A scientific hunch. Then silence. Until the world needed a lifesaving vaccine.

“You’ve made hugs and closeness possible again.”

“Thank you for your research efforts and persistence.”

Weissman is bewildered by the outpouring — and even more incredulous at requests for autographs and photos. The world’s appreciation is jarring to this researcher who doesn’t talk much and whose face rarely flickers with emotion. He is just as straight-faced in accepting some of the biggest awards in science and medicine, including the Lasker-DeBakey Clinical Medical Research Award that often precedes a Nobel Prize, as he is unflustered and matter-of-fact in recounting the long, frustrating run-up to this moment.

This article is part of a series about the vaccine vanguard, the scientists who helped create coronavirus vaccines. Read about Katalin Kariko and Barney Graham.

For more than two decades, Weissman and Kariko worked shoulder-to-shoulder at the lab bench to turn messenger RNA, the genetic instruction books that tell cells how to build proteins, into medicine. If DNA is the blueprint of life, messenger RNA is the work order that makes it happen. They were convinced this natural process could be harnessed to revolutionize how vaccines are made and transform how diseases are treated.

But the typical gatekeepers in science — journal editors, grant reviewers, investors — weren’t convinced. Messenger RNA was unstable, prone to fall apart. When it was injected into animals, it triggered an inflammatory response, making them sick, not better.

In 2005, Weissman and Kariko found a way to vastly increase mRNA’s therapeutic potential — a simple chemical tweak to one letter of its genetic code. This changed everything, they thought. Then, nothing happened.

“Our phones never rang. Nobody cared,” Weissman said. “But we knew the potential and never stopped working on it.”

Interest in the field had begun to heat up in the specialized world of biotechnology in recent years, but it was the pandemic that abruptly propelled the technology onto the biggest stage imaginable. The first-of-their-kind Pfizer-BioNTech and Moderna vaccines use messenger RNA to teach the body how to recognize and block the coronavirus. Their technology has become mainstream, overnight.

But the pandemic is the beginning, not the end of the scientific story.

Weissman wants to use messenger RNA vaccines to defeat influenza, stop the next coronavirus pandemic, prevent herpes, end HIV. He sees even broader opportunities on the horizon: a cure for sickle cell anemia that could be scaled up and deployed in Africa, unlike current treatments, and pave the way for other therapies.

In contrast to their reserved boss, the scientists who work in Weissman’s rapidly growing lab are ebullient. They share aphorisms from the places they grew up to describe their pursuit.

“Somebody else peels the orange, and the other people drink the juice,” said Xiomara Mercado-López, a senior investigator working on vaccines for influenza and a therapy for herpes, invoking a saying from Puerto Rico, where she grew up.

“Somebody takes the walnuts from the fire, but you enjoy them all,” said Elena Atochina-Vasserman, an adjunct assistant professor originally from Russia, who is working on a vaccine against the stomach bug norovirus. She keeps a sleeping bag stowed at her desk so she can work more efficiently.

“Somebody else planted the tree, but we have the shade,” said Qin Li, a senior research investigator focused on a universal influenza vaccine.

He ‘was born 40’

Growing up in Lexington, Mass., Weissman was noticeably more disciplined, self-possessed and capable than other kids, his younger sister, Stephanie Weissman, recalled. When they went sailing with cousins, Drew would sail and everyone else would be crew — which meant he did everything.

“He is one of those people who was born 40,” Stephanie said.

At Brandeis University, he met his future wife, Mary Ellen Weissman. A friend introduced them when Mary Ellen was having trouble with calculus. It was hard to get to know him at first, and they wouldn’t start dating right away. But he was smart — and funny.

When she was having trouble grasping the concept of infinity, he broke it down for her. “Imagine you could have all the clothes that you wanted,” Weissman said. “That’s infinity.”

Laura Friedman, a classmate who shared an apartment with Weissman during senior year, said an image from graduation is seared in her mind: Weissman arriving on a moped, clad in cap and gown, but different from the rest. Weissman had also received his master’s degree in biochemistry in the same time his classmates took to get their undergraduate diploma.

“We were all hard-working. And Drew worked a level harder than all of us,” Friedman said.

He decided to pursue a joint medical and scientific graduate degree at Boston University School of Medicine. He worked hard, but efficiently. When other students were studying the night before a big test, he and Mary Ellen would play tennis.

He seemed to be going through life with a firm sense of who he was and what he wanted to do, although he didn’t talk much about it. His family jokes that he has a daily word quota. Mary Ellen recalls her husband turning to interrupt her once and saying, without malice, “We’ve already talked today.”

What was always clear was that science was central. He was curious. He trained to be a doctor because he wanted to be a better scientist, said Mary Ellen, a child psychologist. He dreamed his work could lead to a vaccine or therapy that could benefit people.

“He just wants to do his thing, think about things, make his brain happy and move on,” Mary Ellen said.

A chance encounter

In 1991, Weissman went to work in the laboratory of Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. Working in Fauci’s lab introduced him to new connections between the lab and people’s health. Before Google, when there was a diagnostic question anywhere in the world, people would call Fauci’s lab to figure it out.

“If you put a person in a situation like that, the learning is immense,” Mary Ellen said.

He became fascinated by a recently discovered immune cell that branched like a tree under the microscope, with limbs that extended and retracted. These dynamic dendritic cells were key to how the immune system learned to defeat pathogens — and Weissman thought they would be the best target for vaccines.

“They travel around the body looking for foreign things,” Weissman said.

When he started his own laboratory, he wanted to work on targeting these cells.

Two things mattered in looking for a spot for Weissman and his family to land, Mary Ellen recalled: an institution with the potential for fruitful collaborations and a place with access to good schools for their daughters, Rachel and Allison.

Harvey Friedman recruited Weissman to the medical school at the University of Pennsylvania, where he was chief of the infectious-diseases division.

Weissman was an unconventional hire — he wasn’t trained as an infectious-diseases doctor, so Friedman had to battle his department chair to bring him in.

Not long after the move to Penn in 1997, Weissman ran into an intense Hungarian scientist at the photocopier, Kariko. Before science journals were online, scientists laboriously copied articles to keep apprised of the latest developments. Kariko and Weissman worked in different departments, but they were always competing for time at the same copier.

Kariko told Weissman about messenger RNA and her intention to turn it into a powerful medicine, certain it could become a method of delivering therapeutic proteins to cure disease. Weissman wondered if it could also be a way of delivering a foreign viral protein to the dendritic cells that he wanted to target for vaccine development. He asked Kariko if she could synthesize some messenger RNA for him to try in an experiment.

Weissman had been successful securing grants and had start-up funds left over from the university. He initially used those to help underwrite his scientific work on messenger RNA, a side project for a lab primarily focused on HIV. Weissman brought his expertise as an immunologist and his interest in vaccine development. Kariko brought exhaustive knowledge of RNA, a biochemistry background and unbounded enthusiasm for the work.

“He understood that [Kariko] had something a lot of people didn’t understand,” said Mark Dybul, a longtime colleague of Weissman’s who trained with him in Fauci’s laboratory.

‘We didn’t give up’

The first obstacle was scientific. The RNA triggered a harmful inflammatory response.

This was a major setback for Kariko, who had been hoping to use messenger RNA as a therapeutic in the brain. If they could not find a way to quell the inflammation, it could be a dead end for RNA as a therapy. Weissman remained intrigued that the molecule might make a good vaccine.

This was the kind of scientific frustration they were both used to, and for seven years they worked on messenger RNA, trying to understand how to turn it from a biological process into a medical technology.

Messenger RNA is a code written with a four-letter alphabet — C, G, A and U. Kariko and Weissman discovered that if they made a tiny chemical modification to the U, it had a profound effect — the messenger RNA no longer triggered inflammation and made much more protein.

Rachel Weissman, Drew’s older daughter, was in middle school when her dad told her he was excited because he had discovered something in the lab.

Her first question was whether he had named it after their family. It was something called mRNA, he told her.

“You did name it after us!” she said. Her mom is Mary Ellen, she was Rachel, ’n Allison was her younger sister.

But top scientific journals were not interested. Weissman recalled that even at the solid but specialized journal Immunity, it was a long back and forth to publish. The work was so far ahead of its time that few people recognized its significance.

Over the years, Kariko and Weissman tried everything to push their ideas forward. They sought grants. They founded a company to turn their technology from a novel finding into something that could save people’s lives.

Haitao Hu, a scientist who joined the lab to pursue his graduate degree shortly around the time of their breakthrough in 2005, said Weissman’s lab was a remarkable place to learn how to be a scientist.

A paradox of science is that as investigators grow more successful, they often end up with huge labs, doing so much traveling, giving talks and writing grants that they drift farther from the lab bench.

Weissman was curious, not ambitious, following the ideas where they led and more focused on mentoring scientists in his lab than traveling.

“He enjoys science. He loves basic research,” Hu said.

When Weissman ran into a problem in the lab, he would often start a project at home. Build a deck. Do some plumbing. Put an addition onto the house.

Often, while he labored on something completely different, he would find a way to solve the problem he was ramming into at work.

“He’d use that as an outlet when he was frustrated, and often that meant there was something broken or halfway done,” Rachel recalled recently.

There were still more hurdles before messenger RNA could become useful for medicine: its fundamental instability. Norbert Pardi, a scientist who trained with Weissman and Kariko, spent three years trying to find a safe and efficient way to deliver it intact. After a long string of failures, he made what felt like a last-ditch effort to see if a lipid nanoparticle — a submicroscopic bubble of fat — developed by the Canadian company Acuitas Therapeutics could be used to protect the molecule and deliver it to cells in living animals.

For the test experiment, he created messenger RNA encoding an enzyme called firefly luciferase. As the name suggests, if cells made the enzyme, then they would light up once he injected another protein.

Pardi injected it into a mouse and saw light. To this day, Pardi, who now runs his own lab at Penn, remembers the date — Aug. 20, 2014.

When he talked about it with Weissman the next day, they both knew what it meant. This was going to work.

Weissman recently received an honorary degree from Drexel University’s College of Medicine, and at commencement, he wished an audience of young physicians a lifetime of frustration.

“The person who achieves his goal is the one that has faced frustration and dealt with it, understood it, and used it to their advantage,” Weissman said. “We repeatedly fell, were knocked down, ignored. And we kept getting up, and we didn’t give up.”

Prepared for battle

When outbreaks of the Zika virus occurred in 2015 and 2016, Weissman began working on a vaccine. His family thought this might be his breakthrough moment.

Rachel, more than anyone in the family, could talk science with her dad. She followed in many of his footsteps, taking many of the science classes he did at Brandeis. She spent a summer working in his lab. Her senior year, she welded a sculpture of the molecule that made messenger RNA work, pseudouridine.

But even Rachel, conversant in science, realized her dad wasn’t keeping them in the loop and so set up a Google alert with his name.

The Zika vaccine was successful in protecting monkeys, but it went back on the shelf as the threat receded. It turned out to be a dry run.

When the coronavirus pandemic hit, Rachel called him.

“You’re on this, right?” she asked.

“Yeah, yeah,” he told her.

Mary Ellen and daughter Allison volunteered for a vaccine trial. Weissman felt he couldn’t, because he didn’t want to have the appearance of bias. His lab has received funding from BioNTech, and he consulted with the company, but his and Kariko’s inventions are crucial to both the Moderna and Pfizer-BioNTech vaccines.

Weissman found out the Pfizer-BioNTech vaccine was remarkably effective when Mary Ellen interrupted his work early one morning in November. She had heard it on the news.

Weissman let the moment sink in and then told his wife he needed to get back to work. He did call his parents, who are in their 80s, to let them know.

When the Pfizer-BioNTech vaccine was given an overwhelming thumbs up by an expert federal advisory panel, all but ensuring it would get a regulatory green light, Rachel FaceTimed him.

“Dad, your vaccine,” she said. “It can go into people.”

His face, she recalled, was characteristically blank. He had been in meetings all day.

Scientists will debate how much the chemical modifications Kariko and Weissman discovered contribute to the vaccines’ success. A messenger RNA vaccine that did not incorporate those changes flopped.

Weissman thinks he knows why. More than a year before the pandemic, he and colleagues showed that modified RNA is key to a robust immune response. It triggers key immune cells called T follicular helper cells. Those T cells then drive the immune cells that produce virus-fighting antibodies. Unmodified messenger RNA, on the other hand, triggers molecules that block those T cells.

When Friedman, the Brandeis classmate, got her shot, she called Weissman minutes afterward.

“I cry when I think about Drew in so many different ways. I called him after both my vaccines, saying, ‘Thank you for saving my life and for saving the world, and also — as a friend,’ ” Friedman said.

“You’re welcome,” she thinks he replied.

Then, ever the consummate physician and friend, he reminded her: She should really stay there for the full 15 minutes after her shot in case of any adverse reaction.

Alice Crites contributed to this report.

Editing by Stephen Smith. Photo editing by Bronwen Latimer. Design by Tara McCarty. Copy editing by Melissa Ngo.