An aerial view shows the P4 laboratory at the Wuhan Institute of Virology in Wuhan in China's central Hubei province on April 17, 2020. - The P4 epidemiological laboratory was built in co-operation with French bio-industrial firm Institut Merieux and the Chinese Academy of Sciences. The facility is among a handful of labs around the world cleared to handle Class 4 pathogens (P4) - dangerous viruses that pose a high risk of person-to-person transmission.
February 23, 2022 2:39 PM EST
Dr. Gallo is Homer & Martha Gudelsky Distinguished Professor in Medicine and Professor in Microbiology and Immunology, Co-Founder & Director, Institute of Human Virology at the University of Maryland School of Medicine, Baltimore, and Co-founder and International Scientific Director, Global Virus Network, Baltimore. Dr. Jamison is Edward A. Clarkson Professor, Emeritus, Department of Epidemiology and Biostatistics and Institute for Global Health Sciences, University of California, San Francisco, and a Scientific Advisor to the Global Virus Network, Baltimore.

Over two years since the first cases started appearing in Wuhan, China, there is much we don’t know about the origins of SARS-CoV-2, the virus causing COVID-19. But a quick resolution to that question is possible: scientists could find bats in a cave somewhere in China or in southeast Asia and trace a chain leading from those bats to the COVID-19 outbreak in Wuhan. Realistically, however, recent history offers little promise for this to happen quickly. For example, about 14 years elapsed between the identification of HIV as the virus that caused AIDS and a demonstration of its modern transition to humans from a specific group of chimpanzees, although this had been suspected some years earlier. About a decade passed from the time of the 2003-4 epidemic of SARS and definitive delineation of the origin of its causal coronavirus, and seven years passed before the 2009-10 influenza pandemic was shown to have originated in Mexican swine. The alternative possibility to a natural origin—a laboratory leak—will be difficult to definitively prove or disprove.

More importantly, focusing on origins begs a question were there really major health policy or research directional changes for previous pandemics when the origins were determined? Take HIV for instance: we learned the chimp to man transmission occurred in rain forests, but we did not interrupt visits or human life in rain forests. We learned HIV likely came to cities because of population movements and increased prostitution, and then became global by changes such as frequent travel by large numbers, increased sexual contacts, blood and plasma medical use, and IV drug addiction. Needless to say, public policy changed little. SARS origin was learned but we now have SARS-CoV-2. The great influenza pandemic may have originated in WW I army barracks, but we moved on to WW II and did not stop soldiers being in barracks. In short, knowing origins made little difference in how we treated and dealt with the disease—in most if not all cases.

Yet the World Health Organization (and much of the scientific community) initially agreed with the Trump Administration’s claim that understanding the origin of SARS-CoV-2 was of vital immediate importance. The administration’s concern was, plausibly, less a matter of dispassionate interest in science but more an effort to open a new front in the U.S. response to a rising China, or an effort to divert attention from a delayed and chaotic U.S. response to the pandemic. Those who advocate for an intensive effort to discover the origins of SARS-CoV-2 assert there would be value in terms of establishing public or public health policy based on that understanding. Just what should be done differently to counter Delta or, now, Omicron by understanding the origin of SARS-CoV-2 better? Knowing origins could bring closure to the ongoing politically charged debate and contribute importantly to scientific understanding. We doubt, however, that knowledge of origins would change anything about how we should respond to the challenges of SARS-CoV-2, or how we would prepare for a future pandemic. We can act now on the assumption that either hypothesis (nature or laboratory leak) could be correct.

Here is where the origins discussion now stands: One idea is that there was a natural origin; bat to man directly or through an intermediary animal. The other is that the cause was research error. Scientists studying bats in the field could have become infected themselves or have brought infected bats back to the laboratory. Then by accidental release the virus spread. It is also possible that “gain-of-function” research could have created SARS-CoV-2, followed by its accidental release. Early expression of support for the gain-of-function hypothesis concerned CGG, one of the codons specifying the amino acid arginine for its insertion into the virus’s newly forming spike protein thereby enabling a human protease (furin) to more efficiently cut the coronavirus spike protein which can facilitate infection. Nobel Laureate David Baltimore has expressed the view that CGG coding for arginine was so exceptional it would be suggestive of man-made origins, but this proves unconvincing. Other coronaviruses, such as ones causing the common cold, do have the CGG codon for arginine, albeit only a limited number in the so-called beta subgroup to which SARS-CoV-2 belongs.

President Biden gave agencies of the U.S. intelligence community (IC) 90 days to assess the likelihood of natural causes versus research error, and they reported their findings in late August. While one agency concluded that research error was more likely, four other agencies concluded that likelihood lay with natural causes, and the summary conclusion of the National Intelligence Council (NIC) likewise favored the natural origins hypothesis although both the individual agencies and the NIC placed only low to moderate confidence in their conclusions. The declassified version of the IC report also pointed to the Chinese government’s “…frustration [that] the international community is using the issue to exert political pressure on China…” as a reason why further Chinese cooperation in establishing origins remains unlikely. While research error remains a possibility, we doubt that a definitive answer will be soon coming. That said, evidence increasingly accumulates in favor of the natural origins hypothesis, and earlier assessments that pointed toward a laboratory leak, like the furin hypothesis discussed above, have weakened with scrutiny.

We return to the question of how much it really matters. We know how to respond to each scenario for origin. There is a very limited number of directions to take, and prudence dictates that each should be taken.

  • Disease surveillance. Increased investment in disease surveillance at the human-wildlife interface, and in interrupting potential pathways of spillover of viral infection from animal to human are clearly priorities. Even if SARS-Cov-2 originated from research error this remains true.
  • Research safety. Safety expectations for laboratory research on dangerous pathogens should be enhanced. We have ample evidence in past decades of accidental releases from laboratories in all parts of the world. Safety protocols for field research and specimen management should also be reviewed and strengthened. Better standards of training should be defined in order to work with a given kind of pathogenic virus, accompanied by some form of accreditation. Research funding should more carefully weigh the (often important) knowledge to be gained against the residual risk of studying dangerous microbes.
  • Gain-of-function research. To most virologists this phrase as currently used indicates research that seeks to determine whether certain genetic changes deliberately made in the laboratory with a virus can lead to enhanced capacity of the virus to infect cells. In the case of human coronaviruses, it means greater capacity to infect human cells. The goal is to try to learn how to be better prepared in developing protection against such viruses that may develop these changes in nature and possibly cause a serious human epidemic or pandemic. No doubt this goal is a worthy one as it would give the medical community advance knowledge for diagnostics, vaccines and therapy if such a virus did emerge. Again, we must weigh risk versus benefit. Virologists are well aware that escape of viruses from research laboratories can happen. In each such experiment the risk to reward estimate must be made. Gain of function research is now reviewed by established virologists with these points in mind, yet we must admit that the involved scientists are generally tempted to go forward confident of their ability and confident that they have adequate control of the laboratory situation. Most scientists will want to push forward. If reviews are positive such research is more than likely to be funded by NIH, and their reviews are not very transparent. We might take a page from the molecular biologists and their meetings held in Asilomar, Ca. where detailed discussions occurred on the ethics and potential hazards of some kinds of gene cloning experiments. These discussions led to guidelines of the acceptable and unacceptable. One idea we feel has merit is to include non-specialists, including even nonscientists, as part of the review process to provide added independent oversight on the funding of the research.

There is much scientific interest in understanding the origins of SARS-CoV-2. And, let’s be honest, it would be nice to know. At the same time knowing origins may add little to what we already know in terms of addressing Delta, Omicron and whatever might come next. The best way forward may be to minimize the distraction of a politicized attempt to assess origins while, instead, investing in long-term international collaborative endeavors on SARS-CoV-2 and in preparation for future epidemics and pandemics.

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