February 1999

International

• Penn Advance Marks New Era in Gene Therapy 
• New Painkillers: Too Good To Be True? 
• It’s Radical, But It Works 
• I’d Rather Be In Philadelphia 

National

• Blame It On My DNA

Local

• Are We Having Fun Yet?

Perspectives

Snips & Clips

When the first human gene-therapy tests started nearly 10 years ago, expectations ran high. Some suggested that gene therapy would offer a quick cure for diseases ranging from cystic fibrosis to cancer. But the therapy proved thornier than first thought; new genes proved ineffective, caused harmful side effects, or were destroyed by the immune system before they had a chance to do much good.

In January, Penn researchers announced an advance that overcomes these shortcomings. Working with Ariad Pharmaceuticals Inc., the researchers have devised a way to turn gene therapy treatment on and off. The system has already been shown to work for months in mice and monkeys. If it can be made to work in humans, it would represent a major step forward in the development of gene therapy. A report on the study was printed in the January 1 Science. 

“This system will allow us to modulate the expression of a delivered gene in response to changes in a patient’s disease,” James M. Wilson, MD, PhD, director of the Institute for Human Gene Therapy and senior author of the report, told the BBC News. “The problem up till now was that the door was always wide open,” he added in The Philadelphia Inquirer. With the new technique, “we can partially open the door, open it fully, or shut it.” 

To develop their new method, the Penn and Ariad scientists first inserted a protein-producing gene into an adeno-associated virus. Unlike other viruses that were used in earlier gene-therapy experiments, this virus doesn’t generate a particularly aggressive immune response, allowing the genes to survive inside the body for long periods. But the scientists also added to the virus, among other things, a molecular switch that ensures that the gene can only be activated in the presence of a drug called rapamycin. 

“Our goal is to give an injection of a gene and feed the patient a pill and the pill would activate the gene,” Wilson told The Philadelphia Inquirer. “If you wanted to activate more of the gene, you take more of the pill, and if you wanted to activate less, you give less of the pill. And if you wanted to stop it altogether, you stop taking the pill.”

Because the new method is more convenient and safer than injectable drugs, it could potentially replace other injected therapeutic proteins such as interferon for hepatitis or cancer or even insulin for diabetes. As Wilson told The Wall Street Journal: “We think [gene therapy] will ultimately be a safer and more effective method than giving therapeutic proteins” with injections. 

Reports began January 1. 

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A much-anticipated series of new drugs just coming on the market promises to ease the pain of arthritis, menstrual cramps, headaches, and other afflictions equally as well as aspirin and other over-the-counter painkillers but without the sometimes serious side effects of those drugs. Stomach ulcers are among the worst of these side effects, leading to tens of thousands of hospitalizations and thousands of deaths annually.

A Penn study, however, raises the possibility of a downside to these so-called “super aspirins,” or COX-2 inhibitors, reported The Globe and Mail. The researchers discovered that COX-2 blocks prostacyclin, a hormone-like substance that dilates blood vessels and inhibits blood clotting. This raises questions about whether the super aspirin might increase the risk of thrombosis, dangerous clotting that can result in heart attacks and strokes. A report on the study appeared in the January 5 Proceedings of the National Academy of Science.

“The clinical trials designed to show that the COX-2 inhibitors work in treating arthritis have not shown evidence of a cardiovascular risk,” noted Garret A. FitzGerald, MD, chairman of the department of pharmacology and senior author of the study. “However, they would have been roughly an order of magnitude too small in their sample sizes to detect what we see as a possible problem associated with the use of these drugs. So, the question hangs out there for future experience: Will a cardiovascular risk emerge over time as the COX-2 inhibitors reach more and more patients?” 

Many over-the-counter painkillers suppress prostacyclin, but they also simultaneously paralyze platelets, thus limiting their ability to collect and clot. For this reason, doctors often prescribe low-dose aspirin regiments for cardiovascular disease patients to reduce the odds of thrombotic events. The COX-2 inhibitors do not offer this additional protective action while they do remove the body’s inherent ability to control platelet aggregation.

“One option may be for patients who are at particular risk for adverse cardiovascular events to combine COX-2 therapies with low-dose aspirin,” said FitzGerald. “But this is a strategy that would need to be tested in clinical trials.” 

Reports began January 19. 

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A study has found that women with a family history of breast cancer who have their breasts surgically removed reduce the likelihood of getting the disease by 90 percent, confirming for the first time that the treatment is effective. For decades, doctors had debated the dubious benefits of the extreme measure. 

The study, published in the January 11 New England Journal of Medicine, examined the medical histories of 639 women with a family history of breast cancer who received prophylactic mastectomies at the Mayo Clinic from 1960 to 1993. The typical follow-up period was 14 years. Of these women, 214 were determined to be high risk (both mother and a sister with breast cancer, a family with a case occurring before age 45, or a family with either multiple cases of breast cancer or both breast and ovarian cancers). 

These 214 women had 403 sisters, 156 of whom (39 percent) were found to have had breast cancer. With this information, the researchers used three approaches to calculate how many such cancers would have been expected in the 214 patients if they had not had surgery. The predicted numbers of cancers ranged from 30 to 53; the number actually diagnosed in women after preventive surgery was three. The operation was calculated to have reduced the women’s breast cancer risk by 90 percent to 94 percent.

Seven breast cancers had developed in the 639 women who had the procedure. Five were confined to the chest wall and were successfully treated; two had spread and the patients eventually died. 

Barbara L. Weber, MD, director of the breast cancer program at the University of Pennsylvania Cancer Center, co-wrote an accompanying editorial calling the study “good news” for women who are considering prophylactic mastectomy but also added her voice among those experts emphasizing that the measure is an option that should be considered only when there is strong evidence of inherited breast cancer within a woman’s family. 

“The estimates are that somewhere around 20 percent of women have a family history of breast cancer and maybe around a quarter of those have a really significant family history,” Weber told The Washington Post. “”If you’re worried . . . it probably makes sense to see someone who specializes in cancer risk assessment.” (The National Cancer Institute’s hotline—1-800-4CANCER—offers a directory of cancer risk-assessment programs.) 

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In a profile of the City of Brotherly Love, The Economist began its story on 21 Penn Tower: 

“William N. Kelley, [MD], chief executive of the University of Pennsylvania Health System, strides over to his Penn Tower window and, like a latter-day emperor, reviews his territory: ‘We have 1.3 million square feet of new research space in this campus. . . . We have the advantage here of a fully integrated health system. We own four hospitals. . . . We take care of 20 percent of the people in the Greater Philadelphia market.’”

The article “City Life: The Better Streets of Philadelphia” made the case that, although “few outsiders connect Philadelphia with medical and scientific excellence; they think, instead, of Boston or of sunny parts of southern California,” the truth is “rather more encouraging than the reputation.” 

Penn was the lead-off example in a review of the city’s many medical and scientific riches, which include more than 80 colleges and universities, six schools of medicine, and 24 teaching hospitals. 

“Since like attracts like, it is easy to see how clusters of excellence form in health care and pharmaceuticals, and in associated financial and data services. Mr. Kelley, for instance, talks of the ‘synergies’ with chemical and bio-engineering schools, notes the competitive success in getting research money from the National Institutes of Health, and happily provides visitors with a photocopy of a patent for a ‘viral-mediated gene transfer system,’ awarded two years ago to him and two colleagues at Ann Arbor in Michigan. In other words, Mr. Kelley could work anywhere — but has chosen Philadelphia.”

Printed January 16. 

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Scientists are increasingly aware that personality traits are biologically based. “We know genes influence our behavior and personality, but we don’t yet know which genes do so or to what degree,” R. Arlen Price, PhD, professor of psychiatry, told First For Women. “But, we’re quickly gaining understanding. Once we do, we’ll be able to select certain combinations of genes and say, ‘Yes, this is the genetic cocktail responsible for Sally’s gregariousness.’” 

In some instances, genetic makeup is already a clear indicator. The inherited factor is especially strong in depression, where having a first-degree relative “means you are twice as likely to have the condition yourself,” said Price, who directs Penn’s Center for Neurobiology and Behavior. “Since both extreme shyness and mania — a mental disorder characterized by extreme mood swings — have components of depression, these traits are probably also biological.” 

Price continued: “The most surprising recent finding is that family environment and upbringing do not play as large a role as previously thought in influencing personality. Some 20 percent to 40 percent of individual personality traits such as shyness and gregariousness could be attributed to inherited factors, with the balance due to a person’s lifestyle choices and personal experiences.” 

Printed December 14. 

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If you’re a menopausal woman who feels her memory isn’t as sharp as it used to be, you’re not alone. Michelle M. Battistini, MD, assistant professor of obstetrics and gynecology, says she hears the complaint “all the time.” And it’s not just your imagination: Depleted estrogen levels can impair memory. The brain has receptors for estrogen in the areas responsible for memory and learning. 

Estrogen is also known to affect the chemicals in your nervous system that facilitate memory function, Battistini explained in the Philadelphia Daily News. “A change in memory is a very disturbing symptom,” she says. “You forget your keys, and all of a sudden you’re afraid you’re developing Alzheimer’s.” Estrogen-replacement therapy can help (a study in Canada found that it improved name recall) as can another, non-medical intervention: sleep. When it comes to memory, fatigue can play just as large a role as estrogen levels, Battistini says. “Part of this is lifestyle-related . . . being overloaded with obligations. Midlife women happen to be at the time when they’re balancing many things, and menopause occurs as well,” she says. “If you’re not eating well and not sleeping well, you don’t remember as well. It’s all tied in together.” 

Battistini’s advice: “Step back, see what applies to you, make some changes. You probably will see some restoration” of your memory. “Sometimes women notice an improvement. Sometimes the improvement isn’t real, but they’ve adjusted. They’ve started to write notes to themselves, and they’re not multi-task-oriented. Some women improve with changes in lifestyle, taking better care of themselves and just expecting less of themselves.” 

Printed January 13. 

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“Human beings were not really designed to give birth to litters.”
— David Magnus, PhD, Center for Bioethics
[Subject: Texas octuplets stun the medical community]
Fox News Channel, 1/2 

“The joke is it’s something that works like aspirin but costs much, much more.”
— Peter Callegari, MD, assistant professor of rheumatology
[Subject: “Super Aspirin”]
The Philadelphia Inquirer, 1/11

 “This is a tragedy, since George Lundberg is a giant in the field of American medical publishing, and under his leadership, the journal flourished.”
— Arthur L. Caplan, PhD, Director of Penn’s Center for Bioethics
[Subject: JAMA editor fired for publishing a what-is-sex survey of 
college students to coincide with President Clinton’s impeachment trial]
Portland Oregonian, 1/16

“In 1966, Penn [gave] me a brain. Thirty-one years later, just as the Wizard granted to the Tin Woodsman, Penn gave me a heart.” 
— Rick Selvin, Penn Class of ’66 and ’97 heart transplant patient 
and columnist for the Philadelphia Daily News
[Subject: Editorial from a grateful alum — and patient]
The Daily Pennsylvanian, 1/14 

“I think the Cartesian era is going to be a footnote in history. And a curious footnote at that. It’s just so obvious the mind and body are profoundly related.”
— Paul Root Wolpe, PhD, Center for Bioethics 
[Subject: The link between mood disorders and health]
Hippocrates, December 1998 issue

“We have our ducks lined up and we just have to shoot ’em down to find out which ones work. We’re in a whole new era I couldn’t have imagined 10 years ago. But finding a robust drug takes time and money.”
— John Q. Trojanowski, MD, PhD, professor of pathology 
and laboratory  medicine
“Alzheimer Drugs Fail The Test: Reversals Dampen Optimism”
Star-Ledger, 1/3 

“I always thought he would do something great. We’re real proud of him.”
— Margie Sweeney, mother of Lee Sweeney, PhD, professor of physiology 
“Bringing New Life to Old Muscles: 
Scientist’s Love of Research Began Locally”
The Dallas Morning News, 12/21

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PAYING FOR THE PILL. . . An estimated 29 percent of the 10 million U.S. women who use birth control rely on oral contraceptives, according to American Health Magazine. Yet only about half of the country’s group health plans pay the monthly cost for the pill. Female employees of large companies fare better than their counterparts working for small businesses; almost 70 percent of large employers’ HMO plans cover oral contraceptives, according to a national survey conducted by Mercer/Foster Higgins. The University of Pennsylvania Health System’s insurance plans are among them, Elyse Kaplan, associate vice president for human resources, explained to the Philadelphia Daily News. In addition to covering birth-control pills, the Penn Health System’s plans pick up the tab for in vitro fertilization. “Every organization has its own benefits philosophy,” said Kaplan. “It’s a balance between what you want and what you can afford.” Printed January 13. 

CLUB MED. . . A Penn orthopaedic surgery resident recently founded the Middle Eastern Medical Society, a group to promote dialogue among Middle Eastern doctors. Raz Winiarsky, MD, explained his mission to Modern Healthcare magazine: “If I work with you for a common goal, I can learn about you. Our aim is to create a dialogue. . . and let the politicians take it from there.” Winiarsky hopes to exchange not only scientific information but to help bridge the cultural and political divides in the region. “I’d never met a Palestinian and never spent more than five minutes with a Muslim or Arab person” as a child in Israel, he said. Printed in the December 21-28 issue. 

NO GRAIN OF TRUTH?. . . Wheaties might be the “Breakfast of Champions,” but the cereal won’t help win any battles against colon cancer. Contrary to years of dietary wisdom, fiber has no protective effect against the disease. So concludes a study published in the January 21 New England Journal of Medicine. The Harvard-based study tracked the colon and rectal health of 88,757 women from 1980 to 1996. During those years, 787 of the women developed cancer of the colon or the rectum. The risk was the same, regardless of how much fiber they ate. Still, fiber should be a mainstay of any healthy diet, UPHS dietitian Charlene Compher, MS, told The Philadelphia Inquirer. Fiber-rich diets reduce risks of heart disease, high blood pressure, and certain types of diabetes. “It’s a healthier diet overall in terms of gastrointestinal function, lower calories, lower fat,” Compher said. The American Heart Association recommends 30 grams a day. Printed January 21. 

ADJUST-A-BOSOM. . . Women considering breast enlargement have a new option: the Becker expander, an adjustable implant. The device, which was originally developed for patients who had mastectomies, has a fill tube through which saline can be added or removed. The tube can remain in place for six months, giving a woman time to become used to her new breast size or make changes. The new implants can be filled gradually, minimizing discomfort, and for mastectomy patients, who are often sore after surgery, the implants can remain empty until pain has subsided. “You run the same risk of infection [as with traditional implants], and there’s the additional procedure of removing the filling port,” Don LaRossa, MD, professor of surgery, told the Philadelphia Daily News. But, he added, there’s no “serious downside” to the Becker expander. Printed January 6. 

PET PEEVE. . . A team of University of Pennsylvania Medical Center researchers thinks that positron emission tomography, or PET, imaging should be used more widely in identifying life-threatening microscopic cancers, reported Consumers Digest magazine. Penn is one of only 70 medical centers in the United States with PET equipment. A study by Abass Alavi, MD, professor of radiology and chief of the nuclear medicine division, and Daniel Sterman, MD, assistant professor of medicine and director of the interventional pulmonary division, showed that PET imaging is more effective at finding microscopic cancers than X-rays, CT scans, or MRIs. It also demonstrated the technology’s use in revealing the effectiveness or inadequacy of a chosen course of cancer therapy. The study was published in Chest, the journal of the American College of Chest Physicians. Printed in the January/February issue. 

NO BIG DEAL. . . Aetna Inc, the nation’s largest health insurance company, announced in December that it would acquire Prudential HealthCare, adding 6.6 million subscribers to its membership base. Putting the acquisition in perspective, David Shulkin, MD, chief medical officer for the Health System, told The Philadelphia Inquirer: “We are used to operating in an environment where Aetna and Independence Blue Cross have over 85 percent of the market share, so this is not going to have a profound effect on how we deal with the managed-care companies,” he said. “The market in Philadelphia is already consolidated and a little greater consolidation is not going to fundamentally change the relationship between providers and payers.” Printed December 11.  

WHEN TO SAY WHEN. . . One of the hardest parts of a doctor’s job is telling terminally ill patients how long they have to live. Knowing when and how to discuss the issue can be difficult. “It’s the patients’ call,” whether they want an estimate of their time remaining, Arthur L. Caplan, PhD, director of Penn’s Center for Bioethics, told the Journal of the National Cancer Institute. Doctors should be cautious and ask some questions to determine how specific an answer a patient wants — or to find out if the patient wants any direct answer at all. “Some don’t want to hear until they’re ready to hear, and they find this kind of conversation robs them of hope,” said Caplan. “There are certainly some cultural groups who do not want to discuss it because they think it’s arrogant and even may make death happen if you talk about it.” Printed December 16. 

KING KUNG. . . A new imaging agent called Trodat may yield a better understanding of brain disorders like Parkinson’s and Alzheimer’s diseases. Hank Kung, PhD, professor of radiology and chief of radiopharmaceutical research, helped develop and study the tracer. “The dopamine system in the brain contains receptors that control basic functions like movement, memory, and emotion,” Kung explained in Hospital & Healthcare News. “Trodat can be used to determine whether the dopamine transporter is working correctly, or if it is unbalanced, which leads to neurological and psychological illnesses that are linked to dopamine changes.” Kung’s study, published in the European Journal of Nuclear Medicine, garnered the journal’s award for Best Science Paper. Printed in the November issue. 

DON’T BELIEVE THE HYPE. . . How useful is genetic testing for women who might carry a breast cancer-causing mutation? Don’t take the word of the companies that market the tests. Mildred Cho, PhD, assistant professor of molecular and cellular engineering, says these companies often overstate the accuracy and predictive value of the tests. Cho analyzed marketing materials from the companies. “If the FDA used similar criteria as they do for drug labeling and marketing, most of what I saw wouldn’t pass,” she told Hippocrates magazine. Printed in the December issue.  

ONE WAY OR ANOTHER. . . In angiography, a catheter is threaded into the heart via a groin artery. But that access point comes with a risk of bleeding if the patient moves soon after the procedure. So patients are immobilized uncomfortably for hours to ensure that a proper clot forms. A new approach uses the radial artery in the wrist, where the risk of bleeding is much lower. Popular in Europe, the wrist approach has been slow to catch on in the United States. The American College of Cardiology is drafting a policy statement saying that its members should be trained to use both arterial paths. John W. Hirshfeld Jr., MD, professor of medicine, director of HUP’s cardiac catheterization lab, and chairman of the organization’s Committee on Cardiac Catheterization, says the change will take time. “When you’re confronted with the choice of deciding whether you’re going to become a skilled trans-radial-angiography practitioner, you have to determine whether you want to put several hundred patients through the learning curve while you struggle with your new technique,” he told the Times-Picayune (New Orleans). Printed January 3.  

IGNORING THE CRITICS. . . In December, a team of fertility doctors in South Korea announced that they had made a major step toward cloning a human being. The Korean team did not make a baby — just a microscopic, four-cell embryo that it later destroyed. But the announcement confirmed the fears of many in the medical community: Attempts to clone humans are moving forward despite widepread ethical objections. “People in other countries are saying to hell with the U.N. and to hell with the ethics panels and to hell with the World Health Organization,” Glenn McGee, PhD, assistant professor of bioethics, told The Philadelphia Inquirer. Pasquale Patrizio, MD, assistant professor of obstetrics and gynecology, said that while he would never participate in cloning, it didn’t surprise him that others would: “It’s like following a recipe — you don’t need any new ideas or special equipment.” Printed December 18.  
 

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