September 19, 1997

Grant bolsters program development in young field of functional genomics

Grant bolsters program development in young field of functional genomics

As scientists work to identify and map the entire human genome, researchers at Vanderbilt University Medical Center are poised to begin answering the next questions:

What do all these genes do? And how can this information be used to diagnose, treat and prevent human disease?

With the support of a $1 million grant from a private, Texas-based foundation, VUMC is developing an integrated program in the emerging field of "functional genomics," the study of what genes do when they're behaving correctly and what they do when things go wrong.

"Within the next five or 10 years, we'll know what the 100,000 human genes are and where they sit in relation to each other within the 23 pairs of human chromosomes," said David W. Threadgill, Ph.D., assistant professor of Cell Biology.

"The problem is that we won't know what they all do.

"Functional genomics is an emerging field of research. We're starting to realize that knowing the complete sequence of the human genome is a far stretch from being able to use that information to advance treatment, diagnosis and prevention of human disease."

The grant to the Vanderbilt Cancer Center comes from the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, based in San Antonio, Texas. In the 47 years since its establishment, the foundation has provided the bulk of its support to medical research. However, it also funds work in veterinary and animal sciences, wildlife research and preservation, health services, higher education, community service organizations and the arts and humanities.

Threadgill is one of three scientists leading Vanderbilt research teams in this new area of exploration. Others are H. Earl Ruley, Ph.D., professor of Microbiology and Immunology, and Brigid L.M. Hogan, Ph.D., Hortense B. Ingram Professor of Molecular Oncology and professor of Cell Biology.

"David, Earl and Brigid are key members of the Vanderbilt Cancer Center, and we are excited by the synergy their collaboration will create," said Lawrence J. Marnett, Ph.D., Mary Geddes Stahlman Professor of Cancer Research and associate director for Research of the Vanderbilt Cancer Center.

"Although the technologies they are developing will initially focus on cancer, functional genomics is at the frontier of all biomedical research and their discoveries will have a tremendous impact on many different disciplines.

"This is a great opportunity for Vanderbilt to play an important leadership role, and we are grateful to the Kleberg Foundation for their support," Marnett said.

Two immediate goals will be to create new technologies for studying broad regions of genes in mice and to create a library of cells with specific genes "knocked out" in order to study their specific role in development.

An initial focus of the program will be on tumor suppressor genes, which act as a vital "brake" on cell growth. When these gene are malfunctioning or missing, the result is the out-of-control cell growth that characterizes cancer.

However, the development of an integrated functional genomics program at VUMC holds promise for the study of many diseases and other biologic processes.

"This grant and an integrated program in functional genomics will be a resource of tremendous importance to everybody in the medical center," Hogan said.

In Ruley's lab, scientists begin with the disruption of genes in a special cell called an embryonic stem cell that is then used to clone mice. The researchers then identify a gene's function by observing what happens to mice when that gene is "knocked out." This work is building a library of cells that can serve as a resource to other researchers, including scientists studying tumor suppressors in Threadgill's lab. They genetically alter mice to remove large sections of the genome, encompassing many genes, and then work backward from the outcome — in this case, development of cancer — to find the gene or genes that are responsible for that effect.

"That's where this work parallels other genome efforts to identify the genes and where they reside in the chromosomes," Threadgill said.

"In a few years, we'll have a map of where all the genes are positioned. Knowing what tissues of the mutant animals these cancers arise in, we'll have a good idea of what gene or genes are responsible. We will be able to use the "knock-out" library of cells to prove which gene is the causative agent."

Hogan's lab is particularly interested in the genes that are important in the embryonic development of the skeleton, blood vessels, lungs, kidneys, and other body systems. She and her colleagues are also interested in so-called modifying genes that alter the effect of a mutation in another gene.

"We know that in families that inherit mutations, some members may be affected much more so than the other members," she said. "We believe that there are other genes that are influencing the effects of a particular mutation.

"In our work, we've looked at mice where a mutation is placed against a particular genetic background, and we see deformities of the kidney, lung, eye and limb development. But on another genetic background — in another strain of mice — we see few effects at all. It appears that some genes may slow the process down, while other may speed it up.

"Everything is a balance between opposing processes."

The potential synergy between researchers in functional genomics is very important, Hogan said.

"In many ways, the work will be complementary," she said. "For instance, many tumor suppressor genes are important in normal embryonic development. One lab studying tumor suppressors may find some interesting things and pass them along to us to study in embryonic development. We may see things in our work that have implications for the tumor suppressor research.

"This program really advances VUMC in this whole area of mammalian genetics."

The private sector is an essential source of funding for leading-edge research such as this, the investigators say.

"Functional genomics is in some ways ahead of its time," Ruley said. "It's difficult to obtain funding for research that is so new, so this kind of support is critical."