This month, Dr. Sydney Spiesel discusses new research that saves mice from breast cancer, the life-extending properties of red wine, the risks of long-distance running, and an unwelcome new cause of anemia in the Third World. For his last two columns, please click here and here.
Breast cancer—new hope?
Question: Does progesterone, the hormone of pregnancy, play some role in the development or progression of breast cancer? There is some evidence that the answer is yes. Now research may point the way toward blocking the role the hormone plays in developing tumors in women at high risk of developing breast cancer because of a genetic predisposition.
Gene: Sometimes breast cancer runs in families, controlled by one or more genes. The best-known of these is the gene BRCA1 ("breast cancer 1"). For most of us, this gene serves a powerful protective function, stabilizing our genetic structure by controlling a mechanism that repairs broken strands of DNA and, thus, reversing changes that would otherwise cause gene mutation. But the BRCA1 gene is itself subject to mutation. And certain of these (including a mutation found fairly frequently among Ashkenazic Jews) weaken the gene's customary protective effect. In addition, there is increasing evidence that BRCA1 regulates the effect of hormones on normal and malignant tissues. About one woman in 800 carries an abnormal BRCA1 gene; these women are at great risk for developing breast or ovarian cancer.
Experiment: Using the tools of genetic engineering, scientists can produce mice with a completely inactive BRCA1 gene, in effect mimicking a BRCA1 gene with a severe mutation—exactly the condition we encounter in women at high risk for breast and ovarian cancer. For reasons that aren't known, the breast tissue of these mice develops like the breast tissue of normal pregnant mice but is extra sensitive to the hormone progesterone. Every one of these BRCA1 "knockout" mice goes on to develop breast cancer before 9 months of age.
Findings: A research group headed by Aleksandra Poole and Eva Lee at the University of California at Irvine reasoned that progesterone might be playing a role in this tumor development. So they tried administering a medication, mifepristone. Also known as RU-486, * mifepristone blocks the action of progesterone. Poole and Lee's team were far more successful than they ever imagined: Not a single mifepristone-treated mouse developed breast cancer. Results this clear and dramatic are rare in science.
Conclusion: It is way too early to take this treatment from mice to humans, but it is an extraordinarily attractive research lead. I'm sure the search is already under way for suitable progesterone-blocking drugs for humans. The prospect of blocking the terrible effect of some mutant versions of the BRCA1 gene is exciting indeed.
Living forever while drinking red wine
New research: Living long and living well have always seemed to be mutually exclusive. Eat oysters and sweetbreads and expect your big toe to swell with gout. Limit your diet to a notch north of starvation and you might live longer. Now there is some evidence that calls these axioms into question. A research group headed by Joseph Bauer and David Sinclair (of Harvard Medical School) and Raphael de Cabo (of the National Institute on Aging) has reported on a treatment using a chemical found in red wine that insulates overindulgent mice from the effects of dietary excess. The chemical, resveratrol, had been shown to extend the life expectancy—and sometimes improve the health—of yeast cells, tiny worms, fruit flies, and fish. The research conducted on these simple organisms suggests that resveratrol may extend life span through the same mechanism that semi-starvation can.
Findings: The new research showed that when a middle-aged mouse was made obese on a fat-enriched diet and then treated with resveratrol, the chemical increased its life span, mimicking the expected effect of switching to a calorie-deficient diet. Administering resveratrol to half of the fat mice didn't slim them down (well, maybe it did a tiny bit, but they were still chunksters). The treatment did, however, increase their life spans to those of normal-weight mice. And it prevented many of the complications we are used to seeing in animals and humans on high-fat diets—poorly functioning fatty livers and resistance to insulin, which results in Type II diabetes. Thus, in this study resveratrol didn't prevent the overindulged mice from becoming fat. But it protected the fat mice from the expected change in their metabolism that leads to diabetes and, in addition, extended their lifespan beyond the expected.
Implications: What does this have to do with us—can I take resveratrol, eat that triple-dip banana split, and still live to see my grandchildren graduate? Maybe, but only time will tell, since it's exceptionally difficult to think of an ethical way to conduct the definitive experiment. But here are some preliminary observations:
1) In the laboratory, resveratrol protects nerve cells against certain toxic materials and may also protect the heart. It also inhibits the growth of certain cancer cells. We don't know yet whether these effects take place in living organisms.
2) Much has been made of the presence of resveratrol in red wine (it comes from the skins of the grapes and the pits). The discovery has been invoked to explain why the French are not felled by their rich sauces. The good news is that resveratrol isn't toxic to rats in doses equivalent to 1,000 glasses of red wine a day for humans. The bad news is that the dose of resveratrol shown to extend the life of the obese mice is also equivalent to 1,000 glasses of red wine a day for humans.
The risks of long-distance running
Question: A number of dermatologists at the University of Graz in Austria are serious long-distance runners. They recently realized that over the past 10 years, they had treated eight ultra-marathon (100 to 160 kilometers) runners for malignant melanoma—the most dangerous skin cancer. The number of cases may not be high, since they were scattered among 3,000 or so over the same period of time. But this group of physicians began to muse about whether there's something about long-distance running that puts those who do it at increased risk.
New research: Writing in Archives of Dermatology, Christina Ambros-Rudolph and her colleagues decided to compare 210 marathoners who signed up at a race with a group of 210 nonrunners who signed up at a recreation center. The groups were matched for age and sex distribution. Because the risk of developing melanoma is clearly related to sun exposure, a dermatologist evaluated each participant for evidence of sun damage to the skin and for skin cancer or precancerous conditions. He or she also asked the runners about their efforts to limit sun exposure.
Findings: The findings must have been a little anxiety-provoking for the authors. In most ways the runners and nonrunners were similar. They had similar histories of sunburns earlier in life and similar hair color. The skin of the runners was even slightly less sun-sensitive than that of the others. Nonetheless, the runners showed markedly more sun damage and a higher rate of atypical moles. They were almost twice as likely to have a mole removal recommended to prevent progression to skin cancer.
Explanation: Why the difference? Sun exposure. Marathoners are outdoors for long stretches of time, training and racing, and they wear shorts and sleeveless shirts. They don't always wear sunscreen, and when they do, sweating may wash it away. In addition, sweating increases sensitivity to sun because moisture in the skin's outer layer increases absorption of damaging ultraviolet light. The authors also speculate that the intense exercise of the ultra-marathon may weaken the body's immune response and thus decrease the natural defense mechanism against cancer. But I am skeptical of this explanation since the evidence doesn't seem strong.
Conclusion: The bottom line for all of us? Marathoner or not, respect the sun and its capacity to do harm. Use clothing and sunscreen to protect your skin, and reapply sunscreen every few hours—even without intense sweating, its effectiveness wears off with time. One other thing: 40 percent of the malignant melanomas in the original eight patients began to grow in moles the patients had since birth. Pediatricians have learned to pay especially close attention to these congenital moles, often referring them early for possible removal.
Anemia in the Third World—another unwelcome cause
Problem: About 8 percent of American children are anemic. Kids here with this condition tend not to learn well (though other factors may play a role), and doctors and teachers have long recognized the great benefit in correcting the condition. However, in the developing world, the prevalence of anemia is much higher, affecting as many as three out of four people, and the consequences are far more severe.
Causes: Third World anemia has several well-known causes: malaria, which causes red blood cells to break down; hookworm, which causes chronic blood loss in the bowel; lack of access to meat, the most efficient form of dietary iron; and loss of significant amounts of blood in childbirth. And now another cause has come to light: Fifth Disease. This common viral malady generally causes trivial illness in the United States. But it temporarily turns off the production of red blood cells, and this effect endangers fetuses early in pregnancy and people whose red cell status is already marginal, including markedly anemic children, people with malaria, and people with sickle cell disease. A recent study of children in Papua New Guinea by a team headed by James Wildig and Yvonne Cossart of the University of Sydney found that Fifth Disease plays a significant role in severe anemia in this region.
Effects: In the developing world, the effects of anemia extend beyond weakness, easy exhaustion, and interference with concentration. Worse, because severe anemia is often treated with blood transfusions, anemic people (and especially women) are at risk of HIV in the developing world, where transfusion now accounts for 5 percent of HIV/AIDS transmission.
Prevention: What can be done to prevent anemia? A $1 tablet given to women after giving birth cuts postpartum hemorrhage rates by 50 percent to 80 percent. A $3.50 bed net treated with insecticide significantly decreases malaria transmission. It costs $10 per person per year to construct latrines, which cut the rate of hookworm infection. Peter Hotez and his colleagues at George Washington University and the Sabin Vaccine Institute have been pioneers at developing even more cost-effective treatments for hookworm. These include deworming medications that cost less than $1 per person per year (in part because of donations by pharmaceutical firms). And the most exciting possibility: They are developing a vaccine that would provide lasting protection against the hookworm parasite. Because the long-term consequences of anemia are so costly, the economic return for each of these initiatives will surely be great.
* Correction, Dec. 5, 2006: Due to an editing error, this sentence originally called RU-486 the morning-after pill. Though RU-486 at a low dose has been used for that purpose, the "morning-after pill" usually refers to birth-control pills taken in high doses after unprotected sex. Here's more. Click here to return to the corrected sentence.