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Screening Genes for Fun and Profit

By Sean Henahan, Access Excellence

hausslerWASHINGTON, D.C. (2/19/00) The Human Genome Project, ahead of schedule and under budget has almost completed its first objective, identifying the complete DNA sequence of the human genome. Now the hard part begins, as researchers begin to develop strategies to more quickly identify those genes and gene products that may have therapeutic potential.

left: Dr. David Haussler, UC Santa Cruz

Numerous research groups and a number of private companies are working feverishly to screen genetic gold from the dross. At stake are not only potential cures for cancer, heart disease and other ailments, but billions if not trillions of dollars for those companies that identify important sequences. The combination of hardware and software techniques from the molecular biology lab and the computer lab to sort out useful proteins has spawned a new subspecialty, bioinformatics. Several researchers were on hand at the annual meeting of the American Association for the Advancement of Science to present their latest findings in this field.

The problem facing researchers in this field is the sheer volume of gene sequence data produced by the Human Genome Project and related undertakings. The challenge is to identify genes in the less than 10 percent of the human genome that is thought to comprise protein-coding gene sequences. Once the gene is identified, researchers then try and determine what the protein product is and how it is regulated.

"The driving force behind bioinformatics is the availability of these large databases and the need to come up with sophisticated computer models for extracting useful information from them. Computer analysis will be an integral part of identifying genes and understanding their functions," said David Haussler, professor of computer science at the University of California, Santa Cruz. Haussler also recently joined the Human Genome Project's bioinformatics team.

Dr. Haussler and colleagues have pioneered several important computational techniques to aid in finding genes. They have pioneered the use of a new statistical method based on an idea known as the theory of support vector machines (SVMs). SVMs are able to handle high-dimensional datasets in which each data point has many features or attributes. Using powerful computers, this system will help the scientists put the currently disorganized DNA sequence information of the Human Genoma Project in an order more suitable for gene hunting. Once target genes are identified, bioinformatic techniques will also be essential in the development of applications such as screening tests and medical treatments.

"Our vision for bioinformatics spans a broad spectrum, from basic molecular biology all the way up to clinical diagnostics," Haussler said.

NY Shows Initiative

A group of New York City scientists are developing a bold strategy to take advantage of the data hidden within the Human Genoma project databases. The 'structural genomics initiative' aims to use bioinformatic technologies to identify promising drug targets. They will focus on proteins that cause disease in humans, as well as those that are used in treating disease.

"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 Andrej Sali, assistant professor, Alfred P. Sloan research fellow and Sinsheimer scholar at The Rockefeller University. "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."

right: Dr. Andrej Sali

Human genome research has become a vast international effort involving thousands of research groups. Researchers can avail of free (and commercial) databases of known sequences via the Internet, where they can also post their own findings. The New York team hopes to accelerate its own work by putting its findings on the web. It is their hope that any protein structure they discover will be of immediate relevance to academic and/or industrial research teams studying that biological system. By publicizing target lists on the Internet, the structural genomics pilot studies they conduct could generate scientific interest and expertise and attract suggestions for additions to their respective target lists. The pilot studies will serve as an important resource for distribution of tools and reagents for research.The pilot studies will be able to serve as an important resource for distribution of tools and reagents for research, Sali says adding:

"One can imagine that some future NIH grant applications would include both a request for funds and a request for a supply of a particular purified protein deposited in a centralized cold-storage facility."

Ultimately, Sali believes research in the area of structural genomics could provide the means to address one of the great unsolved problems in molecular biology, that is, the the relationship between one-dimensional sequence information (the order of amino acids in a protein) and three-dimensional structure (the folds of the complete protein).

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