Persistence Pays Off: Recognizing Katalin Karikó and Drew Weissman, the 2023 Nobel Prize Winners in Physiology or Medicine
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Last week, biochemist Katalin Karikó and immunologist Drew Weissman earned the Nobel Prize in Physiology or Medicine for their discoveries that enabled the development of effective messenger RNA (mRNA) vaccines against COVID-19. On behalf of the NIH community, I’d like to congratulate Karikó and Weissman and thank them for their persistence in pursuing their investigations. NIH is proud to have supported their seminal research, cited by the Nobel Assembly as key publications.1,2,3
While the lifesaving benefits of mRNA vaccines are now clearly realized, Karikó and Weissman’s breakthrough finding in 2005 was not fully appreciated at the time as to why it would be significant. However, their dogged dedication to gaining a better understanding of how RNA interacts with the immune system underscores the often-underappreciated importance of incremental research. Following where the science leads through step-by-step investigations often doesn’t appear to be flashy, but it can end up leading to major advances.
To best describe Karikó and Weissman’s discovery, I’ll first do a quick review of vaccine history. As many of you know, vaccines stimulate our immune systems to protect us from getting infected or from getting very sick from a specific pathogen. Since the late 1700s, scientists have used various approaches to design effective vaccines. Some vaccines introduce a weakened or noninfectious version of a virus to the body, while others present only a small part of the virus, like a protein. The immune system detects the weak or partial virus and develops specialized defenses against it. These defenses work to protect us if we are ever exposed to the real virus.
In the early 1990s, scientists began exploring a different approach to vaccines that involved delivering genetic material, or instructions, so the body’s own cells could make the virus proteins that stimulate an immune response.4,5 Because this approach eliminates the step of growing virus or virus protein in the laboratory—which can be difficult to do in very large quantities and can require a lot of time and money—it had potential, in theory, to be a faster and cheaper way to manufacture vaccines.
Scientists were exploring two types of vaccines as part of this new approach: DNA vaccines and messenger RNA (mRNA) vaccines. DNA vaccines deliver an encoded protein recipe that the cell first copies or transcribes before it starts making protein. For mRNA vaccines, the transcription process is done in the laboratory, and the vaccine delivers the “readable” instructions to the cell for making protein. However, mRNA was not immediately a practical vaccine approach due to several scientific hurdles, including that it caused inflammatory reactions that could be unhealthy for people.
Unfazed by the challenges, Karikó and Weissman spent years pursuing research on RNA and the immune system. They had a brilliant idea that they turned into a significant discovery in 2005 when they proved that inserting subtle chemical modifications to lab-transcribed mRNA eliminated the unwanted inflammatory response.1 In later studies, the pair showed that these chemical modifications also increased protein production.2,3 Both discoveries would be critical to advancing the use of mRNA-based vaccines and therapies.
Earlier theories that mRNA could enable rapid vaccine development turned out to be true. By March 2020, the first clinical trial of an mRNA vaccine for COVID-19 had begun enrolling volunteers, and by December 2020, health care workers were receiving their first shots. This unprecedented timeline was only possible because of Karikó and Weissman’s decades of work, combined with the tireless efforts of many academic, industry and government scientists, including several from the NIH intramural program. Now, researchers are exploring how mRNA could be used in vaccines for other infectious diseases and in cancer vaccines.
As an investigator myself, I’m fascinated by how science continues to build on itself—a process that is done out of the public eye. Luckily every year, the Nobel Prize briefly illuminates for the larger public this long arc of scientific discovery. The Nobel Assembly’s recognition of Karikó and Weissman is a tribute to all scientists who do the painstaking work of trying to understand how things work. Many of the tools we have today to better prevent and treat diseases would not have been possible without the brilliance, tenacity and grit of researchers like Karikó and Weissman.
- K Karikó, et al. Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity DOI: 10.1016/j.immuni.2005.06.008 (2005).
- K Karikó, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Molecular Therapy DOI: 10.1038/mt.2008.200 (2008).
- BR Anderson, et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Research DOI: 10.1093/nar/gkq347 (2010).
- DC Tang, et al. Genetic immunization is a simple method for eliciting an immune response. Nature DOI: 10.1038/356152a0 (1992).
- F Martinon, et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. European Journal of Immunology DOI: 10.1002/eji.1830230749 (1993).
Katalin Karikó: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke
Drew Weissman: National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute
Posted on by Dr. Francis Collins
Each year, thousands of Americans are bitten by deer ticks.These tiny ticks, common in and around wooded areas in some parts of the United States, can transmit a bacterium into the bloodstream that causes Lyme disease. Those infected experience fever, headache, stiff necks, body aches, and fatigue. A characteristic circular “target” red rash can mark the site of the tick bite, but isn’t always noticed. In fact, many people don’t realize that they’ve been bitten, and weeks can pass before they see a doctor. By then the infection has spread, sometimes causing additional rashes and/or neurological, cardiac, and rheumatological symptoms that mimic those of other conditions. All of this can make getting the right diagnosis frustrating, especially in areas where Lyme disease is rare.
Even when Lyme disease is suspected early on, the bacterium is unusually slow growing and present at low levels, so it can take a while before blood tests detect antibodies to confirm the condition. By then, knocking out the infection with antibiotics can be more challenging. But research progress continues to be made toward improving the diagnosis of Lyme disease.
An NIH-supported team recently uncovered a unique gene expression pattern in white blood cells from people infected with the Lyme disease-causing bacterium Borrelia burgdorferi . This distinctive early gene signature, which persists after antibiotic treatment, is unique from other viral and bacterial illnesses studies by the team. With further work and validation, the test could one day possibly provide a valuable new tool to help doctors diagnose Lyme disease earlier and help more people get the timely treatment that they need.
Posted on by Dr. Francis Collins
A new year has arrived, and it’s going to be an amazing one for biomedical research. But before diving into our first “new science” post of 2016, let’s take a quick look back at 2015 and some of its remarkable accomplishments. A great place to reflect on “the year that was” is the journal Science’s annual Top 10 list of advances in all of scientific research worldwide. Four of 2015’s Top 10 featured developments directly benefited from NIH support—including Science’s “Breakthrough of the Year,” the CRISPR/Cas9 gene-editing technique. Here’s a little more on the NIH-assisted breakthroughs:
CRISPR Makes the Cut: I’ve highlighted CRISPR/Cas9 in several posts. This gene-editing system consists of a short segment of RNA that is attached to an enzyme. The RNA is preprogrammed to find a distinct short sequence of DNA and deliver the enzyme, which acts like a scalpel to slice the sequence out of the genome. It’s fast and pretty precise. Although CRISPR/Cas9 isn’t brand-new—it’s been under development as a gene-editing tool for a few years—Science considered 2015 to be “the year that it broke away from the pack.”
Posted on by Dr. Francis Collins
After watching this music video, you might wonder what on earth it has to do with biomedical science, let alone Ebola research. The answer is everything.
This powerful song, entitled “One Truth,” is dedicated to all of the brave researchers, healthcare workers, and others who have put their lives on the line to save people during the recent outbreak of Ebola virus disease. What’s more, it was written and performed by seven amazing scientists—one from the United States and six from West Africa.
Posted on by Drs. Anthony S. Fauci and Francis S. Collins
Updated Oct. 22, 2014: The National Institutes of Health (NIH) today announced the start of human clinical trials of a second Ebola vaccine candidate at the NIH Clinical Center in Bethesda, MD. In this early phase trial, researchers from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) are evaluating the vaccine, called VSV-ZEBOV, for its safety and ability to generate an immune response in healthy adults who receive two intramuscular doses, called a prime-boost strategy.
The Walter Reed Army Institute of Research is simultaneously testing the vaccine candidate as a single dose at its Clinical Trials Center in Silver Spring, MD. VSV-ZEBOV, which was developed by researchers at the Public Health Agency of Canada’s National Microbiology Laboratory, has been licensed to NewLink Genetics Corp. through its wholly owned subsidiary BioProtection Systems, both based in Ames, Iowa.
Early human testing of another Ebola vaccine candidate, co-developed by NIAID and GlaxoSmithKline, began in early September at the NIH Clinical Center. Initial data on that vaccine’s safety and ability to generate an immune response are expected by the end of 2014.
We are all alarmed by the scope and scale of the human tragedy occurring in West African nations affected by the Ebola virus disease epidemic. While the cornerstones of the Ebola response remain prompt diagnosis and isolation of patients, tracing of contacts, and proper protective equipment for healthcare workers, the National Institutes of Health (NIH), led by its National Institute of Allergy and Infectious Diseases (NIAID), is spearheading efforts to develop treatments and a vaccine for Ebola as quickly as possible.
For example, NIAID has supported and collaborated with Mapp Biopharmaceutical, Inc., San Diego, in its development of the product known as ZMapp, which has been administered experimentally to several Ebola-infected patients. While it is not possible at this time to determine whether ZMapp benefited these patients, NIAID is supporting a broader effort to advance development and clinical testing of ZMapp to determine if it is safe and effective. In addition, the U.S. Biodefense Advanced Research and Development Agency (BARDA) has announced plans to optimize and accelerate the manufacturing of ZMapp, which is in limited supply, to enable clinical safety testing to proceed as soon as possible.
Posted on by Dr. Francis Collins
Updated August 28, 2014: Today, the National Institutes of Health (NIH) announced plans to begin initial human testing of an investigational vaccine to prevent Ebola virus disease. Testing of the vaccine, co-developed by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline, will begin next week at the NIH Clinical Center in Bethesda, MD.
As the outbreak of Ebola Virus Disease continues to spread in West Africa, now affecting four countries in the region, I am reminded how fragile life is—and how important NIH’s role is in protecting it.
NIH research has helped us understand how Ebola initially infects people and how it spreads from person to person. Preventing this spread is currently our greatest defense in fighting it. Through research, we know that the Ebola virus is transmitted through direct contact with bodily fluids and is not transmitted through the air like the flu. We also know the symptoms of Ebola and the period during which they can appear. This knowledge has informed how we manage the disease. We know that the virus can be contained and eradicated with early identification, isolation, strict infection control, and meticulous medical care.
Posted on by Dr. Francis Collins
When Stanford University bioengineer Manu Prakash traveled to a mosquito-infested rainforest in Thailand a couple of years ago, he visited a clinic with a sophisticated, $100,000 microscope that sat unused in a locked room. It was then Prakash realized that what global health workers really need is an ultra-low cost, simple-to-use, portable microscope that could be deployed in the field to diagnose disease—and he took it upon himself to develop one!
The result is the Foldscope, a ‘use and throwaway’ microscope that Prakash demonstrated last week at the first-ever Maker Faire at the White House. While I saw many amazing inventions and met many incredible inventors at this event, I came away particularly impressed by the practicality of this device and the ingenuity of its maker.