According to the journal Nature, the struggle to contain the spread of the influenza virus is one of the biggest concerns in public health (5). One challenge in preventing an influenza pandemic is the need for biosafe research to study the potential of such pathogens. In June of 2012, two papers were published in Nature – one written by Yoshihiro Kawaoka and the other written by Ron Fouchier – that identified five mutations in the avian H5N1 influenza A virus that render the virus transmissible through the air in ferrets (2). Because this virus is transmissible by air in mammals, if leaked from labs it has the potential to infect humans, provided it can bind human-type receptors. In response to this danger, in October of 2014 the Department of Health and Human Services established a moratorium on all “gain-of-function” research on Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), influenza, and other pathogenic viruses (2). “Gain-of-function” refers to research in which a pathogen is artificially made more virulent in order to study how it is transmitted. Recently, the NIH had lifted this funding pause as a result of the Department of Health and Human Services Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (HHS P3CO Framework). The HHS P3CO Framework lays out the responsibilities of the Department of Health and Human Services in overseeing all processes involved in the creation, transfer, or use of gain-of-function pathogens that have the potential to infect the public (6). Many argue that such research poses a threat to public safety and biosecurity, and poses the risk of an influenza pandemic. They emphasize that laboratory leakage is not impossible, since laboratory pathogens are known to have escaped in the past.  As evidence they point to the 1977 escape of H1N1 swine flu influenza, and the escape of SARS from virology labs in Singapore, Taiwan, and Beijing in 2003 (3), which led to a total of nearly 700 deaths (5).

     Airborne transmission of pathogenic viruses as a result of laboratory leakages poses a threat due to the ability of viruses to evade the body’s immune system. When a virus infects a human, the immune system produces antibodies for specific viral antigens, initiating immune cell destruction of the virus. But viruses have evolved the ability to alter their antigens through self-mutation, essentially rendering them invisible to the host cell’s immune system, and in this way allowing them to avoid destruction (4). In the published study by Kawaoka, researchers used reverse genetics to study the effects of mutations in the viral haemagglutinin (HA) protein – the protein that binds to the host cell receptor. Influenza virus genomes exist as eight segments, which can mix and match in a type of recombination known as “reassortment.” Via experimental reassortment of genes between H5N1 and a virus capable of respiratory droplet transmission in ferrets, H1N1, researchers generated a virus (“H5 HA/H1N1”) that was capable of recognizing human-type receptors. H5 HA/H1N1 carries the H5 receptor-binding protein (HA), but the remaining genes are from the H1N1 virus. Researchers found that the ability of H5 HA to bind the human receptor arose from just a handful of mutations, suggesting how a pathogenic avian H5N1 virus might mutate to a form that could infect humans (7).

     Paul Thomas, a researcher at St. Jude Children’s Hospital in Memphis, TN, explains that “the influenza has been circulating in birds since 1997 without efficiently jumping to mammals. This fifteen year lag has led some in the influenza community to argue that the virus will not and cannot switch to mammalian hosts ” (7). Researchers who support the idea that the fifteen year lag time suggests that it would take a long time for the virus to randomly accumulate the necessary mutations to pose an airborne threat have ignored the debate between gradualism and punctualism in regard to evolution. Gradualism supports the notion that populations evolve over a long period of time in which small changes or mutations occur gradually and consistently. On the other hand, punctualism argues that a population is morphologically stable with few changes occurring in the population over a long period of time. This stability is “punctuated” by a sudden, fast change (due to mutation) in the population that confers an adaptive advantage for survival (8). Because neither theory has been proven, researchers must take into consideration the possible consequences of manipulating genes that can confer adaptive advantage to the already dangerous influenza virus. Although the possibility of this specific set of mutations accumulating in nature is rare, Fouchier commented on the fact that the set of mutations that his group identified was a little different than a set that was identified by Kawaoka’s group. Fouchier explained, “mutations that are not identical still have a similar phenotypic trait (7),” expressing the fact that various mutations can confer adaptability to human-type receptors, not just one. This indicates that just one or a few mutations can have big phenotypic effects on the ability of these pathogens to bind to human-type receptors. Just as cancer can arise from a spontaneous accumulation of mutations that results in the new cancerous phenotype, the virus’s ability to transmit between mammals may also arise from punctuated changes in the genome.

     Scientists who experimentally confer such advantages to these pathogenic viruses must anticipate the possible dangerous consequences of gain-of-function research and take biosafety measures to secure their labs. The World Health Organization updated The Laboratory Biosafety Manual in 2004. The manual lists guidelines to help researchers conduct work responsibly in an environment that embodies safety and security. Additionally, in order to assess the biological risk associated with working with emerging, pathogenic viruses, scientists must be familiar with the characteristics of the viruses being studied. The equipment and procedures followed in the laboratories should then be adapted to deal with the level of risk a particular virus presents (1). Therefore, while recognizing the need to study mechanisms of virulence in the influenza virus, scientists must be conscious of the risk of transmission and its consequences As psychiatrist Carl Jung explained, “It soon becomes dangerous to know more, because one does not learn at the same time how to balance it through a conscious equivalent. It is really the mistake of our age: We think it is enough to discover new things, but we don’t realize that knowing more demands a cor­responding development of morality” (9).

 


REFERENCES

  1. Artika, Made, and Chairin Ma’roef. “Laboratory Biosafety for Handling Emerging Viruses.”Asian Pacific Journal of Tropical Biomedicine, No Longer Published by Elsevier, 7 Jan. 2017, www.sciencedirect.com/science/article/pii/ S2221169116306414.
  2. Fouchier, Ron A. M., et al. “Pause on Avian Flu Transmission Studies.” Nature News, Nature Publishing Group, 20 Jan. 2012, www.nature.com/articles/481443a.
  3. Furmanski, Martin. “Threatened Pandemics and Laboratory Escapes: Self-Fulfilling Prophecies.” Bulletin of the Atomic Scientists, 31 Mar. 2014, thebulletin.org/threatened-pandemics-and-laboratory-escapes-self-fulfilling-prophecies7016.
  4. Hartmann, Boris M., et al. “Pandemic H1N1 Influenza A Viruses Suppress Immunogenic RIPK3-Driven Dendritic Cell Death.” Nature News, Nature Publishing Group, 5 Dec. 2017, www.nature.com/articles/s41467-017-02035-9. (destruction)
  5. Imai, Masaki, et al. “Experimental Adaptation of an Influenza H5HA Strain Confers Respiratory Droplet Transmission to Reassortant H5H/H1N1 Virus Strain in Ferrets.” Nature, U.S. National Library of Medicine, 21 June 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3388103/.
  6. “NIH Lifts Funding Pause on Gain-of-Function Research.” National Institutes of Health, U.S. Department of Health and Human Services, 19 Dec. 2017, www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-lifts-funding-pause-gain-function-research.
  7. Richards , Sabrina. “Five Mutations Make H5N1 Airbone.” The Scientist, Exploring Life, Inspiring Innovation, 21 June 2012, www.the-scientist.com/?articles.view/ articleNo/32247/title/Five-Mutations-Make-H5N1-Airborne/.
  8. Vermont, University of. “University of Vermont.” The Study of Change Over Time: Evolution 101 : University of Vermont, 2006,www.uvm.edu/perkins/ evolution/darwin/?Page =record%2Fplas.html&SM=record%2Frecordmenu.html.
  9. Quotes About Carl Jung (24 Quotes).” www.goodreads.com/quotes/tag/carl-jung.

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