Johns Hopkins Magazine -- June 1997
Johns Hopkins Magazine

JUNE 1997

H E A L T H    &    M E D I C I N E

Fighting cancer through vaccines... a bone-building antibiotic?... till MD do us part... dialysis disparity... two new conspirators in colon cancer... how antioxidants may block cancer... illustrator extraordinaire

Making strides toward a cancer vaccine

Elizabeth Jaffee and Jonathan Simons hope that harnessing the immune system will help win the war on cancer.
Elizabeth Jaffee envisions the day when a woman at high risk of developing breast cancer receives a vaccine that protects her against the disease.

Jonathan Simons dreams of similar vaccines for prostate or kidney cancer.

Though their dreams may sound far-fetched, these passionate young investigators and their colleagues recently demonstrated that a kidney cancer vaccine activated the immune systems of 18 patients with advanced kidney cancer. The vaccine, which employs gene therapy, caused one of the patients to go into remission, they report in the April 15 issue of Cancer Research. Senior author of the report is Fray Marshall, professor of urology and oncology.

The patient eventually relapsed, and none of the patients was cured, but the researchers say the results are a promising first step. The study was designed to test the safety of the vaccine and see if it could trigger an immune response in the patients, all of whom were thought to be incurable.

Simons, an assistant professor of oncology and urology, is also directing a study of a gene therapy vaccine for prostate cancer, whose first results are imminent. Gene therapy vaccines against breast and pancreatic cancer are also in the works.

Though the type of cancer varies, in each of these trials the scientists are using a gene for GM-CSF, or granulocyte-macrophage colony-stimulating factor, which in test tube studies has proved to be a potent stimulator of the immune system.

To create the kidney cancer vaccine, the Hopkins team took cells from tumors that had been surgically removed from each patient, irradiated the cells to stop their growth, and tucked the gene for GM-CSF into the cells. They then injected those cells back into the patient.

The vaccine triggered the production of a panoply of immune cells in all of the patients, says Jaffee, an assistant professor of oncology. One patient, who had been given six months to live, had cancer that had spread to his lungs and formed 35 tumors. The vaccine shrank much of his tumors, and his remission lasted eight months.

What the researchers believe is happening is this: The GM-CSF gene directs the production of a protein that, along with antigens from the tumor's surface, alerts the immune system to seek out and kill cells bearing the tumor antigens.

The strategy used by the Hopkins team is markedly different from earlier attempts at gene therapy for cancer, in that it activates the immune system rather than targets cancer cells directly.

The researchers do not know whether the treatment is a potential cure for cancer. Many questions remain, such as how many doses of the vaccine would be required to combat the millions and even billions of transformed cells that arise in cancer. Answers may come from tests of the vaccine in patients with less advanced kidney cancer, now under way in Japan. The National Cancer Institute of Japan is sponsoring the $3 million trial.

In the meantime, Simons reports that the immune system response of patients given the prostate cancer vaccine "looks very interesting," but his team has not finished analyzing the results. Conceivably, the vaccine could be given to men following prostate cancer surgery, perhaps in conjunction with chemotherapy or radiation "to mop up the few million evil cells left," says Simons. X-rays cannot detect cancers smaller than one billion cells, he notes. "But every cell is lethal." The prostate cancer vaccine trial is supported by the non-profit foundation CapCure and a SPORE (specialized program of research excellence) grant from the NIH.

The breast cancer vaccine employs a slightly different strategy. Jaffee is testing several vaccines in mice that target an abnormal protein called HER2/neu, which breast cells produce prior to becoming cancerous. Ideally, physicians would one day administer the vaccine to women at the first sign of the protein. "In the long term, I'm hoping we'll prevent cancer," says Jaffee. "Ideally, before my career is over, I hope we have a vaccine."

Jaffee and Simons are so earnest and enthusiastic that one wants desperately to believe in them. But many others have thought they had the answer. With this, as with other promising new cancer treatments, only time will tell. --MH

A new strategy for fighting osteoporosis
What do antibiotics and bone disease have in common? Turns out, the former may stall, and even reverse, the latter- at least that's what a study under way at the Johns Hopkins
School of Medicine is trying to determine. Endocrinologist Jay Shapiro is running the yearlong trial to see if minocycline, a common derivative of tetracycline, effectively treats osteoporosis, a potentially crippling condition that affects an estimated 20 million American women.

"Minocycline has been used fairly widely in studies of its anti-inflammatory effect in arthritis and it's also used as an antibiotic," says Shapiro, a professor of medicine in the Division of Geriatrics. "So this is a trial to see whether [and how] it affects bone mineral density." Shapiro plans to enroll 48 post-menopausal women in the randomized, placebo-controlled study.

The clinical trial, which is funded by the National Institutes of Health, comes on the heels of an animal study performed by C. T. Liang, a scientist at the National Institute on Aging whose lab is nearby Shapiro's Bayview campus office. In a paper published last December in the journal Bone, Liang showed that minocycline was as effective as estrogen in preventing a 15 percent bone loss in rats whose ovaries had been removed-a procedure that simulates the onset of menopause and, thus, bone deterioration. Equally important, Liang found that the generically available drug was a skeleton builder, actually boosting the rats' bone mineral density.

Liang hypothesizes that minocycline blocks the synthesis of an enzyme known as collagenase, which breaks down collagen. Collagen is a protein that paves the way for new layers of surface bone to form, and serves as protection against special bone-eating cells called osteoclasts. Without collagenase, the thinking goes, bone can form unmolested because the osteoclasts are hard-pressed to find a meal.

Should minocycline prove clinically effective, it may be a safe, relatively inexpensive alternative to estrogen and other available osteoporosis treatments. Many women are reluctant to use estrogen replacement therapy because it has been linked to a slight increase in the risk of breast and uterine cancers. It also can cause unpleasant side effects in some women, such as swollen breasts, weight gain, and high blood pressure.

In addition to their potential effects on bone, tetracycline-like compounds also boast anti-inflammatory properties. That could be helpful for many osteoporosis patients who also suffer from osteoarthritis-a disease that causes pain and swelling in the joints and skeleton. Shapiro says the Hopkins trial is looking at minocycline's effectiveness in this area, too.

Of course, antibiotics aren't without their own problems. Although Shapiro said the dosage of minocycline prescribed in the Hopkins trial is most likely too small to be toxic to a patient's liver, it is possible that its widespread use-or use of others like it-could increase resistant strains of bacteria. However, earlier rheumatologic studies of the drug did not lead to such resistance, Shapiro says. --AM

Till MD do us part

If you're a med student looking to have a lasting marriage, you might avoid becoming a psychiatrist, surgeon, or an internist. Those specialists, in that order, have the highest divorce rates among physicians, according to a study of 1,118 graduates of the Johns Hopkins School of Medicine.

Johns Hopkins associate professor of medicine Michael Klag and internist Bruce Rollman, of the University of Pittsburgh Medical Center, analyzed specialty choices, marital status, marriage length, and psychological characteristics of the study volunteers, who graduated from Hopkins between 1948 and 1964.

In the March 13 New England Journal of Medicine, the researchers report that the divorce rate over 30 years was 50 percent for psychiatrists, 33 percent for surgeons, 24 percent for internists, and 22 percent for pediatricians and pathologists.

Female physicians had a divorce rate of 37 percent, compared to 28 percent for male physicians; and physicians who married before graduating from medical school had a rate of 33 percent, versus 23 percent for physicians who married after.

Is it the nature of the beast, or the nature of the job? The researchers cannot say whether the physical and psychological demands of certain specialties drive those specialists toward divorce or that certain specialties attract personality types that are prone to divorce.

Klag suggests that physicians consider participating in marital counseling during residency training. --MH

Differences in dialysis

More white children undergo this home-based dialysis method, while more black children use hospital dialysis.
Black children who have severe kidney disease are more than twice as likely as white children to be on a dialysis treatment that requires hospital supervision rather than a method that can be done at home. A Hopkins team, which reported the racial differences in the April issue of Pediatrics, say they plan to follow up on their study to understand why there are differences.

"There are a lot of possibilities," says pediatric nephrologist Susan Furth, who led the study. "There could be biases on the part of doctors." It could be, for example, that many physicians believe that blacks could not perform the home-based dialysis themselves, and thus steer black patients toward the hospital-based method.

It is also possible that the diff erence stems from the patients themselves. Perhaps more black patients and their families prefer the hospital-based method, and more whites prefer the home-based method. Four thousand children in the United States have end-stage renal disease, or kidney failure. Patients generally undergo dialysis while waiting for a transplant-a period that could last weeks, months, or even years.

Both methods of dialysis substitute for a diseased kidney by filtering impurities from the blood, but they do it differently. In hospital-based hemodialysis, patients are hooked up to a dialyzer, or filter, through an intravenous line placed in their arm. The dialyzer filters their blood, and returns cleaned blood to their body. Hemodialysis patients generally spend several hours at the hospital three times a week.

In home-based peritoneal dialysis, the lining of the abdomen, or peritoneum, serves as the filter. Patients add several liters of an electrolyte solution to their abdomen through a catheter inserted near the naval. The peritoneum filters impurities out of blood vessels and into the solution. Patients drain and replenish the fluid about four times a day. Certain continuous cycling systems require fewer fluid changes. Patients must use sterile technique to keep the catheter entryway free of infection.

Canadian researchers recently reported that peritoneal dialysis costs roughly $36,000 and hemodialysis roughly $57,000 per year. The annual bill for all patients with kidney disease, which is mostly paid through Medicare, was more than $11 billion in 1994.

The home-based dialysis technique allows children to miss less school and fewer other activities, notes Furth. What's more, some studies suggest that patients on peritoneal dialysis fare better medically, emotionally, and socially. "We think that peritoneal dialysis is better for kids," says Furth. Thus, she says, she and her colleagues are eager to find the reason for differences in dialysis choice. --MH

Colon cancer: The plot thickens
Johns Hopkins cancer researchers recently identified two key players in a biological pathway that leads to as much as 95 percent of colon cancers. The two proteins now offer hope of promising new targets for anti-cancer drugs.

Mutations in the betacatenin gene account for 5 to 10 percent of colon cancers, in addition to the 80 to 85 percent of colon cancer attributed to mutated APC.
In 1991, Hopkins scientists led by professor of oncology Bert Vogelstein discovered that mutations in a gene called APC (adenomatous polyposis coli tumor suppressor) occur in 80 to 85 percent of all colon cancers. A healthy APC gene, it was learned, keeps a grip-lock on cell growth. When the APC gene is mutated (through inheritance or environmental factors), colon cells flaunt normal cell regulatory processes. They multiply rapidly, do not die, or migrate to places they do not belong. This uncontrolled growth is cancer.

Now, researchers led by research associate Patrice Morin implicate two more genes as conspirators in APC's dirty deeds: a gene called beta-catenin and another called Tcf. The Hopkins team, along with researchers from University Hospital in Utrecht, the Netherlands, report their results in two papers in the March 21 Science. In a third paper, researchers at Onyx Pharmaceuticals in Richmond, California, implicate the same set of genes in melanoma.

Following the discovery of APC, the scientists examined the 15 to 20 percent of tumors lacking mutations in the gene. A significant fraction of those tumors had mutations in another gene called beta-catenin. An accompanying editorial in Science calls beta-catenin a "smoking gun" in colon cancer.

In normal cells, the beta-catenin protein binds to the Tcf protein. The complex then activates a set of still unidentified genes, which stimulates cell growth. Normally, APC acts as the "off switch," says Kenneth Kinzler, associate professor of oncology. It turns off beta-catenin and Tcf when the cell has grown enough or when it is time for the cell to die.

But when the APC gene is mutated, the beta-catenin/Tcf complex continues to stimulate cell growth. Alternatively, even if the APC gene is normal, a mutation in beta-catenin apparently leads to the same unchecked growth. It is as if a mutated beta-catenin eludes the supervision of APC. "In 95 percent of colon cancers, there are mutations in APC or in one of these other two genes," concludes Kinzler.

The two genes expand the potential therapeutic strategies for combating colon cancer. Approximately 131,000 cases of colon cancer will be diagnosed in the United States this year, according to the American Cancer Society. When the APC gene was discovered, says Kinzler, "it met with a lot of excitement and fanfare in the press and among scientists because these mutations provide us with a target unique to cancer cells." Mutations in APC occur during an early stage of cancer. Theoretically, a drug could substitute for APC, or scientists could use gene therapy to introduce a healthy APC gene. But as it turns out, it is very difficult to replace a protein, says Kinzler.

The new genes offer another possibility. The Hopkins team hopes that by inhibiting Tcf and beta-catenin, they will prevent the two proteins from spurring overactive cell growth. They are now in the process of developing a protocol for screening experimental compounds to see if any block beta-catenin and Tcf. --MH

How antioxidants may block cancer
In medicine's arsenal against cancer, antioxidants may someday qualify as big guns. Health-conscious consumers are already buying A, C, and E vitamin supplements or getting doses of those known antioxidants in green leafy vegetables. These extra helpings of spinach apparently reduce the risk of cancer, studies show. Now, a team of Hopkins researchers may have identified just how antioxidants suppress the rampant cell growth found in cancer. The Hopkins study, published in the March 14 Science, reveals at least one method the cells use to signal growth. Understanding how the signal works can lay the groundwork for future research on blocking molecular messages that trigger tumors.

Scientists have known that the body's cells contain oxidants, molecules that when highly unstable can be called free radicals. Certain free radicals are thought to contribute to cancer by damaging the cell's DNA; smoking for example is believed to produce a highly reactive free radical that leads to cancer. In previous studies, antioxidants have been shown to reduce the risk of cancer and even suppress the growth of tumors. But how?

The Hopkins study suggests that a specific protein in the cell uses a free radical called superoxide, to tell cells to reproduce. Antioxidants, when added to cells, appear to act as protein inhibitors, interfering with the signal and blocking cell division.

The cancer research paradoxically was launched by a group of Hopkins cardiologists and led by Pascal Goldschmidt-Clermont, a former Hopkins cardiologist now at Ohio State University. The heart doctors wanted to find out how atherosclerosis leads to the growth of damaging lesions on the walls of arteries. These lesions may not be cancerous, but they can grow quickly. So, scientists focused on a protein, called Ras, that in normal cells transmits growth-stimulating messages to the cell's interior. Hopkins researchers introduced an oncogenic, or cancer-causing, form of the Ras protein into cells. Ras apparently produced extra superoxide, the free radical that signals high-speed cell reproduction. Previously, the roles of Ras and superoxide-and how they interact-in cell growth was unclear.

"In a cancerous cell there's constant high-level reproduction, but no one knew why," says Kaikobad Irani, the study's lead author and a Hopkins cardiology fellow. "We've shown that the oncogenic form of Ras found in many tumors leads to the production of superoxide and other oxides in the cells. That production is responsible for the runaway growth in cancer cells."

The bottom line: understanding how the cells signal their own growth can lead to better ways to stop the growth mechanism when it gets out of control. In the future, it may be possible to program antioxidants to target only cancerous cells, a process not yet possible.

The Hopkins study has limits. For instance, it's not yet known how superoxide transmits the message or which other molecules are getting into the act. "We don't know the whole picture," Irani points out.

And Hopkins cardiologists looked only at fibroblasts, cells that make up membranous connective tissue and hold internal organs together. The research has not been applied to other cells, although reviewing scientists project that superoxides and Ras will be involved in cell reproduction elsewhere in the body.

So, if antioxidants apparently block rampant cell growth, why not simply take large amounts of A, C, and E vitamin supplements or other antioxidants? For one thing, certain vitamins such as A can become toxic when taken in high doses. For another, Ras and low levels of superoxide apparently do the same jobs in non-cancerous cells: they work together to signal controlled cell growth.

Thus, says Irani, "It would be foolhardy to throw a lot of antioxidants at the body as a whole because normal cell growth would be suppressed. The growth of cells is needed for life." --JC

Illustrator extraordinaire
In 1894, Max Brödel came to Johns Hopkins from Leipzig, Germany, with his art supplies, no formal training in medicine, and what would soon reveal itself as a tremendous aptitude for medical illustration and knowledge of anatomy and physiology. Brödel became the medical illustrator for professor of gynecology Howard Kelly, and later the first director of the
Department of Art as Applied to Medicine, founded in 1911, with an endowment from philanthropist Henry Walters. It was the first medical art department in the country. He taught generations of illustrators--"Poppa," his students called him in private-- continuing almost until his death in 1941. He is known as the father of modern medical illustration.

Through July 27, the Walters Art Gallery, in Baltimore, features an exhibit of three dozen of Brödel's illustrations including the two shown here.

Brödel was admired not only for his anatomically precise illustrations showing the surgeon's eyeview, but for his uncanny ability to figuratively slice through tissues to draw with astonishing accuracy what even the surgeon could not see. He used various techniques to accentuate relevant concepts while maintaining topographical accuracy. "Mere copying of a medical object is really not medical illustrating at all," he once wrote.

Thus, in the lefthand image above, he has drawn a fibroma at the base of a patient's tongue, as a surgeon would see it. At right, he has drawn a conceptual sagital view showing the depth of the tumor.

To contrast the two points of view, Brödel would often alternate realistic continuous tone or half-tones for the surgeon's viewpoint with pen-and-ink for "his voice," says Ranice Crosby, who studied under Brödel in the 1930s and then directed the department for 40 years. The pair of illustrations above, says Crosby, shows why a camera would not be able to tell the whole story. --MH

Written by Joanne Cavanaugh (MA'97), Melissa Hendricks, and Adam Marcus (MA'96).