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. MORE>>
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January 15, 2001
| No. 2
COVER
STORIES
MEDICINE:
The Future of Drugs
Now that our dna has been decoded, the search for better, faster and more
effective medications begins in earnest
THE
LABS: Inside the Brave New Pharmacy
At a leading genomics company, the star of the show is a robot
DISEASES:
The Search for Cures
For AIDS, cancer, mental illness, obesity, Alzheimer's, etc.
Antibiotics:
The microbes are winning
Delivery:
Beyond pills and needles
Natural remedies:
Turning poisons into potions
Recreational
drugs: What comes after K and ecstasy?
THE
YEAR IN MEDICINE: An A-to-Z guide
T
H E A R T S
CINEMA:
East meets West
in a film with universal appeal
Robert de Niro and Ben Stiller team up in a funny
farce
Three generations of Ralph Fiennes in Sunshine
MUSIC:
Erykah Badu's new CD has soul and guts
TRAVELER'S
ADVISORY
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