Why this dangerous, expensive research when alternatives are available?

 

Gain of function mutation in a virus is a mutation that confers new or enhanced activity to the virus. Gain of function research (GOFR) can be practised by many techniques. The method used in Wuhan is to obtain a genetically altered animal like a humanised mice. Then by the “serial passaging of viruses” (repeated multiplication of selected progeny of the virus) on tissues cultured from such an animal under suitable laboratory conditions, one can artificially accelerate the gain of function mutation. This is in contrast to natural mutations that occur over the years and often require decades of evolution. Gain of function can also be achieved by genetic engineering by “editing” the genetic code of the virus. The US government stated the purpose of GOFR as: “Research with an ultimate goal of better understanding disease pathways. Gain-of-function studies aim to increase the ability of infectious agents to cause disease by enhancing its pathogenicity or by increasing its transmissibility.” This was supposedly intended to create and study probable mutants before they actually emerge in nature and then develop vaccines and therapeutic drugs to prevent future pandemics. Fears were expressed by many that a devastating pandemic may follow a laboratory accident involving GOFR. Dr Anthony Fauci wrote in an article in 2012 that “It is more likely that a pandemic would occur in nature, and the need to stay ahead of such a threat is a primary reason for performing an experiment that might appear to be risky.” He also admitted that GOFR on a virus with serious pandemic potential may be replicated by a scientist in a less safe facility, leading to an outbreak that would ultimately trigger a pandemic.

In 2010, the World Health Organization issued a “guidance document” for Dual Use Research of Concern (DURC) in the life sciences. DURC refers to technology developed for peaceful purposes that can be used for warfare. In December 2012, a group of Japanese researchers at the University of Wisconsin published a paper in the journal Nature on their success in changing the viral haemagglutinin (HA) protein (that mediates the flu virus binding to host-specific cellular receptors) of the bird flu H5N1 virus to enable it to infect mammals. They acknowledged that the research was funded by the Bill & Melinda Gates Foundation, ERATO, National Institute of Allergy and Infectious Diseases with support gifts from the National Institutes of Health and the Vietnamese National Institute of Hygiene and Epidemiology. In 2013, researchers at National Avian Influenza Reference Laboratory in China mixed parts of the H1N1 human flu virus and the bird flu H5N1 virus to produce a deadly chimeric virus, leading to an outcry against any manipulation that is of no use for vaccine and drug development. In 2014, after a series of accidents involving mishandled pathogens at the US Centre for Disease Control and Prevention, the NIH announced that it would stop funding GOFR that have the potential to unleash a pandemic or epidemic in the event of an escape from the lab. Some researchers said the broad ban threatened necessary flu-surveillance and vaccine research. Kenneth Bernard, a National Science Advisory Board for Biosecurity (NSABB) member said, “Defending against bio-threats by developing countermeasures looks a lot like an offensive bioweapons programme.”

In October 2014, the US government placed a moratorium on 18 GOFR projects for three years but later seven of these GOFR projects were exempted. Funding for GOFR was directly and indirectly received from government agencies, pharmaceutical companies, venture capital funds, universities and even non-profit research institutions, foundations, and charities. In October 2015, the European Academies’ Science Advisory Council with 29 individual members—all highly experienced scientists nominated one each by the national science academies of EU Member States—released a 45-page document: Gain of function-experimental applications relating to potentially pandemic pathogens. It said recent GoF experiments to modify avian H5N1 influenza have been controversial because of concerns about potential safety and security implications.

It is obvious now that for many years GOFR has been in progress in many research facilities in many nations, with funding from multiple agencies despite doomsday warnings from many who became aware of it. The question arises: Was the need to create dangerous viruses justified by the need to future proof drugs and vaccines? Is there no safe alternative?

On 12 June 2007, using published data, a robot called Adam identified gene code for key enzymes in the yeast Saccharomyces cerevisiae and proceeded to synthesise and test their ability to catalyse reactions. For many years now, exhaustive search by natural language processing (NLP) algorithms of available data trapped in research papers, patents, clinical trials and patient records has been used to identify previously overlooked patterns and relationships by threading together structured data from multiple sources into a densely interconnected “knowledge graph”. This has been used with Artificial Intelligence, computational statistics and statistical machine learning (an algorithmic technique) to cost effectively and quickly develop effective new drugs for infections, cancer etc. These techniques have also been used to repurpose known drugs; for improving existing drugs; for antibody development and also to modify RNA sequences to block disease-related genes. For example, Pfizer is using IBM Watson system to power its search for immuno-oncology drugs. Niven Narain, co-founder and chief executive of biotechnology company Berg, near Boston, USA said, “We are turning the drug-discovery paradigm upside down by using patient-driven biology and data to derive more-predictive hypotheses, rather than the traditional trial-and-error approach”. Anthony Bradley, a computational medicinal chemist at Oxford University, UK who uses artificial neural networks with the aim of identifying molecules that will bind to and act on protein drug targets had said “it might be that wet-lab skills to perform practical chemical or biological experiments might be of no use ten years from now”. A survey by BenchSci, a start-up in Toronto, Canada, found 41% of drug-discovery researchers are unaware of the capabilities of AI. Drug-discovery firm WuXi AppTec in Shanghai, China, in 2015 acquired NextCODE Health from an Icelandic company deCODE Genetics “to develop drugs and assess them in clinical trials with very sophisticated pattern recognition”. It now uses AI to look for connections between RNA-sequence variations, expression levels, molecular function and gene location.

Viruses, unlike other living organisms, are just a piece of genetic code with a protective cover and are technically dead until they enter a host cell. They have to reach out to a victim, find a suitable site to which they can attach and then enter the host cell and make the host cell produce multiple copies of itself. The SARS-CoV-2(Covid 19) virus has a spike protein which attaches to the ACE2 receptor of the cells lining the airway of the host after it is inhaled. Mutations in the spike protein create many variations, some of which suit a different animal host. Genetic variation in the human ACE2/SARS-CoV-2 S-binding interface is rare as confirmed by a team of researchers in Proceedings of the National Academy of Sciences USA. Data from analysis of the human ACE2 protein sequence is available in the public domain. Hence, instead of tinkering around with the coronavirus, it would be far simpler and safer to use AI, computer 3D modelling, machine learning based image analysis to find the few variations of the spike protein that would efficiently attach to the human ACE2 receptor. Vaccines can then be developed for each of these variations. We will then have a suitable vaccine for each dangerous mutant strain that may appear in nature. These could be combined into a polyvalent vaccine if more than one mutant strain appears simultaneously. Technology used for mRNA vaccines can be adapted to stimulate our body to produce suitable antibodies to attack each variant of the spike protein.

So what was the purpose of GOFR projects? Was it to justify funding for virology research and facilities? Was it to gain recognition by achieving something dramatically new? Or was there an ulterior motive of developing a weapon of mass destruction, for use after developing a suitable vaccine for a selected population? What if such a virus falls in the hands of a suicidal terrorist or a powerful autocratic megalomaniac? It’s high time implications of GOFR are discussed at an international forum and brought under the purview of the Geneva Protocol. When we try to outsmart nature, nature invariably outsmarts us.

Dr P.S.Venkatesh Rao is Consultant Endocrine, Breast & Laparoscopic Surgeon; National Delegate (India) to International Society of Surgery; President 2014-15, Indian Association of Endocrine Surgeons; former Professor of Endocrine Surgery; former Faculty CMC (Vellore), AIIMS (New Delhi), UCMS (Delhi), MSRMC (Bengaluru).