TIME EUROPE
January 15, 2000, Vol. 157 No. 2
Brave New Pharmacy
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Sifting through the human genome for therapeutically useful gems, though, requires a well-designed search strategy combined with powerful technology. At Millennium, housed in a factory that once stamped out heart-shaped candy boxes for Valentine's Day, that strategy is embodied in Zeus, whose job is to find the handful of genes among the genome's tens of thousands that are key to individual diseases — and thus key to making effective medications.
To make this search as easy as possible, Millennium chief scientific officer Dr. Robert Tepper has chosen to focus on the low-hanging fruit — going first for the most obvious targets. In looking for anticancer drugs, for example, his researchers are concentrating on monoclonal antibodies, a type of biological "smart bomb" that targets cancer cells and leaves normal cells alone. Like all antibodies, these man-made cancer missiles seek out particular receptors — molecules on the cancer cell's surface that help the cell recognize and react to nearby enzymes and proteins. Almost a dozen such drugs are already on the market, including one called Herceptin. It zeroes in on the HER-2/neu receptor that sits on the surface of some breast-cancer cells, blocking the binding of growth factors. For the 30% of tumors involving the receptor, the drug may be helpful.
But Tepper's group wants to go a step further, identifying the one or two or three receptors common to all the major cancers — breast, prostate, lung and colon — and thus create a one-stop superdrug. Before the genome was available, this would have been almost impossible. Now Millennium scientists can take known genetic fragments of cancer-cell receptors and plug them into the genome database posted on the National Institutes of Health's GenBank website, searching for sequences in the genome that match and eventually getting to the genes that regulate cell-surface receptors. Almost immediately, they were able to discard as irrelevant some 23,000 of the genome's 30,000 or so genes.
Subsequently the researchers at Millennium had only 7,000 genes to sift through for those specifically active in cancer cells. For that they needed to compare the gene sequences with living cancer cells. That's where Zeus came in: after its custom-made microarrays had marinated for 18 hours in the genetic stew from human tissue cells, technicians scanned them to see which bits of DNA lighted up the brightest with radioactive dye. By comparing the cancer-covered arrays with those immersed with normal cells, the scientists could see which receptors were active in all the cancers yet inactive in normal cells — in this case, just 200 of the original 7,000. "These are experiments that we could only dream of but could never do before the genome," says Tepper.
But they still had too many targets for drug designers to deal with. To narrow the possibilities further, Millennium scientists took breast-cancer cells from two dozen patients and ran additional array screenings to get a better idea of how prevalent a particular receptor was on breast-cancer cells in the population at large. Then they focused on the most widespread and active among them. That brought the hundreds of choices down to just a few dozen, among which are a handful that are expressed in more than 80% of patients.
In just three months, Millennium had finished a winnowing process that would once have taken five or 10 years. Says Tepper: "Drug discovery could never be done this way before. You wouldn't know that a drug was effective or potentially effective in a given percentage of your patient population until very late in clinical development."
Once genomics has identified a potential target protein on cancer cells, scientists still have to find or create a compound — the monoclonal antibody — to lock onto that target and block its normal activity, or at least stick a red flag on it to make it vulnerable to destruction by the body's immune system. At this point, Millennium's process finally begins to look like the "wet lab" that drug companies have relied on for decades. To come up with a monoclonal antibody to fight cancer, Tepper's group uses a strain of mice whose immune systems are genetically engineered to generate human antibodies. Choosing whichever receptor protein Zeus has found for them, the scientists inject the mice with it, then extract the antibodies the animals create to fight the invader.
The antibodies then go through testing to make sure they will bind to cancer cells with the designated receptor, that they can be absorbed by the body and that they won't have toxic side effects. Some of these studies can be done in the lab, but they quickly move into animal and finally human subjects. Already, Millennium has 40 potential targets for monoclonal-antibody drugs against various cancers, and Tepper's goal is to generate 10 to 12 new ones each year.
Access to the genome has drastically improved the efficiency of another traditional drug-finding strategy — and again, Millennium's approach typifies what other firms are doing. Drug companies have often found new medicines by seeking compounds similar to ones they already know, and since most pharmacologically active compounds are based on proteins — that is, on chemicals manufactured naturally from genetic instructions — at least some of those genes should be hidden in the genome.
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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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