Potential Pandemic Pathogens – Risks, Regulation and Reform :Part I

Ragini Gupta, LLM expected 2023

Where might the next epidemic disease come from? It might, like AIDS or Ebola, jump to humans from a natural reservoir. It might also come from a laboratory. While this sounds like something out of a science fiction movie, “lab-leaks” have happened in the past and are likely to take place again.

In 2014,  a CDC lab employee in Atlanta accidentally contaminated a sample of comparatively mild H9N2 bird flu virus with a more dangerous H5N1; the vial was then shipped to the U.S. Department of Agriculture’s Southeast Poultry Research Laboratory (“SEPRL”). The contamination was not noticed until SEPRL had propagated the H9N2 sample, inoculated chickens with it and observed mortality in the chickens inconsistent with H9N2 infection.

In 2019, an accident at Lanzhou Veterinary Research Institute in China released aerosolized Brucella which spread through the wind and caused more than 10,000 human brucellosis cases. The impact of this outbreak is unclear. Details of the patients’ conditions were not published, however more than 3000 people signed compensation agreements with the government. According to one source, many of those infected developed chronic illnesses.

While these incidents did not result in epidemics, disease outbreaks caused by such occurrences are a possibility. Genetic engineering makes it possible to impart new properties to an organism (‘gain of function’ research). A subset of this research involves creating more contagious or more virulent forms of a microorganism. Such research usually aims to improve understanding of pathogens so that medical countermeasures (therapeutics, vaccines and diagnostics) can be developed and public health preparedness can be better informed. However, an accidental or deliberate release of microorganisms so engineered could cause a worse disease outbreak than any previously known. Are current laws and policies equipped to address these risks?  I believe they are not.  U.S. law needs reforms, and an international framework also needs to be planned since disease outbreaks will often not be restrained by national borders.  This blog post (Part I) will talk about some of the gaps in the framework and explain why they are concerning. Part II will discuss a recent report by the National Science Advisory Board for Biosecurity (“NSABB”), which has recommended amendments to close some of these gaps.

HHS P3CO Framework

The Department of Health and Human Services Framework for Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens (“HHS P3CO Framework”) applies to research on “potential pandemic pathogens (PPPs).” It defines these as pathogens that have both of following characteristics: (i) likely highly transmissible and likely capable of wide and uncontrollable spread in human populations (ii) likely highly virulent and likely to cause significant morbidity and/or mortality in humans. The HHS P3CO framework sets out the principles and procedures HHS will use to decide whether to fund for proposed research involving PPPs.

But this framework only applies to HHS’s funding decisions. Privately funded research, or even U.S. government research with funding outside HHS, is beyond the HHS’s oversight in this respect. A framework restricted to federally funded research is inadequate in the age of DIY Biology, where it is possible to conduct experimentation relatively cheaply in garages and community labs. (One pioneer of DIY Biology wrote in 2005 that a molecular biology lab could be bought on eBay for $1000; A 2017 piece suggests basic lab equipment can be bought for $500 or less.)

Federal Select Agent Program

Unlike the HHS P3CO framework, the Federal Select Agent Program does apply to private research. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 was a Congressional response to the  9/11 attacks and to the anthrax-laced letters that followed it. This law requires the HHS to establish and maintain a list of biological agents and toxins that have “the potential to pose a severe threat to public health and safety.” Similarly, the Agricultural Bioterrorism Protection Act of 2002 requires the Department of Agriculture to establish and maintain a list of biological agents and toxins that can potentially pose a severe threat to animal or plant health, or to animal or plant products.

The relevant regulations, subject to certain exceptions, forbid use, possession and transfer of select agents or toxins without a certificate of registration This certificate of registration is issued by the Administrator, Animal and Plant Health Inspection Service or by the HHS Secretary  depending on whether the agent threatens public health, or that of plants or animals.[1] Registration requires a security risk assessment.[2] Individuals or entities so registered are subject to certain compliance requirements like developing and implementing security,[3] biosafety[4] and incident response[5]plans; maintaining records;[6] and notifying appropriate authorities in case of theft, loss or release of a select agent.[7]

Working with potentially dangerous organisms is therefore subject to a number of restrictions – however these restrictions only apply to organisms that appear in the list of select agents. It is thus possible that an organism satisfies the definition of “potential pandemic pathogen” but is not subject to the FSAP program because it is not included in the list of select agents. The FSAP’s approach is list-based rather than attribute based, like the HHS P3CO. This may leave out threats which may come from previously unknown sources.

For example, a group of Canadian researchers funded by a US company called Tonix, synthesized the horsepox virus, (a relative of the smallpox virus) which no longer exists in nature, at a cost of about $100,000, using genetic pieces ordered in the mail. The fact that this was possible is cause for serious consideration. Although this research took place in Canada,  assume US regulations applied.  The horsepox virus is not listed as a select agent under the FSAP program, understandably, because it is not harmful to humans as well as being extinct in nature, but what if researchers were to synthesize a more virulent variant? This is the difficulty with the list-based approach – it may not govern actions, no matter how risky, if the organism isn’t listed as a pre-defined select agent.  And improvements in editing and synthesizing nucleic acids, both DNA and RNA, make more organisms into potential starting points toward creating dangerous pathogens.

Dual Use Research of Concern framework

Dual-use research (“DURC”) is research conducted for legitimate purposes that can be utilized for both benevolent and harmful purposes. A subset of this is dual use research of concern which is governed by the U.S. government’s Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern (2014)  and Policy for Oversight of Life Sciences DURC (2012) . The 2012 policy guides government agencies in funding life science research and the 2014 policy lays down responsibilities of institutions that receive federal funding for life science research. These policies define DURC as life sciences research that can be “reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat… to public health and safety, agricultural crops and other plants, animals, the environment, material or national security.” The DURC framework covers 15 agents and toxins and 7 categories of experiments (experiments that produce certain effects, such as enhancing harmful consequences of an agent toxin), It applies to three types of organizations:

  1. U.S. departments and agencies that fund or conduct life sciences research,
  2. Institutions within the U.S. that receive U.S government funds to conduct or sponsor life sciences research and that conduct or sponsor research involving any of the 15 agents or toxins even if the research is not supported by U.S. government funds, and
  3. Institutions outside the U.S. that receive U.S. government funds to conduct or sponsor research that involves any of the 15 agents or toxins.

The DURC framework creates a review process for determining whether life sciences research meets the definition of DURC and if so, procedures to be followed in the conduct of the research. These include a preparing a risk mitigation plan, and oversight by the federal funding agency. The oversight for research that is not federally funded is extremely limited – the framework says that results of the review process should be provided to the NIH, which will receive the notification “for administrative purposes” and that the NIH will refer the notification to an appropriate agency.[8] Like the FSAP, the DURC is also limited to the same 15 agents (the research involving the 7 “effects” only falls under the framework if the 15 agents are also involved). Further, the only penalties for non-compliance under the framework are suspension, limitation or termination of federal funding.  This makes the penalties for  such non-federally funded research toothless.

The above review of these laws and policies shows that there are several overlaps but also many loopholes. Many procedures apply to federally funded research, but the increasing role of private funding and the possibility of research being carried out with relatively lower sums of money means that the P3CO and DURC frameworks will fall short. The FSAP extends to privately funded research but only for “select agents”, an approach which will be inadequate in a world where horsepox can be brought back to life and previously unknown viruses can be synthetized from scratch. There is a need for policies that acknowledge these realities and close the regulatory gaps. One possible measure could be a legislation that would make a HHS P3CO-like framework  cover all research involving PPPs irrespective of funding source. The FSAP could be expanded to include, in addition to select agents, certain categories of research such as those specified in the DURC framework (arguably a revamping and not merely an expansion, since then the program would no longer be restricted to “select agents”) This too, would need Congressional approval since it would require amendment of the Agricultural Bioterrorism Act and the Public Health Security and Bioterrorism Preparedness and Response Act. A January 2023 report by the NSABB has recommended expansion of the DURC framework beyond the existing list to include research involving “any human animal, or plant pathogen, toxin or agent” and that is reasonably anticipated to result in one of the 7 experimental effects. The NSABB’s recommendations will be discussed in Part II of this post.

There is another, critical angle. In today’s highly interconnected world, it is possible for an epidemic to quickly turn into a pandemic as was the case with COVID-19. Since pathogens are perfectly capable of crossing borders, national laws are insufficient to effectively address the risks. The Biological Weapons Convention forbids parties from developing, producing, stockpiling or otherwise acquiring or retaining “microbial or other biological agents or toxins that…have no justification for prophylactic, protective or other peaceful purposes.[9]” Further, the Convention requires parties to “take necessary measures to prohibit and prevent the development, production, stockpiling of such “agents, toxins, weapons, equipment or means of delivery[10].”

According to one argument, a failure to effectively regulate synthetic biology is a violation of the Biological Weapons Convention because it would be a failure to “prevent” development of biological weapons. However, the focus of the Convention being weapons, it does not effectively address all the issues that arise when research is meant for peaceful purposes but may inadvertently result in release of pathogens.

Since the consequences of a “lab-leak” could be global, there is a need for international cooperation on research involving PPPs. If a pathogen were to escape a laboratory and cause a pandemic, the entire world and not only the funding/approving nation would be affected. Arguably, since the stakes are global, a nation that funds or approves research involving PPPs owes certain duties to other countries which would at minimum include transparency, information sharing and reasonable efforts to prevent transboundary harm. A more extreme argument but one worth reflecting on especially in light of global inequity in access to vaccines and medicines is that states should ethically refrain from funding or approving  research involving PPPs without the consent of other states, particularly those that for economic or other reasons are at a disadvantage in respect of pandemic preparedness.  The international aspects of research involving PPPs deserve to be the subject of further writing. I have touched upon some of the issues only to show that even a comprehensive domestic legal framework is inadequate in an increasingly interconnected world.

Past lab-leaks, as mentioned in this post, did not lead to epidemics; perhaps the present framework is sufficient as the threat in question seems so remote. But unlikely scenarios demand preparation when the potential impact is severe. The advances of life sciences research and lowering of barriers to entry into such research mean that past experience may not accurately represent the risks involved. Fixing the governance gaps and developing internationally agreed principles on research involving PPPs, in addition to preparing us to address emerging challenges, would also improve public confidence and reduce mistrust among nations leading to more effective cooperation in this crucial field.

Part II of this blog post will discuss the NSABB’s recommendations on U.S. policy on life sciences research, which if accepted, might address some of the gaps in this framework.

REFERENCES

  1. Donald G. McNeil Jr., C.D.C. Closes Anthrax and Flu Labs After Accidents, The New York Times (11 July 2014) available at https://www.nytimes.com/2014/07/12/science/cdc-closes-anthrax-and-flu-labs-after-accidents.html
  2. Centers for Disease Control and Prevention, Report on the Inadvertent Cross Contamination and Shipment of Laboratory Specimen with Influenza Virus H5N1 (15 August 2014) available at https://www.cdc.gov/labs/pdf/InvestigationCDCH5N1contaminationeventAugust15.pdf
  3. Georgios Pappas, The Lanzhou Brucella Leak: The Largest Laboratory Accident in the History of Infectious Diseases? 75 (10) Clinical Infectious Diseases 1845 (15 November 2022).
  4. Zhiguo Liu et al., A systematic analysis of and recommendations for public health events involving brucellosis from 2006 to 2019 in China 54(1) Annals of Medicine
  5. Yuan Ye, Lanzhou Brucellosis Patients to Receive Payouts From Factory, Sixth Tone (5 October 2020) available athttps://www.sixthtone.com/news/1006262/lanzhou-brucellosis-patients-to-receive-payouts-from-factory (2022)
  6. Michael J. Selgelid, Gain of Function Research: Ethical Analysis 22(4) Science and Engineering Ethics 923 (2016)
  7. Global Pandemics: Gain of Function Research of Concern, Congressional Research Service: In Focus (21 November 2022) available at https://crsreports.congress.gov/product/pdf/IF/IF12021
  8. S. Department of Health and Human Services, Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (2017)
  9. Bart Kolodziejczyc, Do-it-yourself biology shows safety risks of an open innovation movement, Brookings – Tech Tank (9 October 2017)
  10.  Rob Carlson, Splice it Yourself, Wired (1 May 2005) available at https://www.wired.com/2005/05/splice-it-yourself/
  11.  Patrick D’haesleer, How to Set Up Your Own DIY Bio Lab, Make: (11 April 2017) available at https://makezine.com/article/science/health-science/how-to-set-up-your-own-lab/
  12.  Kai Kupferschmidt, How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA, Science Insider (6 July 2017) available at https://www.science.org/content/article/how-canadian-researchers-reconstituted-extinct-poxvirus-100000-using-mail-order-dna
  13.  United States Government, United States Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern (24 September 2014)
  14.  Braden Leach, Necessary Measures: Synthetic Biology and the Biological Weapons Convention, 25 Stanford Technology Law Review 141 (2021)
  15.  Claire Healy, Worries Over Growing Vaccine Shortages, U.S. News (4 January 2022) available at https://www.usnews.com/news/best-countries/articles/2022-01-04/vaccine-apartheid-risks-rising-global-shortages-in-2022 

[1] 42 CFR 73.7(a), 7 CFR 331.7(a) and 9 CFR 121.7(a)

[2] 42 CFR 73.7(d), 7 CFR 331.7(d), and 9 CFR 121.7(d)

[3] 42 CFR 73.11(a), 7 CFR 331.11(a) and 9 CFR 121.11(a)

[4] 42 CFR 73.12(a) and 9 CFR 121.12(a)

[5] 42 CFR 73.14(a), 9 CFR 121.14(a), and 7 CFR 331.14(a)

[6] 42 CFR 73.17, 9 CFR 121.17(a), and 7 CFR 331.17(a)

[7] 42 CFR 73.19, 9 CFR 121.19(a), and 7 CFR 331.19(a)

[8] Section 7 E, Policy for Institutional Oversight of Life Sciences DURC

[9] Article I

[10] Article IV

 

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