Johns Hopkins Magazine - April 1996 Issue

In Short - Health & Medicine

By Melissa Hendricks and Elise Hancock
A chimeric vaccine against cervical cancer kidney risks from hypertension five-star hospital suites one lethal missing gene

Cervical cancer vaccine holds promise

Cervical cancer is the leading cancer of women in developing countries. Each year, 200,000 women die of the disease, including 5,000 in the United States.

A new genetically engineered vaccine developed by Hopkins researchers could significantly diminish that toll. The vaccine abolishes tumors in mice and prevents new tumors from taking hold, the investigators report in the January 1 Cancer Research.

The vaccine may eventually help halt the growth of cervical cancers in women or even prevent the disease. "I'm very, very optimistic that within 10 years, new innovative vaccine strategies like this will translate into success," says Drew Pardoll, associate professor of oncology.

However, Pardoll and his colleagues caution that the vaccine must first go through extensive safety and efficacy testing in humans before it is made available.

The new vaccine relies upon the fact that the vast majority of cervical cancers--at least 93 percent--are caused by a family of sexually transmitted viruses called the human papillomaviruses (HPV).

The vaccine employs a strategy called cancer immunotherapy. Rather than attacking the cancer with a chemical poison or radiation, immunotherapy commissions the immune system to fight the cancer.

Immunotherapy against cervical cancer has been tried before. The general approach has been to insert the gene for an HPV antigen, or protein, called E7 into a harmless virus carrier. The viral vector theoretically infects a type of cell called an antigen-presenting cell. These cells should translate the E7 gene into E7 protein, then display the protein on their surface. Presentation of the antigen should "prime" the immune system, preparing it to seek and destroy tumor cells that display E7.

But although immunotherapy is a good idea in theory, says Pardoll, in practice "it has not gotten there." Vaccines employing the technique have not been able to rouse a sufficient immune response.

The problem, Pardoll believed, was that the immune system cannot "see" a whole viral antigen. To be recognized by the immune system, the antigen should be broken down into component peptides, he proposed.

So Pardoll and a team led by assistant professor of pathology Tzyy-Choou Wu created a chimeric vaccine, which contains the gene for E7 connected to a gene for a molecular tag. The tag transports E7 to special compartments called lysosomes that act like the stomach of the cell, digesting proteins into their component peptides. Once the E7 antigen is degraded, its peptides are delivered to the cell surface, where they are visible to the immune system, particularly immune cells called CD4.

The strategy appears to be on target. The team inoculated one group of mice with the chimeric vaccine and another group with a control vaccine containing E7 minus the molecular tag. They then injected the mice with tumor cells. Three months later, 80 percent of the mice that had received the chimeric vaccine remained tumor-free, while all mice that had received the E7 control vaccine had tumors.

In another set of experiments, the chimeric vaccine cured mice that had small, established tumors, while the E7 control vaccine showed no effect.

The vaccine may one day be given preventively as routinely as are Pap smears (the test for cervical abnormalities that could signal cancer). It may also be used to treat patients in the early stages of cervical cancer, says Pardoll.

In patients with advanced disease, the vaccine may not be able to overcome the large number of tumor cells. But the researchers have discussed the possibility of using the vaccine on patients with metastatic disease who have gone through conventional treatment such as chemotherapy or radiation therapy, but still have some last stubborn bits of residual tumor.

Clinical trials to demonstrate safety of the vaccine may begin as early as a year from now.

Moderate hypertension can be risky

Even slightly elevated blood pressure can greatly increase the risk of kidney disease, Hopkins epidemiologists report.

Optimal blood pressure is 120 or lower over 80 or lower (systolic over diastolic). The investigators find that men with blood pressure in the high normal range (a systolic pressure as high as 139 over 90) have twice the risk of kidney failure as do men with optimal blood pressure. Men with mild hypertension (as high as 159 over 99) have three times the risk. And men with moderate hyper tension (179 over 110) have six times the risk.

While physicians have been aware that elevated blood pressure raises the risk of kidney disease, as well as heart attack and stroke, this study appears to be the first to show the impact on kidney disease of very small increases in blood pressure.

In the study, a team led by associate professor of medicine Michael Klag followed more than 332,544 men over a 15-year period. Of those, 814 developed kidney failure, the team reported in the January 4 New England Journal of Medicine. The researchers controlled for age, race, income, use of diabetes medication, number of cigarettes smoked, history of heart attacks, and cholesterol levels.

One surprising result was that systolic blood pressure was a stronger predictor of kidney failure than was diastolic pressure.

Though kidney failure is relatively rare, it is extremely costly, says Klag. Dialysis for a single patient costs about $40,000 per year; annually the United States spends more than $9 billion to dialyze patients. Taking steps to reduce even mild high blood pressure could significantly cut the incidence of this disease. Although the study did not include women volunteers, according to Klag, "there's no reason to think the results would be different for women."

In other blood pressure news, a Hopkins research team led by Frederick Brancati may have found a new way to reduce high blood pressure: potassium tablets. The study involved 87 African Americans without high blood pressure who followed a low-potassium diet and took either potassium tablets or placebo for 21 days. The average blood pressure for the volunteers who took the potassium tablets decreased by 6.9 over 2.5, Brancati's team reported in the January 8 Archives of Internal Medicine.

Foods rich in potassium include fresh produce, lean meats, whole grains, and beans. African Americans, who as a group have a risky level of high blood pressure, are also known to eat a low-potassium diet.

A better test for breast cancer

A new, radiation-free method for detecting breast cancer apparently can spot cancers so small that they elude mammography, reports William Dooley, assistant professor of surgery and oncology. The technique, which measures skin surface electrical conductance, is also more accurate than mammography. Not mincing words, Dooley praises the new technique as "absolutely phenomenally amazing." He presented preliminary results of the test in Toledo, Ohio, in March at a meeting of the Cell Proliferation Society.

Dooley and colleagues at the School of Medicine administered the new test to 50 women who were scheduled to undergo breast biopsy surgery following a suspicious mammogram result. The test identified all the cases that biopsy revealed to be cancerous or precancerous--six invasive cancers and seven premalignant lesions. Further, says Dooley, "we have detected very small breast cancers of 1 to 2 millimeters." Such cancers are often curable, he says.

In mammography, a woman stands while a "plastic vice grip" (as Dooley calls it) compresses each of her breasts, and low radiation X-rays are taken. Compressing the breasts accentuates the contrast in the tissue so that any abnormality will stand out. One limitation of mammography is that it generally does not inform about breast cancer in young women. Most young women lack the breast fat tissue that allows the breasts to be compressed enough to show this contrast. Many women also find the procedure uncomfortable.

The new method, on the other hand, does not compress the breasts and involves no discomfort, says Dooley. At the start of the exam, several electrodes are affixed with an electrolyte jelly to the breasts. The electrodes are attached to a suitcase-sized detector--basically a laptop computer with software programmed to interpret information about electrical conductance. The woman remains seated during the 20-minute exam.

The test, which was invented by the Biofield Corp. in Roswell, Georgia, is based upon the fact that malignant and benign cells have different electrical characteristics, explains Dooley. In normal breast epithelial tissue, cell membranes are polarized. When cells proliferate rapidly, as they do in cancer, the cell membranes lose this polarity, or become depolarized. Biofield's test picks up such depolarizations. The technology is similar to electrocardiography (ECG), which is used to diagnose heart conditions.

The device is now undergoing U.S. FDA trials, in which Dooley's team is participating. If approved, it will first be used in conjunction with other diagnostic tools, such as mammography, ultrasound, or palpation. But eventually, says Dooley, the Biofield exam could become a routine breast cancer screening test for all women.

Only the best

When you arrive for a stay at Hopkins's Marburg Pavilion, a guest services coordinator greets you, picks up your suitcases, and escorts you inside. Your suite of paneled rooms is tastefully decorated with antiques and contemporary furniture upholstered in designer fabrics. After stashing your jewels in the room safe, you can toss off your shoes, sink into a bed, then flip on the CD player or VCR. Or, if you have business to do, you can send out a letter on your room's private fax. Hungry? Ring up the chef for some beef Wellington, veal scallopine, or curried lamb.

In between these activities, you'll need to fit in visits from nurses, physicians, and lab techs.

The Marburg, you see, is not a five-star hotel, but a deluxe, newly renovated 16-room unit at Johns Hopkins Hospital with Ritz-quality service and amenities for patients who are willing to pay an additional $125 to $650 per day.

The drive behind the $1 million renovation, says Toby Gordon, vice president of planning and marketing, was to attract both a local and international clientele who want top-notch medical care in luxurious surroundings--and who can afford to pay for it. "There is a demand for it," says Gordon. In opening Marburg, Hopkins joins a growing group of hospitals with special services designed to attract the upper crust. A significant number of the Pavilion's patients are expected to come from the Middle East.

Gordon stresses that patients throughout the hospital get the same quality of medical care that Marburg patients do. Though the floor has its own group of salaried nurses, there is no separate pool of physicians.

In addition to the elegant furnishings, which include refurbished antiques from the collection of former Hopkins surgeon William Halsted, Marburg guests dine on gourmet meals, including any special requests that chef Robert Blake and his staff can fulfill. Since his arrival, Blake's collection of cookbooks has burgeoned to include several Arabic cookbooks, which he translates with the help of a dictionary. The kitchen is redolent of curry, cardamom, cilantro, and garam masala, as Blake and his staff prepare a multiethnic array of dishes, which are also available to visiting family members.

A guest services coordinator acts something like a hotel concierge in seeing that every patient's needs are met, whether it's having their pajamas hemmed or providing theater tickets and limousine service for visiting friends and family. These visitors can sleep in adjoining rooms equipped with sleep ottomans and sofas.

With the opening of the new pavilion, in January, Marburg has come full circle in its history. When the Marburg Building was constructed around the turn of the century, it featured the hospital's first private rooms. It catered to wealthy and famous patients from around the world, including the King of Siam and Clark Gable. Eventually, however, it evolved into a regular medical service unit open to all patients.

Could a more comfortable hospital stay promote a quicker recovery? "There's no evidence that recovery rates will be quicker," says Gordon. "But I think patients will leave in the best frame of mind."

Pancreatic cancer gene discovered

Genetic oncologists at Hopkins have discovered and sequenced a gene that, when out of commission, appears in about half of all pancreatic cancers, and may contribute to other cancers. It is called DPC4 (for Deleted in Pancreatic Cancer), and it may even help explain the extraordinary virulence of pancreatic cancer, one of the few that leaves modern medicine helpless. In the United States, pancreatic cancer kills about 25,000 men and women each year. Half the patients die within months of diagnosis, and five-year survival is less than 1 percent.

DPC4 is a tumor suppressor (one that only causes cancer when it is inactivated), and a powerful one. Mutations of this gene are "a major mutation for pancreatic cancer," says Scott Kern, assistant professor of oncology and pathology. His research group found that the gene is deleted or mutated in 52 percent of pancreatic cancers. That's a lot, as these things go.

Now that the gene is known, work on deciphering the protein it codes for can begin, so eventually the discovery may provide a new approach to treatment. "It might be possible to devise an agent that would come in and supply the signal that the cell is not getting," Kern speculates. "We do that with medicines all the time. Why not cancer?"

Already, however, it's clear that the finding is a steaming hot research lead. Kern's phone rang constantly during the first few weeks after the work was published, in the February 1 issue of Science. He says other researchers are fascinated because of the gene's location, and because it is "the first big example of a mutation in a developmental pathway," a chemical cascade that controls the growth of cells.

The gene sits on the long arm of chromosome 18, in the area known as 18q--an oddity in that its size can vary. Some people have an 18q that is larger than normal, some a small one, and a few even have three copies--"something the body won't tolerate on most chromosomes," says Kern. (Chromosomes normally come in pairs.) Apparently the genes on 18q are loosely packed, leaving room for "a little bit of mischief."

Within 18q is an even odder zone, 18q21, which is implicated in a number of tumor types--colon cancer, for example. The gene DCC (for Deleted in Colon Cancer) is right next door to DPC4. That makes sense, because 18q21 is prone to deletions, in which small to substantial chunks of genome go missing.

Furthermore, those deletions are peculiarly lethal. Back in 1989, working with colon cancer, Kern had showed that deletions in 18q were associated with metastasis, cancer that colonized away from its initial site. "People with loss of 18q had more than a four-fold increase in death from metastatic cancer," he says, looking down at the floor. "Surgeons overwhelmingly cure colon cancer in patients whose 18q is okay, but not those with a defect."

Now along comes DPC4, suggesting an explanation because it, too, is found in 18q, and because its cancers are also highly metastatic. And it offers a plausible mechanism for such lethality, because of its role in a cellular mechanism you can think of as a controller for excess growth. No wonder researchers are excited.

The version of this pathway that is best understood involves a gene called TGF-B (for Transforming Growth Factor). It begins with a receptor on the cell's exterior. When the right chemical lands on the receptor, says Kern, "the receptor sends a signal that triggers a chemical cascade within the cell, telling the cell to stop growing." TGF-B's role is the signal: it codes for the protein that lands (or not) on the receptor. DPC4 is in a similar pathway, but as part of the cell's internal workings.

Kern says these control pathways are so powerful that cancers literally must inactivate them, and do. TGF-B, for instance, suppresses almost all normal cells in tissue culture--but not carcinoma cells. And other types of epithelial cells undoubtedly have their own versions, which will have their own mutations. "So this is how cancers outwit the social controls," says Kern.

No wonder pancreatic cancer is so aggressive, if its major cause is a defect in the stop signal. And no wonder deletions in 18q portend so badly for cancer patients. "There will be other genes on 18q," says Kern, at least for colon cancer. DCC is already known.

Kern also expects to find familial forms of DPC4 defect, families that pass along one defective copy of DPC4. A single deletion is harmless, he says, unless and until the other copy of the 18q pair mutates, as can happen from old age, chance, or environmental insult.

He suspects that smoking may trigger the mutations. Only one-third of Americans smoke, he notes, but three-fourths of pancreatic cancer patients do. "It's entirely plausible that where there's a familial tendency, an environmental insult is also necessary. That's true in melanoma. There's a family tendency, but you seldom get it if you stay out of the sun."

Activating the DPC4 defect would not necessarily mean pancreatic cancer, but rather other cancers. For example, take the p53 gene, which is considered a gene for colorectal cancers. "But when it's found in families, it causes lots of cancers, except not colon cancer." BRCA2 is a breast-cancer gene, but it's found in 5 to 10 percent of pancreatic cancers. "We were looking for a simple answer," says Kern. "We're not going to get one."

All the same, as you read this, you can bet that geneticists all over the world are trolling the gene banks. They're looking for cousins of DPC4 and TGF-á, other genes that control cell growth. The more that's known, the better treatments can become. Kern says, "There might be some alternate pathway [to stop cell proliferation] that nature doesn't use, but a doctor could."

A better solution?

If there ever was a godsend, it is oral rehydration therapy (ORT). The administration of a sugar-salt solution to replenish fluids during diarrheal disease has saved countless lives, especially of children in developing countries.

But though it rehydrates, oral rehydration solution (ORS) generally does not halt diarrhea, which has meant that parents sometimes stop administering the solution because they believe that it is not helping.

Now, Hopkins professor of international health Mathuram Santosham reports that a simple change in the ORS formula dramatically improves its effectiveness, at least in cases of moderate diarrhea.

With grant support from the World Health Organization (WHO), Santosham recently led a team of investigators in Egypt who compared the standard ORS formula used by the WHO to a revised formula containing significantly less salt and sugar. WHO's standard ORS contains 90 millimoles per liter of sodium and 111 mmol/L of glucose. The revised formula contains 75 mmol/L each of sodium and glucose.

The researchers evaluated the two solutions in Cairo over the course of a year, in a total of 190 boys ages 1 month to 24 months who had acute diarrhea with dehydration. The children, none of whom had severe malnutrition, infections, or diseases requiring special treatment, were randomly assigned to receive either the standard ORS solution or the revised version.

Boys fed the revised ORS formula had 20 to 30 percent less stool output than the group who received the standard formula. "This new solution actually reduces the duration of diarrhea," concludes Santosham, whose report appears January 5 in The Journal of Pediatrics.

Furthermore, only one child from the group receiving the revised ORS had to be given intravenous fluids, compared to eight children from the standard ORS group. "Worldwide," says Santosham, "that could save millions of dollars." It would also save lives, since many regions of the world still lack access to IV equipment. Furthermore, says Santosham, since the revised solution actually reduces the severity of diarrhea, "it will be accepted by more parents."

However, the study has at least one skeptic. Professor of international health William Greenough notes that it did not examine the new formula's effectiveness on children with severe diarrhea such as occurs with cholera. (Such a study is currently underway.) Greenough advocates using ORS formulas that contain complex carbohydrates such as rice, which he says are more effective for patients with severe diarrhea.

Written by Elise Hancock and Melissa Hendricks.

Welcome to Marlboro country.

This modern-day image of Death, conceived by Hopkins epidemiologist Jonathan Samet and New Mexico artist Elizabeth Kay, is appearing on T-shirts throughout New Mexico. "It's another message about the dangers of smoking," says Samet, who is an authority on tobacco and health. Kay specializes in creating folk art that incorporates medieval Hispanic imagery into portrayals of contemporary themes. She based Se¤or Cigar¡llo on a 15th-century illustration of Death.

If the butt-puffing skeleton does not dissuade you from lighting up, the inscription on the back of the T-shirt might. It concludes: "For years, Se¤or Cigar¡llo hid behind a commercial smoke screen, disguised as carefree, joyful, and sexy. But though his malevolent identity has been revealed, vast numbers of devotees daily light the Holy Smoke while chanting, 'Inhale to the Chief!' Se¤or Cigar¡llo is invoked for lung cancer, emphysema, and more. His feast day is linked with the Day of the Dead."

Send EMail to Johns Hopkins Magazine

Send EMail to Melissa Hendricks

Send EMail to Elise Hancock

Return to table of contents.