Katalin Karikó: The Demoted Scientist Who Won the Nobel

In 1985 Hungary had a Communist government. The government strictly limited the amount of money that citizens could take abroad. Katalin Karikó has said the family could leave with only $100. Karikó and her husband, Béla Francia, sold their car on the black market. Karikó hid the money inside the teddy bear of their daughter, Susan, so that border officials would not find it. Accounts give the sum as about $1,200. The family travelled to the United States on one-way tickets. In Philadelphia, Karikó began work at Temple University.

At Temple University, Katalin Karikó worked as a postdoctoral researcher in the laboratory of Robert Suhadolnik. In 1988 Karikó accepted a job offer elsewhere, which upset Suhadolnik, Karikó later said. The journalist Gregory Zuckerman described the dispute in his 2021 book, “A Shot to Save the World”. CNBC reported that, according to Zuckerman, Suhadolnik had told immigration officials that Karikó was living in the country illegally. Karikó hired a lawyer to fight deportation, and because of the legal fight, the new employer withdrew its offer. Wired reported, from Karikó’s own account, that her boss tried to have her deported. Karikó then moved to the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

The medical school of the University of Pennsylvania (Penn) is now called the Perelman School of Medicine. At US medical schools, researchers outside the tenure system usually pay for their research with grants. Researchers without grants risk the loss of their laboratory space. Katalin Karikó’s post at Penn carried no tenure. The cardiologist Elliot Barnathan paid Karikó’s salary from his own grants, so the job depended on that grant money. Karikó and Barnathan tried to use mRNA to make cells produce new proteins. At the time, many scientists did not believe that mRNA could become a medicine.

Around 1990, mRNA was a difficult molecule to use as a medicine. Lab-made mRNA was unstable and hard to deliver into cells. Lab-made mRNA also caused strong inflammatory reactions. As a result, scientific enthusiasm for mRNA medicines was limited. Funders rejected many of Katalin Karikó’s grant applications. The Nobel Committee later noted Karikó’s difficulty in convincing funders that the project was important. At Penn, the lack of grants weakened Karikó’s position, because her salary and laboratory space depended on outside money.

At US universities, research posts outside the tenure system depend on grants. By 1995 Katalin Karikó had no grant money for her work. Penn gave Karikó a choice: leave the university or accept a demotion. Around the same time, Karikó was diagnosed with cancer. A visa problem also kept her husband, Béla Francia, in Hungary. Karikó accepted the demotion. The demotion ended Karikó’s chance of a full professorship. The decision also allowed Karikó to continue her mRNA research.

At Penn, a researcher without grants depended on senior scientists for laboratory space. Katalin Karikó had worked in the laboratory of the cardiologist Elliot Barnathan. Barnathan then left Penn for a biotechnology company. David Langer, a neurosurgery resident, had worked with Karikó in Barnathan’s laboratory. Langer persuaded the chairman of neurosurgery to take Karikó into the department. The department gave Karikó a laboratory and a salary. Karikó and Langer then tried to use mRNA to help patients after brain surgery. The idea was to make blood vessels produce nitric oxide, a substance that widens vessels.

Drew Weissman is a physician and immunologist. In 1997 Weissman moved to Penn from the US National Institutes of Health, where he had worked in the laboratory of Anthony Fauci. Weissman wanted to develop a vaccine against HIV. In the 1990s, scientists still read most journals on paper. Researchers read new articles by copying them from printed journals in the library or department. Katalin Karikó met Weissman at a department photocopier at Penn. Their first joint project used mRNA to carry part of HIV into immune cells.

Dendritic cells are immune cells that watch for invaders and start immune responses. They are important for vaccines. Katalin Karikó and Drew Weissman found that dendritic cells recognised lab-made mRNA as foreign. The cells then released inflammatory signalling molecules. Mammalian RNA from inside cells did not cause the same reaction. Karikó tried to change other structural parts of the mRNA: the cap at the start of the molecule and the tail at the end. These changes did not stop the inflammation. Unwanted inflammation was one of the main hurdles for mRNA medicines, the Nobel Committee later wrote.

RNA is built from four chemical letters, called nucleosides. In cells, some of these letters are chemically modified. RNA from mammal cells contains many modified letters, while lab-made mRNA contains none. Transfer RNA, or tRNA, helps cells build proteins and has many such modified letters. Katalin Karikó and Drew Weissman made mRNA with modified letters, including pseudouridine, a changed form of the letter uridine. The modified mRNA caused almost no inflammation. Karikó and Weissman also identified two immune sensors, Toll-like receptors 7 and 8, that reacted to the unmodified RNA.

Katalin Karikó and Drew Weissman sent their paper to the journal Nature first. Nature returned the paper without sending it for review. Karikó later recalled that the reply described the work as “incremental”. Karikó has said she had to find the word in a dictionary. Weissman has said that Science and Cell also refused to review the paper. The paper appeared in the journal Immunity in August 2005. The title included the phrase “the impact of nucleoside modification”.

After the Immunity paper appeared, Drew Weissman told Katalin Karikó that the phone would ring with invitations to give talks. Nothing happened, Karikó and Weissman have said. Weissman has said that the two scientists talked to drug companies and venture capitalists, but no one cared. The 2005 paper showed that modified mRNA caused much less inflammation in immune cells. Karikó and Weissman continued to work on the method. The two scientists worked to remove impurities from their mRNA.

A university usually owns the patents on discoveries made by its staff. Penn owned the patents on the modified-mRNA work of Katalin Karikó and Drew Weissman. In 2006 Karikó and Weissman founded a company, RNARx, to develop modified mRNA as a medicine. RNARx applied for a grant from the Small Business Technology Transfer programme of the US National Institutes of Health. The programme funds small companies that do research in partnership with a university. RNARx proposed to use modified mRNA to make erythropoietin in animals. Erythropoietin is a hormone that increases the number of red blood cells.

A useful mRNA medicine must make the body produce enough protein. Unmodified lab-made mRNA produced only small amounts. In 2008 Katalin Karikó, Drew Weissman and colleagues published a study in Molecular Therapy. The study showed that mRNA containing pseudouridine produced much more protein than ordinary mRNA. The researchers tested the mRNA in cells and in mice. The modified mRNA was also more stable and caused less immune activation. The Nobel Committee later named this increase in protein production as a key step towards mRNA vaccines.

Susan Francia was born in Hungary. Francia came to the United States with her parents at the age of two. Francia’s mother is the biochemist Katalin Karikó. Francia studied at the University of Pennsylvania and rowed for the university team. The women’s eight race at the 2008 Olympic Games took place on a rowing course in Shunyi, near Beijing. At the Games, Francia rowed in the United States women’s eight. The crew won the final and the gold medal.

A licence gives a company the right to use a patented invention, usually in return for fees and royalties. Penn owned the modified-mRNA patents, so RNARx needed a licence from Penn. Katalin Karikó and Drew Weissman did not obtain the licence for their company, according to both scientists and the journalist Gregory Zuckerman. Penn gave an exclusive licence to mRNA RiboTherapeutics, a company in Madison, Wisconsin. mRNA RiboTherapeutics then gave a further licence, called a sublicence, to an affiliated company, Cellscript.

Derrick Rossi was a stem-cell biologist at Harvard University. Rossi wanted to change adult cells into stem cells by using mRNA. Ordinary mRNA caused an antiviral response in the cells. Rossi’s laboratory used modified mRNA, based on the work of Katalin Karikó and Drew Weissman, to avoid this response. In 2010 Rossi, Kenneth Chien and Robert Langer founded a company to develop the method, with support from Flagship Ventures. The company was named Moderna. The name is a play on the words “modified” and “RNA”.

On 21 March 2013, AstraZeneca agreed to pay Moderna $240 million upfront to develop mRNA medicines. Moderna could earn another $180 million for three technical milestones. Katalin Karikó has said the deal was one reason she left academic research. Penn refused to restore Karikó to her former faculty position. Karikó has said she was forced to retire from Penn. Karikó kept an adjunct title at Penn and joined BioNTech in Mainz, Germany. BioNTech then worked mainly on cancer treatments. Karikó started as a vice president at BioNTech.

In February 2017 the journal Nature published a Zika vaccine study by Norbert Pardi, Drew Weissman and colleagues. The study reported that a single low dose of modified mRNA, packed in fat nanoparticles, protected mice and monkeys against the Zika virus. Katalin Karikó introduced Weissman to Uğur Şahin, the chief executive of BioNTech, the two scientists have said. BioNTech then began to fund Weissman’s laboratory at Penn, and in 2018 BioNTech and Penn signed a formal research agreement.

A sublicence passes on rights that a company itself holds under a licence. Cellscript sublicensed the modified-mRNA patents to Moderna with effect from 26 June 2017. Cellscript and mRNA RiboTherapeutics granted rights to BioNTech with effect from 14 July 2017. Both sublicences were non-exclusive, so other companies could also obtain rights. The agreements became public in filings with the US Securities and Exchange Commission. The sublicences gave rights that both companies used three years later in their COVID vaccines.

On 11 January 2020, the virologist Edward Holmes posted the genome of the new coronavirus on the website Virological. Holmes, a virologist at the University of Sydney, posted it for a consortium led by Zhang Yongzhen of Fudan University in Shanghai. With the genome, vaccine makers could design mRNA that coded for a viral protein. The consortium also deposited the sequence in GenBank, a public genetic database.

On 11 March 2020 the US government barred entry to most foreign travellers who had been in Europe’s Schengen area. The restriction took effect at 11:59 p.m. Eastern time on 13 March. The ban did not apply to US citizens, permanent residents or their close family members. On 13 March President Donald Trump declared a national emergency over COVID-19. Katalin Karikó had worked in Mainz for years while her family lived in Pennsylvania. Karikó has said she returned to the United States on 13 March, her husband’s birthday.

BioNTech was a company based in Mainz, Germany. Pfizer was a large drug company based in New York. Uğur Şahin, a co-founder of BioNTech, was its chief executive. BioNTech had started its own COVID vaccine programme, Project Lightspeed, in late January. The two companies had worked together on mRNA flu vaccines since 2018. On 17 March 2020, the companies signed a letter of intent, a first written agreement to work together on the vaccine, code-named BNT162. Work began at once, in the United States and Germany. The financial terms were still to be agreed.

Pfizer and BioNTech tested the vaccine against a placebo in a large phase 3 trial. The trial had enrolled about 43,500 participants. Katalin Karikó has said that Uğur Şahin, the chief executive of BioNTech, phoned her with the first results on Sunday, 8 November 2020. The vaccine showed more than 90% efficacy against COVID-19 in the first analysis, which the companies announced the next day. Karikó celebrated by eating Goobers, chocolate-covered peanuts.

The Medicines and Healthcare products Regulatory Agency, or MHRA, regulates medicines in the United Kingdom. The MHRA reviewed the trial data in stages, as the data arrived. The government asked the MHRA to assess the vaccine under Regulation 174 of the Human Medicines Regulations. That rule allows the temporary supply of a medicine in response to a public health need. The vaccine had to be stored at very cold temperatures. The UK government described the country as the first in the western world to authorise a COVID vaccine. Pfizer and BioNTech called the decision the first authorisation in the world.

Margaret Keenan received the injection at 6:31 a.m. at University Hospital, Coventry. The matron May Parsons gave the injection. Keenan was 90 and had her 91st birthday the following week. The day marked the start of the UK’s mass vaccination programme. The Pfizer-BioNTech vaccine does not use pseudouridine itself. It uses a related modified letter, N1-methylpseudouridine, which later studies found worked even better. Researchers describe this approach as building directly on the work of Katalin Karikó and Drew Weissman.

Katalin Karikó and Drew Weissman were the two scientists behind modified mRNA. On Friday, 18 December 2020, the two scientists received their first doses of the Pfizer-BioNTech vaccine together at Penn. Penn Medicine published the news on 23 December. Penn also released footage and photos of the two scientists receiving their injections. At that time Karikó held an adjunct post at Penn and was a senior vice president at BioNTech. Weissman was a professor of infectious diseases at Penn’s medical school. In her 2023 memoir, Karikó recalled a roar of cheers in the hallway.

The Nobel Assembly at Karolinska Institutet in Stockholm awards the Nobel Prize in Physiology or Medicine. The call reached the home of Katalin Karikó, near Philadelphia, before 4 a.m. local time. The caller was Thomas Perlmann, the Assembly’s secretary. Karikó’s husband, Béla Francia, answered the phone and passed it to Karikó. The Nobel Committee could not reach Drew Weissman, so Karikó gave Perlmann Weissman’s number. Karikó and Weissman then waited for the public announcement from Stockholm. The prize recognised discoveries about changes to the chemical letters of mRNA. Those changes made effective mRNA vaccines against COVID-19 possible.

On 10 December 2023, King Carl XVI Gustaf of Sweden presented the Nobel Prizes at the Stockholm Concert Hall. Gunilla Karlsson Hedestam, chair of the Nobel Committee for Physiology or Medicine, introduced Katalin Karikó and Drew Weissman. Karikó and Weissman then received their prizes from the King. The World Health Organization reported that more than 13 billion COVID-19 vaccine doses had been given worldwide by June 2023. Those doses included mRNA vaccines and vaccines of other types.