A few days ago, a scientist colleague made me aware of a YouTube video entitled ‘New Boston virus’ that raised our concern. After listening to it, I decided to read the paper in question, ‘Role of spike in the pathogenic and antigenic behaviour of SARS-CoV-2 BA.1 Omicron’, in which researchers used a chimeric recombinant SARS-CoV-2 virus (Omi-S virus) that expresses Omicron’s S protein (the spike protein) in the backbone of the ancestral SARS-CoV-2 isolate. It is worthwhile to note that the paper hasn’t been peer reviewed yet, but of course, its research has been carried on.
Summarising the paper very briefly, the authors first of all compared the infection efficiency of Omi-S virus with an ancestral virus and Omicron in cell culture. The first two spread faster while Omicron not so much. They also noticed high levels of cytotoxicity caused by Omi-S virus in comparison to Omicron virus. They proceeded to examine the same in human lung epithelial cells. The ancestral virus produced the highest levels of infectious virus particles, followed by Omi-S and the Omicron, which produced the lowest. Their studies in vivo showed that the ancestral virus caused 100% mortality rate in the transgenic mice (in this case, mice expressing human ACE2 receptors — from where the virus enters the cells), Omi-S caused 80% and Omicron virus didn’t cause deaths.
Gain of function research (GoFR)
According to Dr Campbell’s comments in his YouTube video, this study is based on gain-of-function research (GoFR), which he considers too dangerous in this case.
GoFR is research that involves altering the genetic code of an organism in such a manner that its biological functions are enhanced, such as pathogenicity and transmissibility. This type of research is intended to discover targets in order to produce vaccines, drugs and also to better predict emerging infectious diseases. It’s been used for a good while now.
However, the director of the Boston University laboratory of this study refutes the assumption that the aforementioned study is GoFR as news outlets have been reporting. According to him, the recombinant virus is less virulent than the original ancestral virus. His argument was the same when he challenged the Daily Mail report here in the UK. Is this a valuable response?Certainly, the new virus doesn’t kill 100% of the mice as the ancestral one does, but it is much more pathogenic than the Omicron. And this is why this study is raising concerns. It’s important to note however, that the ancestral virus didn’t cause 100% of death in humans, so these transgenic mice are more susceptible. Another defensive argument is that because the Omi-S virus is derived from two strains that have been outcompeted by successive variants, it is unlikely it would spread widely.
Would these reasons still be enough to negate the GoFR? I think it is still frightening and that they are playing with fire. Have the researchers co-cultured cells with Omicron and Omi-S or even further, co-cultured cells with Omi-S and the current Omicron strain to check which one would prevail?
How is GoFR regulated and what are the levels of safety related to it?
The big debate with regard to GoFR is which experiments are beneficial enough that they outweigh the risks. What are the safety precautions applied to this kind of research?
In a past workshop about the subject, Dr. Yoshihiro Kawaoka has classified types of GoFR according to the results of the experiments. The first category was called “gain of function research of concern”. It includes the generation of viruses with properties that don’t circulate in nature. The second category is the one that involves viruses that can be more pathogenic or more transmissible than the ancestral or wild type virus but are still less ‘dangerous’ than the ones that circulate in nature. The third category is in between the first two. It deals with generation of high pathogenic and transmissible viruses in animal models that do not appear to be a major public health concern. So, in which category do you think the study in Boston would fit, if it really fits into any? Is it an easy call? No!
The key considerations in risk assessment from the workshop were:
- the properties of newly created strains, their consequences, and alternative approaches;
- science and technology;
- the global distribution of risks and benefits, their relative weights, and questions of justice;
- the types of possible misuse, in particular, safe and security;
- moral and ethical responsibilities of scientists and issues of public trust; and
- risk assessment and mitigation.
According to The US Department of Health and Human Services (HHS)’s 2017 guidelines — of which the NIH is part — “research that is reasonably anticipated to create, transfer, or use an enhanced potential pandemic pathogen (PPP) may require additional risk mitigation strategies which may include, but are not limited to: modification of the design or conduct of the research; application of specific or enhanced biosecurity or biosafety and biocontainment measures; evaluation of existing evidence of medical countermeasures (MCM) efficacy, or experiments conducted to determine MCM efficacy against agents or toxins resulting from the research; and methodologies for responsible communication of results”.
As of now, the committee at HHS, which is responsible for reviewing potential GoFROC (Gain of function research of concern) hasn’t publicly released its 2020’s guidelines, though a draft is already available.
By looking at these considerations and guidelines, it is hard to define precisely the classification of GoFR. As Gerald Keusch, associate director of National Emerging Infectious Diseases Laboratories at Boston University, says: “What we mean by the term depends on who’s using the term”.
GoFR regulation in the UK?
Here in the UK, according to the Genetically modified organisms (Contained Use) regulations 2014, GoFR seems to fall under ‘synthetic biology’ that is defined as the use of techniques that involves incorporating synthesised DNA or RNA into an organism. The Regulations are made under the powers of the Health and Safety at Work Act 1974 (‘the HSW Act’) and the European Communities Act 1972 and are concerned with the prevention of harm to human health that arises from contained use involving genetically modified microorganisms (GMMs).
The guidance covers the key requirements of carrying out the risk assessment, classifying the contained use case, notifying to the relevant authority, applying the relevant control measures and accident reporting.
In 2015, the European Academies Science Advisory Council published its guidelines. Its focus has been particularly on biosafety, where they recommend a layered approach with integration of responsibilities and action at researcher, research institution, research funder and national levels within the EU context.
After Brexit as we can predict, the UK’s regulation is not under the European Communities Act.
GoFR and its caveats
Nowadays, GoFR is ‘easily’ performed. The technology used for this kind of research is well described and it is well used in the world of science, even for other types of research. This raises the issue of biosafety and bioterrorism. And with this in mind, I think of the reasoning behind scientific papers not normally being publicly available.
As I mentioned above, the GoFR terminology needs more precise and restricted definitions.
How many countries around the world have national policies that oversee biomedical research projects that can impose risk to society? Not only that, there is a need for a global body responsible for this kind of research that continuously updates the principles, the guidelines and the rules for GoFR as science evolves rapidly. Any research grant proposal involving GoFR should have authorisation from this international body before carrying out research.
Research transparency is of fundamental importance to obtain credibility from the public. Concerns and risks should be well scrutinised during experiment design. Countermeasures need to be clearly stated before continuing to the next phase of the project. A restricted protocol should be in place with rapid responses to new problems that could arise during the course of the experiment. However, what happens when researchers withhold or hide information when an inconvenient situation arises? Are there any safeguards in place for this? How do we find out that this has happened?
