Oversight of Gain-of-Function Research with Pathogens: Issues for Congress
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Oversight of Gain of -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
Updated March 10, 2025
(R47114)
Jump to Main Text of Report
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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Contents
Introduction ..................................................................................................................................... 1
History of Concern with Gain-of-Function Research ............................................................... 2
Benefits and Risks of GOF Research with Pathogens ..................................................................... 4
Oversight of Gain of Function Research Involving Pathogens ....................................................... 7
Biosafety in Microbiological and Biomedical Laboratories (BMBL) Guidelines .................... 8
Federal Select Agent Program ................................................................................................... 9
Dual Use Research of Concern (DURC) ................................................................................. 10and biosecurity policies are necessary to minimize risks, maximize benefits, and better incorporate and address stakeholder concerns involves weighing complex and intertwined policy issues. Experts on each side invoke the public's well-being as reasoning for their positions.
Framework for Guiding Funding Decisions About Proposed Research Involving
Enhanced Potential Pandemic Pathogens (P3CO) ................................................................ 11
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid
Molecules ............................................................................................................................. 12
Considerations for Congress.......................................................................................................... 13
Status Quo ............................................................................................................................... 13
Await Recommendations ......................................................................................................... 14
Eliminate or Restrict Funding ................................................................................................. 14
Ban or Restrict GOF Research ................................................................................................ 15
Laboratory Design and Oversight Standards .......................................................................... 16
Increase Support for Research Programs That Focus on Alternatives to GOF Research
on Pathogens ........................................................................................................................ 16
Address Transparency and Public Engagement ...................................................................... 17
Support for a Coordinated Biorisk Management Framework ................................................. 18
Increased Support for Biosafety and Biosecurity Research .................................................... 20
Conclusion ..................................................................................................................................... 20
Figures
Figure 1. Comparison and Overlap of Select Oversight Mechanisms for Life Science
Research ....................................................................................................................................... 8
Appendixes
Appendix A. Select Biosafety/Security Events and Associated U.S. Policy
Implementation Through 2018 ................................................................................................... 21
Appendix B. Select U.S. Policies for Biosafety and Biosecurity Oversight ................................. 22
Appendix C. Laboratory Biosafety Levels .................................................................................... 26
Contacts
Author Information ........................................................................................................................ 26
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Oversight of Gain of Function Research with Pathogens: Issues for Congress
Introduction
Gain-of-FunctionEnhanced Potential Pandemic Pathogens (P3CO), would still apply to federally funded GOF research. Topics for congressional oversight could include how agencies might implement the 2024 policy, its impact on scientific research and risk management generally, and its impacts on U.S. government and industry scientific competitiveness.
enhanced ability.enhanced ability.11 Such changes often occur naturally. Additionally, scientists can induce some Such changes often occur naturally. Additionally, scientists can induce some
changes to organisms through experimentation. changes to organisms through experimentation. GOF researchGOF is a research term that covers a broad area covers a broad area
of scientific inquiry. The term entered of scientific inquiry. The term enteredthe public policy debates and became more commonly used public policy debates and became more commonly used
in 2011 when it was used to describe two controversial research projects on H5N1 avian influenza 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).virus funded by the National Institutes of Health (NIH).22 Subsequent U.S. Subsequent U.S. policypolicies have narrowly 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
defined GOF research such that it refers only to studies of pathogens with pandemic potential.3
experimentally induced changes in viruses. Such research aims to improve understanding of virus experimentally induced changes in viruses. Such research aims to improve understanding of virus
transmission, infection, and pathogenesis.transmission, infection, and pathogenesis.44 Some of this research involves changing the genetic 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 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, experiments, scientists hope to improve their understanding of human-pathogen interactions,
better understand how viruses evolve and mutate, and further public health preparedness by better understand how viruses evolve and mutate, and further public health preparedness by
making better vaccines and treatments.making better vaccines and treatments.
Naturally occurring and experimentally induced GOF mutations 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 traitsmay affect several different traits of a virus. The environmental conditions.
The environment in which a virus operates (e.g., inside a in which a virus operates (e.g., inside a human or animal), or is studied (e.g.,
laboratory conditions),host vs. in a laboratory) can also impact can also impact anypotential mutation 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 Experiments where researchers did not intend to increase virulence or transmissibility could do
just that. Thus, biosafety and biosecurity processes emphasize accounting for unintended just that. Thus, biosafety and biosecurity processes emphasize accounting for unintended
consequences to protect laboratory workers and prevent accidental releases.consequences to protect laboratory workers and prevent accidental releases.6
5
This report discusses biosafety- and biosecurity-related issues associated with a subset of GOF 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 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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entails, the history of concerns with such research, the potential benefits and risks of conducting such research, U.S. oversight mechanisms for such research, and issues that Congress may such research, U.S. oversight mechanisms for such research, and issues that Congress may
consider in the context of research involving potential pandemic pathogens.consider in the context of research involving potential pandemic pathogens.
History of Concern withGain-of-Function Research
GOF Research Concern with research involving pathogens and other life sciences is not new. 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/There have been long-standing biosafety and biosecurity concerns biosecurity concerns involvingsurrounding the use of pathogens and the use of pathogens and
other life-other life-science related research impacts more broadly dating back to historic periods where
sciences-related research since infectious diseases were recognized as infectious diseases were recognized asa potential potential weaponweapons against people and armies. against people and armies.8 In more
recent history6 In one instance, representatives from various Army facilities , representatives from various Army facilities met togetherconvened in 1955 to share in 1955 to share
knowledge and experiences regarding the three principal biological warfare laboratories of the 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.United States. This meeting was the first Biological Safety Conference in the United States.9
7 Subsequent concerns arising from biosafety and biosecurity events associated with life sciences 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) research have have
prompted subsequent actions to establish oversight mechanisms and address perceived risksprompted subsequent actions to establish oversight mechanisms and address perceived risks.
(see Figure A-1).
Concerns over certain types of GOF research—specifically the risk of accidental release of a Concerns over certain types of GOF research—specifically the risk of accidental release of a
deadly pathogen and security risks associated with publishing study deadly pathogen and security risks associated with publishing studyresultresults—emerged in 2011-—emerged in 2011-
2012 around a set of studies funded by NIH on respiratory transmission of the highly pathogenic 2012 around a set of studies funded by NIH on respiratory transmission of the highly pathogenic
avian influenza virus H5N1.avian influenza virus H5N1.8 Since then, policymakers, scientists Since then, policymakers, scientists, and the public have debated the and the public have debated the
magnitude of potential risks and benefits of GOF research involving pathogens, how to weigh 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 those risks and benefits appropriately, and to what extent community engagement and transparent
decisionmaking should have a role in determining those risk and benefits.decisionmaking should have a role in determining those risk and benefits.10
9
Policy concerns and debates regarding the H5N1 studies, along with a series of contemporaneous 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 but unrelated government laboratory biosafety incidents, led the White House Office of Science
and Technology Policy (OSTP) to issue 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. in October 2014. This initial pause affected 18 federally funded10 As part of this pause, NIH's National Institute of Allergy and Infectious Diseases sent 18 letters to 14 institutions identifying research research
projects and contractsprojects and contracts; 7 of them subsequently received exemptions from they believed were subject to the pause.11
the pause.
As part of the 2014 pause, OSTP initiated a deliberative process to evaluate the risks and potential 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 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),12Potential Pandemic Pathogen Care and Oversight (P3CO), which described attributes of which described attributes of
federal agency review and reporting processes for the additional oversight of federally funded 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.research that is anticipated to create, transfer, or use enhanced pathogens with pandemic potential.
Agency implementation12 Implementation of a review and reporting process with the described attributes of a review and reporting process with the described attributes would
allow itallowed agencies to support GOF research on pathogens of this type. Responding to the OSTP guidance, to support GOF research on pathogens of this type. Responding to the OSTP guidance,
the Department of Health and Human Services (HHS) released the Department of Health and Human Services (HHS) released its“Framework for Guiding Funding
Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens
(P3CO)”13 in December 2017.in December 2017. HHS appears to be13 HHS was the only agency that the only agency that has developed and developed and
released a GOF review process that released a GOF review process thataddressesaddressed the 2017 OSTP GOF guidance the 2017 OSTP GOF guidance, and the only federal and the only federal
agency that has reported GOF research funding involving enhanced potential pandemic agency that has reported GOF research funding involving enhanced potential pandemic
pathogens.pathogens.
A focus of recent concerns over GOF research, particularly in light of the COVID-19 pandemic,
has been on a
The coronavirus disease 2019 (COVID-19) pandemic and interest in its origin have refocused attention on GOF research (see the text box Origins of COVID-19 and Gain of Function (GOF)). One 2014 NIH-funded study by the EcoHealth Alliance 2014 NIH-funded study by the EcoHealth Alliance. This study, , "Understanding the
Risk of Bat Coronavirus Emergence,14,"14 was conducted at the Wuhan Institute of Virology in China was conducted at the Wuhan Institute of Virology in China,
with results. Results were published in 2016. published in 2016.1515 In that experiment, researchers inserted spike proteins from eight In that experiment, researchers inserted spike proteins from eight
different coronaviruses into a single bat coronavirus called WIV1. Spike proteins help a virus 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 bind to its host. The study showed that the virus modified with the additional eight spike proteins
could infect human cells.could infect human cells.16
16
Some stakeholders have argued that the 2014 pause on GOF research should have included this 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.study and that it should have been subsequently reviewed under the 2017 HHS P3CO guidance.17
17 Others have argued that the research did not meet the requirements of the 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)” 2014 pause because the research did not enhance transmissibility, as both the modified because the research did not enhance transmissibility, as both the modified
and the original virus are able to infect human cells.and the original virus are able to infect human cells.1818 NIH reportedly concluded that the research NIH reportedly concluded that the research
project did not meet the criteria of the 2014 pause on GOF researchproject 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 or the 2017 HHS P3CO guidance.19
investigation into the origins of COVID-19, stating that investigation into the origins of COVID-19, stating that“We"we must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data."20 During the 118th Congress in December 2024, the House Committee on Oversight and Accountability's Select Subcommittee on the Coronavirus Pandemic examined whether a laboratory incident potentially involving GOF experiments could have contributed to the COVID-19 pandemic. The subcommittee's report states that "SARS-CoV-2, the virus that causes COVID-19, likely emerged because of a laboratory or research[-]related accident."21 A separate report released by the subcommittee's minority Members states that the subcommittee did not conclusively identify the virus's origin. Rather the minority's report asserts that two hypotheses of its origin remain plausible: a natural origin or a laboratory or research-related accident.22 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 The debates around the
origins of COVID-19 continue to evolve as new information becomes available.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.For many infectious diseases, the primary medical countermeasure is vaccination.2323 However, However,
vaccines can lose their efficacy vaccines can lose their efficacybased onas a result of changes in the pathogen. For example, the first vaccines changes in the pathogen. For example, the first vaccines
for influenza were introduced in the 1940s; new influenza vaccines are developed annually as 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 influenza viruses undergo antigenic drift (small changes or mutations) that can reduce vaccine
efficacy.efficacy.2424 A main argument for conducting GOF experiments is that viruses are constantly A main argument for conducting GOF experiments is that viruses are constantly
mutating. As one virologist stated, mutating. As one virologist stated,“"We can either wait for something to arise, and then fight it, or 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 we can anticipate that certain things will arise, and instead we can preemptively build our
arsenals; that’s where gain of functionarsenals. ... That's where [GOF] research can come in handy. research can come in handy.”25"25 Proponents of GOF Proponents of GOF
research assert that understanding and predicting how these changes occur could aid in the research assert that understanding and predicting how these changes occur could aid in the
development of vaccines that work against mutations of a virus.development of vaccines that work against mutations of a virus.2626 Some scientists argue that Some scientists argue that
attention to mutations specifically identified by GOF studies mutations specifically identified by GOF studies allow[s]allows experts to assess the relevance experts to assess the relevance
of specific molecular determinants in relation to virologic and epidemiological of specific molecular determinants in relation to virologic and epidemiological factors factors
considered for pandemic preparedness and is of particular relevance for decisions relating 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.to the production of manufacturing seeds and trial lots and the stockpiling of vaccines.27
27
Others similarly argue that GOF experimentation is needed to better understand medical Others similarly argue that GOF experimentation is needed to better understand medical
countermeasures across virus families and move the field from countermeasures across virus families and move the field from“"one bug, one drugone bug, one drug”" to to “"one drug, one drug,
many bugs.many bugs.”28
"28
Another argument raised in favor of continued GOF experimentation is Another argument raised in favor of continued GOF experimentation is tothat it will help us better understand how better understand how
viruses become viruses becomezoonoticzoonotic, or obtain the ability to transmit from animals to humans. In the early , 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 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 diseasewith birds increased. This zoonotic transmission raised particular concern because the disease’s
's case fatality rate was estimated at about 60%.case fatality rate was estimated at about 60%.2929 For comparison, one estimate of the U.S. case For comparison, one estimate of the U.S. case
fatality rate for COVID-19 is 1.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 transmission1%.30 At that time, H5N1 had not yet acquired mammalian transmissibility, and there were no confirmed cases of human-to-human transmission.31 Currently, H5N1 influenza is not known to spread easily from human to human. To date, most human H5N1 influenza cases have been associated with animal exposures, with very few cases due to human-to-human transmission. Yet many uncertainties persist around if and when the H5N1 influenza virus might adapt to spread more easily among humans, potentially resulting in a pandemic. Proponents of GOF research . Proponents of GOF research
argue that experiments are needed to understand how a virus argue that experiments are needed to understand how a viruslike H5N1 was able to move from
infecting birds to infecting humans and how or whether it could acquiresuch as H5N1 can adapt, particularly as it relates to human-to-human human-to-human
transmissibility.transmissibility.
A major concern among some biosafety and biosecurity experts is that an accidental or deliberate A major concern among some biosafety and biosecurity experts is that an accidental or deliberate
release of a modified virus could pose a release of a modified virus could pose a“grave"grave, and completely novel and completely novel, threat to human health, threat to human health,”31
"32 potentially causing a pandemic by evading natural immunities or effectiveness of potentially causing a pandemic by evading natural immunities or effectiveness ofcurrently
available medical countermeasures. Some observers have raised additional concerns that available medical countermeasures. Some observers have raised additional concerns that
publication of datapublication of data and information from original from GOF research could pose a safety and security GOF research could pose a safety and security
threat even if the research is conducted under governmental oversight measures.threat even if the research is conducted under governmental oversight measures.32
33
Conducting a riskConducting a risk/-benefit assessment could aid in determining the potential benefit assessment could aid in determining the potential benefitsadvantages of any of any
medical countermeasure that may result from GOF researchmedical countermeasure that may result from GOF research, and the risks associated with a and the risks associated with a
potential laboratory accident or deliberate misuse. However, some potential laboratory accident or deliberate misuse. However, some researchers have suggested that a have suggested that a
risk/risk-benefit assessment is unlikely to determine reliably whether the risks of GOF benefit assessment is unlikely to determine reliably whether the risks of GOF research outweigh the outweigh the
benefits, benefits,due, in part, topartly because of the absence of data, presumption of future events, and subjectivity in the absence of data, presumption of future events, and subjectivity in
evaluation of risk tolerance.evaluation of risk tolerance.3334 Publicly available data on the number of laboratory incidents Publicly available data on the number of laboratory incidents
associated with life sciences research associated with life sciences researchisare difficult to obtain. Certain data on laboratory incidents difficult to obtain. Certain data on laboratory incidents
must be reported to NIH and other federal agencies depending on the biological agent used and 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 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 not reported outside the institution where the work is being done. Reporting requirements for
institutions varyinstitutions vary, and no single repository collects all of this information. The lack of consolidated 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 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 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 riskincident data does not mean that researchers and oversight bodies should avoid risk/-benefit benefit
assessments, noting that these types of assessments are routinely done in other scientific fields 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 basiswith incomplete data.35
Questions have also been raised about the ethicality of GOF research on potential pandemic pathogens. Some . Some
observers and researchers argue that ethical principles would observers and researchers argue that ethical principles wouldonly allow GOF research on allow GOF research on
potential pandemic pathogens potential pandemic pathogens only if public health benefits cannot be achieved by other, safer if public health benefits cannot be achieved by other, safer
methods.methods.3536 Some have suggested that safer experimental approaches exist that can enhance 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
surveillance, prevention, and treatment of disease resulting from pandemic pathogens. They cite examples such as developing universal vaccines and antiviral drugs, and improving technologies and capabilities for rapid vaccine development and manufacturing,37 including via the use of artificial intelligence with certain biological design tools and modeling.38
The general public is at the center of the debate, with experts on each side invoking the publicThe general public is at the center of the debate, with experts on each side invoking the public’s
's well-being as reasoning for their positions.well-being as reasoning for their positions.3739 In this context, the public consists of all individuals In this context, the public consists of all individuals
who could become ill or die who could become ill or diedue toas a result of infection with a pathogen of pandemic potential, whether that infection with a pathogen of pandemic potential, whether that
occurs naturally, accidentally, or occurs naturally, accidentally, orby intentional means.38intentionally.40 An accident An accident, or a deliberate misuse of a or a deliberate misuse of a
GOF virus strainGOF virus strain, has the potential to impact the larger public as well as those conducting or has the potential to impact the larger public as well as those conducting or
participating (e.g., as human subjects) in the research. Similarly, participating (e.g., as human subjects) in the research. Similarly,the successful outcomes ofsuccessful GOF GOF
research that leads to, for example, new medical countermeasures or increased vaccine efficacy research that leads to, for example, new medical countermeasures or increased vaccine efficacy
provideprovides broadly applicable benefits to the larger public. Some experts have called for GOF 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 research to be evaluated under a broader ethical framework that includes input from and
evaluation of risks to the public.evaluation of risks to the public.3941 Others argue that the public should be included more broadly 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 in the process of research assessment to determine what levels of risk are acceptable in contexts
beyond GOF.beyond GOF.40
42
Incorporating public input may be hampered by the lack of public engagement. There has been Incorporating public input may be hampered by the lack of public engagement. There has been
limited public engagement around GOF and the role limited public engagement around GOF and the role that the U.S. government has in both the funding the U.S. government has in both the funding
and oversight of GOF research.and oversight of GOF research.4143 Additionally, the use of different terms—GOF, Additionally, the use of different terms—GOF, gain of function
research of concern, ePPPGOF research of concern, pathogens with enhanced pandemic potential (PEPP), and engineered viruses—in public debates, media, and policies may , 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 cause confusion as to what research is being funded, what the risks and benefits are, and what
policespolicies do and do not cover.
Oversight of GOF Research Involving Pathogens
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 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 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, has multiple, overlapping policies that provide guidance and oversight for life sciences research,
depending on the types of experiments and biological agents used (seedepending on the types of experiments and biological agents used (see Figure 1). Many of these . Many of these
policies and guidelines are framed around biosafety and biosecurity and were developed in policies and guidelines are framed around biosafety and biosecurity and were developed in
response to specific events (response to specific events (see Appendix A for a timeline of select events and policy responses).
see Figure A-1). While some oversight mechanisms are required by law, others are guidance issued by funding 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 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 funded research, or research conducted outside the United States, may therefore not be covered
by certain U.S. oversight mechanisms. 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 According to a 2023 study by Gryphon Scientific, a physical and life science consulting firm, an estimated "one quarter of human pathogen research performed in the United States occurs in the private sector."44
This section discusses specific policies and This section discusses specific policies and
guidance that govern life guidance that govern lifesciencesciences research broadly and could impact GOF research specifically, research broadly and could impact GOF research specifically,
depending on the virus being used and the specific types of experiments being proposed. 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
For a more in-depth analysis of federal policies and guidance that govern life sciences research, see CRS Report R48155, Oversight of Laboratory Biosafety and Biosecurity: Current Policies and Options for Congress, by Todd Kuiken. Adapted from National Science Advisory Board for Biosecurity, from National Science Advisory Board for Biosecurity, Recommendations for Thethe Evaluation and
Oversight of Proposed Gain-Ofof-Function Research, , May 2016, p. 28, https://osp.od.nih.gov/wp-content/uploads/2016/06/NSABB_Final_Report_Recommendations_Evaluation_Oversight_Proposed_Gain_of_Function_Research.pdf.
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
Biosafety in Microbiological and Biomedical Laboratories (BMBL) Guidelines The Centers for Disease Control and Prevention (CDC) and The Centers for Disease Control and Prevention (CDC) andthe NIH partner NIH partner together to publish to publish
the Biosafety in Microbiological and Biomedical Laboratories (BMBL)Biosafety in Microbiological and Biomedical Laboratories (BMBL) guidelines, which serve
as, which is the overarching guidance document for U.S. biosafety practices for protecting workers and 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 preventing exposures in biological laboratories. The BMBL provides guidance for addressing the
safe handling and containment of infectious microorganisms and hazardous biological materials.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 controls45 Some federal agencies include adherence to the BMBL as a condition for receiving certain federal grants. In addition, some federal laws (see "Federal Select Agent Program (FSAP)") recommend the BMBL as guidance to assist entities in the development of biosafety and biocontainment plans.46
The BMBL describes four biosafety levels (BSLs)—a minimum set of safety practices and procedures, required safety equipment, and administrative and engineering controls—that must be applied to projects or activities conducted in laboratories. Each BSL is described in ascending order of containment based on the degree of the health-related risk associated with the work being conducted.47 Each BSL builds on the previous one (see Table A-1). The appropriate BSL for a research project is determined by the institution . 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 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. 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 have raised concerns from an international context that while some BSL-3certain high-containment laboratories are laboratories are
state of the art, others may not be as well-equipped in terms of the facility itselfstate of the art, others may not be as well-equipped in terms of the facility itself, as well as training as well as training
and screening of personnel and materials.and screening of personnel and materials.4948 While the BMBL serves as an While the BMBL serves as an “"advisory document advisory document
recommending best practices for the safe conduct of work in biomedical and clinical recommending best practices for the safe conduct of work in biomedical and clinical
laboratories,laboratories,”50"49 the Government Accountability Office (GAO) reported in 2013 that there the Government Accountability Office (GAO) reported in 2013 that there arewere no no
national standards for how to design, construct, commission, operate, or maintain a highnational standards for how to design, construct, commission, operate, or maintain a high
-containment laboratory.containment laboratory.5150 Subsequent GAO studies have reviewed individual agency Subsequent GAO studies have reviewed individual agency policespolicies and and
made recommendations on how to improve laboratory safety and oversight.made recommendations on how to improve laboratory safety and oversight.52
Federal Select Agent Program
The 51
Federal Select Agent Program (FSAP)Federal Select Agent Program (FSAP) is one of the federal
FSAP is a regulatory regulatory programsprogram addressing addressing
biosecurity. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 biosecurity. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002
((P.L. 107-188P.L. 107-188, as amended; 42 U.S.C. §362a) requires HHS to establish and regulate a list of biological agents and toxins that ) 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.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. 107-188The 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 requires the U.S. Department of Agriculture (USDA) to establish andregulatemaintain a list of biological a list of biological
agents that have the potential to pose a severe threat to animal agents that have the potential to pose a severe threat to animalhealth and safety,or plant health and plant health and
safety,safety or to the safety of animal or plant products. FSAP is managed or to the safety of animal or plant products. FSAP is managed jointly by the Division of Select by the Division of Select
Agents and Toxins at Agents and Toxins atthe CDC and the Division of CDC and the Division of AgricultureAgricultural Select Agents and Toxins at 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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USDA. CDC and USDA share responsibility for some agents because they potentially threaten both humans and animals. both humans and animals. By statute (42 U.S.C. §262a and 7 U.S.C. §840142 U.S.C. §262a and 7 U.S.C. §8401 require), CDC and USDA CDC and USDA are required to to
review and republish the lists of select agents and toxins on at least a biennial basis.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.52
FSAP has oversight of the people who have access to select agents and the facilities where select agents are used and stored, both of which must be registered with the program. According to the 2023 FSAP annual report, 8,599 individuals53 and 226 entities54 were registered with FSAP.55 Entities possessing select agents are required Entities possessing select agents are required under by law (42 U.S.C. §262a 42 U.S.C. §262a
and 7 U.S.C. §8401and 7 U.S.C. §8401) to develop explicit biosecurity and biosafety plans to develop explicit biosecurity and biosafety plans and procedures, as well as an incident response plan, all of which are 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 Guidancereviewed and certified by the FSAP agency that has jurisdiction over the particular select agent. FSAP provides guidance documents that describe attributes that each plan must have.56 The HHS Inspector General has authority to conduct investigations and to impose civil monetary penalties against any individual or entity for violations of the regulations.57
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules
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,and Oversight (P3CO) (P3CO Framework).65 It would also replace the HHS Framework for Guiding Funding Decisions aboutAbout 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 functionResearch Involving Enhanced Potential Pandemic Pathogens.66
The 2024 policy combines what had been two separate policies, the 2014 DURC Policy and 2017 P3CO Framework. It is anticipated that the 2024 policy will create two categories of research—Category 1 and Category 2, respectively (see Figure 1 and Figure 2)—that require certain oversight based on the biological agent or toxin used and the type of research being conducted.
important societal benefits but important societal benefits but that also has inherent risks. As discussed above, also has inherent risks. As discussed above,the United States has
multiplemultiple federal policies policies that provide guidance and oversight for life sciences researchprovide guidance and oversight for life sciences research within the United
States, including GOF research, including GOF research, within the United States. While some oversight mechanisms are required by law, others . While some oversight mechanisms are required by law, others
are required only if the research is funded by the U.S. government.are required only if the research is funded by the U.S. government.
As shown As shown inin Figure 1, GOF, DURC, and other life sciences research is covered by a patchwork GOF, DURC, and other life sciences research is covered by a patchwork
of regulations and guidance. Congress may evaluate the U.S. governmentof regulations and guidance. Congress may evaluate the U.S. government’'s biosafety and s biosafety and
biosecurity policies as they apply to life sciences research generallybiosecurity policies as they apply to life sciences research generally, and GOF and GOF and ePPP research research
specifically. It may consider whether changes to U.S. biosafety and biosecurity policies are 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 necessary to minimize risks, maximize benefits, and better incorporate and address public and
stakeholder concerns. In doing so, Congress might consider the following optionsstakeholder 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.
, among other actions. Status Quo Supporters of the status quoSupporters of the status quo might argue that based on the small number of explicit GOF projects argue that based on the small number of explicit GOF projects
focusing on potential pandemic pathogens previouslyfocusing on potential pandemic pathogens previously reported and currently funded, existing policies are and currently funded, existing policies are
sufficient and provide adequate oversight. sufficient and provide adequate oversight.Other criticsCritics of the status quo have suggested that the oversight and have suggested that the oversight and
reporting mechanisms of current policies are insufficient to address the potential risks of GOF reporting mechanisms of current policies are insufficient to address the potential risks of GOF
research on potential pandemic pathogens, andresearch and that additional oversight mechanisms are needed. additional oversight mechanisms are needed.67
69
Critics of the status quo Critics of the status quo mightalso argue that the number and overlap of the current policies creates a argue that the number and overlap of the current policies creates a
burden on the affected institutions, potentially impacting their ability to conduct scientific burden on the affected institutions, potentially impacting their ability to conduct scientific
research effectively. Stakeholders research effectively. Stakeholderscould 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 assert that the current regulatory burden is potentially onerous and that efforts to increase biosecurity and biosafety requirements would come at some efforts to increase biosecurity and biosafety requirements would come at some
commensurate cost. These costs would commensurate cost. These costs wouldeither be borne by the research institutions, the research be borne by the research institutions, the research
funders (as part of research overhead costs), or the private sector.funders (as part of research overhead costs), or the private sector. Additionally, those in favor of
maintaining the status quo might perceive additional oversight costs70 Such additional oversight costs could also be seen as anticompetitive or as anticompetitive or
inhibiting innovationinnovation inhibiting, potentially leading to research being performed in more permissive , 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. Legislationoversight environments, such as overseas. Congress may examine what impacts executive orders and presidential memorandums issued during the beginning of the second Trump Administration have on maintaining the status quo.
Impact of "Regulatory Freeze Pending Review" Presidential Memorandum
pandemic pathogens pandemic pathogenshas beenwas introduced in both chambers introduced in both chambers during the 117th Congress. S. 3012
(Viral Gain of Function Research Moratorium Act) would ban. For example, S. 3012, the Viral Gain of Function Research Moratorium Act, introduced during the 117th Congress, would have banned all federal funding of GOF all federal funding of GOF
research that research thatmay becould have been reasonably anticipated to confer attributes to influenza, MERS, or SARS reasonably anticipated to confer attributes to influenza, MERS, or SARS
viruses such that the virus would haveviruses that enhanced pathogenicity or transmissibility in any organism enhanced pathogenicity or transmissibility in any organism
or involvesor that involved the enhancement of potential pandemic pathogens or related risky research with 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
potentially dangerous pathogens. This bill was reintroduced as S. 81 in the 118th Congress. A separate but similar bill introduced in the 118th Congress, H.R. 1827, would have prohibited NIH from conducting or supporting GOF research. S. 738, the Dangerous Viral Gain of Function Research Moratorium Act, introduced in the 119th Congress, would institute a moratorium on all federal research grants provided to any institution of higher education or other research institute that is conducting dangerous GOF research, as defined in the bill.
defining definingitGOF would likely become an important consideration. As discussed previously, would likely become an important consideration. As discussed previously, “gain-of-
function”"gain of function" is a research term that covers a broad area of scientific inquiry. A broad definition may is a research term that covers a broad area of scientific inquiry. A broad definition may
impact research impact researchwhichthat does not raise biosafety and biosecurity concerns does not raise biosafety and biosecurity concerns;, while a narrow while a narrow
definition maydefinition may, by intention, have limited have limitedintended effect. How the definition is interpreted may also be
considered to avoid definitional manipulation which could enableeffect. Another consideration is how the definition might be interpreted, because the definition could be manipulated in a way that enables research to continue outside a 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. particular policy.
While other While other
oversight mechanisms might apply to privately funded research (e.g., oversight mechanisms might apply to privately funded research (e.g.,Select Agent program); the
P3CO review process is only applicableFSAP), the current GOF policy and the proposed 2024 policy are applicable only to federally funded grants to federally funded grants/ and contracts. To address GOF contracts. To address GOF
experiments that may be taking place outside the experiments that may be taking place outside theP3CO policy, policymakers could consider
legislation banning or restricting2024 policy, one legislative option could be to specifically cover GOF research not funded by the U.S. government. GOF research not funded by the U.S. government.
Depending on how GOF is defined, eliminating funding for GOF research on pathogens, or Depending on how GOF is defined, eliminating funding for GOF research on pathogens, or
limiting where GOF research is allowed in the United Stateslimiting where GOF research is allowed in the United States, could encourage could encourageresearchers
performing GOF researchGOF researchers to move such research to countries with fewer restrictions or, in the 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 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. oversight. Such a shift could have implications both for biosafety and biosecurity and for U.S.
competitiveness. In addition, a broad definition could competitiveness. In addition, a broad definition couldeasily capture gain of functioninadvertently capture GOF experiments experiments
that are not part of the current debate on GOF involving pathogens. Such a prohibition might that are not part of the current debate on GOF involving pathogens. Such a prohibition might
disrupt multiple areas of research, such as into disrupt research in multiple areas, such as health, bioenergy, remediation, and others.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 In 2020, 190 entities with BSL-3 laboratories and 8 entities with BSL-4 laboratories were
registered in registered inthe Federal Select Agent ProgramFSAP in the United States, operated by a variety of in the United States, operated by a variety of
actors (federal, commercial, actors (federal, commercial,academiaacademic, and private)., and private).7372 As discussed in As discussed in "“Biosafety in
Microbiological and Biomedical Laboratories (BMBL) Guidelines,”," there are no national there are no national
standards for how to design, construct, commission, operate, or maintain a highstandards for how to design, construct, commission, operate, or maintain a high -containment containment
laboratory,laboratory,7473 although recommendations are provided in the BMBL. Congress could consider although recommendations are provided in the BMBL. Congress could consider
limitingspecifying in what laboratories GOF research on pathogens is permitted based on prescribed 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. laboratory standards.
However, such standards may create financial and However, such standards may create financial and
administrative burdens for affected research institutions, especially if new standards are more administrative burdens for affected research institutions, especially if new standards are more
stringent than previous recommendations. Such a situation might require additional investment by 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 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 pathogens to laboratories that meet specific requirements might limit the number of investigators
able to conduct such research. able to conduct such research.Congress might therefore considerCongressional considerations might include weighing the biosafety and weighing the biosafety and
biosecurity advantages of limiting where such research can be conducted against the biosecurity advantages of limiting where such research can be conducted against thepotential
loss of scope, researchers, and research outcomes.
Increaseimpacts of limiting who can conduct such research, including whether those researchers operate outside the United States.
Increased 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 Some of the debates around GOF research focus on the safety and security of experiments that
attempt to attempt tounderstandclarify whether and how viruses become transmissible to humans. Other debates whether and how viruses become transmissible to humans. Other debates
are on virulence and the chimeric natureare on virulence and the chimeric nature74 of the experiments. Some stakeholders suggest that of the experiments. Some stakeholders suggest that
approaches exist to studying pathogenesis and transmission that are safer than GOF research on approaches exist to studying pathogenesis and transmission that are safer than GOF research on
potential pandemic pathogens.potential pandemic pathogens.7575 Congress could Congress could seek to support the development of safer support the development of safer
approaches to expanding scientific understanding of how viruses evolve into potential pandemic approaches to expanding scientific understanding of how viruses evolve into potential pandemic
pathogens and the ability to monitor and combat them.pathogens and the ability to monitor and combat them.
Researchers have proposed alternatives to GOF research on potential pandemic pathogensResearchers have proposed alternatives to GOF research on potential pandemic pathogens. For
, for example, by inactivating mutations and manipulating key functional domains in attenuated genetic backgrounds76 or by modifying an animal to reproduce the human disease of interest.77example, 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 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 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 transmissibility or virulence, only GOF research can conclusively prove that a wild-type virus can
acquire the potential to cause a human pandemic.acquire the potential to cause a human pandemic.78 Advances in artificial intelligence and its use within the biological sciences could also provide alternatives to GOF research. For additional details on the convergence of artificial intelligence and the biological sciences, see CRS Report R47849, Artificial Intelligence in the Biological Sciences: Uses, Safety, Security, and Oversight, by Todd Kuiken. Address Transparency and Public Engagement Part of the scientific method involves confidential peer review, which occurs at different stages, including a merit review of the research proposal and of publications that may result from the research. The extent to which federal oversight of GOF research78
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 should be
transparent and open to public engagement is an area of policy debate, as is whether GOF transparent and open to public engagement is an area of policy debate, as is whether GOF
research researchon ePPP is sufficiently different is sufficiently different thanfrom traditional life sciences research to necessitate traditional life sciences research to necessitate
differential treatment more generally.differential treatment more generally.
Some stakeholders have called for increased transparency of the review process for GOF Some stakeholders have called for increased transparency of the review process for GOF
research.research.79 HHS has79 In the current P3CO policy, HHS stated that it stated that it intendsintended to link to information about projects approved under the 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 P3CO review process and publicly identify individual projects approved under the 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 doesP3CO policy; however, the website that formerly contained this information is no longer active. It did not make available the assessments conducted by the advisory body for P3CO. HHS did not publicly release data on how many projects, if any, not publicly release data on how many projects, if any, have beenwere referred referred
for P3CO review but for P3CO review but were subsequently retracted. It also did not make public any pre-funding review information for specific proposals. This is also the policy of other federal agencies sponsoring research. According to HHS, this preserves confidentiality and allows for candid critique and discussion of individual proposals.80 It is not clear what information agencies might provide that is publicly related to the 2024 policy review process. One legislative option would be to specify that information on projects that may be reviewed under Category 2 of the 2024 policy (if it takes effect), including the results of the risk-benefit assessment, should be made publicly available to help policymakers and the public understand why certain projects have been approvedsubsequently 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 . Providing this type of transparency could
improve public engagement and trust around how GOF work is approved. However, disclosing 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 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 methods that have been determined to raise biosafety/biosecurity risks. In addition, public
disclosure of information about research proposals could potentially create reputational and disclosure of information about research proposals could potentially create reputational and
intellectual property risks for proposers. Research proposals describe new ideas and potential intellectual property risks for proposers. Research proposals describe new ideas and potential
outcomes; outcomes;releasingif this information this information could be used by other researchers potentially impacting
claims tois released, other researchers could use it when making claims about future scientific discoveries. Further, publicly disclosing proposals that have been future scientific discoveries. Further, publicly disclosing proposals that have been
rejected could reflect poorly on a researcherrejected could reflect poorly on a researcher’'s perceived expertise or research capabilities. If s perceived expertise or research capabilities. If
Congress were to contemplate public disclosure of the review process and results, Congress were to contemplate public disclosure of the review process and results,theyit may may
consider considerhow to balanceboth transparency transparency againstand these concerns. these concerns.
Support for a Coordinated Biorisk Management Framework
Oversight of life sciences research is governed by multiple regulations, policies, and guidance, 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 many of which are implemented at the institutional level and compulsory only whenreceiving
grantees receive federal funding or contracts. To ensure compliance, many research institutions use a biorisk 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 management approach. Biorisk management is a system designed to minimize biosafety and
biosecurity risks associated with research involving biological agents and toxins.biosecurity risks associated with research involving biological agents and toxins.8381 The approach The approach
can include at least three can include at least threedifferent review mechanisms for determining which regulations and review mechanisms for determining which regulations and
federal guidance may apply to proposed research:federal guidance may apply to proposed research:84
1. 821. The knowledge and expertise of the researcher and laboratory personnel.The knowledge and expertise of the researcher and laboratory personnel.
2.
2. A formal review of the proposed research by a trained biosafety professional.A formal review of the proposed research by a trained biosafety professional.
3.
3. A committee review by fellow researchers evaluating the research on behalf of A committee review by fellow researchers evaluating the research on behalf of
the institution.the institution.
These review processes are designed to meet the obligations of the institution under federal 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 regulations and guidance and to determine whether experiments can be performed at an
acceptable level of safety and security by utilizing risk-mitigation measures.acceptable level of safety and security by utilizing risk-mitigation measures.8583 However, However,
programs of this type vary widely programs of this type vary widelybetween institutions baseddepending on each institution on each institution’'s expertise, s expertise,
resources, and biosafety/biosecurity cultural norms.resources, and biosafety/biosecurity cultural norms.
Congress could consider mandating
One legislative option could be to require the establishment of an overarching federal biorisk the establishment of an overarching federal biorisk
management policy that management policy thatbrings togetherunites all of the recommendations, guidance, and policies the recommendations, guidance, and policies shown in
Figure 1 and Appendix B discussed previously into a single into a single commoncomprehensive framework of protocols and procedures. This framework of protocols and procedures. This
could better align oversight of life could better align oversight of lifesciencesciences research across federal agencies and provide a 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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consistent review process for research institutions.
If Congress were to require development of an overarching federal biorisk management policy, If Congress were to require development of an overarching federal biorisk management policy,
factors likely to be considered arefactors likely to be considered are:
determining which body should develop the policy—a single agency, such as HHS, or which body should develop the policy—a single agency, such as HHS, or through
an interagency bodyan interagency body, such as the National Science and Technology Council such as the National Science and Technology Council
(NSTC)(NSTC),86
;84
providing guidance to the body tasked with developing the policy to design it to 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 anticipate emerging science and novel public health threats, so that the policy can
could cover timely research and avoid needing to be reactively revised when science cover timely research and avoid needing to be reactively revised when science
advances or each time an event occursadvances or each time an event occurs,; and and
determining whether a new regulatory oversight body, independent from agencies funding whether a new regulatory oversight body, independent from agencies funding
research, is necessary to coordinate and enforce the policy, as suggested by some research, is necessary to coordinate and enforce the policy, as suggested by some
experts.experts.87
85 A new oversight body could be tasked with addressing real or perceived conflicts of interest, such 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. as when funding agencies perform risk assessments and reviews of their own or funded research.
For example, under the For example, under thecurrent P3CO2024 policy, HHS policy, HHS reviewswould review research proposals that have been research proposals that have been
recommended for funding by its own proposal review panels. Some scholars suggest that recommended for funding by its own proposal review panels. Some scholars suggest that "the risk the risk
assessment process should be assessment process should beconducteddirected by those without by those without “a clear personal stake in the outcome, a clear personal stake in the outcome,
just as peer review of science is performed by those without a direct interest in the outcome,just as peer review of science is performed by those without a direct interest in the outcome,”" to to
bolster the credibility of any assessment.bolster the credibility of any assessment.88
86
While some oversight mechanisms are required by law, others are required only if the research is 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 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 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 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. 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 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 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 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 is being conducted and whether a particularly laboratory has violated any restrictions defined in
the policy.the policy.
Creating a single common framework could result in a Creating a single common framework could result in a “"one size fits allone size fits all”" solution that may have solution that may have
differing and detrimental effects on research institutions or clinical laboratories depending on differing and detrimental effects on research institutions or clinical laboratories depending on
their size. Potential disadvantages of these approaches their size. Potential disadvantages of these approachesmay include direct financial costs to include direct financial costs to
research institutions arising from new oversight requirements; indirect costs arising from research institutions arising from new oversight requirements; indirect costs arising from
administrative burdens, such as staff time to develop and implement oversight policies and 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 training programs; and impacts on research programs, such as the potential for research to not be
taken up or conducted taken up or conducteddue tobecause of the increased oversight. the increased oversight.
Current research and regulatory requirements of agencies and their different research portfolios 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 would likely need to be harmonized under such a system, potentially creating conflict between
agencies. Such harmonization might includeagencies. This could raise various questions, including what the scope of such what the scope of such harmonized regulations should be, what regulations should be, what
entity would be responsible for compliance across the different agencies, and who would bear the 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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Oversight of Gain of Function Research with Pathogens: Issues for Congress
Increasedcosts.
Federal Support for Biosafety and Biosecurity Research
GOF research involving viruses and potential pandemic pathogens falls within the broader life 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 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 and biosecurity to become its own field of research to help inform risk mitigation across the life
sciences.sciences.8987 There currently is limited funding for programs that study applied biosafety and There currently is limited funding for programs that study applied biosafety and
biosecurity. biosecurity. Options for Congress could Congress couldconsider includeproviding funding to agencies for additional staff or existing providing funding to agencies for additional staff or existing
programs; or establishprograms and
establishing new agency programs to support extramural biosafety and biosecurity new agency programs to support extramural biosafety and biosecurity
research at universities or other outside institutions, identify and study best practices for effective 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.biosafety and biosecurity, or explore novel solutions for biosafety and biosecurity concerns.
Conclusion
Gain-of-function
life sciences research that poses biosafety and biosecurity concerns. Certain research that poses 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 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 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, 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.epidemic, or pandemic is extremely difficult, as is predicting potential scientific benefits.9088 The The
benefits of most research may not be realized, or sometimes even imagined, until years after 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 work has been completed. Risks, both real and potential, may never be realized, occur during
experiments, or occur immediately after their completion.experiments, or occur immediately after their completion.9189 The weight placed on a particular The weight placed on a particular
data point, the questions asked, or even who is asking the questions can shift the perception of 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 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 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 benefit and risk parameters and how they are evaluated. Alternatively, narrowing the risk
assessment process to those who are most expert in specified areas assessment process to those who are most expert in specified areasof expertise may increase the may increase the
quality of the risk assessment around a particular set of parameters.quality of the risk assessment around a particular set of parameters.
U.S. policies address multiple aspects of biosafety and biosecurity—some impose requirements, 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 some provide guidance, some policies overlap, some apply only to research with select biological
agents, and some policies agents, and some policiesonly apply apply only to federally funded research and may not cover certain to federally funded research and may not cover certain
research institutions or private companies. Discussion of these issues sometimes focuses on research institutions or private companies. Discussion of these issues sometimes focuses on
defining the scope of GOF research, distinguishing it from other related categorizations, 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 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 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 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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Oversight of Gain of Function Research with Pathogens: Issues for Congress
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., “and technology.
Appendix. Biosafety Levels and Events
Table A-1. Laboratory Biosafety Levels (BSLs)
Source: Paul J. Meechan and Jeffrey Potts, Biosafety in Microbiological and Biomedical Laboratories, 6th ed. (Washington, DC: 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.
Systems-Based Approach,Systems-Based Approach,”" Health Security,, vol. 17, no. 2 (2019), pp. 83–99, https://doi.org/10.1089/hs.2018.0082.
Notes: Figure represents a selection of major events and should not be interpreted as comprehensive. BW = bioweapons; BWC = UN Bioweapons Convention; CDC = Centers for Disease Control and Prevention; DNI = Director of National Intelligence; FESAP = Federal Experts Security Advisory Panel; GAO = Government Accountability Office; HHS = Department of Health and Human Services; H5N1 = a strain of a highly pathogenic avian influenza virus; NIH = National Institutes of Health; NSABB = National Science Advisory Board for Biosecurity; P3CO = 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 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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Oversight of Gain of Function Research with Pathogens: Issues for Congress
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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Oversight of Gain of Function Research with Pathogens: Issues for Congress
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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Oversight of Gain of Function Research with Pathogens: Issues for Congress
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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Oversight of Gain of Function Research with Pathogens: Issues for Congress
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
Disclaimer
This document was prepared by the Congressional Research Service (CRS). CRS serves as nonpartisan
shared staff to congressional committees and Members of Congress. It operates solely at the behest of and
under the direction of Congress. Information in a CRS Report should not be relied upon for purposes other
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copy or otherwise use copyrighted material.
Congressional Research Service
R47114 · VERSION 1 · NEW
27
Pandemic Pathogen Care and Oversight; rDNA = recombinant DNA; UNSCR = UN Security Council Resolution; WMD = weapon of mass destruction.
1.
2.
3.
4.
5.
6.
7.
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," American Biological Safety Association, https://absa.org/about/hist01/.
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Contents
- Introduction
- History of Concern with GOF Research
- Benefits and Risks of GOF Research with Pathogens
- Oversight of GOF Research Involving Pathogens
- Biosafety in Microbiological and Biomedical Laboratories (BMBL) Guidelines
- Federal Select Agent Program (FSAP)
- NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules
- U.S. Government Policy for Oversight of Dual Use Research of Concern and Pathogens with Enhanced Pandemic Potential
- Considerations for Congress
- Status Quo
- Impact of "Regulatory Freeze Pending Review" Presidential Memorandum
- Eliminate or Restrict Funding
- Laboratory Design and Oversight Standards
- Increased Support for Research Programs That Focus on Alternatives to GOF Research on Pathogens
- Address Transparency and Public Engagement
- Support for a Coordinated Biorisk Management Framework
- Federal Support for Biosafety and Biosecurity Research
- Concluding Observations
Figures
Appendixes
Summary
The term gain of function (GOF) refers to any genetic mutation in an organism that confers a new or enhanced ability. Such changes often occur naturally. Additionally, scientists can induce such changes to organisms through experimentation. GOF research covers a broad area of scientific inquiry. One 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 that involves altered or enhanced pathogens with the potential to cause a pandemic. Some scientists 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. Others argue that GOF research does not lead to the development of medical countermeasures and that other types of research, such as computer modeling, could be as effective as GOF. They further argue that an accident or deliberate misuse of GOF 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.
Congress may be faced with competing and, in some instances, conflicting national and international priorities when weighing options addressing the risks and benefits of GOF and life sciences research more broadly. Determining whether changes to U.S. biosafety U.S. biosafetyOverlapping policies and guidance address aspects of biosafety and biosecurity associated with GOF research in the United States—some impose requirements, some provide guidelines, some apply only to research with select biological agents, and some apply only 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, and agency guidance on funding research with dual use potential and pathogens with enhanced pandemic potential, addressing the institutions and researchers conducting such research. Policies related to GOF research have evolved over time. In 2024, the United States Government Policy for Oversight of Dual Use Research of Concern and Pathogens with Enhanced Pandemic Potential (2024 policy), covering GOF and other issues, was released. It is scheduled to take effect in May 2025.
The outlook for the oversight system for life sciences research is uncertain under the Trump Administration. On January 20, 2025, the White House issued a presidential memorandum directing executive agencies to consider postponing the effective date of any rules that have been issued but have not taken effect, in order to review any questions of fact, law, and policy that the rules may raise. Until a decision has been made pursuant to the presidential memorandum on whether the 2024 policy will be instituted in May 2025, previous policies issued by the White House, such as the Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight and the Department of Health and Human Services' Framework for Guiding Funding Decisions About Proposed Research InvolvingPolicy options for Congress on GOF research could include
- independent federal review or a ban on federally funded GOF research (see S. 738, S. 854, and H.R. 1864);
- limits on where such research is permitted (e.g., restrictions based on prescribed standards for how to design, construct, commission, operate, or maintain laboratories where such research is conducted);
- development of safer alternatives that could still expand scientific understanding of how viruses evolve into potential pandemic pathogens and how to monitor and combat them;
- increased support for biosafety and biosecurity research; and
- establishment of a federal biorisk management policy intended to align oversight across federal agencies and provide a consistent review process for research institutions.
Introduction
Gain of function (GOF) refers to any genetic mutation in an organism that confers a new or (GOF) refers to any genetic mutation in an organism that confers a new orenhanced ability.enhanced ability.
changes to organisms through experimentation. changes to organisms through experimentation. GOF research
of scientific inquiry. The term entered of scientific inquiry. The term entered
in 2011 when it was used to describe two controversial research projects on H5N1 avian influenza 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).virus funded by the National Institutes of Health (NIH).
Congress may face competing and, in some instances, conflicting national and international priorities when weighing options to address the risks and benefits of GOF and life sciences research more broadly. These assessments may involve complex and intertwined policy issues that revolve around whether changes to U.S. biosafety and biosecurity policies are necessary to minimize risks, maximize benefits, and better incorporate and address stakeholder concerns.
A key area of emerging infectious disease research is the study of both naturally occurring and A key area of emerging infectious disease research is the study of both naturally occurring andexperimentally induced changes in viruses. Such research aims to improve understanding of virus experimentally induced changes in viruses. Such research aims to improve understanding of virus
transmission, infection, and pathogenesis.transmission, infection, and pathogenesis.
code of an organism or virus to observe how such changes affect its key properties. Through such 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, experiments, scientists hope to improve their understanding of human-pathogen interactions,
better understand how viruses evolve and mutate, and further public health preparedness by better understand how viruses evolve and mutate, and further public health preparedness by
making better vaccines and treatments.making better vaccines and treatments.
Experiments where researchers did not intend to increase virulence or transmissibility could do Experiments where researchers did not intend to increase virulence or transmissibility could do
just that. Thus, biosafety and biosecurity processes emphasize accounting for unintended just that. Thus, biosafety and biosecurity processes emphasize accounting for unintended
consequences to protect laboratory workers and prevent accidental releases.consequences to protect laboratory workers and prevent accidental releases.
research involving pathogens. It provides an overview of what GOF research on such pathogens research involving pathogens. It provides an overview of what GOF research on such pathogens
consider in the context of research involving potential pandemic pathogens.consider in the context of research involving potential pandemic pathogens.
History of Concern with
GOF Research Concern with research involving pathogens and other life sciences is not new. Concern with research involving pathogens and other life sciences is not new.
other life-other life-
sciences-related research since infectious diseases were recognized as infectious diseases were recognized as
knowledge and experiences regarding the three principal biological warfare laboratories of the 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.United States. This meeting was the first Biological Safety Conference in the United States.
7 Subsequent concerns arising from biosafety and biosecurity events associated with life sciences Subsequent concerns arising from biosafety and biosecurity events associated with life sciences
prompted subsequent actions to establish oversight mechanisms and address perceived risksprompted subsequent actions to establish oversight mechanisms and address perceived risks
deadly pathogen and security risks associated with publishing study deadly pathogen and security risks associated with publishing study
2012 around a set of studies funded by NIH on respiratory transmission of the highly pathogenic 2012 around a set of studies funded by NIH on respiratory transmission of the highly pathogenic
avian influenza virus H5N1.avian influenza virus H5N1.8 Since then, policymakers, scientists Since then, policymakers, scientists, and the public have debated the and the public have debated the
magnitude of potential risks and benefits of GOF research involving pathogens, how to weigh 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 those risks and benefits appropriately, and to what extent community engagement and transparent
decisionmaking should have a role in determining those risk and benefits.decisionmaking should have a role in determining those risk and benefits.
but unrelated government laboratory biosafety incidents, led the White House Office of Science but unrelated government laboratory biosafety incidents, led the White House Office of Science
and Technology Policy (OSTP) to issue 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 Viruses
projects and contractsprojects and contracts
benefits of GOF research with potential pandemic pathogens. In January 2017, OSTP released benefits of GOF research with potential pandemic pathogens. In January 2017, OSTP released
Recommended Policy Guidance for Departmental Development of Review Mechanisms for
federal agency review and reporting processes for the additional oversight of federally funded 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.research that is anticipated to create, transfer, or use enhanced pathogens with pandemic potential.
the Department of Health and Human Services (HHS) released the Department of Health and Human Services (HHS) released its
Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens
(P3CO)
released a GOF review process that released a GOF review process that
agency that has reported GOF research funding involving enhanced potential pandemic agency that has reported GOF research funding involving enhanced potential pandemic
pathogens.pathogens.
Risk of Bat Coronavirus Emergence
different coronaviruses into a single bat coronavirus called WIV1. Spike proteins help a virus 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 bind to its host. The study showed that the virus modified with the additional eight spike proteins
could infect human cells.could infect human cells.
study and that it should have been subsequently reviewed under the 2017 HHS P3CO guidance.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 Others have argued that the research did not meet the requirements of the
and the original virus are able to infect human cells.and the original virus are able to infect human cells.
project did not meet the criteria of the 2014 pause on GOF researchproject did not meet the criteria of the 2014 pause on GOF research
Origins of COVID-19 and Gain of Function (GOF)
The coronavirus disease 2019 (COVID-19) pandemic and interest in its origin have refocused attention on GOF. In 2021, a group of scientists called for called forinvestigation into the origins of COVID-19, stating that investigation into the origins of COVID-19, stating that
origins of COVID-19 continue to evolve as new information becomes available.origins of COVID-19 continue to evolve as new information becomes available.
Benefits and Risks of GOF Research with Pathogens
For many infectious diseases, the primary medical countermeasure is vaccination.For many infectious diseases, the primary medical countermeasure is vaccination.
vaccines can lose their efficacy vaccines can lose their efficacy
for influenza were introduced in the 1940s; new influenza vaccines are developed annually as 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 influenza viruses undergo antigenic drift (small changes or mutations) that can reduce vaccine
efficacy.efficacy.
mutating. As one virologist stated, mutating. As one virologist stated,
we can anticipate that certain things will arise, and instead we can preemptively build our we can anticipate that certain things will arise, and instead we can preemptively build our
research assert that understanding and predicting how these changes occur could aid in the research assert that understanding and predicting how these changes occur could aid in the
development of vaccines that work against mutations of a virus.development of vaccines that work against mutations of a virus.
considered for pandemic preparedness and is of particular relevance for decisions relating 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.to the production of manufacturing seeds and trial lots and the stockpiling of vaccines.
countermeasures across virus families and move the field from countermeasures across virus families and move the field from
many bugs.many bugs.
viruses become viruses become
2000s, the number of human infections with avian H5N1 influenza resulting from close contact 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 diseasewith birds increased. This zoonotic transmission raised particular concern because the disease
's case fatality rate was estimated at about 60%.case fatality rate was estimated at about 60%.
fatality rate for COVID-19 is 1.fatality rate for COVID-19 is 1.
argue that experiments are needed to understand how a virus argue that experiments are needed to understand how a virus
transmissibility.transmissibility.
release of a modified virus could pose a release of a modified virus could pose a
"32 potentially causing a pandemic by evading natural immunities or effectiveness of potentially causing a pandemic by evading natural immunities or effectiveness of
available medical countermeasures. Some observers have raised additional concerns that available medical countermeasures. Some observers have raised additional concerns that
publication of datapublication of data
threat even if the research is conducted under governmental oversight measures.threat even if the research is conducted under governmental oversight measures.
medical countermeasure that may result from GOF researchmedical countermeasure that may result from GOF research
potential laboratory accident or deliberate misuse. However, some potential laboratory accident or deliberate misuse. However, some researchers have suggested that a have suggested that a
benefits, benefits,
evaluation of risk tolerance.evaluation of risk tolerance.
associated with life sciences research associated with life sciences research
must be reported to NIH and other federal agencies depending on the biological agent used and 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 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 not reported outside the institution where the work is being done. Reporting requirements for
institutions varyinstitutions vary, and no single repository collects all of this information. The lack of consolidated 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 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 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 riskincident data does not mean that researchers and oversight bodies should avoid risk
assessments, noting that these types of assessments are routinely done in other scientific fields assessments, noting that these types of assessments are routinely done in other scientific fields
observers and researchers argue that ethical principles would observers and researchers argue that ethical principles would
potential pandemic pathogens potential pandemic pathogens only if public health benefits cannot be achieved by other, safer if public health benefits cannot be achieved by other, safer
methods.methods.
's well-being as reasoning for their positions.well-being as reasoning for their positions.
who could become ill or die who could become ill or die
occurs naturally, accidentally, or occurs naturally, accidentally, or
GOF virus strainGOF virus strain
participating (e.g., as human subjects) in the research. Similarly, participating (e.g., as human subjects) in the research. Similarly,
research that leads to, for example, new medical countermeasures or increased vaccine efficacy research that leads to, for example, new medical countermeasures or increased vaccine efficacy
research to be evaluated under a broader ethical framework that includes input from and research to be evaluated under a broader ethical framework that includes input from and
evaluation of risks to the public.evaluation of risks to the public.
in the process of research assessment to determine what levels of risk are acceptable in contexts in the process of research assessment to determine what levels of risk are acceptable in contexts
beyond GOF.beyond GOF.
limited public engagement around GOF and the role limited public engagement around GOF and the role that the U.S. government has in both the funding the U.S. government has in both the funding
and oversight of GOF research.and oversight of GOF research.
cause confusion as to what research is being funded, what the risks and benefits are, and what cause confusion as to what research is being funded, what the risks and benefits are, and what
GOF research concerns are part of a larger policy debate on how best to manage biosafety and 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 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, has multiple, overlapping policies that provide guidance and oversight for life sciences research,
depending on the types of experiments and biological agents used (seedepending on the types of experiments and biological agents used (see Figure 1). Many of these . Many of these
policies and guidelines are framed around biosafety and biosecurity and were developed in policies and guidelines are framed around biosafety and biosecurity and were developed in
response to specific events (response to specific events (
see Figure A-1). While some oversight mechanisms are required by law, others are guidance issued by funding 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 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 funded research, or research conducted outside the United States, may therefore not be covered
by certain U.S. oversight mechanisms. by certain U.S. oversight mechanisms.
guidance that govern life guidance that govern life
depending on the virus being used and the specific types of experiments being proposed. depending on the virus being used and the specific types of experiments being proposed.
For a more in-depth analysis of federal policies and guidance that govern life sciences research, see CRS Report R48155, Oversight of Laboratory Biosafety and Biosecurity: Current Policies and Options for Congress, by Todd Kuiken.
Figure 1. Overlap of Selected U.S. Policies for Biosafety and Biosecurity Oversight
(oversight applies to specific agents, toxins, and/or types of experiments)
Source: CRS, adaptedOversight of Proposed Gain-
Notes: Circles depicting policies with oversight are meant to be estimates and are subject to interpretation and change. BMBL = Biosafety in Microbiological and Biomedical Laboratories; NIH = National Institutes of Health.
Biosafety in Microbiological and Biomedical Laboratories (BMBL) Guidelines The Centers for Disease Control and Prevention (CDC) and The Centers for Disease Control and Prevention (CDC) and
preventing exposures in biological laboratories. The BMBL provides guidance for addressing the preventing exposures in biological laboratories. The BMBL provides guidance for addressing the
safe handling and containment of infectious microorganisms and hazardous biological materials.safe handling and containment of infectious microorganisms and hazardous biological materials.
in which the work is being conducted, in consultation with the principal investigator, depending 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. on the specific organism and types of experiment to be performed.
state of the art, others may not be as well-equipped in terms of the facility itselfstate of the art, others may not be as well-equipped in terms of the facility itself, as well as training as well as training
and screening of personnel and materials.and screening of personnel and materials.
recommending best practices for the safe conduct of work in biomedical and clinical recommending best practices for the safe conduct of work in biomedical and clinical
laboratories,laboratories,
national standards for how to design, construct, commission, operate, or maintain a highnational standards for how to design, construct, commission, operate, or maintain a high
-containment laboratory.containment laboratory.
made recommendations on how to improve laboratory safety and oversight.made recommendations on how to improve laboratory safety and oversight.
biosecurity. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 biosecurity. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002
have the potential to pose a severe threat to public health and safety.have the potential to pose a severe threat to public health and safety.
requires the U.S. Department of Agriculture (USDA) to establish and requires the U.S. Department of Agriculture (USDA) to establish and
agents that have the potential to pose a severe threat to animal agents that have the potential to pose a severe threat to animal
Agents and Toxins at Agents and Toxins at
review and republish the lists of select agents and toxins on at least a biennial basis.review and republish the lists of select agents and toxins on at least a biennial basis.
and 7 U.S.C. §8401and 7 U.S.C. §8401) to develop explicit biosecurity and biosafety plans to develop explicit biosecurity and biosafety plans
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 researchers are creating and handling recombinant and synthetic nucleic acid molecules58 and organisms and viruses containing such molecules.59 Compliance with NIH Guidelines is a condition of grant awards for recipients of funding from NIH. The guidelines are structured in a manner that applies to an entire research institution, even if a particular research project/experiment is not funded by NIH. Implementing certain aspects of the required safety practices and procedures may impact institutional research practices and policies more broadly.
For example, the NIH Guidelines describe and designate the responsibilities of institutions, investigators, and Institutional Biosafety Committees (IBCs). IBCs provide local review and oversight of research utilizing recombinant or synthetic nucleic acid molecules. Many institutions have chosen to assign their IBCs the responsibility of reviewing a variety of experiments that involve biological materials and other potentially hazardous agents. This additional responsibility is assigned entirely at the discretion of the institution.60 The guidelines classify organisms into four risk groups based on their pathogenicity toward humans:
- Risk Group 1 agents "are not associated with disease in healthy adult humans."
- Risk Group 2 agents "are associated with human disease [that] is rarely serious and for which preventive or therapeutic interventions are often available."
- Risk Group 3 agents "are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available."
- Risk Group 4 agents "are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available."61
Category 1 research is considered DURC, the meaning of which has been expanded from previous DURC policies. One major change is that all individual agents and toxins listed under FSAP now constitute a criterion to be considered as Category 1, potentially expanding the number of research proposals that meet the qualifications of DURC compared with previous policies. This research is subject to oversight both by research institutions and the federal agency that issues the funding. Category 2 includes research involving PEPP, which could be interpreted as GOF research. This research involves pathogens with two characteristics:
- Pathogen with pandemic potential (PPP): "A pathogen that is likely capable of wide and uncontrollable spread in a human population and would likely cause moderate to severe disease and/or mortality in humans."
- PEPP: "A type of [PPP] resulting from experiments that enhance a pathogen's transmissibility or virulence, or disrupt the effectiveness of pre-existing immunity, regardless of its progenitor agent, such that it may pose a significant threat to public health, the capacity of health systems to function, or national security."67
Figure 2. Overview of Review Process for Category 1 and Category 2 Research Source: White House Office of Science and Technology Policy, Implementation Guidance for the United States Government Policy for Oversight of Dual Use Research of Concern and Pathogens with Enhanced Pandemic Potential, May 2024, https://bidenwhitehouse.archives.gov/wp-content/uploads/2024/05/USG-DURC-PEPP-Implementation-Guidance.pdf.
Notes: IRE = institutional review entity; PI = principal investigator.
Considerations for Congress GOF research is part of a larger life sciences research enterprise that has produced research is part of a larger life sciences research enterprise that has producedimportant societal benefits but important societal benefits but that also has inherent risks. As discussed above, also has inherent risks. As discussed above,
are required only if the research is funded by the U.S. government.are required only if the research is funded by the U.S. government.
of regulations and guidance. Congress may evaluate the U.S. governmentof regulations and guidance. Congress may evaluate the U.S. government
biosecurity policies as they apply to life sciences research generallybiosecurity policies as they apply to life sciences research generally
specifically. It may consider whether changes to U.S. biosafety and biosecurity policies are 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 necessary to minimize risks, maximize benefits, and better incorporate and address public and
stakeholder concerns. In doing so, Congress might consider the following optionsstakeholder concerns. In doing so, Congress might consider the following options
, among other actions. Status Quo Supporters of the status quoSupporters of the status quo
focusing on potential pandemic pathogens previouslyfocusing on potential pandemic pathogens previously reported and currently funded, existing policies are and currently funded, existing policies are
sufficient and provide adequate oversight. sufficient and provide adequate oversight.
reporting mechanisms of current policies are insufficient to address the potential risks of GOF reporting mechanisms of current policies are insufficient to address the potential risks of GOF
burden on the affected institutions, potentially impacting their ability to conduct scientific burden on the affected institutions, potentially impacting their ability to conduct scientific
research effectively. Stakeholders research effectively. Stakeholders
commensurate cost. These costs would commensurate cost. These costs would
funders (as part of research overhead costs), or the private sector.funders (as part of research overhead costs), or the private sector.
Policymakers may continue the current oversight framework for GOF and other life sciences research, including the 2024 policy scheduled to take effect in May 2025. However, implementation of the policy may be delayed or canceled by the new Administration.71 Until a decision has been made pursuant to the January 2025 presidential memorandum, previous policies pertaining to GOF studies would still apply to federally funded research. Topics for Congress could include how agencies potentially implement the 2024 policy, its impact on scientific research and risk management generally, and its impacts on U.S. government and industry scientific competitiveness.
Eliminate or Restrict Funding Policymakers could address concerns regarding GOF research on particular viruses and PEPP through eliminating or restricting federally funded GOF research. During previous Congresses, legislation banning GOF research on particular viruses, pathogens, and potential banning GOF research on particular viruses, pathogens, and potentialpandemic pathogens pandemic pathogens
research that research that
potentially dangerous pathogens. This bill was reintroduced as S. 81 in the 118th Congress. A separate but similar bill introduced in the 118th Congress, H.R. 1827, would have prohibited NIH from conducting or supporting GOF research. S. 738, the Dangerous Viral Gain of Function Research Moratorium Act, introduced in the 119th Congress, would institute a moratorium on all federal research grants provided to any institution of higher education or other research institute that is conducting dangerous GOF research, as defined in the bill.
In the 118th Congress, the Senate Committee on Homeland Security and Governmental Affairs reported S. 4667, the Risky Research Review Act, which would have established a life sciences research security board within the executive branch to review proposed federal funding for high-risk life sciences research. After reviewing the research proposal, this board would vote on whether or not the agency in which the proposal was submitted could fund the project. In the 119th Congress, the bill was reintroduced in the Senate (S. 854), and a similar bill was introduced in the House (H.R. 1864).
Congress may choose to examine the relationship among the intentions of S. 854, H.R. 1864, and the 2024 policy, should they all take effect. For example, could the federal department-level review prescribed in the 2024 policy, which is slated to take effect May 2025 (see Figure 2), be replaced with the research security board prescribed in S. 854 and H.R. 1864, which specify that such a board serve as an additional level of review with final decisionmaking authority? If Congress were to consider banning or restricting GOF research on particular pathogens, If Congress were to consider banning or restricting GOF research on particular pathogens,defining defining
impact research impact research
definition maydefinition may, by intention, have limited have limited
oversight mechanisms might apply to privately funded research (e.g., oversight mechanisms might apply to privately funded research (e.g.,
experiments that may be taking place outside the experiments that may be taking place outside the
limiting where GOF research is allowed in the United Stateslimiting where GOF research is allowed in the United States, could encourage could encourage
oversight. Such a shift could have implications both for biosafety and biosecurity and for U.S. oversight. Such a shift could have implications both for biosafety and biosecurity and for U.S.
competitiveness. In addition, a broad definition could competitiveness. In addition, a broad definition could
that are not part of the current debate on GOF involving pathogens. Such a prohibition might that are not part of the current debate on GOF involving pathogens. Such a prohibition might
Laboratory Design and Oversight Standards
In 2020, 190 entities with BSL-3 laboratories and 8 entities with BSL-4 laboratories were In 2020, 190 entities with BSL-3 laboratories and 8 entities with BSL-4 laboratories were
registered in registered in
actors (federal, commercial, actors (federal, commercial,
Microbiological and Biomedical Laboratories (BMBL) Guidelines
standards for how to design, construct, commission, operate, or maintain a highstandards for how to design, construct, commission, operate, or maintain a high
laboratory,laboratory,
administrative burdens for affected research institutions, especially if new standards are more administrative burdens for affected research institutions, especially if new standards are more
stringent than previous recommendations. Such a situation might require additional investment by 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 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 pathogens to laboratories that meet specific requirements might limit the number of investigators
able to conduct such research. able to conduct such research.
biosecurity advantages of limiting where such research can be conducted against the biosecurity advantages of limiting where such research can be conducted against the
to GOF Research on Pathogens
Some of the debates around GOF research focus on the safety and security of experiments that Some of the debates around GOF research focus on the safety and security of experiments that
attempt to attempt to
are on virulence and the chimeric natureare on virulence and the chimeric nature74 of the experiments. Some stakeholders suggest that of the experiments. Some stakeholders suggest that
approaches exist to studying pathogenesis and transmission that are safer than GOF research on approaches exist to studying pathogenesis and transmission that are safer than GOF research on
potential pandemic pathogens.potential pandemic pathogens.
approaches to expanding scientific understanding of how viruses evolve into potential pandemic approaches to expanding scientific understanding of how viruses evolve into potential pandemic
pathogens and the ability to monitor and combat them.pathogens and the ability to monitor and combat them.
, for example, by inactivating mutations and manipulating key functional domains in attenuated genetic backgrounds76 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 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 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 transmissibility or virulence, only GOF research can conclusively prove that a wild-type virus can
acquire the potential to cause a human pandemic.acquire the potential to cause a human pandemic.78 Advances in artificial intelligence and its use within the biological sciences could also provide alternatives to GOF research. For additional details on the convergence of artificial intelligence and the biological sciences, see CRS Report R47849, Artificial Intelligence in the Biological Sciences: Uses, Safety, Security, and Oversight, by Todd Kuiken. Address Transparency and Public Engagement Part of the scientific method involves confidential peer review, which occurs at different stages, including a merit review of the research proposal and of publications that may result from the research. The extent to which federal oversight of GOF research
transparent and open to public engagement is an area of policy debate, as is whether GOF transparent and open to public engagement is an area of policy debate, as is whether GOF
research research
differential treatment more generally.differential treatment more generally.
research.research.
for P3CO review but for P3CO review but were subsequently retracted. It also did not make public any pre-funding review information for specific proposals. This is also the policy of other federal agencies sponsoring research. According to HHS, this preserves confidentiality and allows for candid critique and discussion of individual proposals.80 It is not clear what information agencies might provide that is publicly related to the 2024 policy review process. One legislative option would be to specify that information on projects that may be reviewed under Category 2 of the 2024 policy (if it takes effect), including the results of the risk-benefit assessment, should be made publicly available to help policymakers and the public understand why certain projects have been approved
improve public engagement and trust around how GOF work is approved. However, disclosing 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 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 methods that have been determined to raise biosafety/biosecurity risks. In addition, public
disclosure of information about research proposals could potentially create reputational and disclosure of information about research proposals could potentially create reputational and
intellectual property risks for proposers. Research proposals describe new ideas and potential intellectual property risks for proposers. Research proposals describe new ideas and potential
outcomes; outcomes;
rejected could reflect poorly on a researcherrejected could reflect poorly on a researcher
Congress were to contemplate public disclosure of the review process and results, Congress were to contemplate public disclosure of the review process and results,
consider consider
Support for a Coordinated Biorisk Management Framework
Oversight of life sciences research is governed by multiple regulations, policies, and guidance, 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 many of which are implemented at the institutional level and compulsory only when
grantees receive federal funding or contracts. To ensure compliance, many research institutions use a biorisk 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 management approach. Biorisk management is a system designed to minimize biosafety and
biosecurity risks associated with research involving biological agents and toxins.biosecurity risks associated with research involving biological agents and toxins.
can include at least three can include at least three
federal guidance may apply to proposed research:federal guidance may apply to proposed research:
regulations and guidance and to determine whether experiments can be performed at an regulations and guidance and to determine whether experiments can be performed at an
acceptable level of safety and security by utilizing risk-mitigation measures.acceptable level of safety and security by utilizing risk-mitigation measures.
programs of this type vary widely programs of this type vary widely
resources, and biosafety/biosecurity cultural norms.resources, and biosafety/biosecurity cultural norms.
management policy that management policy that
could better align oversight of life could better align oversight of life
factors likely to be considered arefactors likely to be considered are
(NSTC)(NSTC)
could cover timely research and avoid needing to be reactively revised when science cover timely research and avoid needing to be reactively revised when science
advances or each time an event occursadvances or each time an event occurs
experts.experts.
as when funding agencies perform risk assessments and reviews of their own or funded research. as when funding agencies perform risk assessments and reviews of their own or funded research.
For example, under the For example, under the
recommended for funding by its own proposal review panels. Some scholars suggest that recommended for funding by its own proposal review panels. Some scholars suggest that "the risk the risk
assessment process should be assessment process should be
just as peer review of science is performed by those without a direct interest in the outcome,just as peer review of science is performed by those without a direct interest in the outcome,
bolster the credibility of any assessment.bolster the credibility of any assessment.
funded by the U.S. government. The threat of withholding future funding can serve as an 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 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 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. 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 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 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 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 is being conducted and whether a particularly laboratory has violated any restrictions defined in
the policy.the policy.
differing and detrimental effects on research institutions or clinical laboratories depending on differing and detrimental effects on research institutions or clinical laboratories depending on
their size. Potential disadvantages of these approaches their size. Potential disadvantages of these approaches
research institutions arising from new oversight requirements; indirect costs arising from research institutions arising from new oversight requirements; indirect costs arising from
administrative burdens, such as staff time to develop and implement oversight policies and 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 training programs; and impacts on research programs, such as the potential for research to not be
taken up or conducted taken up or conducted
would likely need to be harmonized under such a system, potentially creating conflict between would likely need to be harmonized under such a system, potentially creating conflict between
entity would be responsible for compliance across the different agencies, and who would bear the entity would be responsible for compliance across the different agencies, and who would bear the
GOF research involving viruses and potential pandemic pathogens falls within the broader life 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 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 and biosecurity to become its own field of research to help inform risk mitigation across the life
sciences.sciences.
biosecurity. biosecurity. Options for Congress could Congress could
research at universities or other outside institutions, identify and study best practices for effective 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.biosafety and biosecurity, or explore novel solutions for biosafety and biosecurity concerns.
Providing additional funding for agency staff and programs may present a conflict of priorities with the Trump Administration's goal of reducing the overall size of the federal government.
Concluding Observations GOF research is a broad field of scientific inquiry within an even broader context of research is a broad field of scientific inquiry within an even broader context oflife sciences research that poses biosafety and biosecurity concerns. Certain research that poses 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 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 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, 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.epidemic, or pandemic is extremely difficult, as is predicting potential scientific benefits.
benefits of most research may not be realized, or sometimes even imagined, until years after 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 work has been completed. Risks, both real and potential, may never be realized, occur during
experiments, or occur immediately after their completion.experiments, or occur immediately after their completion.
data point, the questions asked, or even who is asking the questions can shift the perception of 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 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 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 benefit and risk parameters and how they are evaluated. Alternatively, narrowing the risk
assessment process to those who are most expert in specified areas assessment process to those who are most expert in specified areas
quality of the risk assessment around a particular set of parameters.quality of the risk assessment around a particular set of parameters.
some provide guidance, some policies overlap, some apply only to research with select biological some provide guidance, some policies overlap, some apply only to research with select biological
agents, and some policies agents, and some policies
research institutions or private companies. Discussion of these issues sometimes focuses on research institutions or private companies. Discussion of these issues sometimes focuses on
defining the scope of GOF research, distinguishing it from other related categorizations, 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 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 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 reactionary as new biological threats emerge and lag relative to rapid developments in science
|
BSL |
Description |
|
BSL 1 |
Biosafety Level 1 (BSL-1) is suitable for work involving well-characterized agents not known to consistently cause disease in immunocompetent adult humans and that present minimal potential hazards 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. |
|
BSL 2 |
Biosafety Level 2 (BSL-2) is suitable for work with agents associated with human disease and [that] 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. |
|
BSL 3 |
Biosafety Level 3 (BSL-3) is suitable for work with indigenous or exotic agents that may cause 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. |
|
BSL 4 |
Biosafety Level 4 (BSL-4) is required for work with dangerous and exotic agents that pose a high 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. |
Notes: Each BSL describes standard practices, safety equipment, and facility specifications that are generally appropriate for the organism(s) being worked on.
Figure A-1. Timeline of Selected Biosafety and Biosecurity Events and Associated U.S. Policy Implementation 1960-2024 Source: CRS, adapted from Diane DiEuliis et al., "Biodefense Policy Analysis—A Biodefense Policy Analysis—A
Systems-Based Approach,Systems-Based Approach,
Pandemic Pathogen Care and Oversight; rDNA = recombinant DNA; UNSCR = UN Security Council Resolution; WMD = weapon of mass destruction.
Rachael Roan, Research Librarian; Sandra Edwards, User Support Specialist; and Jamie Hutchinson, Visual Information Specialist contributed to the first version of this report.
Footnotes
Amber Dance, "The Shifting Sands of 'Gain-of-Function' Research," Nature, vol. 598, no. 7882 (2021), pp. 554-557, https://doi.org/10.1038/d41586-021-02903-x.
Kelsey Lane Warmbrod et al., "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), https://doi.org/10.15252/embr.202153739 (hereinafter Warmbrod et al., "COVID‐19 and the Gain of Function Debates").
White House Office of Science and Technology Policy (OSTP), 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; OSTP, Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO), 2017, https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/p3co-finalguidancestatement.pdf; U.S. Department of Health and Human Services (HHS), Framework for Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens (P3CO), 2017; and OSTP, United States Government Policy for Oversight of Dual Use Research of Concern and Pathogens with Enhanced Pandemic Potential, May 2024 (hereinafter 2024 policy).
Pathogenesis is the process by which a disease develops, including its onset and progression.
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 from, 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.
Stefan Riedel, "Biological Warfare and Bioterrorism: A Historical Review," Baylor University Medical Center Proceedings, vol. 17 (2004), pp. 400-406.
Martin Enserink, "Scientists Brace for Media Storm Around Controversial Flu Studies," Science, November 23, 2011.
Michael J. Selgelid, "Gain-of-Function Research: Ethical Analysis," Science and Engineering Ethics, vol. 22, no. 4 (2016), pp. 923-964.
OSTP, 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.
Jocelyn Kaiser, "Moratorium on Risky Virology Studies Leaves Work at 14 Institutions in Limbo," Science, 2014, https://www.science.org/content/article/moratorium-risky-virology-studies-leaves-work-14-institutions-limbo. Follow-up letters sent to some institutions clarified which research project may have been subject to the pause. CRS was unable to identify with certainty which of the 36 initial projects were ultimately paused.
OSTP, Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO), 2017, https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/p3co-finalguidancestatement.pdf.
HHS, Framework for Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens (P3CO), 2017.
National Institutes of Health (NIH), "Understanding the Risk of Bat Coronavirus Emergence," NIH RePORTER, https://reporter.nih.gov/project-details/9819304.
Vineet D. Menachery et al., "SARS-Like WIV1-CoV Poised for Human Emergence," Proceedings of the National Academy of Sciences, USA, vol. 113, no. 11 (2016), pp. 3048-3053, https://doi.org/10.1073/pnas.1517719113.
"What Is 'Gain-of-Function' Research?," The Economist, November 1, 2021.
Warmbrod et al., "COVID‐19 and the Gain of Function Debates."
Declan Butler, "Engineered Bat Virus Stirs Debate over Risky Research," Nature, 2015, https://doi.org/10.1038/nature.2015.18787; and U.S. Congress, House Oversight and Government Reform Committee, Select Subcommittee on the Coronavirus Pandemic, After Action Review of the COVID-19 Pandemic: The Lessons Learned and a Path Forward, 118th Cong., 2nd sess., December 4, 2024.
Jesse D. Bloom et al., "Investigate the Origins of COVID-19," Science, vol. 372, no. 6543 (2021), p. 694, https://doi.org/10.1126/science.abj0016.
U.S. Congress, House Committee on Oversight and Accountability, Select Subcommittee on the Coronavirus Pandemic, After Action Review of the COVID-19 Pandemic: The Lessons Learned and a Path Forward, 118th Cong., 2nd sess., December 4, 2024, p. 1, https://oversight.house.gov/wp-content/uploads/2024/12/2024.12.04-SSCP-FINAL-REPORT-ANS.pdf.
U.S. Congress, House Committee on Oversight and Accountability, Select Subcommittee on the Coronavirus Pandemic, Partisan Probes over Pandemic Prevention and Preparedness, minority report, 118th Cong., 2nd sess., December 2024, p. 6, https://oversightdemocrats.house.gov/sites/evo-subsites/democrats-oversight.house.gov/files/evo-media-document/SSCP%20Democratic%20Final%20Report.pdf.
Medical countermeasures are Food and Drug Administration (FDA)-regulated products that may be used in the event of a public health emergency stemming from a terrorist attack with a biological, chemical, or radiological/nuclear material or a naturally occurring emerging disease. See FDA, "What Are Medical Countermeasures?," October 1, 2024, https://www.fda.gov/emergency-preparedness-and-response/about-mcms/what-are-medical-countermeasures.
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 Centers for Disease Control and Prevention, "How Flu Viruses Can Change: 'Drift' and 'Shift,'" https://www.cdc.gov/flu/php/viruses/change.html?CDC_AAref_Val=https://www.cdc.gov/flu/about/viruses/change.htm.
Amber Dance, "The Shifting Sands of 'Gain of Function' Research," Nature, vol. 598, no. 7882 (2021), pp. 554-557, https://doi.org/10.1038/d41586-021-02903-x.
S. Schultz-Cherry et al., "Influenza Gain-of-Function Experiments: Their Role in Vaccine Virus Recommendation and Pandemic Preparedness," mBio, vol. 5, no. 6 (2014), https://doi.org/10.1128/mbio.02430-14 (hereinafter Schultz-Cherry, "Influenza Gain-of-Function Experiments").
Schultz-Cherry, "Influenza Gain-of-Function Experiments."
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. 143-146, https://doi.org/10.2217/fvl-2017-0143.
Michael J. Imperiale et al., "The Silver Lining in Gain-of-Function Experiments with Pathogens of Pandemic Potential," Methods in Molecular Biology, vol. 1836 (2018), pp. 575-587.
For one source of estimates of COVID-19 case fatality rates by country until March 10, 2023, see Johns Hopkins University & Medicine, "Mortality Analyses," March 16, 2023, https://coronavirus.jhu.edu/data/mortality.
The virus has adapted to spread among certain mammal species such as cattle and cats. Currently, H5N1 influenza is not known to spread easily from human to human. To date, most human H5N1 influenza cases have been associated with animal exposures, with very few cases due to human-to-human transmission. See CRS In Focus IF12895, H5N1 Avian Influenza: The Human Health Response, by Kavya Sekar, Amanda K. Sarata, and Hassan Z. Sheikh.
Marc Lipsitch and Barry R. Bloom, "Rethinking Biosafety in Research on Potential Pandemic Pathogens," mBio, vol. 3, no. 5 (2012), https://doi.org/10.1128/mbio.00360-12; see also Declan Butler, "Engineered Bat Virus Stirs Debate over Risky Research," Nature, 2015, https://doi.org/10.1038/nature.2015.18787; and Kevin M. Esvelt, "Manipulating Viruses Is Too Dangerous," Washington Post, October 7, 2021.
Marc Lipsitch and Alison P. Galvani, "Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens," PLOS Medicine, vol. 11, no. 5 (2014) (hereinafter Lipsitch and Galvani, "Ethical Alternatives"); and Arturo Casadevall et al., "Redaction of Sensitive Data in Publication of Dual Use Research of Concern," mBio, vol. 5, no. 1 (2013), https://doi.org/10.1128/mbio.00991-13.
Daniel J. Rozell, "Assessing and Managing the Risks of Potential Pandemic Pathogen Research," mBio, vol. 6, no. 4 (2015), https://doi.org/10.1128/mbio.01075-15.
Arturo Casadevall and Michael J. Imperiale, "Risks and Benefits of Gain-of-Function Experiments with Pathogens of Pandemic Potential, Such as Influenza Virus: A Call for a Science-Based Discussion," mBio, vol. 5, no. 4 (2014).
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); and Lipsitch and Galvani, "Ethical Alternatives."
Lipsitch and Galvani, "Ethical Alternatives."
CRS Report R47849, Artificial Intelligence in the Biological Sciences: Uses, Safety, Security, and Oversight, by Todd Kuiken.
Monica Schoch-Spana, "Public Engagement and the Governance of Gain-of-Function Research," Health Security, vol. 13, no. 2 (2015), pp. 69-73 (hereinafter Schoch-Spana, "Public Engagement").
Schoch-Spana, "Public Engagement."
Nicholas G. Evans et al., "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.
Schoch-Spana, "Public Engagement."
Gryphon Scientific, Characterizing Private-Sector Research on Human Pathogens in the United States, 2023, p. 4, https://pandorareport.org/gryphon-scientific-characterizing-private-sector-research-on-human-pathogens-in-the-united-states-july-2023-funded-by-open-philanthropy.
Paul J. Meechan and Jeffrey Potts, Biosafety in Microbiological and Biomedical Laboratories, 6th ed., (Washington, DC: HHS, 2020), https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf.
42 U.S.C. §73.12.
HHS, "Science Safety Security: Biosafety Levels," November 13, 2015.
Ian W. Lipkin, "Biocontainment in Gain-of-Function Infectious Disease Research," mBio, vol. 3, no. 5 (2012).
Paul J. Meechan and Jeffrey Potts, Biosafety in Microbiological and Biomedical Laboratories, 6th ed. (Washington, DC: HHS, 2020), p. iii, https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf.
U.S. Government Accountability Office (GAO), High-Containment Laboratories: Assessment of the Nation's Need Is Missing, GAO-13-466R, February 25, 2013, https://www.gao.gov/products/gao-13-466r. According to GAO, in May 2013, OSTP reported that it had been examining the need for national standards relating to designing, constructing, commissioning, maintaining, and operating high-containment laboratories through its Interagency Biorisk Management Working Group chartered in May 2012. According to GAO, an OSTP official stated that the group was chartered to collaborate on mechanisms for strengthening research laboratory biorisk management, which includes biosafety, biocontainment, and biosecurity.
U.S. GAO, High-Containment Laboratories: Comprehensive and Up-to-Date Policies and Stronger Oversight Mechanisms Needed to Improve Safety, GAO-16-305, March 21, 2016, https://www.gao.gov/products/gao-16-305; U.S. GAO, High-Containment Laboratories: Coordinated Actions Needed to Enhance the Select Agent Program's Oversight of Hazardous Pathogens, GAO-18-145, October 19, 2017, https://www.gao.gov/products/gao-18-145; U.S. GAO, Laboratory Safety: FDA Should Strengthen Efforts to Provide Effective Oversight, GAO-20-594, September 8, 2020, https://www.gao.gov/products/gao-20-594; and U.S. GAO, HHS Could Improve Oversight of Research Involving Enhanced Potential Pandemic Pathogens, GAO-23-105455, January 18, 2023, https://www.gao.gov/products/gao-23-105455.
Federal Select Agent Program, "Select Agents and Toxins," May 6, 2024, https://www.selectagents.gov/sat/index.htm.
42 C.F.R. §73.7(a) states that "an individual or entity shall not possess, use, or transfer any HHS select agent or toxin without a certificate of registration issued by the HHS Secretary," and 7 C.F.R. §331.7(a) states that "an individual or entity shall not possess, use, or transfer any select agent or toxin without a certificate of registration issued by the Administrator."
An entity is defined in 7 C.F.R. §331.1 and 42 C.F.R. §73.1 as "any government agency (Federal, State, or local), academic institution, corporation, company, partnership, society, association, firm, sole proprietorship, or other legal [organization]." 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.
Federal Select Agent Program, Select Agents and Toxins Biosafety/Biocontainment Plan Guidance, July 2018, https://www.selectagents.gov/compliance/guidance/biosafety/index.htm, and Federal Select Agent Program, Incident Response Plan Guidance, August 2021, https://www.selectagents.gov/compliance/guidance/incident-response/index.htm.
42 U.S.C. §73.21.
National Human Genome Research Institute, "Recombinant DNA Technology," March 7, 2025, https://www.genome.gov/genetics-glossary/Recombinant-DNA-Technology.
HHS, NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, April 2024, https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf.
HHS, NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, April 2024, p. 39, https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf.
2024 policy.
White House, United States Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern, September 24, 2014.
HHS, Framework for Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens, 2017.
2024 policy.
Executive Office of the President, "Regulatory Freeze Pending Review," 90 Federal Register 8249, January 20, 2025, https://www.federalregister.gov/documents/2025/01/28/2025-01906/regulatory-freeze-pending-review.
W. Paul Duprex et al., "Gain-of-Function Experiments: Time for a Real Debate," Nature Reviews Microbiology, vol. 13, no. 1 (2015), pp. 58-64, https://doi.org/10.1038/nrmicro3405 (hereinafter Duprex et al., "Gain-of-Function Experiments"); Ryan Ritterson et al., "A Call for a National Agency for Biorisk Management," Health Security, vol. 20, no. 2 (2022), https://doi.org/10.1089/hs.2021.0163 (hereinafter Ritterson et al., "A Call for a National Agency for Biorisk Management"); and Lipsitch and Galvani, "Ethical Alternatives."
Ritterson et al., "A Call for a National Agency for Biorisk Management."
Executive Office of the President, "Regulatory Freeze Pending Review," 90 Federal Register 8249, January 20, 2025, https://www.federalregister.gov/documents/2025/01/28/2025-01906/regulatory-freeze-pending-review.
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 and BSL-4 laboratories in operation; laboratories that do not work with select agents would not need to register under the Select Agent Program. Therefore, the total number of BSL-3 and BSL-4 laboratories may be higher.
U.S. GAO, High-Containment Laboratories: Assessment of the Nation's Need Is Missing, GAO-13-466R, February 25, 2013, https://www.gao.gov/products/gao-13-466r.
Josephine Johnston et al., "Clarifying the Ethics and Oversight of Chimeric Research," Hastings Center Report, vol. 52, no. 2 (2022).
Simon Wain-Hobson, "Gain-of-Function Research Can't Deliver Pandemic Predictions: Are There Alternatives?," Bulletin of the Atomic Scientists, June 27, 2022; and Lipsitch and Galvani, "Ethical Alternatives."
Duprex et al., "Gain-of-Function Experiments."
Duprex et al., "Gain-of-Function Experiments."
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); Warmbrod et al, "COVID‐19 and the Gain of Function Debates"; and Arturo Casadevall et al., "An Epistemological Perspective on the Value of Gain-of-Function Experiments Involving Pathogens with Pandemic Potential," mBio, vol. 5, no. 5 (2014), https://doi.org/10.1128/mbio.01875-14.
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).
See NIH, "NIH Commitment to Transparency on Research Involving Potential Pandemic Pathogens," March 5, 2019, https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-commitment-transparency-research-involving-potential-pandemic-pathogens.
Sabrina Brizee et al., "Development of a Biosecurity Checklist for Laboratory Assessment and Monitoring," Applied Biosafety, vol. 24, no. 2 (2019), pp. 83-89. Jennifer Gaudioso et al., "Developing a Risk Assessment and Management Approach to Laboratory Biosecurity," Applied Biosafety, vol. 11, no. 1 (2006), pp. 24-31.
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).
David Gillum and Rebecca Moritz, "Why Gain-of-Function Research Matters," The Conversation: Science + Technology, June 21, 2021.
Ritterson et al., "A Call for a National Agency for Biorisk Management."
Marc Lipsitch and Thomas V. Inglesby, "Moratorium on Research Intended to Create Novel Potential Pandemic Pathogens," mBio, vol. 5, no. 6 (2014), https://doi.org/10.1128/mbio.02366-14.
Warmbrod et al., "COVID‐19 and the Gain of Function Debates."
Talha Burki, "Ban on Gain-of-Function Studies Ends," The Lancet Infectious Diseases, vol. 18, no. 2 (2018), pp. 148-149.
Michael J. Imperiale et al., "The Silver Lining in Gain-of-Function Experiments with Pathogens of Pandemic Potential," Methods in Molecular Biology, vol. 1836 (2018), pp. 575-587.