How mRNA went from a scientific backwater to a pandemic crusher

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 In 1995, Katalin Karikó was at her lowest ebb. A biochemist at the University of Pennsylvania , 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. By the mid 1990s, Karikó’s bosses at UPenn had run out of patience.

It transpired that mRNA was the answer. 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. «So mRNA was always more interesting to me». 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.

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. 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. This was a serious problem, but one Karikó was determined to solve. 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. While undergoing surgery, Karikó assessed her options. 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. While Karikó’s academic status at UPenn remained lowly, Weissman had the funding to finance her experiments, and the two began a partnership. In the early 2000s, Karikó happened across a study which showed that one of these letters, Uridine, could trigger certain immune receptors. 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. » 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 , 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. In April, Moderna received $483 million 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. «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.

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Source: David Cox | Wired UK