The rockefeller university

Robert G. Roeder, Ph.D., a biochemist whose research has led to major advances in understanding how human genes are switched “on” and “off,” is this year’s recipient of the highly prestigious Albert Lasker Award for Basic Medical Research, the Albert and Mary Lasker Foundation announced today.

Roeder investigates a biological process called transcription, a crucial activity occurring at all times in every one of the billions of cells that make up the human body. Since 1969, when he made his initial groundbreaking discovery of the three protein machines responsible for “reading” human genes, Roeder has gone on to elucidate the incredibly complex manner in which this vital process is orchestrated.

“Virtually all of what we know about gene activation and its regulation in animal cells can be traced back to Bob Roeder’s seminal studies,” says Rockefeller University President Paul Nurse, Ph.D., past recipient of the Albert Lasker Award for Basic Medical Research as well as the Nobel Prize in Physiology or Medicine. “While there have been many contributors in this area, none have provided more seminal discoveries than Roeder.

“The biochemical approaches pioneered by Roeder’s laboratory allow a more detailed understanding of the molecular events that occur in normal cellular processes and in disease states such as cancer,” Nurse adds. “Ultimately, the application of Roeder’s findings may lead to new drugs that selectively switch genes on or off for the treatment of diseases like cancer , heart disease, Alzheimer’s, AIDS and any other medical condition in which normal gene activity is disrupted.”

“We need to understand not only the mechanisms underlying normal gene activation, but to relate these to important medical problems,” says Roeder. “As we become familiar with the fundamentals of how genes work, we get closer to understanding diseases like cancer or viral infections such as HIV.”

Roeder is the Arnold and Mabel Beckman Professor, head of the Laboratory of Molecular Biology and Biochemistry and a member of the Pels Family Center for Biochemistry and Structural Biology at Rockefeller University.

Roeder is the 19th scientist associated with Rockefeller University to be honored with the Lasker Award, widely regarded not only as the “American Nobel” but also as a strong predictor of future Nobel Prize winners.

Since the Lasker Awards were first presented in 1945, 47 percent of the Basic Lasker Winners have gone on to win the Nobel Prize, while 37 percent of all Nobel Prize winners have received Lasker Awards. Among the 22 Nobel Prize winners who have been associated with Rockefeller University, six received the Lasker Award: Nurse, Günter Blobel, M.D., Ph.D., Bruce Merrifield, Ph.D., George E. Palade, M.D., Peyton Rous, M.D., and Karl Landsteiner, M.D. In all, 19 scientists associated with the university have received Lasker Awards.

Over the years, Roeder has trained dozens of graduate students and postdoctoral researchers, many of whom now head their own major laboratories around the world. [Note to editors: contact information for many of the scientists is available upon request.]

Roeder acknowledges the National Institutes of Health, National Science Foundation and American Cancer Society for support of his research early in his career and, more recently, extremely generous support from Rockefeller University.

“The Rockefeller University is a spectacular place, an institution with much tradition and a record of outstanding contributions to science and medicine,” says Roeder, who joined the university in 1982. “Rockefeller gave me an opportunity to build a group of people with whom I could begin to analyze in more detail the problems on which we had embarked.

“Rockefeller University, with its primary emphasis on research, is truly the easiest place to do science in an unimpeded fashion with high quality colleagues, graduate students and postdocs.”

Model for studying life

The human body consists of over 200 distinct types of cells, all containing an identical set of genetic instructions. But if a skin cell has the same genes as a muscle cell, then how does each cell type function in its specialized role? The difference between the various types of cells is largely determined by which of the cell’s specific genes are being “read” or expressed by the cell’s own machinery. This essential cellular activity is known as transcription.

One of the biggest questions in biology is how cells control or regulate transcription, and how this process breaks down in certain diseases, such as cancer.

For the last 30 years, Roeder’s research has provided more than the beginnings of an answer to this important question: in addition to outlining virtually all of what we know today about the basic principles of transcription and its regulation by proteins in animal cells, Roeder and his colleagues have created the model from which scientists throughout the world continue to study this basic mechanism of life.

Roeder’s research includes the following advances:

• discovery of the enzymes, called RNA polymerases, that directly read out and copy the messages encoded in DNA;
• identification of these enzymes’ associated helper factors, called the general transcription machinery; and
• definition of the first of many hundreds of DNA-binding regulatory proteins, called activators and repressors, that control the rate of gene transcription.

These three advances could not have been made without another important development by Roeder, one that allows researchers to recreate the essence of transcription in a test tube: a biochemical tool called a cell-free system.

What’s more, in the last decade, Roeder and his colleagues have discovered several members of another class of regulatory proteins, called coactivators, that represent a third level of transcriptional regulation in addition to the basal transcription machinery (polymerases and general transcription factors) and the DNA-binding regulatory factors (activators and repressors).

The coactivators are large protein complexes that act like mediators or bridges between activators or repressors and the general transcription machinery, thereby providing the cell with added control over gene activity. Control of gene expression — the proper activation or silencing of genes in cells — is crucial in the developing embryo, and many diseases arise when gene activity is not tightly controlled

Today, the Roeder laboratory continues to uncover novel mechanisms by which these coactivators, which he calls “multicomponent control panels,” integrate positive and negative regulatory signals, ultimately “deciding” whether to turn up or down a given gene’s expression or activity pattern.

Graduate student’s groundbreaking discovery

Roeder’s pioneering work in transcription began while he was a graduate student in the laboratory of W.J. Rutter, Ph.D., at the University of Washington in the late 1960s. While working on his own independent project, Roeder identified in animal cells three different RNA polymerases, as well as specific locations within the cell’s nucleus that provided an early indication of the polymerases’ distinct functions.

In subsequent research at Washington University School of Medicine, he showed that these three enzymes recognize and read the messages encoded in distinct classes of genes in eukaryotes, organisms whose cells contain DNA in a nucleus: RNA polymerase I converts or transcribes DNA into ribosomal RNA (rRNA); RNA polymerase II transcribes DNA into messenger RNA (mRNA); and RNA polymerase III transcribes DNA into transfer RNA (tRNA). Both rRNA and tRNA aid in the production of proteins, while mRNA itself provides the recipe for a new protein.

This last discovery was particularly remarkable considering that, at the time, the tools of molecular biology had yet to be invented.

“This was the Dark Ages,” recalls Roeder. “We didn’t have many isolated and characterized genes to work with like we do now.” For this research he was honored with the American Chemical Society Eli Lilly Award in Biological Chemistry in 1977.

Nature’s secrets revealed in test tube

In the late 1970s, Roeder developed cell-free systems that allowed him and others to study the function of individual genes and transcription-related proteins outside of living cells, in effect recreating transcription in a test tube in a way that faithfully mimics the real process in cells. Using this powerful test-tube technique, composed of purified RNA polymerases and components extracted from cell nuclei, Roeder identified distinct sets of proteins, called accessory factors, essential for the individual RNA polymerases to recognize start sites on specific target genes.

Significantly, he simultaneously identified the first gene-specific activator, called TFIIIA, in eukaryotes. TFIIIA and similar proteins bind to specific DNA sequences and enhance the “reading” of corresponding target genes by the appropriate subset of the general transcription machinery. Repressors perform the opposite task by inhibiting a gene’s activity.

Hundreds of these transcription activators and repressors subsequently have been identified by Roeder and other scientists, and many more are expected for the regulation of genes during such physiological processes as cell growth and division, hormonal processes, virus infection and tumor growth.

“The challenge we now face is understanding the differential regulation of about 30,000 human genes,” says Roeder.

Complexity demystified

Over the last decade at Rockefeller University, Roeder and his colleagues have identified several coactivators, thereby ushering in a modern age in biology. Says Roeder, “We have uncovered a third layer of complexity in the transcription process.” His laboratory demonstrated that coactivators can be both ubiquitous, monitoring many genes in a variety of cells, or specific to one particular cell type. This latter concept of cell-specificity was first introduced by Roeder and Rockefeller colleagues after they demonstrated that the coactivator OCA-B, first isolated in Roeder’s laboratory, was unique to B cells, a type of immune system cell that makes antibodies.

“What began to emerge,” says Roeder, “is that these coactivators, like the RNA polymerases, are incredibly complicated machines.”

King of coactivators

Between 1991 and 1996, Roeder’s lab discovered the major conduit for communication between gene-specific activators and the general transcription machinery in animal cells: the researchers elaborated the biochemical details of a giant coactivator (TRAP/SMCC) consisting of about 25 different protein chains and referred to as the “the human Mediator” after its counterpart in yeast.

Currently, Roeder’s laboratory is homing in on precisely how this massive protein complex regulates transcription. Many of their projects look at the interaction between it and specific activators such as nuclear hormone receptors, proteins involved in development and homeostasis, and p53, a protein implicated in at least 60 percent of human cancers. The researchers previously revealed that thyroid hormone receptor and p53, which both are known to activate several genes as part of their normal cellular activity, require separate components of the human Mediator to properly function.

“More precise knowledge of coactivators could offer the potential to design more specific drugs with fewer side effects,” says Roeder.

Moreover, Roeder has begun to apply what he has learned in a test tube to the study of living cells. For example, in a 2002 Nature report, Roeder and colleagues showed that a single component of the mediator is absolutely essential for the formation of fat cells — a finding that may one day contribute to new treatments for diabetes, heart disease, cancer and other conditions in which the fat-making process breaks down.

More recently, in the journal Cell, Roeder’s lab has reported that a coactivator called OCA-S — a relative of coactivator OCA-B — is activated during a specific phase of the cell cycle, when the DNA is duplicated and the number of chromosomes doubles. The activation of OCA-S in turn leads to the production of new histones. Histones are spool-like proteins that DNA wraps around to condense and compact itself in the nucleus of all body cells.

An unexpected but extremely exciting finding was that a key component of this complex proved identical to a cellular (cytoplasmic) enzyme long implicated in metabolism and energy production, thus linking the regulation of cell growth and proliferation (through the control of histone biosynthesis) to the metabolic state of the cell. These findings add to a growing body of research from the Roeder lab that is beginning to define more specific physiological roles for the poorly understood coactivators.

Four decades of honors

Roeder was born in Boonville, Indiana, in 1942. He received a B.A. degree summa cum laude in chemistry from Wabash College in 1964, an M.S. in chemistry from the University of Illinois in 1965, and a Ph.D. in biochemistry from the University of Washington, Seattle, in 1969. He completed postdoctoral work at the Carnegie Institution of Washington, in Baltimore, from 1969 to 1971.

He was named assistant professor of biological chemistry at Washington University in St. Louis in 1971, associate professor in 1975, and professor in 1976. In 1978, he was appointed professor of genetics, and in the following year, was named James S. McDonnell Professor of Biochemical Genetics. In 1982, he accepted a professorship at Rockefeller University and organized a new Laboratory of Molecular Biology and Biochemistry, which he currently heads. In 1985, he was named Arnold and Mabel Beckman Professor.

In addition to the Lasker award, Roeder received the 2002 ASBMB-Merck Award, which he shared with Stanford University’s Roger D. Kornberg, Ph.D., for their outstanding contributions to research in biochemistry and molecular biology, and the 2001 University of Pittsburgh Dickson Prize in Medicine.

Roeder shared the 2000 Gairdner Foundation International Award with Kornberg for studies on the transcription machinery and elucidation of the basic mechanisms of transcription in eukaryotic cells. He shared the 1999 Alfred P. Sloan Prize, which honors the most outstanding recent basic science contributions to cancer research, with Robert Tjian, Ph.D., of the University of California, at Berkeley. In conjunction with Tjian, he also has received the Passano Award (1995), Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Sciences (1995) and (with Pierre Chambon, M.D.) the Louisa Gross Horwitz Prize (1999).

Roeder was elected to the National Academy of Sciences in 1988. He received the Academy’s U.S. Steel Award in Molecular Biology in 1986. He also is a recipient of the Dreyfus Foundation Teacher-Scholar Award.

Roeder is a member of the American Society of Biological Chemists, American Chemical Society, New York Academy of Sciences, American Society for Virology, Society for Developmental Biology and American Society for Microbiology. He is a fellow of the American Association for the Advancement of Science, American Academy of Microbiology and American Academy of Arts and Sciences.

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