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Hopkins Medical School: Research is the Hallmark

When the Johns Hopkins University School of Medicine opened its doors in 1893, it changed the way medicine was taught. It soon became what no medical college had ever been: a center of basic as well as applied science.

A century ago, American medical education was in a deplorable state. Students learned medical practice by rote. There were no laboratories in which to develop new treatments, no teaching at the bedside. Hopkins was the first American school to insist on rigorous premedical training, at both the bedside and at the laboratory bench.

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Applying the basic sciences to human disease was a Hopkins hallmark from the start. The school was the first to give doctors the luxury of being paid to do research. And what that luxury spawned endures to this day: a long list of Hopkins "firsts" that helped revolutionize the practice of medicine over the course of the last century.

Today, that tradition continues. Hopkins basic scientists Daniel Nathans and Hamilton Smith, for example, paved the way for ever-more sophisticated genetic engineering when they found the body's own chemical scissors for cutting DNA. This discovery, for which they won the Nobel Prize in 1978, may one day allow physicians to remove, replace or repair genes before ++ they can cause such problems as cancer or diabetes.

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Current research that combines the science of the brain, behavioral science and clinical neurology promises a profound understanding of ourselves and entirely new approaches to neurologic and behavioral disorders. In many specialties, the wave of the future will be to emphasize the prevention of illness, rather than treatment of end-stage disease.

Every decade, a very few studies emerge as milestones that move medicine forward. When, a century from now, our great-grandchildren look back on today's research, which advances will be considered the "greats" that completely changed our approach to disease?

Here are five of the most fertile research areas at Hopkins now -- all likely candidates for that future list of greats.

1. Phantom messengers in the brain.

The journal Science declared the gas nitric oxide "molecule of the year" in 1992, when research from neuroscientist Solomon Snyder's lab helped elevate the status of this gas from toxic molecule to crucial carrier of messages between brain cells. The gas was previously known to be a relaxer of blood vessels, but the discovery of nitric oxide's function in the brain established gases as an entirely new class of messengers within the body.

Dr. Snyder's studies on the basics of nitric oxide -- how it works, where it's found and how it can go awry -- may have implications for the treatment of stroke, Alzheimer's disease and Huntington's disease.

Recently, a second gas -- carbon monoxide -- was found to carry signals between nerve cells in the brain as well. And other research -- a collaboration between urologists and neuroscientists -- solved an age-old mystery by demonstrating that nitric oxide transmits nerve signals in the penis and is thus responsible for penile erection. This discovery one day may yield new treatments for impotence, which affects one in 10 American men.

2. Fighting cancer with the body's own "smart bombs."

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Cancer researcher Drew Pardoll has stopped tumor growth in mice by genetically stimulating the animals' own immune systems. He discovered a way to manipulate the body's own natural defense systems so that they kill cancer cells and leave normal ones unharmed.

In the fall of 1991, Dr. Pardoll and his team were the first to show that gene therapy could cure an animal of an established tumor. Already, researchers at Hopkins are in the early stages of testing gene therapy on human cancers.

Dr. Pardoll's approach involves calling cancer-fighting chemicals into action from within the tumor cells. He genetically engineered tumor cells from mice to secrete large doses of a natural chemical called Interleukin-4, which destroys cancer cells.

Ordinarily, immune cells called T-cells produce IL-4, but for an as-yet-unknown reason, T-cells are not properly activated in cancer. Dr. Pardoll's genetic manipulation "turned on" the T-cells. Once activated, these cells function like smart bombs, killing the specific target but leaving little collateral damage.

3. Genes that can start or stop cancer.

In Bert Vogelstein's lab at the Johns Hopkins Oncology Center, researchers have laid bare the molecular genetics of colorectal cancer, the second most common form of cancer in the United States.

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Last month, Dr. Vogelstein and researchers from the University of Helsinki in Finland announced the discovery of a the genetic basis for one of the most common forms of colon cancer. They estimate that one in every 200 people carries a mutant gene that leads to colon cancer, making it the most common inherited disease yet identified in humans.

Within the next year or two, this discovery will bring a life-saving diagnostic test to the millions of people at risk of developing colon and other types of cancer. The simple blood test will predict who will or will not get the inherited form of colon cancer and enable doctors to detect it early, when it is almost always curable. Now, more than 58,000 Americans die each year from colon cancer.

A few years ago, Dr. Vogelstein and his colleagues at Hopkins showed that other types of colon cancers can form when mutations arise in "suppressor genes" -- such as p53 -- that normally put the breaks on cancer growth.

In 1990, Dr. Vogelstein found that replacing just one mutated p53 gene with a normal copy is enough to stop the growth of cancer cells -- at least in a test tube.

Though it may be difficult to insert a normal copy of this gene into people with colon cancer, understanding how suppressor genes such as p53 work may lead to the development of drugs that could "turn off" the cell growth switches.

Dr. Vogelstein's team discovered that p53 also is associated with tumors of the breast, lung, brain, ovary and bladder, making it the most common genetic alteration that occurs in human cancers.

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Recently, the researchers found that the normal job of the p53 suppressor gene is to help healthy cells respond to DNA damage caused by environmental carcinogens. When p53 functions properly, it tells genetically-damaged cells to stop making new DNA. But if the gene is missing or mutated, the injured cells continue to divide, and that contributes to the development of a cancer.

Further research on how this mechanism works is essential, since as many as 80 percent of all cancers may be due to exposure to environmental carcinogens.

4. Preventing cancer by protecting cells: the broccoli connection.

Although current research offers great hope for developing new ways to treat cancer, many scientists believe the greatest hope of all lies in prevention, and it should therefore be a research priority.

Molecular pharmacologist Paul Talalay, who heads a program to develop strategies for protection against cancer, points out that despite tremendous advances in our understanding of the process of carcinogenesis, survival rates have not changed much over the last two decades.

Dr. Talalay studies chemicals that increase the resistance of cells to external carcinogens. Last year, he identified and isolated a potent chemical found in broccoli and other vegetables that appears to protect human cells against cancer, a finding that attracted worldwide attention.

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He found that one variety of broccoli contained especially high levels of this cancer-fighting chemical, called sulforaphane. His lab now is testing sulforaphane's ability to block tumor formation in animals.

Human epidemiological studies have repeatly shown that eating cruciferous vegetables such as broccoli and Brussels sprouts lowers the risks of developing some types of cancer. Dr. Talalay's work has forged a new link in our understanding of how this process works on a cellular level.

5. Pioneers in the treatment of Marfan syndrome.

Preventive treatment -- both medical and surgical -- developed at Hopkins now can help avert the life-threatening symptoms of a genetic defect known as Marfan Syndrome. This inherited connective tissue disorder results in a dangerous stretching of blood vessels leading out of the heart, as well as abnormal height and eye lens dislocation. It affects one in 10,000 Americans.

Almost two decades ago, medical geneticist Victor McKusick was the first to suspect that these disparate symptoms could result from a single defect in one gene. Finding the genes for inherited diseases soon became a consuming interest: "McKusick's Catalog" now includes more than 6,000 different gene defects, and is expanding at the rate of several a week.

In 1991, Harry Dietz and Clair Francomano, in collaboration with scientists at an Oregon hospital, discovered that a gene responsible for making connective tissue protein is in fact the one responsible for Marfan Syndrome. Now Marfan patients can be diagnosed earlier, even prenatally, before symptoms appear. And beginning treatment earlier greatly increases patients' chances of long-term, quality survival.

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Basic research such as Dr. Dietz's on how and when genetic messages are read and translated may create more opportunities to intervene at an early stage and change the course of severe Marfan syndrome and other inherited diseases.

The Hopkins School of Medicine celebrates its centennial this week, in the eye of a storm of proposals to reform this country's ailing health care system. Johns Hopkins will remain steadfast in a century-old commitment to inspiring the exploration of the mysteries of human biology and encouraging the application of this knowledge to human health problems. This important mission, one that is shared by America's other academic medical centers, will translate into high-quality health care for the American public.

The intellectual architect of the Hopkins Medical Institutions, John Shaw Billings, summarized the Hopkins goal more than a century ago: "To give to the world men [and women] who cannot only sail by the old charts but who can make new and better ones for the use of others." As in the past, the "new and better" charts of the next hundred years will arise from the integration of scientific research and clinical practice.

David Blake is senior associate dean at the Johns Hopkins University School of Medicine. Rachel Wilder is senior science writer at the Johns Hopkins Medical Institutions Office of Public Affairs. An expanded version of this article, marking the centennial of the Hopkins School of Medicine, will be published in a forthcoming issue of the Maryland Medical Journal.


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