After a very difficult year which shocked mankind with a large and aggressive pandemic, the world tries slowly to return to its former “normal” functioning. Will this goal be fully realized? I doubt it, although many people would like to continue their life unchanged. I hope that mankind cannot forget the thousands of people dying all over the world, the long line of trucks carrying hundreds of COVID-19 victims from Bergamo for cremation in other cities. We cannot forget either the pictures of panic-ridden New York or the view of the hundreds of newly excavated graves in Brazil. In spite of these highly visible shortcomings of our present civilization and culture, millions of human beings continued their traditional lifestyle and cultural rituals unchanged. Can mankind afford not to change its approach to living on our planet? Looking more specifically into the medical-scientific response to control pandemics, we have to ask whether our responses were scientifically trend-braking, adequate, timely, and corresponding the severity and spreading speed of the disease. Furthermore, could we improve the efficiency of worldwide scientific cooperation for minimizing the effects of medical disasters in the future?
The medical profession fought heroically, unfortunately without much success at the beginning, the accepted treatment methods failed frequently. In this desperate situation, old drugs were increasingly used off-label for controlling the virus infection, unfortunately without previous proper scientific repositioning. Successes were rapidly communicated without critically appraising their real benefit/safety ratios. The scientific journals supported this emergency approach, generously making available much space for COVID-19 related publications and offering the downloading of these publications charge-free for the medical community worldwide. In order to speed up the distribution of the new results, unfortunately, they decreased, in parallel, the scientific rigor of the quality control of the publications. The scientific literature became loaded with uncontrolled studies heralding success. This led to the outcry of experts to discourage the compassionate use of not properly evaluated drugs, which frequently do more harm than benefit. In order to avoid scientific confusion and endanger the patients, A.C. Kalil encouraged the scientific community in his excellent viewpoint paper to rely on the traditional controlled clinical trial approach for recommending drugs to treat the virus. He reminded the medical community that none of the drugs recommended for compassionate care during the Ebola endemic in 2014 proved to be effective later under a controlled situation (Kalil, 2020).
The unexpected rapid development of broad medical cooperation overcoming traditional barriers was the positive lesson which we learned to appreciate. Although the epidemic hitting China was only sluggishly acknowledged by the local political authorities, the genetic code of the virus was rapidly made available by Chinese colleagues for the scientific community. The access to this information initiated true worldwide cooperation to develop suitable vaccines and drugs to prevent and combat the disease. It was great luck that at this moment the concept of mRNA-based immunological treatment of cancers was just ripe for medical application. The platforms for producing specific mRNA molecules against individual cancer antigens were ready and well tested. Knowing the code for the spike protein of the COVID-19 virus, the system could be rapidly converted to manufacture mRNA vaccines against the infection. The unexpectedly high efficiency of this vaccination method was the final coronation of the many years of the devoted scientific work of the Hungarian Dr. K. Kariko. She was one of the leading scientists developing mRNAs as therapeutic agents for directing deficient cells to produce their own protein drugs, including vaccines (Kariko et al., 2008). For many years the concept of using mRNA as therapeutic agents was not particularly attractive due to the difficulties directing mRNAs to the right cells. Much additional basic and industrial research was needed for delivering mRNA safely into the desired cells by wrapping the molecule into cationic lipid cholesterol nanoparticles (Pardi et al., 2018).
The production method of mRNA containing medicinal products was ready. Still, no experience was available on how safe and large-scale industrial production can be organized. Most importantly, nobody knew the expected efficacy of the vaccine produced. A hitherto-unknown readiness for the cooperation of medically and non-medically qualified research personnel working in various countries, frequently in competing pharmaceutical companies, emerged to meet this super-urgent medical need. Together with the regulatory agencies, non-clinical, clinical, and regulatory processes were streamlined for accelerating the development process. Indeed, it was a convincing demonstration that with meticulous planning, goal-oriented cooperation, and much goodwill, the critical path for medical product development (US FDA) can be extended beyond the pharmaceutical industry, involving also the regulatory agencies. The regulators were helpful, permitting the partial overlap of the various phases of drug development for abbreviating research time without jeopardizing the needed observational periods for correct evaluation of the final product.
Besides vaccines, there is a great need for specific and highly effective antiviral treatments against COVID-19. The most promising target is the main protease enzyme of the virus, which is needed for the entry of the virus into the cells. The crystal structure of the protease was elucidated by Chinese investigators and made immediately available on the Internet. A completely voluntary, digitally connected cooperative team of over 150 specialists, scattered all over the world, established a new type of cooperative working model, the so-called “moonshot project,” for planning an antiviral molecule specifically fitting into the known protease structure. Various ultramodern methods, and supercomputer capacity, were offered charge-free by various academic and industrial organizations to perform the necessary experiments and computer calculations. Within several months, the group succeeded in identifying molecular fragments able to form covalent binding with the protease. Putting all this information on the website, they invited the global scientific community to recommend possible molecular structures for the planned protease inhibitor. To the great surprise of the group, over 4000 suggestions were communicated within a short time. The most promising designs were synthesized, and their inhibitory activities were checked in a parallelly developed test system. Within a year, this voluntarily cooperating group successfully created a promising molecule ready for entry into non-clinical evaluation.
What did the experience of the last year teach us? It proved that valid scientific methods must be adhered to avoid serious, potentially dangerous mistakes, both in drug development and in their medical application. It also demonstrated that various experts with medical and non-medical backgrounds can very successfully cooperate for rapidly developing effective treatments. A mutual appreciation of the respective scientific know-how and ethical principles, and their joint commitment to a common, well-defined goal, is the basis for these super achievements. These important principles were summarized in the ethical concept entitled “IFAPP International Ethics Framework for Pharmaceutical Physicians and Medicines Development Scientists,” available as an attachment to the paper “The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams,” published in the Research Topics presented.
When trying to look into the future, we have to consider both the beauties and possible negative aspects of these remarkable developments. It is quite likely that such mega international cooperation will be organized by powerful scientific managers in the future, practically “chaining” many scientists to mega international “research conveyor belts.” Good-bye individual scientific creativity! Or possibly not, who knows? It was also sad to observe that many politicians, especially with autocratic tendencies, frequently overruled valid scientific professional advice and propagated unscientific rapid remedies, harming not only their national population but mankind. in general. It was also very unfortunate that political and economic interests significantly distorted worldwide cooperation and hampered universal access to the results of these super achievements. Nevertheless, let us hope that based on the fantastic experiences of the last year, digitally supported broad scientific cooperation will be used more extensively for solving rapidly globally dangerous medical emergencies.
- Kalil AC: Treating COVID-19—Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. JAMA Published online: March 24, 2020, Published Online: March 24, 2020; doi:10.1001/jama.2020.4742
- Pardi N, Hogan MJ, Porter FW, and Weissman D. mRNA vaccines — a new era in vaccinology. NATURE REVIEWS | DRUG DISCOVERY, 17:261-279, 2018
- Kariko, K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S and Weismann D. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008).
- S. Department of Health and Human Services. Food and Drug Administration: Challenge and opportunity on the critical path to new medical products http://wayback.archive-it.org/7993/20180125035500/https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/UCM113411.pdf
- Von Delft F, Chodera J, Griffen E, Lee A, London N, Matvluk T, Perry B, Robinson M, Calmiano M and von Delft A.A white-knuckle ride of open COVID drug discovery. Nature 594:330-332, 2021.
- IFAPP international ethics framework for pharmaceutical physicians and medicines development scientists. https://www.frontiersin.org/articles/10.3389/fphar.2018.00843/full
- Kerpel-Fronius S, Becker S, Barrett J, Brun J, Carlesi R, Chan A, Collia LF, Dubois DJ, Kleist P, Koski G, Kurihara C, Laranjeira LF, Schenk J and Silva H (2018) The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams. Front. Pharmacol. 9:843. doi: 10.3389/fphar.2018.00843. 2018
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