The central dogma of molecular biology says that the DNA code is transcribed to messenger RNA, or mRNA, which, in turn, is translated to proteins. Researchers from different fields (stem cells, cancer, vaccines) who understood the role of mRNA as a recipe book for the body’s trillions of cells had long dreamed about being able to transcribe it in vitro, otherwise to produce a human-edited mRNA. Their concept was that by making precise tweaks to mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory. More than 40 years had to pass between the 1970s, when a Hungarian born scientist named Katalin Karikó pioneered early mRNA research, and the day the first authorized mRNA vaccine was administered in the United States, on December 14, 2020.
A timeline of the mRNA technology
Headlines around the world have focused on how quickly vaccines against Covid-19 were developed, but there is no such thing as an “overnight success” in science. Actually the opposite had happened. These vaccines, particularly the ones that use mRNA, were inspired by the discovery of DNA in 1951 and mRNA in 1961. However, it took a long period of gestation – more than four decades – to build these vaccines.
The story behind the mRNA vaccines and their related technologies involves generations of scientists and hundreds of people all over the world, who have worked in fundamental and applied areas of research for decades. Their efforts helped to create a foundation of knowledge that led to the amazing breakthroughs in vaccine development we’re seeing at work today. This knowledge base has been built through hard work via small steps of progress spread out many decades. Every surprising study, every failed experiment, every paper published, every rejection, in addition to a lack of funding and skepticism from contemporaries – in the world of science, these are the small steps of progress taken by the mRNA pioneers. The synthetic mRNA is a beautiful scientific story, but its long road to viability nearly destroyed several careers and almost bankrupted several companies.
The Canadian Institutes of Health Research have put together a timeline of decades of scientific research that led to the Covid-19 vaccines. An updated version of their timeline, which includes the discoveries of DNA and mRNA, is presented below. Credit for collecting the information related to the DNA and mRNA‘s discoveries goes to the Maclean‘s science journalist Christina Frangou.
- 1951
Rosalind Franklin, an English chemist and X-ray crystallographer, takes X-ray photographs that capture DNA’s helical shape; one of these is the famous photo 51. - 1953
James Watson and Francis Crick of Cambridge University publish the first report describing DNA’s double helix, for which they receive the Nobel Prize in Physiology or Medicine 1962 (together with Maurice Wilkins).
Dr. Franklin dies of ovarian cancer in 1958; her contributions had been largely overlooked in her lifetime, if not really stolen. - 1957
While doing post-doctoral work at the California Institute of Technology (Caltech), Matthew Meselson and Frank Stahl demonstrate how DNA replicates itself, a model that has been suggested but never shown. Science historian Frederic Lawrence Holmes will characterize their work as “the most beautiful experiment in biology”, having revealed how life worked. But many unanswered questions remain about what happens inside our cells.
Dr. Meselson and colleagues know 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 1957
French scientists discover that cells make proteins through the ribosomes. DNA, despite holding the critical codes for life, is a relatively passive molecule. Ribosomes do the busy labor, building proteins to carry out the biological processes of survival. The question is how?
One French scientist, François Jacob, theorize that there must be an “unstable intermediary” that goes between the DNA and the RNA, passing messages from DNA to RNA and then disappearing. He calls this theoretical intermediary “X”. In his memoir, The Statue Within, Dr. Jacob recalls what happened when he presented his theory: other researchers “rolled their eyes in horror”; “with a little encouragement, my audience would have jeered and left”. - 1960
Dr. Jacob and Sydney Brenner, a South African biologist at the Cambridge University, meet at Dr. Meselson’s lab at Caltech to find “X“. Meselson, who is in his first year on faculty, has developed a technique to track smaller molecules inside a cell. Jacob believes this technique will help identify “X“.
During the summer, with Dr. Jacob and Dr. Brenner in his lab, Dr. Meselson sets up initial cultures and tests. Brenner takes over the operations, while Jacob sits in a chair taking notes. For three weeks, they meet with one failure after another. The ribosomes keep falling apart. Other scientists poke their heads in periodically and ask sarcastically for news of “X“. Jacob writes that they “come 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“, leaves. He will flight to Boston to propose to his first wife. Dejected, Jacob and Brenner go to Malibu Beach. The duo lay on the beach, watching huge waves of the Pacific crashing onto the sand and contemplating where their idea has gone wrong. Jacob writes in his memoir: “Suddenly, Sydney gives a hoot. He leaps up, yelling: “The magnesium! It’s the magnesium!’”. They race back to the lab to run the experiment one last time, with additional magnesium. The result is spectacular. “X” exists.
The pair gives a seminar the same day at Caltech to demonstrate “X“. Even then, no one believes them. They will contact Dr. Meselson in Boston that night to tell him. He is delighted. “It didn’t occur to me that they would figure out what was going wrong on the very last day”, he says. - 1961
Drs. Jacob, Brenner, and Meselson rename “X” as messenger RNA and publish their findings. - 1980s
Pieter Cullis, a professor of biochemistry and molecular biology at the University of British Columbia (UBC) in Canada, and his team study lipids. This fundamental research is designed to better understand how lipids work. - 1987-1990
Late 1987, Robert Malone, a graduate student at the Salk Institute for Biological Studies in California, performs a landmark experiment. He mixes strands of mRNA with droplets of fat to create a kind of molecular stew. Human cells bathed in this genetic stew absorb the mRNA and begin producing proteins from it. Realizing that this discovery might have far-reaching potential in medicine, Malone writes down some notes, which he signs and dates. The notes are signed by one more member of the Salk lab, for posterity. This is what Malone writes on 11 January 1988: “if cells could create proteins from mRNA delivered into them, it might be possible to treat RNA as a drug”. Late 1988, Malone’s experiments show that frog embryos absorb such mRNA. It is the first time anyone has used fatty droplets to ease mRNA’s passage into a living organism.
Malone was the first author on a 1989 PNAS paper demonstrating how RNA could be delivered into cells using lipids and a co-author on a 1990 Science paper showing that if you inject pure RNA or DNA into mouse muscle cells, it can lead to the transcription of new proteins. If the same approach worked for human cells, the latter paper said in its conclusion, this technology “may provide alternative approaches to vaccine development.” - 1990s
Katalin Karikó, a researcher at the University of Pennsylvania in the United States, has already spent a decade studying RNA to unlock its potential for use in medicine. - 1995
Dr. Cullis and his team turn their attention to using lipid nanoparticles (LNP) in medicine, in particular for gene therapy drugs that use nucleic acids (like RNA). The LNPs form a protective bubble around the medicine so that it can be delivered to cells safely and effectively. - 2005
Dr. Karikó and her research partner, Drew Weissman, an immunologist studying vaccines, publish scientific papers about their breakthrough. They have figured out how to make synthetic RNA safe for injection into cells. This is a huge step forward for developing RNA-based medicines. - 2007+
Derrick Rossi, a Canadian stem cell biologist, starts his lab at Harvard Medical School in 2007. He sets out to build on the work of Drs. Karikó and Weissman, as well as the work of stem cell researcher Shinya Yamanaka. In 2009, his lab uses mRNA to make adult cells function like embryonic stem cells. This accomplishment will lead to the creation of Moderna in 2010. - 2010s
Dr. Cullis and his team begin working with Drs. Karikó and Weissman on vaccines that could use mRNA + LNP. This will lead to collaborations with BioNTech and Pfizer. - 2014+
Kizzmekia Corbett, a researcher with the National Institutes of Health (NIH) in the United States, begins work on coronavirus biology and vaccine development. The world had already seen two coronavirus outbreaks: one with Severe Acute Respiratory Syndrome (SARS) in 2003 and one with Middle East Respiratory Syndrome (MERS) in 2012. Dr. Corbett and her team study these coronaviruses, including the signature spike protein and the role it could play in vaccine development. This will lead to collaborations between NIH and Moderna. - December 2019
New illness is reported in Wuhan, China. - January 10, 2020
Complete genetic sequence of novel coronavirus is published and shared with scientists around the world. - January 2020+
Originally focused on MERS, Dr. Corbett’s team pivot quickly and start working with Moderna to develop a Covid-19 vaccine using mRNA.
Originally focused on Zika and influenza, Dr. Karikó, Dr. Weissman, and Dr. Cullis halt other projects to focus on SARS-CoV-2 and develop a Covid-19 vaccine using mRNA and LNP. - October 2023
Dr. Karikó and Dr. Weissman receive the Nobel Prize in Physiology or Medicine 2023 “for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19″.
Katalin Karikó
The story of mRNA began three decades ago, with a little-known scientist who refused to quit. Before mRNA was a multi billion-dollar idea, it was a scientific backwater. And for the scientist behind a key mRNA discovery, it was a career dead-end.
Born in 1955, Karikó is the daughter of a butcher in the small Hungarian town of Kisujszallas. Fascinated by science from a young age, Karikó earned a PhD at the University of Szeged and worked as a postdoctoral fellow at its Biological Research Center. In 1985, when the university’s research program ran out of money, Karikó moved to the United States with her husband and two-year-old daughter as a postdoctoral student at Temple University in Philadelphia.
In 1989, she landed a low-level position as research assistant professor at the University of Pennsylvania where she worked with Dr. Elliot Barnathan, a cardiologist. She was not able to receive grant money, and when Barnathan left the university after accepting a position at a biotech firm, Karikó was left without a lab or financial support. Luckily, another colleague believed in her: Dr. David Langer, a neurosurgeon who urged the head of the neurosurgery department to give Karikó‘s research a chance. Langer recalled that unlike other scientists, Karikó never cared about patent or how to make money out of a new discovery. Langer also left the university afterward.
In 1990, researchers at the University of Wisconsin managed to make synthetic RNA work in mice. Karikó wanted to go further. The problem, she knew, was that synthetic RNA was notoriously vulnerable to the body’s natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.
Karikó spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues. Leading scientific journals refused to publish her papers. “Every night I was working grant, grant, grant”, she remembered, referring to her efforts to obtain funding. “And it came back always no, no, no”.
By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. There’s no opportune time for demotion, but that year had already been uncommonly difficult for Karikó. She had recently endured a cancer scare and her husband was stuck in Hungary sorting out a visa issue. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on. She was back to the lower rungs of the scientific academy.
The work to which she’d devoted countless hours was slipping through her fingers. “Usually, at that point, people just say goodbye and leave because it’s so horrible”, Karikó said in an interview. She also said: “I thought of going somewhere else, or doing something else”. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: everything is here, and I just have to do better experiments”. She did not give up in the face of these difficulties. She persisted. “From outside, it seemed crazy, struggling, but I was happy in the lab”, she told Business Insider.
By 1997, Karikó was spending hours at the office’s Xerox machine, photocopying scientific journals to take home for reading. It was a fateful meeting by a photocopier that turbocharged Karikó‘s career. There she met Dr. Drew Weissman, an immunologist who was working on an anti-HIV vaccine. The duo started collaborating and writing grants. “We didn’t get most of them. People were not interested in mRNA. The people who reviewed the grants said mRNA will not be a good therapeutic, so don’t bother”, Weissman said.
The stumbling block, as Karikó’s many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response: the body sensed a chemical intruder and went to war. Every strand of mRNA is made up of four molecular building blocks called nucleosides[1]. In its altered, synthetic form, one of those building blocks was throwing everything off by signaling the immune system, very much like a misaligned wheel on a car. The pair of researchers soon worked out why: the synthetic mRNA was arousing a series of immune sensors known as toll-like receptors, which act as first responders to danger signals from pathogens.
“The solution, Karikó and Weissman discovered, was the biological equivalent of swapping out a tire”, the journalists Damian Garde and Jonathan Saltzman wrote for the science website Stat. In 2005, Karikó and Weissman reported that rearranging the chemical bonds on one of mRNA’s nucleosides, uridine, to create an analogue called pseudouridine, seemed to stop the body identifying the mRNA as an enemy. So, by replacing a specific nucleoside with a slightly tweaked version, Karikó and Weissman created a hybrid mRNA that could sneak its way into cells without alerting the body’s defenses. Thus, after a decade of trial and error, Karikó and Weissman discovered a remedy for mRNA’s Achilles’ heel, which allowed synthetic RNA to bypass the body’s immune system. “That was a key discovery”, said Dr. Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. “Karikó and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone”.
Their discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman; however, it offered absolution to the mRNA researchers who had kept the faith during the technology’s lean years. And it was the starter pistol for the vaccine sprint to come.
However, the studies by Dr. Karikó and Dr. Weissman caught the attention of some key scientists: Dr. Derrick Rossi, a Canadian stem cell biologist, and Dr. Uğur Şahin and Dr. Özlem Türeci, a married team of researchers of Turkish origin established in Germany, who have long been interested in immunotherapy. Rossi will later help found Moderna, while Şahin and Türeci will found BioNTech. Not only did Rossi recognize Karikó and Weissman‘s discovery as groundbreaking, he now believes they deserve the Nobel Prize in chemistry. “If anyone asks me whom to vote for some day down the line, I would put them front and center”, he said. “That fundamental discovery is going to go into medicines that help the world”, he added.
When trials found the BioNTech-Pfizer coronavirus vaccine to be safe and 95 percent effective in November 2020, Karikó‘s first reaction was a sense of “redemption”, she told The Daily Telegraph. Despite this triumph after her long struggle, Karikó said she is waiting for mass vaccinations to eradicate the virus’s threat. “Then, I will really be celebrating”, she told CNN.
Figure 1: Dr. Katalin Karikó and Dr. Drew Weissman invented the mRNA technology for the Covid-19 vaccines produced by BioNTech and Moderna.