Science Tuesday - Squirrels, Cancer, Genetic Testing, Plague, and Global Warming

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Findings: Love at First Sniff: How to Tell a Squirrel by Her Singular Bouquet
By JOHN SCHWARTZ, The New York Times, January 17, 2006


For Belding's ground squirrels, it's a smell world, after all. New research reveals at least five sources of body scent that the squirrels, Spermophilus beldingi, use as a symphony of smell to identify one another.

Individual identification is important, said Jill M. Mateo, an assistant professor in the department of comparative human development at the University of Chicago and the author of the study.

The squirrels can live a decade or more and dwell in high density. They develop distinctive personalities, laid back or cantankerous, so "it pays to be able to know who's who," Dr. Mateo said. Other scientists have studied the many ways social animals identify one another, and research by Robert E. Johnston of Cornell has yielded similar results with hamsters.

Dr. Mateo measured familiarity from the amount of interest squirrels showed in the scents; new smells got more attention than old. She previously showed that squirrels recognize kin, but the new work suggests that they can "tell the difference between Sue and Mary." Each source - glands next to the mouth, back, feet, anus and above the eyes - has a different smell, she said, but each is tied to the individual. "Five different odors say, 'Sue, Sue, Sue, Sue, Sue,' " she said.

"Together, these results indicate a rich olfactory milieu mediating the social lives of S. beldingi," she wrote in the current edition of Animal Behavior.

JOHN SCHWARTZ





A Therapy Fell Out of Favor, but Didn't Stop Saving Lives
By DENISE GRADY, The New York Times, January 17, 2006


Two months ago, when her surgeon recommended a series of treatments that would pump drugs directly into her abdominal cavity to fight advanced ovarian cancer, Gail Hilvers called her chemotherapy doctor to request it. He flatly refused.

"He said no research showed it was effective," said Ms. Hilvers, who is 51.

But she trusted her surgeon, so she decided to have the abdominal treatments, even though it would mean repeated 92-mile trips from her home in Ripon, Calif., to Stanford University Hospital.

Now, she is feeling especially lucky that she took the surgeon's advice. On Jan. 5, a large study was published showing that abdominal treatment, combined with the usual intravenous chemotherapy, could add 16 months or more to the lives of many women with advanced ovarian cancer - a survival increase so large that it would be considered a major advance in any type of cancer.

The study, in The New England Journal of Medicine, was actually the third in a decade to show that abdominal chemotherapy could help patients. It employed two widely used generic drugs, cisplatin and paclitaxel.

Experts said medical practice should change immediately, and the National Cancer Institute took the rare step of issuing a formal announcement to encourage doctors to offer the treatment to all women who met the medical criteria for it.

At major cancer centers and some other hospitals, the abdominal treatment was already in use, often as part of research, sometimes outside of studies. And although the latest findings were in women with newly diagnosed ovarian cancer, some doctors also use abdominal chemotherapy to treat recurrences of the disease.

As Ms. Hilvers quickly learned, the treatment a woman gets can depend heavily on who her doctor is and whether she can travel to a distant clinic.

Many cancer specialists, like the doctor who refused to treat Ms. Hilvers, have been skeptical about the abdominal technique, also known as intraperitoneal therapy, or IP. There are numerous reasons. The procedure is more difficult and time-consuming than dripping chemotherapy into a vein, and doctors and nurses need special training to administer it.

IP uses higher drug doses that can have severe side effects, including permanent nerve damage. Surgeons have to learn how to implant a special device called a port and a catheter in the abdomen to deliver the chemotherapy. Not every woman can have the implants; some have too much scar tissue.

Another strike against IP in some doctors' minds may be that it is not new. Many doctors lost interest in it years ago because different formulations were tried for ovarian cancer in the 1980's and 90's, but none proved better than traditional treatments. And drug companies, a source of information for many doctors, have not been promoting IP: there is relatively little profit in it for them, since the most effective formula for ovarian cancer uses generic drugs.

Ms. Hilvers's surgeon, Dr. Nelson Teng, director of gynecologic oncology at Stanford University Hospital, said that in the past some doctors gave up on the treatment because the implanted catheters tended to become clogged by scar tissue or caused infections.

"There are many little tricks," Dr. Teng said, adding that he had been implanting the ports and catheters for about 20 years. "It's almost like an art, how to place this catheter correctly. That's another reason why it's not widely used."

The need to overcome doctors' reluctance is part of what drove the cancer institute to campaign for the treatment, said Dr. Edward Trimble of the division of cancer treatment and diagnosis. Details about the treatment, including a list of hospitals around the country that can provide it, are posted at ctep.cancer.gov/highlights/ovarian.html. Information is also available by telephone from the institute's Cancer Information Service: (800) 4-CANCER.

"Since there has been a prejudice against this, it's important for women and their families to ask about it," Dr. Trimble said. "If patients ask, the doctor is more likely to raise the issue and say, 'I need to learn how to do this.' Advocacy groups have to get the word out to patients."

Dr. Joan L. Walker, a gynecologic oncologist at the University of Oklahoma and an author of the latest study, said: "The two previous studies had flaws that gave people excuses for why they didn't use it. Now we have three papers that all say same thing. One study can be a fluke, a statistical anomaly. Three probably isn't."

The latest study included 415 patients with advanced ovarian cancer, most ages 41 to 70, at 40 hospitals around the United States. All had surgery, and then were picked at random to get either intravenous chemotherapy alone, or both intravenous and IP therapy.

The median survival in the intravenous group was 49.7 months, but in those who got IP therapy it was 65.6 months - a difference of 15.9 months. This was the largest survival increase ever seen in any gynecologic cancer.

In response to a news article about the study, several patients contacted The New York Times to say they had IP therapy for ovarian cancer long ago and may owe their lives to it. One, Helen Palmquist, of Lincolnshire, Ill., had high doses of IP cisplatin 18 years ago at Northwestern University when she was 42.

The treatments made her violently ill, she wasted away from 120 to 80 pounds and she suffered some permanent nerve damage. But as the mother of two children, she said, "I was willing to do anything to stay alive."

Another patient, Kathleen Finn, from Shelburne, Vt., had the treatments nine years ago at the University of Vermont, also when she was 42.

"It has certainly seemed to work for me - so far," Ms. Finn said by e-mail. "How little did we realize how forward-thinking this medical team was."

If there is some urgency about getting the information out, it is because ovarian cancer is so deadly. In 2005, there were 22,220 new cases in the United States, and 16,210 deaths. Breast cancer is nearly 10 times as common, but its death rate is much lower. From 1995 to 2000, 87.7 percent of women with breast cancer survived five years - compared with only 44 percent of those with ovarian cancer.

The disease is so dangerous because it often has no symptoms until it has become advanced and has started spreading inside the abdomen. There is no reliable means of early detection, nothing like a Pap test or mammogram.

Sonograms and blood tests for a protein called Ca 125, known as a tumor marker, sometimes pick up the disease, but they are not recommended for screening because they too often miss the disease in women who have it and can cause false alarms in those who do not.

Even when symptoms do occur, delays in diagnosis are common because the symptoms can be vague - bloating, weight gain, bowel problems - and easily mistaken for other illnesses, especially in older women. In most cases the disease is not detected until it has reached Stage 3; Stage 4 is the most advanced.

Ms. Hilvers and Ms. Palmquist, for instance, had no idea that anything was wrong until their abdomens began to swell. Ms. Finn suddenly developed a bump near her navel that she thought might be a hernia or a boil. But it was actually part of a tumor. All three women had Stage 3 disease.

The standard treatment is surgery first, then chemotherapy. Most cancer specialists say it is essential for women with ovarian cancer to have their operations performed by gynecologic oncologists, surgeons with several years of specialized training in cancer surgery. But only about half the ovarian cancer patients in the United States have their surgery done by these specialists.

One problem is that sometimes the disease is not diagnosed until an operation is already under way, being performed by a gynecologist or general surgeon.

For that reason, anytime there is even a possibility of ovarian cancer in a woman having pelvic or abdominal surgery, a gynecologic oncologist should be present or at least on call, said Dr. Deborah K. Armstrong, the director of the recent study and a medical oncologist at the Johns Hopkins Kimmel Cancer Center, who is not a surgeon.

The expertise is needed because removing as much of the cancer as possible, known as debulking, is especially important in ovarian cancer: studies have shown that it improves survival. It may require difficult and lengthy surgery to remove the spleen, parts of the intestine and even the lining of the diaphragm.

So-called optimal debulking removes all tumors bigger than a centimeter in diameter, or 0.39 inches. Major cancer centers report that 80 percent of ovarian cancer patients have optimal debulking, but in hospitals that lack expertise the rate may be only 30 percent.

Debulking helps chemotherapy do its job, by reducing the number of tumor cells that the drugs have to kill and by shrinking masses, making it easier for the chemotherapy to penetrate.

It is not entirely clear why IP therapy is so effective. Compared with intravenous treatment, it exposes the abdomen to much more concentrated doses of chemotherapy, essentially soaking the tumors in cancer-killing drugs. But there may be more to it than that.

Dr. Teng said that since the IP drugs gradually seep into the bloodstream, the treatment may act like a continuous form of chemotherapy that fights cancer cells for a long time all over the body.

Dr. Trimble suggested that the IP drugs might somehow activate the body's own immune cells within the abdomen to fight the cancer.

However the treatment works, survivors are grateful.

"I turned 60 on the Fourth of July," Ms. Palmquist said. "That's one thing about this disease. I never complain about getting older."





Cases: Genetic Testing Creates New Versions of Ancient Dilemmas
By ROBERT KLITZMAN, M.D., The New York Times, January 17, 2006


"I pleaded with my sister, Susan, to get genetic testing, but she refused," a woman recently told me in my office.

Susan, the woman said, already had breast cancer, so her health insurance company would have paid for the testing.

"I am at high risk for developing breast cancer," she said. If she knew that Susan was gene positive, she would consider having her own breasts removed.

The woman in my office couldn't afford the genetic testing herself: it costs over $3,000. Her insurance wouldn't pay for the testing because she had not yet had cancer. Yet she had had multiple calcifications in her breasts. Tumors could be hiding there, undetected. The woman's mother and aunt had died of the disease.

Genetic tests for the breast cancer genes known as BRCA1 and BRCA2 account for only 40 to 80 percent of all breast cancers. Researchers are still trying to identify BRCA3 and BRCA4 genes that may account for the rest.

In the meantime, Susan's refusal to be tested affected this woman's life, as well. In the new genetic age, the notion that family members are "bound by ties of blood" takes on new meaning.

I admired this woman's courage. I realized that I wouldn't want to have to face these choices myself. She wanted to know her fate. But not everyone does. Countless patients struggle daily, unsure what to do.

What role should physicians play here? How much should a doctor encourage patients or family members to be tested if they do not want to be?

The fact that every family has its own unspoken, unwritten rules complicates these decisions. In coming years, these familial tensions will only increase. Every month, new genetic tests are marketed, but the data they provide are often unclear.

Until a few years ago, scientists had hoped to find single genes that caused diseases. But illnesses that are determined by single genes seem to be rare.

Rather, whether someone develops a particular disease often depends on multiple genes. Having a breast cancer gene, for example, means that you have a 36 to 85 percent chance of developing the cancer. Environmental factors and additional, modifying genes and are also likely to play major roles.

These dilemmas bring to mind the ancient Greek belief that three Fates measured out the length of each human life, and that oracles foretold the future. But the predictions of the oracles were rarely either simple, or what was sought. Misinterpretation was always a danger.

The Oracle at Delphi predicted that Oedipus would kill his father and marry his mother. Oedipus thought he could escape this destiny. But in the end, he willingly performed both these acts, without knowing at the time that he was doing so. Herodotus tells of King Croesus in Asia Minor, who, when consulting an oracle, was told that if he mounted an invasion, a mighty empire would fall. He attacked, and in the end, as Herodotus writes, "the Oracle was fulfilled; Croesus had destroyed a mighty empire - his own."

Since the Renaissance, literature and art have presented the Greek fates ambivalently, either as divine beings fulfilling the work of God or old hags mercilessly dashing human hopes.

As science progresses, as more genes are found, their meaning uncertain, we will be unsure how to proceed. Much like the ancients, we will get information that we don't want to know and don't know how to use.

In the past, a doctor cared only for a patient's health and well-being. Yet with increasing understanding of infectious and genetic diseases and improving treatment for them, physicians are recognizing the extent of their responsibilities not only for a patient's health but for the public health.

In the future, doctors may even decide to violate patients' rights to privacy to protect the lives of a third parties.

In the future, the courts might rule that doctors should break patient confidentiality to warn family members of genetic risks.

As we enter the new genetic age, more education is needed to help doctors, nurses, genetics counselors, patients and their families face these quandaries. We have much to learn from the Greeks: to be cautious in interpreting prognostications, to beware that genetic information, like oracles, may offer an illusion of certainty.

In the end, Susan finally did get testing, and her tests were negative. Perhaps she had a gene that has not yet been identified.

In any case, Susan's sister still faces difficult choices, and she is trying to decide whether to undergo prophylactic radical mastectomies.

I'm not sure what I would do.

The ancient Greeks would have said that an oracle could predict her decision. Yet, at least for now, her choice cannot be foretold.

Robert Klitzman is co-director of the Columbia University Center for Bioethics.





Vital Signs: Prevention: New Plague Vaccine: It Works on Guinea Pigs
By ERIC NAGOURNEY, The New York Times, January 17, 2006


Researchers say they have taken a step toward developing a reliable vaccine against plague.

The disease takes two forms: bubonic, which is spread by flea bites, and the more serious pneumonic, which is spread in the air.

Government officials are concerned that it could also be used as a weapon.

Although vaccines against the plague have been produced, they have not proved to be very effective, especially against the pneumonic form, and they are hard to administer.

Now, however, researchers report in The Proceedings of the National Academy of Sciences that they have produced a vaccine that is cheaper and easier to use.

In vaccinated guinea pigs, nearly three-fourths of them survived after being exposed to the pneumonic form of plague.

"I think it's very encouraging," said a co-author of the report, Dr. Charles J. Arntzen of Arizona State University.

Researchers developed the vaccine by taking plague proteins and growing them in tobacco leaves.

The military paid for the study for counterterrorism purposes, but if a better human vaccine can be developed, it will help people in Africa, Asia and other regions where plague is a problem.







Frog Killer Is Linked to Global Warming
By ANDREW C. REVKIN, The New York Times, January 12, 2006


Scientists studying a fast-dwindling genus of colorful harlequin frogs on misty mountainsides in Central and South America are reporting today that global warming is combining with a spreading fungus to kill off many species.

The researchers implicate global warming, as opposed to local variations in temperature or other conditions. Their conclusion is based on their finding that patterns of fungus outbreaks and extinctions in widely dispersed patches of habitat were synchronized in a way that could not be explained by chance.

If the analysis holds up, it will be the first to link recent climate changes to the spread of a fungus lethal to frogs and salamanders and their kin. The chytrid fungus, Batrachochytrium dendrobatidis, has devastated amphibian communities in many parts of the world over the last several decades.

But experts on amphibian disease and ecology are divided over the finding, which is being published today in the journal Nature. Several scientists criticized the paper yesterday, saying it glossed over significant sources of uncertainty; others said it was important evidence that warming caused by humans was already harming wildlife. Climate scientists have linked most of the recent rise in the earth's average temperature to the buildup of greenhouse emissions from smokestacks and tailpipes.

The new study was led by J. Alan Pounds, the resident biologist at the Monteverde Cloud Forest Preserve in Costa Rica. In an accompanying commentary, two scientists not involved in the research say it provides "compelling evidence" that warming caused by human activity was already disrupting ecology.

"The frogs are sending an alarm call to all concerned about the future of biodiversity and the need to protect the greatest of all open-access resources - the atmosphere," write the scientists, Andy Dobson, a Princeton University ecologist, and Andrew R. Blaustein, a zoologist at Oregon State University.

More than 110 species of brightly colored harlequin frogs, in the genus Atelopus, once lived near streams in the tropics of the Western Hemisphere, but about two-thirds of them have vanished since the 1980's.

A leading suspect is the chytrid fungus, which in recent decades has killed amphibians from deserts to lowland tropical forests to mountainsides. It is not clear whether the fungus has been spread around the world by human trade in amphibians or whether it has laid largely undetected and has only recently erupted.

Paradoxically, the fungus thrives best in cooler conditions, challenging the theory that global warming is at fault. But Dr. Pounds and his team, in studying trends in temperature and disease around the American tropics, found patterns that they say explain the situation.

Because warming increases evaporation, it can create clouds that tend to make days cooler by blocking sunlight, and make nights warmer by trapping heat. In an interview, Dr. Pounds said those conditions could have created favorable conditions for the spread of the chytrid fungus.

He said that because the seeming extinctions had occurred in lockstep over dispersed field sites, they were hard to attribute to anything other than the broad warming trend that scientists have linked to rising concentrations of greenhouse gases.

But some experts who have read the paper said they were troubled by definitive statements like "Our study sheds light on the amphibian-decline mystery by showing that large-scale warming is a key factor."

Cynthia Carey, an amphibian disease expert at the University of Colorado, said that while both climate and amphibian die-offs were serious problems, this particular paper failed to offer anything beyond circumstantial evidence.

"It is difficult to prove cause and effect on the ground where multiple factors interact in complex ways," she said.

Stephen H. Schneider, a climate expert at Stanford, who has worked with Dr. Pounds on other studies and consulted on this one, acknowledged that uncertainties remained but said the work was significant.

"It's like anything else that's complex," he said. "When you're in the early phases of learning you look for multiple lines of argument, and when they converge with basic theory, you increase your confidence in a connection."