For the discovery of the superfamily of nuclear hormone receptors and elucidation of a unifying mechanism that regulates embryonic development and diverse metabolic pathways.
The 2004 Albert Lasker Award for Basic Medical Research honors three scientists who opened up the field of nuclear hormone receptor research. Their work elucidated the unexpected common mechanism by which a diverse group of signaling molecules – steroid hormones, thyroid hormone, and fat-soluble molecules such as Vitamin A and D — regulate a plethora of physiological pathways that operate from embryonic growth through adulthood.
A new model for hormone action
Hormones control a vast array of biological processes, including embryonic development, growth rate, and body weight. Scientists had known since the early 1900s that tiny hormone doses dramatically alter physiology, but they had no idea that these signaling molecules did so by prodding genes. The 1950s, when Elwood Jensen began his work, was the great era of enzymology. Conventional wisdom held that estradiol — the female sex hormone that instigates growth of immature reproductive tissue such as the uterus — entered the cell and underwent a series of chemical reactions that produced a particular compound as a byproduct. This compound — NADPH — is essential for many enzymes' operations, but its small quantities normally limit their productivity. A spike in NADPH concentrations would stimulate growth or other activities by unleashing the enzymes, the reasoning went.
In 1956, Jensen (at the University of Chicago) decided to scrutinize what happened to estradiol within its target tissues, but he had a problem: The hormone is physiologically active in minute quantities, so he needed an extremely sensitive way to track it. He devised an apparatus that tagged it with tritium — a radioactive form of hydrogen — at an efficiency level that had not previously been achieved. This innovation allowed him to detect a trillionth of a gram of estradiol.
When he injected this radioactive substance into immature rats, he noticed that most tissues — skeletal muscle, kidneys and liver, for example — started expelling it within 15 minutes. In contrast, tissues known to respond to the hormone — those of the reproductive tract — held onto it tightly. Furthermore, the hormone showed up in the nuclei of cells, where genes reside. Something there was apparently grabbing the estradiol.
Jensen subsequently showed that his radioactive hormone remained chemically unchanged once inside the cell. Estrogen did not act by being metabolized and producing NADPH, but presumably by performing some job in the nucleus. Subsequent work by Jensen and Jack Gorski established that estradiol converts a protein in the cytoplasm, its receptor, into a form that can migrate to the nucleus, embrace DNA, and turn on specific genes.
From 1962 to 1980, molecular endocrinologists built on Jensen's work to discover the receptors for the other major steroid hormones — testosterone, progesterone, glucocorticoids, aldosterone, and the steroid-like vitamin D. In addition to Jensen and Gorski, many scientists — notably Bert O'Malley, Jan-Ake Gustafsson, Keith Yamamoto, and the late Gordon Tompkins — made crucial observations during the early days of steroid receptor research.
Clinical applications of estrogen-receptor detection
Clinicians knew that removing the ovaries or adrenal glands of women with breast cancer would stop tumor growth in one out of three patients, but the molecular basis for this phenomenon was mysterious. Jensen showed that breast cancers with low estrogen-receptor content do not respond to surgical treatment. Receptor status could therefore indicate who would benefit from the procedure and who should skip an unnecessary operation. In the mid-1970s, Jensen and his colleague Craig Jordan found that women with cancers that contain large amounts of estrogen receptor are also likely to benefit from tamoxifen, an anti-estrogen compound that mimics the effect of removing the ovaries or adrenal glands. The other patients — those with small numbers of receptors — could immediately move on to chemotherapy that might combat their disease rather than waiting months to find out that the tumors were growing despite tamoxifen treatment. By 1980, Jensen's test had become a standard part of care for breast cancer patients.
In the meantime, Jensen set about generating antibodies that bound the receptor — a tool that provided a more reliable way to measure receptor quantities in excised breast tumor specimens. His work has transformed the treatment of breast cancer patients and saves or prolongs more than 100,000 lives annually.
By the early 1980s, interest in molecular endocrinology had shifted toward the rapidly developing area of gene control. Pierre Chambon and Ronald Evans had long wondered how genes turn on and off, and recognized nuclear hormone signaling as the best system for studying regulated gene transcription. They wanted to know exactly how nuclear receptors provoke RNA production in response to steroid hormones. To manipulate and analyze the receptors, they would need to isolate the genes for them.
By late 1985 and early 1986, Evans (at the Salk Institute in La Jolla) and Chambon (at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France) had pieced together the glucocorticoid and estrogen receptor genes, respectively. They noticed that the sequences resembled that of v-erbA, a miscreant viral protein that fosters uncontrolled cell growth. This observation raised the possibility that v-erbA and its well-behaved cellular counterpart, c-erbA, would also bind DNA and control gene activity in response to some chemical activator, or ligand. In 1986, Evans and Björn Vennström simultaneously reported that c-erbA was a thyroid hormone receptor that was related to the steroid hormone receptors, thus uniting the fields of thyroid and steroid biology.
Award presentation by Michael Brown
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 US 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 receptors — or as George Bush would say, nucular receptors.