Hardest work to come

Last month's national fanfare for the first interpretations of the human-genome sequence was no signal to scientists to put down their pipets.

In fact, said Dr. Barbara Trask, director of the Human Biology Division, the hardest work for understanding the genome - to be done by scientists in all disciplines - may be yet to come.

"The real challenge , and value, of the sequence will be in making sense of how all of those genes are regulated, including understanding cellular pathways, how viruses alter cell development, how proteins fold to function in the cell...The list goes on," she said. "Scientists in every division at the Hutch are working on problems critical to interpreting the genome, and information from the sequence will play an important role in helping many of us further our research."

The ultimate use

Basic Sciences Division investigator Dr. Steve Henikoff, who has developed computer databases for sequence interpretation, agreed that translating the sequence into an understanding of human biology is the ultimate use of genetic information.

"There's the sequence - a collection of data," he said. "By itself, this tells us very little. Then there's the annotation, which converts the data into information. This information provides a very useful infrastructure that can be used by someone who knows what question to ask to gain knowledge about biology, in this case, about human biology.

"There is increasing value as one goes from data to information to knowledge. We have seen how, in model organisms, a reasonably complete sequence allows us to quickly ascend the hierarchy from data to information to knowledge. So I have no doubt that the same will be true for the human genome sequence."

A critical piece of knowledge is understanding how specific genes are turned on or off at different times in each cell type, said Dr. Steve Hahn, a scientist in the Basic Sciences Division and an expert on gene regulation.

"One thing that distinguishes one cell type from another is what proteins they express, a result of gene regulation," he said. "Differences in protein expression occur not only during development, but even after a cell is fully differentiated. To get this to happen correctly, the right regulators need to be present at the same time. Ultimately, this is the process that scientists want to understand."

Enormous impact

Lab scientists will not be the only beneficiaries of the new-found wealth of genetic information.

Dr. Stephen Schwartz, an epidemiologist in the Public Health Sciences Division, said human-sequence data will have an enormous impact on epidemiology and other population studies.

"Our research attempts to determine whether inherited variation in genes, in combination with lifestyle and environmental influences, affect a person's risk of cancer," he said.

"With the entire genome in hand, we can study that variation much more comprehensively and efficiently than before. Complete sequence information will help us identify genes and variants in the population that scientists had never before considered as predisposing people to cancer."

Dr. Jerry Radich of the Clinical Research Division said that genome information will improve cancer care as scientists uncover genetic changes associated with cancer.

Radich has developed molecular techniques for detecting extremely rare leukemia cells - a condition called minimal residual disease - in patients who appear cured, enabling prediction of patients who have a high risk of relapse.

"We are limited in our ability to detect and treat minimal residual disease in most tumors, since thegenetic changes responsible for many types of cancer are unknown," he said. "The knowledge of the genome will allow for genetic diagnostics to eventually be applicable to most, if not all, types of cancers."

In addition to predicting relapse, Radich expects to see advances in understanding the genetics of cancer progression and response to therapy. Scientists are using DNA microarrays, tiny chips that allow thousands of genes to be studied at once, to study the patterns of genes whose expression is altered in cancer cells.

The limitation now, he said, is that many of the genes on the microarrays are unknown.

"The knowledge of the human genome will greatly increase the information derived from these types of experiments, and will allow for a much speedier translation to diagnostic and therapeutic approaches," he said.

Mapping sequencing, interpreting: contributions by Hutch scientists

Key contributions of Hutch scientists to mapping, sequencing and interpreting aspects of human-genome research include:

• Dr. Dan Geraghty of the Clinical Research Division and international colleagues sequenced a portion of human chromosome 6 that points to the major histocompatibility complex, which contains the information that enables the body to fight disease. In addition to controlling aspects of immune-system function, the genes in the complex are associated with nearly 100 diseases, more than any other location in the human genome. These include autoimmune diseases such as diabetes, rheumatoid arthritis and multiple sclerosis. This sequencing project was completed in 1999.
• While the human-genome sequence provides a basis for understanding human genetic complexity, the next phase of research will focus on determining how and where the sequence varies among individuals. Many biologists predict that an understanding of genetic variation will lead to individually tailored medicine, as scientists learn more about which genetic differences predispose people to disease. Drs. John Hansen, Dan Geraghty, Lee Nelson and Effie Petersdorf in the Clinical Research Division lead a consortium known as the International Histocompatibility Working Group that analyzes the genetic variation that exists in the major histocompatibility complex, a cluster of about 300 genes important for the human immune response. The region contains far more variation than any other in the genome. Genes in the major histocompatibility complex influence risk of several immune-related diseases, including diabetes and rheumatoid arthritis. Matching for genes in the complex determines the outcome of transplantation. The working group, collaborating with the National Center for Biotechnology Information, will establish a new database to help investigators identify clinically important variants in the gene complex.
• Genetic maps and genome sequences of other organisms provide useful comparative tools for scientists to learn more about human genes and understand the evolution of the human genome. Dr. Elaine Ostrander and colleagues initiated a project to develop a genetic map of the dog genome as a way to uncover the genetic basis for canine diseases as well as behavioral and physical traits. Since many canine genes have human counterparts, the Dog Genome Project provides a way to ultimately identify and characterize human genes, including those implicated in development and disease.
• Dr. Leonid Kruglyak and colleagues in the Human Biology Division have developed computational tools for locating the positions of disease genes on chromosomes. Kruglyak is interested in mapping genes for complex diseases, such as cancer and diabetes, which result from mutations in more than one gene. Kruglyak developed software for and participated in the construction of the first physical map of the human genome, published in1995. He also has performed extensive analysis of single-nucleotide polymorphisms, small changes in genes that contribute to the enormous amount of variation in the genome. Based on his studies, he proposed the number of such polymorphisms needed for mapping disease genes.
• Dr. Barbara Trask, director of the Human Biology Division, belongs to a consortium that has developed a resource of molecular tools that will help link known chromosomal abnormalities, which can be visualized by microscopy, with their corresponding segments of sequenced DNA. Many abnormalities have been identified by examining patterns of bands on dye-stained chromosomes - a field of study known as cytogenetics - but determining the precise locations of these genetic changes has been an arduous process until this resource became available.