2023 Nobel Prize in Physiology or Medicine: Karikó and Weissman, Pioneering Nucleoside Modification for mRNA Vaccines

What You Will Learn in This Article

The 2023 Nobel Prize in Physiology or Medicine recognized the groundbreaking discovery that transformed mRNA into a safe and effective therapeutic tool. Katalin Karikó, of Hungarian origin, and Drew Weissman, both affiliated with the University of Pennsylvania in the United States, are the recipients. Their 2005 publication forms the cornerstone of this achievement. They unveiled a remarkably elegant chemistry: replacing uridine in mRNA with pseudouridine (Ψ) prevents the body's innate immune system from recognizing this mRNA as a danger signal, resulting in cells translating the mRNA normally and producing large quantities of the desired protein. Without this discovery, the COVID-19 mRNA vaccines (Pfizer-BioNTech's Comirnaty, Moderna's Spikevax) would not have existed, and the pandemic response would have taken a completely different course. Thirty years of dedicated basic research became a crucial weapon in the first pandemic of the 21st century, and it paved the way for cancer mRNA vaccines, rare disease gene therapies, and personalized medicine.

A Paradigm Shift: The Body Recognizes Extracellular mRNA as a Danger Signal

The common understanding that "mRNA is a molecule that carries genetic information" only considers the normal processes within cells. However, when mRNA produced outside the cell is introduced into the cell, a completely different situation arises. The body's innate immune system recognizes extracellular mRNA as a danger signal for viral infection and triggers a strong immune response to destroy that mRNA. This is a normal function of the evolutionary-developed antiviral defense system, but it posed a critical obstacle to attempts to deliver mRNA into cells for therapeutic purposes.

The innate immune receptors, such as TLR3, TLR7, and TLR8, are activated when mRNA encounters them inside and outside the cell. The result is a strong inflammatory response, rapid degradation of the mRNA, and, ultimately, failure to produce the protein encoded by the mRNA. In the late 20th century, many laboratories attempted to produce proteins by introducing mRNA into cells, but most failed due to this immune response.

Karikó and Weissman revealed an elegant solution to this problem. Certain types of RNA inside natural cells—particularly tRNA and rRNA—already have various chemical modifications, and these modifications prevent the innate immune system from recognizing that RNA as a danger signal. If these modifications are incorporated into artificial mRNA, the body will mistake it for natural RNA and will not recognize it as a danger signal.

In the context of a conceptual framework, this can be viewed as payload signing. The cell's firewall (the innate immune system) blocks payloads with unsigned or invalid signatures. Nucleoside modification is a method of attaching a valid signature to the payload, allowing it to pass through the firewall. The pseudouridine substitution is a disguise, signaling "this code is safe, self-RNA," and this disguise enables the normal execution of the payload (the encoded protein sequence).

The Landscape of the Time: Generative AI Boom and the Aftermath of the Pandemic

In 2023, the world began with the explosive growth of generative AI. In March, GPT-4 was released, marking a leap forward in the capabilities of large language models, and ChatGPT became the fastest-growing service in the world in a matter of months. Along with image-generating AIs (Midjourney, Stable Diffusion, DALL-E), fundamental questions about copyright, creativity, and education moved to the center of social debate. The November event involving the dismissal and subsequent reinstatement of Sam Altman from the OpenAI board symbolically revealed the tension between the safety and commercialization of AI development.

On October 7, Hamas launched a surprise attack on Israel, triggering the Israel-Hamas war. Israel's full-scale invasion of Gaza followed, leading to a severe humanitarian crisis and international debate that lasted for several months. The war in Ukraine entered its second year, with Western support fatigue becoming a central issue of debate.

South Korea experienced a tumultuous second half of the year. On August 24, the release of treated water from the Fukushima Daiichi Nuclear Power Plant sparked political and environmental controversy, and opposition parties and civil society groups held protests. The New Songdo International City World Scout Jamboree in August became an international embarrassment due to failures in responding to the heatwave, lack of facilities, and safety management issues, leading to its early termination. On September 27, the arrest warrant for Lee Jae-myung, leader of the Democratic Party, was rejected, which helped the opposition party regain political momentum and subsequently influenced the political landscape.

In the technology and economic world, the bankruptcy of Silicon Valley Bank (SVB) in March sent shockwaves through the startup ecosystem, and this spread to several other regional banks. In August, India's Chandrayaan-3 successfully landed on the lunar south pole, marking a symbolic moment for the Indian space program.

In the scientific community, this award was a recognition of the technology that was crucial in responding to the pandemic. The COVID-19 mRNA vaccines were developed and administered to the public in just 10 months, the fastest vaccine development in human history, and this would have been impossible without Karikó and Weissman's more than 20 years of accumulated basic research. The Nobel Committee's prompt recognition of this discovery is an indicator of how immediate and global its impact was.

Human Story: 30 Years of Dedication by an Immigrant, and a Chance Encounter in a Hospital Corridor

Katalin Karikó (1955–) was born in a rural village in Hungary. Her childhood story is well-known. She grew up helping in her mother's butcher shop and went on to study biology at the University of Szeged. Her interest was in the therapeutic potential of RNA from the beginning. After the collapse of the Soviet Union, research funding in Hungary declined, and in 1985, she immigrated to the United States with her husband and young daughter. She secretly carried 900 pounds, the money she earned by selling her daughter's dolls.

Her journey in the United States was difficult. She continued her research at Temple University, Johns Hopkins, and the University of Pennsylvania, but there was considerable skepticism about her idea of mRNA therapeutics. She was repeatedly denied research funding, and in the 1990s, she was removed from the tenure track at the University of Pennsylvania and remained on the lecturer track. Despite this, she continued to dedicate herself to mRNA research, maintaining a small lab and a few students.

Drew Weissman (1959–) was born in Boston, Massachusetts. He received his bachelor's degree from Boston University and his M.D.-Ph.D. from Boston University School of Medicine and did his postdoctoral training in the Fair Labor Laboratory (where he later met Anthony Fauci at the NIH). He was a clinician-scientist who was interested in mRNA from the perspective of vaccine development.

The two met in the late 1990s in a corridor at the University of Pennsylvania. Karikó was waiting by the photocopier when Weissman struck up a brief conversation with her. Karikó was developing a technology to deliver mRNA into cells to produce proteins, and Weissman was interested in whether this technology could be used to help develop an HIV vaccine. Their collaboration began, and they initially encountered a wall in the observation that introducing mRNA into cells caused a severe immune response.

The key insight came from Karikó's observation. Several types of RNA in natural cells—particularly cellularly produced tRNA—have many chemically modified nucleosides. The idea of why these modifications exist and whether they are related to immune recognition arose at this moment. The two experimented by incorporating various nucleoside modifications into mRNA, and they discovered that pseudouridine substitution had a decisive effect.

The 2005 Immunity paper published this discovery to the world. mRNA with uridine substituted with pseudouridine avoids innate immune recognition and produces proteins much more strongly and persistently than normal mRNA. The impact of this paper was not immediately recognized. It slowly permeated the skeptical academic community, and a handful of startups began to utilize this principle to develop mRNA therapeutics. Moderna (founded in 2010) and BioNTech (founded in 2008) played a crucial role in the commercialization of this technology, and Karikó joined BioNTech as a vice president in 2013.

In 2020, the COVID-19 pandemic brought this 20-year dedication to the world stage. Pfizer-BioNTech's Comirnaty and Moderna's Spikevax were developed and granted emergency use authorization in a matter of months, and both vaccines were based on Karikó and Weissman's pseudouridine principle. Three years later, the Nobel Prize marked the culmination of this story.

In her Nobel Prize lecture, Karikó reflected on her journey. Immigration, repeated rejections, long years on the lecturer track, and a chance encounter in a corridor. The story of an immigrant female scientist's dedication in the late 20th century becoming a crucial weapon in the pandemic of the early 21st century is one of the most inspiring stories in Nobel Prize history.

Key Achievements: Payload Signing in the Context of a Conceptual Framework

If we diagram the mRNA therapeutic pipeline, it looks like this:

• Design: Determine the amino acid sequence of the desired protein (e.g., SARS-CoV-2 spike protein). Reverse translate this into mRNA codons to design an artificial mRNA sequence.
• Synthesis: Synthesize this mRNA in large quantities in vitro. At this stage, uridine is replaced with pseudouridine to create nucleoside-modified mRNA. The 5' cap and 3' polyadenine tail are also added to mimic natural mRNA in cells.
• Delivery: Encapsulate the mRNA in lipid nanoparticles (LNPs). LNPs are a separate critical technology that delivers mRNA into cells by fusing with the cell membrane. This technology has been developed by several laboratories since the late 20th century.
• Translation: Once inside the cell, the mRNA is translated by ribosomes to produce the target protein (spike). Thanks to pseudouridine substitution, the innate immune system does not recognize this mRNA, and translation continues for several days.
• Immune Response: The produced spike protein is presented on the cell surface and recognized by T cells and B cells. An antibody and T cell response is generated, preparing the body to defend against actual viral infection.

The essence of this pipeline is the architecture for safely delivering and executing custom genetic code in cells. Pseudouridine substitution is payload signing, LNP is the container, and the mRNA sequence is the payload itself. These three layers combine to create a functional system.

The special features of mRNA vaccines are:

• Speed: Vaccine candidates can be designed within days of obtaining pathogen sequences. The COVID-19 vaccines were designed within days of the release of the SARS-CoV-2 sequence, and clinical trials began within weeks.
• Flexibility: A new vaccine can be created simply by changing the sequence. This makes it possible to develop vaccines against variants, new pathogens, and personalized cancer antigen vaccines.
• Safety: mRNA does not integrate into the genome, unlike DNA, and it is degraded after a few days. This gives it a favorable biosafety profile.
• Manufacturing Scalability: Because it is close to a chemical synthesis process, large-scale manufacturing is relatively fast.

It is also important to point out the limitations of this analogy. The payload of mRNA vaccines is short and transient. Since the mRNA is degraded after a few days and protein production stops, repeated vaccinations are required for sustained effects. This is suitable for vaccines that induce antibody responses, but different approaches are needed for gene therapies that require sustained protein replacement. Various extended forms of mRNA therapeutics are being developed to overcome this limitation.

Why It Matters: Pandemic Response, Personalized Medicine, and the Value of Dedication

First, it was a critical technology in responding to the COVID-19 pandemic. Without the mRNA vaccines from Pfizer-BioNTech and Moderna, the trajectory of the pandemic would have been completely different. These two vaccines were developed and approved for emergency use within months, and have since been administered billions of times, significantly reducing global mortality. This was faster than any vaccine development in the 20th century, and this speed was made possible by the 20 years of accumulated basic research by Karikó and Weissman.

Second, it opened the door to mRNA vaccines for cancer. Each patient's tumor has neoantigens, which are unique mutations specific to that patient. With mRNA technology, it is now possible to design and manufacture vaccines that encode these individual antigens within days, leading to personalized cancer vaccines entering clinical trials. Early clinical results are promising in melanoma, pancreatic cancer, and other cancers, and this approach has the potential to become a major pillar of cancer treatment in the latter half of the 21st century.

Third, it is a new approach to treating rare genetic diseases. In genetic diseases where a specific protein is deficient, it is now possible to deliver that protein to cells using mRNA. Clinical trials of mRNA therapeutics are underway for metabolic diseases such as protoporphyria and methylmalonic acidemia, and if successful, it will change the landscape of treatment for these rare diseases.

Fourth, a new infrastructure for vaccine development has been established. Several vaccines, including those for influenza, RSV, HIV, and herpes, are being developed using mRNA technology. In particular, the influenza mRNA vaccine has the potential to significantly improve the speed of response to annual mutations and is poised to become a major component of pandemic preparedness.

Fifth, it has symbolic value in recognizing immigrant and female scientists. Karikó's life is a story of dedication by an immigrant scientist in the latter half of the 20th century, and she was finally recognized dramatically during the pandemic after being overlooked by the academic mainstream for a long time. Her Nobel Prize sends a strong symbolic message to female and immigrant scientists in many countries, and is also cited as an indicator of the Nobel Committee's awareness of diversity.

Sixth, it reaffirms the importance of supporting basic science. Karikó remained on the lecturer track for a long time, and her mRNA research was repeatedly rejected for funding. Nevertheless, she continued her research, and the results became a critical weapon in responding to the pandemic 20 years later. The value of continuously supporting basic research that may not seem to have immediate practical applications is reaffirmed by this story, and it is cited in scientific policy debates in many countries.

Seventh, it marks the transition to the era of personalized medicine. With mRNA technology, simply changing the sequence creates a new therapeutic. This provides an infrastructure for customized treatments based on the unique genetic information of each patient. Combined with the decreasing cost of genome sequencing, the latter half of the 21st century is likely to usher in a true era of personalized medicine, and mRNA is one of the key technologies.

Eighth, it concretizes international cooperation for pandemic preparedness. The WHO is promoting a plan to expand the transfer of mRNA technology to low- and middle-income countries in the Southern Hemisphere, which aims to reduce the gap in vaccine access during future pandemics. mRNA vaccine manufacturing hubs are being established in countries such as South Africa and Brazil, and this infrastructure has the potential to play a critical role in the next pandemic.

The 30-year dedication of an immigrant became a critical weapon in the pandemic. This story contains a strong message about scientific policy, immigration policy, and the status of female scientists in the early 21st century. The twenty-third Nobel Prize in Physiology or Medicine of the new century has been given to this story, and the various applications of the mRNA era that will unfold thereafter will be based on the elegant chemistry of pseudouridine by Karikó and Weissman.

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