Oversight of Gain of Function Research with Pathogens: Issues for Congress

May 26, 2022 R47114

Oversight of Gain of Function Research with
May 26, 2022
Pathogens: Issues for Congress
Todd Kuiken
The term gain of function refers to any genetic mutation in an organism that confers a new or
Analyst in Science and
enhanced ability. Such changes often occur naturally. Additionally, scientists can induce such
Technology Policy
changes to organisms through experimentation. Gain of function (GOF) research is a broad area

of scientific inquiry involving organisms that gain a new property or have an existing property
altered. A key area of GOF research is the study of both naturally occurring and experimentally

induced changes in viruses to better understand transmission, infection, and pathogenesis.
Current U.S. policy focuses on GOF research involving enhanced potential pandemic pathogens. Some in the scientific
community argue that this research is needed to better understand how viruses evolve in order to develop better medical
countermeasures and surveillance regimes for emerging pathogens. However, an accident, or deliberate misuse of this
research, has the potential to impact the larger public, potentially globally. This concern leads some observers to argue that
the risks of such research outweigh any potential benefits.
An overlapping set of policies and guidance address aspects of biosafety and biosecurity associated with GOF research with
pathogens in the United States—some impose requirements, some provide guidance, some apply only to research with select
biological agents, and some policies only apply to federally funded research. These policies and guidance include federal
regulation of research with select biological agents and toxins, best practice guidance for microbiological and biomedical
laboratories, agency guidance on funding research with potential pandemic pathogens, and the institutions and researchers
conducting it.
The general public is at the center of the GOF debate, with experts on each side invoking the public’s well-being as reasoning
for their positions. Currently there is limited public engagement around GOF research on pathogens and the role the U.S.
government has in its funding and oversight.
When weighing options addressing these complex and intertwined policy issues, Congress may have to balance competing
and, in some instances, conflicting national and international priorities.
Congress may consider whether policy changes are necessary to minimize risks, maximize benefits, and better incorporate
and address public and stakeholder concerns associated with GOF research on pathogens. Congress may continue with
current oversight or choose to defer any action until they obtain the recommendations of two reviews of the U.S. biosafety
and biosecurity oversight system, one conducted by the Government Accountability Office, and the other by the National
Science Advisory Board for Biosecurity, a federal advisory board.
Congress might consider a ban on federally funded GOF research on pathogens. Legislation banning such research in varying
capacities has been introduced in both chambers during the 117th Congress. A ban on federal funding of GOF research
conducted in China has passed the Senate as S. 1260 and is in conference committee. Congress might consider limiting where
such research is permitted based on prescribed standards for how to design, construct, commission, operate or maintain
laboratories where such research is conducted. Congress might also support the development of safer alternatives that can
still expand scientific understanding of how viruses evolve into potential pandemic pathogens and the ability to monitor and
combat them.
Gain of function research is part of a larger life sciences research enterprise that has produced important societal benefits but
also has inherent risks. Congress might consider whether increased support for biosafety and biosecurity research is needed.
Congress could also consider whether the establishment of a federal biorisk management policy that aligns oversight across
federal agencies and provides a consistent review process for research institutions would be more efficient than the current
oversight system.
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Oversight of Gain of Function Research with Pathogens: Issues for Congress

Introduction
Gain-of-Function (GOF) refers to any genetic mutation in an organism that confers a new or
enhanced ability.1 Such changes often occur naturally. Additionally, scientists can induce some
changes to organisms through experimentation. GOF is a research term that covers a broad area
of scientific inquiry. The term entered the public policy debates and became more commonly used
in 2011 when it was used to describe two controversial research projects on H5N1 avian influenza
virus funded by the National Institutes of Health (NIH).2 Subsequent U.S. policy narrowly
addressed GOF research as research involving enhanced potential pandemic pathogens (ePPP).
The Coronavirus Disease 2019 (COVID-19) pandemic and interest in its origin have refocused
attention on GOF. There has been debate in the press and from lawmakers about whether GOF
experiments could have produced the SARS CoV-2 virus.3
A key area of emerging infectious disease research is the study of both naturally occurring and
experimentally induced changes in viruses. Such research aims to improve understanding of virus
transmission, infection, and pathogenesis.4 Some of this research involves changing the genetic
code of an organism or virus to observe how such changes affect its key properties. Through such
experiments, scientists hope to improve their understanding of human-pathogen interactions,
better understand how viruses evolve and mutate, and further public health preparedness by
making better vaccines and treatments.
Naturally occurring and experimentally induced GOF mutations in viruses do not necessarily
cause an increase in virulence or pathogenesis. One mutation may affect several different traits.
The environment in which a virus operates (e.g., inside a human or animal), or is studied (e.g.,
laboratory conditions), can also impact any mutation that may occur, whether naturally or through
experimentation. It could enhance fitness in one environment but not in another.5 For example, a
trait found to be enhanced under laboratory conditions might not be similarly enhanced, or be
found to exist at all, outside of the laboratory or in an infected host. The opposite is also true.
Experiments where researchers did not intend to increase virulence or transmissibility could do
just that. Thus, biosafety and biosecurity processes emphasize accounting for unintended
consequences to protect laboratory workers and prevent accidental releases.6
This report discusses biosafety- and biosecurity-related issues associated with a subset of GOF
research involving pathogens. It provides an overview of what GOF research on such pathogens
entails, the history of concerns with such research, the potential benefits and risks of conducting

1 Amber Dance, “The Truth About Gain of Function Research,” Nature, vol. 598, no. 7882 (2021), pp. 554-557.
2 Kelsey Lane Warmbrod, Michael G. Montague, and Gigi Kwik Gronvall, “COVID‐19 and the Gain of Function
Debates: Improving Biosafety Measures Requires a More Precise Definition of Which Experiments Would Raise
Safety Concerns,” EMBO Reports, vol. 22, no. 10 (2021).
3 For one review, see Gigi Kwik Gronvall, “The Contested Origin of SARS-CoV-2,” Survival, vol. 63, no. 6
(November 2, 2021), pp. 7-36. The SARS-CoV-2 virus is the cause of the COVID-19 pandemic.
4 Pathogenesis is the process by which a disease develops; including its onset and progression.
5 See Gigi Kwik Gronvall, “The Contested Origin of SARS-CoV-2,” Survival, vol. 63, no. 6 (November 2, 2021), pp.
7-36.
6 Biosafety is a framework that describes the use of specific practices, training, safety equipment, and specially
designed buildings to protect the worker, community, and environment from an accidental exposure or unintentional
release of infectious agents and toxins. Biosecurity refers to the protection, control of, and accountability for high-
consequence biological agents and toxins, and critical relevant biological materials and information within laboratories
to prevent unauthorized possession, loss, theft, misuse, diversion, and accidental or intentional release. See
https://www.phe.gov/s3/BioriskManagement/biosecurity/Pages/Biosecurity-FAQ.aspx.
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such research, U.S. oversight mechanisms for such research, and issues that Congress may
consider in the context of research involving potential pandemic pathogens.
History of Concern with Gain-of-Function Research
Concern with research involving pathogens and other life sciences is not new. The Subcommittee
on Biological Defense Research and Development Committee on Homeland and National
Security of the National Science and Technology Council stated that “work with infectious agents
in the laboratory always involves risk.”7
There have been longstanding biosafety/biosecurity concerns involving the use of pathogens and
other life-science related research impacts more broadly dating back to historic periods where
infectious diseases were recognized as a potential weapon against people and armies.8 In more
recent history, representatives from various Army facilities met together in 1955 to share
knowledge and experiences regarding the three principal biological warfare laboratories of the
United States. This meeting was the first Biological Safety Conference in the United States.9
Subsequent concerns arising from biosafety and biosecurity events associated with life sciences
research (for a graphical representation of certain events since the 1960s, see Appendix A) have
prompted subsequent actions to establish oversight mechanisms and address perceived risks.
Concerns over certain types of GOF research—specifically the risk of accidental release of a
deadly pathogen and security risks associated with publishing study result—emerged in 2011-
2012 around a set of studies funded by NIH on respiratory transmission of the highly pathogenic
avian influenza virus H5N1. Since then, policymakers, scientists and the public have debated the
magnitude of potential risks and benefits of GOF research involving pathogens, how to weigh
those risks and benefits appropriately, and to what extent community engagement and transparent
decisionmaking should have a role in determining those risk and benefits.10
Policy concerns and debates regarding the H5N1 studies, along with a series of contemporaneous
but unrelated government laboratory biosafety incidents, led the White House Office of Science
and Technology Policy (OSTP) to issue U.S. Government Gain-of-Function Deliberative Process
and Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS,
and SARS Viruses11 in October 2014. This initial pause affected 18 federally funded research
projects and contracts; 7 of them subsequently received exemptions from the pause.
As part of the 2014 pause, OSTP initiated a deliberative process to evaluate the risks and potential
benefits of GOF research with potential pandemic pathogens. In January 2017, OSTP released
Recommended Policy Guidance for Departmental Development of Review Mechanisms for

7 Subcommittee on Biological Defense Research and Development, Committee on Homeland and National Security,
Fast Track Action Committee Report: Biosafety and Biosecurity, National Science and Technology Council, 2017,
https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/NSTC/ftac-bio-report.pdf.
8 Stefan Riedel, “Biological Warfare and Bioterrorism: A Historical Review,” Baylor University Medical Center
Proceedings, vol. 17 (2004), pp. 400-406.
9 See Manuel S. Barbeito and Richard H. Kruse, A History of the American Biological Safety Association, Part I: The
First 10 Biological Safety Conferences 1955-1965, The Association of Biosafety and Biosecurity, https://absa.org/
about/hist01/.
10 Michael J. Selgelid, “Gain-of-Function Research: Ethical Analysis,” Science and Engineering Ethics, vol. 22, no. 4
(2016), pp. 923-964.
11 Office of Science and Technology Policy, U.S. Government Gain-of-Function Deliberative Process and Research
Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses, 2014,
https://www.phe.gov/s3/dualuse/documents/gain-of-function.pdf.
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Potential Pandemic Pathogen Care and Oversight (P3CO),12 which described attributes of
federal agency review and reporting processes for the additional oversight of federally funded
research that is anticipated to create, transfer, or use enhanced pathogens with pandemic potential.
Agency implementation of a review and reporting process with the described attributes would
allow it to support GOF research on pathogens of this type. Responding to the OSTP guidance,
the Department of Health and Human Services (HHS) released “Framework for Guiding Funding
Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens
(P3CO)”13 in December 2017. HHS appears to be the only agency that has developed and
released a GOF review process that addresses the 2017 OSTP GOF guidance, and the only federal
agency that has reported GOF research funding involving enhanced potential pandemic
pathogens.
A focus of recent concerns over GOF research, particularly in light of the COVID-19 pandemic,
has been on a 2014 NIH-funded study by the EcoHealth Alliance. This study, Understanding the
Risk of Bat Coronavirus Emergence,14 was conducted at the Wuhan Institute of Virology in China,
with results published in 2016.15 In that experiment, researchers inserted spike proteins from eight
different coronaviruses into a single bat coronavirus called WIV1. Spike proteins help a virus
bind to its host. The study showed that the virus modified with the additional eight spike proteins
could infect human cells.16
Some stakeholders have argued that the 2014 pause on GOF research should have included this
study and that it should have been subsequently reviewed under the 2017 HHS P3CO guidance.17
Others have argued that the research did not meet the requirements of the “Framework for
Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic
Pathogens (P3CO)” because the research did not enhance transmissibility, as both the modified
and the original virus are able to infect human cells.18 NIH reportedly concluded that the research
project did not meet the criteria of the 2014 pause on GOF research.19
The virus used in 2014 EcoHealth Alliance study is not genetically close to any known laboratory
samples of the SARS-CoV-2 virus that causes COVID-19.20 A group of scientists have called for
investigation into the origins of COVID-19, stating that “We must take hypotheses about both

12 Office of Science and Technology Policy, Recommended Policy Guidance for Potential Pandemic Pathogen Care
and Oversight (P3CO), 2017, https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/p3co-
finalguidancestatement.pdf.
13 U.S. Department of Health and Human Services, Framework for Guiding Funding Decisions About Proposed
Research Involving Enhanced Potential Pandemic Pathogens (P3CO), 2017.
14 National Institutes of Health, Understanding the Risk of Bat Coronavirus Emergence, NIH RePORTER,
https://reporter.nih.gov/project-details/9819304.
15 Vineet D. Menachery, Boyd L. Yount, and Amy C. Sims, et al., “SARS-like WIV1-CoV poised for human
emergence,” PNAS, vol. 113, no. 11 (2016).
16 “What Is ‘Gain-of-Function’ Research?” The Economist, November 1, 2021.
17 Kelsey Lane Warmbrod, Michael G. Montague, and Gigi Kwik Gronvall, “COVID‐19 and the Gain of Function
Debates: Improving Biosafety Measures Requires a More Precise Definition of Which Experiments Would Raise
Safety Concerns,” EMBO Reports, vol. 22, no. 10 (2021).
18 Ibid.
19 Declan Butler, “Engineered Bat Virus Stirs Debate over Risky Research,” Nature, 2015.
20 Gigi Kwik Gronvall, “The Contested Origin of SARS-CoV-2,” Survival, vol. 63, no. 6 (November 2, 2021), pp. 7-36.
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natural and laboratory spillovers seriously until we have sufficient data.”21 The debates around the
origins of COVID-19 continue to evolve as new information becomes available.22
Benefits and Risks of GOF Research with Pathogens
For many infectious diseases, the primary medical countermeasure is vaccination.23 However,
vaccines can lose their efficacy based on changes in the pathogen. For example, the first vaccines
for influenza were introduced in the 1940s; new influenza vaccines are developed annually as
influenza viruses undergo antigenic drift (small changes or mutations) that can reduce vaccine
efficacy.24 A main argument for conducting GOF experiments is that viruses are constantly
mutating. As one virologist stated, “We can either wait for something to arise, and then fight it, or
we can anticipate that certain things will arise, and instead we can preemptively build our
arsenals; that’s where gain of function research can come in handy.”25 Proponents of GOF
research assert that understanding and predicting how these changes occur could aid in the
development of vaccines that work against mutations of a virus.26 Some scientists argue that
mutations specifically identified by GOF studies allow[s] experts to assess the relevance
of specific molecular determinants in relation to virologic and epidemiological factors
considered for pandemic preparedness and is of particular relevance for decisions relating
to the production of manufacturing seeds and trial lots and the stockpiling of vaccines.27
Others similarly argue that GOF experimentation is needed to better understand medical
countermeasures across virus families and move the field from “one bug, one drug” to “one drug,
many bugs.”28
Another argument raised in favor of continued GOF experimentation is to better understand how
viruses become zoonotic, or obtain the ability to transmit from animals to humans. In the early
2000s, the number of human infections with avian H5N1 influenza resulting from close contact
with birds increased. This zoonotic transmission raised particular concern because the disease’s
case fatality rate was estimated at about 60%.29 For comparison, one estimate of the U.S. case
fatality rate for COVID-19 is 1.2%.30 H5N1 did not acquire mammalian transmissibility, and

21 Jessee D. Bloom, Yujia Alina Chan, and Ralph S. Baric, et al., “Investigate the Origins of COVID-19,” Science, vol.
372, no. 6543 (2021).
22 For additional information on the debates on the origins of COVID-19, see CRS In Focus IF11822, Origins of the
COVID-19 Pandemic, coordinated by Tiaji Salaam-Blyther.
23 Medical countermeasures are Food and Drug Administration (FDA)-regulated products that may be used in the event
of a potential public health emergency stemming from a terrorist attack with a biological, chemical, or
radiological/nuclear material, or a naturally occurring emerging disease. See https://www.fda.gov/emergency-
preparedness-and-response/about-mcmi/what-are-medical-countermeasures.
24 Surface proteins of influenza viruses are “antigens,” which means they are recognized by the immune system and are
capable of triggering an immune response, including production of antibodies that can block infection. See
https://www.cdc.gov/flu/about/viruses/change.htm.
25 Amber Dance, “The Truth About Gain of Function Research,” Nature, vol. 598, no. 7882 (2021), pp. 554-557.
26 S. Schultz-Cherry, R.J. Webby, and R.G. Webster, et al., “Influenza Gain-of-Function Experiments: Their Role in
Vaccine Virus Recommendation and Pandemic Preparedness,” mBio, vol. 5, no. 6 (2014).
27 Ibid.
28 Timothy P. Sheahan and Ralph S. Baric, “Is regulation preventing the development of therapeutics that may prevent
future coronavirus pandemics?,” Future Virology, vol. 13, no. 3 (2018), pp. 413-146.
29 Michael J. Imperiale, Don Howard, and Arturo Casadevall, “The Silver Lining in Gain-of-Function Experiments
with Pathogens of Pandemic Potential,” Methods in Molecular Biology, vol. 1836 (2018), pp. 575-587.
30 For one source of estimates of COVID-19 case fatality rates by country, see https://coronavirus.jhu.edu/data/
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there were no confirmed cases of human-to-human transmission. Proponents of GOF research
argue that experiments are needed to understand how a virus like H5N1 was able to move from
infecting birds to infecting humans and how or whether it could acquire human-to-human
transmissibility.
A major concern among some biosafety and biosecurity experts is that an accidental or deliberate
release of a modified virus could pose a “grave and completely novel threat to human health,”31
potentially causing a pandemic by evading natural immunities or effectiveness of currently
available medical countermeasures. Some observers have raised additional concerns that
publication of data and information from original GOF research could pose a safety and security
threat even if the research is conducted under governmental oversight measures.32
Conducting a risk/benefit assessment could aid in determining the potential benefits of any
medical countermeasure that may result from GOF research, and the risks associated with a
potential laboratory accident or deliberate misuse. However, some have suggested that a
risk/benefit assessment is unlikely to determine reliably whether the risks of GOF outweigh the
benefits, due, in part, to the absence of data, presumption of future events, and subjectivity in
evaluation of risk tolerance.33 Publicly available data on the number of laboratory incidents
associated with life sciences research is difficult to obtain. Certain data on laboratory incidents
must be reported to NIH and other federal agencies depending on the biological agent used and
funding mechanisms governing the research. Other data associated with laboratory incidents are
not reported outside the institution where the work is being done. Reporting requirements for
institutions vary and no single repository collects all of this information. The lack of consolidated
or comprehensive data arguably hampers the ability to predict how likely it is for a GOF virus to
escape containment. However, some researchers assert that the lack of prior GOF research
incident data does not mean that researchers and oversight bodies should avoid risk/benefit
assessments, noting that these types of assessments are routinely done in other scientific fields
with incomplete data.34
GOF research on potential pandemic pathogens has also been questioned on an ethics basis. Some
observers and researchers argue that ethical principles would only allow GOF research on
potential pandemic pathogens if public health benefits cannot be achieved by other, safer
methods.35 Some have suggested that safer experimental approaches exist that can enhance
surveillance, prevention, and treatment of disease resulting from pandemic pathogens. They cite

mortality.
31 Marc Lipsitch and Barry R. Bloom, “Rethinking Biosafety in Research on Potential Pandemic Pathogens,” mBio,
vol. 3, no. 5 (2012). Declan Butler, “Engineered Bat Virus Stirs Debate over Risky Research,” Nature, 2015. Kevin M.
Esvelt, “Manipulating Viruses Is Too Dangerous,” Washington Post, October 7, 2021.
32 Marc Lipsitch and Alison P. Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic
Pathogens,” PLOS Medicine, vol. 11, no. 5 (2014). Arturo Casadevall, Lynn Enquist, and Michael Imperiale, et al.,
“Redaction of Sensitive Data in Publication of Dual Use Research of Concern,” mBio, vol. 5 (2013).
33 Daniel J. Rozell, “Assessing and Managing the Risks of Potential Pandemic Pathogen Research,” mBio, vol. 6, no. 4
(2015).
34 Arturo Casadevall and Michael J. Imperiale, “Risks and Benefits of Gain-of-Function Experiments with Pathogens of
of Pandemic Potential, Such as Influenza Virus: A Call for a Science-Based Discussion,” mBIO, vol. 5, no. 4 (2014).
35 Nicholas G. Evans, “Ethical and Philosophical Considerations for Gain-of-Function Policy: The Importance of
Alternate Experiments,” Frontiers in Bioengineering and Biotechnology, vol. 6 (2018). Marc Lipsitch and Alison P.
Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens,” PLOS Medicine, vol. 11, no.
5 (2014).
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examples including developing universal vaccines, antiviral drugs, and improving technologies
and capabilities for rapid vaccine development and manufacturing.36
The general public is at the center of the debate, with experts on each side invoking the public’s
well-being as reasoning for their positions.37 In this context, the public consists of all individuals
who could become ill or die due to infection with a pathogen of pandemic potential, whether that
occurs naturally, accidentally, or by intentional means.38 An accident, or a deliberate misuse of a
GOF virus strain, has the potential to impact the larger public as well as those conducting or
participating (e.g., as human subjects) in the research. Similarly, the successful outcomes of GOF
research that leads to, for example, new medical countermeasures or increased vaccine efficacy
provide broadly applicable benefits to the larger public. Some experts have called for GOF
research to be evaluated under a broader ethical framework that includes input from and
evaluation of risks to the public.39 Others argue that the public should be included more broadly
in the process of research assessment to determine what levels of risk are acceptable in contexts
beyond GOF.40
Incorporating public input may be hampered by the lack of public engagement. There has been
limited public engagement around GOF and the role the U.S. government has in both the funding
and oversight of GOF research.41 Additionally, the use of different terms—GOF, gain of function
research of concern, ePPP, and engineered viruses—in public debates, media, and policies may
cause confusion as to what research is being funded, what the risks and benefits are, and what
polices do and do not cover.
The limited amount of public polling around these issues may reflect the lack of public
engagement. CRS identified one poll, conducted during the debate over COVID-19’s origins
(June 29-30, 2021) and after HHS instituted its P3CO policy that examined the U.S. public’s view
towards research involving the enhancement of viruses.42 A separate study examined the U.S.
public’s awareness, acceptability, and risk perception about infectious disease research and dual-
use research of concern (DURC).43 Although the questions asked could be construed to meet
certain definitions of GOF, neither poll used the term GOF specifically. Based on the limited
available data it is difficult to assess the U.S. public’s views towards GOF research.

36 Marc Lipsitch and Alison P. Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic
Pathogens” PLOS Medicine, vol. 11, no. 5 (2014).
37 Monica Schoch-Spana, “Public Engagement and the Governance of Gain-of-Function Research,” Health Security,
vol. 13, no. 2 (2015), pp. 69-73.
38 Ibid.
39 Nicholas G. Evans, Marc Lipsitch, and Meira Levinson, “The Ethics of Biosafety Considerations in Gain-of-
Function Research Resulting in the Creation of Potential Pandemic Pathogens,” Journal of medical ethics, vol. 41, no.
11 (2015), pp. 901-908.
40 David Gillum, Rebecca Moritz, and Yong-Bee Lim, et al., “Charting a New Course for Biosafety in a Changing
World,” Issues in Science and Technology, May 23, 2022. Marc Lipsitch and Barry R. Bloom, “Rethinking Biosafety
in Research on Potential Pandemic Pathogens,” mBio, vol. 3, no. 5 (2012).
41 Monica Schoch-Spana, “Public Engagement and the Governance of Gain-of-Function Research,” Health Security,
vol. 13, no. 2 (2015), pp. 69-73.
42 “Poll: Majority of Voters Support Gain of Function Virus Research,” The Hill, https://thehill.com/hilltv/what-
americas-thinking/561078-poll-majority-of-voters-support-gain-of-function-research.
43 Chandini R. MacIntyre, Dillon C. Adam, et al. “Public Awareness, Acceptability and Risk Perception About
Infectious Diseases Dual-Use Research of Concern: A Cross-Sectional Survey,” BMJ Open, vol. 10, no. 1, (2020).
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Oversight of Gain of Function Research Involving
Pathogens
GOF research concerns are part of a larger policy debate on how best to manage biosafety and
biosecurity associated with emerging technologies and life sciences research. The United States
has multiple, overlapping policies that provide guidance and oversight for life sciences research,
depending on the types of experiments and biological agents used (see Figure 1). Many of these
policies and guidelines are framed around biosafety and biosecurity and were developed in
response to specific events (see Appendix A for a timeline of select events and policy responses).
While some oversight mechanisms are required by law, others are guidance issued by funding
agencies and are mandatory only if the research is funded by the U.S. government. Privately
funded research, or research conducted outside the United States, may therefore not be covered
by certain U.S. oversight mechanisms. One analysis suggested that the U.S. life sciences research
biosafety and biosecurity policymaking process is reactive, leading to inconsistent policies that
limit U.S. ability to address emerging threats. 44 This section discusses specific policies and
guidance that govern life science research broadly and could impact GOF research specifically,
depending on the virus being used and the specific types of experiments being proposed. (See
Appendix B for brief descriptions of these select U.S. government policies and how they may
impact GOF research oversight.)

44 Diane DiEuliis, Venkat Rao, and Diane Billings, et al., “Biodefense Policy Analysis—A Systems-Based Approach,”
Health Security, vol. 17, no. 2 (2019), pp. 83-99.
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Figure 1. Comparison and Overlap of Select Oversight Mechanisms for Life Science
Research
Oversight Applies to Specific Agents and/or Types of Experiments

Source: Adapted from National Science Advisory Board for Biosecurity, Recommendations for The Evaluation and
Oversight of Proposed Gain-Of-Function Research, 2016, p. 28.
Notes: GOF Pause refers to the 2014 U.S. Government Gain-of-Function Deliberative Process and Research Funding
Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses issued by the White House
Office of Science and Technology Policy (OSTP). BMBL: Biosafety in Microbiological and Biomedical
Laboratories; DURC: Dual Use Research of Concern; HHS P3CO: Framework for Guiding Funding Decisions
about Proposed Research Involving Enhanced Potential Pandemic Pathogens; SARS: Severe acute respiratory
syndrome; MERS: Middle East Respiratory Syndrome.
Biosafety in Microbiological and Biomedical Laboratories (BMBL)
Guidelines
The Centers for Disease Control and Prevention (CDC) and the NIH partner together to publish
the Biosafety in Microbiological and Biomedical Laboratories (BMBL) guidelines, which serve
as the overarching guidance document for U.S. biosafety practices for protecting workers and
preventing exposures in biological laboratories. The BMBL provides guidance for addressing the
safe handling and containment of infectious microorganisms and hazardous biological materials.45
Adherence to the BMBL is a term and condition of certain grant awards for recipients of funding
from certain federal agencies.
The BMBL describes BSLs, which are designations applied to projects or activities conducted in
laboratories, in ascending order of containment based on the degree of the health-related risk

45 Paul J. Meechan and Jeffrey Potts, Biosafety in Microbiological and Biomedical Laboratories, U.S. Department of
Health and Human Services, 6th Edition, 2020, https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-
WEB-final-3.pdf.
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associated with the work being conducted.46 Each biosafety level (BSL 1-4) builds upon the
previous level (see Appendix C for descriptions of the BSLs). Each level describes a minimum
set of safety practices and procedures, required safety equipment, and administrative and
engineering controls. The appropriate BSL for a research project is determined by the institution
in which the work is being conducted, in consultation with the principal investigator, depending
on the specific organism and types of experiment to be performed. In 2020, 190 entities with
BSL-3 laboratories and 8 entities with BSL-4 laboratories were registered in the Federal Select
Agent Program in the United States, operated by a variety of actors (federal, commercial,
academia, and private).47 Not all of these laboratories are research labs; for example, they could
also include clinical laboratories in public health settings that deal with select agents.48
Some have raised concerns from an international context that while some BSL-3 laboratories are
state of the art, others may not be as well-equipped in terms of the facility itself as well as training
and screening of personnel and materials.49 While the BMBL serves as an “advisory document
recommending best practices for the safe conduct of work in biomedical and clinical
laboratories,”50 the Government Accountability Office (GAO) reported in 2013 that there are no
national standards for how to design, construct, commission, operate, or maintain a high
containment laboratory.51 Subsequent GAO studies have reviewed individual agency polices and
made recommendations on how to improve laboratory safety and oversight.52
Federal Select Agent Program
The Federal Select Agent Program (FSAP) is one of the federal regulatory programs addressing
biosecurity. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002
(P.L. 107-188) requires HHS to establish and regulate a list of biological agents and toxins that
have the potential to pose a severe threat to public health and safety.
The Agricultural Bioterrorism Protection Act of 2002 (Title II, Subtitle B, of P.L. 107-188)
requires the U.S. Department of Agriculture (USDA) to establish and regulate a list of biological
agents that have the potential to pose a severe threat to animal health and safety, plant health and
safety, or to the safety of animal or plant products. FSAP is managed by the Division of Select
Agents and Toxins at the CDC and the Division of Agriculture Select Agents and Toxins at
USDA. CDC and USDA share responsibility for some agents because they potentially threaten

46 Department of Health and Human Services, Science Safety Security, https://www.phe.gov/s3/BioriskManagement/
biosafety/Pages/Biosafety-Levels.aspx.
47 Federal Select Agent Program, 2020 Annual Report of the Federal Select Agent Program, 2020,
https://www.selectagents.gov/resources/publications/docs/FSAP_Annual_Report_2020_508.pdf.
48 This is a subset of the total number of BSL-3/4 laboratories in operation; laboratories which do not work with select
agents would not need to register under the Select Agent Program. Therefore, the total number of BSL-3/4 laboratories
may be higher.
49 Ian W. Lipkin, “Biocontainment in Gain-of-Function Infectious Disease Research,” mBio, vol. 3, no. 5 (2012).
50 See Biosafety in Microbiological and Biomedical Laboratories (BMBL) 6th Edition; https://www.cdc.gov/labs/
BMBL.html.
51 U.S. Government Accountability Office (GAO), High-Containment Laboratories: Assessment of the Nation’s Need
Is Missing, 2013.
52 U.S. Government Accountability Office, High-Containment Laboratories: Comprehensive and Up-to-Date Policies
and Stronger Oversight Mechanisms Needed to Improve Safety, GAO-16-305, 2016, https://www.gao.gov/products/
gao-16-305. U.S. Government Accountability Office, High-Containment Laboratories: Coordinated Actions Needed to
Enhance the Select Agent Program’s Oversight of Hazardous Pathogens, GAO-18-145, 2017, https://www.gao.gov/
products/gao-18-145. U.S. Government Accountability Office, Laboratory Safety: FDA Should Strengthen Efforts to
Provide Effective Oversight, GAO-20-594, 2020, https://www.gao.gov/products/gao-20-594.
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both humans and animals. 42 U.S.C. §262a and 7 U.S.C. §8401 require CDC and USDA to
review and republish the lists of select agents and toxins on at least a biennial basis.53 Whether
FSAP would apply to GOF research depends upon the virus or agent being used in such
experiments. If the pathogen does not appear on the HHS or USDA lists, the research would not
be subject to FSAP; however, it may be captured by other policies (see Figure 1).
FSAP focuses on both the people who have access to select agents and the facilities where select
agents are used and stored. Entities possessing select agents are required under 42 U.S.C. §262a
and 7 U.S.C. §8401 to develop explicit biosecurity and biosafety plans and procedures which are
reviewed and certified by FSAP.54 Some have argued that a list-based approach “assumes that we
already know what to worry about” and is not able to keep pace with emerging threats that may
not yet appear on such a list.55
Dual Use Research of Concern (DURC)
The U.S. Government Policy for the Institutional Oversight of Life Sciences Dual Use Research
of Concern went into effect on September 24, 2015. The policy articulates the practices and
procedures required to ensure that dual use research of concern is identified at the institutional
level and risk mitigation measures are implemented as necessary.56 It defines dual use research of
concern as
life sciences research that, based on current understanding, can be reasonably anticipated
to provide knowledge, information, products, or technologies that could be directly
misapplied to pose a significant threat with broad potential consequences to public health
and safety, agricultural crops and other plants, animals, the environment, materiel, or
national security.
It covers research that uses one or more of the 15 agents or toxins listed within the policy and 7
categories of experiments. The policy applies to:
1. All U.S. government departments and agencies that fund or conduct life sciences
research.
2. Institutions within the United States that both:
a. Receive U.S. government funds to conduct or sponsor life sciences research;
and
b. Conduct or sponsor research that involves one or more of the 15 agents or
toxins listed within the DURC policy, even if the research is not supported by
U.S. government funds.
Certain GOF experiments could be captured by the DURC policy depending on the agent being
used and the specific types of experiments being proposed. However, institutions or private
companies that do not receive U.S. government funding are not subject to the DURC policy. The

53 Federal Select Agent Program, https://www.selectagents.gov/sat/index.htm.
54 An entity is defined as any government agency (federal, state, or local), academic institution, corporation, company,
partnership, society, association, firm, sole proprietorship, or other legal entity. An entity is thus not limited to a single
facility or to a single laboratory. An entity may possess one or multiple facilities, each facility containing one or
multiple laboratories.
55 Sam Weiss Evans, Jacob Beal, and Kavita Berger, et al., “Embrace Experimentation in Biosecurity Governance,”
Science, vol. 368, no. 6487 (2020).
56 The United States Government, United States Government Policy for Institutional Oversight of Life Sciences Dual
Use Research of Concern, September 25, 2015, https://www.phe.gov/s3/dualuse/Documents/durc-policy.pdf.
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terms biosafety and biosecurity are used differently in various international regulations and
frameworks. Global consensus around what DURC should consist of or what the appropriate
safety levels for DURC experiments should be is lacking, except that these types of experiments
should be conducted under the safest conditions practicable.57 Some have argued that instead of
developing DURC policies that prohibit or limit certain types of experiments, the focus should be
on reviewing the scientific questions proposed.58
In January 2020 and again in February 2022, the Secretary of HHS charged the National Science
Advisory Board for Biosecurity (NSABB),59 a federal advisory committee that addresses issues
related to biosecurity and dual use research, with reviewing and providing recommendations on
the DURC policies. The NSABB is expected to complete its review and provide
recommendations in December 2022.
Framework for Guiding Funding Decisions About Proposed
Research Involving Enhanced Potential Pandemic Pathogens
(P3CO)
In January 2017, OSTP released Recommended Policy Guidance for Departmental Development
of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO),60 which
described attributes of federal agency review and reporting processes for the additional oversight
of federally funded research that is anticipated to create, transfer, or use enhanced pathogens with
pandemic potential. Agency implementation of a review and reporting process with the described
attributes would allow an agency to support GOF research on potential pandemic pathogens.
Responding to the OSTP guidance, HHS released “Framework for Guiding Funding Decisions
About Proposed Research Involving Enhanced Potential Pandemic Pathogens (P3CO)”61 in
December 2017.
Sections III and IV of the HHS P3CO framework establishes an additional review process for
HHS-sponsored research proposals that have gone through the normal scientific review process,
have been determined to be scientifically sound, and are reasonably anticipated to create, transfer,
or use ePPPs. An ePPP is defined as a potential pandemic pathogen resulting from the
enhancement of the transmissibility and/or virulence of a pathogen; which can occur via GOF-
type research. To be subject to this extra scrutiny, an ePPP must satisfy two criteria:
1. it is likely highly transmissible and likely capable of wide and uncontrollable
spread in human populations; and
2. it is likely highly virulent and likely to cause significant morbidity and/or
mortality in humans.
The HHS P3CO review process examines both what is being experimented on (a PPP) and what
the experiment will produce (an enhanced PPP). If a research proposal meets these criteria, it may

57 Michael J. Imperiale and Arturo Casadevall, “A New Approach to Evaluating the Risk-Benefit Equation for Dual-
Use and Gain-of-Function Research of Concern,” Frontiers in Bioengineering and Biotechnology, vol. 6 (2018).
58 Ibid.
59 See https://osp.od.nih.gov/biotechnology/national-science-advisory-board-for-biosecurity-nsabb/#about.
60 Office of Science and Technology Policy, Recommended Policy Guidance for Potential Pandemic Pathogen Care
and Oversight (P3CO), 2017, https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/p3co-
finalguidancestatement.pdf.
61 U.S. Department of Health and Human Services, Framework for Guiding Funding Decisions about Proposed
Research Involving Enhanced Potential Pandemic Pathogens (P3CO), 2017.
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be required to go through an independent, HHS-level, multidisciplinary P3CO review committee
to determine, in part, whether:
 the research is scientifically sound;
 the 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 alternative method to address the same question in a manner
that poses less risk;
 the investigators have demonstrated the capacity and commitment to conduct the
research safely and securely;
 the research results are expected to be responsibly communicated;
 the research will be subject to ongoing federal oversight; and
 the research is ethically justifiable.
Based on this review, the P3CO review committee reports to the HHS funding agency (e.g., NIH)
whether the research is acceptable, not acceptable, acceptable on the condition that certain
experiments are modified, or acceptable on the condition that certain risk mitigation measures are
employed at the federal and institutional level. The funding agency makes the final determination
on whether the project will be funded and must report its decision to HHS and OSTP.
Since the implementation of the P3CO policy, three research projects have been reviewed and
approved.62 Two of these projects had originally been awarded in 2013 and were subject to the
2014 pause. Those projects were subsequently reviewed in 2018 under the P3CO policy and were
approved to continue. Both projects concluded in 2019. The third project was approved by the
P3CO review process with additional risk mitigation measures. However, the grant sponsoring
agency, which has the final decisionmaking authority for approval of grants, decided to redirect
all funds under the award to support alternative approaches that do not involve enhanced potential
pandemic pathogen research.63
In January 2020 and again in February 2022, the Secretary of HHS charged the NSABB,64 a
federal advisory committee that addresses issues related to biosecurity and dual use research, with
reviewing and providing recommendations on the P3CO guidance. The NSABB is expected to
complete its review and provide recommendations in December 2022.
NIH Guidelines for Research Involving Recombinant or Synthetic
Nucleic Acid Molecules
The NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules
(NIH Guidelines) require certain safety practices and procedures to be in place when creating and
handling recombinant and synthetic nucleic acid molecules, and organisms and viruses containing
such molecules.65 Compliance with the NIH Guidelines is a term and condition of grant awards
for recipients of funding from the NIH and certain other federal agencies. The guidelines are

62 For a description of the projects see https://www.phe.gov/s3/dualuse/Pages/ResearchReview-PPP.aspx.
63 See Research Review Under the HHS P3CO Framework: https://www.phe.gov/s3/dualuse/Pages/ResearchReview-
PPP.aspx.
64 See https://osp.od.nih.gov/biotechnology/national-science-advisory-board-for-biosecurity-nsabb/#about.
65 Department of Health and Human Services, NIH Guidelines for Research Involving Recombinant or Synthetic
Nucleic Acid Molecules, 2019, https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf.
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structured in a manner that can apply to an entire research institution, even if a particular research
project/experiment was not funded by NIH. The NIH Guidelines describe and designate the
responsibilities of institutions, investigators, and its Institutional Biosafety Committees. The
guidelines classify organisms into four risk groups based on their pathogenicity towards humans:
1. Risk Group 1 agents are not associated with disease in healthy adult humans.
2. Risk Group 2 agents are associated with human disease which is rarely serious
and for which preventive or therapeutic interventions are often available.
3. Risk Group 3 agents are associated with serious or lethal human disease for
which preventive or therapeutic interventions may be available.
4. Risk Group 4 agents are likely to cause serious or lethal human disease for which
preventive or therapeutic interventions are not usually available.66
GOF-type experiments could fall under the NIH Guidelines, depending on whether any
components of the virus were synthesized or used recombinant DNA and whether they are
associated with human disease.
Considerations for Congress
Gain of function research is part of a larger life sciences research enterprise that has produced
important societal benefits but also has inherent risks. As discussed above, the United States has
multiple policies that provide guidance and oversight for life sciences research within the United
States, including GOF research. While some oversight mechanisms are required by law, others
are required only if the research is funded by the U.S. government.
As shown in Figure 1, GOF, DURC, and other life sciences research is covered by a patchwork
of regulations and guidance. Congress may evaluate the U.S. government’s biosafety and
biosecurity policies as they apply to life sciences research generally, and GOF and ePPP research
specifically. It may consider whether changes to U.S. biosafety and biosecurity policies are
necessary to minimize risks, maximize benefits, and better incorporate and address public and
stakeholder concerns. In doing so, Congress might consider the following options.
Status Quo
Policymakers may decide to continue the current oversight system for GOF and ePPP research.
Supporters of the status quo might argue that based on the small number of explicit GOF projects
focusing on potential pandemic pathogens previously and currently funded, existing policies are
sufficient and provide adequate oversight. Other critics have suggested that the oversight and
reporting mechanisms of current policies are insufficient to address the potential risks of GOF
research on potential pandemic pathogens, and additional oversight mechanisms are needed.67
Critics of the status quo might argue that the number and overlap of the current policies creates a
burden on the affected institutions, potentially impacting their ability to conduct scientific
research effectively. Stakeholders could assert that the current regulatory burden is potentially

66 Ibid.
67 Paul W. Duprex, Ron A.M. Fouchier, and Michael J. Imperiale, et al., “Gain-of-Function Experiments: Time for a
Real Debate,” Nature Reviews. Microbiology, vol. 13, no. 1 (2015), pp. 58-64. Ryan Ritterson, Linette Kingston, and
Adam E. J. Fleming, et al., “A Call for a National Agency for Biorisk Management,” Health Security, vol. 20, no. 2
(2022). Marc Lipsitch and Alison P. Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic
Pathogens” PLOS Medicine, vol. 11, no. 5 (2014).
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onerous and efforts to increase biosecurity and biosafety requirements would come at some
commensurate cost. These costs would either be borne by the research institutions, the research
funders (as part of research overhead costs), or the private sector. Additionally, those in favor of
maintaining the status quo might perceive additional oversight costs as anticompetitive or
inhibiting innovation, potentially leading to research being performed in more permissive
oversight environments, such as overseas.
Await Recommendations
Policymakers might choose to obtain a better understanding of the current oversight system and
the recommendations of two forthcoming reviews of the U.S. biosafety and biosecurity oversight
system, including the P3CO policy.
The NSABB,68 a federal advisory committee that addresses issues related to biosecurity and dual
use research, was charged by the Secretary of HHS in January 2020 with reviewing and providing
recommendations on DURC policies and the P3CO guidance.69 NSABB was to review and
provide recommendations to HHS regarding the balance between security and public
transparency when sharing information about PPP research and on whether or how to incorporate
the P3CO policy into DURC policies. The COVID-19 pandemic disrupted NSABB activities. It
reconvened in February 2022 when it was given an updated charge to review both P3CO and
DURC policies. 70 The updated charge is similar to the one given in January 2020, with additions
in regards to the P3CO policy: (1) considerations for funding international research involving PPP
and (2) the policy’s effectiveness in terms of preserving benefits of ePPP research while
minimizing potential biosafety and biosecurity risks. The NSABB is anticipated to deliver its
recommendations by December 2022.
The GAO is currently conducting a review of high-risk research oversight at HHS, including the
NIH and the CDC. This study is to examine what constitutes high-risk life sciences research and
the extent to which HHS oversight addresses biosafety and biosecurity risks through DURC,
FSAP, and P3CO.71
Eliminate or Restrict Funding
Policymakers could address concerns regarding GOF research on particular viruses and enhanced
potential pandemic pathogens through eliminating or restricting federally funded GOF and ePPP
research. Legislation banning GOF research on particular viruses, pathogens, and potential
pandemic pathogens has been introduced in both chambers during the 117th Congress. S. 3012
(Viral Gain of Function Research Moratorium Act) would ban all federal funding of GOF
research that may be reasonably anticipated to confer attributes to influenza, MERS, or SARS
viruses such that the virus would have enhanced pathogenicity or transmissibility in any organism
or involves the enhancement of potential pandemic pathogens or related risky research with
potentially dangerous pathogens. H.R. 3593 (Department of Energy Science for the Future Act)
and S. 3699 (Department of Energy Science for the Future Act of 2022) would ban the

68 For more information about the NSABB, see https://osp.od.nih.gov/biotechnology/national-science-advisory-board-
for-biosecurity-nsabb/#about.
69 For more information about this charge, see NSABB January 2020 Meeting Slides: https://osp.od.nih.gov/
biotechnology/national-science-advisory-board-for-biosecurity-nsabb/#meetings.
70 For more information about this charge, see NSABB February 2022 Meeting Slides: https://osp.od.nih.gov/
biotechnology/national-science-advisory-board-for-biosecurity-nsabb/#meetings.
71 CRS communication with GAO, March 2022.
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Department of Energy’s Office of Science from funding GOF research with the potential to
generate pathogens with high transmissibility and high virulence in humans. H.R. 4071 (Foreign
Gain-of-Function Research Prevention Act of 2021) would prohibit the use of federal funds to
conduct or support certain GOF research by a foreign adversary to include China, Russia, Iran,
North Korea, and any other country the Secretary of State, in consultation with the Secretary of
Defense, the Director of National Intelligence, or any other appropriate federal official,
determines to be a foreign adversary for the purposes of this section. Four bills—H.R. 5988,
(Fairness and Accountability in Underwriting Chinese Institutions Act” or the “FAUCI Act”), S.
3159 (Fairness and Accountability in Underwriting Chinese Institutions Act” or the “FAUCI
Act”), S. 3463 (Coronavirus Origin Validation, Investigation, and Determination Act of 2022” or
the “COVID Act of 2022”), and S. 1260 (United States Innovation and Competition Act of
2021)—would prohibit funding of GOF research on certain viruses and research involving the
enhancement of potential pandemic pathogens in China. These bills would also prohibit
researchers and institutions based in the United States that receive federal funding from engaging
in collaborative projects involving GOF research on certain viruses and research involving the
enhancement of potential pandemic pathogens with individuals or institutions based in China. S.
1260 has passed the Senate and a conference committee is resolving differences. On May 4, 2022,
the Senate agreed by voice vote to instruct the Senate conferees to insist on the inclusion of
provisions that would prohibit the use of federal funds for “gain-of-function” research in China.
Gain-of-Function (GOF) refers to any genetic mutation in an organism that confers a new or
enhanced ability.72 It’s a research term that covers a broad area of scientific inquiry. As noted
above, legislation introduced in the 117th Congress defines GOF research in different contexts;
from identifying research on specific viruses (e.g., MERS) to generalizing research involving
potential pandemic pathogens. Legislation banning or restricting GOF research may consider how
GOF research is defined in terms of the organisms and attributes being studied to avoid
inadvertently capturing research that does not raise concern or may be needed for national
security or public health purposes.
Ban or Restrict GOF Research
If Congress were to consider banning or restricting GOF research on particular pathogens,
defining it would likely become an important consideration. As discussed previously, “gain-of-
function” is a research term that covers a broad area of scientific inquiry. A broad definition may
impact research which does not raise biosafety and biosecurity concerns; while a narrow
definition may have limited intended effect. How the definition is interpreted may also be
considered to avoid definitional manipulation which could enable research to continue outside a
particular policy. Since 2017, the P3CO policy has reported three experiments that it has reviewed
and approved since the policy went into effect.
Currently, oversight of GOF research involving enhanced potential pandemic pathogens, as
defined by the P3CO policy, is limited to federally funded research projects. While other
oversight mechanisms might apply to privately funded research (e.g., Select Agent program); the
P3CO review process is only applicable to federally funded grants/contracts. To address GOF
experiments that may be taking place outside the P3CO policy, policymakers could consider
legislation banning or restricting GOF research not funded by the U.S. government.
Depending on how GOF is defined, eliminating funding for GOF research on pathogens, or
limiting where GOF research is allowed in the United States could encourage researchers
performing GOF research to move such research to countries with fewer restrictions or, in the

72 Amber Dance, “The Truth About Gain of Function Research,” Nature, vol. 598, no. 7882 (2021), pp. 554-557.
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absence of legislation covering private companies, to institutions outside the reach of federal
oversight. Such a shift could have implications both for biosafety and biosecurity and for U.S.
competitiveness. In addition, a broad definition could easily capture gain of function experiments
that are not part of the current debate on GOF involving pathogens. Such a prohibition might
disrupt multiple areas of research, such as into health, bioenergy, remediation, and others.
Laboratory Design and Oversight Standards
In 2020, 190 entities with BSL-3 laboratories and 8 entities with BSL-4 laboratories were
registered in the Federal Select Agent Program in the United States, operated by a variety of
actors (federal, commercial, academia, and private).73 As discussed in “Biosafety in
Microbiological and Biomedical Laboratories (BMBL) Guidelines,” there are no national
standards for how to design, construct, commission, operate, or maintain a high containment
laboratory,74 although recommendations are provided in the BMBL. Congress could consider
limiting in what laboratories GOF research on pathogens is permitted based on prescribed
standards for how to design, construct, commission, operate or maintain laboratories where GOF
research on pathogens is conducted. However, such standards may create financial and
administrative burdens for affected research institutions, especially if new standards are more
stringent than previous recommendations. Such a situation might require additional investment by
affected institutions in order to meet any more stringent standard. Restricting GOF research on
pathogens to laboratories that meet specific requirements might limit the number of investigators
able to conduct such research. Congress might therefore consider weighing the biosafety and
biosecurity advantages of limiting where such research can be conducted against the potential
loss of scope, researchers, and research outcomes.
Increase Support for Research Programs That Focus on Alternatives
to GOF Research on Pathogens
Some of the debates around GOF research focus on the safety and security of experiments that
attempt to understand whether and how viruses become transmissible to humans. Other debates
are on virulence and the chimeric nature of the experiments. Some stakeholders suggest that
approaches exist to studying pathogenesis and transmission that are safer than GOF research on
potential pandemic pathogens.75 Congress could seek to support the development of safer
approaches to expanding scientific understanding of how viruses evolve into potential pandemic
pathogens and the ability to monitor and combat them.
Researchers have proposed alternatives to GOF research on potential pandemic pathogens. For
example, by inactivating mutations and manipulating key functional domains in attenuated

73 Federal Select Agent Program, 2020 Annual Report of the Federal Select Agent Program, 2020,
https://www.selectagents.gov/resources/publications/docs/FSAP_Annual_Report_2020_508.pdf. This is a subset of the
total number of BSL-3/4 laboratories in operation; laboratories which do not work with select agents would not need to
register under the Select Agent Program. Therefore, the total number of BSL-3/4 laboratories may be higher.
74 U.S. Government Accountability Office, High-Containment Laboratories: Assessment of the Nation’s Need Is
Missing, GAO-13-466R, 2013, https://www.gao.gov/products/gao-13-466r.
75 Marc Lipsitch and Alison P. Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic
Pathogens,” PLoS Medicine, vol. 11, no. 5 (2014).
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genetic backgrounds;76 or by modifying an animal to reproduce the human disease of interest.77
However, proponents of GOF research have argued that while other types of experiments could
demonstrate the potential for a pathogen to alter its host range or experience enhanced
transmissibility or virulence, only GOF research can conclusively prove that a wild-type virus can
acquire the potential to cause a human pandemic.78
Address Transparency and Public Engagement
Part of the scientific method is based on confidential peer-review which occurs at different stages;
including a merit review of the research proposal and publications that may result from the
research. Prior GOF research involving H5N1 had been reviewed by the NSABB before
publication of the results. Since 2017, the P3CO process relies on an additional review by subject
area experts before a project can be funded. The extent to which these processes should be
transparent and open to public engagement is an area of policy debate, as is whether GOF
research on ePPP is sufficiently different than traditional life sciences research to necessitate
differential treatment more generally.
Some stakeholders have called for increased transparency of the review process for GOF
research.79 HHS has stated that it intends to link to information about projects approved under the
P3CO review process on their Science, Safety, Security website “to further demonstrate our
commitment to transparency.”80 HHS identifies publicly individual projects approved under the
P3CO policy.81 It does not make the assessments conducted by the advisory body for P3CO
available. It also does not make pre-funding review information for specific proposals public.
This is also the policy of other federal agencies sponsoring research. According to HHS, this is in
order to preserve confidentiality and to allow for candid critique and discussion of individual
proposals.82 HHS does not publicly release data on how many projects, if any, have been referred
for P3CO review but subsequently retracted.
Congress could decide that information on how many projects are referred to the P3CO review
process and the results of the risk/benefit assessment of those reviews should be made publicly

76 Paul W. Duprex, Ron A.M. Fouchier, and Michael J. Imperiale, et al., “Gain-of-function experiments: time for a real
debate,” Nature Reviews. Microbiology, vol. 13, no. 1 (2015), pp. 58-64.
77 Paul W. Duprex, Ron A.M. Fouchier, and Michael J. Imperiale, et al., “Gain-of-Function Experiments: Time for a
Real Debate,” Nature Reviews. Microbiology, vol. 13, no. 1 (2015), pp. 58-64.
78 Nicholas G. Evans, “Ethical and Philosophical Considerations for Gain-of-Function Policy: The Importance of
Alternate Experiments,” Frontiers in Bioengineering and Biotechnology, vol. 6 (2018). Kelsey Lane Warmbrod,
Michael G. Montague, and Gigi Kwik Gronvall, “COVID‐19 and the gain of function debates: Improving biosafety
measures requires a more precise definition of which experiments would raise safety concerns,” EMBO Reports, vol.
22, no. 10 (2021). A. Casadevall, D. Howard, and M. Imperiale, “An epistemological perspective on the value of gain-
of-function experiments involving pathogens with pandemic potential,” mBio, vol. 5 (2014).
79 Michael J. Imperiale and Arturo Casadevall, “Rethinking Gain-of-Function Experiments in the Context of the
COVID-19 Pandemic,” mBio, vol. 11, no. 4 (2020).
80 National Institute of Health, “NIH Commitment to Transparency on Research Involving Potential Pandemic
Pathogens,” https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-commitment-transparency-
research-involving-potential-pandemic-pathogens.
81 For a list of research projects approved under the P3CO policy, see https://www.phe.gov/s3/dualuse/Pages/
ResearchReview-PPP.aspx. All projects funded by NIH, including those approved under P3CO, are listed in the NIH
RePORTER database, https://reporter.nih.gov/.
82 To read the NIH commitment to transparency on research involving potential pandemic pathogens see
https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-commitment-transparency-research-involving-
potential-pandemic-pathogens.
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available to help policymakers and the public understand why certain projects have been
approved and whether, or how many, research projects are referred for P3CO review and do not
go forward due to the requirements of the P3CO policy. Providing this type of transparency could
improve public engagement and trust around how GOF work is approved. However, disclosing
this type of information could present information hazards by publicly disclosing research
methods that have been determined to raise biosafety/biosecurity risks. In addition, public
disclosure of information about research proposals could potentially create reputational and
intellectual property risks for proposers. Research proposals describe new ideas and potential
outcomes; releasing this information could be used by other researchers potentially impacting
claims to future scientific discoveries. Further, publicly disclosing proposals that have been
rejected could reflect poorly on a researcher’s perceived expertise or research capabilities. If
Congress were to contemplate public disclosure of the review process and results, they may
consider how to balance transparency against these concerns.
Support for a Coordinated Biorisk Management Framework
Oversight of life sciences research is governed by multiple regulations, policies, and guidance,
many of which are implemented at the institutional level and compulsory only when receiving
federal funding or contracts. To ensure compliance, many research institutions use a biorisk
management approach. Biorisk management is a system designed to minimize biosafety and
biosecurity risks associated with research involving biological agents and toxins.83 The approach
can include at least three different review mechanisms for determining which regulations and
federal guidance may apply to proposed research:84
1. The knowledge and expertise of the researcher and laboratory personnel.
2. A formal review of the proposed research by a trained biosafety professional.
3. A committee review by fellow researchers evaluating the research on behalf of
the institution.
These review processes are designed to meet the obligations of the institution under federal
regulations and guidance and to determine whether experiments can be performed at an
acceptable level of safety and security by utilizing risk-mitigation measures.85 However,
programs of this type vary widely between institutions based on each institution’s expertise,
resources, and biosafety/biosecurity cultural norms.
Congress could consider mandating the establishment of an overarching federal biorisk
management policy that brings together the recommendations, guidance, and policies shown in
Figure 1 and Appendix B into a single common framework of protocols and procedures. This
could better align oversight of life science research across federal agencies and provide a
consistent review process for research institutions.

83 Sabrina Brizee, Mark W. J. van Passel, and Linda M. van den Berg, et al., “Development of a Biosecurity Checklist
for Laboratory Assessment and Monitoring,” Applied Biosafety, vol. 24, no. 2 (2019), pp. 83-89. Jennifer Gaudioso,
Reynolds M. Salerno, and Natalie Barnett, “Developing a Risk Assessment and Management Approach to Laboratory
Biosecurity,” Applied Biosafety, vol. 11, no. 1 (2006), pp. 24-31.
84 Rebecca L. Moritz and David R. Gillum, “Adaptation of Research Infrastructure to Meet the Priorities of Global
Public Health,” Frontiers in Bioengineering and Biotechnology, vol. 8 (2020).
85 David Gillum and Rebecca Moritz, “Why Gain-of-Function Research Matters,” The Conversation: Science +
Technology, June 21, 2021.
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If Congress were to require development of an overarching federal biorisk management policy,
factors likely to be considered are:
 which body should develop the policy—a single agency, such as HHS, or through
an interagency body such as the National Science and Technology Council
(NSTC),86
 providing guidance to the body tasked with developing the policy to design it to
anticipate emerging science and novel public health threats, so that the policy can
cover timely research and avoid needing to be reactively revised when science
advances or each time an event occurs, and
 whether a new regulatory oversight body, independent from agencies funding
research, is necessary to coordinate and enforce the policy, as suggested by some
experts.87
A new oversight body could be tasked with addressing real or perceived conflicts of interest, such
as when funding agencies perform risk assessments and reviews of their own or funded research.
For example, under the current P3CO policy, HHS reviews research proposals that have been
recommended for funding by its own proposal review panels. Some scholars suggest that the risk
assessment process should be conducted by those without “a clear personal stake in the outcome,
just as peer review of science is performed by those without a direct interest in the outcome,” to
bolster the credibility of any assessment.88
While some oversight mechanisms are required by law, others are required only if the research is
funded by the U.S. government. The threat of withholding future funding can serve as an
incentive for institutions that receive such funding, but that approach is likely to be less effective
for other institutions. Congress may consider whether a biorisk management policy should be
expanded to cover private research labs that do not receive federal research funding or contracts.
If expanded, such a biorisk management framework may include an enforcement mechanism that
goes beyond the withholding of future government grants or contracts. This may require the
granted authority to conduct laboratory inspections and audits to determine what type of research
is being conducted and whether a particularly laboratory has violated any restrictions defined in
the policy.
Creating a single common framework could result in a “one size fits all” solution that may have
differing and detrimental effects on research institutions or clinical laboratories depending on
their size. Potential disadvantages of these approaches may include direct financial costs to
research institutions arising from new oversight requirements; indirect costs arising from
administrative burdens, such as staff time to develop and implement oversight policies and
training programs; and impacts on research programs, such as the potential for research to not be
taken up or conducted due to the increased oversight.
Current research and regulatory requirements of agencies and their different research portfolios
would likely need to be harmonized under such a system, potentially creating conflict between
agencies. Such harmonization might include what the scope of such regulations should be, what
entity would be responsible for compliance across the different agencies, and who would bear the
costs.

86 The National Science and Technology Council, https://www.whitehouse.gov/ostp/nstc/.
87 Ryan Ritterson, Linette Kingston, and Adam E. J. Fleming, et al., “A Call for a National Agency for Biorisk
Management,” Health Security, vol. 20, no. 2 (2022).
88 Marc Lipsitch and Thomas V. Inglesby, “Moratorium on Research Intended to Create Novel Potential Pandemic
Pathogens,” mBio, vol. 5, no. 6 (2014).
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Increased Support for Biosafety and Biosecurity Research
GOF research involving viruses and potential pandemic pathogens falls within the broader life
sciences and associated biosafety and biosecurity risks. Some experts have called for biosafety
and biosecurity to become its own field of research to help inform risk mitigation across the life
sciences.89 There currently is limited funding for programs that study applied biosafety and
biosecurity. Congress could consider providing funding to agencies for additional staff or existing
programs; or establish new agency programs to support extramural biosafety and biosecurity
research at universities or other outside institutions, identify and study best practices for effective
biosafety and biosecurity, or explore novel solutions for biosafety and biosecurity concerns.
Conclusion
Gain-of-function research is a broad field of scientific inquiry within an even broader context of
life sciences research that poses biosafety and biosecurity concerns. Certain research that poses
biosafety and biosecurity risks undergo risk assessments at various stages, from the initial
proposal to eventual product development. Risk science, ethics, and values underlie those risk
assessments. Predicting whether an incident (intentional or accidental) could lead to an outbreak,
epidemic, or pandemic is extremely difficult, as is predicting potential scientific benefits.90 The
benefits of most research may not be realized, or sometimes even imagined, until years after the
work has been completed. Risks, both real and potential, may never be realized, occur during
experiments, or occur immediately after their completion.91 The weight placed on a particular
data point, the questions asked, or even who is asking the questions can shift the perception of
risk and outcome of assessments. Increasing the transparency of risk assessment processes, and, if
desired, enabling broader public input might clarify, legitimize, or even inform the choice of
benefit and risk parameters and how they are evaluated. Alternatively, narrowing the risk
assessment process to those who are most expert in specified areas of expertise may increase the
quality of the risk assessment around a particular set of parameters.
U.S. policies address multiple aspects of biosafety and biosecurity—some impose requirements,
some provide guidance, some policies overlap, some apply only to research with select biological
agents, and some policies only apply to federally funded research and may not cover certain
research institutions or private companies. Discussion of these issues sometimes focuses on
defining the scope of GOF research, distinguishing it from other related categorizations,
identifying the types of experiments that are of concern, or listing specific biological agents to be
addressed in particular ways. This patchwork of biosafety and biosecurity policies can be
reactionary as new biological threats emerge and lag relative to rapid developments in science
and technology, issues the NSABB and GAO are both currently examining.

89 Kelsey Lane Warmbrod, Michael G. Montague, and Gigi Kwik Gronvall, “COVID‐19 and the Gain of Function
Debates: Improving Biosafety Measures Requires a More Precise Definition of Which Experiments Would Raise
Safety Concerns,” EMBO Reports, vol. 22, no. 10 (2021).
90 Talha Burki, “Ban on Gain-of-Function Studies Ends,” The Lancet Infectious Diseases, vol. 18, no. 2 (2018), pp.
148-149.
91 Michael J. Imperiale, Don Howard, and Arturo Casadevall, “The Silver Lining in Gain-of-Function Experiments
with Pathogens of Pandemic Potential,” Methods in Molecular Biology, vol. 1836 (2018), pp. 575-587.
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Appendix A. Select Biosafety/Security Events and
Associated U.S. Policy Implementation Through
2018

Source: Adapted from Diane DiEuli s, Venkat Rao, and Emily A. Bil ings, et al., “Biodefense Policy Analysis—A
Systems-Based Approach,” Health Security, vol. 17, no. 2 (2019).
Notes: Figure represents a selection of major events and should not be interpreted as a comprehensive list.
Acronyms: Bio weapons (BW); U.N. Bioweapons Convention (BWC); National Science Advisory Board for
Biosecurity (NSABB); U.N. Security Council Resolution (UNSCR); Federal Experts Security Advisory Panel
(FESAP); Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential
Pandemic Pathogen Care and Oversight (P3CO); Director of National Intelligence (DNI); Weapon of Mass
Destruction (WMD).
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Appendix B. Select U.S. Policies for Biosafety and
Biosecurity Oversight
Analysis/Applicability to
GOF Studies Involving
Oversight Measures
Risks Addressed
Description of Oversight Pathogens
Biosafety in
Biosafety risks
Applies to: Life sciences
BMBL is applicable to those
Microbiological and
research involving infectious
studies even though it
Biomedical Laboratories
microorganisms or
doesn’t address them
(BMBL), 6th Edition (June
hazardous biological
expressly. BMBL is a
2020)
materials.
guidance document and
https://www.cdc.gov/labs/
Description: General
generally considered the
pdf/SF__19_308133-
biosafety practices and
authoritative reference for
A_BMBL6_00-BOOK-
biological containment for
laboratory biosafety. While
WEB-final-3.pdf
various classifications (risk
it is not a regulatory
groups) of microorganisms
document, adherence to the
and etiological agents.
BMBL is a term and
condition of grant awards
for recipients of funding
from certain federal
agencies.
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Analysis/Applicability to
GOF Studies Involving
Oversight Measures
Risks Addressed
Description of Oversight Pathogens
NIH Guidelines for
Biosafety risks
Applies to: Basic or clinical
The NIH Guidelines have
Research Involving
life sciences research that
been amended to include
Recombinant or
involves recombinant or
additional guidance for work
Synthetic Nucleic Acid
synthetic nucleic acid
with Risk Group 3 influenza
Molecules (November
molecules and is conducted
viruses (1918 H1N1, H2N2,
2013)
at an institution receiving
highly pathogenic avian
http://osp.od.nih.gov/
NIH funding for any such
influenza [HPAI] H5N1) to
office-biotechnology-
research.
specify enhancements to
activities/biosafety/nih-
Description: Describes roles
biosafety level 3
guidelines
and responsibilities of
containment, practices, and
institutions and investigators
occupational health
in safely conducting
requirements.
research. Requires
NIH Guidelines were
institutional review with a
amended again to require
focus on the concepts of risk further enhancements to
assessment, risk group
facilities, biosafety
classification of agents,
equipment and practices,
physical and biological
including occupational health
containment levels,
practices, for research
practices, personal
involving HPAI H5N1 strains
protective equipment, and
transmissible among
occupational health.
mammals by respiratory
Advised by: NIH
droplets.
Recombinant DNA Advisory NIH Guidelines are often
Committee (RAC).
used as a model of biosafety
guidance by the broader
scientific community.
Compliance is required of
institutions receiving funding
from the NIH.
The scope is also limited to
research involving
recombinant or synthetic
nucleic acids. Some
Institutional Biosafety
Committees (IBCs) also
review and approve
nonrecombinant pathogen
research; however, not all
institutions require their
IBCs to do so.
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Analysis/Applicability to
GOF Studies Involving
Oversight Measures
Risks Addressed
Description of Oversight Pathogens
HHS and USDA Select
Biosecurity (physical
Applies to: Specified
Studies that could be
Agent Program (as of July and personnel) and
biological agents and toxins
considered GOF studies,
2014)
biosafety risks
deemed by HHS or USDA
which involve pathogens on
http://www.selectagents.g
to pose a severe threat to
the select agent list, are
ov/
public health and safety,
subject to oversight by the
based on a set of criteria.
FSAP. Researchers and
Description: Regulates the
institutions performing such
possession, use, and transfer
studies must receive
of select agents and toxins.
favorable security risk
Overseen by the Federal
assessments by the Federal
Select Agent Program
Bureau of Investigation,
(FSAP). Requires registration register with the FSAP,
of individuals and entities;
receive training on the
federal background
proper procedures and
investigations; federal review practices for handling such
of restricted experiments;
agents, and abide by other
training; institutional
aspects of the regulations.
compliance; etc.
SARS-CoV, HPAI H5N1
Advised by:
influenza, and 1918 influenza
Intragovernmental Select
viruses are select agents and
Agents and Toxins Technical GOF studies involving these
Advisory Committee.
pathogens are subject to
oversight by the FSAP.

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Analysis/Applicability to
GOF Studies Involving
Oversight Measures
Risks Addressed
Description of Oversight Pathogens
U.S. Government (USG)
Biosecurity risks; and
Applies to: Life sciences
The federal DURC policy
Policy for Federal
knowledge,
research conducted at an
requires federal funding
Oversight of DURC
information,
institution receiving U.S.
agencies to identify and
(March 2012)
products, or
government funding that
oversee certain pathogen
http://www.phe.gov/s3/
technologies that
involves any of the specified
research involving 7
dualuse/Pages/
could be directly
15 pathogens and toxins
experimental types, some of
USGOversightPolicy.aspx misapplied to pose a
deemed to pose the greatest which can be described as
significant threat with risk of deliberate misuse
GOF experiments (e.g.,
and USG Policy for
broad potential
with most significant
enhancing the harmful
Institutional Oversight of
consequences to
potential for mass casualties
consequences of an agent;
DURC (September 2014) public health and
or devastating effects to the
increasing transmissibility;
http://www.phe.gov/s3/
safety, agricultural
economy.
altering host range).
dualuse/Pages/
crops, and other
The institutional DURC
InstitutionalOversight.asp
plants, animals, the
policy requires federally
x
environment,
funded institutions to
materiel, or national
implement the federal
security
DURC policy by establishing
a system for the
identification and oversight
of certain pathogen research
involving the same 7
experimental types.
DURC policies only apply to
research involving 15
pathogens and toxins.
Institutions may review
other studies for DURC
potential but are not
required to do so. Certain
GOF studies that involve
other agents would not be
subject to DURC oversight
under the policies.
HHS Framework for
Biosafety and
Applies to: Gain-of-function
Focused on specific studies
Guiding Funding
biosecurity risks
studies that are reasonably
that must satisfy two
Decisions about
associated with
anticipated to develop
criteria: (1) it is likely highly
Proposed Research
experiments that are
enhanced potential pandemic transmissible and likely
Involving Potential
reasonably
pathogens resulting from the capable of wide and
Pandemic Pathogens
anticipated to create,
enhancement of the
uncontrol able spread in
(2017)
transfer, or use
transmissibility and/or
human populations; and (2)
https://www.phe.gov/s3/
enhanced potential
virulence of a pathogen.
it is likely highly virulent and
dualuse/Documents/
pandemic pathogens
Description: Describes an
likely to cause significant
P3CO.pdf
HHS Department-level
morbidity and/or mortality
review and approval process
in humans.
for certain GOF studies,
which can result in funding,
not funding, or funding with
certain conditions and
ongoing oversight.
Source: Adapted from National Science Advisory Board for Biosecurity, Recommendations for The Evaluation and
Oversight of Proposed Gain-Of-Function Research, 2016, pp. 57-58.
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Appendix C. Laboratory Biosafety Levels
BSL Level
Description
Biosafety
Biosafety Level 1 (BSL-1) is suitable for work involving wel characterized agents not known to
Level 1
consistently cause disease in immunocompetent adult humans and that present minimal potential
hazard to laboratory personnel and the environment. Work is typically conducted on open
benchtops using standard microbiological practices. Special containment equipment or facility
design is not generally required but may be used as determined by appropriate risk assessment.
Laboratory personnel receive specific training in the procedures conducted in the laboratory and
are supervised by a scientist with training in microbiology or a related science.
Biosafety
Biosafety Level 2 (BSL-2) builds upon BSL-1. BSL-2 is suitable for work with agents associated with
Level 2
human disease and pose moderate hazards to personnel and the environment. BSL-2 differs from
BSL-1 primarily because (1) laboratory personnel receive specific training in handling pathogenic
agents and are supervised by scientists competent in handling infectious agents and associated
procedures; (2) access to the laboratory is restricted when work is being conducted; and (3) all
procedures in which infectious aerosols or splashes may be created are conducted in biosafety
cabinets or other physical containment equipment.
Biosafety
Biosafety Level 3 (BSL-3) is suitable for work with indigenous or exotic agents that may cause
Level 3
serious or potentially lethal disease through the inhalation route of exposure. Laboratory
personnel receive specific training in handling pathogenic and potentially lethal agents, and they are
supervised by scientists competent in handling infectious agents and associated procedures. A BSL-
3 laboratory has special engineering and design features.
Biosafety
Biosafety Level 4 (BSL-4) is required for work with dangerous and exotic agents that pose a high
Level 4
individual risk of aerosol-transmitted laboratory infections and life-threatening diseases that are
frequently fatal, agents for which there are no vaccines or treatments, or work with a related
agent with unknown risk of transmission. Laboratory staff receive specific and thorough training in
handling extremely hazardous infectious agents. The laboratory supervisor controls access to the
laboratory in accordance with institutional policies.
Source: Adapted from Biosafety in Microbiological and Biomedical Laboratories, 6th Edition, U.S. Department of
Health and Human Services, 2020, https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-
final-3.pdf.
Notes: Each BSL describes standard practices, safety equipment, and facility specifications that are generally
appropriate for the organism(s) being worked on.

Author Information

Todd Kuiken

Analyst in Science and Technology Policy

Acknowledgments
Contributors to this report included Rachael Roan, Research Librarian; Sandra Edwards, User Support
Specialist; and Jamie Hutchinson, Visual Information Specialist.
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Oversight of Gain of Function Research with Pathogens: Issues for Congress

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