TIME EUROPE
January 15, 2000, Vol. 157 No. 2
The Hunt for Cures
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When leptin enters the brain, it follows numerous pathways, some of them manipulating appetite stimulators, some appetite suppressors. In one route, the leptin triggers the release of a large protein known as pomc, which is broken down into individual peptides by an enzyme dubbed pc1. One of these peptides, known as msh, in turn binds to a receptor known as mc4. This receptor helps put the brakes on appetite. To most people, this is little more than neurochemical gibberish, except that researchers are now discovering that there are genes controlling the production of all these proteins and that damaging any one of them can derail the entire process. "Problems in all of these steps can be associated with specific gene lesions in humans," says O'Rahilly.
The simple answer would seem to be genetic engineering — repair what's wrong with the bum genes, and appetite should fall into line. But genetic engineering is anything but simple. Instead, drug companies are turning to genetic diagnosis. If doctors could screen the genes of obese people to see which ones were on the fritz, they could prescribe drugs that would pick up the slack — elevating pc1 levels, say, or stimulating an understimulated mc4 receptor. Says molecular biologist Joe Grippo of Roche pharmaceuticals: "We are working to mimic the brain's natural appetite-suppressing substances and block out appetite stimulators."
For now, no one knows how successful these strategies will be. The further science travels along the leptin trail, the more genetic stops it will find — and the more therapies these will suggest. What is clear is that obesity is a fantastically complicated condition, with a fantastic number of spots for science to step in and set things right. "What recent research has done," says O'Rahilly, "is take obesity out of the realm of sociology and put it in the realm of biology." For many obese people, that is a welcome start.
Alzheimer's Disease
New Insights into Its Cause Lead to New Drug Strategies
By J. MADELEINE NASH
For two solid years, Dr. Perry Molinoff and his colleagues methodically tinkered with a couple of molecules they had identified the old-fashioned way — by testing tens of thousands of compounds on cultures of growing cells. Among other things, they adjusted certain structural features to reduce the chance that the molecules would cause gastric distress and to increase the likelihood that they would cross over the blood-brain barrier. And all the while, they checked and rechecked to make sure that during this biochemical shuffling they did not lose the key property that made these particular molecules potentially so valuable: their ability to block the activity of gamma secretase, an enzyme thought to play a critical role in the development of Alzheimer's disease.
Out of more than 100,000 candidates in the initial screen, says Molinoff, head of neuroscience drug discovery at Bristol-Myers Squibb, only two were deemed promising enough to continue working on. That was in 1996. Now, thanks to the efforts of nearly 40 scientists — some at Bristol-Myers' Wallingford, Conn., research institute, others at SIBIA Neurosciences, based in La Jolla, Calif. — the number of compounds derived from these two templates has expanded to more than a thousand.
Last year one of these highly refined derivatives became the first so-called secretase inhibitor to enter clinical trials with Alzheimer's patients, and others seem sure to follow. In fact, not just Bristol-Myers Squibb but also Amgen, Elan Pharmaceuticals, Eli Lilly, Merck and SmithKline Beecham are racing to develop similar compounds. The reason? Over the past five years, an explosion of insights into the genetics of Alzheimer's has bolstered confidence that gamma secretase and a related enzyme called beta secretase are not innocent bystanders but rather are intimately involved in the disease process.
The rapidity with which this new class of drugs has emerged is nothing short of stunning. Of course, until the clinical trials now under way render a verdict, no one knows whether any of these novel compounds will turn into a pharmaceutical Cinderella, but at least the possibility is there. "Compared with what (Alzheimer's researchers) had coming down the pipeline a couple of years ago, it's night and day," says Dale Schenk, vice president of neurobiology at Elan Pharmaceuticals in South San Francisco. "Finally we have moved out of the laboratory and into the clinic."
Alzheimer's disease, many experts are all but convinced, starts with the abnormal buildup of a protein known as beta amyloid. The chief constituent of the scarlike plaques found in the brain of Alzheimer's patients, beta amyloid is made by nerve cells when beta and gamma secretase execute a one-two snip that cuts a larger precursor protein into a shorter fragment. Sometimes the fragment is 40 units long, sometimes 42. The slightly longer variant, scientists have found, is directly toxic to nerve cells. Among other things, it appears to stimulate the release of oxygen free radicals, thereby setting off in the brain a destructive biochemical cascade.
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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
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