Harrison, I haven't had a chance to get the New Yorker article yet. However, LLY has anti-estrogens (Raloxifene) front and center and the article below was in the Dallas Paper. However, I found it through a search of the San Diego Union, so the story is probably syndicated through Knight-Ridder and may pop up fairly frequently in other locations. You don't have to read between the lines to find Ligand, and LGND has extensive orphan receptor programs, including LXR.
Scientists on treasure hunt for new hormones
Sue Goetinck
THE DALLAS MORNING NEWS
04-Jun-1997 Wednesday
Welcome to "What's My Hormone."
It's not a combination of "What's My Line" and "The Dating Game." But it is
a game that scientists are playing in hopes of discovering 15 or so
still-unknown hormones that researchers suspect are lurking inside the
body.
"It's like a treasure hunt," said David Mangelsdorf, a molecular biologist
at the University of Texas Southwestern Medical Center at Dallas.
The hormones that Mangelsdorf, as well as scientists at other institutions,
are hunting for are called steroid hormones -- chemical cousins to
well-known molecules such as estrogen and testosterone. Since those
familiar hormones are crucial for keeping the body running smoothly,
researchers believe the unknown steroids will be important, too.
And because many widely used drugs -- such as birth control pills and some
antidiabetic medications -- are similar to natural hormones, scientists are
betting that discovery of the mystery hormones will lead to the development
of valuable drugs.
"I think there are a lot of potential applications down the road," said
Keith Parker, an endocrinologist with the Howard Hughes Medical Institute
and Duke University Medical Center in Durham, N.C.
Although the hormones themselves are still a mystery, scientists do have a
few clues to go on. First, the hormones' chemical properties are almost
certainly similar to those of other steroids, a fact that narrows down the
hormone hunt. Second, researchers already know the hormones' targets in the
body.
All hormones influence the body by sticking to molecules called receptors.
In the case of steroids, the receptors are inside cells. If a molecule of
estrogen, for instance, floats into a cell that contains an estrogen
receptor, hormone-receptor pairs can activate genes, changing the
properties of the cell.
When researchers began studying steroid receptors, they noticed that
receptors for different hormones -- such as testosterone, estrogen and
progesterone -- were very similar to one another. And once a few of the
receptors had been discovered, it was easy to find more. At present,
Mangelsdorf said, there are more than 70 versions of such receptors known
in the animal kingdom.
Hormones have yet to be discovered for 17 of the steroid receptors that can
be found in people, said Mangelsdorf. Since the receptors don't have a
known hormone, they're referred to as orphan receptors. Scientists hope to
get as many of the receptors "adopted" as possible.
Last fall, Mangelsdorf reported in the journal Nature the discovery of the
hormones for a receptor called LXR-alpha. Using laboratory tricks to
imitate what happens in the body, the scientists were able to identify
three molecules that can coax the receptor into activating genes.
"Mother Nature has defined this system," Mangelsdorf said. "And we say,
`Mom, you did a good job and we're going to do the same thing.' "
To find the molecules, the researchers took advantage of the fact that
hormones fit into receptors like keys fit into locks. Using genetic
engineering techniques, the scientists generated cells that contained the
LXR-alpha "lock" and a gene that could be activated by LXR-alpha.
If the receptor is the lock, the gene can be thought of as a door -- one
that can only be activated, or opened, if the right hormone "key" is used.
Then the researchers set out to find the right key. They added different
chemical compounds to the cells and watched to see which ones would
activate the gene. The gene was the one that fireflies use to glow. So when
the scientists saw the cells glowing, they knew they had found the right
hormone keys.
Once the keys were found, Mangelsdorf said, the researchers realized that
the LXR-alpha molecule might be involved in controlling cholesterol levels
in the body. The three keys turned out to be molecules produced when too
much cholesterol builds up in the body.
One possibility, Mangelsdorf said, is that the molecules function as
hormones that sense when cholesterol levels get too high, and then trigger
genes that will lead to cholesterol breakdown. If that's the case, a drug
that activates the LXR-alpha molecules might reduce the amount of
cholesterol in the body, Mangelsdorf said.
Receptors like LXR-alpha are perfect targets for drugs, Mangelsdorf said.
Even though some of the receptors might not have naturally occurring
hormones, it still may be possible to design drugs that can influence them.
And since scientists know a lot about the chemical properties of the
hormones as a group, it's easy to manufacture similar compounds for
testing.
Recently San Diego and Houston researchers reported in Nature two lab-made
chemicals that can activate receptors involved in diabetes. The compounds
bind to a receptor, RXR, that was once considered an orphan. In some cells,
the RXR receptor works by pairing with another receptor called PPAR-gamma.
And antidiabetic drugs known as TZDs work by sticking to PPAR-gamma.
By combining one type of TZD with the new chemicals, the researchers, led
by molecular biologist Rich Heyman of Ligand Pharmaceuticals Inc. in San
Diego, were able to get diabetic mice to improve their blood sugar
profiles. The two chemical types together worked better than either did
alone.
"That's kind of neat because you can hit it with a double-whammy,"
Mangelsdorf said.
Heyman said the new compounds could potentially help people with diabetes.
"TZDs don't work in everybody," he said. "If you identify another class of
drugs that works, you might increase the number of patients that respond."
Ligand is starting to test the new compounds in people in Europe, Heyman
said, and could have preliminary results by the end of the year.
Researchers say that more study of orphan receptors is bound to tell
biologists more about how the body works. The body has a need for hormones
that can cause long-lasting changes, as estrogen and testosterone do. And
studying orphan receptors has so far been a good way to find them, Heyman
said.
"I think there are recurring themes here that the orphans will be
important," he said. |
