Retrospective in ASBMB

January 1, 2019

Thomas A. Steitz (1940 — 2018)

Published January 01 2019

By Martin Schmeing

Thomas A. SteitzTom Steitz at the Nobel Prize press conference at the Royal Swedish Academy of Sciences in 2009.PROLINESERVER/WIKIMEDIA COMMONS Thomas Arthur Steitz was a remarkable person, scientist and mentor. He was a Sterling professor of molecular biophysics and biochemistry at Yale University, a Howard Hughes Medical Institute investigator, a Nobel laureate and a giant in the field of structural biology. His death on Oct. 9 left a void in the scientific community and for those who knew him as well as a legacy of fundamental discoveries.

Tom was born Aug. 23, 1940, in Milwaukee, Wisconsin. His childhood in a family of five siblings was filled with classic Americana — tennis and skating and summers spent picking vegetables on his grandfather’s farm. In high school, Tom became a skilled saxophonist, developing his lifelong love for music. He also excelled academically, initially spurred on by his younger brother’s higher grades.

Tom earned a scholarship to Lawrence College, where he majored in chemistry and credited the humanities courses for maturing his world view. Robert Rosenberg, a mentor at Lawrence, inspired him to pursue a career in science. As a rising senior, Tom attended a conference at the Massachusetts Institute of Technology held by the American Biophysical Society to promote graduate study in biophysics; impressive talks by Alex Rich and Paul Doty had the desired effect. Tom enrolled at Harvard for graduate studies in biophysics in 1962.

Tom intended to study nucleic acids at Harvard until he was wowed by lectures given by Max Perutz, who was visiting from England. Max showed 3D slides of the structure of myoglobin, the first atomic resolution protein crystal structure, an achievement that had won Max a Nobel Prize in 1962. To Tom, seeing was believing: Visualizing a macromolecule was clearly the way to understand its function. This was echoed throughout Tom’s career as generations of graduate students at Yale were asked, “Why don’t you just crystallize it?”

Upon learning that Bill Lipscomb (Nobel laureate for chemistry, 1976) was using crystallography to study proteins, Tom joined his group at Harvard. Working with five postdocs, and most closely with Martha Ludwig, Tom calculated progressively higher electron density maps of bovine carboxypeptidase A, culminating in a 2.0 Å structure of the protein.

At Harvard, Tom met Joan Argetsinger, a fellow Midwesterner and a graduate student in Jim Watson’s lab. Tom and Joan married in 1966, and from then on they were the power couple of molecular biology. Their careers were independent, and they published together only rarely, but it is hard to imagine a more balanced, honored and impactful couple in modern science.

Tom joined David Blow’s lab at the Laboratory of Molecular Biology in Cambridge, England, as a postdoctoral fellow and worked with then-graduate student Richard Henderson (Nobel laureate for chemistry, 2017) on solving structures of chymotrypsin bound to its substrates. These studies led to a mechanistic understanding of the serine protease family and of its substrate recognition. Tom often said the years in Cambridge were his most scientifically fulfilling, and they shaped his view of the optimal scientific environment. He recalled stimulating discourse, always about science, with whichever world-leading scientist (perhaps Fred Sanger, Francis Crick or Sidney Brenner — Nobel laureates all) was sitting next to him in the canteen for lunch. It was a stress-free and wonderful time, he said, with no worries, just exciting science. Asked later about the pressure to produce results to secure a faculty position, Tom replied, “Ah, yes, well. I did have a faculty position waiting for me at Berkeley.”

Tom Steitz poses with his ribosome traineesTom Steitz poses with his ribosome trainees in Stockholm after winning the 2009 Nobel Prize in chemistry. Pictured, from left, Poul Nissen, Tom Steitz, Martin Schmeing, Jeff Hansen and Nenad Ban.courtesy of Martin schmeing As it turns out, he was only at Berkeley for two months. Starting as an assistant professor in 1970, Tom asked the department chair to consider interviewing Joan for a faculty position, as she had also done successful postdoc research in Cambridge. The chair told him promptly that females were best suited to be research assistants and that no female scientist would be considered for a faculty position. (This seems shocking now, when Berkeley is thought of as liberal, but Tom said back then, in general, the students were liberal and the faculty members were conservative, which helped explain why it was a frequent site of protests.) Tom and Joan both received offers at Yale, so they left California for New Haven.

At Yale, Tom started working on the structure of hexokinase, the first enzyme in the glycolysis pathway, a subject recommended to him by Brian Hartley at Cambridge. Hexokinase structures with and without substrates were Tom’s first big success as an independent researcher. This work with his postdoc Robert Fletterick visualized Dan Koshland’s induced fit model, according to which binding of the cognate substrate to an enzyme caused a conformational change to enable activity. These hexokinase crystals were notoriously robust. In later years, if a trainee was short on crystals for soaking experiments, Tom would recall that when more hexokinase crystals were required, they would simply saw them in half and, “Voila! Twice the crystals.”

Tom had been recruited to Yale by pioneering structural biologist Fred Richards. At about the same time, Don Engelman and Peter Moore were hired, and together with Hal Wyckoff, they formed what became the Yale Center for Structural Biology. By the mid-1990s, this group included Jennifer Doudna, Paul Sigler and Axel Brünger. This concentration of leading structural biologists made for an exciting and dynamic environment that powered each group’s research.

After hexokinase, Tom embarked on a broad research scheme that defined the rest of his career: studies of Crick’s central dogma of molecular biology. Starting in the late 1970s, Tom and his lab made seminal discoveries that provided fundamental understanding about every part of the central dogma.

Most famously, in a collaboration with Yale colleague Peter Moore spearheaded by postdocs Nenad Ban and Poul Nissen, Tom determined the first structures of the large ribosomal subunit. The ribosome structures provided insight into how proteins are made and showed the ribosome to be a ribozyme, making the logical link between the primordial “RNA world” and the modern world dominated by protein enzymes. He also solved structures (with the author) representing each chemical step of the ribosome linking amino acids together, and (with Jeff Hansen) of the ribosome bound by clinically important antibiotics. For this ribosome work, he shared the Nobel Prize in 2009 with Venki Ramakrishnan and Ada Yonath.

Tom Steitz and his familyTom Steitz and his family in Stockholm for Nobel week in early December 2009. Pictured from left, daughter-in-law Katherine, son Jon, wife Joan and Tom.Courtesy of Martin Schmeing Tom trained generations of outstanding students at Yale. He had a reputation for bluntness but was a supportive mentor. He effectively conveyed his excitement for important fundamental science and knowledge for the sake of knowledge. Continuing the advocacy that inspired him to leave Berkeley, he believed that talent and drive, not gender, should be determinants of success and embodied this with egalitarian mentoring. He fostered a rigorous attitude to performing science where the most direct route to a clear answer was prized, a virtue visible in many of his lab alumni.

All his trainees fondly recall go-to Tomisms such as “if it doesn’t crystallize, add another component to the complex,” “always set up crystal trays before you go on vacation so experiments are still happening while you are skiing” and “if your crystallization drop doesn’t have precipitate in it, you haven’t done the experiment.”

Complementing his no-nonsense attitude to science, Tom had an earnest sense of humor, full of dad jokes and puns, often made with a pause and a telling smile. The antibiotics that blocked peptide movement through the ribosomal tunnel caused “molecular constipation.” The so-called “thumb” domain in polymerases structures that resemble a right hand had to be coloured green in reference to gardening. In his Nobel autobiography, he referred to a spanking as an application of the “board of education” to his “seat of knowledge.” And he would start serious advice in the style of Yogi Berra, “The hardest thing to predict is the future …”

Outside the lab, Tom loved skiing, which led to the annual Steitz-Engelman lab ski trip; the annual “Riboski” trip with RNA-loving colleagues including Tom Cech, Jim Dahlberg, John Abelson and Olke Uhlenbeck; and trips with his son, Jon. Tom was a loving and proud father to Jon, who was born in 1980. Tom and Joan hosted memorable lab picnics and Halloween parties, sometimes serving bottles from Tom’s prized wine collection. He was a keen gardener, at times battling the local Stony Creek rabbits and deer. He also enjoyed hiking in the mountains and sailing among the Thimble Islands.

Tom was at his home overlooking these Thimble Islands when he died from pancreatic cancer. He will be dearly missed.

Some information for this article was sourced from the Thomas A. Steitz Biographical Essay.