But business disputes got in the way. The first time, she cornered him at a conference and begged him for his lipids. He said no because her university insisted on getting the rights to Protiva’s intellectual property, Dr. MacLachlan said. The second time, around when Dr. Karikó began working for BioNTech, Dr. MacLachlan flew to their offices in Mainz, Germany, to try to make a deal. Dr. Karikó visited Vancouver, too. But Dr. MacLachlan said the company’s offer was not serious. “Our shareholders would’ve crucified us,” he said.
Protiva was also engaged in an intellectual property fight with a new firm co-founded by Dr. Cullis. Disenchanted, Dr. MacLachlan quit the company and bought a motor home to travel with his family.
Eventually it was Dr. Cullis’s teams that worked with vaccine makers on wrapping an mRNA shot in lipids — a major departure from the scientists’ original goals. “We were not going in that direction at all,” Dr. Cullis said.
Wobbly Spikes
The work on mRNA and the lipid coats were two pieces of the puzzle that came together in 2020 in the Covid vaccines. But the third component was figuring out the precise mRNA code that would direct cells to make the most effective version of the coronavirus’s spike protein.
And that crucial bit of information came out of the longstanding collaboration between Drs. McLellan and Graham, who had been working together ever since their days sitting near each other at the Vaccine Research Center.
As Dr. McLellan prepared to open his own lab at Dartmouth in 2013, he and Dr. Graham discussed what the new lab should focus on. His mentor had a surprising answer: coronaviruses. It was a class of viruses that usually caused nothing worse than a cold, attracting scant interest from funding bodies. Devoting a lab to them would be a gamble.
But MERS had recently begun spreading in camel barns and slaughterhouses in the Middle East. Only 11 years earlier, another deadly coronavirus, SARS, had emerged in Southern China. And for a young researcher trying to make his mark, the lack of attention to coronaviruses meant less direct competition for research grants and signature findings.
“As we were talking about it, it seemed like we were maybe on a 10-year clock for new spillover events,” Dr. McLellan said.
MERS, like all coronaviruses, had a curious feature reminiscent of the shape-shifting proteins on H.I.V.: squirmy spikes on its surface that latch onto human cells. They had thwarted all efforts to make a vaccine. The MERS spike was especially fearsome, so much so that the scientists struggled to reproduce and isolate it in the lab. It was large, covered in a thick bush of sugars and highly unstable.
“It was pretty much a nightmare,” Dr. McLellan said.
Making matters more difficult, Dr. Graham had failed to secure samples from anyone infected with MERS in the Middle East.
After years of Western scientists parachuting into lower-income countries for studies that excluded local researchers, especially during the AIDS crisis, governments had “become very protective of their samples,” Dr. Graham said.
When a young Lebanese-American flu researcher in his lab, Hadi Yassine, recovered from an illness after a trip to Mecca, Dr. Graham thought he might have been infected with MERS. But it turned out to be a cold virus known as HKU1.
It was then that Dr. Graham had his insight: The world’s most boring coronaviruses may hold critical lessons about the most dangerous ones.
Like other coronaviruses, HKU1 had the dreaded spike — and, with some modifications, it held steadier than the one on the MERS virus. Within a few years, the team — which now included Andrew Ward, an expert, at the Scripps Research Institute, in freezing proteins to hold them still under an electron microscope — had published intricate images of the HKU1 spike in Nature. It was the first time scientists had visualized a human coronavirus spike protein in the initial form it took before latching onto cells.
“You can consider it luck,” Dr. Yassine said recently of his long-ago cold, “or you can consider it a blessing.”
Now, the team set out to use what they had learned about the spike on the common cold virus to steady the proteins on their real adversary, MERS. Making a vaccine depended on it.

Image

A MERS coronavirus particle.
Credit...
NIAID
The trouble was, any spikes they made in the lab — by adding genetic instructions to mammalian cells in a flask — were rarely stable and kept changing shape, making them much less effective for use in a vaccine.
The scientists needed to lock the spike in place. It was a complex task, so Dr. McLellan turned to the map he had built of the cold virus spike for clues.
Working alongside Dr. McLellan on that problem in his Dartmouth lab was Nianshuang Wang, a postdoctoral fellow from China, who believed that SARS and MERS presaged worse coronavirus outbreaks to come.
Dr. Wang’s job, like those of many junior scientists in American research labs, was to put in the lonely hours at the lab bench needed to realize his boss’s improbable ideas. The biggest discoveries often depended on those researchers, many of them ambitious students from outside the United States, who work on launching their own careers even as they play background parts in someone else’s.
In this case, Dr. Wang was working on a virus he knew well. The son of peasant farmers from a small village in eastern China, he as a child had become interested in the scientific concepts behind animal life, and later helped a Chinese team make crucial discoveries about MERS. Having read about Dr. McLellan’s R.S.V. research, Dr. Wang applied to join his Dartmouth lab, and was soon assigned the task of holding the MERS virus’s ungainly spike proteins still.
Part of what made them so prone to shape shifting was that they had pockets of empty space. So Drs. McLellan and Wang first tried filling them with a molecular glue — “cavity filling,” Dr. McLellan called it. Next they tried inserting two molecules that, when close enough, formed a bond, cementing a moving part of the spike to a steadier one. But both of those methods failed.
A third approach produced excellent results. Using their map of HKU1 as a rough guide, they zeroed in on a particularly loose joint of the spike and added two stiff amino acids. Those changes made the entire thing more rigid.
By the time they refined the method, however, the MERS epidemic was long over, and interest in coronaviruses had faded. Rejected by five prestigious scientific journals, the study ended up buried in a less prominent publication and a 2017 patent filing.
That was Dr. Wang’s only first-author journal article to come out of some three years of work — far short of what he needed for the prestigious academic job in the United States that he craved.
The lack of recognition stung, Dr. Wang said: It had been punishing, often boring work that had starved him of time with his wife and young daughter and left the family without much money.
But any lingering resentment disappeared when, in early 2020, a few months before leaving Dr. McLellan’s new lab at the University of Texas at Austin for a pharmaceutical company, Dr. Wang helped unearth his old findings to make a coronavirus vaccine.
“A small little thing can actually change the field, and even change the world,” Dr. Wang said. “That was the first thought for me.”
‘Back in the Saddle’

Image

Building 40 of the Dale and Betty Bumpers Vaccine Research Center in Bethesda, Md.
Credit...
NIAID
At 5:30 a.m. on Dec. 31, 2019, Dr. Graham, who regularly started his days before dawn, was working in his home office when he saw a news release from ProMed, a listserv for infectious disease experts around the world. A new pneumonia was spreading in Wuhan, China. At 5:54, he sent an email to his lab group: “We should keep an eye on this.”
A week later, he heard that the frightening new disease was caused by a coronavirus, the same class of pathogen that he had trained his focus on years earlier when most other scientists were ignoring them.
He called his old collaborator Dr. McLellan, whose lab had been splitting time between coronaviruses and other pathogens. When his cellphone rang, Dr. McLellan was browsing in a ski shop in Park City, Utah, while waiting for his snowboarding boots to be heat-molded. When he saw the caller ID, he thought Dr. Graham was calling to wish him a belated Merry Christmas.
Instead Dr. Graham told Dr. McLellan the grim news. “We need to get back in the saddle,” he said. “This is our time.”
Dr. McLellan texted his lab to let them know the news. Several days later, when Chinese researchers posted the virus’s genetic sequence online, they got to work.
Using what they had learned working on Dr. Yassine’s cold virus and MERS, the team zeroed in on the spikes and came up with genetic sequences within days, incorporating the crucial cementing technique that Drs. McLellan and Wang had refined.
And on Feb. 15, Dr. Graham and Dr. McLellan published a paper detailing the spike’s structure on a website for scientific manuscripts. The study was later published in Science.
“That meant a lot,” Dr. McLellan said. “Because we published where to put the stabilizing mutations, other companies could use it.”
The team’s stabilizing technique was crucial to the mRNA vaccines made by BioNTech (which by then had partnered with Pfizer) and Moderna, as well as certain non-mRNA vaccines.
Once Moderna and BioNTech scientists had genetic sequences for the spike, they then synthesized the mRNA molecules in their labs, applying the same chemical tweak that Drs. Weissman and Karikó had learned 15 years earlier. They wrapped their genetic cargo in protective fatty coats like those first dreamed up by the Canadians. They poured the resulting clear liquid into tiny glass vials and shipped them off for the first human tests.
<image>
From left: Dr. Graham, President Biden, Dr. Francis Collins and Kizzmekia Corbett. The scientists were explaining the role of spike proteins to Mr. Biden during a visit to the Viral Pathogenesis Laboratory at the N.I.H. last year.
Credit...
Pete Marovich for The New York Times
For Moderna’s all-important clinical trials, the government once again relied on its past investments in H.I.V. On March 3, 2020, as the coronavirus was spreading, Dr. Fauci called Dr. Larry Corey, a virologist at the Fred Hutchinson Cancer Research Center and the director of the government’s 21-year-old network of clinical trial sites for testing H.I.V. vaccines. “It’s time to pivot,” Dr. Fauci said.
At about 100 sites, the program would simultaneously test four vaccines: the mRNA shot from Moderna, as well as non-mRNA formulations from Johnson & Johnson, AstraZeneca and Novavax. (Pfizer decided to test the BioNTech vaccine on its own.)
“We wanted them all to succeed,” Dr. Corey said.
The team recruited 30,000 volunteers, a daunting task. It required enrolling 2,000 people a day — far more, Dr. Corey said, than had ever been attempted for a trial.
By November, the first results were in from the trial of Pfizer-BioNTech’s mRNA vaccine.
It was the culmination of decades of fundamental discoveries that had once been shrugged off as uninteresting. To get here, hundreds of researchers had tried, failed, reversed course and made incremental progress in different fields, never knowing for sure that any of their efforts would ever pay off.
If these Covid vaccines worked, Dr. Graham knew, they could pave the way for other new shots against diseases as varied as the common cold, flu and cancer — and even against that most elusive virus, H.I.V.
He was in his home office on the afternoon of Nov. 8 when he got a call about the results of the study: 95 percent efficacy, far better than anyone had dared to hope.
“It works!” he told his wife. Two of his grandchildren, 5 and 13, approached his office desk and hugged him from the front. His wife and son hugged him from the back. And the virologist began to sob.
But business disputes got in the way. The first time, she cornered him at a conference and begged him for his lipids. He said no because her university insisted on getting the rights to Protiva’s intellectual property, Dr. MacLachlan said. The second time, around when Dr. Karikó began working for BioNTech, Dr. MacLachlan flew to their offices in Mainz, Germany, to try to make a deal. Dr. Karikó visited Vancouver, too. But Dr. MacLachlan said the company’s offer was not serious. “Our shareholders would’ve crucified us,” he said. Protiva was also engaged in an intellectual property fight with a new firm co-founded by Dr. Cullis. Disenchanted, Dr. MacLachlan quit the company and bought a motor home to travel with his family.
Eventually it was Dr. Cullis’s teams that worked with vaccine makers on wrapping an mRNA shot in lipids — a major departure from the scientists’ original goals. “We were not going in that direction at all,” Dr. Cullis said. Wobbly Spikes
The work on mRNA and the lipid coats were two pieces of the puzzle that came together in 2020 in the Covid vaccines. But the third component was figuring out the precise mRNA code that would direct cells to make the most effective version of the coronavirus’s spike protein. And that crucial bit of information came out of the longstanding collaboration between Drs. McLellan and Graham, who had been working together ever since their days sitting near each other at the Vaccine Research Center. As Dr. McLellan prepared to open his own lab at Dartmouth in 2013, he and Dr. Graham discussed what the new lab should focus on. His mentor had a surprising answer: coronaviruses. It was a class of viruses that usually caused nothing worse than a cold, attracting scant interest from funding bodies. Devoting a lab to them would be a gamble. But MERS had recently begun spreading in camel barns and slaughterhouses in the Middle East. Only 11 years earlier, another deadly coronavirus, SARS, had emerged in Southern China. And for a young researcher trying to make his mark, the lack of attention to coronaviruses meant less direct competition for research grants and signature findings. “As we were talking about it, it seemed like we were maybe on a 10-year clock for new spillover events,” Dr. McLellan said.
MERS, like all coronaviruses, had a curious feature reminiscent of the shape-shifting proteins on H.I.V.: squirmy spikes on its surface that latch onto human cells. They had thwarted all efforts to make a vaccine. The MERS spike was especially fearsome, so much so that the scientists struggled to reproduce and isolate it in the lab. It was large, covered in a thick bush of sugars and highly unstable. “It was pretty much a nightmare,” Dr. McLellan said. Making matters more difficult, Dr. Graham had failed to secure samples from anyone infected with MERS in the Middle East. After years of Western scientists parachuting into lower-income countries for studies that excluded local researchers, especially during the AIDS crisis, governments had “become very protective of their samples,” Dr. Graham said. When a young Lebanese-American flu researcher in his lab, Hadi Yassine, recovered from an illness after a trip to Mecca, Dr. Graham thought he might have been infected with MERS. But it turned out to be a cold virus known as HKU1. It was then that Dr. Graham had his insight: The world’s most boring coronaviruses may hold critical lessons about the most dangerous ones. Like other coronaviruses, HKU1 had the dreaded spike — and, with some modifications, it held steadier than the one on the MERS virus. Within a few years, the team — which now included Andrew Ward, an expert, at the Scripps Research Institute, in freezing proteins to hold them still under an electron microscope — had published intricate images of the HKU1 spike in Nature. It was the first time scientists had visualized a human coronavirus spike protein in the initial form it took before latching onto cells. “You can consider it luck,” Dr. Yassine said recently of his long-ago cold, “or you can consider it a blessing.”
Now, the team set out to use what they had learned about the spike on the common cold virus to steady the proteins on their real adversary, MERS. Making a vaccine depended on it.

Image  A MERS coronavirus particle. Credit... NIAID The trouble was, any spikes they made in the lab — by adding genetic instructions to mammalian cells in a flask — were rarely stable and kept changing shape, making them much less effective for use in a vaccine. The scientists needed to lock the spike in place. It was a complex task, so Dr. McLellan turned to the map he had built of the cold virus spike for clues. Working alongside Dr. McLellan on that problem in his Dartmouth lab was Nianshuang Wang, a postdoctoral fellow from China, who believed that SARS and MERS presaged worse coronavirus outbreaks to come. Dr. Wang’s job, like those of many junior scientists in American research labs, was to put in the lonely hours at the lab bench needed to realize his boss’s improbable ideas. The biggest discoveries often depended on those researchers, many of them ambitious students from outside the United States, who work on launching their own careers even as they play background parts in someone else’s. In this case, Dr. Wang was working on a virus he knew well. The son of peasant farmers from a small village in eastern China, he as a child had become interested in the scientific concepts behind animal life, and later helped a Chinese team make crucial discoveries about MERS. Having read about Dr. McLellan’s R.S.V. research, Dr. Wang applied to join his Dartmouth lab, and was soon assigned the task of holding the MERS virus’s ungainly spike proteins still.
Part of what made them so prone to shape shifting was that they had pockets of empty space. So Drs. McLellan and Wang first tried filling them with a molecular glue — “cavity filling,” Dr. McLellan called it. Next they tried inserting two molecules that, when close enough, formed a bond, cementing a moving part of the spike to a steadier one. But both of those methods failed. A third approach produced excellent results. Using their map of HKU1 as a rough guide, they zeroed in on a particularly loose joint of the spike and added two stiff amino acids. Those changes made the entire thing more rigid. By the time they refined the method, however, the MERS epidemic was long over, and interest in coronaviruses had faded. Rejected by five prestigious scientific journals, the study ended up buried in a less prominent publication and a 2017 patent filing. That was Dr. Wang’s only first-author journal article to come out of some three years of work — far short of what he needed for the prestigious academic job in the United States that he craved. The lack of recognition stung, Dr. Wang said: It had been punishing, often boring work that had starved him of time with his wife and young daughter and left the family without much money. But any lingering resentment disappeared when, in early 2020, a few months before leaving Dr. McLellan’s new lab at the University of Texas at Austin for a pharmaceutical company, Dr. Wang helped unearth his old findings to make a coronavirus vaccine. “A small little thing can actually change the field, and even change the world,” Dr. Wang said. “That was the first thought for me.”
‘Back in the Saddle’

Image  Building 40 of the Dale and Betty Bumpers Vaccine Research Center in Bethesda, Md. Credit... NIAID At 5:30 a.m. on Dec. 31, 2019, Dr. Graham, who regularly started his days before dawn, was working in his home office when he saw a news release from ProMed, a listserv for infectious disease experts around the world. A new pneumonia was spreading in Wuhan, China. At 5:54, he sent an email to his lab group: “We should keep an eye on this.” A week later, he heard that the frightening new disease was caused by a coronavirus, the same class of pathogen that he had trained his focus on years earlier when most other scientists were ignoring them. He called his old collaborator Dr. McLellan, whose lab had been splitting time between coronaviruses and other pathogens. When his cellphone rang, Dr. McLellan was browsing in a ski shop in Park City, Utah, while waiting for his snowboarding boots to be heat-molded. When he saw the caller ID, he thought Dr. Graham was calling to wish him a belated Merry Christmas. Instead Dr. Graham told Dr. McLellan the grim news. “We need to get back in the saddle,” he said. “This is our time.” Dr. McLellan texted his lab to let them know the news. Several days later, when Chinese researchers posted the virus’s genetic sequence online, they got to work. Using what they had learned working on Dr. Yassine’s cold virus and MERS, the team zeroed in on the spikes and came up with genetic sequences within days, incorporating the crucial cementing technique that Drs. McLellan and Wang had refined.
And on Feb. 15, Dr. Graham and Dr. McLellan published a paper detailing the spike’s structure on a website for scientific manuscripts. The study was later published in Science. “That meant a lot,” Dr. McLellan said. “Because we published where to put the stabilizing mutations, other companies could use it.” The team’s stabilizing technique was crucial to the mRNA vaccines made by BioNTech (which by then had partnered with Pfizer) and Moderna, as well as certain non-mRNA vaccines. Once Moderna and BioNTech scientists had genetic sequences for the spike, they then synthesized the mRNA molecules in their labs, applying the same chemical tweak that Drs. Weissman and Karikó had learned 15 years earlier. They wrapped their genetic cargo in protective fatty coats like those first dreamed up by the Canadians. They poured the resulting clear liquid into tiny glass vials and shipped them off for the first human tests.
<image> From left: Dr. Graham, President Biden, Dr. Francis Collins and Kizzmekia Corbett. The scientists were explaining the role of spike proteins to Mr. Biden during a visit to the Viral Pathogenesis Laboratory at the N.I.H. last year. Credit... Pete Marovich for The New York Times For Moderna’s all-important clinical trials, the government once again relied on its past investments in H.I.V. On March 3, 2020, as the coronavirus was spreading, Dr. Fauci called Dr. Larry Corey, a virologist at the Fred Hutchinson Cancer Research Center and the director of the government’s 21-year-old network of clinical trial sites for testing H.I.V. vaccines. “It’s time to pivot,” Dr. Fauci said. At about 100 sites, the program would simultaneously test four vaccines: the mRNA shot from Moderna, as well as non-mRNA formulations from Johnson & Johnson, AstraZeneca and Novavax. (Pfizer decided to test the BioNTech vaccine on its own.)
“We wanted them all to succeed,” Dr. Corey said. The team recruited 30,000 volunteers, a daunting task. It required enrolling 2,000 people a day — far more, Dr. Corey said, than had ever been attempted for a trial. By November, the first results were in from the trial of Pfizer-BioNTech’s mRNA vaccine. It was the culmination of decades of fundamental discoveries that had once been shrugged off as uninteresting. To get here, hundreds of researchers had tried, failed, reversed course and made incremental progress in different fields, never knowing for sure that any of their efforts would ever pay off. If these Covid vaccines worked, Dr. Graham knew, they could pave the way for other new shots against diseases as varied as the common cold, flu and cancer — and even against that most elusive virus, H.I.V. He was in his home office on the afternoon of Nov. 8 when he got a call about the results of the study: 95 percent efficacy, far better than anyone had dared to hope.
“It works!” he told his wife. Two of his grandchildren, 5 and 13, approached his office desk and hugged him from the front. His wife and son hugged him from the back. And the virologist began to sob.