New Directions in Genome Science

		Dr. Celeste Berg, holding an enlarged model of a fruit fly wing, studies how genes direct egg and embryonic development in fruit flies.

With the human genome sequence all but complete and a growing number of animal, plant, and bacterial genomes also sequenced, genome scientists are turning toward interpreting these enigmatic codes. The University of Washington is creating technologies and experimental methods to understand genomes and apply this knowledge to medical studies.

The UW’s reputation as a center of genome research was further enhanced by Dr. Robert Waterston’s appointment as chair of the Department of Genome Sciences. Two national Centers of Excellence in genome research have been established at the UW. One studies genetic variation and the other works on miniaturizing technologies.

Cross-departmental and cross-disciplinary collaboration is burgeoning, as genome science becomes a tool in many research areas from medical genetics to infectious disease.

Genome science will increasingly be of central relevance to a wide variety of research activities, according to Waterston.

As genome science matures, massive sequencing projects continue. A draft sequence of the entire rice genome for the subspecies indica, the most widely cultivated rice in China, was published in Science in April 2002. Counter-intuitively, this rice genome has many more genes than the human genome. Although the sequencing was done at the Beijing Genomics Institute in China, two UW research scientists, Drs. Jun Yu and Gane Ka-Shu Wong, led the project. Rice is the second plant ever and the first cereal crop completely sequenced. The rice sequencing is expected to lead to better crop strains.

What next after such big sequencing projects? One new direction is genetic variation studies.

Sequencing projects produce a reference genome, which is a mosaic drawn from different individuals. Each person’s genome varies about 0.1 percent from that of any other person. This variation is due in part to evolutionary mutation. Pathogenic microbes target the common genetic variants in the population. Those people resistant to the infection survive, and their rarer, variant mutations are passed along to their offspring. A key question in genetic research is, How does genetic variation relate to individual susceptibility to disease?

Dr. Maynard Olson, professor of genome sciences and of medicine, and Dr. Deborah Nickerson, associate professor of genome sciences, lead major research projects on genomic variation. Much of their work is on how human genes correlate with disease. To develop models for how differences arise, new methods of large-scale analysis are needed to accurately sequence large segments of genomes from many individuals.

Olson’s group also investigates the corresponding evolving variation that plays out, in much shorter cycles, on the microbe side. Cystic fibrosis patients, for example, each have a different strain of the bacteria Pseudomonas aeruginosa, an opportunistic pathogen that destroys their lungs. Using genome analysis of specimens taken over many years from patients at Children’s Hospital in Seattle, Olson is uncovering the genetic processes within this bacterium. He believes that a cascade of bacterial mutations is central to progress of the disease. Olson’s group is part of one of the UW’s two Centers of Excellence in Genomic Science.

The other UW Center of Excellence in Genomic Science has been established at the College of Engineering. The project, informally dubbed “Life-on-a-Chip,” will develop microsystem devices, which are machines made of silicon, glass, and plastic to be used for experimental analysis of complex cellular processes. These devices will be distinct modules that can be pieced together to run a biological experiment.

The first device under development is a micro-environmental chamber. Cells can be held within the chamber while fluid flows through it. Relevant parameters are monitored as the environment changes.

“Right now we’re using hundreds to thousands of cells,” said Dr. Deirdre Meldrum, professor of electrical engineering. “Eventually we want to be able to detect parameters within a single cell.”

UW medical researchers are already devising applications. Throat cancer investigators are working to miniaturize and automate biopsy screening so that regular biopsies can be easily taken to track changes over the course of the disease. Researchers interested in how HIV infection affects the host genome over time want to track how the virus replicates within an individual cell. Another lab is studying Salmonella-induced cell death, specifically the chain of biochemical events, common to other diseases including stroke and heart attacks, that produce inflammation. A team using a yeast model to investigate protein signaling wants to look at protein expression from a single cell. Another group, studying DNA and aging, is trying to automate the laborious separation of daughter yeast cells from the mother cell. Investigators seeking to measure metabolic events within a single bacterium aim to relate genomic and expression data to metabolic outcomes.

The Department of Genome Sciences is building upon its strengths in computational biology and development of novel techniques of large-scale analysis.

Of specific interest are networks of gene interaction, whereby one gene affects or even regulates the expression of other genes. Using the nematode worm Caenorhabditi elegans as a model, Waterston, the department chair, wants to pinpoint the time during development and the place within the embryo that any gene is turned on. He intends to automate this pinpointing and apply it to many genes to reveal gene expression patterns in fine detail.

In other promising aspects of genome research, Dr. Mary-Claire King, professor of genome sciences and of medicine, works on identifying and characterizing the genes behind such complex human disorders as breast and ovarian cancer, lupus, and inherited deafness.

Outside the UW genome research centers, genomic science is increasingly ubiquitous at the UW. It has, for example, become the foundation for modern drug design. In the “Structural Genomics of Pathogenic Protozoa” project, candidate molecules that are potential targets for anti-infection drugs are selected by identifying relevant genes and the encoded protein structures.

“Within a few years,” said Dr. Philip Green, professor of genome sciences, “investigators likely will require genome sequence information for research in any area of biology.”