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Connecting Gene Sequence to Function by 3D Structure Determination -- A New Paradigm for Drug Discovery


The New Jersey Initiative in Structural Genomics and Bioinformatics (NJISGB), sponsored by the New Jersey Commission on Science and Technology (NJCST), is a pilot project aimed at developing technologies for high-throughput macromolecular structure determination and their application in analyzing the massive stream of data flowing from the Human Genome Project (HGP). The initiative builds upon existing technological know-how and interdisciplinary strengths of the Center for Advanced Biotechnology and Medicine (CABM) and Rutgers' Laboratory for Computer Science Research (LCSR).

The initiative represents an interdisciplinary research effort at the interface between computation, structural biology, biomedical research, and information sciences. In addition to NJCST support, the project also receives support from industrial, federal, and university sponsors. The long-range goal of this initiative is to create a powerful new drug-discovery paradigm for the pharmaceutical industry and to develop new approaches to functional genomics by taking a genomic approach to protein structure analysis.

The focus of the current pilot project is on technology development. For this reason, the precise choice of targets has been designed to address important issues in human health and to be consistent with the opportunistic nature of our structure-function analysis process. The biomedical gene targets that we are using for developing and testing our technology include:

  1. Products of human genes that have been implicated in specific human diseases.
  2. Products of broadly conserved genes of metazoan model organisms which are represented in the human genome. These genes are thought to be fundamental to the biology of human, and therefore likely to be involved in human disease.
  3. Gene products of human pathogens, including bacteria and viruses.

The specific objectives of the technology development portion of this project are:

  • Develop and refine bioinformatic methods for segmenting or "parsing" DNA sequences of novel genes into domain-encoding regions;
  • Develop robust and general "domain trapping" methods for producing correctly-folded recombinant protein domains of novel biomedically-important human disease gene products;
  • Develop robust and general methods for high level expression and isotopic enrichment of these domains for NMR and X-ray crystallographic studies;
  • Apply standard screening methods to identify protein domain constructs that exhibit the properties required for structural analysis by NMR or X-ray crystallography;
  • Complete development of computer software, NMR pulse sequences, and related NMR technologies that will provide fully automated analyses of protein structures from NMR data;
  • Apply NMR spectroscopy or X-ray crystallography for determining 3D structures of these domains;
  • Develop improved methods for mapping new domain structures to proteins in the Protein Data Bank that have similar structures and biochemical functions;
  • Design and implement a relational data base of the empirical properties of expressed domains for organizing and integrating the biophysical and biological information derived from these studies;
  • Integrate all of the above into a large-scale, high-throughput macromolecular "structure-function analysis engine," and apply this to the discovery of biochemical functions of human genes.
The long term goals of this work are to develop a general strategy for discovering the biochemical functions of novel genes identified by the Human Genome Project, and to work together with NJ pharmaceutical and biotechnology start-up companies to exploit this technology in the discovery of new pharmaceuticals.

This NJISGB will have a major impact on the economy of the region by
  1. significantly enhancing the competitiveness of the NJ pharmaceutical industry in the world-wide race to find and develop new, cost-effective, and efficacious therapeutics;
  2. spawning start-up biotechnology companies in the rapidly growing area of genomics research; and
  3. establishing New Jersey as a center of excellence in emerging medically-related information technologies.

The bioinformatics "industry", though in a fledgling condition at present, could in the next 20 - 30 years actually rival the drug industry in size in the United States. The reason for this is that "genome awareness" is ramping up sharply in the health care community, and clinicians are already framing specific decisions regarding patient treatment in the context of the individual's unique genetic makeup. Increasingly, and sooner than one might think, therapies (at least in the industrialized world) will be tailored to match the special characteristics of a person's genes. The bioinformatics infrastructure necessary to service the healthcare industry transformed in this manner -- the "post-genome" era starting around 2005 -- will eventually become staggeringly large.

The business of "medical bioinformatics," powered by strong and irreversible economic and scientific trends in our society, has the potential to be a multibillion dollar, non-polluting, high-wage service industry for New Jersey in the 10 - 20 year time-frame. Therefore, if the state becomes a world leader in structural bioinformatics in the next ten years, it is not unreasonable to suppose that NJ bioinformatics-related enterprises may represent one of the most influential sectors -- and largest employers -- of science and technology-based commerce early in the next century.

Today, the New Jersey pharmaceutical industry represents one of the largest and most profitable sectors of the state's economy. However, the international pharmaceutical business is changing rapidly, and it is crucial to the state and national economy that NJ pharmaceutical companies remain healthy and competitive. Thanks to the HGP, there is a rapidly increasing "backlog" of sequenced human proteins of unknown structure (and function). The completion date for the human genome sequence is projected to be 2003, but the interpretation of the gene sequence data from this massive exercise will be greatly hampered until structures and functions can be assigned to the corresponding proteins. It will require a scaled-up, high-throughput approach such as we are embarking upon before many of the benefits inherent in the human genome sequence can be realized. Thus, the downstream pharmaceutical fruits of the HGP will require the delineation of biochemical functions for literally thousands of new gene products. The "structure-function analysis engine" described here has the potential to discover the functions of novel genes identified in the human genome faster than existing genetic or purely computational bioinformatics methods. Access to this information on potential drug targets in the human genome is crucial to the economic success of the NJ pharmaceutical industry because losing the intellectual property rights on these newly-discovered gene products to competitors would severely constrain future product development.

Our goal is to become one of the world's leading centers in structural bioinformatics for drug discovery. Scientists from the NJISGB are actively involved in national and international discussions in this emerging field. If we can maintain our technological edge, we have the potential to make significant contributions to the evolving international efforts in structural genomics and bioinformatics.

A New Jersey Commission on Science and Technology Initiative
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