The Rosetta stone of immunology

Hutch leads global team to accelerate investigation of immune-related genes

Why do transplants sometimes fail despite close donor-recipient matches?

What makes certain people more susceptible to specific diseases?

Why do vaccines protect some individuals better than others?

A cluster of nearly 220 genes known as the human leukocyte antigen (HLA) gene complex holds clues to these and many other unsolved medical mysteries.

In search of the answers, the National Institutes of Health has launched an initiative to catalog the HLA gene complex and explore its differences among populations worldwide.

Nearly $20 million over five years will go to the International Histocompatibility Working Group, a network of nearly 200 laboratories in more than 70 countries led by the Hutchinson Center’s Dr. John Hansen. The group will set up a centralized HLA gene database and develop new and improved tools to decipher this genetic Rosetta stone of immunology.

Hansen, head of the Hutch’s human immunogenetics program and a professor of medicine at the University of Washington, says the project could have immediate clinical benefits, including finding better matches for bone-marrow transplant patients.

“But the potential impact of these new studies goes way beyond the HLA community immunogenetics,” he says. “This project will apply recent advances in genome technology to important questions about specific diseases and help explain how the rich genetic differences in HLA between individuals can either strengthen the immune response or open the door to autoimmune disease and infection.”

The effectiveness of a person’s immune defenses for detecting and destroying trespassing antigens depends largely on his or her HLA gene complex. Similarly, these genes are suspected to play a role when the immune system mistakenly targets the body’s own cells as foreign, which is the case with autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes.

The international group will accelerate investigations seeking to discover the fundamental mechanics of how HLA genes direct beneficial and harmful immune responses.

“The group represents more than 30 years of collaborative research among the world’s leading scientists in population-based genetics,” says Dr. Daniel Rotrosen, director of the National Institute of Allergy and Infectious Diseases’ Division of Allergy, Immunology and Transplantation.

“Its extensive international network of laboratories will contribute importantly to our efforts to address the global health problems caused by infectious and immune-mediated diseases.”

—Susan Edmonds

Anti-cancer drug could result from study of common lab chemical

Could a well-known chemical used in laboratories for 50 years hold the key to combating the most resistant forms of breast, colon and prostate cancers?

Laboratory scientists at the Hutchinson Center think it might. In fact, it could lead to an anti-cancer drug built molecule by molecule.

Researchers commonly use a compound called antimycin A to study cellular metabolism. Dr. David Hockenbery’s laboratory team found that antimycin A’s structure preferentially binds to a well-known cancer gene suspect named Bcl-xL.

Dr. Shie-Pon Tzung in Hockenbery’s lab conducted experiments aimed at finding compounds that initiate cell death in liver cells. He found that antimycin A selectively killed cells expressing Bcl-xL, with minimal effects on matched cells with lower levels of these proteins.

“We found that the higher the level of Bcl-xL in these cells, the easier they were to kill with antimycin,” Hockenbery says. “But at the same time, these cells are the most resistant to multiple chemotherapy drugs. It is almost as if antimycin uncovers an Achilles’ heel in these cells.”

The team aims to design a drug based on the chemical and structural features of antimycin A, building it one molecule at a time. This approach holds great promise for specifically attacking cancer cells and causing fewer, milder side effects.

Drug that combats virus may encourage resistance to itself

Alifesaving antiviral drug for solid-organ transplants may be leading to an alarming rise in viral resistance to the drug, according to a study by researchers at the Hutchinson Center and the University of Washington.

The antiviral agent ganciclovir is prescribed routinely for organ-transplant recipients at high risk for cytomegalovirus (CMV) infection, such as those who harbor dormant CMV and those who receive transplants from infected donors.

CMV infection is a common complication of bone-marrow and stem-cell transplantation.

Unchecked spread of CMV in immunocompromised individuals—such as transplant patients and AIDS patients—can cause retinitis, an inflammation of the retina that can lead to blindness. In stem-cell transplant recipients, pneumonia and gastrointestinal disease are the most prevalent illnesses caused by CMV infection.

Recent data suggest that oral ganciclovir use, when combined with potent immunosupressive drugs used to minimize transplant rejection, correlates with increased incidence of ganciclovir-resistant virus.

“These results are very significant for Hutch investigators because we are planning to develop similar strategies for preventing CMV infection in those who undergo stem-cell transplants,” says Dr. Michael Boeckh of the Hutch’s viral-research lab.

Hutch investigators plan to use the drug valganciclovir to prevent CMV infection in stem-cell transplant patients.

“Valganciclovir is an oral drug that is absorbed by the blood at much higher levels than ganciclovir and therefore should be more effective at controlling CMV infection,” Boeckh says. “Based on the results of this study, we’ll be paying particular attention to the development of resistance in our experimental design to ensure patient safety.”

Hartwell’s cell-cycle research wins prestigious Griffuel, Massry prizes

Two top scientific awards—the Leopold Griffuel Prize and the Massry Prize—have been awarded to Dr. Lee Hartwell, Hutchinson Center president and director, for his cell-cycle research.

The Griffuel Prize, sponsored by the French Association for Cancer Research, is intended to reward the world’s leading cancer researchers.

The Massry Prize, which honors those who have made outstanding contributions to biomedical sciences and the advancement of health, is given each year by the Meira and Shaul G. Massry Foundation, a non-profit organization.

In his 30 years of studying yeast, Hartwell has identified more than 50 genes crucial to controlling the intricate program of instructions by which a cell grows, rests and divides to replicate itself. Among Hartwell’s discoveries in budding yeast is a gene called CDC28, which cells need to progress through their various life stages.

Learning when and why the cell cycle goes awry— often leading to the uncontrolled growth that is characteristic of cancer—is the centerpiece of his work.

The conviction that the development of cells, including human cells, could be discerned from yeast was a “fairly risky assumption,” Hartwell says, looking back on the early days of his career in the 1960s. Now, after 30 years of working with yeast, he is committed to the application of knowledge that he and his many colleagues have acquired.

At the Hutch, Hartwell’s yeast-related research is used to develop drugs for use against cancer and other diseases.

Hutchinson Center ranks near top in influential papers

The Hutchinson Center ranks among the top 20 universities and research institutions worldwide for publishing the greatest number of high-impact papers in molecular biology, cell biology and genetics, according to a recent survey.

Science Watch, a newsletter that analyzes scientific journal literature, reviewed the 1,000 most frequently cited papers between 1994 and 1998. Institutions with at least 10 high-impact papers were ranked based on the overall number of times a paper was cited by others as well as the number of citations per paper.

The Hutch was ranked 18th, with an average of 336.5 citations per each high-impact paper.

Fat substitute linked to lower cholesterol levels

People who eat potato chips and other snack foods made with the fat substitute olestra may reduce their serum-cholesterol levels, but they are unlikely to lose much weight, according to a study by Hutchinson Center researchers.

The heaviest consumers of olestra—those who reported eating one to two servings of chips per week for a year— experienced a decrease in total serum cholesterol of more than 10 percent. They also lost about one pound per year on average.

These effects cannot be explained entirely by eating olestra, since even the heaviest consumers ate a relatively small amount of the fat substitute. Instead, the researchers attribute the decrease in fat intake, weight and serum cholesterol to a combination of factors, biological and behavioral.

“While there are some plausible biologic reasons for these changes, such as the possibility that olestra sequesters dietary cholesterol in the gut before it has a chance to get to the bloodstream, olestra consumption is probably also an indicator of a healthier lifestyle in general,” says Dr. Ruth E. Patterson, the report’s lead author. “Instead of being a marker for bad behavior, we’ve found it’s a marker of good behavior; people who eat olestra tend to exercise more, eat better and be more health-conscious.”

New book: Regular exercise reduces breast-cancer risk

Regular exercise can cut the risk of developing breast cancer by more than a third. That’s the message from a new book the Hutch’s Dr. Anne McTiernan—a leader in research on exercise and breast-cancer prevention—and colleagues have written a new book on the subject.

Breast Fitness, published this fall by St. Martin’s Press, includes exercise and health tips for women to help prevent breast cancer. Research by McTiernan and others has shown that aerobic exercise three to four hours per week reduces risk 30 to 40 percent.

McTiernan co-wrote the book with Dr. Julie Gralow, a professor of medical oncology at the University of Washington and the Hutchinson Center, and fitness expert Lisa Talbott.

Private Donations Helped Nelson Discover Genes That May Play a Role In Prostate Cancer

Without donations from people like you, Fred Hutchinson Cancer Research Center's work to advance knowledge and save lives would not be possible. Your gifts fund preliminary studies that lead to grants for in-depth research. Here's an example of your dollars at work.

Dr. Peter Nelson arrived at Fred Hutchinson in 1999 ready to use molecular biology to identify genes that may play a role in prostate cancer development and diagnosis.

Using funds from private donations to begin his research program, Nelson discovered five new genes whose regulation is affected by male hormones like testosterone. Another well-known cellular component whose levels are similarly affected by male hormones is the prostate-specific antigen (PSA), an enzyme used in a common test to diagnose prostate cancer.

Nelson's promising initial results helped him secure $1.5 million of funding from the National Institutes of Health for further study.

"Our next goal is to figure out exactly what these genes do. In addition to having possible diagnostic or therapeutic value, we hope that they will teach us a lot about the biology of prostate cancer," Nelson says.