Gain of function (GoF) research involves the deliberate modification of organisms, typically pathogens, to alter their biological properties. This scientific work is performed with the intention of better understanding infectious diseases and preparing for future outbreaks. The experiments are powerful tools for illuminating how pathogens might evolve in nature, yet they also carry inherent risks related to biosafety and biosecurity. This combination of potential benefits for global health and the possibility of catastrophic consequences places GoF research at the center of ongoing scientific and public debate.
Defining Gain of Function Research
Gain of function research, in the context of infectious disease, is defined as any study that increases a pathogen’s ability to cause disease by enhancing its transmissibility, virulence, or host range. The “function” gained refers to a new characteristic, such as the ability to infect a new species or spread more efficiently through the air. These experiments simulate the natural evolutionary processes that occur when a virus mutates in the wild, but in a controlled laboratory setting.
The goal is to determine the minimum number of genetic changes required for a mild pathogen to become a significant threat to human health. Researchers achieve this through advanced genetic engineering, where specific genes are inserted or altered, or through simpler methods like serial passaging. Serial passaging involves repeatedly moving a virus from one host or cell culture to the next, selecting for strains that exhibit the desired enhanced trait. This approach contrasts with “loss-of-function” studies, which aim to weaken a pathogen to understand which genes are responsible for its disease-causing capability.
Scientific Applications and Purpose
The primary purpose of conducting GoF research is to improve pandemic preparedness by allowing scientists to anticipate and counter emerging threats. By identifying the exact mutations that enable an animal virus to jump to humans, researchers can better focus surveillance efforts on circulating strains that are only a few mutations away from causing a human spillover event. This knowledge allows public health authorities to intervene earlier and implement mitigation measures before a widespread outbreak occurs.
GoF experiments also accelerate the development of medical countermeasures by providing models for testing. Creating a modified virus that can infect a common laboratory animal, like a mouse or ferret, allows researchers to test the effectiveness of new vaccines and antiviral drugs against a potential pandemic strain. GoF studies on highly pathogenic avian influenza (H5N1) have successfully identified specific mutations that confer resistance to existing antiviral drugs, enabling the development of novel or combination therapies before a drug-resistant strain emerges naturally.
Understanding the enhanced function of a pathogen reveals the molecular mechanisms of infection, providing targets for drug development. For example, GoF research can pinpoint the exact protein changes a virus uses to bind to human cells, allowing scientists to design small-molecule inhibitors that physically block that interaction.
The Inherent Risks of Enhanced Pathogens
The greatest risk associated with GoF research is the potential for the accidental release of an artificially enhanced pathogen from the laboratory, known as a biosafety failure. Studies show that human error accounts for a significant majority of accidental exposures in high-containment facilities. These errors include noncompliance with safety procedures, improper use of personal protective equipment (PPE), or mishandling of infectious samples, such as a needle-stick injury.
Equipment failure also contributes to biosafety risks. Historically, accidents have resulted in laboratory-acquired infections (LAIs), such as the SARS infections reported in Singapore and China in the early 2000s following procedural lapses. Since the enhanced pathogens created in these labs may have no existing treatment or vaccine, an accidental release could lead to a pandemic with a high fatality rate.
Biosecurity concerns address the intentional misuse of the research due to the dual-use nature of the information generated. The knowledge about how to make a pathogen more transmissible or virulent could be deliberately used to cause harm by a malicious actor. To mitigate these dangers, GoF experiments involving highly dangerous agents must be conducted in specialized high-containment laboratories, designated as BSL-3 or BSL-4.
BSL-3 laboratories require stringent engineering controls:
- Self-closing double doors.
- Sustained negative air pressure to ensure air flows inward.
- High-efficiency particulate air (HEPA) filtration on all exhausted air to prevent airborne release.
BSL-4 facilities, reserved for the most lethal pathogens like Ebola or Marburg virus, incorporate even more extreme measures, such as a full-body, positive-pressure suit with a dedicated air supply worn by personnel, and all work conducted within a hermetically sealed Class III biological safety cabinet. The possibility of an accidental lab-induced pandemic remains the central ethical and safety concern surrounding this field.
Regulation and Oversight
The contentious nature of GoF research has prompted governments, particularly in the United States, to implement specific regulatory frameworks. Following biosafety incidents and public debate, the US government instituted a moratorium on federal funding for certain GoF studies in October 2014. This pause targeted research involving influenza, MERS, and SARS viruses anticipated to increase transmissibility or pathogenicity via the respiratory route in mammals.
The funding moratorium lasted three years, ending in December 2017 with the adoption of the Potential Pandemic Pathogen Care and Oversight (P3CO) framework. This framework guides funding decisions for research involving Enhanced Potential Pandemic Pathogens (ePPPs). The P3CO process requires a robust, multidisciplinary pre-funding review for any proposal that aims to create or use an ePPP.
Under the P3CO framework, researchers must submit a detailed risk-benefit assessment and a comprehensive risk mitigation plan for review by the funding agency, such as the National Institutes of Health (NIH). The review panel, which includes experts in biosafety, biosecurity, ethics, and public health, must determine that the potential public health benefits outweigh the risks and that the proposed safety measures are appropriate. This oversight structure weighs the ethical principle of beneficence—the obligation to prepare for a pandemic—against the principle of nonmaleficence, the duty to avoid creating a new public health threat.