This article was published on page 2 of CityLink, City of Hope's quarterly employee newsletter, in February 1998.

Of "Monster" Genes and Sane Scientists

Part II of "City of Hope Builds World-Class Genetics Program"

This is the second article in a series on City of Hope's efforts to define the leading edge of genetics research. The series introduces several recently recruited geneticists and molecular biologists, and the programs they were developing. Together, these programs form the foundation for a comprehensive approach to genetic research and treatment--one that will lead City of Hope into the 21st Century.

A monster is being studied in the laboratories of the Rose and Howard Fox Research Plaza--a "monster" gene that is. The Ataxia Telangiectasia Foundation (ATF) recently awarded a two-year, $50,000 grant to Steve S. Sommer, MD, PhD, director of the Department of Molecular Genetics and acting chair of the Division of Human Genetics, to look for mutations on the ATM geneÑan extremely large gene.

"The ATM gene is a monster," says Dr. Sommer. "It is one of the largest genes known--about 16,000 base pairs long, compared to about 1,200 base pairs for a typical-sized gene." A person who inherits two mutated copies of this gene develops ataxia telangiectasia (pronounced "ay-TACK-see-uh teh-LAN-jick-TAY-sha")--A-T for short--a rare, genetic disorder that results in progressive nerve degeneration and affects several systems within the body.

"Although A-T is a rare condition, what makes this gene so compelling to research is not only its size," says Dr. Sommer, "but the implications it has for genetics research. Because people with A-T are much more sensitive to the effects of ionizing radiation, like X-rays, researchers believe that the gene plays a role in the repair of radiation damage to DNA, the genetic material. Also, individuals with this condition are much more likely to develop early onset cancer, most commonly Leukemias and Lymphomas. This also suggests that the gene plays a role in mutation repair."

Cracking the Genetic Code

To analyze mutations, sensitive and rapid mutation scanning methods are needed. "Most gene-scanning techniques detect only some mutations," says Dr. Sommer. Unfortunately, for certain research applications and for most clinical molecular diagnostic applications, it is necessary to detect virtually all mutations. Dr. Sommer's laboratory is developing a rapid scanning methodology that will do just that.

The ATF grant gives Dr. Sommer an excellent opportunity to test these new methods out. "I see this grant as the first step of a major project," Dr. Sommer says. In collaboration with Richard Gatti, MD, of UCLA, he will be using novel techniques to search for mutations in the ATM gene of 27 patients in which mutations were not found using standard methods. "If we can do this one rapidly," he says, "we can do just about any gene."

"Once this first project is completed," says Dr. Sommer, "we hope to work with the A-T community to look in more detail at the molecular epidemiology of this very interesting gene. In particular, we are interested in the effect that carrying one mutated ATM gene has on the health of carriers."

Researchers have found that the mutated gene affects "carriers"--those people who carry one normal and one mutated ATM gene, and therefore don't develop A-T. Studies have found that cells from carriers also are sensitive to radiation, but at a level that is intermediary between the average person and a person with A-T. In addition, it has been suggested that they are at higher risk of developing cancer or toxicity to radiation therapy.

Since about 1 percent of the general population carries a mutated ATM gene (which equals approximately 2 million people in the United States), Dr. Sommer's research on the ATM gene could significantly impact health care.

Molecular Diagnosis Leads to Better Treatment Options

"We are on the threshold of a new era in molecular medicine," says Dr. Sommer. This developing branch of science promises to move the predominant focus of health care from providing care to patients after they have been diagnosed to disease prevention. "In the years ahead," he says, "the focus will instead be on the diagnosis of genetic mutations that make individuals susceptible to developing major complex diseases over their lifetime.

Using information gained from molecular diagnosis and with early intervention, we may one day prevent or delay the onset of common diseases such as cancer."

By uncovering the different mutations of the ATM gene, Dr. Sommer hopes to find out if certain types of mutations affect the developmental path of A-T, since each individual with the disease expresses it differently. In particular, he hopes to determine if certain types of mutations predispose individuals to cancer more than other types.

Different types of mutations within the same gene can sometimes cause different diseases. For this reason, Dr. Sommer's laboratory will also use the results of this work to see if disorders other than A-T are also caused by mutations within the ATM gene.

Once the ATM gene and its mutations have been mapped, diagnostic tests can be developed to determine if a person carries any specific mutations. In addition, pre-natal tests could be developed that would let parents know if their unborn child has A-T.

Discovering How Mutations Occur

Dr. Sommer is also interested in mutational processes, which is how genetic diseases are created. "In my laboratory, we are looking at the causes of mutations. Does the environment create them? Or do normal processes within the cell cause them?" Studying the mutations found within the ATM gene might help illuminate the answers to these questions and more.

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Side Bar:
Four Components of an Integrated Program

"My research interests focus two different biological questions," says Dr. Sommer. "'How do mutations form?' and 'How can we efficiently find the mutations that predispose individuals to common genetically complex disease such as heart disease, cancer and diabetes?'" In pursuit of these goals, he is developing molecular genetics and diagnostics programs at City of Hope that encompass four components: the mutational process; the genetics of complex disease; methodology development; and clinical molecular diagnosis.

The ATF grant touches on all four components of Dr. Sommer's program. Learning how mutated ATM genes affect DNA repair will help illuminate the mutational process. By decoding such a large gene, Dr. Sommer will further his research of complex disease as well as improve the methods he is developing to scan the genetic code. These methods also can provide rapid DNA-based diagnostic testing to patients from families with A-T.