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MRNA VACCINES HAVE SAVED MILLIONS OF LIVES
BY KENT BOTTLES, MD
The rapid development of mRNA vaccines against the SARSCoV-2 coronavirus is truly one of the most spectacular scientific achievements of all time. A 2022 Lancet Infectious Diseases UK global study estimated that the vaccine saved 19.8 million lives over a one-year period from December 8, 2020 to December 8, 2021. Although the production of mRNA vaccines in just one year after the world learned the genetic sequence of the virus is by far the fastest vaccine development on record, this success story has much to teach us about the complicated and long process of all innovation in science and medicine.
Whenever a significant scientific breakthrough occurs there is a tendency to identify a genius individual who is celebrated and written into the history books as a hero. Think Edward Jenner and the small pox vaccine or Thomas Edison and the light bulb. In Philadelphia there is talk of future Nobel Prizes for Katalina Kariko and Drew Weissman of the University of Pennsylvania whose important contributions to mRNA science helped save those nearly 20 million lives.
Society’s need for heroes obscures the reality about how scientific innovations actually happen. A Nature article titled The Tangled History of mRNA Vaccines paints an alternative picture of decades of basic science research, twists and turns, bitter personal rivalries, and incredible persistence to get to the point that Kariko and Weissman could succeed in developing a way to get mRNA into human cells without eliciting a fatal immune response. mRNA was first discovered in 1961, but for decades researchers had difficulty studying it because of the molecule’s incredible instability. The basic science behind the development of the lipid nanoparticles that encapsulate the mRNA in vaccines dates back to 1965.
The researchers who made important contributions to the development of mRNA vaccines did not always play nice and get along with each other. As a graduate student at the Salk Institute in California, Robert Malone in 1988 inserted strands of mRNA mixed with fat into human cells that then produced proteins. Tensions and disagreements between Malone and his academic supervisor led to Malone dropping out of the PhD program, and patent agreements between Salk and an involved biotech company did not include Malone. Malone, who did complete an MD degree at Northwestern, has called himself “the inventor of mRNA vaccines” and claims to have been written out of history. He also recently created a controversy when he was interviewed on the Joe Rogan podcast on Spotify and attacked the safety of mRNA vaccines. That interview led to protests from hundreds of physicians about Malone’s vaccine misinformation on Spotify and Neil Young and Joni Mitchell asking that their music be removed from the popular internet platform.
No one person invented the mRNA vaccine. As the Nature article makes clear, many investigators made significant contributions that paved the way for the Moderna and Pfizer vaccines. Kariko makes this point when she says, “Everyone just incrementally added something — including me.” One of the pioneers behind the development of lipid nanoparticles, Pieter Cullis, agrees when he states “You really cannot claim credit, we’re talking hundreds, probably thousands of people who have been working together to make these LNP systems so that they’re actually ready for prime time.” Many do not realize that the development of the lipid layer that coats the mRNA in the vaccine is an essential element for the vaccine to work in humans.
Many of the investigators who made important discoveries about the basic science of mRNA and lipid nanoparticles did not know if and how their work would ever contribute to medical therapies. Most basic scientists are really motivated by curiosity about how nature works, and they are now pleasantly surprised that mRNA has saved those 20 million lives. In the early days of mRNA research nobody really thought about vaccine developments as a possibility. The Nature article quotes one scientist who states “RNA was so hard to work with if you had asked me back then if you could inject RNA into somebody for a vaccine I would have laughed in your face.”
Politicians and bureaucrats who are deciding where to put research dollars would be well advised to understand that one cannot predict which basic projects will result in “useful” results that can be applied in the clinical setting. The track record of prestigious institutions such as Harvard and University of Pennsylvania is not impressive in this regard. The Harvard Technology Development Office did not patent the early RNA research and gave away the reagents to a biotech startup company. The company sent Harvard a case of Veuve Clicquot Champagne in return. The University of Pennsylvania famously in the late 1990s did not support Kariko and demoted her with a pay cut. They also did not recognize the importance of her work and sold off some early patents. Kariko’s belief in her work and perseverance in the face of rejection is truly remarkable and admirable.
Lessons learned from the “tangled history of mRNA vaccines” have important public policy ramifications. Steven Johnson in his book Extra Life makes the case that “network narratives” are more accurate than “genius narratives” for understanding scientific innovation and medical breakthroughs. A breakthrough is often just the latest in a series of small incremental advances, and the general public does not understand this fact. A two-year internet search revealed 1096 media citations over a 2-year period for the word breakthrough, and the public love of moon shot research (think Joe Biden’s cancer program) endangers funding for the necessary but unsexy small incremental research projects. Behind every home run like the mRNA vaccine in addition to many basic science researchers, there are connectors, amplifiers, funders, champions, and evangelists who are necessary if the breakthrough is to benefit society. And many of these network roles are played by non-scientific individuals.
In addition to forever transforming the vaccine field, mRNA has other potential uses in medicine. mRNA is involved in almost all aspects of human cell biology, and important research is on the way to better understand its function. mRNA can make antigens for vaccines, antibodies, cytokines, and other immune proteins, and pharmaceutical companies are studying ways that mRNA could be leveraged in cancer immunotherapy, other infectious diseases, cystic fibrosis, multiple sclerosis, allergies, diabetes insipidus, anemia, myocardial infarctions, and genetic reprogramming. Scientists are learning how to control the amount of protein manufactured, how long it lasts, the best route of administration, which cells express the protein, and whether the mRNA produces protein that activates or suppresses the immune system.“The versatility of mRNA creates a huge design space. We have designed a diversified toolbox and by mixing and matching the modules we can design mRNA with the features we need for a particular purpose. It is a bit like writing code — by mastering programming language that is rich in terms, one can give any instructions one wants,” states Ozlem Tureci of BioNTech in a Scientific American article.
mRNA vaccines have saved millions of lives from the current pandemic, and their development highlights the complicated and convoluted path that is behind the story of any scientific breakthrough. Thousands of scientists and lay individuals have made small incremental contributions that make home runs in medicine possible, and adequately funded basic science research is needed in order to create new medical treatments as we better understand the basic biology of the human being.
