How did mRNA based vaccine come from?

CrisisInvesting

In 1995, Katalin Karikó was at her lowest ebb. A biochemist at the University of Pennsylvania (UPenn), Karikó had dedicated much of the previous two decades to finding a way to turn one of the most fundamental building blocks of life, mRNA, into a whole new category of therapeutics.

More often than not, Karikó found herself hitting dead ends. 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. ”They initially promised to give us money, but then they never returned my phone calls,” she says.

By the mid 1990s, Karikó’s bosses at UPenn had run out of patience. Frustrated with the lack of funding she was generating for her research, they offered the scientist a bleak choice: leave or be demoted. It was a demeaning prospect for someone who had once been on the path to a full professorship. For Karikó’s dreams of using mRNA to create new vaccines and drugs for many chronic illnesses, it seemed to be the end of the road.

Thirty four years earlier, the discovery of mRNA had been announced amidst a clamour of scientific excitement in the summer of 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.

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It transpired that mRNA was the answer. 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 so some have dubbed mRNA the ‘software of life.’

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.

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.”

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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, 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. “For scientists working on mRNA, this was very empowering,” said Karikó. “Suddenly we felt like we could do anything.”

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 ￡900 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 UPenn 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 many other scientists were turning away from the field, and her bosses at UPenn 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.

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”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.”

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, Drew Weissman, a respected immunologist, moved to UPenn. This was long before the days where scientific publications were available online, and so the only way for scientists to peruse the latest research was to photocopy it from journals. “I found myself fighting over a photocopy machine in the department with this scientist called Katalin Karikó,” he remembered. ”So we started talking, and comparing what each other did.”

While Karikó’s academic status at UPenn remained lowly, Weissman had the funding to finance her experiments, and the two began a partnership. “This gave me optimism, and kept me going,” she said. “My salary was lower than the technician who worked next to me, but Drew was supportive and that’s what I concentrated on, not the roadblocks I’d had to face.”

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.

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In 2005, Karikó and Weissman published a 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. “I just remember Drew saying, ’Oh my god, it’s not immunogenic,’” said Karikó. “We realised at that moment that this would be very important, and it could be used in vaccines and therapies. So we published a paper, filed a patent, established a company, and then found there was no interest. Nobody invited us anywhere to talk about it, nothing.”

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 now one of the leaders in the Covid-19 vaccine race and valued at approximately $35 billion (￡26b), after reporting that its mRNA based vaccine showed 94 per cent efficacy in a Phase III clinical trial.

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 a Turkish born entrepreneur called Ugur Sahin - 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.

Vaccines were also on the horizon. 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.

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That has 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. In April, Moderna received $483 million (￡360m) from the US Biomedical Advanced Research and Development Authority to fasttrack its Covid-19 vaccine program.

Karikó has been at the helm of BioNTech’s Covid-19 vaccine development. In 2013, she accepted an offer to become Senior Vice President at BioNTech after UPenn refused to reinstate her to the faculty position she had been demoted from in 1995. “They told me that they’d had a meeting and concluded that I was not of faculty quality,” she said. ”When I told them I was leaving, they laughed at me and said, ‘BioNTech doesn’t even have a website.’”

Now, BioNTech is a household name, following reports last month that the mRNA Covid-19 vaccine it has co-developed with Pfizer works with more than 95 per cent efficacy. Along with Moderna, it is set to supply billions of doses around the globe by the end of 2021.

For Karikó, seeing the results of BioNTech’s Phase III trial, simply brought a sense of quiet satisfaction. “I didn’t jump or scream,” she said. “I expected that it would be very effective.”

But 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.

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“I always wanted to help people, to try and get something into the clinic,” she said. “That was the motivation for me, and I was always optimistic. But to help that many people, I never imagined that. It makes me very happy to know that I’ve played a part in this success story.”

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