January 19, 2022
Global Pandemics: Gain-of-Function Research of Concern
Introduction
funded research projects and contracts; seven of them
Gain-of-Function (GOF) research is a broad area of
subsequently received exemptions from the pause.
scientific inquiry where an organism gains a new property
or an existing property is altered. The terms gain of function
Current Oversight Mechanisms
and loss of function refer to any genetic mutation in an
As part of the 2014 pause on GOF research, OSTP initiated
organism that either confers a new or enhanced ability or
a deliberative process to evaluate the risks and potential
causes the loss of an ability. Such changes often occur
benefits of GOF research with potential pandemic
naturally. Additionally, scientists can induce some changes
pathogens. In January 2017, OSTP released Recommended
to organisms through experimentation. A key area of GOF
Policy Guidance for Departmental Development of Review
research is the study of both naturally occurring and
Mechanisms for Potential Pandemic Pathogen Care and
experimentally induced changes in organisms to better
Oversight, [P3CO] which described attributes of federal
understand the transmission, infection, and pathogenesis of
agency review and reporting processes for the additional
viruses. Through such knowledge, scientists hope to
oversight of federally funded research that is anticipated to
improve our understanding of human-pathogen interactions,
create, transfer, or use enhanced pathogens with pandemic
aid in assessments of potential pandemic pathogens, and
potential. Agency implementation of a review and reporting
further public health preparedness. Some analysts have
process with the described attributes would allow an agency
raised concerns that studies designed to understand how
to support GOF, GOFROC, or PPP research.
viruses might evolve may have the potential to generate
pathogens that affect humans with the potential to cause a
Following the OSTP guidance, the Department of Health
pandemic. To focus attention on this small subset of
and Human Services (HHS) released Framework for
studies, the scientific and policy communities have begun
Guiding Funding Decisions About Proposed Research
to use the terms gain of function research of concern
Involving Enhanced Potential Pandemic Pathogens (P3CO)
(GOFROC) and enhanced potential pandemic pathogens
in December 2017. The HHS P3CO framework releases
(PPP). However, all three terms (GOF, GOFROC, PPP)
HHS from the 2014 GOF research pause. HHS appears to
have been used interchangeably in some public discussions
be the only agency that has developed a GOF review
and media.
process that addresses the 2017 OSTP GOF guidance, and
the only federal agency that has reported GOF research
Risks and Benefits
funding.
Scientists and the public have debated the risks and benefits
of GOF research. Some in the scientific community argue
Key Components of HHS P3CO Framework
that the research is needed to better understand how viruses
P3CO establishes an additional review process for research
evolve, in order to develop better medical countermeasures
proposals that have gone through the normal scientific
and surveillance regimes for emerging pathogens. Further,
review process, have been determined to be scientifically
they assert that this research can be conducted responsibly
sound, and are reasonably anticipated to create, transfer, or
with proper biosafety and security protocols. Others argue
use enhanced potential pandemic pathogens (PPPs), defined
that the risks outweigh any potential benefits and that
as PPPs resulting from the enhancement of the
alternative experiments should be considered.
transmissibility and/or virulence of a pathogen. To be
subject to this extra scrutiny, an enhanced PPP must satisfy
Concerns over GOF research first emerged in 2011-2012
two criteria:
around a set of studies funded by the National Institutes of
1. It is likely highly transmissible and likely
Health (NIH) on respiratory transmission of the highly
capable of wide and uncontrollable spread
pathogenic avian influenza virus H5N1. At that time, the
in human populations; and
debate centered on the security risks of publishing the
2. It is likely highly virulent and likely to
results of these studies and whether the research should
cause significant morbidity and/or
have been allowed to proceed considering the risk of
mortality in humans.
accidental release. These debates, along with a series of
government laboratory biosafety incidents, not associated
The P3CO review process examines both what is being
with the H5N1 studies, led the White House Office of
experimented on (a PPP) and what the experiment will
Science and Technology Policy (OSTP) to issue U.S.
produce (an enhanced PPP). If a proposal meets these
Government Gain-of-Function Deliberative Process and
criteria, it is to go through an independent, HHS-level,
Research Funding Pause on Selected Gain-of-Function
multidisciplinary P3CO review committee to determine, in
Research Involving Influenza, MERS, and SARS Viruses in
part, whether the research is scientifically sound; the
October 2014. This initial pause affected 18 federally
pathogen is considered to be a credible source of a potential
future human pandemic; the potential risks compared to the
potential benefits to society are justified; there is no feasible
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link to page 2 Global Pandemics: Gain-of-Function Research of Concern
alternative method to address the same question in a
recommendations on dual use research of concern (DURC)
manner that poses less risk; the investigators have
policies and the P3CO guidance.
demonstrated the capacity and commitment to conduct the
research safely and securely; research results are expected
Table 1. Select Policies for Life Science Research
to be responsibly communicated; the research will be
subject to ongoing federal oversight; and the research is
Federal Policy/Guidelines
Description
ethically justifiable.
NIH Guidelines for Research
Outlines science-based safety
Involving Recombinant or
practices for creating and
Based on this review, the P3CO review committee reports
Synthetic Nucleic Acid
handling recombinant and
to the HHS funding agency (i.e., NIH) whether the research
Molecules
synthetic nucleic acid
is acceptable, not acceptable, acceptable on the condition
molecules, and organisms and
that certain experiments are modified, or acceptable on the
viruses containing such
condition that certain risk mitigation measures are
molecules. Also articulates
employed at the federal and institutional level. The funding
responsibilities of institutions,
agency makes the final determination on whether or not the
investigators, and Institutional
project will be funded and must report its decision to HHS
Biosafety Committees.
and OSTP.
HHS Screening Framework
Aims to reduce the risk that
Since the implementation of the P3CO policy, three
Guidance for Providers of
synthetic DNA wil be
research projects have been reviewed and approved. Two of
Synthetic Double-Stranded
deliberately misused to
these projects had originally been awarded in 2013 and
DNA
create dangerous organisms.
were subject to the 2014 pause. Those projects were
United States Government
Addresses institutional
subsequently reviewed in 2018 under the P3CO policy and
Policy for Institutional
oversight of DURC, which
were approved to continue. Both projects concluded in
Oversight of Life Sciences
includes policies, practices,
2019. The third project, while approved with additional risk
Dual Use Research of
and procedures to ensure
mitigation measures, ultimately shifted to utilize alternative
Concern (DURC)
DURC is identified and risk
approaches that do not involve enhanced PPP research.
mitigation measures are
implemented, where
CRS has not identified any publicly released data on how
applicable.
many projects, if any, have been referred into P3CO review
and subsequently retracted from consideration by their
Federal Select Agent Program Oversees the possession,
principal investigators. Such data might help policymakers
(FSAP)
use, and transfer of biological
understand whether, and how many, research projects do
select agents and toxins,
not go forward due to the requirements of the P3CO policy.
which have the potential to
pose a severe threat to
COVID-19 and GOF
public, animal or plant health,
The emergence of COVID-19 and debates on its origin
or to animal or plant
have refocused attention on GOF. A particular focus has
products.
been the NIH funding of the EcoHealth Alliance study,
Source: HHS; U.S. Federal Select Agent Program.
Understanding the Risk of Bat Coronavirus Emergence,
which collaborated with scientists at the Wuhan Institute of
NSABB is to review and provide recommendations
Virology. Some have argued this project should have been
regarding the balance between security and public
captured by the 2014 pause on GOF research and reviewed
transparency when sharing information about PPP research.
under the HHS P3CO guidance. NIH asserts that the
NSABB also is to provide recommendations on whether or
research project did not meet the criteria of either policy.
how to incorporate the P3CO policy into DURC—some
Looking Ahead
have suggested that these are duplicative in some aspects
and areas of oversight. The COVID-19 pandemic has
In addition to P3CO, multiple federal policies and
disrupted NSABB activities, however. NSABB was
guidelines governing the funding and oversight of life
originally scheduled to deliver its recommendations by
sciences research could also capture components of GOF
spring 2021. No further activity of the NSABB has been
research (Table 1). These require certain biosafety and
reported since January 2020. When NSABB will resume its
biosecurity protocols to be implemented at the institutions
activities has not been announced.
where the research will be conducted. Several near-term
federal activities are examining how these federal
The Government Accountability Office (GAO) is currently
regulations, policies , and guidelines address GOF research
conducting a review of HHS oversight of high-risk
and whether they produce duplicative requirements,
research. Required under Section 19010 of the Coronavirus
inefficiencies, or coordination challenges in regard to
Aid, Relief, and Economic Security (CARES) Act (P.L.
oversight.
116-136), this study is to examine the extent to which HHS
oversight addresses biosafety and biosecurity risks and is to
The National Science Advisory Board for Biosecurity
include consideration of DURC, FSAP, and P3CO. One
(NSABB), a federal advisory committee that addresses
issue it may consider is whether any of these programs are
issues related to biosecurity and dual use research, was
duplicative (similar to the charge given to NSABB).
charged in January 2020 with reviewing and providing
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Global Pandemics: Gain-of-Function Research of Concern

IF12021
Todd Kuiken, Analyst in Science and Technology Policy


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