Should GOF research and ePPPs still be studied or researched?

ePPPs and GOFR have been a controversial topic among many scientists due to its major risks if a human error were to be made. So, people have been debating for years whether or not this sort of research should be stopped or limited. So, my project is dedicated to whether or not we should limit this type of research, if we should stop, and what we can do about it.

I will try to simplify my findings as much as possible so that it can be easily understood by both me and other people.

Background Research

First, I will be doing background research to find out basic information about ePPPs, what they are used for, what research leads to the making of ePPPs and what we can do about it.

Data

For the data part, I will be putting in my thesis/arguement about the topic, and different things researchers can do about it.

Conclusion

I will conclude whether GOF research should be conducted and what scientists can do about it so that it's less risky and more comprehensible to the public.

Background Research

The way I first started this project was to find out more about ePPPs. I learned that ePPPs stand for Enhanced Potential Pandemic Pathogens. But, they are most commonly referred to as PPPs (Potential Pandemic Pathogens) so, I will be using the terms interchangeably.

What is GOF vs LOF research?

The term GOF stands for Gain-of-Function. While LOF stands for Loss-of-function. GOF research is a type of research that gives pathogens more abilities and can make the virus spread faster. It can also make the pathogen more fatal to mammalian life forms. LOF research focuses on breaking down the virus by making it not as transmissible and less fatal. Either way, both types of research are used to learn the genetic makeup of a pathogen.

What are ePPPs/PPPs?

ePPPs/PPPs, are sort of like a byproduct of GOF research. Famous examples of strains that have been worked on, are the H5N1 influenza, SARS-Cov, and SARS-CoV2. They some strains have been made to be more transmissible and fatal to mammalian species.

GOF Research (the term) and When GOFR it Was Popularized/Started

The term GOF was coined around the early 2000s when the H5N1 avian influenza and 2 labs decided to conduct research on them. Resulting in genetically modified strains of the H5N1 influenza virus was created and those strains were highly transmissible. But, before the labs could publish their research, they were halted by the US National Science Advisory Board for Biosecurity, halted and examined the reports before they could be released to the public because they were afraid that if too much information was released on that report, that bioterrorists could use that information and make their own PPPs and unleash it onto normal people.

Controversy Surrounding the Topic

GOF research is very controversial in the scientific field. People remain very divided about GOF research due to its many pros and cons. While one side is against such research and offers alternatives to it, GOF advocates claim alternatives to be inadequate.

GOF Research Pros

GOF research has served an important part in our understanding of viruses. it is one of the ways we have been able to better understand CoVs (coronaviruses) before the SARs-CoV-2 (Covid-19) pandemic. It has also helped figure out what vaccines to stockpile on as well. This research has very much contributed into making vaccines preventive enough, and lets researchers test their vaccines against more virulent pathogens.

GOF Research Cons

But, people who oppose such method of research argue that it would be too risky if a lab leak were to happen. Ex. in 2014 when a few CDC researchers were exposed to anthrax, Then, the CDC accidentally sent highly transmissible influenza strains to some medical labs, then the US Department of Defense accidentally sent some anthrax spores to numerous labs, and then someone discovers an abandoned and unprotected box of smallpox vials that should've been handed over to the WHO, or destroyed decades ago. All of these instances has made people weary of GOF research and what could happen if some unfortunate human errors were to happen. Even with these cons, it doesn't necessarily mean that GOF research is a horrible thing that should be stopped. It is still as necessary as it's counterpart LOFR (Loss-of-Function Research.) They are both fundamental parts of understanding pathogens. But even then, lab leaks should still be taken exremely seriously.

General Framework For GOFR (Gain-of-function Research)

 FIgure 2

• General framework/criteria for GOF research

• 1) The virus anticipated to be generated could be produced through a natural evolutionary process; 

2) The research addresses a scientific question with high significance to public health; 

3) There are no feasible alternative methods to address the same scientific question in a manner that poses less risk than does the proposed approach; 

4) Biosafety risks to laboratory workers and the public can be sufficiently mitigated and managed; 

5) Biosecurity risks can be sufficiently mitigated and managed; 

6) The research information is anticipated to be broadly shared in order to realize its potential benefits to global health; and 

7) The research will be supported through funding mechanisms that facilitate appropriate oversight of the conduct and communication of the research. 

If a proposal meets these criteria and is being contemplated for funding, the agency will submit the proposal for Department-level review. The Department-level review will provide multidisciplinary expertise—including public health, scientific, security, intelligence, countermeasures, and preparedness and response—to evaluate these proposals. The Department-level review will also identify any additional risk mitigation measures that are required, and determine whether a given proposal is acceptable for HHS funding. For proposals that are deemed acceptable for HHS funding, the funding agency within HHS will make the final funding decision. Proposals that have been determined to be unacceptable for HHS funding through Department-level review are not eligible for funding agency support. Figure 1 outlines the review process described by the Framework.

 

Data and Possible Next Steps

Among all the papers I've had to read, researchers are extremely divided on the topic of GOF research. On one hand, many people support GOF research. But on the other hand, many other people are highly against this research. Personally, I feel like I think that we should continue this research.

My Thesis/Argument About GOF research.

I think that GOF research should still be continued because this type of research might be one of the only ways available to us at the moment that can actually provide reliable information to us. At a symposium in 2014 attended by many researchers such as Dr. Kanta Subbarao, Dr. Yoshihiro Kawaoka, Dr. Ralph Baric, and many others alike, have expressed that even though GOF (gain-of-function) research may be risky, but, it is just as needed as LOF (loss-of-function) research because it answers key questions that virologists have when conducting research. 

(Key questions that virologists need to answer about influenza/MERS/SARS down below)

Figure 1

 General Virology Questions and Questions Specific to Influenza, SARS, and MERS Research

• Why/how does the virus infect and kill mammals?
  • What are the critical host range and virulence determinants of MERS-CoV?
  • Why are some influenza strains more virulent than others?
• Do antiviral drugs work, and how does the virus become resistant?
  • Can we identify antiviral drugs that are safe and effective for MERS-/SARS-CoV?
  • What drives the evolution of influenza antigenic change and antiviral resistance?
• Do current or novel vaccines or monoclonal antibodies provide protection, and can the virus escape?
  • Can we develop a SARS-/MERS-CoV candidate vaccine that is safe, immunogenic, and efficacious?
  • Can monoclonal antibodies be used safely for prevention and treatment?
  • Are there some influenza viral targets that will not allow escape from the immune system?
• How does the virus spread within animals or between animals?
  • Why do some influenza strains spread efficiently while others do not?
• Could the virus cause a pandemic?
• What is the likelihood of (re)emergence?
  • Will SARS or a SARS-like CoV re-emerge from bats or other animal hosts?”

SOURCE:  [Dr. Kanta] Subbarao's list of general and influenza/SARS/MERS specific questions in virology, symposium presentation, 2014.

Board on Life Sciences; Division on Earth and Life Studies; Committee on Science, Technology, and Law; Policy and Global Affairs; Board on Health Sciences Policy; National Research Council; Institute of Medicine. Potential Risks and Benefits of Gain-of-Function Research: Summary of a Workshop. Washington (DC): National Academies Press (US); 2015 Apr 13. 3, Gain-of-Function Research: Background and Alternatives. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285579/

People have also recommended that GOF research be divided into more specific terms because it is simply too broad and that it would be helpful into differentiating the type of virological experiments done.

The reason why I think scientists should continue such research is because, the provided alternatives to GOF research have either been inaccurate, or simply just not enough to answer the questions virologists have. Although, virologists have instead provided alternatives in their vivo and vitro models where they test such pathogens. After this, I will try to collect data on what we could do to improve and refine GOF research so that it’s more specific, less controversial, and less risky. Although, I think that alternatives could be good. But, we are still a long way from alternatives that could fully replace GOF research. But, I think it is a worth while thing to explore alternatives to such research.

Next Steps That Researchers Could Do

Some possible things that could be done is maybe have more open discussions to the public. After all, the point of the research is to benefit public health.

So, how exactly could researchers open up the discussion?

The thing researchers and the government could do, is to be specific and (sort of) simple about terms used in GOF research. For example, they could use separate terms for GOF research on bacteria, use different terms for research done on coronaviruses and influenza viruses. Overall, the framework that laboratories have to follow is quite loose. Then, maybe researchers can convince some of the general public to be invovlved in the discussion.

Discovering Alternatives

But, for now, not much of the general public has been included in debates about GOF research. But, researchers alike have been looking for alternatives. Now, for the technologies we have now, we are a long ways from getting a solid alternative for GOF research. Although, a popular "alternative" for GOF research is it's opposite. Loss-of-Function a.k.a. LOF research. But, LOF research doesn't really give the same outcomes as GOF research. I believe that both forms of research should still be continued. 

I don't really think that we have any solid methods but one method that I've been thinking about is computer generated results. Now, this is really far-fetched because as of now, we can't really make computer simulations/generations truly random. if computers were somehow made to be truly random, it coud present results that aren't even possible. At the same time, it might not present enough results. Because if viruses were to mutate, it's outcomes would be almost uncertain. (Which is a big reason why GOF research is done normally anyway.)

In truth, we are a very long way from solid alternatives which I know I have stated time and time again.

Researchers and the government need to take more safety measures and to have more specific terminology when it comes to GOF research. Like what family of viruses they're researching, how mutated the pathogen is, if they're working on a bacteria or virus, etc. Researchers could also strive to achieve some solid researh alternatives as well. So, my conclusion is that for now, we should continue GOF research.

Citations and Sources

Citations

Figure 1: Board on Life Sciences; Division on Earth and Life Studies; Committee on Science, Technology, and Law; Policy and Global Affairs; Board on Health Sciences Policy; National Research Council; Institute of Medicine. Potential Risks and Benefits of Gain-of-Function Research: Summary of a Workshop. Washington (DC): National Academies Press (US); 2015 Apr 13. 3, Gain-of-Function Research: Background and Alternatives. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285579/ accessed jan.21.2024

Figure 2: The U.S. Government Policy for Oversight of Life Science Dual Use Research of Concern (March 29, 2012) 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.” 2 HPAI H5N1 viruses are defined here as influenza viruses that express the virulent form of the hemagglutinin (HA) gene from highly pathogenic H5N1 virus. 3 Proposals aimed at characterizing naturally occurring strains are exempt from this Framework. accessed dec.24.2023

 

Sources

https://cset.georgetown.edu/wp-content/uploads/20220035_Gain-of-Function-Research_FINAL.pdf accessed dec.16.2023

https://www.nih.gov/news-events/research-involving-potential-pandemic-pathogens accessed dec.23.2023

https://www.gao.gov/products/gao-23-105455 accessed dec.23.2023

https://www.gao.gov/assets/gao-23-105455.pdf accessed dec.24.2023

https://www.ncbi.nlm.nih.gov/books/NBK285579/ accessed dec.24.2023

https://www.cidrap.umn.edu/avian-influenza-bird-flu/experts-call-alternatives-gain-function-flu-studies accessed dec.24.2023

https://www.ncbi.nlm.nih.gov/books/NBK549191/#:~:text=The%20chief%20purpose%20of%20in,reproducible%2C%20and%20easily%20assessed%20conditions. Accessed jan.21.2024

 https://www.ncbi.nlm.nih.gov/books/NBK285579/box/box_3-1/?report=objectonly accessed jan.15.2024

Lipsitch M, Galvani AP. Ethical alternatives to experiments with novel potential pandemic pathogens. PLOS Med 2014 May 20;1(5) [Full text] accessed jan.28 2024

https://thebulletin.org/2022/06/gain-of-function-research-cant-deliver-pandemic-predictions-are-there-alternatives/ accessed jan.28.2024

https://www.embopress.org/doi/full/10.15252/embr.202153739 accessed jan.28.2024

https://www.cola.org/striking-a-balance-navigating-the-risks-and-rewards-of-gain-of-function-research-part-3/ accessed jan.28.2024

https://www.criver.com/eureka/what-bsl-3-lab accessed.mar.8.2024

 

 

I would like to acknowledge my science fair organizers Kevin Zych, Elena Lavoie, and Chrissy Osicki.

But I'd like to give a massive thanks to my older brother Carl J. Dizon who encouraged me to go on with my project and also helped me format the informaton I had dug up. :D