, including specialized equipment, facility design, and training.

In the United States, high-risk pathogen research is subject to federal oversight through the P3CO framework from the Department of Health and Human Services (HHS). This framework guides funding for research that could enhance a pathogen’s transmissibility or virulence and requires a review of a project’s benefits, risks, and mitigation strategies.

Research institutions also have their own oversight bodies, like Institutional Biosafety Committees, that approve proposals. Personnel working with high-risk pathogens receive extensive training and may require background checks. These combined layers of oversight ensure this research is conducted responsibly.

The Dual-Use Dilemma

Gain-of-function research is central to the “dual-use dilemma,” where research with beneficial purposes could also be misused. The concern is that knowledge or modified pathogens could be used for bioterrorism or accidentally released from a laboratory.

Research that enhances a pathogen’s virulence or transmissibility is often called “dual-use research of concern” (DURC). The debate intensified in the early 2010s after experiments modified the H5N1 avian influenza virus to be transmissible between ferrets through the air, raising concerns about creating a pandemic-capable virus.

These risks led to policy changes, including a U.S. government funding pause from 2014 to 2017 on certain experiments involving influenza, MERS, and SARS viruses. The pause allowed for an assessment of the research’s risks and benefits and was lifted after the P3CO framework established stricter review processes.

The debate entered public consciousness with theories about the origins of the COVID-19 pandemic. The possibility of a lab accident origin for SARS-CoV-2 highlighted the research’s risks and the importance of stringent biosafety, leading to calls for greater transparency and international cooperation in oversight.