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Robert Baldwin, founding member of Stanford’s biochemistry department, dies at 93

Baldwin propelled leaps in scientists’ understanding of how proteins assemble themselves into the three-dimensional shapes that are essential to their function.

- By Bruce Goldman

         Robert Baldwin

Robert “Buzz” Baldwin, PhD, professor emeritus of biochemistry at the Stanford University School of Medicine, died March 6 of pulmonary failure at his home in Portola Valley, California. He was 93.

Baldwin devoted his career to studying how proteins, which begin life as linear chains of chemical building blocks, quickly assume their characteristic highly complex, functional structures. His research sped a shift in many biologists’ attention from organismic biology, the study of creatures great and small, to molecular biology, which focuses on the individual biochemical reactions that underpin all living processes and on the molecules — usually proteins — responsible for catalyzing those reactions.

“Buzz Baldwin was an outstanding scientist renowned for deep, penetrating thought,” said Lloyd Minor, MD, dean of the School of Medicine. “His discoveries laid the groundwork for our understanding of how a newborn protein accurately folds up into its adult shape within milliseconds — an insight that’s informed molecular biology ever since.”

Baldwin came to Stanford in 1959 to join a small cluster of scientists forming the nucleus of the medical school’s then-new Department of Biochemistry. He was the only member of the group who didn’t hail from Washington University in St. Louis.

“At the time there were a number of critical, unanswered questions about proteins,” said Paul Berg, PhD, emeritus professor of biochemistry and a member of that original group. “How does a protein know how to fold up, without mistakes and almost instantaneously, into a functional three-dimensional structure? Does it just try all the possibilities? Or are there guiding forces?”

Baldwin developed tools and designed rigorous experiments to show that instead of simply switching in binary fashion from their initial linear conformations into correctly folded final shapes, as had been postulated, proteins transition into their final shapes through short-lived intermediate structures. This demonstration and Baldwin’s follow-on findings simplified the analysis of proteins, accelerating the pace of discovery in medicinal chemistry and drug development.

Buzz was a giant in the field of protein folding, and a profoundly influential mentor to many.

Soft-spoken, of moderate height and slight of build, “Buzz was a giant in the field of protein folding, and a profoundly influential mentor to many,” said Peter Kim, PhD, the Virginia and D. K. Ludwig Professor in Biochemistry, who conducted doctorate work under Baldwin’s tutelage in the 1980s. “He exemplified what it means to be a scholar.”

Baldwin trained a number of scientists now ensconced in faculty positions around the world, Kim said. “His style was to give his students a tremendous amount of independence but, at the same time, insist on rigorous thinking. I’ve tried to follow his example with my own students.”

Berg, who won the Nobel Prize in chemistry in 1980, said, “He had an amazing memory. He could pull up the name — middle initial and all — of every coauthor on every paper related to a particular subject, the date it was published, everything.”

Recruited to round out a team

Robert Lesh Baldwin was born Sept. 30, 1927, in Madison, Wisconsin. He acquired the nickname “Buzz,” the only name anybody ever called him, because one of his two older sisters couldn’t pronounce the word “brother.”

On obtaining a bachelor’s of arts degree in chemistry in 1950 at the University of Wisconsin, Baldwin studied biochemistry at the University of Oxford as a Rhodes scholar, receiving his D.Phil. degree (the British equivalent of a PhD) in 1954.

After further postdoctoral training in physical chemistry at the University of Wisconsin, Baldwin joined that school’s faculty in 1955 as an assistant professor of biochemistry. In 1958, he was promoted to associate professor.

The same year, Arthur Kornberg, MD, then-chair of Washington University’s department of microbiology, approached Baldwin. Kornberg and the rest of his six-member group of researchers had resolved to move to Stanford to establish the latter school’s biochemistry department.

Kornberg was specifically looking for a physical chemist to round out the nascent department. He asked Baldwin if he’d like to be considered as a candidate for an associate professorship in biochemistry. Baldwin said yes and began his Stanford tenure in 1959.

After spending a year at the Max Planck Institute in Gottingen, Germany, and the Pasteur Institute in Paris between 1963 and 1964, Baldwin was promoted to full professor at Stanford in 1964.

In 1965, he married Anne Norris, PhD, then a postdoc in Paul Berg’s lab whom he came to know when a department secretary, playing Cupid, bought them side-by-side tickets on the same flight to a conference. Although Norris had been offered an assistant professorship at Harvard University that coming fall, she instead married Baldwin and stayed in California with him. In 1971-72, the couple took their two young children along to Paris on Baldwin’s second stint at the Pasteur Institute.

The Levinthal paradox

Baldwin’s already pronounced inquisitiveness about proteins was further piqued when, in 1968, he listened to a guest lecture delivered at Stanford by molecular biologist Cyrus Levinthal, PhD, who was then transitioning from Columbia to MIT.

The conventional wisdom at the time, based on scanty experimental proof, was that a protein folds all at once, assuming its optimal structure in the blink of an eye. But how?

In his talk, Levinthal posed this paradox: If folding proceeds by a random “guesswork” mechanism in which a moderate-sized protein of, say, 200 chemical units in length simply tries out every possible combination of bonding between these constituent chemical units, it would take longer than the life of the universe to exhaust all the possibilities. Yet proteins fold rapidly and reproducibly into stable, functional structures, often within milliseconds or even microseconds.

Intrigued, Baldwin used a number of clever biophysical techniques over the course of a decade to prove that the folding process was hastened by the formation of transient intermediate structures. These became known as protein-folding intermediates.

For example, it was known that some building blocks along the sequence of a protein dissolved in water can exchange hydrogen atoms with the surrounding solution. This exchange proceeds more slowly when the protein is in a folded structure than when it’s simply an unfolded linear sequence. Baldwin was able to show that hydrogen exchange was proceeding at a faster pace in some sections of a particular dissolved protein than in others — meaning some, but not all, parts of the protein must be in a folded state. Moreover, he showed, the folding process proceeded, piecewise, until the protein assumed its full structure. There were, in other words, intermediate states.

Later, Baldwin identified particular fragments of proteins that, isolated in a cool aqueous solution, assembled into helical structures by themselves — and that these so-called secondary structures were essentially identical to the ones those fragments formed when ensconced in the intact protein.

“This paved the way for scientists to investigate the initial steps in folding by analyzing small fragments rather than the entire protein,” Kim said.

Baldwin served as the biochemistry department chair from 1989 through 1994. He went emeritus in 1998 but, said Berg, continued to make major theoretical advances until the last five years of his life.

Baldwin published close to 200 peer-reviewed journal papers and served on the editorial boards of the Journal of Molecular Biology, Trends in Biochemical Science, Biochemistry, Proteins and Protein Science. He was a member of the National Academy of Sciences and of the American Academy of Arts and Sciences and a fellow of the Biophysical Society. He received the Stein and Moore Award of the Protein Society in 1992 and the Wheland Award in chemistry in 1995.

In addition to his wife, he is survived by two sons, David of Seattle and Eric of Urbana, Illinois; and five grandchildren.

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