In many ways the world was cruel to Hungarian biochemist Katalin Karikó, until she saved it. By Rick Morton.
Part one: The true story of the Covid-19 vaccines
Katalin Karikó grew up behind the Iron Curtain, in Hungary, in a small town “in the middle of nowhere”, the daughter of a butcher and a bookkeeper, destined to change the world. It is expected she will win the next Nobel prize, but only a few years ago no one was interested in her work.
In telling the story of how scientists developed the vaccines currently freeing the world from Covid-19, it is easy to look back on the career of researchers such as Karikó and ascribe to it some sense of cosmic inevitability. Here is a woman who never received a single medical research grant for her work with DNA’s single-strand cousin, RNA; who lost repeated positions at institutions around the world and in the United States; who was threatened with deportation by a former supervisor for trying to get another job, which fell through on account of her potential “alien” status; and who was demoted at the age of 40 because she could not win any funding to support her dogged research for an idea that many, including her own colleagues, believed was far-fetched or impossible.
Karikó, now 66, is the co-inventor of the technology that led to the messenger RNA, or mRNA, vaccine platforms used by both Moderna and Pfizer-BioNTech, which have been used to inoculate hundreds of millions of people around the world. Billions of doses have been provided with more to come. She is now a senior vice-president at the German tech firm BioNTech on account of her expertise, but until relatively recently, Karikó was still defrosting her own lab freezers.
“When I was at University Pennsylvania at age 58 I still worked with my own hands. I did the samples, pick up the materials, sometimes cleaned and defrosted the freezer,” she said in an address to the Cambridge Union last month.
“At that point in life I never had one or two years ahead of me to know that I had salary. But that is a double-edged sword because if you have all of the money and tenure maybe you sit back and don’t work. So that little stress, maybe you need.
“Let’s say, when you are fired – it happened to me several times – then I was thinking about new opportunities. If you see he get promoted or she get promoted and more salary … do not do that. You cannot change that. Immediately you take away your attention from what you cannot change. Then you are lost.”
Karikó was never taught English as a child. It was not offered. But there was always the lab bench, there was always the science.
“Once a colleague introduced me and said, ‘Oh, meet Kati, she works for me.’ And I said, ‘No, no, I don’t work for you.’ I won’t be coming in Sunday, Saturday to work for friend. I am here because I want to understand.”
Karikó was not the only person working on a vaccine for Covid-19. Another was Oxford University Professor Sarah Gilbert, who was recognised with a damehood earlier this year for leading the team that produced the AstraZeneca vaccine. Her story traces back to the Ebola outbreak in West Africa, in 2013.
As with the space race, the reason a proto-vaccine for Ebola even existed at that time was because of fear. The US had begun developing one as part of a bio-defence program because, as Gilbert said while delivering the Rosalind Franklin Lecture in March, “this is such a scary virus and there have been concerns about it being used as a weapon”.
The candidate vaccine already in development, with which Gilbert and her colleagues aimed to make a viable product, used a viral vector platform built on an adenovirus that “usually circulates in chimpanzees rather than in humans”.
This was important, because the human body doesn’t make antibodies for this strain. As work ground on, the outbreak flared and then began to subside. While it was catastrophic, it was over before the vaccine had a chance to enter final efficacy trials.
There was, however, a second vaccine provided by another team whose results ended up proving it was incredibly effective. It also had to be stored at minus 70 degrees Celsius to be useful, a huge logistical challenge in Africa.
Gilbert’s work here laid the foundation for her ongoing vaccine studies. Importantly, she was now familiar with using a chimpanzee adenovirus (the ChAdOx acronym for the Covid-19 vaccine is also derived from this) in viral vector platforms. Second, Gilbert now understood that any lightning-quick vaccine development project would fail if the final stages were not agreed to in advance.
Between 2015 and 2020, Gilbert and her colleagues at Oxford’s Jenner Institute set about developing vaccines for each of the priority diseases listed by the World Health Organization, including the Nipah virus, Rift Valley fever, Zika, Middle East respiratory syndrome (MERS), Lassa fever and severe acute respiratory syndrome (SARS). There was also the mysterious Disease X, the great unknown pathogen that would come, sooner or later.
“With my team I had been planning for what the WHO called Disease X, which is the unknown virus that’s out there, the one that was at some point going to cause outbreaks, cause pandemics,” Gilbert said during her March lecture.
“Although to be honest, we were thinking more in terms of outbreaks rather than a pandemic with a new virus in our planning. And we’ve been thinking about how to make the very early parts of that development go really quickly so that we could very rapidly move into clinical development and then expand the clinical development until we had a vaccine that was licensed and ready to use around the world.”
On New Year’s Day 2020, just 24 hours after the WHO learnt of the outbreak of a viral pneumonia in China, Gilbert was reading early reports about the new disease. The Oxford team had just days to decide if this was the big one and whether they should push the vaccine development button.
“We’d had some plans that we wanted to work on. We hadn’t been able to put them into place. We haven’t been funded to do the work that we wanted to do. So we knew we had a technology that was suitable, but we hadn’t done all the optimisation to really cut out any unnecessary time in the early vaccine development,” Gilbert says.
“But then we had a few days to decide, are we doing this or not? Because what we did know was that if you’re going to go, you have to start straightaway, as soon as the sequence was available, and we were waiting for that.”
A week later, Gilbert had her sequence thanks to the record-setting efforts of Chinese scientists.
Her lab already had a MERS vaccine in early-stage clinical trials and producing promising signs. It was safe and triggered good antibody and T-cell responses. Coronaviruses share a common feature: the active spike protein on the viral surface.
If it was good enough for MERS, it was good enough for the brand new SARS-CoV-2. The Oxford University vaccine was designed just days after the virus sequence was made available and made it into its first human 104 days after the sequence.
For Katalin Karikó, the path to saving millions of lives, if not tens of millions, was more circuitous. Although RNA had been discovered many decades earlier, its subtype mRNA was only announced to the world in 1960, five years after Karikó was born.
This mRNA is like an instruction manual from which the ribosomes in cells can produce proteins. There are other systems involved, but for the sake of simplicity this is the process most fundamental to Karikó’s innovation.
The great conundrum for Karikó and other researchers was how to make the mRNA survive long enough in human cells to trigger the production of new proteins. For decades, they could not do so in any meaningful way.
Harvard scientists managed to produce biologically active mRNA in a lab in 1984 but development biologist Paul Krieg says the stuff had a reputation for “unbelievable instability” and the team did not apply for patents. By their own admission, they weren’t even thinking about using these developments for therapeutics or medical interventions.
In late 1987, a graduate student at the Salk Institute for Biological Studies in California, Robert Malone, performed an experiment in which human cells responded exquisitely to mRNA doused in droplets of fat. This, too, built on years of research in which lipids were used to achieve some stability of the genetic material.
But it was Karikó and her then colleague Drew Weissman at the University of Pennsylvania who, in 2005, published the biggest breakthrough of them all. It would solve another critical problem with the substance: the fact that certain types of synthetic mRNA triggered deadly immune responses, stripping mitochondria from cells.
In addition, by modifying naturally occurring nucleosides, the researchers were able to produce mRNA that acted faster in producing functioning proteins and, by its very nature, was incapable of being absorbed into the host genome. In short, they were able to make the passage of the mRNA into the human cell safe for the host.
Weissman and Karikó lodged patents for the discovery.
“Drew is a very calm person and he told me that calls were coming in and they would invite us to talk, but it didn’t happen,” Karikó says.
“But we were not sitting and waiting and watching the telephone. We are not celebratory people but we knew that it was good. Of course, never in our wildest dreams we thought that it would be a pandemic and millions and millions of people would be injected with nucleoside-modified RNA.”
In his book A Shot to Save the World, Gregory Zuckerman recounts a scene from Karikó’s early career in the US when she accepted a better-paying job at Johns Hopkins University but neglected to tell her adviser, Robert Suhadolnik. When he found out, he presented her with an ultimatum: work in his lab or go home.
Suhadolnik acted on the threat, telling immigration authorities she was now working illegally in the country. The Hungarian woman, working dutifully on $17,000 a year, lost both the new job and the one she had with Suhadolnik.
When asked recently if all this really happened, Karikó responded with extraordinary grace. “Yes, but more importantly I was always grateful to him sending me the IAP66 form in 1985, for the opportunity he gave me to work in his lab,” she said.
“I have no hard feeling and when I gave a lecture there couple of years later, I thanked him for the science I learned from him.”
All this woman ever wanted was to learn. Not content to be working just on coronavirus, Karikó says her mRNA technology is already advanced in both prevention and therapy with several clinical and preclinical trials under way for diseases such as cytomegalovirus (CMV) and the chikungunya virus.
AstraZeneca, meanwhile, has started injecting mRNA therapeutics into heart tissue during bypass surgery, which increases blood flow in the tissue of the heart. Similarly, the technology can be used for necrotic wound healing in diabetic patients. There is also a clinical trial, started before the pandemic, where mRNA is being used to target melanoma.
In the early 2000s, David Scales joined a “tumble-down laboratory in a dusty corner” of an old medical building at Penn University where an already demoted Karikó was working on HIV replication in T-cells. Scales studied under her and saw the best of science mangled by the worst of scientific institutions where “tremendous financial pressure” is placed on “eager young medical researchers”.
Writing for a Boston radio website in February, he said: “Karikó lived this nightmare, but stuck to her passions. She was too committed to the promise of mRNA to switch to other, perhaps more easily fundable, projects. Eventually, the university stopped supporting her.”
Karikó did not stop, however. Science is built from failure as much as it is from success. The team at the University of Queensland have reflected on this, after their “molecular clamp” vaccine platform was halted at the trials phase after producing false positives for HIV.
When Scales received his Pfizer vaccine earlier this year, he described its development as “one of the most spectacular victories in the history of science”.
Considering his early mentor and the extraordinary breakthrough she had made, one that has forever changed the world, he thought, “You were right, Kati. You were right.”
Read part two of this series: How Covid-19 began an ‘mRNA revolution’
This article was first published in the print edition of The Saturday Paper on Dec 11, 2021 as "Part one: The true story of the Covid-19 vaccines".
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