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April 21, 2003

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GENETICS RESEARCH BUILDS ON LEGACY OF DOUBLE HELIX

In April 1953, James Watson and Francis Crick published their report describing for the first time the correct, double helical structure of the DNA molecule. Twenty-five years later, Johns Hopkins researchers Hamilton Smith and Daniel Nathans were awarded the Nobel Prize for finding proteins in bacteria that could cut DNA at specific, predictable places, ushering in the era of genetic engineering.

Other researchers at The Johns Hopkins University School of Medicine now are building on the Nathans-Smith and other advances that have dramatically altered medical science. In celebration of these important scientific anniversaries, reporters are invited to pursue the following stories involving genetic approaches to understanding and treating cancer, heart attack, Marfan syndrome, schizophrenia and bipolar disorder.

OXYGEN-RESPONSIVE PROTEIN GIVES INSIGHT TO HEART ATTACK, CANCER

In 1992, Gregg L. Semenza, M.D., Ph.D., a pediatric geneticist with the Johns Hopkins Children's Center and the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, isolated hypoxia-inducible factor 1 (HIF-1), a protein that regulates responses to reduced oxygen levels in the body. When oxygen levels drop, HIF-1 accumulates and activates multiple genes that control vital processes, such as red cell production and the formation of new blood vessels, both of which help to increase oxygen delivery throughout the body.

Today, Semenza is investigating the role of HIF-1 in animal models of heart attack, stroke, and cancer -- the three most common causes of death in the United States. This research may lead to the development of therapeutic strategies to promote or inhibit new blood vessel growth in patients, as needed.

"In many patients with coronary artery disease, heart tissue does not respond to reduced blood flow by forming new blood vessels as it should. This may be due, in part, to inadequate production of HIF-1," says Semenza. "If so, then HIF-1 gene therapy may be an effective means of correcting the deficiency and stimulating new blood vessel formation."

In cancers, for which new blood vessels fuel tumor growth, Semenza says efforts are ongoing at academic institutions and pharmaceutical companies worldwide to develop drugs against HIF-1 that may block blood vessel growth in tumors. Already, evidence suggests that high levels of HIF-1 can identify subsets of patients with several types of cancers who are significantly more likely to die of their disease.

Media Contact: Jessica Collins
410-516-4570;
jcolli31@jhmi.edu


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NEW TARGET FOUND FOR ATTACKING MARFAN SYNDROME

By studying mice, Johns Hopkins scientists have discovered that excessive activity of an important signaling protein, TGF-beta, may be responsible for a variety of problems seen in Marfan syndrome, including the tendency to develop emphysema.

In a recent issue of Nature Genetics, the research team reports that the mouse work dramatically improves understanding of TGF-beta's regulation and function and offers the most feasible target yet identified for preventing life-threatening problems that stem from the connective tissue disorder.

"TGF-beta pulls together what we know clinically about Marfan syndrome with what we know genetically," says study leader Hal Dietz, M.D., who directs the Smilow Center for Marfan Research at Johns Hopkins. "If our findings in mice are supported by clinical evidence of high TGF-beta activity in people with Marfan syndrome, blocking TGF-beta activity may be a reasonable approach to reduce or prevent many features of the syndrome."

In 1991, scientists tied Marfan syndrome to genetic mutations that create a non-functioning fibrillin-1 protein, which normally coats the elastic fibers that help give tissues form and strength. Without fibrillin-1, elastic fibers form, but they are more prone to breaking, explaining some problems seen in Marfan syndrome, including rupture of the aorta, which carries blood away from the heart.

Structural weakness has also been the primary explanation for emphysema, the gradual inflammation and destruction of the tiny air pockets in the lungs. However, the new research shows that not only is TGF-beta activity high, but blocking it during development can prevent lung damage in mice without fibrillin-1, says first author Enid Neptune, M.D., assistant professor in the division of pulmonary and critical care medicine at Johns Hopkins.

Media Contact: Joanna Downer
410-614-5105;
jdowner1@jhmi.edu

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SEVERE FORM OF BIPOLAR DISORDER EASES SEARCH FOR DISEASE GENES

After years of searching for genes that contribute to mental illness, researchers at Johns Hopkins studying families with a severe form of manic depressive illness, called psychotic bipolar disorder, may be one step closer to finding the genetic underpinnings of both bipolar disorder and schizophrenia.

"Finding a gene for bipolar disorder is like finding a needle in a haystack, but by focusing our search on families with a distinctive form of the illness we were able to pinpoint a region of the genome where disease genes are likely to be found," says James Potash, M.D., assistant professor of psychiatry at Johns Hopkins and lead author of a report on the study in the April issue of the American Journal of Psychiatry.

Because certain broad regions of the DNA sequence, especially on human chromosomes 13 and 22, may contain genes that contribute to both bipolar disorder and schizophrenia, Potash and colleagues focused on families with the psychotic form of bipolar disorder. Psychotic bipolar disorder has psychotic symptoms such as hallucinations and delusions often accompanying the seesawing episodes of depression and mania that alone characterize bipolar disorder.

The researchers carefully evaluated and took blood samples from 65 patients with bipolar disorder and from their extended families. Out of 65 bipolar disorder families studied, the 10 families in which three or more members had psychotic bipolar disorder showed strong genetic "linkage" to specific regions on chromosomes 13 and 22.

"These results confirmed our expectation that genes for the psychotic form of bipolar disorder are likely to be found in the same regions that show linkage to both bipolar disorder as a whole and to schizophrenia," says Potash.

One important implication of the study is that these "overlap genes" may contribute to brain abnormalities that are shared by bipolar disorder and schizophrenia, and could help explain why the same antipsychotic medications are effective treatments for both diseases, says Potash.

Media Contact: Trent Stockton
410-955-8665;
tstockt1@jhmi.edu



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