Katalin Karikó and Drew Weissman pioneered the discoveries that made modern messenger RNA (mRNA) vaccines possible. Their work on stabilizing and modifying the mRNA molecule earned them the 2023 Nobel Prize in Physiology or Medicine. For years, the scientific community dismissed the idea of using mRNA as a therapeutic tool due to significant technical barriers. These two researchers overcame those obstacles, ushering in a new era of medical treatments and disease prevention.
The Scientists and Their Decades-Long Partnership
Katalin Karikó, originally from Hungary, believed strongly in the potential of mRNA for medical applications, despite facing considerable professional setbacks. Throughout the 1990s at the University of Pennsylvania (UPenn), she struggled for funding and institutional support. In 1995, she was demoted from her research track position due to her focus on what was then considered a dead-end technology.
The crucial partnership began after a chance meeting with Drew Weissman at UPenn in the late 1990s, near a shared photocopier. Weissman, an immunologist, was working on developing an HIV vaccine and was exploring new delivery systems for genetic material. Their respective expertise—Karikó’s deep biochemical knowledge of RNA and Weissman’s focus on the immune system—proved to be perfectly complementary.
The collaboration continued despite the constant rejection of grant applications and the skepticism of their peers. They toiled for years in the lab, driven by the shared goal of turning the fragile mRNA molecule into a viable medical platform. Their joint effort eventually yielded the breakthrough that transformed the field.
The Initial Hurdle: Early mRNA Instability and Immune Response
The concept of using mRNA to instruct cells to produce a specific protein had existed for decades, but early attempts were thwarted by two major biological problems. First, when synthetic mRNA was introduced into a cell, enzymes called nucleases quickly degraded it. This fragile nature meant the instructions often failed to last long enough to produce protein, making it difficult to stabilize and deliver effectively.
The second issue was the immune response it triggered. The body’s innate immune system is designed to detect foreign nucleic acids, such as those from invading viruses, initiating an immediate inflammatory response. When the lab-made mRNA entered the body, innate immunity sensors like Toll-like receptors recognized it as “non-self” and sounded an alarm.
This recognition led to the rapid production of inflammatory molecules, attacking the therapeutic mRNA before it could deliver its instructions. This inflammatory reaction prevented the mRNA from being used as a safe and effective therapeutic agent in humans. Ultimately, the early synthetic mRNA produced too little protein and caused too much inflammation to be clinically useful.
The Core Discovery: Nucleoside Modification
Karikó and Weissman realized that solving the immunogenicity problem required understanding the difference between lab-synthesized mRNA and the mRNA naturally found in human cells. They discovered that natural human RNA contains chemical alterations, called nucleoside modifications, which allow it to circulate without triggering an immune response. These modifications mark the body’s own RNA as “self” and harmless.
Their core breakthrough, published in 2005, involved swapping one of the four basic building blocks of RNA, uridine, with a slightly altered version, pseudouridine. This alteration made the synthetic mRNA look like the body’s own genetic material, making it “stealthy” to the innate immune sensors. By incorporating modified nucleosides, they were able to reduce the inflammatory response that had plagued previous research attempts.
The modification had a second effect: it increased the efficiency of protein production. The altered mRNA was not only hidden from immune detection but was also translated into protein more effectively by the cell’s machinery. This dual achievement—reducing inflammation and boosting protein expression—transformed mRNA into a viable therapeutic platform. This modified mRNA technology, paired with a protective lipid nanoparticle delivery system, served as the foundation for the rapid development of the COVID-19 vaccines.
Broadening the Platform: Applications Beyond Viral Vaccines
The success of the modified mRNA platform extends far beyond its initial application in viral disease prevention. This flexible technology is now being investigated across a wide range of therapeutic areas, signaling a new era of RNA-based medicine. The speed and adaptability of the platform allow researchers to quickly design and manufacture therapies by simply changing the genetic code.
One of the most promising areas is therapeutic cancer vaccines, which aim to train the immune system to recognize and attack malignant cells. These vaccines can be personalized to a patient’s specific tumor mutations, encoding unique antigens that prompt the immune system to seek out and destroy cancer cells. The platform is also being utilized for protein replacement therapies, which address genetic disorders where a patient is missing a necessary protein.
In this application, the modified mRNA delivers the instructions for the missing protein, allowing the patient’s own cells to produce it. Research is also exploring the use of this technology to treat autoimmune disorders by reprogramming the immune system to restore immune tolerance. The ability to rapidly generate a tailored therapeutic has positioned modified mRNA as a key tool in regenerative medicine and for combating a variety of chronic diseases.