TIME EUROPE
January 15, 2000, Vol. 157 No. 2
The Hunt for Cures
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Gamma secretase emerged as an attractive target shortly after 1995, when scientists working with DNA donated by families prone to early-onset Alzheimer's disease finally succeeded in cloning two genes known as presenilin 1 and presenilin 2. In a series of experiments, researchers established that these genes exercised tight control over the activity of gamma secretase. They found that the particular mutations in the Alzheimer's-prone families not only increased the rate at which gamma secretase produces beta amyloid but also enhanced its penchant for making the more toxic version.
Beta secretase, the gene for which was cloned only in 1999, also provides drug designers with a target. Inside nerve cells it competes with a third enzyme known as alpha secretase, whose activity, some think, may help protect the brain against Alzheimer's disease. When alpha makes the first cut in the precursor protein, gamma secretase makes a second cut that produces not beta amyloid but an innocuous protein fragment known as p3. Elan and Pharmacia, based in Peapack, N.J., among others, are actively working to develop beta secretase inhibitors.
Logically it would seem that compounds that block the activity of either beta or gamma secretase should slow the progression of Alzheimer's disease. But there are reasons to remain cautious. For one thing, it may turn out that both these secretases play vital roles in other aspects of cellular metabolism, so that interfering with them will come at the price of serious side effects. For another, it is still far from proven that beta amyloid is as central to Alzheimer's disease as, say, cholesterol is to heart disease. Says molecular neurologist Dr. Peter St. George-Hyslop of the University of Toronto: "We have a theory and experimental data that support that theory, but we won't know the theory is right until we have a drug that actually prevents Alzheimer's disease."
A suggestion that drug designers might be on the right track comes from studies of mice that have been genetically engineered to develop Alzheimer's-like plaques. These mice exhibit at least some symptoms of memory loss, performing less well on tests that measure how long it takes them to get back to the one dry platform researchers have positioned out of sight in a watery maze. There are now strong hints that retarding the development of plaques helps preserve intellectual performance, at least in rodents. And that raises an intriguing question: Might getting rid of plaques once they have developed do more than slow a patient's decline?
"I used to think plaques were like bits of concrete scattered throughout the brain," says Bristol-Myers' Molinoff. "But there's now intriguing evidence that suggests you can get plaque regression." Some of the most striking evidence comes from studies of a vaccine against beta amyloid that Schenk and his co-workers at Elan have developed. In 1999 they administered their vaccine to mice whose brains were filled with plaques. A short time later, the plaques shrank. Currently the Elan vaccine, like the Bristol-Myers' secretase inhibitor, is in early-phase clinical trials, in which the primary objective is to test for safety as opposed to effectiveness.
At present, the likelihood that this particular vaccine or this particular secretase inhibitor will end up in the therapeutic arsenal has to be considered slim. Of all the compounds his team brings forward, says Molinoff, only 10% to 15% manage to pass the rigorous series of tests that lead to approval by the U.S. Food and Drug Administration. And even when they do, Harvard University neurologist Dr. Kenneth Kosik emphasizes, precious few new drugs prove to be anything close to magic bullets. Indeed, Kosik, along with many others, thinks it is quite likely that controlling Alzheimer's disease will require more than one type of drug. In addition to compounds that inhibit plaques, for example, patients may need drugs that prevent the formation of tangles that disrupt nerve cells from within.
For this reason, people whose advancing years place them at high risk for Alzheimer's disease would be wise to place their hopes not in any particular treatment strategy but in the broad range of options that the genetic toolbox is so rapidly opening up. Right now, it is encouraging to note, researchers are homing in on at least three more genes involved in Alzheimer's, each potentially a fat new target for drug developers.
Heart Disease
Rethinking Treatments For the Heart
By CHRISTINE GORMAN
For decades surgery seemed to be the best bet for the treatment of heart disease. Researchers thought of atherosclerosis, or the clogging of arteries with fatty plaques, as basically a plumbing problem. Bypass the choke points with new grafts and you would more than likely bypass any future heart attacks. Over the past five to 10 years, however, doctors have come to realize that heart disease is more complicated than that. They're not by any means ready to abandon surgery, but now they rely more heavily on different types of drugs to treat both the long-term and short-term effects of heart disease.
Drugs will play an even greater role in the near future, says Dr. Valentin Fuster, director of the Cardiovascular Institute at Mt. Sinai School of Medicine in New York City. For one thing, the wealth of data coming out of the human-genome project will allow physicians to tailor pharmaceutical treatments to an individual's specific genetic profile in ways that have never before been possible. For another, men and women at risk of developing heart disease are being identified at earlier and earlier stages of their condition, a situation in which drug therapy presents fewer risks than surgery.
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COVER STORY
Special Report: The Future of Medicine
With the mapping of the human genome the process by which new drugs are developed is being turned upside down. These drugs will also change our lives
Brave New Pharmacy
Using high-speed robots and the secrets of the human genome, scientists are changing forever the way they discover new medicine
The Hunt for Cures
Genetic information could lead to treatments for everything from AIDS to obesity
EUROPE
Prague Winter
When Jiri Hodac was named director of state television, Czech journalists saw a return to government meddling in the media
See Vous in Court
France is the latest nation to join the litigation game
Going up in Smoke
Switzerland, land of luxury watches and bank secrecy, has a new growth industry: marijuana
UNITED STATES
The True Blue Bush Cabinet
Its ethnic and gender balance is correct, but can a divided nation deal with the superconservative bent?
BUSINESS
Transparency has its Price
Executives at many German companies are finding it hard to adjust to the more rigorous financial disclosure required by global investors
On Spreading the Word
When it comes to selling merchandise, word-of-mouth marketing may be a company's best weapon
Essay: Meat Matters
Critics of industrialized farming may be forgetting about world hunger, writes TIME's Rod Usher
THE ARTS
Rebel with a Cause
The real-lifestory of an anti-Mafia activist in Sicily makes for a handsome film with a political message
The Upmarketeer's Tale
Bernard Arnault built his house by selling at deluxe prices and in his book he's still giving nothing away
The Art of Noise
For Europe's freely improvised music, the only rule is no rule
DEPARTMENTS
Techwatch
World Watch
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