Basic Medical Research Award
This year's Lasker Basic Research Award honors three brilliant scientists who taught us how cells communicate. To understand their work, we must first appreciate that our bodies are composed of 10 trillion cells. That's 1 with 13 zeroes. If each cell operated as an individual, our bodies would be as chaotic as the U.S. Senate. Fortunately, cells are not senators. They are like musicians playing in a well-conducted orchestra. Each cell has a special task that it performs only when instructed by another cell. How do cells receive these instructions? How do they interpret the instructions so as to perform the right task? The answer was discovered by our three honorees. It is a family of proteins called nuclear receptorsor as George Bush would say, nucular receptors.
Nuclear receptors are so named because they function in the nucleus of cells where our genes reside. The receptors lie in wait for a signal molecule that is sent by another cell. The signal molecule enters the receiving cell, and it is caught by the nuclear receptor, like a first baseman catching a ball thrown by the shortstop. After the catch, the receptor changes its shape, and it attaches to certain prespecified genes, turning these genes on or off. This on-off pattern dictates the cell's behavior. Some genes make cells divide; others make them stop dividing. Some genes make cells migrate to new locations or switch their identity to become another cell. Some genes cause a cell to increase its metabolism or its production of proteins. Others turn the process off.
To understand the beauty and complexity of this system, I'd like to tell you a bedtime story. This is appropriate because some of you are falling asleep already. The story is called the story of youI mean Y-O-U.
Nine months before you were born, your mother made an egg. She made one every month, usually to no avail, but this month was special. This egg was fertilized, and the result was you. You began life as a single cella tiny fertilized egg tumbling down a fallopian tube. With a thump you landed in the uterus. With remarkable foresight, the uterus had recently grown a thick and lush lining, just waiting for your arrival. You buried yourself in this lining and began the process of cell division that eventually formed you. What made the uterine lining grow so lush? How did the uterus know in advance that you were about to arrive? The uterus responded to a signal, a hormone called estrogen secreted by your mother's ovary. The estrogen entered the cells of the uterus where it reported that the ovary had just made an egg, and the uterus should be ready for your arrivaljust in case the egg was fertilized. In response to this estrogen signal, the lining cells of the uterus multiplied to prepare a thick carpet in which you could take root and grow. How did the uterus translate the information from the estrogen? The answer is nuclear receptors. The estrogen entered the cell, bound to a nuclear receptor and turned on all of the genes necessary to make the cells proliferate.
After you embedded yourself in the uterus, your single cell began to divide over and over again. Within nine months your single cell had become 500 billion cells, each with a special task. Some cells became heart cells, brain cells, skin cells, kidney cells, and so on. All of this cell development was orchestrated by nuclear receptors. Let me give an example that applies to half of youthe ones with a Y chromosome. Your Y chromosome instructed some of your cells to form a testis, and the testis sent out a signaling molecule called testosterone. The testosterone traveled to other cells and instructed them to form a uniquely male organ that projected from your body. Nowadays, even before you are born, this organ will be photographed by an ultrasound camera and your parents will rush out and paint your room blue. How did your cells receive the message from testosterone? The answer? Nuclear receptors.
At the time of birth, your brain was not fully developed. That's why it took a year for you to say "da da." During this year, your brain enlarged in response to a signal sent out by the thyroid gland. Without this thyroid hormone you would have been severely retardedwe call this condition cretinism. How did the thyroid hormone make your brain develop? The answer? You got itnuclear receptors.
But your nuclear receptors didn't only function early in lifethey are still working. They are responsible for the organs of pleasure that grow in boys and girls during puberty, and they are responsible for the excess growth of those organs in old ageI refer to cancer of the breast and prostate. Fortunately, when nuclear receptors cause cancer we can abolish their signal by removing the hormone that activates them. That's why women with breast cancer have their ovaries removed, and why men with prostate cancer have their testicles removed. This radical surgery isn't always necessary now because there are drugs like tamoxifen that fool the receptors and silence them even when the hormone is still present.
Throughout your life nuclear receptors have controlled your metabolism. Your thyroid receptor dictates how efficiently you convert food into energyif you had too little thyroid hormone your metabolism would become sluggish and you would get fat. Other nuclear receptors called glucocorticoid receptors increase your ability to mobilize your energy stores in response to stressful conditions like infections. And nuclear receptors called PPARs dictate how much adipose tissue you have, and how actively your body burns fat.
Nuclear receptors don't only respond to molecules made by other cells. They also respond to vitamins in our diets. For example, vitamin D causes your bones to become strong, and it works through nuclear receptors in bone-forming cells. Most surprising was the discovery that vitamin A works through nuclear receptors. Scientists had known that vitamin A is essential for embryonic development, but they had no idea how the vitamin worked until our honorees discovered a nuclear receptor for vitamin A.
Scientists got another surprise when they learned that nature uses nuclear receptors to defend against toxic chemicals that we ingest. These chemicals travel to our liver where they attach to nuclear receptors. The receptors activate genes that produce enzymes that convert the chemicals to nontoxic metabolites that are excreted from the body.
So far, 48 different nuclear receptors have been found in the human body. For many of these we have not yet found the signaling molecule. We call these orphan nuclear receptors. Just imagine the great strides in medicine when the correct signaling molecules are discovered.
Our knowledge of nuclear receptors can be traced directly to the work of the three men we honor todayElwood Jensen, Ronald Evans, and Pierre Chambon. I don't have time to tell you how these scientists designed the ingenious experiments that teased out the nuclear receptors from nature's box of secrets. Their work is described in detail in the brochures at your tables. Suffice it to say that the field was initiated by the biochemical studies of Elwood Jensen in Chicago in the late 1950s, way before the era of molecular biologyand it was exploded in the 1980s by the molecular studies of Ronald Evans in La Jolla and Pierre Chambon in Strasbourg. Of course, these three did not do everything. They were aided by talented students in their own laboratories and by scientific contributions from other laboratories throughout the world. Given the ubiquity of nuclear receptors, the field has attracted huge numbers of scientists. But the atomic energy that triggered the chain reaction of nuclear receptors started with the nuclear family of Jensen, Chambon, and Evans. We are honored to honor them today.