Albert Lasker Award Laureate: Robert G. Roeder
Arnold and Mabel Beckman Professor
Every one of the tens of trillions of cells in the human body carries the exact same genetic information in the form of DNA. The key to how the dozens of different cell types perform their individual functions lies in RNA — the blueprint that is written from DNA for the creation of proteins. The elaborate process of writing RNA, known as transcription, has been one of the most intensely researched, and richly productive, subjects of the last few decades, thanks largely to the fundamental discoveries of Robert G. Roeder. Beginning in the 1960s and continuing through his years at Rockefeller University, Dr. Roeder has mapped the innumerable molecular players involved in genetic transcription. For these accomplishments, he received the 2003 Albert Lasker Basic Medical Research Award.
Examining nuclei isolated from sea urchin embryos as a graduate student at the University of Washington, Seattle, Dr. Roeder found that unlike in bacteria, the enzymes present are all bound to the DNA and associated proteins. He devised a series of chemical techniques to first dissolve the enzymes out of the group while leaving the DNA and other proteins lumped together and then to separate the individual enzymes in the resulting solution. By adding pieces of DNA and ribonucleic building blocks to his several individual enzyme solutions, Dr. Roeder identified not one enzyme, as was expected, but three capable of building RNA. He named them RNA polymerase I, II and III (aka Pol I, Pol II and Pol III).
Later, as a faculty member at Washington University School of Medicine in St. Louis, he examined the individual polymerases in more detail. By adding a toxin called amanitin — known to inhibit RNA synthesis — to a separate solution of each polymerase, he found that each has a different level of sensitivity to the poison. Then adding amanitin to a culture containing all three polymerases and observing disturbances in the synthesis of different RNAs, he concluded that the three are responsible for different classes of RNA: Pol I creates ribosomal RNA; Pol II transcribes protein-encoding RNA; and Pol III builds small structural RNA. Chemical analysis of the three polymerases furthermore showed them to be unique molecules, rather than slightly altered versions of one master enzyme, distinguishing eukaryotic transcription from its bacterial counterpart.
Dr. Roeder’s next question delved further into transcription specificity. Confronted by a whole, double-helical DNA — rather than a single piece of it, as in his previous experiments — does a polymerase know how to locate the section of the genome it needs to create a specific RNA? Experiments in the mid-1970s to recreate complete transcription in a test tube, which he was the first to accomplish, led Dr. Roeder to the hypothesis that the cell must contain certain proteins whose job is to lead the RNA polymerases to the correct promoter — the region of DNA that signals the beginning of each individual gene. Removing various components from the nuclei, he corralled a mass of unidentified cellular proteins that accurately effect transcription. He then separated those proteins chemically and experimented with various combinations of them with the three polymerases. He thus identified numerous polymerase-specific transcription factors and one gene-specific factor, revealing yet another level of complexity exhibited by eukaryotic cells.
Dr. Roeder further found that not only do polymerases require transcription factors to lead them to the right promoter, but the transcription factors often need whole assemblies of other proteins to help latch onto and pry open the tightly wound double helix and to regulate the speed of the process. By tagging a particular transcription factor — thyroid hormone receptor — with a molecular handle, Dr. Roeder extracted it from an experimental culture in the middle of the process and analyzed the molecular machine that was forming from the two dozen proteins it had attracted to itself. Dr. Roeder’s laboratory, as well as others, characterized several such assemblies in subsequent years, and revealed an ever-increasing intricacy in the concert of efforts they coordinate.
With these discoveries, Dr. Roeder opened the floodgates on transcription research, and examination of the process has reached an atomic level. Laboratories across the world have contributed in laying out the structures of transcription factor assemblies whose proteins number in the dozens. Together these revelations have helped explain the stunning variety and sophistication our cells possess in the construction of our anatomy and the working of its physiology.
Dr. Roeder received his Ph.D. in biochemistry in 1969 from the University of Washington, Seattle, where he worked with William Rutter. He did postdoctoral work with Donald D. Brown at the Carnegie Institution of Washington from 1969 to 1971. He was a member of the faculty at Washington University School of Medicine in St. Louis from 1971 until 1982, when he joined Rockefeller University. In 1985 he was named Arnold and Mabel Beckman Professor. In addition to the Lasker Award, Dr. Roeder received the 2002 ASBMB-Merck Award, the 2000 Gairdner Foundation International Award, the 1999 Louisa Gross Horwitz Prize and the 1999 General Motors Cancer Research Foundation’s Alfred P. Sloan Prize. He is a member of the National Academy of Sciences.