plastic model John McLachlan holds in his hand looks like a mass
of colored bubble-gum balls. It is the size and general shape of
a small loaf of Italian bread.
than two decades after he first embarked on his exploration of DES,
McLachlan is sitting on the edge of a table in his office at the
National Institute of Environmental Health Sciences, giving a lesson
in chemical messengers 101-the basics on how the body communicates
through hormones. Like many natural teachers, he has a theatrical
flair and a penchant for metaphor. He reaches automatically for
a prop to demonstrate his point. This isn't simply science, it is
a fascinating story-the tale of the estrogen receptor, which consorts
so readily with foreigners that it has earned a reputation. Some
scientists call it "promiscuous."
plastic model is a gargantuan representation of estradiol, one of
the three principal types of estrogen manufactured by the ovaries
and dispersed into the bloodstream.
a 50-year-old man with a head of curly gray locks and merry dark
eyes that gleam like onyx, then cups his free hand. This is an estrogen
receptor, a special protein found inside cells in many parts of
the body, including the uterus, the breasts, the brain, and the
liver. The receptor receives the chemical message, in this case
estrogen, sent from the ovaries, picking up signals from the bloodstream
in the same way a cellular phone picks up radio signals in the air.
A receptor isn't supposed to receive all the chemical signals flying
about. Like a cellular phone, it is supposed to receive only those
intended for it.
body has hundreds of different kinds of receptors, each one designed
for a particular kind of chemical signal. Some receive messages
from the thyroid gland, which may cue cells to consume more oxygen
and generate more heat. Others are tuned to the adrenal glands,
which send messages that regulate blood pressure and the body's
response to stress. The hypothalamus in the brain has all kinds
of receptors to monitor hormone levels in the blood so the brain
can signal the hormone-producing glands when adjustments are needed.
And there is a whole class of mystery receptors, known as "orphan"
receptors, that are tuned to messages that scientists have not yet
hormone and its particular receptor have a "made for each other"
attraction, which scientists describe as a "high affinity."
When they encounter one another, they grab hold, engaging in a molecular
embrace known as "binding."
demonstrates by moving the plastic model through the air toward
the receptor, showing how the estradiol docks in the pocket of the
receptor like a Star Trek vehicle returning to the much larger mother
ship. Hormone molecules are tiny compared to the sprawling receptors.
fit together, he notes, like a lock and key, and, once joined, they
move into the cell's nucleus to "turn on" the biological
activity associated with the hormone. This union of hormone and
receptor targets genes that trigger the production of particular
proteins. In the case of estrogen, these proteins accelerate cell
division. So when estrogen joins with receptors in the uterus, it
will cause the lining of that organ to thicken. Estrogen produces
such a response in the first half of the menstrual cycle to prepare
the uterus in the event an egg is fertilized when ovulation occurs
lock-and-key notion has dominated the theory of how the body communicates
through hormones. In endocrinology textbooks, one still finds flat
assertions that receptors are highly discriminating about chemical
structure and will bind only to their intended hormone or a very
closely related compound. Although theory holds true in a general
way, reality is proving considerably messier and unpredictable,
not only in the case of the estrogen receptor but with other hormone
receptors as well.