The Persistence and Determination of Dr Katalin Karikó

For decades, Dr. Katalin Karikó’s work into mRNA therapeutics was overlooked by her colleagues. Now it’s at the heart of the two leading coronavirus vaccines.

Dr. Katalin Karikó

It was 1961 when scientists first discovered mRNA was how DNA got translated into the proteins that make up the body. It was the missing link, the way genes get expressed in everyday life.

Over the next couple decades, researchers began to explore whether they could use mRNA to teach the body to make its own medicine. But with few advancements, the topic fell out of fashion.

Except for one Hungarian biochemist.

Every cell in the body contains a copy of the genome — the vast DNA information repository often referred to as the blueprint of life. While the phrase may be over simplistic, it captures an important truth about what the genome is: a genetic instruction manual for the synthesis of proteins whose myriad functions provide the foundation of life.

Almost every biological event and process in the body depends on proteins, and human disease is often the result of a breakdown in the proper functioning of one or more proteins. In between DNA and protein, however, is a third class of biomolecules: messenger RNA (mRNA). These ancient molecules effectively translate the information stored in the DNA of the genome to temporary templates that cells use to manufacture specific proteins.

The discovery of mRNA was announced amidst a clamour of scientific excitement in 1961. For more than a decade, researchers in the US and Europe had been attempting to unravel exactly how DNA is involved in the creation of proteins – the long strings of amino acids that are vital to the growth and functioning of all life forms.

It transpired that mRNA was the answer. mRNA may seem at first glance to have an unglamorous intermediary role, but its functions are central to multicellular life, encoding the more than 20,000 proteins that keep the body working. These molecules act like digital tape recorders, repeatedly copying instructions from DNA in the cell nucleus, and carrying them to protein-making structures called ribosomes. Without this key role, DNA would be nothing but a useless string of chemicals, and the proteins it codes for would never get made and we wouldn’t exist! Some have dubbed mRNA the ‘software of life.’

On May 13, 1961, two articles appeared in Nature, authored by a total of nine people, including Sydney Brenner, François Jacob and Jim Watson, announcing the isolation of messenger RNA (mRNA). In the same month, François Jacob and Jacques Monod published a review in Journal of Molecular Biology in which they put mRNA into a theoretical context, arguing for its role in gene regulation. Aside from the technical prowess involved, these papers were feats of the imagination, for they represented an entirely new way of thinking about gene function. Although mRNA is of decisive importance to our understanding of gene function, no Nobel Prize was awarded for its discovery. The large number of people involved, the complex nature of the results, and the tortuous path that was taken to the discovery, all show that simple claims of priority may not reflect how science works.

At the time, the nine scientists credited with discovering mRNA were purely interested in solving a basic biological mystery, but by the 1970s the scientific world had begun to wonder if it could exploit this cellular messaging system to turn our bodies into medicine-making factories.

Artificial mRNA, designed and created in a petri dish and then delivered to the cells of sick patients through tiny packages called nanoparticles, offered a way of instructing the body to heal itself. Research groups around the world began looking into whether mRNA could be used to create the vaccines of the future by delivering messages to cells, teaching them to create specific antibodies to fight off a viral infection. Others started investigating whether mRNA could help the immune system recognise and destroy cancerous tissue.

Katalin Karikó was first exposed to these ideas as an undergraduate student in 1976, during a lecture at the University of Szeged in her native Hungary. Intrigued, she began a PhD, studying how mRNA might be used to target viruses. While the concept of gene therapy was also beginning to take off at the same time, capturing the imagination of many scientists, she felt mRNA had the potential to help many more people.

“I always thought that the majority of patients don’t actually need new genes, they need something temporary like a drug, to cure their aches and pains,” she said. “So mRNA was always more interesting to me.”

At the time, the technology required to make such grand ambitions a reality did not yet exist. While scientists knew how to isolate mRNA from cells, creating artificial forms was not possible. But in 1984, the American biochemist Kary Mullis invented polymerase chain reaction (PCR), a method of amplifying very small amounts of DNA so it can be studied in detail. By 1989, when other researchers had found a way to utilise PCR to generate mRNA from scratch, by amplifying DNA strands and using an enzyme called RNA polymerase to create mRNA molecules from these strands, Karikó was in the US.

Karikó started studying gene therapy at the University of Szeged in Hungary. She finished her PhD in 1982, with an unrelenting passion for mRNA advancements. But communist Hungary’s laboratories lacked resources, and in 1985 the university sacked her. With an mRNA boom taking place on the other side of the Atlantic, Karikó decided it was time to leave Hungary and head for the US. So in 1985, she accepted a job at Temple University and moved to Philadelphia along with her husband, two year old daughter, and a teddy bear with $US1250 sewn into it – the proceeds from the sale of their car on the black market.

It did not take long for the American dream to sour. After four years, she was forced to leave Temple University for neighbouring University of Pennsylvania after a dispute with her boss, who then attempted to have her deported. There she began working on mRNA therapies which could be used to improve blood vessel transplants, by producing proteins to keep the newly transplanted vessels alive.

However, by the early to mid 1990s, some of the early excitement surrounding mRNA was beginning to fade. While scientists had cracked the problem of how to create their own mRNA, a new hurdle had emerged. When they injected it into animals it induced such a severe inflammatory response from the immune system that they died immediately. Any thoughts of human trials were impossible.

This was a serious problem, but one Karikó was determined to solve. She recalls spending one Christmas and New Year’s Eve conducting experiments and writing grant applications. But numerous grant applications were rejected, and an attempt to raise funding from venture capitalists in New York to form a spin-off company had proved to be a fruitless endeavour. Many other scientists were turning away from the field, and her bosses at University of Pennsylvania felt mRNA had shown itself to be impractical and she was wasting her time. They issued an ultimatum, if she wanted to continue working with mRNA she would lose her prestigious faculty position, and face a substantial pay cut.

”It was particularly horrible as that same week, I had just been diagnosed with cancer,” said Karikó. “I was facing two operations, and my husband, who had gone back to Hungary to pick up his green card, had got stranded there because of some visa issue, meaning he couldn’t come back for six months. I was really struggling, and then they told me this.”

Today the university is touting its contribution to the COVID vaccine in news releases and TV ads, of course, but it had failed to recognise a pioneer working right under their noses and of course is totally quiet on its horrible treatment of Karikó.

While undergoing surgery, Karikó assessed her options. She decided to stay, accept the humiliation of being demoted, and continue to doggedly pursue the problem. This led to a chance meeting which would both change the course of her career, and that of science.

In 1997, Karikó met Dr. Drew Weissman who had just joined the university, and they realized their shared interests and started working together. It took seven years, but the pair eventually figured out how to make mRNA therapy work. In 2005, Karikó and Weissman published their groundbreaking study – Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA.

Karikó and Weissman realised that the key to creating a form of mRNA which could be administered safely, was to identify which of the underlying nucleosides – the letters of RNA’s genetic code – were provoking the immune system and replace them with something else. In the early 2000s, Karikó happened across a study which showed that one of these letters, Uridine, could trigger certain immune receptors. It was the crucial piece of information she had been searching for.

In 2005, Karikó and Weissman published their study announcing a specifically modified form of mRNA, which replaced Uridine with an analog – a molecule which looked the same, but did not induce an immune response. It was a clever biological trick, and one which worked. When mice were injected with this modified mRNA, they lived. They realised this could be used in vaccines and therapies, so they published a paper, filed a patent (the patent is held by the University of Pennsylvania, as it’s standard for researchers’ patents to be held by the institutions where they work), established a company, and then found there was no interest. Nobody called them.

Unbeknown to them, however, some scientists were paying attention. Derrick Rossi, then a postdoctoral researcher at Stanford University, read Karikó and Weissman’s paper and was immediately intrigued. In 2010, Rossi co-founded a biotech company called Moderna, with a group of Harvard and MIT professors, with the specific aim of using modified mRNA to create vaccines and therapeutics. A decade on, Moderna is set to supply billions of doses of mRNA Covid-19 vaccine around the globe.

But it was not novel infectious disease vaccines which got the world interested in mRNA again. Around the same time Rossi was establishing Moderna, Karikó and Weissman were also finally managing to commercialise their finding, licensing their technology to a small German company called BioNTech, after five years of trying and failing.

Both Moderna and BioNTech – which had been founded by husband and wife team Dr. Uğur Şahin and Dr. Özlem Türeci – had their eye on the lucrative fields of cancer immunotherapy, cardiovascular and metabolic diseases. Now that Karikó and Weissman’s discovery made it possible to safely administer mRNA to patients, some of the original goals for mRNA back in the 1970s, had become viable possibilities again.

Karikó stayed on at Penn for another eight years, but was never reinstated her to the tenure track position she held before she was demoted. In 2013, she gave up on the Ivy League institution and took a senior VP role at BioNTech, the company that partnered with Pfizer to make the first COVID vaccine.

“They told me that they’d had a meeting and concluded that I was not of faculty quality,” Karikó said. ”When I told them I was leaving, they laughed at me and said, ‘BioNTech doesn’t even have a website.’”

Who’s laughing now? Now, BioNTech has a website 🙂 and is a household name. Along with Moderna, it is set to supply billions of doses of mRNA Covid-19 vaccine around the globe by the end of 2021.

I suppose the university is unhappy for being outed for bad behaviour. Here’s a thought, don’t engage in bad behaviour and then nobody will call you to please explain! While Karikó’s academic status at the university remained lowly, Weissman had the funding to finance her experiments. Her salary was lower than the technician who worked next to her, but she concentrated on the positives, not the roadblocks she had to face. Karikó was also on the receiving end of sexism, with colleagues asking her the name of her supervisor when she was running her own lab.

“We are grateful for Dr. Karikó’s important contributions both during her time at Penn, where she continues to hold an appointment as an adjunct associate professor.” Oohh… It almost sounds sincere… It might sound better without the obvious putdown in the statement. The school’s promo video about mRNA technology focuses on Weissman, mentioning Karikó only in passing.

In 2017, Moderna began developing a potential Zika virus vaccine, while in 2018 BioNTech entered into a partnership with Pfizer to develop mRNA vaccines for influenza, although the large scale funding which drives vaccine projects was still nowhere to be seen.

That all changed in 2020. With the Covid-19 pandemic requiring vaccine development on an unprecedented scale, mRNA vaccine approaches held a clear advantage over the more traditional but time consuming method of using a dead or inactivated form of the virus to create an immune response. And funding poured in.

Karikó has been at the helm of BioNTech’s Covid-19 vaccine development. And after so many years of adversity, and struggling to convince people that her research was worthwhile, she is still trying to comprehend the fact that her breakthrough in mRNA technology could now change the lives of billions around the world, and help end the global pandemic.

Katalin Karikó and Drew Weissman are now favourites to win the Nobel Prize for Medicine and for Chemistry and… Just award them all I say!

Categories: Beary Scientist

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