Johns Hopkins Magazine -- February 1997
Johns Hopkins Magazine


H E A L T H    &    M E D I C I N E

The genetics of prostate cancer... heartwarming breakthroughs... surprises in nerve regeneration... iron pills and learning... insurance against stroke damage?

Researchers track prostate cancer gene

Patrick Walsh (top) and William Isaacs and their collaborators have located a gene for prostate cancer.
Ten years ago, Hopkins director of urology Patrick Walsh met a patient whose father, three brothers, and grandfather had died of prostate cancer. Now the man himself, at the relatively young age of 49, had the disease. The patient started Walsh "on a mission" to discern whether such familial clustering of prostate cancer stems from environmental factors, inheritance, or merely coincidence.

That mission has now yielded the first location of a gene that, when flawed, appears to substantially increase the risk of prostate cancer. Walsh and colleagues at Hopkins, along with scientists from the National Center for Human Genome Research and Umea University in Sweden, report the finding in the November 22 Science.

The gene, which is called HPC-1 (hereditary prostate cancer 1), resides within a region of chromosome 1. Once the location is pinpointed, it will be relatively simple to develop a genetic test to identify men who bear a mutation in the gene, says William Isaacs, associate professor of urology and oncology at Hopkins.

Prostate cancer is second only to skin cancer as the most commonly diagnosed cancer in American men. In the United States alone, 340,000 men are diagnosed with prostate cancer and more than 40,000 men die of the disease each year.

According to researchers, an inherited flaw in the HPC-1 gene accounts for an estimated 3 percent of prostate cancers, about 10,000 newly diagnosed prostate cancers each year--not insignificant but not tremendously large, as cancer statistics go. However, HPC-1 may be implicated in other, non-inherited prostate cancers, says Isaacs. Some patients may not inherit but acquire mutations in the gene, which could be one step in a pathway of events that lead to prostate cancer. (In colon cancer, patients who inherit a mutated version of a gene called APC have nearly a 100 percent chance of developing colon cancer. But mutation of APC is one of several genetic changes that occur in non-inherited forms of colon cancer as well.)

Following his meeting with the 49-year-old patient, and with other men diagnosed at a young age, Walsh began painstakingly compiling a database from the families of prostate cancer patients. As of this year, the database includes 2,500 families.

Walsh and his colleagues first discovered that there were families in which predisposition to prostate cancer was inherited, and that the inheritance followed the classical Mendelian pattern. They then focused on 91 families in which at least three men had developed prostate cancer.

The researchers scanned the genomes of the families for genetic markers of known location. Specifically, they looked for markers that were inherited along with a predisposition to develop prostate cancer. Such markers were likely to reside close to (and thus be "linked" to) a gene for prostate cancer. The linkage analysis tracked the gene to within a roughly 6 million base pair region of chromosome 1 (about 0.1 percent of the genome).

The scientists are now, of course, hunting for the gene within this region, as well as for other prostate cancer genes. "I wouldn't be surprised if we had a diagnostic test within one to two years," says Isaacs.

Such a test, says Isaacs, will alert men who are at risk of prostate cancer to take steps to reduce their risk, for example, by cutting down on fat in their diet, which has been linked to the disease. These men may also want to undergo prostate cancer screenings more frequently. In treating prostate cancer, says Isaacs, "early detection is key," since treatment is most effective at that point. --Melissa Hendricks

News to warm the cockles of your heart
As thoughts turn to the emotions of the heart this Valentine's month, we consider, as well, the health of those cockles, with a bounty of heart research recently issued from Hopkins.

Aspirin is widely prescribed for patients who suffer from angina, which accounts for more than 570,000 hospital admissions each year in the United States. But two Hopkins studies indicate that a new drug called Integrelin performs as well as aspirin in men and better than aspirin in women at preventing angina.

In studies of 227 angina patients, the researchers found that women who received high intravenous doses of Integrelin had eight times fewer angina attacks and shorter attacks than women who received aspirin.

Angina occurs when blood platelets clump together, reducing blood flow to the heart and causing chest pain, says associate professor of medicine Pascal Goldschmidt-Clermont. Integrelin directly blocks a protein on the surface of platelets that promotes clumping. (Aspirin works through a less direct mechanism.) Women's platelets may have a greater tendency to stick together, says Goldschmidt. Thus, "inhibitors blocking the activity of platelets might need to be stronger in women."

Goldschmidt-Clermont, associate professor of medicine Steven Schulman, and colleagues report their findings in the November Clinical Cardiology and in the November 1 Circulation.

Anyone who has been to the doctor for high blood pressure--and there are 50 million of you out there, in the United States alone--has probably been advised to follow a low-salt diet, restrict alcohol consumption, and reduce or keep weight down. Now, two Hopkins studies demonstrate that by heeding this advice and possibly modifying their diet, many patients can control their blood pressure and significantly reduce their need for medication. The results of both studies were reported in November at the meeting of the American Heart Association. Researchers stress that patients should consult their physicians before reducing blood pressure medication.

The first study, called Trials of Nonpharmacologic Interventions in the Elderly (TONE), involved 975 hypertensive patients, age 60 to 80, who were seen at Hopkins and three other medical centers. TONE is chaired by Paul Whelton, former director of the Welch Center for Prevention, Epidemiology and Clinical Research, at Hopkins's School of Public Health. The study showed that patients who reduced salt intake and lost weight reduced their need for high blood pressure medication by 40 percent.

The Dietary Approaches to Stop Hypertension (DASH) study, a multicenter clinical trial led at Hopkins by associate professor of medicine Lawrence Appel, demonstrated that a diet low in fat and cholesterol and rich in fruit, vegetables, and low-fat dairy products significantly reduced blood pressure. Those reductions are similar to ones achieved with medication. The special diet included 10 servings of fruit and vegetables and three servings of low-fat dairy products daily, which is twice the amount most Americans eat. In DASH, investigators did not vary volunteers' intake of salt or alcohol, or allow them to lose weight.

In standard heart bypass surgery, doctors slice an eight-inch incision in the chest, saw through the breastbone, and crack open the rib cage to expose the heart.

With new bypass techniques, Hopkins cardiac surgeons are now keeping the heart under wraps. At Johns Hopkins Hospital, cardiac surgeon Scott Stuart recently introduced an endoscopic technique called Port-Access that obviates the need for sawing. Instead, Stuart's team makes only finger-length incisions in the left breast through which they insert an endoscope containing a miniature camera and light source, and special surgical tools. As in the conventional procedure, the objective is to graft a healthy vessel onto coronary tissue to form a detour around a blockage.

With a standard bypass, patients take two to three months to recover, and even a laugh or a cough can hurt. With the new method, which was recently approved by the FDA, patients are generally back to work within two to three weeks, says Stuart.

Stuart has used the new technique, which was developed by a California medical device company called Heartport, to perform single-graft bypasses, and expects to use it for double or triple bypasses within the next 14 months.

Unlike conventional bypass surgery (left), a new endoscopic bypass keeps the heart under wraps.
Hopkins cardiac surgeon James Fonger has been using another form of minimally invasive heart bypass surgery, called MIDCAB (Minimally Invasive Direct Coronary Artery Bypass). It involves small incisions, but no endoscope. What's more, surgeons work on a beating heart, in contrast to the Heartport technique, in which the heart is temporarily stopped and the patient is attached to a heart-lung machine.

MIDCAB is far less costly than conventional bypass surgery, says Fonger, who has performed more than 200 of the procedures at Sinai Hospital in Baltimore. MIDCAB costs about $10,000, compared to $17,000 for a standard single-graft bypass, he reported in November at the American Heart Association meeting.

On a typical day, a Yi farmer in southwestern China rises early, eats a bowl of boiled, unsalted buckwheat, and heads out for a day of strenuous physical activity before his evening meal of rice and beans. This relatively simple rural lifestyle confers significant health benefits, says Jiang He, an instructor in epidemiology at Hopkins's School of Hygiene and Public Health. The Yi are an ethnic group in China, of Mongolian descent.

Jiang He found that a rural lifestyle is heart healthy for China's Yi.
Yi who have migrated to the city have significantly higher levels of serum cholesterol than do their rural counterparts reports He. The 30-point difference (30 mg/dl) correlates with a 76 percent higher risk of cardiovascular disease, says He, who backpacked into the mountainous Yi region to survey its villagers. In contrast, Yi who remain living in rural areas have virtually no cardiovascular disease.

The cholesterol levels of the Yi city dwellers are on a par with ethnic Han Chinese living in the same urban area. This indicates that lifestyle factors (less physical activity, a diet higher in animal fat), rather than genetics, account for the higher risk of heart disease among the urban Yi, says He. His findings appear in the November 1 American Journal of Epidemiology. --MH

Organ transplant drugs heal nerves
Drugs that are used to suppress the immune system, and thus convince the body to accept an organ transplant, also appear to help regenerate damaged nerves, reports Hopkins neuroscientist Solomon Snyder. Similar drugs might benefit patients with Alzheimer's or Parkinson's disease, as well as patients who have had a stroke or nerve injury, according to Snyder and assistant professor of neurology Ted Dawson.

Snyder, Distinguished Service Professor of Neuroscience at the School of Medicine, reported on tantalizing (though preliminary) experimental results of the drugs in October, at a meeting in Baltimore of the Council for the Advancement of Science Writers.

In one set of experiments, the Hopkins researchers found that the transplant drugs cyclosporin A and FK506 enhance the growth of neuron-like cells in culture.

Given the success of those experiments, Snyder then asked scientists at Guilford Pharmaceuticals in Baltimore to develop a drug with the neuron-enhancing properties of FK506 and cyclosporin A but lacking the immune-suppressing properties of those agents.

Guilford scientists then synthesized several drugs including one called GPI 1046. In one experiment that still has neuroscientists shaking their heads in amazement, Guilford biologist Joe Steiner, PhD '89, used GPI 1046 to regenerate nerves in a rat model of Parkinson's disease. In ongoing experiments in Chicago, scientists are now testing that drug in monkeys. "The animal studies look very, very encouraging," says Dawson.

On a cautionary note, says Dawson, "It's a long process to go from rats to humans. If the drugs pass every hurdle, it will be years before they are tried in patients." But if they are shown to be safe and prove their muster at helping injured nerves regrow, they could be a new tool for treating patients with a variety of neurological illnesses.

The jump from transplant drug to potential nerve-enhancing agent came as a surprise.

While investigating how immunosuppressant drugs work, scientists discovered that they bind to proteins in the immune system, which they called immunophilins.

Snyder's team then probed throughout the body to see where else immunophilins occur. To their amazement, they found immunophilins "in the brain, the spinal cord, and the peripheral nervous system," says Snyder. In fact, immunophilin levels are 10 to 40 times higher in the brain than elsewhere. "Immunophilin may be a misnomer," says Snyder, who has coined a more appropriate term: neuroimmuno- philin. "It was just an accident that they were discovered in the immune system. They work more in the nervous system." --MH

Iron pills can boost learning
Adolescent girls who are iron deficient can improve their ability to learn by taking iron pills, according to a study by Hopkins pediatricians.

Researchers led by pediatrician Ann Bruner selected adolescent girls from Baltimore high schools who were iron deficient but not anemic. Half the girls were given iron pills (650 mg twice daily), and half took placebo pills for eight weeks. At the beginning and end of the study period, Bruner's group administered a series of standard cognitive tests designed to measure attention, verbal learning, and memory. Nine girls developed anemia or did not complete the study and were excluded.

In the October 12 Lancet, the researchers report that of the 73 girls who completed the study, girls who took iron performed better on the test of verbal learning and memory than girls in the placebo group. They found no difference between the two groups on measures of attention.

Iron deficiency is the most common nutritional disorder in the world, note the researchers. The neurological underpinnings of iron deficiency and cognition are not understood, says Bruner. A number of explanations have been proposed. Iron deficiency may, for example, alter the concentration, function, or binding of neurotransmitters. --MH

Estrogen's healing effects
Estrogen may be a natural form of insurance against stroke damage. A Hopkins team reports that female rats sustain a third of the brain damage and fewer neurologic impairments following a stroke than do their male counterparts. Given that female rats have twice the estrogen that males do, natural levels of estrogen appear to be "neuroprotective," concludes Patricia Hurn, an assistant professor of research anesthesiology and critical care medicine.

Hurn's group simulated stroke in rats by blocking blood flow through the middle cerebral artery, the vessel most often involved in stroke in humans. The researchers occluded the vessel for two hours, and then restored blood flow for a day before examining the animals' brains. They studied male and female rats, and female rats who had had their ovaries removed. Such oophorectomized females produce approximately half the amount of estrogen as normal female rats.

On average, stroke damage encompassed 34 percent of brain volume in male rats, 25 percent in female rats lacking ovaries, and only 12 percent in normal female rats.

In addition, male rats and oophorectomized females experienced more abnormal neurological behaviors--weakness on one side, abnormal circling movements, unresponsiveness--throughout the experiment. Nabil Alkayed, a fellow in anesthesiology and critical care medicine at Hopkins, reported the findings in November at the annual meeting of the Society for Neuroscience, in Washington, D.C.

"It looks like when there is acute stress to the brain, female rats can continue to support a small amount of blood flow to the area, which can salvage the brain," concludes Hurn.

Estrogen, which has been shown to aid blood flow to the heart, posits Hurn, "may be a natural vasodilator. It may allow vessels to get larger when necessary."

While Hurn's study involved estrogen that is naturally present, it raises the question of administering estrogen to prevent stroke or reduce its damage.

"But there is a lot we don't know," says Hurn. For example, it is not clear whether estrogen must be present always, or whether it could be administered acutely--as an injection following a stroke, for example. Hurn is pursuing these questions in ongoing studies. --MH