The molecule behind the Pfizer and Moderna jabs has turned the Covid tide. Can it revolutionise medicine?
Not for the first time, Katalin Kariko was trying to convince a sceptic to take her scientific discoveries seriously. It was 2004, and she had spent about 15 years investigating messenger RNA, the genetic material that acts as a kind of courier in the human body, transporting recipes from our DNA to the part of the cell that produces proteins.
After countless false starts and wrong turns, she had made a breakthrough and wanted to file a patent. But to do so she had to win over an intellectual property officer at the University of Pennsylvania, where she then worked as a researcher. Their meeting was going badly. "He was not very enthusiastic, he kept on asking, 'What's it good for?'" recalls Kariko. "I was just so disappointed that he wasn't getting it."
As she prepared to admit defeat, she noticed that the IP officer was going bald. "I said, 'You know what? mRNA would be good for growing hair.' All of a sudden, he perked up. 'Really?' he asked. And I said, 'Yes, it could be,' and he was very enthusiastic." By the end of the meeting, he had agreed to file the patent.
At the time, it was a rare victory for Kariko, whose research on modified mRNA went on to pave the way for the coronavirus vaccines that have been developed at lightning speed by BioNTech/Pfizer and Moderna.
Now lauded as one of the luminaries whose work allowed the world to push back the tide of the pandemic, for decades her research was dismissed as a sideshow by most of her scientific peers. On campus, she became known as the "mRNA hustler" for her tendency to push her molecules on to other scientists, most of whom just "put them in the freezer and forgot about them".
Kariko's struggle to convince the doubtful IP officer is just one of several near misses that might have stopped the mRNA vaccines from ever being developed. Many other scientists experienced frustrating stumbles over the decades, while few private investors, vital to commercialising new technologies, were keen to back a new vaccine platform.
Now the pendulum has swung the other way. Though mRNA had been tested relatively little on humans before the pandemic, the vaccines that use its technology work extremely well — with efficacy rates of more than 90 per cent, considerably higher than rival inoculations.
They also appear, so far, to be safer than other vaccines; they have not been connected with the rare but serious blood clotting attributed to the adenovirus jabs made by Oxford/AstraZeneca and Johnson & Johnson. And those early investors who did risk their money have been rewarded to the tune of billions.
Supporters of mRNA claim that Covid-19 vaccines are just the start. Now that the technology is proven, they say it can be deployed to tackle a multitude of illnesses, from cancer and cystic fibrosis to HIV and heart defects. Yet a sizeable group of scientific specialists think that it will be decades before the technology is fit for purpose — and that the risks of outright failure remain high. Despite its role against Covid-19, is mRNA a scientific step change, or a spectacular one-hit wonder?
The existence of mRNA was first suggested in 1961 by two French scientists, Jacques Monod and François Jacob. Their hypothesis was prompted by the discovery a decade earlier of DNA, which contains our genetic code, spewing out signals that direct the body to produce the proteins we need to function healthily.
While groundbreaking, this discovery had resulted in a fresh conundrum. DNA lives tightly wound up in the nucleus, but proteins are made in the cytoplasm, a totally distinct cellular compartment. Monod and Jacob posited there had to be an intermediate molecule that somehow transmitted the information to the body's protein-making factory — the "messenger" that is the "m" in mRNA.
Their hypothesis should have been transformative. A long list of human illnesses can be accounted for by mutated DNA, including haemophilia, Parkinson's and possibly Alzheimer's. If scientists could interrupt the process of carrying faulty messages by inserting corrected copies of mRNA into the body, they could stop related diseases. A man-made biological courier would be able to intercept the incorrect set of genetic instructions and deliver the right copy instead. Yet, far from upending medical science, the discovery of mRNA led to a near silence that lasted for more than 40 years.
Kariko first started working on RNA molecules in the 1980s at the Szeged Biological Research Centre in her native Hungary. But in what was to become a constant refrain, she ran out of funding to pursue her work and started scouting around for a new academic institution to support her. By her own admission, she is a terrible salesperson. When explaining her work, her mind goes a million miles a minute. Most people cannot keep up.
In 1985, she secured a job at Temple University in Pennsylvania — but leaving Hungary, then still behind the Iron Curtain, was not straightforward. Currency controls imposed by the communist government made it effectively impossible to swap forints for dollars. So she and her husband sold their second-hand Lada car for $1,000, arranged an illegal currency swap with some foreign students, and flew to Philadelphia. "I wrapped the money up, inserted it into my two-year-old daughter's teddy bear and sewed it back up," says Kariko.
She embarked on an academic career in the US that was marked by insecurity. Persistently on the brink of running out of funding, she recalls: "I was always at the mercy of somebody." But Kariko never lost faith in the potential of mRNA as a molecule that might one day be turned into a human therapeutic — a drug or a vaccine that could save lives.
Her lab at the University of Pennsylvania, where she moved in 1989, was opposite a medical ward and its occupants preyed on her mind. "I told my colleague, we had to take our science to the patients. I pointed through the window — we could see them — and I said: 'We have to take it there.'"
In 1997, Kariko started working with Drew Weissman, a fellow academic at the university who was studying dendritic cells, which play a critical role in the body's immune system. The pair met while taking turns on a microfiche machine they used for reading scientific papers. "Kati and I used to fight over the machine," says Weissman. "We kept talking and decided to try adding her mRNA to my cells. We were very surprised by the results."
When he added the mRNA to his cells, Weissman found they elicited an inflammatory immune response, recognising the material as foreign and mounting an angry defence. This was perplexing because the human body is teeming with naturally produced mRNA; it was also bad news for Kariko, because it suggested it might be impossible to turn her molecules into a therapy for human ailments. The pair had alighted on a problem that helps explain why the field of mRNA research was a scientific backwater for decades.
"My guess is that people tried it and it just failed," says Weissman. "It was too inflammatory, too difficult to work with, and they just gave up." Yet he and Kariko kept going. From the outside, the pair made an unlikely duo. "I am the enthusiastic, noisy one, and he's the quiet, thinking one," says Kariko. "But we have different knowledge, and we educated each other."
Despite their contrasts, they settled into a working rhythm that was helped by their night-owlish tendencies. "In the middle of the night, three o'clock, I'd send him something and he'd instantly respond," recounts Kariko. "You felt that the other person was there, shoulder to shoulder."
In 2005, after working together for eight years, the pair made a major breakthrough, without which the mRNA Covid-19 vaccines would not exist: they found that by making chemical modifications to mRNA they could then insert it into the dendritic cells without activating an immune response — in effect tricking cells into thinking the molecules had been made inside the body rather than a lab. This meant, in theory at least, that mRNA could be turned into a therapy for humans. "It was like a dream come true," says Kariko. "'Oh my God,' I said. 'Now we can use it.'"
And yet progress remained elusive. Even after they published their findings, the stack of rejection letters from providers of scientific funding kept piling up. "We both knew there was enormous potential," says Weissman. "The problem was, we couldn't convince anybody else."
It was another scientist who helped turn their dream into reality. Derrick Rossi had never heard of Kariko and Weissman, who "were not at all well-known scientists", he says. But in 2008, he was working as an assistant professor at Harvard Medical School and trying to use mRNA to make stem cells — immature cells that have not yet developed into a specific type, for example a brain or muscle cell.
Rossi was inspired by Shinya Yamanaka, a Japanese scientist who had proved it was possible to turn any cell in the human body into an embryonic stem cell-like state by inserting four genes. Yamanaka's discovery eventually won him the Nobel prize. But there was a problem: the genes he inserted ended up back in the DNA, a mutagenic event that increased a person's chance of developing cancer.
Rossi's idea was to replicate the Japanese scientist's achievement using mRNA instead, to reprogramme human skin cells so they could act as though they were stem cells.
"Yamanaka's experiment was beautiful, but the approach was not really useful for medical translation," he says. "So we thought, 'Let's just eliminate the whole integration in the DNA business by using mRNA.' mRNA does not integrate into the DNA. It doesn't go back in and permanently, genetically alter anything."
Rossi started by turning green fluorescent protein, which gives jellyfish their ethereal glow, into mRNA before applying it to cells in a dish. If the cells in the dish lit up, the experiment would be a success. Instead, he encountered the same stumbling block that had vexed Kariko and Weissman. "The cell was responding as though a virus was coming in, they were killing themselves," he says.
As Rossi hunted for a solution, he happened upon Kariko and Weissman's research paper from 2005, which had gone largely unnoticed in the wider scientific world. He was particularly intrigued by a tantalising paragraph buried at the end of the article, suggesting there was more to their work than they were letting on: "Insights gained from this study could . . . give future directions into the design of therapeutic RNAs."
"We saw that paper and thought maybe we can take these damn mRNAs and get them to flip into the cell and not be recognised," Rossi says. After making the chemical modifications to the mRNA that Kariko and Weissman had pioneered, he repeated the experiment using the fluorescent protein. This time the cells turned bright green.
I realised that, if it worked, it would change medicine for ever." - Stéphane Bancel, Moderna chief executive
So the torch passed from Kariko and Weissman to Rossi. His findings were published in 2010 to great acclaim but to turn his discovery into a medical reality, Rossi needed money — and lots of it. This meant creating a private company capable of raising cash from investors.
He soon found a believer in Bob Langer, a chemical engineer at the Massachusetts Institute of Technology and a colossus in the world of biotech. "[Rossi] showed me a slide deck and said he was interested in starting a company, and I thought, 'Gee, that would be terrific,'" recalls Langer.
He subsequently introduced Rossi to Noubar Afeyan, a venture capitalist who had founded Flagship Pioneering in 2000 and who in 2010 would start up a company to commercialise the science. Its name was Moderna.
Stéphane Bancel was attending the World Economic Forum in Davos in January last year when he concluded that the world was on the brink of the worst pandemic in more than 100 years. By that point, the existence of Covid-19 was well known and Moderna, the company where Bancel has been chief executive since 2011, was already working on a vaccine with the US National Institute of Allergy and Infectious Diseases.
Bancel had initially been of the view that Covid-19 was an outbreak that could be contained like Sars and Mers. But his mind was changed by two scientists who also happened to be at Davos — Jeremy Farrar of the Wellcome Trust and Richard Hatchett from the Coalition for Epidemic Preparedness Innovations. The pair, members of what Bancel calls the "infectious diseases mafia", spent days with the Moderna CEO sketching disaster scenarios on napkins, prompting him to realise the potential seriousness of the outbreak.
"I remember pulling out my iPad and asking, 'Where is Wuhan?'" Bancel says. A search on Google Maps showed him just how big the city was, while Wikipedia informed him that it was a major exporter to the automotive industry. "And then I went on Google Flights and I saw there [had been] direct flights to all the capitals in Asia, to the West Coast cities in the US, to all the capitals in Europe. Everything fell into place and I thought, 'Shit, this is already everywhere — this is going to be a pandemic like 1918.'"
That Moderna, a young company by biotech standards, was ready to develop a Covid-19 vaccine in record time when the pandemic struck is testament in part to the blistering speed at which it has grown during Bancel's decade at the helm. When Afeyan approached him in early 2011 about becoming chief executive, Bancel, then working at a French diagnostic testing company, initially demurred.
"At first I told him he was crazy, that this will never work," Bancel says, referring to the idea of running a company focused on mRNA. "But [then] I realised that, if it worked, it would change medicine for ever."
Bancel, who speaks at lightning speed, has become known for his ability to raise billions of dollars of cash for Moderna, from both private and public sector sources. In 2018, the company completed the biggest initial public offering for a biotech on record, securing a valuation of $7.5bn. Other biotech executives have privately expressed disbelief that investors were willing to hand so much cash to a company working in what was — and to a large extent still is — an untested area of science.
Even today, Moderna has not secured full-blown regulatory approval for a single vaccine or drug: its Covid-19 jab is being given to humans under emergency-use authorisations that fall short of a proper stamp of approval. "The highest form of insult they would hurl at Stéphane was that he was a 'great fundraiser', which was damning by [faint] praise," says Afeyan of the criticism directed at Bancel.
Yet had Moderna hired a chief executive who moved more cautiously and raised less money, the company might not, by the time of the Covid-19 outbreak, have already worked on mRNA vaccines for other infectious diseases such as Zika and Cytomegalovirus. And it almost certainly wouldn't have broken ground on its factory in Massachusetts in July 2018.
Kati, it is a moral obligation for us to do infectious-disease vaccines. Those are a money-sucker, but it is a moral obligation." - Ugur Sahin, BioNTech chief executive
Moderna acknowledges the debt it owes to Kariko and Weissman — "You can't tell this story without them and their fundamental insights," says Stephen Hoge, its president and Bancel's de facto deputy. But the company insists it did more than simply commercialise their scientific discoveries; it decided, for example, to use modified, non-immunogenic mRNA inside a vaccine, and then to deliver the jab using lipid nanoparticles — little droplets of fat that stop our enzymes from destroying the genetic material.
The company tested its first such vaccine in humans in 2015, a second in 2016 and then a further nine jabs between 2016 and 2019. By the time the pandemic hit, it already knew that its technology worked. But Covid-19 was the first time it was used at scale.
Thanks in part to Moderna's success, the potential of mRNA vaccines also captured the attention of Big Pharma. In 2018, Pfizer signed a partnership deal worth up to $425m with BioNTech, a German group. At the time, BioNTech was mostly focused on using mRNA to develop cancer drugs injected directly into tumours.
Kariko, who now works at BioNTech, recalls that chief executive Ugur Sahin felt a responsibility to research jabs for infectious diseases as well, but worried that they would be unprofitable. "He told me, in 2015, 'Kati, it is a moral obligation for us to do infectious disease vaccines. Those are a money-sucker, but it is a moral obligation.'"
In this next stage of the story of the Covid-19 mRNA vaccines, the torch passed to Moderna and BioNTech. But such vaccines still might not have happened were it not for the intervention of the US government: lots of promising discoveries made in academic labs do not end up being commercialised for human use because of a reluctance among investors to plough money into medical research that may result in expensive failure.
In Moderna's case, the gap was filled in part by officials at a unit of the US Department of Defense known as the Defense Advanced Research Projects Agency or Darpa. Set up in 1958, in response to the launch a year earlier of Russia's Sputnik 1, the first artificial earth satellite, Darpa has been credited with fostering some of the biggest technological advances in history, from the creation of the internet to the GPS.
In 2013, the US government issued a string of grants to private companies, including up to $25m for Moderna to work on an mRNA drug to combat Chikungunya — a potentially deadly virus spread by mosquitoes that affects millions of people mostly in Africa, Asia and the Indian subcontinent. That funding from Darpa, though tiny by comparison with the billions Bancel had raised in private funding, nudged the company into the field of infectious diseases, an unloved area among biotech investors who prefer to put money into more profitable endeavours.
"It's not even clear that, without some pretty heavy pressuring, this activity — even at Moderna — would have been pursued versus other potential applications for mRNA that had a much clearer path to monetisation, such as cancer treatment," says Regina Dugan, the former director of Darpa, who signed off on the grants.
In recent months, mRNA vaccines have shown that they are a formidable weapon in the battle against the pandemic. In Israel, which has fully vaccinated more than half of its population with the BioNTech/Pfizer jab, life has all but returned to normal, and things are heading that way in the US and UK. But many developing and even some richer countries have been unable to secure supplies.
Earlier this month, the Biden administration broke with US orthodoxy to back a waiver of Covid-19 patents during the pandemic, potentially opening the door for drugmakers across the world to copy the vaccine formulas pioneered by Pfizer, Moderna and others. The EU responded by saying that America's decision to hoard vaccines was the real drag on the global inoculation race.
There is acrimony, too, among the researchers who made mRNA vaccines a reality. No story of scientific success would be complete without an element of discord, especially when a Nobel prize is almost certainly up for grabs, and many of them nurse grievances. Kariko feels that she was poorly treated by her employers at the University of Pennsylvania, and struggled to secure grants for her research.
Sahin, the BioNTech chief executive, worries that focusing on Kariko crowds out the other scientists who worked on the Covid-19 vaccines and bristles at the idea of a neat narrative that begins with her work (even though she now works for him). "I think this is now [getting] more and more simplified in the whole storytelling," he says. Weissman, who still works at the University of Pennsylvania, sees it differently: "Everything that Moderna does uses our patent, our technology. BioNTech has other programmes that don't use it, but the vaccine they made uses our technology."
There is also bad blood between Rossi and Moderna, the company he helped found in 2010 but left roughly three years later. Several people briefed on the split say that Rossi wanted Moderna to dedicate more time to his stem-cell discovery and was eventually shunted aside when it zeroed in on drugs and vaccines instead. Rossi dismisses the idea that he was too focused on stem cells, pointing out that he was talking about the potential for mRNA to be used as a backbone for human therapeutics as early as 2010. "It's offensive, but it's typical of these business pricks to basically say, 'That was our idea.'"
But by far the biggest disagreement in the wider biotech community is about whether the mRNA Covid-19 will represent a step change in medical development. Moderna's market capitalisation, which has soared by more than 600 per cent since Covid-19 was declared a global pandemic, now stands at $63bn. That is a staggering valuation for a company that has no fully approved products and which generated $803m in revenue last year.
By contrast, Biogen, a company founded in 1978 that makes drugs for multiple sclerosis, and which hopes to secure approval for the first medicine that can slow Alzheimer's, generated $13.4bn of revenue last year: its market capitalisation is just $40bn.
Implicit in Moderna's valuation is a belief among investors that not only will it upend the vaccines industry by making mRNA the crux of many more inoculations, but that its experimental drugs for illnesses such as heart defects and cancer will also end up working too.
One biotech investor, who asks to keep their criticism off the record, describes the company as the "Tesla of biotech", referring to the electric car company that is worth more than several traditional automakers combined. "I think that investors underappreciate how much time it's going to take to succeed in other areas and the risk, the probability, that it is not going to succeed."
Another healthcare investor, who is betting that Moderna's share price will eventually fall, agrees. He worries that the company will struggle to raise the price of its vaccine, which is roughly $15 per shot, when the pandemic ends and companies can start charging so-called endemic prices. "Wall Street is pretty brutal," he says. "It's going to be an uphill battle."
Bancel insists the company has huge potential to reshape pharmaceuticals. The success of the mRNA Covid-19 vaccines — with their extremely high efficacy rates — and the economic toll of the pandemic are proof that inoculations will become a bigger industry, he says, predicting that this market, worth about $35bn today, could almost treble in size.
He also foresees an eventual "cancer and cardiology wave" for the company, which has a large but early-stage pipeline of drugs for oncology and heart defects. He points to a recent, small trial of one of its cancer drugs, which showed that it helped patients who were not responding to an approved immunotherapy drug.
All of a sudden, everyone believes in [mRNA] for all the right reasons." - Stephen Hoge, Moderna president
Yet in reality, despite Bancel's enthusiasm, there is very little proof that mRNA could be as transformative for other areas of medicine as it has been for vaccines. In March, Translate Bio, a company researching mRNA drugs for cystic fibrosis — seen as one of the illnesses that might best be tackled by the approach — reported disappointing results from a trial of its experimental medicine, which did not improve patients' lung function.
Brad Loncar, a biotech investor who runs a cancer-focused fund, says he has seen scant evidence that mRNA will work for cancer either. "We're very early, but the cancer data that we've seen so far from all the companies has been really disappointing," he says. "The verdict is still out on all these other diseases, they are going to take years and years to be proven. And there is no guarantee that it's going to succeed."
Yet the undeniable accomplishment of the Covid-19 mRNA vaccines means the field is unlikely to enter another dark age. Hoge, Moderna's president, says the success of the jabs gave the industry the "home run" that it had always craved. "What happens with the pandemic is that all of a sudden, a year forward, everyone believes in [mRNA] for all the right reasons." It will happen by fits and starts, but scientists like Kariko will no longer have to work in the shadows.
"Of course there are a lot of things that have to be done but the model is there and it can be done," she insists during one of our telephone interviews. "People would probably tell me to put down the phone right now, and to go and read more and work on it. Because people are suffering."
Written by: David Crow
© Financial Times
