$4.5 million grant from NIH will help to turn genomic knowledge into promising drug targets
In the wake of the completion of the human genome sequencing project, five New York research institutions have joined together in a collaborative effort to turn that knowledge into promising drug targets. Today, the National Institute of General Medical Sciences (NIGMS), part of the U.S. government's National Institutes of Health, awarded the New York Structural Genomics Research Consortium (NYSGRC) $4.5 million to develop high-speed methods to decipher the three-dimensional structures of proteins. The award will fund the first year of a five year pilot program launched by NIGMS called the Protein Structure Initiative
The member institutions of the consortium are Albert Einstein College of Medicine, Brookhaven National Laboratory, Mount Sinai School of Medicine, The Rockefeller University and Weill Medical College of Cornell University.
"We are embarking on a program, which, if proven effective, will provide a way for researchers to come to grips with the impending flood of genetic data and speed its translation into therapeutic use," says consortium leader Stephen K. Burley, M.D., D.Phil., who is the Richard M. and Isabel P. Furlaud Professor at The Rockefeller University and an investigator at the Howard Hughes Medical Institute. "The initiative is aimed at developing a comprehensive mechanistic understanding of human and microbial physiology at the molecular level. This strategy should lead us to medically relevant data more quickly."
The human genome sequencing project was often portrayed as an end in itself, but most scientists recognize that its completion represents only a starting point from which to ask questions about other biological processes. While genes carry the "blueprints" for life, proteins perform the vital functions necessary for life to exist.
Proteins, long chains of building blocks called amino acids that fold into compact yet flexible shapes, carry out virtually all of life's essential functions through chemical reactions. Their structures are determined by the order of the amino acids, which is prescribed by the genes carrying instructions for making the proteins.
It would take decades to determine every three-dimensional structure of every protein encoded by the human genome, and this undertaking would yield many of the same shapes over and over. Because of this, the scientists in the NYSGRC suggest focusing primarily on disease-related proteins, or "likely suspects," to bring a quicker payoff. Such an approach is possible only through dramatic advances in both X-ray crystallography and computational biology. Synchrotron X-ray sources, like the National Synchrotron Light Source at Brookhaven National Laboratory, have accelerated the pace of crystallography enormously. At the same time, computational tools are helping to decode complete genetic blueprints for organisms ranging from microbes to humans.
The scientists say that choosing medically relevant protein targets will provide benefits whether its folds are "new" (i.e., different from those in other proteins already solved) or "old," and whether the protein's function is already known or is unknown. They also think choosing these targets will have important consequences for disease and patient-oriented research:
- First, any newly determined structure will be of immediate relevance to academic and/or industrial research teams studying that biological system.
- Second, by publicizing target lists on the Internet, the structural genomics pilot studies could generate scientific interest and expertise and attract suggestions for additions to their respective target lists.
- Third, the pilot studies will be able to serve as an important resource for distribution of tools and reagents for research.
NIGMS is awarding almost $30 million this year to seven projects, each totaling around $4 million for the first year. The Institute anticipates spending a total of around $150 million on these projects over five years, making NIGMS the world's single largest funder of structural genomics.
"These research centers are true pilots," said John Norvell, Ph.D., director of the NIGMS Protein Structure Initiative. "Each will include every experimental and computational task of structural genomics and will develop strategies for use in the subsequent large-scale research networks. By the fifth year of the award, we expect each pilot center to reach a production level of 100 to 200 protein structures annually, which is significantly greater than the current rate of protein structure determination."
Backgrounder on Member Institutions of the New York Structural Genomics Research Consortium
More information about the New York Structural Genomics Research Consortium can be found at http://www.nysgrc.org .
Albert Einstein College of Medicine
Contact: Sue Brody, (718) 430-3650
brody@aecom.yu.edu
Investigators:
Mark Chance
Steven Almo
Albert Einstein Center for Synchrotron Biosciences is a shared resource facility at the Albert Einstein College of Medicine and the National Synchrotron Light Source at Brookhaven National Laboratory. The Center facilitates the study of the structure and function of the living cell using extremely high flux and high brightness electromagnetic radiation and energies ranging from the infrared through the ultraviolet. Using this technology, researchers at Einstein have developed a method of analyzing the folding process of biological molecules as hey occur on millisecond timescales. They are using infrared spectroscopy to study the molecular changes in bone structure in an effort to understand the degradation of bone in osteoporosis and to create effective therapeutic regimens for this disease. Utilizing high-resolution X-ray crystallography, they are exploring the structure of individual proteins in order to understand their formation and regulation at the macromolecular level.
This crystallography effort has been significantly expanded as part of structural genomic studies to understand the meaning of the sequence information determined by the Human Genome Project.
Investigators at Einstein use high-resolution X-ray crystallography to explore the structure of individual proteins that regulate major aspects of cell biology in order to understand their function at the molecular and atomic level. Research teams have already solved the first structures of allergens, which are responsible for the clinical symptoms of allergy, including rhinitis, conjunctivitis and asthma. This work is providing novel approaches to the design of therapeutic agents that block the allergic response. Einstein scientists are focusing on the structural analysis of a number of proteins involved in regulating cell motility and the immune response. These proteins are prime targets for the development of novel therapies to combat autoimmune disease, graft rejection and tumor proliferation and metastasis.
Albert Einstein College of Medicine of Yeshiva University is one of the leading centers for biomedical research and education in the United States. Its research strengths include molecular genetics, cancer, heart disease, diabetes, liver diseases, immunology and neuroscience, among others. It is among the most selective medical schools in the nation; approximately 7,500 applicants vied for the 180 places in its entering class this year.
Brookhaven National Laboratory
Contact: Karen McNulty, (631) 344-8350
or Mona S. Rowe, (631) 344-5056
Investigators:
F. William Studier
S. Swaminathan
Robert Sweet
Jian-Sheng Jiang
Dawei Lin
Scientists at the U.S. Department of Energy's Brookhaven National Laboratory have been active in piloting procedures for high-throughput production of proteins and rapid determination of their structures by X-ray crystallography. An efficient system for producing proteins from cloned genes, which was developed at Brookhaven Lab, will be used to produce the many different proteins for crystallization and structure determination by the consortium. Facilities optimized for X-ray crystallography of proteins at Brookahven's National Synchrotron Light Source, which provides an intense source of X-rays, will be used for determining protein structures. Brookhaven scientists are also working on database and informatics tools to aid in selecting the most appropriate proteins for structure determination and for tracking the progress of the overall effort.
Mount Sinai School of Medicine
Contact: Debra Kaplan, (212) 659-9045
debra.kaplan@mssm.edu
Investigator: Lawrence Shapiro
Research in the Shapiro lab focuses on using structural information as a springboard to discover and better understand biochemical and functional roles of specific proteins. Toward this goal, we have concentrated on understanding the biology of obesity. For example, the structure of the obesity-related protein tubby, determined in our laboratory, led to implication of its function in controlling gene transcription. Understanding the functions of proteins identified through genomics is a requisite step in the application to of genomic information to medical science. Our involvement in the Protein Initiative will allow us to participate in this effort at an unprecedented level.
Commitment to excellence in research, education and patient care form the foundation that makes Mount Sinai School of Medicine of New York University (MSSM) in Manhattan one of the world's foremost centers for medical and scientific training. MSSM scientists conduct basic research, while never losing sight of the ultimate goal of translating discoveries made in the laboratory into new techniques for fighting disease and improving health. MSSM is a regional leader in numerous areas, including AIDS, Alzheimer's Disease, Cancer, Cardiology, Diabetes, Gastroenterology, Gene Therapy, Geriatrics, Hemophilia, High-Risk Pregnancy, Neonatal Specialty Care, Organ Transplantation, Palliative Care, Pediatric Respiratory Disease, Space Medicine, and Spinal Cord and Traumatic Brain Injury. The School is also known for unique educational programs, such as the Humanities in Medicine program which creates opportunities for liberal arts students to pursue medical school, and instructional innovations like The Morchand Center, the nation's largest program teaching students and physicians with "standardized patients" to become not only highly skilled, but compassionate caregivers.
The Rockefeller University
Contact: Joseph Bonner, (212) 327-7900
bonnerj@mail.rockefeller.edu
Investigators:
Stephen K. Burley
Brian T. Chait
Theresa Gaasterland
John Kuriyan
Andrej Sali
Scientists at The Rockefeller University working on the Protein Structure Initiative combine biophysics, biochemistry and computational biology to study protein structure and function. Among the tools used to determine the three-dimensional structures of proteins are mass spectrometry, magnetic resonance spectroscopy and X-ray crystallography. Rockefeller researchers have also developed computer programs to predict protein structures from amino acid sequences and to compare gene sequence data from the genomes of organisms ranging from bacteria to humans.
John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. In 1999 cell biologist Günter Blobel won the Nobel Prize for Medicine for his discovery that proteins are customized with intrinsic "ZIP codes" for delivery to exact destinations within the cell. The University has ties to 20 Nobel laureates. At present, 32 faculty are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D. As it anticipates its Centennial anniversary in 2001, Rockefeller --the nation's first biomedical research center--continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.
Joan and Sanford I. Weill Medical College of Cornell University
Contact: Kathy Robinson, (212) 821-0560
krobinso@med.cornell.edu
Investigator: Christopher Lima
A primary goal of the research in the Lima lab at Weill Cornell Medical College is to understand -- at the atomic level -- the structural, biochemical and functional basis for disease as it pertains to protein interactions with other proteins, lipids, and nucleic acids. They utilize X-ray crystallography (the science of solving the three-dimensional structures of biomolecules), biochemical, cell-base, and genetic approaches to decipher specific mechanisms in these systems.
The Lima lab's interest in the Protein Structure Initiative involves the development of high-throughput techniques in protein crystallography, particularly applied to proteins uncovered by sequence-based genomics with unknown function and/or structure. Lima has been working in the field of structural genomics for some time, having been awarded the Beckman Young Investigators Award in 1999 for a project aimed at elucidating structure/function relationships between four ubiquitous and highly conserved protein families with little to no known function. His involvement in the Protein Structure Initiative will allow Weill Cornell to participate in this national effort at an unprecedented level.
Founded in 1898, Cornell University Medical College (now known as Joan and Sanford I. Weill Medical College of Cornell University) has long ranked among the leading medical schools in the U.S. From the start, the medical college has followed an educational philosophy that emphasizes the importance of combining a strong basic foundation in the medical sciences with extensive clinical training in patient care. In 1927, the Medical College and The New York Hospital entered into a major affiliation agreement, which culminated with the opening, in 1932, of a unified campus on the Upper East Side of Manhattan. Cornell physicians and scientists are engaged in both basic and clinical research in the cutting-edge areas of genetics and gene therapy, neuroscience, structural biology, AIDS, cancer, and psychiatry, among many others. Cornell's biomedical investigators are delving ever deeper into the realms of cellular and molecular biology, which hold the secrets both to the normal functioning of the body and the malfunctions that lead to serious medical disorders. In 1998, during its centennial year, Cornell University Medical College was renamed Joan and Sanford I. Weill Medical College of Cornell University to honor long-time supporters Joan and Sanford Weill. In partnership with New York Presbyterian Hospital (New York Hospital merged with Presbyterian Hospital in 1998) and the New York Presbyterian Healthcare Network, Weill Medical College now provides expanded opportunities for students to gain clinical experience in a variety of settings.