Science

Researchers looking for mRNA were ridiculed by colleagues. Luckily, that didn’t stop them.

Sixty years ago, the scientists who were pioneering the technology that would make today's COVID-19 vaccines possible were mocked and dismissed

A few days before Christmas, Matthew Meselson, a 90-year-old professor at Harvard, called his university’s health service to inquire about being vaccinated against COVID-19. He was eager for his shot. Meselson felt imprisoned in his Cambridge apartment, just blocks from the campus where he’d worked for six decades. He’d officially retired from teaching at the beginning of 2020, but continued his research as much as possible throughout the pandemic, wearing a K95 mask to work in his lab.

He longed to re-engage in the world around him. He missed his weekly date with close friends over lunch at Boston’s best French restaurant; they’d switched to Zoom, but staring into a computer screen is no replacement for lingering at linen-covered tables. He longed for his wife of 32 years, Jeanne Guillemin, who died from cancer late in 2019. Meselson was still figuring out how his world worked without her, and isolation made this hard task harder.

The person on the other end of the phone apologized to the professor. “We don’t have a vaccine schedule yet,” she told him.

The first two COVID-19 vaccines to be approved for use in North America were developed, tested and delivered into freezers before many jurisdictions figured out how to administer them. The vaccines from Pfizer-BioNTech and Moderna are the first approved vaccines ever to employ modified mRNA, which is delivered sealed in a lipid shell. The mRNA slips into our cells, carrying instructions to make the spike protein that is on the outside of the SARS-CoV-2 virus. Our immune system then develops a protective response against this protein.* The vaccines function almost like a wanted poster: if you see these guys, get ’em. Then, the mRNA degrades, leaving no trace.

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The fact that mRNA is the basis of these vaccines contributed to their rapid development. In November, the New York Times reported that within two days of China releasing the genetic sequence of SARS-CoV-2, scientists at Moderna Inc., a 10-year-old company headquartered not far from Meselson’s home in Cambridge, “plugged that data into its computers and came up with a design for an mRNA vaccine.” Meanwhile, BioNTech, a small biotech company in Germany that had been working on mRNA flu vaccines with the pharmaceutical powerhouse Pfizer, soon similarly turned its resources to generating an mRNA COVID vaccine.

But these fastest vaccines in history have been decades in the making. They’re the product of generations of scientists who built on one idea after another, and kept at it despite failed experiments, rejections, threats of deportation, a lack of funding and skepticism from contemporaries. They were inspired by the discovery of DNA: in 1951, a young English physical chemist named Rosalind Franklin took X-ray photographs that captured DNA’s helical shape; two years later, James Watson and Francis Crick of Cambridge University published the first report describing DNA’s double helix, for which they received the Nobel Prize. (Franklin died of ovarian cancer in 1958; her contributions were largely overlooked in her lifetime.) And they were driven not by a race to halt a raging pathogen or by the chance to patent a multi-billion-dollar drug, but by one big, irresistible question: What makes life?

“These weren’t people who wanted to solve little problems,” says Meselson. “These were people who wanted to solve a great big problem.”

He was one of them.

***

Born in Colorado in 1930, Meselson zipped through the sciences at a young age. By 16, he enrolled at the University of Chicago. In 1957, while doing post-doctoral work at the California Institute of Technology (Caltech), Meselson and Frank Stahl demonstrated how DNA replicates itself, a model that had been suggested but never shown. Science historian Frederic Lawrence Holmes later characterized their work as “the most beautiful experiment in biology,” having revealed how life worked.

But many unanswered questions remained about what happens inside our cells. Meselson and colleagues knew that DNA resides in the nucleus, a compartment barricaded off from the rest of the cell by a membrane. On the other side of the membrane is the cytoplasm, a gelatinous liquid that fills the remainder of the cell. This is the home of tiny granules called ribosomes, which house RNA.

Around the same time that Meselson and Stahl published their groundbreaking work on DNA, French scientists discovered that cells made proteins through the ribosomes. DNA, despite holding the critical codes for life, is a relatively passive molecule. Ribosomes do the busy labour, building proteins to carry out the biological processes of survival. The question was how?

One of the French scientists, Dr. François Jacob, theorized that there must be an “unstable intermediary” that went between the DNA and the RNA—sending messages from the DNA to the RNA, and then disappearing.

Jacob, a physician who’d been forced from medical school when Germany invaded France in 1940 and spent the war years fighting with Charles de Gaulle’s Free French Forces, called this theoretical intermediary “X.” Other researchers “rolled their eyes in horror” when he presented his theory, Jacob recalled in his memoir, The Statue Within. “With a little encouragement, my audience would have jeered and left,” he wrote.

Meselson at Caltech in 1958 (Courtesy of the Caltech Archives)

Meselson at Caltech in 1958 (Courtesy of the Caltech Archives)

In spring 1960, Jacob wrote to Meselson with a proposal: he and Sydney Brenner, a South African biologist at the University of Cambridge, would meet at Meselson’s lab at Caltech to find X. Meselson, who was in his first year on faculty, had developed a technique to track smaller molecules inside a cell. Jacob believed this technique would help identify X. That summer, with Jacob and Brenner in his lab, Meselson set up initial cultures and tests. Brenner took over the operations, while Jacob sat in a chair taking notes—pain from bomb fragments in his legs was worsened by the California humidity, says Meselson. For three weeks, they met with one failure after another. The ribosomes kept falling apart. Other scientists poked their heads in periodically and asked sarcastically for news of X. Jacob wrote that they “came to visit as one would visit the zoo.” On the trio’s very last scheduled day in the lab, Meselson, having given up on X, left. He flew to Boston to propose to his first wife.

Dejected, Jacob and Brenner went to Malibu Beach. The duo lay on the beach, watching huge waves of the Pacific crashing onto the sand and contemplating where their idea had gone wrong. Jacob wrote in his memoir: “Suddenly, Sydney gives a hoot. He leaps up, yelling, ‘The magnesium! It’s the magnesium!’ ” They raced back to the lab to run the experiment one last time, with additional magnesium. The result was spectacular. X existed.

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The pair gave a seminar the same day at Caltech to demonstrate X. Even then, no one believed them. They contacted Meselson in Boston that night to tell him. He was delighted. “It didn’t occur to me that they would figure out what was going wrong on the very last day,” he says. When the trio published their findings in 1961, they renamed X as messenger RNA.

They did not imagine that their finding would be used for therapeutics or a vaccine. Their questions were more philosophical. Meselson says, “We wondered what is it that allows you to put together the atoms of the ordinary periodic chart and end up with something that’s alive?”

Their work became the central tenet of molecular biology: DNA makes RNA makes protein makes life. It took another generation of scientists to find a way to harness RNA to treat and prevent illness.

***

As a kid in Kisújszállás, Hungary, Katalin Karikó watched her father, a butcher, dismember the carcasses of pigs. It was her first introduction to science. In the 1970s, while studying biochemistry at the University of Szeged, Karikó heard about a new report from London: interferon, a type of protein made by the body to trigger a defence against a virus, was mediated by an RNA called 2-5A. Karikó remembers a mentor talking to her about the discovery and being thrilled by the possibilities. He suggested to her that if they could make a synthetic version of a 2-5A molecule, they might be able to treat cancer or viral disease. “I immediately thought that what I was doing was tremendously important,” she says. It was the start of a 40-year quest to make synthetic RNA that could cure illness.

But she couldn’t secure funding in Hungary. Married with a two-year-old daughter, Karikó saw no way to continue her work in her home country. She wrote to professors throughout Europe about joining their labs, but no one could hire her. In 1985, she received an offer from Temple University in Philadelphia. If she could get to the United States, a job was waiting for her.

At the time, Hungarian money could not legally be converted to another currency and taken out of the country. Worried about how their family would survive until her first paycheque, Karikó and her husband, Bela Francia, sold their Russian-made car and converted the proceeds on the black market for a total of 900 British pounds. They sewed the money into their daughter’s teddy bear to smuggle it out of the country. The teddy bear’s owner, their daughter, Susan Francia, grew up to become a two-time Olympic gold medallist for the United States in rowing.

Karikó at home in Pennsylvania (Rachel Wisniewski)

Karikó at home in Pennsylvania (Rachel Wisniewski)

In their new home, things did not go as planned. Karikó’s bosses changed, she couldn’t get funding and she lost her job. Her supervisor cited her for deportation. Desperate to stay in the United States as her daughter entered first grade, Karikó accepted a researcher post in Bethesda, Maryland. She commuted from Philadelphia every Monday morning at 3 a.m. and returned late Friday. In Bethesda, she slept at colleagues’ houses or in her office rather than renting a place of her own. On the weekends, she brought home lab equipment for her husband to fix. “From the outside, if somebody looked at me, they could smell sweat and struggle,” she says.

For all its promise, synthetic RNA was proving to be a headache. Around the world, scientists were encountering the same problem: cells dying off in the culture dish.

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In a human body, when a virus like a coronavirus injects its nucleic acids—DNA or RNA—into a cell, the nucleic acids make proteins to build more virus. That way, a virus goes on to infect a whole animal or person. The infection can be halted when a cell identifies the intrusion and rallies its antiviral forces through a variety of immune cells. “The immune cell recognizes that, ‘My God, we are under attack,’ ” Karikó explains, “and they will alert all the other cells. ‘Come, there’s an enemy here.’ ” In the most extreme response, a cell responds by committing a kind of altruistic suicide, killing itself off in order to prevent an infection from running rampant within an organism. That’s what was happening in labs when researchers injected synthetic RNA.

Karikó, who moved to the University of Pennsylvania in 1990, was convinced there was a workaround that would allow her to make RNA that could glide into a cell without triggering an attack from the cell’s defence forces. Evidence suggested it was possible—in 1990, researchers at the University of Wisconsin successfully injected RNA into mice. The same year, Karikó submitted a grant application for mRNA-based gene therapy. It was denied. So were her following applications. Without funding, she was demoted.

But she remained convinced. “I always had a Cassandra feeling,” she says, referring to the priestess in Greek mythology who possessed the gift of prophecy but was cursed to never be believed. Karikó was not a good salesperson for her idea, she admits. “I couldn’t get money. I couldn’t convince people.”

An illustrated cross section of the COVID-19 mRNA vaccine with its lipid coating. (Juan Gaertner/Science Photo Library/Getty Images)

An illustrated cross section of the COVID-19 mRNA vaccine with its lipid coating (Juan Gaertner/Science Photo Library/Getty Images)

By 1997, Karikó was spending hours at the office’s Xerox machine, photocopying scientific journals to take home for reading. There, she met Dr. Drew Weissman, a physician and immunologist. The pair started chatting about their work. Weissman had just joined the faculty, fresh off a post-doctoral fellowship at the National Institutes of Health under Dr. Anthony Fauci. Weissman was working with dendritic cells, human cells that digest parts of foreign invaders and present remnants as evidence to the immune system. They decided to collaborate.

Over the next decade, Karikó and Weissman discovered that cells in the lab were dying because synthetic mRNA provoked an inflammatory reaction. But if they modified one of the four building blocks of RNA, known as nucleosides, the cell no longer flagged synthetic RNA as a foreign invader. It could be delivered into a cell without causing inflammation. “This was a game-changer for the field,” says Dr. Norbert Pardi, a research assistant professor at the University of Pennsylvania who works with the duo.

Pardi’s grandfather worked as a butcher alongside Karikó’s father in Hungary, and he sought her mentorship as a student. Eventually, he became an accomplished mRNA researcher in his own right and followed Karikó to the United States. Working with Karikó and Weissman, Pardi found that if they packaged mRNA inside a coating of lipid nanoparticles, mRNA could be protected from rapidly disappearing after delivery, making it more effective.

Weissman and Karikó immediately recognized that their discovery had huge potential. Usually, when someone invents a new drug, that drug works for one disease, says Weissman. “But RNA had the potential to act on many different diseases,” he says. They believed it could work as a vaccine, a therapy or a gene editing system. “It could treat hundreds, if not thousands, of different diseases.”

Their findings were published in the journal Immunity in 2005. To their frustration, the report went unnoticed in the scientific community. Undeterred, they started a company called RNARx, which received nearly $1 million in small business grants from the U.S. government. But it never really got off the ground, hampered by the university’s constraints over the licensing of the intellectual property.

Asked if he was angry about the business outcomes, Weissman shrugs. “Thinking about the past is kind of useless because you can’t change it and you can’t fix it. It’s just how things happen,” he says.

***

After finishing his first two degrees at the University of Toronto, Canadian-born Derrick Rossi was on his way to completing his Ph.D. when he announced to his colleagues that he was quitting to move to Paris. “They thought I was crazy,” he says. He remained in France for a year, working late in a research lab and partying when he wasn’t working. He left when he couldn’t maintain the pace anymore. He hitchhiked around Europe, spent time researching in Texas and moved to Finland for a third go at his Ph.D., finishing in his late 30s. By that time, stem-cell research was a hot political issue, with American conservatives calling for blocks on federal funding for research that used newly obtained embryonic stem cells.

Rossi was intrigued by the work of Japanese researcher Dr. Shinya Yamanaka, which seemed to offer a way around the use of embryonic stem cells. Yamanaka discovered that mature cells could be converted into stem cells with the addition of four transcription factors, known as Yamanaka factors, a finding for which he received the Nobel Prize. But there was a catch, and a frustrating one. Yamanaka used retroviruses to deliver these transcription factors into the cell. The strategy would not work in humans. Retroviruses, while very good at delivering cargo like transcription factors, can integrate into the cell’s DNA and remain there forever, explains Rossi. He wondered if he could use mRNA as the delivery service. Again, the same problem came back: cells dying in dishes.

Canadian-born, Rossi co-founded Moderna in 2010 (Photograph by Jake Belcher)

Canadian-born, Rossi co-founded Moderna in 2010 (Photograph by Jake Belcher)

Searching for a solution, Rossi came across Karikó and Weissman’s discovery, then almost three years old. In their first experiment using this approach, Rossi and post-doc student Lior Zangi made a modified mRNA for luciferase, the enzyme in fireflies that makes them emit light. They injected the modified mRNA into the thigh muscles of anaesthetized mice and placed the animals in a machine devoid of light. As the researchers watched, the legs of the mice glowed.

“It worked on the very first shot. That tells you something about the robustness [of the technology],” says Rossi. The implications were clear: modified mRNA could be used to express a protein, possibly any protein—whether it was needed to treat disease, cure it or maybe prevent it.

Rossi co-founded Moderna in 2010. A charismatic storyteller with a talent for explaining complex scientific concepts in easy-to-understand terms, he persuaded giants in America’s biotech industry to invest. In 2013, after two years of functioning under the radar, Moderna announced that it was on the verge of introducing an entirely new drug category to the pharmaceutical arsenal in the fight against diseases. Within two years, Moderna Therapeutics brought in more than $950 million from investors and corporate partners—a figure the New York Times called “somewhat remarkable” for a company that did not yet have an experimental drug in clinical trials.

***

Every person has hundreds of millions of copies of mRNA in their body, sending the instructions for vital activities of life in our cells. The mRNA in vaccines differs in two ways from our regular mRNA: one, it’s made by machines rather than in the nucleus of our cells; and two, it’s introduced from outside of the cell. Once inside, it does what mRNA does. Ribosomes read the mRNA and get to work, building the corresponding protein.

In the case of the COVID-19 vaccine, cells build the spike protein of the SARS-CoV-2 virus. Our bodies learn to recognize the spike protein as an invader, putting our immune system on alert. As we go about the world, walking into grocery stores and churches and schools, many of us will unknowingly encounter the virus for the first time. If we are vaccinated, our immune system is already primed to respond to it.

Vancouver-based Acuitas Therapeutics makes the lipid delivery system for several kinds of therapeutics, including the mRNA vaccine by Pfizer-BioNTech and a second one that is still in trials from Germany’s CureVac. Acuitas CEO Thomas Madden likens the lipid packaging around the mRNA to the protective wrapping around a delicate Christmas ornament; ideally, the wrapping comes off just before the ornament is hung on a tree. For mRNA vaccines, a sturdy delivery system means less mRNA is required to get the job done—in other words, a smaller dose. “We can vaccinate far more people from a given amount of the vaccine if the delivery system is very efficient,” says Madden.

The advantages of mRNA vaccines are remarkable: there is no risk of infection from the virus or permanent changes to the genome, and the mRNA rapidly degrades by normal cellular processes so nothing remains. The vaccine can be designed on a computer and rapidly scaled up for manufacturing. Over the last four years, there’s been an explosion of interest in mRNA vaccines, with work under way on vaccines for cancer, influenza, Ebola and Zika. There are questions, too. How long will protection last? Can it eliminate transmission risk? Exactly who is at risk for side effects, and do we know all the side effects?

 Madden (right) and a colleague at an Acuitas lab in Vancouver (Photograph by Alia Youssef)

Madden (right) and a colleague at an Acuitas lab in Vancouver (Photograph by Alia Youssef)

When the hunt for a COVID vaccine began, years of research came to fruition within months, accelerated by infrastructure and financial support from governments around the world. And by November, both Moderna and Pfizer-BioNTech reported results from phase 3 trials, showing the vaccines were more than 90 per cent effective in protecting against severe illness from SARS-CoV-2. Scientists who spoke to Maclean’s called Nov. 9, the day Pfizer-BioNTech reported the trial data, the highlight of an otherwise terrible year. “The results just blew everyone’s mind,” says Weissman, who has lost friends to COVID. In Vancouver, Madden heard the results on the BBC early in the morning and emailed everyone in the 29-person company, many of whom were working in shifts in order to maintain social distancing in the lab. The company sent deliveries of champagne and charcuterie to all its employees.

The pandemic has been “a coming of age” for mRNA vaccines, says Madden. The fact that the first vaccines approved are mRNA vaccines indicates that this technology could be used to respond quickly and effectively to future threats, he says. He adds that he is hopeful the stringent storage criteria for the Pfizer-BioNTech vaccine will change in the next two months, facilitating easier administration. The current requirement of -70° C was selected to expedite approval because testing the vaccine’s stability at warmer temperatures would have delayed the delivery. Those studies are ongoing, he notes.

Karikó, who joined BioNTech in 2014, and Weissman have been suggested as deserving candidates for the Nobel Prize, given their groundbreaking contributions to vaccines. Karikó says she’s not motivated by rewards. “I do not care about any reward. I care about one thing: that this vaccine stops the infection.”

The pair received their first dose of the Pfizer-BioNTech vaccine in Philadelphia on Dec. 18. Rossi is waiting for his shot and says he will happily take either of the approved vaccines. In Vancouver, Madden expects to be vaccinated as part of the rollout to the general population. He, too, will gladly accept either, though he has a soft spot for one using his company’s lipid delivery system.

In Boston, Meselson is working on, among other things, the theory that oxidative damage drives the aging process. He has started taking cello lessons over FaceTime and is reading the unpublished works of his late wife, a renowned anthropologist and writer who exposed a secret biological warfare lab in the Soviet Union as the source of a lethal anthrax outbreak. He’s lost one close friend to COVID who died in the United Kingdom in April, barely a month after Meselson had visited.

The famed scientist believes vaccines are a vital part of the response to the pandemic, but cannot be the only one. Proper ventilation and air filtration of enclosed spaces will be essential for preventing future pandemics, he says. “That’s what we need to do,” he says.

In the meantime, he eagerly waits for his vaccination date.

CORRECTION, February 26, 2021: This story originally reported that mRNA in COVID-19 vaccines carries instructions to make antibodies that target SARS-CoV-2. In fact, the mRNA carries instructions to make the spike protein that is on the outside of the SARS-CoV-2 virus, which triggers a protective response against the protein.


This article appears in print in the March 2021 issue of Maclean’s magazine with the headline, “Shooting the messenger.” Subscribe to the monthly print magazine here.