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2003 Gruber Genetics The Science

David Botstein has been one of the driving forces of modern genetics. He is a geneticist, educator and a pioneer in integrating multiple diverse disciplines into the study of biology.

His work established the ground rules for human genetic mapping and laid the foundation of the human genome project. He also co-discovered transposons in bacteria.

His current research activities include studies of yeast genetics and cell biology, linkage mapping of human genes predisposing to manic depressive illness, hypertension and other complex diseases and the development and maintenance of the Saccharomyces Genome Database on the World Wide Web (http://www-genome.stanford.edu).

Most recently he has been involved in pioneering the application of microarray technology. Microarray studies provide a high-throughput molecular approach to simultaneously assess the behavior of many genes. This technology is being applied to understand how to better target cancer therapies based on gene profiles of the tumor cells. Botstein has applied this novel technology to distinguish four distinct subtypes of breast cancer. Each of the subtypes needs a different type of medical treatment.

One of his earliest, and most significant contributions to the field of genetics was the demonstration of the utility of variations in human DNA sequence. In 1980, Botstein and three colleagues proposed a method for mapping genes that laid the groundwork for the Human Genome Project. They demonstrated that DNA differences inherited in individuals could provide signposts to facilitate creation of human genetic maps and for tracking disease genes in families. The DNA differences were called RFLPs or Restriction Fragment Length Polymorphisms.

The name indicates that variations (polymorphisms) in DNA fragment size can be based on the ability of specific enzymes (restriction enzymes) to cut DNA into varying length fragments based on differences in the DNA sequence. This finding gave rise to the first human genetic linkage maps consisting of RFLP markers and subsequently has stimulated the effort to build even betters maps. These maps have provided the foundation for a critical component of the Human Genome Project.

Botstein's work will continue at the Lewis-Sigler Institute for Integrative Genomics at Princeton University where he was appointed the director in 2003. According to an interview in The Scientist, Botstein did not come to genetics easily. First it was engineering, then physics, then biochemistry. Thus, he came to the field as an integrator. Botstein said his aim is for the institute to become a leader in teaching students in the areas of bioinformatics, computational biology and the like, using computers and mathematics to probe biology.

He said, "I want the institute ... [to take] a stab at the curriculum of the genomicist, or I would say, general scientist of the future. We need more simulation and computational methods that allow you to look at the data set and ask, 'What are the odds that that will arise on different models?' "

Most of his career, he has been heavily engaged in teaching. He said he was attracted to Princeton by the opportunities for both research and teaching. He openly acknowledges that the emergence of the data from the Human Genome Project will completely change the way biology can and will be done. "The question of what kind of preparation young people should have in order to enter into this exciting new world requires serious thought," he said. He has been a leader in thinking about the education of these young scientists and about establishing the databases and computational tools that will be required in the post-genome era to integrate, manipulate and store vast amounts of information.

By Beverly S. Emanuel, Charles E. H. Upham Professor of Pediatrics, Professor of Pediatrics and Genetics, Chief, Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia.