Thomas Steitz

Thomas A. Steitz
Born	Thomas Arthur Steitz 23 8, 1940
Birthplace	Milwaukee, Wisconsin, United States
Died	Template:Death date and age Branford, Connecticut, United States
Nationality	American
Occupation	Biochemist, molecular biologist, academic
Title	Sterling Professor of Molecular Biophysics and Biochemistry
Employer	Yale University; Howard Hughes Medical Institute
Known for	Determining the atomic structure of the ribosome
Education	Ph.D., Harvard University
Awards	Nobel Prize in Chemistry (2009), Gairdner International Award (2007), Keio Medical Science Prize (2006)

Thomas Arthur Steitz (August 23, 1940 – October 9, 2018) was an American biochemist and molecular biologist whose work on determining the atomic structure of the ribosome — the molecular machine responsible for translating genetic information into proteins — earned him a share of the 2009 Nobel Prize in Chemistry. A Sterling Professor of Molecular Biophysics and Biochemistry at Yale University and an investigator at the Howard Hughes Medical Institute, Steitz devoted much of his career to understanding the three-dimensional structures of biological macromolecules at atomic resolution. His landmark crystallographic studies of the large ribosomal subunit revealed that the ribosome is fundamentally a ribozyme, with RNA rather than protein catalyzing the formation of peptide bonds. This discovery reshaped understanding of the origin of life and opened new avenues for antibiotic development. Steitz published extensively over a career spanning more than four decades and mentored generations of structural biologists. He died on October 9, 2018, at the age of 78, leaving behind a body of work that fundamentally altered the understanding of one of biology's most essential molecular processes.

Early Life

Thomas Arthur Steitz was born on August 23, 1940, in Milwaukee, Wisconsin. He grew up in the Milwaukee area, where he developed an early interest in science. As a young man, Steitz attended Lawrence University in Appleton, Wisconsin, where he studied chemistry. It was during his undergraduate and early graduate education that Steitz encountered the emerging field of structural biology, which would define his career. A pivotal moment came when he heard the renowned crystallographer Max Perutz speak about the structure of myoglobin — the first protein whose three-dimensional structure had been determined at atomic resolution. The experience of learning how X-ray crystallography could reveal the architecture of biological molecules at the level of individual atoms left a deep impression on Steitz and oriented his scientific ambitions toward understanding the structural basis of biological function.

Steitz came of age scientifically during a period of transformative advances in molecular biology. The discovery of the double-helix structure of DNA by Watson and Crick in 1953, followed by the elucidation of the genetic code and the mechanisms of protein synthesis in the 1960s, created a vibrant intellectual environment that attracted talented young scientists to the study of biological macromolecules. Steitz was drawn to the challenge of determining how these molecules achieved their functions through their three-dimensional shapes — a question that required mastery of X-ray crystallography, a technically demanding discipline that few laboratories were equipped to pursue at the time.

Education

Steitz completed his undergraduate studies at Lawrence University in Appleton, Wisconsin, earning a degree in chemistry. He then pursued graduate studies at Harvard University, where he received his Ph.D. in biochemistry and molecular biology. At Harvard, Steitz trained in X-ray crystallography and structural biology, developing the technical expertise that would underpin his subsequent career. Following his doctorate, Steitz undertook postdoctoral research at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, England — the same institution where Perutz, John Kendrew, Francis Crick, and other pioneers of structural and molecular biology had carried out their groundbreaking work. This experience at the MRC laboratory immersed Steitz in the traditions and methods of British crystallography and connected him to a global network of structural biologists.

Career

Early Academic Career and Move to Yale

After completing his postdoctoral training in Cambridge, Steitz joined the faculty of Yale University, where he would spend the remainder of his career. At Yale, Steitz established a laboratory focused on the structural biology of proteins and nucleic acids, using X-ray crystallography to determine the three-dimensional structures of biologically important macromolecules. Over the following decades, Steitz rose through the academic ranks, eventually being appointed Sterling Professor of Molecular Biophysics and Biochemistry — one of the highest academic distinctions at Yale. He also held a joint appointment as Professor of Chemistry and served as an investigator of the Howard Hughes Medical Institute (HHMI), which provided substantial research funding and support for his laboratory.

In the early phases of his career at Yale, Steitz focused on determining the structures of enzymes and other proteins involved in DNA replication and gene expression. His laboratory made important contributions to understanding how DNA polymerases — the enzymes responsible for copying DNA — recognize and interact with their substrates. These studies provided molecular-level insight into the fidelity and mechanism of DNA replication. Steitz also studied the structures of other proteins involved in nucleic acid metabolism, building a reputation as one of the leading structural biologists in the United States.

The Ribosome: Background and Significance

The ribosome is the molecular machine present in all living cells that translates the genetic information encoded in messenger RNA (mRNA) into proteins — the molecules that carry out the vast majority of biological functions. Composed of both RNA and protein, the ribosome is one of the largest and most complex molecular assemblies in the cell. In bacteria, the ribosome consists of two subunits: the small (30S) subunit, which is involved in reading the genetic code, and the large (50S) subunit, which catalyzes the formation of peptide bonds between amino acids during protein synthesis.

Determining the atomic structure of the ribosome was one of the great challenges of twentieth-century structural biology. The ribosome is enormous by the standards of crystallography — containing hundreds of thousands of atoms — and early efforts to crystallize ribosomes and obtain high-resolution diffraction data were beset by technical difficulties. For decades, the ribosome's structure remained beyond the reach of X-ray crystallography, and many in the field doubted that it could ever be solved at atomic resolution.

Solving the Structure of the Large Ribosomal Subunit

Beginning in the 1990s, Steitz and his laboratory at Yale embarked on an ambitious effort to determine the atomic structure of the large (50S) ribosomal subunit from the bacterium Haloarcula marismortui. This work required the growth of high-quality crystals of the ribosomal subunit, the collection of X-ray diffraction data at synchrotron radiation facilities, and the development of computational methods to interpret the resulting diffraction patterns and build an atomic model of the structure.

In 2000, Steitz and his colleagues published a landmark study revealing the atomic structure of the large ribosomal subunit at a resolution of 2.4 angstroms — a level of detail sufficient to identify the positions of individual atoms within the molecule. This was one of the largest molecular structures ever determined at such resolution, and the achievement was described as a tour de force of structural biology. The structure contained approximately 100,000 atoms and revealed in exquisite detail the architecture of the ribosomal RNA and proteins that make up the 50S subunit.

One of the most striking and consequential findings from Steitz's structural work was the discovery that the active site of the ribosome — the peptidyl transferase center, where peptide bonds are formed — is composed entirely of RNA, with no protein atoms in the immediate vicinity. This finding provided direct structural evidence that the ribosome is a ribozyme — an enzyme made of RNA rather than protein. The result had profound implications for understanding the evolution of life, supporting the hypothesis that RNA preceded proteins in the early history of life on Earth (the "RNA world" hypothesis). It demonstrated that RNA is capable of catalyzing one of biology's most fundamental chemical reactions, lending weight to the idea that the earliest forms of life relied on RNA both as a carrier of genetic information and as a catalyst for chemical reactions.

Implications for Antibiotic Development

The atomic structure of the ribosome also had significant practical implications. Because the ribosome is essential for bacterial survival and because bacterial ribosomes differ in structure from human ribosomes, the ribosome has long been a major target for antibiotics. Many widely used antibiotics, including erythromycin, chloramphenicol, and clindamycin, work by binding to the bacterial ribosome and disrupting protein synthesis. However, the precise molecular mechanisms by which these drugs bind to and inhibit the ribosome were not fully understood before Steitz's structural work.

Steitz and his collaborators used the atomic structure of the large ribosomal subunit to determine how more than a dozen antibiotics bind to the ribosome. By co-crystallizing the ribosomal subunit with various antibiotic compounds and solving the resulting structures, they were able to visualize the precise binding sites and interactions of each drug at atomic resolution. This work provided a structural framework for understanding antibiotic resistance — revealing, for example, how mutations in ribosomal RNA can alter the drug binding site and prevent antibiotics from functioning. It also opened the possibility of using structure-based drug design to develop new antibiotics that could overcome resistance mechanisms, an area of growing urgency given the global rise of antibiotic-resistant bacterial infections.

Steitz was actively involved in efforts to translate his structural findings into practical applications. He co-founded Rib-X Pharmaceuticals (later renamed Melinta Therapeutics), a biotechnology company based in New Haven, Connecticut, that aimed to develop new antibiotics based on ribosome structure. The company pursued the design of novel compounds that could bind to the bacterial ribosome in ways that existing antibiotics could not, with the goal of creating drugs effective against resistant strains of bacteria.

Broader Contributions to Structural Biology

Beyond the ribosome, Steitz made significant contributions to the understanding of numerous other biological macromolecules over his career. His laboratory determined the structures of DNA and RNA polymerases, recombinases, and other enzymes involved in nucleic acid metabolism. These studies illuminated the mechanisms by which genetic information is replicated, transcribed, and maintained within cells. Steitz's work on DNA polymerases, in particular, contributed to the understanding of how these enzymes achieve the remarkable fidelity required to accurately copy the genome during cell division.

Steitz was also recognized for his mentorship of young scientists. Over the course of his career at Yale, he trained dozens of graduate students and postdoctoral researchers, many of whom went on to establish independent research programs at major universities and research institutions around the world. His laboratory was known for its rigorous approach to crystallography and its commitment to tackling ambitious structural problems.

Personal Life

Steitz was married to Joan Argetsinger Steitz, a fellow molecular biologist and Sterling Professor at Yale University. Joan Steitz is known for her own distinguished scientific contributions, particularly her work on small nuclear ribonucleoproteins (snRNPs) and RNA splicing, and is a member of the National Academy of Sciences. The couple represented one of the most prominent husband-and-wife scientific partnerships in American academia. They had one son, Jon Steitz.

Steitz died on October 9, 2018, in Branford, Connecticut, at the age of 78, following a period of illness. His death was announced by Yale University and was reported in major scientific publications and international news outlets. Colleagues remembered him as a scientist of extraordinary determination and intellectual rigor, whose work on the ribosome had transformed understanding of one of biology's most fundamental processes.

Recognition

Steitz received numerous awards and honors over his career in recognition of his contributions to structural biology and biochemistry. The most prominent was the 2009 Nobel Prize in Chemistry, which he shared with Venkatraman Ramakrishnan of the MRC Laboratory of Molecular Biology in Cambridge, England, and Ada Yonath of the Weizmann Institute of Science in Israel. The three scientists were jointly recognized "for studies of the structure and function of the ribosome."

Prior to the Nobel Prize, Steitz was awarded the Gairdner International Award in 2007 and the Keio Medical Science Prize in 2006, both for his work on the ribosome. He was elected to the National Academy of Sciences and the American Academy of Arts and Sciences, among other learned societies. He also received honorary degrees from several universities.

Steitz was an investigator of the Howard Hughes Medical Institute for much of his career, a distinction that provided both recognition of his scientific accomplishments and support for his research program. His work was published in leading scientific journals, including Science, Nature, and the Proceedings of the National Academy of Sciences.

The Yale Daily News reported on his death, noting that Steitz had been one of the most decorated scientists on the Yale faculty and that his work had brought significant recognition to the university's Department of Molecular Biophysics and Biochemistry.

Legacy

The impact of Steitz's work on the ribosome extended well beyond the immediate scientific community. By revealing the atomic architecture of the molecular machine that translates genetic information into proteins, Steitz and his co-laureates provided a structural foundation for understanding one of the most fundamental processes in all of biology. The discovery that the ribosome's catalytic activity resides in its RNA component, rather than its protein components, fundamentally changed conceptions of the molecular origins of life and reinforced the RNA world hypothesis — the idea that RNA-based life preceded the DNA- and protein-based life of the contemporary world.

The practical implications of Steitz's structural studies were equally significant. His detailed mapping of antibiotic binding sites on the ribosome provided a rational basis for the design of new drugs to combat bacterial infections, an area of increasing importance as antibiotic resistance spread globally. The biotechnology company he co-founded, Rib-X Pharmaceuticals, represented one of the earliest attempts to apply ribosome structural data directly to drug design, and the approach has continued to influence antibiotic research in subsequent years.

Steitz's contributions to the training of scientists also form a lasting part of his legacy. His former students and postdoctoral researchers have carried forward the methods and scientific vision of his laboratory, establishing structural biology programs at institutions around the world. As noted in a tribute published in Nature Structural & Molecular Biology, Steitz's influence extended beyond his own research accomplishments to shape the careers and scientific trajectories of many younger researchers who passed through his laboratory at Yale.

Yale University honored Steitz's contributions by recognizing him as one of the most accomplished members of its faculty in the sciences. His appointment as Sterling Professor — the university's highest faculty honor — reflected the significance of his research within the broader academic community.