David Baltimore’s enduring legacy: Remembering ‘a giant of science’

A month after his passing, a reflection on how the Nobel-winning molecular biologist helped shape the culture and institutions of today’s biotech era

Molecular biologist David Baltimore, a Nobel laureate whose work bridged the worlds of science, medicine and public health, embodied the values that made U.S. biomedical research a global force. His career was a testament to what’s possible when public investment and scientific genius align.

One of the greatest scientists of his generation, Baltimore won the Nobel Prize at age 37 for a landmark discovery that changed the course of science. Baltimore, who passed away last month at 87, went on to found the Whitehead Institute for Biomedical Research; serve as president of the California Institute of Technology and the Rockefeller University; chair the board of scientific counselors at the Broad Institute of MIT and Harvard; lead a key NIH advisory committee during the AIDS epidemic; found, lead, and advise biotech companies; and mentor a generation of top scientists.

Baltimore’s discovery of reverse transcriptase, for which he won the Nobel for Physiology or Medicine in 1975, is a rare example of a finding whose transformative potential was immediately understood.

The discovery upended the central dogma of biology, which maintained that DNA became RNA which became protein, and never the other way around. The discovery, which came before the establishment of the biotech industry, would turn out to be critical for treating HIV and AIDS, a massive priority for Baltimore throughout his life.

“His discovery of reverse transcriptase opened up a whole new world in understanding biology and having application in medical treatments,” Stelios Papadopoulos told BioCentury.

Upon Baltimore’s passing, Hugh Rosen emailed his postdocs and students at Scripps Research to urge them to read Baltimore’s Nobel lecture. “It is especially important that our students and postdocs understand they stand on the shoulders of giants,” Rosen, who served with Baltimore on the board of Regulus Therapeutics Inc., told BioCentury.

“For those of us who knew him, he was the most gifted biochemist and molecular biologist, who rose meteorically but sustained rigor and scientific vigor throughout his life,” Rosen wrote to the members of Scripps’ Department of Molecular and Cellular Biology, of which he is chair. “The press is replete with scientific obituaries which cannot do justice to this singular scientist, who changed our world for much good.”

Baltimore began his Nobel lecture in December 1975 by describing how the “pleasure” of being a biologist is derived from the “continuing realization of how economical, elegant and intelligent are the accidents of evolution.”

“A virologist,” he wrote, “is among the luckiest of biologists because he can see into his chosen pet down to the details of all of its molecules.”

Baltimore’s friends and colleagues describe him as wise, clever, funny and, above all, generous with his time.

He was also fiercely competitive, with a deep passion for fishing.

One day, friend and Harvard Medical School professor Tomas Kirchhausen grew bored while fishing with Baltimore off Cape Cod, where Baltimore and his wife of 56 years, Alice Huang, had a home in Woods Hole. Kirchhausen, a novice fisherman tagging along to keep Baltimore company, decided the fish must be bored as well. He began moving his line in the water, quickly drawing rebukes from Baltimore and the boat captain. Baltimore was “pissed” when they arrived at shore, said Kirchhausen, who had boated the most fish, an ignominy Baltimore would never live down.

A lifetime of scientific rigor

There are two categories of Nobel winners, said Papadopoulos, the longtime investment banker, chairman of Exelixis Inc., and former chairman of Biogen Inc. and Regulus: those for whom the prize reflects a “moment of genius” and those who have that moment and then continuously push the boundaries of science. Baltimore had “a lifetime of being always at the leading edge of scientific rigor.”

That quality made him an invaluable board member for biotech companies, such as Regulus, said Papadopoulos. “He could judge better than anybody what data you could believe, what you needed to do to get greater comfort with the data, and where the data could take you. These questions are some of the biggest challenges young companies face,” said Papadopoulos.

Baltimore served on the board of Amgen for more than 20 years, with his “leadership in research and his advocacy for scientific excellence” leaving “an indelible mark on Amgen and our industry,” the biotech said in a remembrance. Other director posts included seats on the boards of Altos Labs Inc. and MedImmune LLC.

Papadopoulos said Baltimore “had a real vision that microRNA would become a therapeutic modality.” 

Rosen recalled seeing Baltimore’s face when Regulus’ data came out in March for its microRNA therapy in autosomal dominant polycystic kidney disease. “Just to get a glimpse of how intensely satisfying it was for him to see these discoveries go from the earliest glimpse of mechanism in his lab to begin to impact upon people was, I thought, very uplifting,” he said.

The data set up Regulus for its takeout a month later by Novartis for $800 million up front. “We should all be happy that David was around long enough to see validation of his microRNA vision,” Papadopoulos said, noting that farabursen would be the first “real microRNA-related compound out there, if it gets approved.”

Baltimore was a key contributor to the early growth of the biotech sector, notably with Collaborative Genetics. He helped found companies such as Calimmune and Immune Design and, most recently, s2A Molecular.

His “extreme love of science” and “extreme rigor” were paired with a practicality, Papadopoulos said.  He wasn’t one of those “blue sky scientists not realizing that some things we do may and others do not have commercial implications. So [he] was very integrated in that way.”

As founding director of the Whitehead Institute, Baltimore partnered with Edwin “Jack” Whitehead to create a new type of research center in partnership with the Massachusetts Institute of Technology. What set the Whitehead apart was that, although it was intimately associated with MIT, the new independent center had its own endowment and board of directors, and its fellows would have an independent lab and PI status straight out of their Ph.D., skipping the typical three-to-five-year postdoc period. 

Baltimore was also essential in the Broad Institute’s formation, according to a remembrance written by founding director Eric Lander, himself one of the first handful of Whitehead fellows. “Without David Baltimore, the entire scientific enterprise — generations of amazing scientists, many vibrant new institutions, our knowledge of biomedicine — would be much poorer,” Lander said.

Baltimore also advised his friend and Caltech colleague Leroy “Lee” Hood when Hood was establishing the Institute for Systems Biology, drawing on Baltimore’s experience creating an independent, interdisciplinary research institute.

He was “a giant of science,” Papadopoulos said, “and a hell of a lot of fun to be with.”

‘Amazing mentor’

Baltimore’s presence instantly lent additional credibility to universities and foundations, and thousands of scientists benefited from his teaching, mentoring, listening and advice.

“David has trained dozens of people at all levels: undergraduates, graduates, Ph.D. students and postdocs. And most of them had a very successful career,” Fondation Santé President Spyros Artavanis-Tsakonas told BioCentury. “This is a measure of his grandeur.”

Baltimore’s addition to the SAB of Fondation Santé, which supports academic scientists in Greece and Cyprus, gave the foundation’s fellowships further prominence. “Having on your scientific advisory board somebody of David’s stature made these fellowships quite prestigious,” said Artavanis-Tsakonas, a former Yale and Harvard developmental biologist who met Baltimore at Cold Spring Harbor Laboratory roughly 40 years ago.

Baltimore’s hiring by the California Institute of Technology in 1997 changed the perception of Caltech in the biological sciences, instantly giving the university’s biology program more credibility at a time when it was considered second-rate, said Pamela Bjorkman, the David Baltimore professor of biology and biological engineering at Caltech.

Many of her students wanted Baltimore on their thesis committee, she recalled. At students’ thesis defenses, “David would appear to be asleep, then would ask a devastating question,” Bjorkman said. “I never could figure out if it was an act or not.”

For his Whitehead fellows, particularly some of the first cohort, Baltimore took a personal interest in mentoring, said Peter Kim, a biochemistry professor at Stanford Medicine who led research at Merck & Co. Kim was among the first handful of Whitehead fellows, along with Lander and David Page, who would go on to direct Whitehead. 

For Kim, that mentorship would last decades.

“If I needed to talk to him, if I wanted to understand something, or if I wanted to get his advice on something, he would absolutely make the time,” said Kim. He was an “amazing mentor, and I think there are probably more than a hundred people who would say the same thing.”

 Describing his style, Kim said: “He would probe, he would gently nudge, and in ways that would sort of make you smile, but also make you realize that there's probably something to be thinking about here. A real style.”

The Baltimore Committee

During the AIDS epidemic, Baltimore called upon the scientific community to work on HIV at a time when many were afraid to work on the virus. “He took it upon himself to make it a huge priority for himself” and other scientists, recalled Kim.

Kim said that Baltimore instilled in his fellow scientists a sense of duty. “As scientists, we had a moral responsibility to do something about it.”

The AIDS Vaccine Research Committee quickly became known as the Baltimore Committee, with Baltimore demanding expertise even as the crisis was fast-moving. For example, Stanford University’s Irving Weissman said Baltimore and then-NIAID Director Tony Fauci brought in one of Baltimore’s “very best former trainees,” Gary Nabel, to lead the vaccine effort as founding director of NIAID’s Vaccine Research Center.

The Baltimore Committee became the de facto advisory committee for NIH on an AIDS vaccine and for the Vaccine Research Committee.

“That was typical of him to take a leadership position and to go beyond just being a caretaker leader, but to push things to make sure that you were going to make progress and you were using good science,” said Weissman.

At the time, “there were just no way yet to develop a vaccine that could change its proteins as rapidly as the virus did it,” he added.

“David was almost selfless in devoting time, energy and his natural creative talents,” Weissman said.

A river runs through it

It took a huge, cinnamon-colored black bear befriending the camp that Weissman, Baltimore and future NIH Director Harold Varmus and their families had pitched in Montana’s Bob Marshall Wilderness Complex to prompt Baltimore’s wife to say, “Irv, we’re not going to go into the wilderness with you anymore. Why don’t you find a place for us,” Weissman said.

Weissman and Baltimore and their families and friends had been trekking miles into the wilds of Montana by horse for years to camp and fish. 

Naturally, Weissman, a Montana native, found a place near the Rocky Mountain Lab, the NIAID lab where Rocky Mountain spotted fever was discovered. Weissman, Baltimore and Hood built a place there in 1990.

The house, set back from the nearby river, was a refuge for Baltimore during the decade-long controversy over a 1986 Cell paper by Thereza Imanishi-Kari on which Baltimore was one of six co-authors.

The highly charged case, involving accusations of scientific fraud, pitted scientists against scientists and lawmakers against scientists, eventually leading to investigations by Congress. Baltimore resigned, under pressure, as president of Rockefeller University. Imanishi-Kari was cleared of wrongdoing by a federal appeals panel, and Baltimore was ultimately vindicated, but one wonders what else he could have accomplished in his distinguished career had it not been sidetracked by the episode.

“Baltimore was standing up for how science works,” Harvard professor and longtime friend Stephen Harrison told BioCentury, “against how misguided science works.” And, importantly, he was standing up for someone who was being accused of criminal behavior when it was perhaps sloppy work.

Reflecting upon today’s environment, with the White House at loggerheads with universities, Harrison (who met Baltimore in 1969 during MIT’s March 4 movement protesting the Vietnam War) said academia and biotech need to have the courage to navigate these times and reconstruct bioscience when we emerge on the other side.

In addition to being a safe haven in a trying time for Baltimore, the Montana house was also where Baltimore advised Lee on how to establish the Institute for Systems Biology.

“That’s the sort of character that he had,” said Weissman. “He was willing to go the next step and help people out.”

It was Weissman who taught Baltimore how to cast. 

Each year, the friends would take a five-day trip down the Smith River through a Montana canyon where no roads reached the river, floating for five days and 67 miles, canyon walls reaching 300 feet tall. They would invite fellow scientists — Varmus, Jonathon Howard, David Anderson and others — to join them each June at the point when the river was no longer flooding but still had enough water for their rubber rafts. 

Once, Weissman recalled, Baltimore’s fly dropped into a crevice in the canyon wall, just as the Stanford professor was starting to cast. 

“He picked it up and became a master fisherman,” said Weissman.

Baltimore, when asked by the hosts of the This Week in Virology podcast in September 2010 why scientists like to fish, answered, “There is an excitement about catching a fish. Suddenly, you’re connected to this piece of the natural world that has come out of the water, where you didn’t know it was there before.”

He found fly fishing totally absorbing, the constant calculations of where the fish will be, what it wants to eat, and controlling the line.

“It’s because scientists like anything that’s absorbing,” Baltimore told TWiV. “We like things that are hard and take a real concentration.”

In his letter to his department, Rosen turned to a line from the Norman Maclean classic A River Runs Through It. “To him, all good things — trout as well as eternal salvation — came by grace, and grace comes by art; and art does not come easy.”

Rosen added, “I think if we substituted science, David would probably be smiling.”

Baltimore is survived by his wife, Alice Huang, a senior faculty associate in biology at Caltech; his daughter, TK Baltimore, and son-in-law, Jay Konopka; and his granddaughter.