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Yale scientist Sidney Altman (left), shown here with one of his graduate students, shared the 1989 Nobel Prize in chemistry with Thomas Cech of the University of Colorado.

Harnessing the Power of the Genome

Yale recently announced it is investing $200 million to build and renovate facilities across campus devoted to the study of genomes and proteomes. (See related story, page 8.) Called the Center for Genomics and Proteomics, this initiative will support the research by Yale scientists to improve understanding of how DNA and RNA regulate the processes of life and their role in fighting disease. The following is a look at some of the newest programs in genomic research at the University and specific work being done by Yale scientists.

$15 Million Center of Excellence in Genomic Sciences

Yale scientists are delving into the mysteries of how DNA functions with support from a $15 million grant for human genome research from the National Human Genome Research Institute (NHGRI).

Announced in September 2001, the five-year grant is part of the NHGRI's new Centers of Excellence in Genomic Science (CEGS) program.

"We are grateful to receive such generous support and we look forward to continuing our research into the functioning of the human genome," says principal investigator Michael Snyder, professor and chair of molecular, cellular and developmental biology, who will lead Yale's CEGS program.

The goal of his project, explains Snyder, is to build on the pioneering advances he and his team have made with their work on analyzing the functions of the yeast genome. They will develop new approaches to the study of the much larger and more complex human genome.

The team will prepare thousands of small DNA segments from the human genome and use them to develop methods for discovering where key regulatory proteins bind throughout the genome. This will allow them to understand how hundreds or thousands of genes are regulated, which will be important for understanding human development and disease.

"Much of the human genome is comprised of DNA whose function is not known," says Snyder. "Our team's methods will elucidate the functions of many of these regions for the first time, and as a result of these studies, we will emerge with a much more detailed understanding of the human genome and its regulation."

"The completion of the sequencing of the human genome opened up many new areas of study," Snyder adds. "But in order for this information to be useful, scientists need to develop the research tools, approaches and capabilities necessary to take genomic research to the next step."

Each new CEGS grant supports teams of investigators from different fields working together to develop new genomic approaches to address important biological and biomedical research problems. The centers such as the one at Yale will continue the NHGRI's practice of rapid data release, to provide the technologies, methods, data and programs they generate to the scientific community as quickly as possible. Each center will also include programs for training new investigators and bringing together established investigators from different disciplines to develop novel genomics tools and discoveries.

Snyder's team at Yale includes Dr. Sherman M. Weissman, the Sterling Professor of Genetics and Medicine and co-director of the Molecular Oncology and Development Program; Dr. Richard P. Lifton, professor and chair of genetics and professor of medicine and molecular biophysics and biochemistry; Mark Gerstein, associate professor of molecular biophysics and biochemistry; and Dr. Perry L. Miller, director of the Center for Medical Informatics and professor of anesthesiology and of molecular, cellular and developmental biology.

New NIH Center for Biomedical Computing

Yale researchers are tapping into the power of computers and furthering the study of the human genome with help from a grant from the National Institutes of Health (NIH).

The $1.3 million NIH grant -- part of an initiative to support planning for Centers of Excellence in Biomedical Computing at several universities nationwide -- was presented in October of 2001 to Dr. Perry Miller, professor of anesthesiology and of molecular, cellular and developmental biology.

NIH decided to support centers in biomedical computing, says Miller, because computing and informatics are becoming a critical part of all areas of modern biology and clinical medicine. Huge amounts of data are being produced about the genomes of many species.

"This massive amount of information needs to be stored, analyzed and understood in the context of biology as a whole," says Miller. "To allow this, the genome data needs to be integrated with large amounts of related data that are being produced in virtually all fields of bioscience and clinical medicine."

NIH has identified a critical shortage of scientists trained in the interdisciplinary areas of biomedical computing. The new centers will help train new scientists in these areas. Because few, if any, universities are currently ready to undertake this task, the NIH is supporting universities as they plan and prepare to meet the challenge.

The NIH "pre-center" grant provides funds over three years to help prepare Yale to host such a center, which could ultimately be funded at $5 million per year or more. Co-directors of this planning grant at Yale include Michael Snyder, professor and chair of molecular, cellular and developmental biology, and Martin Schultz, the Arthur K. Watson Professor of Computer Science.

Solving the Structure of the Ribosome

In a landmark achievement, Professors Thomas Steitz and Peter Moore determined the atomic structure of the ribosome's large sub-unit, paving the way for more effective drugs to fight infection.

The researchers also offered further evidence that the ribosome is a ribozyme, an enzyme in which catalysis is performed by RNA, not protein.

In addition to enhancing the understanding of protein synthesis, the research offers new clues about evolution and has significant medical implications because the ribosome is a major target for antibiotics. Steitz and Moore said the information that emerges should enable pharmaceutical companies to devise new inhibitors of ribosome function that can be used to control bacterial diseases that have become resistant to older antibiotics.

The structure of the ribosome's large sub-unit was determined using X-ray crystallography, a technique that can produce three-dimensional images at resolutions so high that individual atoms can be positioned. The 3,000 nucleotides of RNA in the large ribosomal sub-unit form a compact, complexly folded structure, and its 31 proteins permeate its RNA.

One of the most remarkable findings to emerge from this research is that the protein synthesis reaction that occurs on the ribosome derives from the two-thirds of its mass that is RNA, not from the one-third that is protein.

Steitz is the Eugene Higgins Professor of Molecular Biophysics and Biochemistry and an investigator at the Howard Hughes Medical Institute, and Moore is the Eugene Higgins Professor of Chemistry.

Exploring the Genetics of Hypertension

Dr. Richard Lifton, professor of genetics, medicine, and molecular biophysics and biochemistry, led a research team that discovered mutations in two different genes could cause a rare inherited form of hypertension.

The finding clears the way for research into new medications to treat both rare and common forms of high blood pressure, as well as congestive heart failure.

Lifton and his team are continuing to look at the genetics of high blood pressure, which affects 25% of most adult populations and is an important risk factor for death from stroke, heart attack and kidney failure.

In another study, Lifton and his colleagues identified a genetic mutation that causes extremely high bone density in people, thus creating a potential target for the prevention or treatment of osteoporosis.

The finding was made when Lifton and Dr. Karl Insogna, professor of internal medicine and director of the Yale Bone Center, identified a Connecticut family with unusually strong bones.

Bone mass is a major determinant of the risk of osteoporotic fracture. Nearly one million fractures occur annually in people over the age of 65, the majority of which are due to osteoporosis. Twin and family studies indicate that genetic factors account for about 75% of the variation in peak bone mass.

Preventing Crop Losses

S.P. Dinesh-Kumar, assistant professor in molecular, cellular and development biology, received $3.4 million from the National Science Foundation to find a way to control plant diseases using the crops' own infection-fighting mechanisms rather than pesticides. "Since the world population is expected to double over the next 50 years, increased knowledge of plant genes, genomes and how to manipulate them will greatly aid in feeding this population," says the scientist.

Nobel Laureate's RNA Research

Yale scientist Sidney Altman (left), shown here with one of his graduate students, shared the 1989 Nobel Prize in chemistry with Thomas Cech of the University of Colorado. Their groundbreaking finding that RNA can act as an enzyme suggested that primitive cells might have used RNA instead of proteins to control biochemical processes, thus elucidating a mystery of how early life could have evolved. Altman, who is Sterling Professor of Molecular, Cellular and Developmental Biology and a professor of chemistry, continues to study RNA's role. His laboratory is currently investigating the function and structure of ribonuclease P in both bacteria and human cells in order to understand the properties of these enzymes and what they are doing in vivo.


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Harnessing the Power of the Genome

Encouraging Women in the Sciences

Forging International Collaborations

Yale Dean Honored With Blue Planet Prize

Engineering the World of Tomorrow

Yale Engineer Receives National Medal of Technology

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Peabody Museum of Natural History:
Preserving the Past, Educating Future Generations

Bringing Yale Discoveries to The Public

Wright Nuclear Structure Laboratory: Probing the Power of Particles

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