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'Towering Figures' in Cell Research to Share America's Most Distinguished Prize in Medicine

Published: Thursday, March 29, 2012
Last Updated: Thursday, March 29, 2012
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Two New York City scientists whose pioneering achievements in understanding how our genes are regulated and expressed are the recipients of the 12th annual Albany Medical Center Prize in Medicine and Biomedical Research.

These scientists have helped medical professionals and researchers improve health and combat diseases.

The two recipients, both from The Rockefeller University, will share the $500,000 award, the largest in medicine and science in the United States. They are:

James E. Darnell Jr., M.D., who is considered the "father" of RNA processing and cytokine signaling, and;

Robert G. Roeder, Ph.D., a pioneer in the field of gene transcription in animal cells.

The scientists will receive the prize on May 11 during a celebration in Albany, N.Y.

According to James J. Barba, president and chief executive officer of Albany Medical Center and chairman of the National Selection Committee, "Understanding how our cells express their genetic information provides insight into all of human health. By helping to define how cells grow, replicate, and become specialized, these two scientists have allowed countless other scientists and physicians to explore new ways to fight disease including viruses, heart disease, anemia and autoimmune disorders. I commend Drs. Darnell and Roeder for their extraordinary lifetime contributions."

The Albany Medical Center Prize was established in 2000 by the late Morris "Marty" Silverman to honor scientists whose work has demonstrated significant outcomes that offer medical value of national or international importance. A $50 million gift commitment from the Marty and Dorothy Silverman Foundation provides for the prize to be awarded annually for 100 years.
A total of three Albany Prize recipients have gone on to win the Nobel Prize.

According to Joseph Goldstein, M.D., chair of the Department of Molecular Genetics at the University of Texas Southwestern Medical Center and 2003 Albany Prize winner, "Darnell and Roeder have contributed perhaps as much as any two individuals to the understanding of mammalian gene expression in all of its phases which has progressed from virtually nothing in 1961 to a remarkably detailed understanding today of what is the most complex of all intracellular synthesis functions."

James E. Darnell Jr., M.D., Vincent Astor Professor Emeritus, Head of the Laboratory of Molecular Cell BiologyThe Rockefeller University

Darnell was a professor at the Massachusetts Institute of Technology in 1963 when he discovered "RNA processing" in human cells while studying messenger RNA - or mRNA. mRNA carries genetic information from DNA out of the nucleus to a cell's protein-making machinery located in the cytoplasm where the machinery gets to work with the goal of replicating the cell.

Darnell wondered how the mRNA in each different cell receives only the specialized genetic information it needs from the vast information store in DNA. By identifying very long strings of RNA inside the nucleus as opposed to the shorter strings of information that mRNA was carrying to the cytoplasm, he discovered that a precursor to mRNA was actually first copied from DNA and then "processed" for a cell's specific purpose.

This pivotal discovery paved the way for the later defining of "RNA splicing," a fundamental biological function in all nucleated cells by which RNA copies of DNA must be "cut and spliced" to furnish useful information for a specific cell.

"His lab gathered the first evidence that the useful form of most RNAs is fashioned by trimming and modifying the originally synthesized molecule in a pre-determined way," explained Joan Steitz, Ph.D., the Sterling Professor of Molecular Biophysics and Biochemistry at the Howard Hughes Medical Institute of Yale University. Steitz was a 2008 recipient of the Albany Prize.
Darnell later made critical discoveries in the area known as "cytokine signaling" - the passage of signals from outside a cell to direct copying of RNA from specific DNA sites (genes). This work uncovered an important signaling route named the JAK-STAT pathway.

"The JAK-STAT pathway of signal transduction explains how cytokines (such as interferons, interleukins, and erythropoietin) exert their myriad actions of cells throughout the body, influencing the body's response to inflammation and hypoxia. Moreover, the JAK-STAT pathway has recently been implicated in malignancy, with several of its components undergoing mutational alteration in cancers such as multiple myeloma and tumors of the head and neck," said Goldstein.

Work is progressing on the so-called anti-STAT compounds that could potentially cure some types of cancer. And, some of the compounds that stimulate the JAK-STAT pathway are currently used as medical treatments, including erythropoietin, which stimulates the production of red blood cells in people with kidney disease and anemia.

Darnell is the co-author of two textbooks considered essential to educating science students, General Virology and Molecular Cell Biology. More recently he published RNA: Life's Indispensable Molecule.

Robert G. Roeder, Ph.D.Arnold O. and Mabel S. Beckman Professor of Biochemistry and Molecular Biology, Head of the Laboratory of Biochemistry and Molecular Biology The Rockefeller University.

The first step in gene expression involves the copying (transcription) of genes (DNA) into RNA, which is then processed and translated into proteins. As a University of Washington graduate student in 1969, Roeder discovered that three enzymes, called RNA polymerases, play this role in animal cells. In the late 1970s, using purified polymerases and synthetic copies of genes (DNA), he was successful in developing the first cell-free systems to study transcription, a scientific breakthrough that allowed scientists to recreate transcription in a test tube to better study the complex processes by which cells turn genes on and off.

Roeder's initial work with these systems, leading to a greater understanding of gene regulation, included the identification of polymerase-associated helper factors, called the general transcription machinery, and the definition of the first of many hundreds of gene-specific DNA-binding regulatory proteins, called activators and repressors, that control the rate of transcription and effect major cell fate decisions. His further demonstration that the prior assembly of DNA and histones into chromatin, the natural template in cells, directly represses the general transcription machinery established a predicted general repression mechanism and indicated the existence of other factors that counteract this repression.

"This area of research is central to understanding gene regulation and thus processes such as oncogenesis and development. He was the first to show accurate initiation in vitro by these enzymes and thus to develop the biochemical basis for current research in factors regulating transcription," said Phillip Sharp, professor at the Koch Institute for Integrative Cancer Research at MIT.

In the early 1990s, Roeder and his colleagues discovered another class of transcriptional regulatory proteins, called "coactivators," that serve as bridges between activators and the general transcription machinery and thereby provide the cell with added control over gene activity. In an important integration of transcription and chromatin studies, Roeder recently has established activation of genes within chromatin dependent upon these co-activators, the general transcription machinery, and various chromatin modifying factors -- offering powerful systems for studying transcriptional regulatory (including epigenetic) mechanisms.

The control of gene expression -- the proper activation or silencing of genes in cells -- is crucial for normal processes such as embryonic development, cell growth and differentiation, and homeostasis; and many diseases, including cancer, arise when gene activity is not tightly controlled. Thus, the gene regulatory studies pioneered by Roeder provide insights into possible therapeutic approaches to maintain or restore proper gene activity.

Roeder's current interests include an understanding of the function of the tumor suppressor p53 in effecting either growth arrest and DNA repair or killing of potential tumor cells, regulators that effect the differentiation and function of fat cells (with implications for treating diabetes, heart disease and obesity), and leukemic fusion proteins that preclude the differentiation of early blood stem cells and lead to leukemia.

Both scientists have extensively published research and have been cited by countless medical and scientific journals. Although they have been close colleagues for years this is their first joint award. Both are members of the U.S. National Academy of Sciences and both have received numerous other prestigious national and international awards and honors that include the Gairdner Foundation International Award and the Lasker Award. Darnell is a recipient of the National Medal of Science.

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