26 January, 2022
To date, the most outstanding product of the awardees’ work has been “the timely and prompt development of SARS-CoV-2 vaccines,” which have proved to “effectively provide protection against severe COVID-19.” The committee notes that the vaccines now containing the pandemic are just the first wave of a technology that is “set to expand to other therapeutical areas such as autoimmunity, cancer, neurodegenerative disorders, enzyme deficiency, and other viral infections.”
“This award recognizes the inventors of two technologies that, together, have not only given us vaccines against COVID-19, but also open up a whole vista of therapeutic possibilities in the most widely diverse areas,” explains Óscar Marín, committee secretary and Director of the Centre for Neurodevelopmental Disorders at King’s College London (United Kingdom). “Vaccines are the first example of the potential of bringing these two technologies together, but clinical trials and further research on their use against other diseases are already underway.”
A technology that teaches the body to “manufacture” its own treatment
Karikó and Weissman, a biochemist and immunologist respectively, and Langer, a chemical engineer, are the authors of critical breakthroughs in the chain of scientific findings that have made messenger RNA therapies a reality, with a technology that gets the body’s own cells to produce the molecules needed to fight off disease.
Karikó and Weissman were nominated for the Frontiers of Knowledge Award by Isabel Varela, President of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), Larry Jameson, Dean of the Perelman School of Medicine and Vice President of the University of Pennsylvania, Eric Topol, Executive Vice President of the Scripps Research Institute, and Elias Zerhouni, Professor Emeritus at Johns Hopkins University. Langer’s nomination was put forward by Antonio López Díaz, Rector Magnificus of the University of Santiago de Compostela, and by María José Alonso, Professor of Pharmacy and Pharmaceutical Technology at the same university.
Timewise, the first contribution came from Robert Langer, a professor at the Massachusetts Institute of Technology (USA). His was the first paper, published in Nature in the 1970s, which showed that it was possible to take nucleic acid molecules – such as RNA, standing for ribonucleic acid – and encapsulate them in nanoparticles for release into the body. This insight, says the committee, enabled “packaging of macromolecule therapeutics including mRNA and delivering them into cells, allowing the cellular translation machinery to synthesize the protein/antigen.”
It was not until the new century that Karikó and Weissman, professors at the University of Pennsylvania (USA), added their part of the equation, by “developing mRNA modification methods to prevent the immune system from recognizing and destroying the mRNA,” in the words of the award citation. This was a pivotal breakthrough.
“Karikó and Weissman discovered how to modify mRNA molecules in a way that made them suitable as a therapeutic agent, and Langer came up with the vehicle, the encapsulation technology that enabled the mRNA to be delivered into the body.” In both cases, says Marín, we are talking about “quintessential advances.”
The molecule that carries instructions to synthesize proteins
DNA and RNA are the molecules (chemically, nucleic acids) that contain the information needed for any living being to manufacture proteins. Each organism’s DNA is unique and housed in all of its cells. What RNA does, put in the simplest terms, is to copy information from DNA and transport it to the protein-making machinery within the cell. Conceptually RNA therapy starts from the assumption that it is possible to design RNA “to order” in the lab, so it contains the information needed to make any protein, be it a therapeutic compound or, as in COVID-19 vaccines, a fragment of a virus. Once inside the cell, this synthetic RNA will be read by the cellular machinery, which will start producing the target proteins.
The mRNA vaccines against COVID-19 contain RNA with instructions to make the S protein of the SARS-CoV-2 coronavirus, which acts as the key for entry into the host cell. So when the vaccine is injected, the macrophages (immune system defense cells) near to the jab site ingest the lipid-enclosed RNA. They then start producing the virus’s S protein and display it on their outer membrane, triggering a defensive response such as the body would mount against a natural SARS-CoV-2 infection.
These vaccines are quicker to manufacture than their traditional counterparts and easier to adapt to mutated variants. They are also theoretically safer, since no live virus is involved, and no genetic material enters the nucleus of the human cell.
The start of a biomedical revolution with multiple applications
After hearing of the award, Katalin Karikó talked about how it felt now the vaccines’ success had placed her work at the forefront of science: “For 40 years not only did I receive no awards, I didn’t even have financial support for my research because I couldn’t get a grant. So I feel greatly honored. I want to use the fact that I am in the media spotlight right now to encourage young people, men and women, to become scientists, because it is so much fun.”
It was in the late 1970s that Karikó began working with synthetic RNA, as a postdoc at the Centre for Biological Research in her home town of Szeged (Hungary). In 1985, she moved with her family to the United States. At the University of Pennsylvania, she continued to work on mRNA technology, a line of research which few saw as holding any promise. The turning point came when she began collaborating with immunologist Drew Weissman at the same university. In 2005, Karikó and Weissman achieved their first breakthrough: discovering how to modify RNA in such a way that it would go undetected by the human immune system.
As Weissman explained after hearing of the award, “our central hypothesis when we started this work was that RNA would be a better delivery system for proteins because it involves using the host as its own production factory. The problem that we ran into when we first started developing this was that the RNA was highly inflammatory which meant that if you injected it into an animal, the animal got sick. So Katalin and I spent years trying to understand why the RNA was so inflammatory. And that’s where we made our key finding, which is how to make the RNA non-inflammatory. That also happened to increase the amount of protein that was produced, which was a great secondary benefit.”
At this stage, developing a vaccine was still far from being in the two researchers’ sights. “We managed to eliminate the inflammatory reaction to mRNA,” Karikó relates. “I wanted to make mRNA encoding for a therapeutic protein that could be given to a patient suffering a stroke or other heart condition because I worked in cardiology and neurosurgery, and I wanted to prevent the inflammation that would make their situation worse”.
For the new laureate, COVID-19 vaccines are just the start of a biomedical revolution in the making. “Now that the technique has proved its usefulness in vaccine development, I am sure we will soon see new versions for other diseases. It is also a very cheap therapy, because the medicine is made in your own body; you are the factory. The applications are endless.”
Karikó cites, for example, the technique’s use in cardiovascular disease, now being explored in advanced-stage clinical trials, “injecting mRNA into the heart during bypass surgery to increase cardiac capacity,” she explains. “We thought that would be the first approved use, but the pandemic pushed vaccines into the front line.”
Trials are also underway to test mRNA vaccines against HIV, malaria and other diseases, including cancer: “We have conducted promising trials in two animal models to combat multiple sclerosis, an autoimmune condition. A lot of trials have begun, and more and more firms are trying out the technology.”
Weissman too is looking at new uses for the technique, for instance as gene therapy for sickle cell anemia. “200,000 people a year are born with sickle cell, we hope to be able to give them a single in vivo injection of mRNA that will target the bone marrow stem cells and fix the genetic disorder, curing the disease. That would change medicine.”
A “symbol of perseverance” in the face of the initial skepticism of the scientific community
Langer, like Karikó, had to face down the skeptics at the start of his research career. He recalled after hearing of the award that until his success in creating micro- and nanoparticles to encapsulate any large molecule, “people didn’t believe it was possible.” This was in 1974. “Even after we published our work, lots of people told me it was wrong,” he continued. “In fact the first nine grants I applied for were rejected, and I couldn’t get a job in a chemical engineering department, which is my discipline.” Langer would eventually join MIT as an Assistant Professor of Nutritional Biochemistry in 1978.
He describes his contribution as “absolutely critical” for mRNA therapies: “If you injected mRNA directly, it would just get destroyed. But you put it in these little particles and that protects it when you inject it into the body, and allows it to survive and do its work.” Also, the particles can modulate the rate at which RNA is administered, and at times also the site where it is released, “so it enables very precise drug delivery.”
Langer is today one of the world’s most cited scientists, and the inventor on over a thousand patents. He is also a co-founder of Moderna, the company that manufactures one of the mRNA vaccines. By demonstrating the concept of particle encapsulation for delivering macromolecules into the body, Langer opened up a new world of possibilities, currently being explored by numerous research groups. “Lots of people have built on our 1974 work, and a lot of companies have been developing things, some of whom I helped to advise or get started. Today, microparticle or nanoparticle drug delivery is used in treating various cancers, mental health diseases such as schizophrenia, and also opioid addiction. It is also used in treating type 2 diabetes, in the prevention of bleeding and eye disease, for relieving pain, and in heart disease.”
With the pandemic ongoing, and anti-COVID vaccines saving lives daily, Langer considers it “an incredible honor to win this prize, given the incredible people who have received it in the past and the ones whom I’m sharing with it this year.”
“Both Langer and Karikó and Weissman are a symbol of perseverance,” Marín affirms. “They suffered rejection after rejection due to the novelty of their research and the short-termism that often characterizes science policy. Their triumph now is testimony to how difficult it is to predict what will work in biology, and how many breakthroughs may have fallen by the wayside because we didn’t take risks.”
Biology and Biomedicine committee and evaluation support panel
The jury in this category was chaired by Angelika Schnieke, Chair of Biotechnology at the Technical University of Munich (Germany). The secretary was Óscar Marín, Professor of Neuroscience and Director of the MRC Centre for Neurodevelopmental Disorders at King’s College London (United Kingdom). Remaining members were Dario Alessi, Director of the MRC Protein Phosphorylation and Ubiquitylation Unit at Dundee University (United Kingdom); Lélia Delamarre, Senior Principal Scientist in the Department of Cancer Immunology at Genentech (United States); Robin Lovell-Badge, Senior Group Leader and Head of the Laboratory of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute (United Kingdom); Ursula Ravens, Senior Professor in the Institute of Experimental Cardiovascular Medicine of the University of Freiburg (Germany); Ali Shilatifard, Robert Francis Furchgott Professor of Biochemistry and Pediatrics at Northwestern University Feinberg School of Medicine (United States); and Bruce Whitelaw, Professor of Animal Biotechnology and Interim Director of the Roslin Institute at the University of Edinburgh (United Kingdom).
The evaluation support panel of the Spanish National Research Council (CSIC) was coordinated by M. Victoria Moreno, Deputy Vice President for Scientific and Technical Areas, and formed by: José Félix de Celis Ibeas, research professor at the Severo Ochoa Molecular Biology Center (CBMSO); Dolores González Pacanowska, Coordinator of the Global Life Area and research professor at the López-Neyra Institute of Parasitology and Biomedicine (IPBLN); José Luis Martínez Menéndez, research professor at the National Center of Biotechnology (CNB); M. Isabel Medina Méndez, Deputy Coordinator of the Global Life Area and research professor at the Institute of Marine Research (IIM); and Isabel Varela Nieto, research professor at the Alberto Sols Biomedical Research Institute (IIBM).
About the BBVA Foundation Frontiers of Knowledge Awards
The BBVA Foundation centers its activity on the promotion of world-class scientific research and cultural creation, and the recognition of talent.
The BBVA Foundation Frontiers of Knowledge Awards recognize and reward contributions of singular impact in science, technology, the humanities and music, privileging those that significantly enlarge the stock of knowledge in a discipline, open up new fields, or build bridges between disciplinary areas. The goal of the awards, established in 2008, is to celebrate and promote the value of knowledge as a public good without frontiers, the best instrument at our command to take on the great global challenges of our time and expand the worldviews of individuals in a way that benefits all of humanity. Their eight categories address the knowledge map of the 21st century, from basic knowledge to fields devoted to understanding and interrelating the natural environment by way of closely connected domains such as biology and medicine or economics, information technologies, social sciences and the humanities, and the universal art of music. They come with 400,000 euros in each of their eight categories, along with a diploma and a commemorative artwork created by artist Blanca Muñoz.
The BBVA Foundation has been aided from the outset in the evaluation of nominees for the Frontiers Award in Biology and Biomedicine by the Spanish National Research Council (CSIC), the country’s premier public research organization. CSIC appoints evaluation support panels made up of leading experts in the corresponding knowledge area, who are charged with undertaking an initial assessment of the candidates proposed by numerous institutions across the world, and drawing up a reasoned shortlist for the consideration of the award committees. CSIC is also responsible for designating each committee’s chair and participates in the selection of its members, thus helping to ensure objectivity in the recognition of innovation and scientific excellence.