Nobel Prize in Physiology or Medicine 2023: mRNA Base Modifications and COVID-19 Vaccines

This note covers the Nobel Prize in Physiology or Medicine 2023: who won it, how chemically modified mRNA almost stopped the body's inflammatory response and boosted protein output, how the discovery unfolded over three decades, why it mattered for COVID-19 vaccines and beyond, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2023 awarded for?

The official citation reads: "for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19". This is the exact wording used by the Nobel Assembly at Karolinska Institutet, which awards the prize officially called the Nobel Prize in Physiology or Medicine.

In plain words, the two laureates found a way to tweak the chemical building blocks of messenger RNA (mRNA) so that when it was injected into the body it almost stopped triggering an unwanted inflammatory reaction, and it also produced far more of the target protein.

This single discovery turned mRNA from a difficult laboratory tool into a practical technology, and it became the scientific basis of the two fastest-approved COVID-19 vaccines.

The prize was announced on 2 October 2023 and carried a total award of 11,000,000 Swedish kronor, shared equally between the two scientists.

Who are the laureates?

Katalin Karikó

Katalin Karikó was born on 17 January 1955 in Szolnok, Hungary. At the time of the award she was affiliated with Szeged University, Szeged, Hungary, and with the University of Pennsylvania, Philadelphia, PA, USA. She received one half of the prize.

Karikó earned her PhD in 1982 at the Biological Research Center in Szeged, did postdoctoral work in Hungary and the United States, and became an assistant professor at the University of Pennsylvania in 1989.

She is described as an expert RNA biochemist who spent decades, often against scepticism from research funders, pursuing the idea that mRNA could become a medicine.

Her systematic testing of different RNA components for optimal protein expression reflected her long-standing drive to advance mRNA as a therapy, in the years before her collaboration with Weissman began.

Drew Weissman

Drew Weissman was born on 7 September 1959 in Lexington, MA, USA. At the time of the award his affiliation was the Penn Institute for RNA Innovations, University of Pennsylvania, Philadelphia, PA, USA. He also received one half of the prize.

Weissman trained as a physician-scientist, earning MD and PhD degrees from Boston University in 1987 and later working on dendritic cells and immune activation.

He joined the University of Pennsylvania in 1997, where he began working with Karikó on how different forms of RNA interact with the immune system, aiming originally at an HIV vaccine.

What problem were they trying to solve?

Before this work, most vaccines used whole viruses (weakened or killed, such as those protecting against yellow fever, measles and polio), or individual viral proteins (as in hepatitis B and HPV vaccines), or a harmless carrier "vector" virus carrying a chosen gene (as used against Ebola).

All these approaches need large-scale cell culture, which is slow and resource-intensive, limiting how fast a vaccine can be produced in an outbreak.

Scientists had long wanted a vaccine platform that skipped cell culture altogether, by injecting genetic material directly so the body's own cells make the protein.

From the 1950s onward, researchers had worked out that DNA is transcribed into messenger RNA (mRNA), which then acts as a template for protein-making machinery in cells.

By the 1980s, scientists could produce mRNA in a test tube using an enzyme process called in vitro transcription.

However, laboratory-made mRNA caused two serious problems. First, when injected into cells it was recognised as foreign and triggered an unwanted inflammatory response, with immune cells releasing signalling molecules. Second, it produced disappointingly little of the target protein.

Together these roadblocks meant that, despite three decades of interest, no mRNA-based vaccine had ever been approved for human use before COVID-19.

How did Karikó and Weissman solve the inflammation problem?

Working together at the University of Pennsylvania from the late 1990s, Karikó and Weissman noticed something puzzling: dendritic cells (immune cells that sense pathogens and trigger responses) reacted strongly to laboratory-made mRNA, but not to mRNA taken from ordinary mammalian cells.

They reasoned that some chemical difference between the two types of RNA must explain this.

RNA is built from four bases, abbreviated A, U, G and C. The two scientists knew that bases in RNA from mammalian cells are often chemically modified after they are made, while laboratory-made mRNA is not.

They tested whether adding such modifications to laboratory-made mRNA would change how dendritic cells reacted. The process they followed can be summarised as:

1. Produce several versions of mRNA, each carrying a different chemically altered base in place of a standard one.
2. Deliver each version of the mRNA to dendritic cells in the laboratory.
3. Measure the release of inflammatory signalling molecules from the cells.
4. Compare the inflammatory response of modified mRNA against unmodified mRNA.
5. Identify which specific base modifications removed the unwanted reaction.

The result, published in 2005, was striking: when certain modified bases, including one called pseudouridine, replaced the standard base, the inflammatory response was almost abolished.

In further studies published in 2008 and 2010, they also showed that base-modified mRNA produced much more protein than unmodified mRNA, because it reduced activation of an enzyme (PKR) that normally shuts down protein-making when it detects double-stranded RNA.

Draw a row of mRNA strands made of four bases (A, U, G, C); mark one strand as unmodified and another with a modified base highlighted.

Beside each, draw a dendritic cell with arrows showing a large burst of inflammatory signal from the unmodified strand and almost none from the modified strand.

Why did this matter for vaccines, and how do mRNA vaccines work?

By removing the inflammatory problem and boosting protein output, Karikó and Weissman had cleared the two biggest obstacles blocking mRNA from clinical use.

From around 2010, several companies began developing base-modified mRNA technology, testing it against diseases such as Zika virus and MERS-CoV (a coronavirus closely related to the one that causes COVID-19).

When SARS-CoV-2 emerged in late 2019 and spread worldwide, this groundwork allowed an extraordinarily fast response. Two base-modified mRNA vaccines, encoding the surface "spike" protein of the virus, were developed and tested at record speed.

The committee's press release noted they showed protective effects of around 95%, and both were approved as early as December 2020.

An mRNA vaccine works broadly like this:

1. Scientists design an mRNA sequence encoding a chosen viral protein, such as the spike protein of SARS-CoV-2.
2. The mRNA is produced in the laboratory using in vitro transcription, with modified bases included.
3. The mRNA is packaged inside tiny fat-based delivery particles so it can enter human cells without breaking down.
4. Once inside cells, the mRNA is used as a template for the cell's own machinery to make the viral protein.
5. The immune system detects this protein as foreign and builds a protective response, including antibodies.

Comparison with older vaccine platforms:

The press release also stated that, together with other vaccine types, more than 13 billion COVID-19 vaccine doses had been given globally, which the committee said had "saved millions of lives".

How did the discovery unfold?

Why does this discovery matter beyond COVID-19?

The press release stated that mRNA vaccines can be designed and produced with remarkable speed and adaptability, opening the door to using the same platform against other infectious diseases.

Because the mRNA sequence can simply be swapped to encode a different protein, new vaccine candidates can be produced quickly without rebuilding an entire manufacturing process.

The sources also note that in future the technology may be used to deliver therapeutic proteins and to treat some types of cancer, though these were described as potential future uses rather than finished treatments at the time of the award.

The committee emphasised that the laureates' basic, curiosity-driven research from 2005, which initially drew little attention, ended up being essential fifteen years later during "one of the greatest threats to human health in modern times", in the words used in the press release.

The discovery also illustrates a broader lesson often highlighted around this prize: fundamental research into how cells recognise foreign RNA, pursued without any pandemic in sight, turned out to be the hidden foundation for an emergency response that reached billions of people.

How does this connect to what you study?

This discovery links directly to school biology topics on the central dogma of molecular biology: how DNA carries genetic information, how it is transcribed into messenger RNA, and how that RNA is translated into protein by ribosomes in the cell's cytoplasm. The Nobel sources describe this DNA-to-mRNA-to-protein pathway as a process common to all forms of life, which is exactly the sequence taught in cell biology chapters on gene expression.

It also connects to lessons on the immune system, including how the body distinguishes self from foreign material using sensors such as Toll-like receptors, and how vaccines work by training that recognition system in advance of a real infection. The scientific background material explains how dendritic cells detect foreign RNA and trigger inflammatory signalling, which is useful context for topics on innate immunity.

Students studying chemistry can connect this to the structure of nucleic acids, since the whole discovery hinges on small chemical changes to one of the four RNA bases. Students studying cell biology can use this prize as a real example of how a molecule most textbooks mention briefly, mRNA, became central to a global health response, and how basic laboratory research on immune cells, done years before any pandemic, can become urgently important later.

How is mRNA delivered safely into human cells?

Discovering that base-modified mRNA avoided inflammation and produced more protein was not enough on its own; the mRNA also had to survive long enough to reach cells and enter them without being broken down. Scientists tackled this separately, through research on delivery systems alongside the base-modification work.

The scientific background material explains that early attempts used liposomes, small bubble-like structures made of fat molecules, to carry mRNA into cells. Researchers trapped mRNA inside these fatty capsules so it could cross the cell's outer membrane without being destroyed by enzymes in the body.

A major improvement came from work on ionizable cationic lipids, which can carry an electric charge that changes depending on the surrounding acidity. At a low pH, these lipids attract and trap the negatively charged mRNA tightly; once injected into the body, where the pH is different, the lipids lose their charge, which reduces unwanted toxic effects.

These fat-based delivery capsules became known as lipid nanoparticles. The sources describe them as being built from four components: an ionizable lipid, a helper lipid, cholesterol, and a protective coating molecule. Together these let mRNA travel safely to cells and release its cargo once inside.

This delivery technology combined with Karikó and Weissman's base-modification discovery to make a workable vaccine platform. The mRNA inside the lipid nanoparticle is taken up by cells, where it is read as a template to build the chosen viral protein, which then alerts the immune system.

Draw a small spherical capsule made of a fatty outer layer with mRNA strands trapped inside; label the ionizable lipid, helper lipid, cholesterol and protective coating.

Draw an arrow showing the capsule merging with a human cell's outer membrane and releasing the mRNA strand into the cell's interior.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2023 was awarded jointly to Katalin Karikó and Drew Weissman for discoveries concerning nucleoside base modifications that enabled effective mRNA vaccines against COVID-19.

It was announced on 2 October 2023 by the Nobel Assembly at Karolinska Institutet. Karikó, born in Szolnok, Hungary, was affiliated with Szeged University and the University of Pennsylvania at the time of the award.

Weissman, born in Lexington, Massachusetts, USA, was affiliated with the Penn Institute for RNA Innovations at the University of Pennsylvania. Each received one half of the prize, worth a total of 11,000,000 Swedish kronor.

Their key 2005 discovery showed that chemically modified mRNA avoided triggering unwanted immune inflammation and produced more protein, the basis of the fast-tracked COVID-19 vaccines approved in December 2020.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Messenger RNA (mRNA) — a molecule that carries genetic instructions copied from DNA to the cell's protein-making machinery.
• Nucleoside base — one of the four chemical units (A, U, G, C in RNA) that make up the genetic code of a nucleic acid strand.
• In vitro transcription — a laboratory method for producing mRNA outside living cells using an enzyme.
• Dendritic cell — an immune cell that detects foreign substances and alerts the rest of the immune system.
• Inflammatory response — the body's reaction to a perceived threat, involving signalling molecules that can cause swelling, fever or related symptoms.
• Pseudouridine — a chemically modified form of the RNA base uridine, used by Karikó and Weissman to reduce unwanted immune activation.
• Vector vaccine — a vaccine that uses a harmless carrier virus to deliver a chosen gene into cells.
• Subunit vaccine — a vaccine made from an isolated viral protein rather than the whole virus.
• Spike protein — the surface protein of SARS-CoV-2 that several COVID-19 vaccines are designed to target.
• Lipid nanoparticle — a tiny fat-based capsule used to deliver mRNA safely into human cells.
• Antibody — a protein made by the immune system that recognises and helps neutralise a specific foreign substance.
• Nobel Assembly at Karolinska Institutet — the body of fifty professors that awards the Nobel Prize in Physiology or Medicine.

Common errors and misconceptions

• Misconception: mRNA vaccines were invented during the COVID-19 pandemic. Correct: the key base-modification discovery was published in 2005, fifteen years before the pandemic.
• Misconception: mRNA vaccines insert genetic material into human DNA. Correct: the sources describe mRNA only as a temporary protein-making template in the cell cytoplasm, not as something that alters DNA.
• Misconception: only one scientist made this discovery. Correct: the prize was shared equally between Katalin Karikó and Drew Weissman for their joint work.
• Misconception: the Nobel Prize was for creating the COVID-19 vaccines themselves. Correct: the citation credits the underlying discovery of nucleoside base modifications that enabled those vaccines, not the vaccine products.
• Misconception: mRNA technology can only be used for infectious disease vaccines. Correct: the sources say it may also be used to deliver therapeutic proteins and to treat some cancer types in future.
• Misconception: all COVID-19 vaccines used this mRNA technology. Correct: the sources note that several other COVID-19 vaccines, based on different methods such as viral vectors, were also introduced.

Exam-style questions with model answers

Q1. Name the two laureates of the Nobel Prize in Physiology or Medicine 2023. [2 marks]

1. Katalin Karikó and Drew Weissman were jointly awarded the prize, each receiving one half of it, for their discoveries on nucleoside base modifications in mRNA.

Q2. State the official citation for the Nobel Prize in Physiology or Medicine 2023. [2 marks]

1. The citation was "for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19".

Q3. Explain the two problems that laboratory-made mRNA faced before Karikó and Weissman's discovery. [4 marks]

1. Laboratory-made mRNA, produced through in vitro transcription, triggered an unwanted inflammatory response when delivered to cells because dendritic cells recognised it as foreign.
2. It also produced disappointingly little of the target protein.
3. This low protein output happened because an immune-related enzyme limited protein-making when it detected the foreign RNA.
4. These two problems together meant that, despite decades of interest, no mRNA-based vaccine had been approved for human use before COVID-19.

Q4. Describe how base modifications solved the inflammation problem in mRNA. [4 marks]

1. Karikó and Weissman noticed that mammalian mRNA, whose bases are often chemically modified, did not trigger the same immune reaction as unmodified laboratory-made mRNA.
2. They produced several versions of mRNA, each with a different modified base, and delivered them to dendritic cells.
3. When certain modifications, including pseudouridine, were included, the inflammatory response was almost abolished.
4. This finding, published in 2005, also helped increase protein production from the mRNA.

Q5. Compare whole virus, subunit, vector and mRNA vaccine platforms as described in the sources. [5 marks]

1. Whole virus vaccines use a weakened or killed virus, such as those protecting against yellow fever, measles and polio.
2. Subunit vaccines use individual viral proteins, as with hepatitis B and human papillomavirus vaccines.
3. Vector vaccines use a harmless carrier virus to deliver a chosen viral gene, as in the Ebola vaccine.
4. mRNA vaccines deliver base-modified mRNA that instructs a person's own cells to make the viral protein, avoiding large-scale cell culture.
5. The two approved COVID-19 mRNA vaccines, built on Karikó and Weissman's discovery, reported around 95% protective effect and were approved in December 2020, faster than traditional methods would allow.

Q6. Discuss why the committee described this discovery as important beyond COVID-19. [6 marks]

1. The press release said mRNA vaccines can be designed and manufactured with impressive flexibility and speed because only the encoded protein sequence needs to be changed.
2. This means the same platform could, in principle, be adapted quickly against other infectious diseases, as was already being tested for Zika virus and MERS-CoV before the pandemic.
3. The two base-modified mRNA vaccines against COVID-19 were approved as early as December 2020, showing in practice how quickly the platform could be adapted once a new pathogen emerged.
4. The sources also mention that the technology may in future be used to deliver therapeutic proteins and to treat some types of cancer, though these were potential future uses rather than finished treatments.
5. The discovery showed how curiosity-driven basic research, carried out with no pandemic in view, became essential fifteen years later during a global health emergency.
6. More than 13 billion COVID-19 vaccine doses of various types were eventually given worldwide, and the committee said vaccines had saved millions of lives, underlining the scale of impact traced back to this basic discovery.

Key takeaways

• Katalin Karikó and Drew Weissman shared the Nobel Prize in Physiology or Medicine 2023 equally, for work on nucleoside base modifications in mRNA.
• Their 2005 discovery showed that chemically modifying mRNA bases almost eliminated an unwanted inflammatory immune response.
• The same modification also increased protein production from the delivered mRNA.
• This solved two major obstacles that had blocked mRNA vaccines for decades.
• Base-modified mRNA vaccines against SARS-CoV-2 were developed and approved in December 2020, reporting around 95% protective effect.
• More than 13 billion COVID-19 vaccine doses of all types were given globally following the pandemic.
• The committee highlighted the flexibility of mRNA technology for future vaccines, therapeutic proteins and some cancer treatments.
• The prize was announced on 2 October 2023 by the Nobel Assembly at Karolinska Institutet.

Test yourself

What official body awards the Nobel Prize in Physiology or Medicine?

The Nobel Assembly at Karolinska Institutet, a group of fifty professors, awards the prize, with its Nobel Committee evaluating nominations.

Which chemically modified base did Karikó and Weissman study that reduced inflammation?

Pseudouridine, a modified form of the RNA base uridine, was shown to reduce the unwanted inflammatory response when included in mRNA.

In what year was the laureates' key breakthrough paper published?

Their breakthrough finding on base-modified mRNA and reduced inflammation was published in 2005.

Name two vaccine types that existed before mRNA vaccines, according to the sources.

Whole virus vaccines, such as those against polio and measles, and subunit vaccines made from viral proteins, such as the hepatitis B vaccine.

What was each laureate's share of the 2023 prize?

Katalin Karikó and Drew Weissman each received one half of the prize, worth a total of 11,000,000 Swedish kronor.

What reported protective effect did the approved COVID-19 mRNA vaccines show?

The press release reported protective effects of around 95% for the two approved mRNA vaccines against COVID-19.