Most readers of this journal know that Thomas Steitz shared the 2009 Nobel Prize in Chemistry with Ada Yonath, and Venki Ramakrishnan for “studies on the structure and function of the ribosome.” While it is appropriate that we remember Tom for this work, it is important that we not let the blinding light cast on this one facet of his career by the Nobel Foundation make us lose sight of all of his other wonderful accomplishments.
Tom was a macromolecular crystallographer to be sure, but he was not enamored of crystallography for its own sake. He practiced the trade because it was the most powerful tool available for addressing the issues he did care about, all of which had to do with enzyme mechanism. All enzymes have mechanisms, of course, and while any old enzyme would do in the ’60s and ’70s, when macromolecular crystallography was in its youth, by ∼1980 it was obvious that crystallographers who wanted to make a difference would have to work on molecules that mattered to the rest of the biological community, and that is what Tom did. His goal was to elucidate the structures and mechanisms of all of the enzymes and protein factors associated with the Central Dogma pathway.
His program was not for the faint of heart. The competition was certain to be fierce because Tom was not the only crystallographer who appreciated the importance of these molecules. Moreover, by the time Tom began, they had all been studied for years, and success depended on his mastering the relevant literatures, which in many cases were enormous. As if that were not enough, he also had to deal with the challenges of preparing and crystallizing precisely the right version of each of the molecules he targeted, and, finally, he had to be patient. It took a decade or more for Tom’s group to solve many of the structures they pursued.
Tom and his group met these challenges time and again, often in collaboration with faculty colleagues. An amazing number of important structures emerged: catabolite activating protein (CAP) and its complex with DNA, the Klenow fragment of DNA polymerase I (Kornberg’s enzyme), Gln-tRNA bound to Gln-tRNA synthetase, HIV reverse transcriptase with a non-nucleotide inhibitor bound, T7 RNA polymerase, rec A, gamma delta resolvase, and, finally, his pièce de résistance, the large ribosomal subunit from Haloarcula marismortui. Tom’s structures were often the first to be reported for enzymes of their respective types, and there were always follow-on structures that taught us about mechanism, for example, how these molecules interact with their substrates, their products, and in some cases, their templates. If there was a Nobel Prize for career achievement, Tom would have been a shoo-in, even if he had never touched a ribosome.
It is impossible to know why Tom had the amazing career he did. His early years appear to have been unremarkable. He was born in Milwaukee, the eldest of five, and attended the public schools in Milwaukee, and Wauwatosa, a nearby suburb where the Steitz family lived during his teenage years. His decision to attend Lawrence College (now University) in Appleton, Wisconsin, may have had something to do with it. The upper Midwest is home many small, liberal arts colleges like Lawrence that count large numbers of distinguished scientists among their graduates. It also did not hurt that Tom chose to get his Ph.D. in the biochemistry program at Harvard, which had an outstanding faculty at the time he entered it (1962). What we do know for sure is why Tom decided to become a macromolecular crystallographer because it is a story he often told.
In the spring of 1963, around the time Tom had to find a thesis advisor, he attended the Dunham Lectures at the Harvard Medical School. The Dunham lecturer that year was Max Perutz, who had shared the Nobel Prize with John Kendrew the preceding October for the crystal structures of hemoglobin and myoglobin. On the way into the lecture hall, the members of the audience were handed polaroid glasses, and after a few minutes of introduction, Max told everyone to put their glasses on, and asked the projectionist to show the first stereo slide. It took the projectionist a few seconds to align the projector’s two lenses, but once he did so, a large, three-dimensional image of myoglobin materialized in the air over Max’s head, and the audience responded with an audible “ooh.” It was the first time most of us, and I say “us” because I was there, had ever seen what a protein looks in three dimensions at atomic resolution; it was astonishing. A few days later, Tom discovered that Professor William (“The Colonel”) Lipscomb, who was a member of the Harvard chemistry department, was working on the crystal structure of carboxypeptidase A (CPA), and he enlisted in the Colonel’s army. The rest, as they say, is history.
In 1967, Tom moved to the MRC Laboratory of Molecular Biology (LMB) in Cambridge. By that time, the structure of CPA had been solved, and Tom had arranged to join the faculty of the Berkeley Biochemistry Department once he was done at the LMB. By that time, Tom had also persuaded James Watson’s first female graduate student, Joan Argetsinger, to marry him, and so it was that they both became postdocs at the LMB, he with David Blow, an up and coming young crystallographer, and she with Francis Crick. The LMB was a wonderful place for young scientists in that era, as I know because I was there at the time. (As it happens, my wife and I had known both Joan and Tom at Harvard.)
I joined the faculty of the Department of Molecular Biophysics and Biochemistry (MB&B) at Yale in 1969, and a little more than a year later, Joan and Tom did the same. Tom had gone to Berkeley, as he had agreed to do, but Berkeley had refused to offer Joan the faculty position she so obviously merited, a decision that has to be one of the all-time worst ever made by an academic institution. Somehow, Frederick Richards, the chairman of MB&B, had caught wind of what was going on, and had offered faculty positions to both of them; Yale 2: Berkeley 0.
Two institutional developments helped Tom move forward at Yale. In the mid-1970s, five of us applied to NIH for a program project grant. The participants were Hal Wyckoff, Donald Engelman, Fred Richards, me (Moore), and Tom, hence the WERMS group, a semi-horrible acronym devised by Tom. It enabled us to set up a core laboratory that supported the diffraction equipment Tom and Hal needed, and to purchase a computer, which we all needed. A decade later, HHMI decided to invest in Yale’s structural biology program, and Tom became an HHMI investigator, which enabled him to pursue his agenda largely immunized from the baleful effects caused by the what-have-you-done-for-us-lately attitude of NIH study sections. HHMI also funded an upgrade of the instrumentation in the core laboratory for which we all benefitted and provided the resources that made it possible for MB&B to add three new structural biologists to its faculty. We were off to the races.
From the late 1980s on, Tom and I occasionally talked at lunchtime about getting into the ribosome crystallography game. I think he would have done so with or without my help, provided the structure of the ribosome was still unsolved at the time he was ready to take it on. As a longtime member of the ribosome community, I could assist with the biochemistry, and provide access to the ribosome equivalent of what London taxicab drivers refer to as “The Knowledge.” The enterprise got off the ground in 1994 when Tom recruited Nenad Ban, a new postdoc eager to take on this near-suicidal project. Initially, I was a somewhat reluctant participant, but at a ribosome conference held in Victoria, BC, in 1995, I became convinced not only that the structures of ribosome crystals could be solved, but also that I might not live to see it happen if we did not engage. Thereafter, I was all in, and the amazing adventure unfolded that is described in Tom’s Nobel lecture.
We talked to each other almost daily while the ribosome project was underway, as we did for years thereafter, and after a while, I began to understand why Tom was so successful. Every morning when you enter the laboratory, he once told me, you need to ask yourself what the one thing is that you can do that day that will have the biggest impact on how you think about your system. Not only does this approach to science help you make best use of your time, it encourages you to move on once the project you have been working on has yielded its biological message rather than succumb to the temptation to dot all the i’s, and cross all the t’s.
Some students and colleagues found Tom’s directness in responding to issues they raised off-putting, and as a result, failed to understand how generous he was. He was always prepared to help his colleagues, and to share the laboratory resources he commanded. The principle downside of dealing with Tom was that you had to put up with his incorrigible tendency to make puns. With his passing we have lost a remarkable scientist, a wonderful colleague, and in my case, a close friend.
FigureTom Steitz contemplating a model of the large ribosomal subunit on October 7, 2009, the day he learned he had won the Nobel Prize. (Photograph provided by Paul Raccuia, Tom’s Laboratory Manager.)