PART 2:

Within six months, though, Dr. McLellan was flummoxed by H.I.V. and wanted to apply its lessons to another pathogen. So he approached his boss, Peter Kwong, with an unconventional proposal: Let’s start working on a more manageable virus. It was time, Dr. McLellan said, to take aim at “something important, but something more tractable.” Dr. Kwong was not keen on taking his eyes off H.I.V. With the virus killing more than one million people globally every year, Dr. Kwong believed that he had an obligation to stay focused. Still, Dr. Kwong put his protégé’s proposal for pursuing other targets to a vote of his entire team, just as he did matters of whom to hire and what equipment to buy. The result was almost unanimous, Dr. Kwong recalled: “Try other things.”

Dr. McLellan didn’t have to look far. He had been working in a spillover area on another floor from Dr. Kwong’s lab, and was seated close to Dr. Graham, who for years had studied not only H.I.V., but respiratory syncytial virus, or R.S.V., a disease that can kill young children. They got to talking, and Dr. McLellan began studying the structure of a protein that helps the virus fuse with cells. Over the next years, their success in stabilizing that protein opened the door to several R.S.V. vaccines now in clinical testing. And though they never expected it, their happenstance collaboration would prove critical for understanding the scary new virus that would emerge more than a decade later. A Pipe Dream

In the 1950s, the molecule at the heart of the mRNA vaccines was cloaked in mystery. Midcentury biologists knew that blueprints for making proteins — DNA — resided in the middle of cells, and that other structures within cells, called ribosomes, actually produced the proteins. But they didn’t know how the genetic blueprints found their way to the cellular factories. On April 15, 1960, at a frenzied and ecstatic meeting in an office at Cambridge University, half a dozen stars of the nascent field of molecular biology — including the future Nobel Prize winners Francis Crick and Sydney Brenner — had an epiphany. An elusive molecule known as X (pronounced “eeks,” because its name had been proposed by French scientists) was the messenger. The scientists figured out that X carried copies of segments of the DNA code to ribosomes, cellular machines that could read the code and pump out its corresponding proteins. The scientists named the molecule messenger RNA, or mRNA.

But for all of their initial excitement, those heavyweights of the field didn’t do much more with mRNA. The molecule was nearly impossible to isolate from cells because it would fall apart as it was being removed. “Molecular biologists were much more excited about DNA and proteins,” said Doug Melton, a Harvard biologist who in 1984 figured out how to make mRNA in a lab. “mRNA was just annoying because it was so easily degraded.”

For decades, few scientists paid attention to these delicate molecules. They might never have made it into the Covid vaccines if not for a chance meeting between two academics at a Xerox machine at the University of Pennsylvania.



Image  A transmission electron microscope image of messenger RNA connecting ribosomes. Credit... Omikron/Science Source Dr. Drew Weissman, a physician and virologist so taciturn that his family liked to joke he had a daily word limit, was desperate for new approaches to an H.I.V. vaccine. Earlier in his career, he had spent years in Dr. Fauci’s lab at the N.I.H. testing a treatment for AIDS that turned out to be toxic. One day in 1998, he was at the copy machine in Penn’s department of medicine when a woman approached him. Katalin Karikó, a 44-year-old scientist from Hungary, was as exuberant as Dr. Weissman was withdrawn. She had come to the United States two decades earlier when her research program at the University of Szeged ran out of money. But she’d been marginalized in American research labs, with no permanent position, no grants and no publications. She was searching for a foothold at Penn, knowing that she would be allowed to stay only if another scientist took her in. Her obsession was mRNA. Defying the decades-old orthodoxy that it was clinically unusable, she believed that it would spur many medical innovations. In theory, scientists could coerce a cell to produce any type of protein, whether the spike of a virus or a drug like insulin, so long as they knew its genetic code.

“I said, ‘I am an RNA scientist. I can do anything with RNA,’” Dr. Karikó recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine? “Oh yeah, oh yeah, I can do it,” Dr. Karikó said. Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions — encoded in mRNA — that would allow the body’s cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did. It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started. By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. Weissman and Karikó inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick. “Their fur got ruffled, they hunched up, they stopped eating, they stopped running,” Dr. Weissman said. “Nobody knew why.” For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA. Eventually, they solved the mystery. The researchers discovered that cells protect their own mRNA with a specific chemical modification. So the scientists tried making the same change to mRNA made in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response.

Their paper, published in 2005, was summarily rejected by the journals Nature and Science, Dr. Weissman said. The study was eventually accepted by a niche publication called Immunity. Just as mRNA itself had been ignored, no one cared that they could get cells to accept mRNA. It seemed of academic interest, at best. Fatty Coats



Image  Katalin Karikó of BioNTech. “I said, ‘I am an RNA scientist. I can do anything with RNA,’” she recalled telling Dr. Drew Weissman in 1998. Credit... Hannah Yoon Despite the naysayers, Drs. Karikó and Weissman believed their discovery could change the world. They now knew how to protect mRNA once it was inside a cell. But to work as a vaccine or a medicine, the fragile molecules would need to be shielded in the bloodstream to prevent degradation on their way to cells. As it turned out, a team of biochemists in Vancouver had spent years quietly revolutionizing ways of ferrying genetic material into cells. It was a partnership as improbable as any that helped lead to mRNA vaccines. The team’s ringleader was a lanky man named Pieter Cullis who had intended to become an experimental physicist, not a biochemist. But he came to feel that the biggest discoveries in physics had been made decades earlier, and went in search of emptier scientific pastures. He found one in the field of biological membranes: the outer layer of fats, called lipids, that encases the trillions of cells in the body, separating the watery outside from the inside. Dr. Cullis wondered if he could design his own lipid membranes to encase drugs or genetic material and transport it to cells. In the 1990s, mRNA-based medicines were on hardly anyone’s radar, but gene therapy was in vogue as a technique to modify certain genes to treat or cure disease. For those drugs to successfully deliver a new gene to a patient, they needed a FedEx package of sorts. And Inex, a firm co-founded by Dr. Cullis, set out to find one.

The project was grindingly difficult. He was working with fat globules one hundredth the size of a cell. Human cells had a system of elaborate defenses to prevent anything but food from entering. And some versions of his lipids were extremely toxic and had electric charges that could rip cell membranes apart. The big breakthrough came when he and his team figured out how to manipulate the positive charge on the fatty coats, said Thomas Madden, who worked with Dr. Cullis at Inex. The fatty bubbles would be charged when scientists loaded DNA inside, but the charge and toxicity disappeared once they were injected into the bloodstream. But technical challenges remained, and the Vancouver chemists decided there was more money to be made in other sorts of drugs. Dr. Cullis shifted focus, licensing the lipid technology for some applications to a new company, Protiva, whose chief scientific officer was a soft-spoken biochemist named Ian MacLachlan. In 2004, Dr. MacLachlan’s team made another crucial step forward: He encased the genetic material inside fatty coats in a way that would allow drug companies to increase production, and changed the ratios of lipids to keep more of the precious cargo from escaping. The team also worked to ensure that cells did not simply break up the genetic material as soon as it arrived. Seeing those advances as critical to making mRNA-based medicine, Dr. Karikó tried to convince Dr. MacLachlan twice over the coming years to work together.

PART 2:

Image  Peter Kwong, chief of the structural biology section at the National Institutes of Health, studies the rare human antibodies that could attack H.I.V. Credit... Shuran Huang for The New York Times Within six months, though, Dr. McLellan was flummoxed by H.I.V. and wanted to apply its lessons to another pathogen. So he approached his boss, Peter Kwong, with an unconventional proposal: Let’s start working on a more manageable virus. It was time, Dr. McLellan said, to take aim at “something important, but something more tractable.” Dr. Kwong was not keen on taking his eyes off H.I.V. With the virus killing more than one million people globally every year, Dr. Kwong believed that he had an obligation to stay focused. Still, Dr. Kwong put his protégé’s proposal for pursuing other targets to a vote of his entire team, just as he did matters of whom to hire and what equipment to buy. The result was almost unanimous, Dr. Kwong recalled: “Try other things.”

Dr. McLellan didn’t have to look far. He had been working in a spillover area on another floor from Dr. Kwong’s lab, and was seated close to Dr. Graham, who for years had studied not only H.I.V., but respiratory syncytial virus, or R.S.V., a disease that can kill young children. They got to talking, and Dr. McLellan began studying the structure of a protein that helps the virus fuse with cells. Over the next years, their success in stabilizing that protein opened the door to several R.S.V. vaccines now in clinical testing. And though they never expected it, their happenstance collaboration would prove critical for understanding the scary new virus that would emerge more than a decade later. A Pipe Dream



Image  Dr. Drew Weissman, third from right, and Dr. Katalin Karikó, third from left, in 2001. Credit... via Katalin Karikó In the 1950s, the molecule at the heart of the mRNA vaccines was cloaked in mystery. Midcentury biologists knew that blueprints for making proteins — DNA — resided in the middle of cells, and that other structures within cells, called ribosomes, actually produced the proteins. But they didn’t know how the genetic blueprints found their way to the cellular factories. On April 15, 1960, at a frenzied and ecstatic meeting in an office at Cambridge University, half a dozen stars of the nascent field of molecular biology — including the future Nobel Prize winners Francis Crick and Sydney Brenner — had an epiphany. An elusive molecule known as X (pronounced “eeks,” because its name had been proposed by French scientists) was the messenger. The scientists figured out that X carried copies of segments of the DNA code to ribosomes, cellular machines that could read the code and pump out its corresponding proteins. The scientists named the molecule messenger RNA, or mRNA.

But for all of their initial excitement, those heavyweights of the field didn’t do much more with mRNA. The molecule was nearly impossible to isolate from cells because it would fall apart as it was being removed. “Molecular biologists were much more excited about DNA and proteins,” said Doug Melton, a Harvard biologist who in 1984 figured out how to make mRNA in a lab. “mRNA was just annoying because it was so easily degraded.” The Coronavirus Pandemic: Latest Updates Updated  Jan. 25, 2022, 4:26 p.m. ET 15 minutes ago 15 minutes ago Pfizer and BioNTech begin a study of an Omicron vaccine, with initial results expected in the first half of the year. California leaders agree to once again require extra paid sick leave. OSHA withdraws its workplace vaccine rule.

For decades, few scientists paid attention to these delicate molecules. They might never have made it into the Covid vaccines if not for a chance meeting between two academics at a Xerox machine at the University of Pennsylvania.



Image  A transmission electron microscope image of messenger RNA connecting ribosomes. Credit... Omikron/Science Source Dr. Drew Weissman, a physician and virologist so taciturn that his family liked to joke he had a daily word limit, was desperate for new approaches to an H.I.V. vaccine. Earlier in his career, he had spent years in Dr. Fauci’s lab at the N.I.H. testing a treatment for AIDS that turned out to be toxic. One day in 1998, he was at the copy machine in Penn’s department of medicine when a woman approached him. Katalin Karikó, a 44-year-old scientist from Hungary, was as exuberant as Dr. Weissman was withdrawn. She had come to the United States two decades earlier when her research program at the University of Szeged ran out of money. But she’d been marginalized in American research labs, with no permanent position, no grants and no publications. She was searching for a foothold at Penn, knowing that she would be allowed to stay only if another scientist took her in. Her obsession was mRNA. Defying the decades-old orthodoxy that it was clinically unusable, she believed that it would spur many medical innovations. In theory, scientists could coerce a cell to produce any type of protein, whether the spike of a virus or a drug like insulin, so long as they knew its genetic code.

“I said, ‘I am an RNA scientist. I can do anything with RNA,’” Dr. Karikó recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine? “Oh yeah, oh yeah, I can do it,” Dr. Karikó said. Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions — encoded in mRNA — that would allow the body’s cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did. It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started. By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. Weissman and Karikó inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick. “Their fur got ruffled, they hunched up, they stopped eating, they stopped running,” Dr. Weissman said. “Nobody knew why.” For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA. Eventually, they solved the mystery. The researchers discovered that cells protect their own mRNA with a specific chemical modification. So the scientists tried making the same change to mRNA made in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response.

Their paper, published in 2005, was summarily rejected by the journals Nature and Science, Dr. Weissman said. The study was eventually accepted by a niche publication called Immunity. Just as mRNA itself had been ignored, no one cared that they could get cells to accept mRNA. It seemed of academic interest, at best. Fatty Coats



Image  Katalin Karikó of BioNTech. “I said, ‘I am an RNA scientist. I can do anything with RNA,’” she recalled telling Dr. Drew Weissman in 1998. Credit... Hannah Yoon Despite the naysayers, Drs. Karikó and Weissman believed their discovery could change the world. They now knew how to protect mRNA once it was inside a cell. But to work as a vaccine or a medicine, the fragile molecules would need to be shielded in the bloodstream to prevent degradation on their way to cells. As it turned out, a team of biochemists in Vancouver had spent years quietly revolutionizing ways of ferrying genetic material into cells. It was a partnership as improbable as any that helped lead to mRNA vaccines. The team’s ringleader was a lanky man named Pieter Cullis who had intended to become an experimental physicist, not a biochemist. But he came to feel that the biggest discoveries in physics had been made decades earlier, and went in search of emptier scientific pastures. He found one in the field of biological membranes: the outer layer of fats, called lipids, that encases the trillions of cells in the body, separating the watery outside from the inside. Dr. Cullis wondered if he could design his own lipid membranes to encase drugs or genetic material and transport it to cells. In the 1990s, mRNA-based medicines were on hardly anyone’s radar, but gene therapy was in vogue as a technique to modify certain genes to treat or cure disease. For those drugs to successfully deliver a new gene to a patient, they needed a FedEx package of sorts. And Inex, a firm co-founded by Dr. Cullis, set out to find one.

The project was grindingly difficult. He was working with fat globules one hundredth the size of a cell. Human cells had a system of elaborate defenses to prevent anything but food from entering. And some versions of his lipids were extremely toxic and had electric charges that could rip cell membranes apart. The big breakthrough came when he and his team figured out how to manipulate the positive charge on the fatty coats, said Thomas Madden, who worked with Dr. Cullis at Inex. The fatty bubbles would be charged when scientists loaded DNA inside, but the charge and toxicity disappeared once they were injected into the bloodstream. But technical challenges remained, and the Vancouver chemists decided there was more money to be made in other sorts of drugs. Dr. Cullis shifted focus, licensing the lipid technology for some applications to a new company, Protiva, whose chief scientific officer was a soft-spoken biochemist named Ian MacLachlan. In 2004, Dr. MacLachlan’s team made another crucial step forward: He encased the genetic material inside fatty coats in a way that would allow drug companies to increase production, and changed the ratios of lipids to keep more of the precious cargo from escaping. The team also worked to ensure that cells did not simply break up the genetic material as soon as it arrived. Seeing those advances as critical to making mRNA-based medicine, Dr. Karikó tried to convince Dr. MacLachlan twice over the coming years to work together. The Coronavirus Pandemic: Key Things to Know

Card 1 of 4 Omicron in retreat. Though the U.S. is still facing overwhelmed hospitals and more than 2,000 deaths a day, encouraging signs are emerging as new cases start to fall nationally. The World Health Organization said the variant offered “plausible hope for stabilization.” New York mask mandate. A New York judge ruled that the state’s mask mandate had been enacted unlawfully and is now void. The rule, renewed by Gov. Kathy Hochul in December, required masks or proof of vaccination at all indoor public places. The state attorney general, Letitia James, filed a motion to stay the ruling. Around the world. The European Union recommended that residents traveling within the bloc who have been vaccinated or have recovered from the virus should not face additional restrictions like testing or quarantine. In China, officials reported a case within a bubble set up to insulate Olympic participants from the rest of the country. Staying safe. Worried about spreading Covid? Keep yourself and others safe by following some basic guidance on when to test, which mask to pick and how to use at-home virus tests. Here is what to do if you test positive for the coronavirus.