2004 Albert Lasker Basic Medical Research Award

Nuclear hormone receptors for regulating genes

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.

Long-lost relatives

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.

Chambon and Evans set to work deconstructing the glucocorticoid and estrogen receptors. By creating mutations at different spots and probing which activities the resulting proteins lost, they dissected the receptor into three domains: one bound hormone, one bound DNA, and one activated target genes. The structure of each domain strongly resembled the analogous one in the other receptor.

Chambon and Evans wanted to match other members of the growing receptor gene family with their chemical triggers. Because the DNA- and ligand-binding regions functioned independently, it was possible to hook the DNA-binding domain of, say, the glucocorticoid receptor to the ligand-binding domain of another receptor whose ligand was unknown. The ligand for that receptor would then activate a glucocorticoid-responsive test gene.

Evans would use this method to identify ligands for several novel members of the nuclear receptor family, and both he and Chambon exploited it to discover a physiologically crucial receptor. In the late 1970s, scientists had suggested that the physiologically active derivative of vitamin A, retinoic acid, could exert its effects by binding to a nuclear receptor. This nutrient is essential from fertilization through adulthood, and researchers were eager to understand its activities on a molecular level. During embryonic development, deficiency of retinoic acid impairs formation of most organs, and the compound can hinder cancer cell proliferation. So Chambon set out to find a receptor that responded to retinoic acid. He isolated a member of the nuclear receptor gene family whose production increased in breast cancer cells that slowed their growth upon exposure to the chemical. Simultaneously, Evans identified the same protein. He tested whether more than a dozen compounds activated an unknown receptor and one passed: retinoic acid.

Remarkably, in 1986, the two scientists had independently — and unbeknownst to each other — identified the same retinoic acid receptor, a molecule of tremendous significance. The discovery of this molecule provided an entry point for detailing vitamin A biology.

Rx for lonely receptors: RXR

The list of presumptive nuclear receptors was growing quickly as scientists realized that the common DNA sequences provided a handle with which to grab these molecules from the genome. Because their chemical activators weren't known, they were called 'orphan' receptors, and researchers were keen on 'adopting' them to ligands. Some of these ligands, they reasoned, would represent previously unknown classes of gene activators. The test system that Chambon and Evans used to match up retinoic acid with its receptor, in which they stitched an unknown ligand-binding domain to a DNA-binding domain for a receptor with known target sequences, could be harnessed to accomplish this task.

Evans had identified some potential nuclear receptors from fruit flies. He decided to pursue a human orphan receptor that closely resembled one of these receptor genes, reasoning that a protein that functioned in both flies and mammals was likely to perform an important job.

This receptor responded to retinoic acid in intact cells but did not bind it in the test tube, so Evans called it the retinoid X receptor (RXR), thinking that its ligand was some retinoic acid derivative. In cells, enzymes convert retinoic acid to metabolites and it seemed possible that one of these compounds was RXR's ligand. In 1992, Evans's group and one at Hoffmann-La Roche discovered that 9-cis-retinoic acid, a stereoisomer of retinoic acid, could activate RXR, identifying the first new receptor ligand in 25 years. This finding launched the orphan receptor field because it provided strong evidence that the strategy could unearth previously unknown ligands.

In the meantime, Chambon had found that the purified retinoic acid receptor, in contrast to the estrogen receptor, did not bind efficiently to its target DNA. Other nuclear receptors, too, needed help grasping genes. In the test tube, the retinoic acid, thyroid hormone, and vitamin D3 receptors could attach well to their target DNA only when supplemented with cellular material, which presumably contained some crucial substance. Chambon and Michael Rosenfeld independently purified a single protein that performed this feat, and it turned out to be none other than RXR. This ability of RXR to pair with other receptors — forming so-called heterodimers — would turn out to be key for switching on many orphan receptors. These heterodimeric couplings yield large numbers of distinct gene-controlling entities.

Chambon revealed the power of mixing and matching in these molecular duos through his thorough and extensive genetic manipulations in mice. He has shown that vitamin A exerts its wide-ranging effects on organ development in the embryo through the action of eight different forms of the retinoic acid receptor and six different forms of RXR, interacting with each other in a multitude of combinations.

Clinical applications of the superfamily work

The concept of RXR as a promiscuous heterodimeric partner for certain nuclear receptors led to the unexpected identification of a number of clinically relevant receptors. These proteins include the peroxisome proliferator-activated receptor (PPAR), which stimulates fat-cell maturation and sits at the center of Type 2 diabetes and a number of lipid-related disorders; the liver X receptors (LXRs) and bile acid receptor (FXR), which help manage cholesterol homeostasis; and the steroid and xenobiotic receptor (PXR), which turns on enzymes that dispose of chemicals that need to be detoxified, such as drugs.

Because the nuclear receptors wield such physiological power, they have provided excellent targets for disease treatment. The anti-diabetes compounds glitazones, for example, work by stimulating PPAR, and the clinically used lipid-lowering medications called fibrates work by binding a closely related receptor, PPAR. Retinoic acid therapy has dramatically altered the prognosis of people with acute promyelocytic leukemia by triggering specialization of the immature white blood cells that accumulate in these individuals. The three-dimensional structure of nuclear receptors with and without their ligands, which Chambon and his colleagues first solved, promises to accelerate drug discovery in the whole field.

Nuclear hormone receptors have touched on human health in other ways as well. Genetic perturbations in the genes for these proteins cause a variety of illnesses. For example, certain forms of rickets arise from mutations in the vitamin D receptor and several disorders of male sexual differentiation stem from defects in the androgen receptor.

The discoveries of Jensen, Chambon, and Evans revealed an unimagined superfamily of proteins. At the start of this work almost 50 years ago, no one would have anticipated that steroids, thyroid hormone, retinoids, vitamin D, fatty acids, bile acids, and many lipid-based drugs transmit their signal through similar pathways. Four dozen human nuclear receptors are now known, and scientists are working out the roles of these proteins in normal and aberrant physiology. These discoveries have revolutionized the fields of endocrinology and metabolism, and pointed toward new tactics for drug discovery.

by Evelyn Strauss

Key publications of Pierre Chambon

Green, S., Walter, P., Kumar, V., Krust, A., Bornert, J.M., Argos, P., and Chambon, P. (1986). Human oestrogen cDNA: sequence, expression, and homology to v-erb-A. Nature. 320, 134–139.

Petkovich, M., Brand N.J., Krust, A., and Chambon, P. (1987). A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 330, 444–450.

Green, S. and Chambon, P. (1987). Oestradiol induction of a glucocorticoid-responsive gene by a chimaeric receptor. Nature. 325, 75–79.

Leid, M., Kastner, P., Lyons, R., Nakshatri, H., Saunders, M., Zacharewski, T., Chen, J.Y., Staub, A., Garnier, J.M., Mader, S., and Chambon, P. (1992). Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 68, 377–395.

Bourguet, W., Ruff, M., Chambon P., Gronemeyer H., and Moras, D. (1995). Crystal structure of the ligand binding domain of the human receptor RXRD. Nature. 375, 377–382.

Chambon, P. (1996). A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954.

Key publications of Ronald Evans

Hollenberg, S., Weinberger, C., Ong, E.S., Cerelli, G., Thompson, E.B., Rosenfeld, M.G., and Evans, R.M. (1985). Primary structure and expression of a functional human glucocorticoid receptor of cDNA. Nature. 318, 635–641.

Giguere, V., Ong, E.S., Segui, P., and Evans, R.M. (1987). Identification of a receptor for the morphogen retinoic acid. Nature. 330, 624–629.

Mangelsdorf, D.J., Ong, E.S., Dyck, J.A., and Evans, R.M. (1990). Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 345, 224–229.

Kliewer, S.A., Umesono, K., , and Evans, R.M. (1992). Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone, and vitamin D3 signaling. Nature. 355, 446–449.

Heyman, R.A., Mangelsdorf, D.J., Dyck, J.A., Stein, R.B., Eichele, G., Evans, R.M., and Thaller, C. (1992). 9-cis Retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 68, 397–406.

Mangelsdorf, D.J. and Evans, R.M. (1995). The RXR heterodimers and orphan receptors. Cell. 83, 841–850.

Keypublications of Elwood Jensen

Jensen, E.V. and Jacobson, H.I. (1960). Fate of steroid estrogens in target tissues. In Biological Activities of Steroids in Relation to Cancer, G. Pincus and E.P. Vollmer, eds., Academic Press, New York, pp. 61–174.

Jensen, E.V. and Jacobson, H.I. (1962). Basic guides to the mechanism of estrogen action. Rec. Prog. of Hor. Res. 18: 387–414.

Jensen, E.V., Suzuki, T., Kawashima, T., Stumpf, W.E., Jungblut, P.W., and DeSombre, E.R.(1968). A two-step mechanism for the interaction of estradiol with rat uterus. Proc. Nat.l Acad. of Sci. USA. 95, 632–638.

Jensen, E.V. and DeSombre, E.R. (1973). Estrogen-receptor interaction: Estrogenic hormones effect transformation of specific receptor proteins to a biochemically functional form. Science. 182, 126–134.

Jensen, E.V., Block, G.E., Smith, S., and DeSombre, E.R. (1973). Hormonal dependency of breast cancer. Rec. Res. of Canc. Res. 42, 55–62.

Jensen, E.V., Greene, G.L., Closs, L.E., DeSombre, E.R., and Nadji, M. (1982). Receptors reconsidered: a 20-year perspective. Rec. Prog. of Hor. Res. 38, 1–34.

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.

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 you — I 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 cell — a 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 arrival — just 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 you — 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 retarded — we call this condition cretinism. How did the thyroid hormone make your brain develop? The answer? You got it — nuclear receptors.

But your nuclear receptors didn't only function early in life — they 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 age — I 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 energy — if 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 today — Elwood 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 biology — and 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.

Pierre Chambon

Acceptance remarks, 2004 Lasker Awards Ceremony

 

 

 

 

 

 

 

 

 

 

 

 

 

Nature Medicine Essay


In accepting the 2004 Lasker Award in Basic Medical Research, I wish to express my deep gratitude to the Albert and Mary Lasker Foundation and to its chairman (Mr. James W. Fordyce) and president (Dr. Neen Hunt) for this prestigious award and the recognition that it conveys.

I am particularly happy and thankful to the Albert Lasker Medical Awards Jury and to Dr. Joe Goldstein, its chairman, because this year's Award that I share with Elwood Jensen and Ron Evans nicely illustrates how science can contribute to forge friendships in an atmosphere of fruitful competition.

It is a great honor and privilege to be a recipient of this Award, in a country which has given such a high priority to the development of higher education, science and medicine. I accept it as the representative of the many members of my laboratory, who have worked and collaborated with me over the last 40 years. Our achievements are the fruit of their enthusiasm and devotion to science.

I have attempted, throughout my scientific life, to address basic problems related to the control of expression of genetic information in animals, notably in mammals, that have to be solved in order to advance our understanding of pathological disorders. The work of my laboratory has contributed to the so-called 'Genetic Revolution' which, over the last 30 years, has drastically changed our ideas on the structural organization, expression, and evolution of the genetic material. What is the organization of the building blocks of this material that we name genes, how are they turned on and off in our cells during development, and then in adult tissues, how are the different cell types generated, and which role do hormones play in these processes? These are some of the questions that we have addressed. We have uncovered some basic principles, and hopefully, some of our studies are leading, and will further lead, to a better understanding of diseases and to more efficient therapies.

Science is the most challenging of modern adventures, a unique chance to discover the unknown. The excitement of being a molecular geneticist and biologist is to participate to the exploration of life and to discover how it operates. It is also the conviction that progress in biological sciences will ultimately result in a molecular understanding of all diseases, paving the way to their successful treatment. Most importantly, being a molecular geneticist gave me a chance to understand from where we, human beings, originate through 4 billion years of biochemical evolution, and to realize that we are all alike, with just a few small differences that are due to genetic and environmental chance. Clearly, if some of us are smarter, it is not their own merit! What modern biochemistry, molecular biology, and genetics have taught us are lessons of tolerance, humility, and responsibility.

Let me thank again — very sincerely — all of those who enabled me to participate in the adventure of science and to be present here today.

Key publications of Pierre Chambon

Green, S., Walter, P., Kumar, V., Krust, A., Bornert, J.M., Argos, P., and Chambon, P. (1986). Human oestrogen cDNA: sequence, expression, and homology to v-erb-A. Nature. 320, 134–139.

Petkovich, M., Brand N.J., Krust, A., and Chambon, P. (1987). A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 330, 444–450.

Green, S. and Chambon, P. (1987). Oestradiol induction of a glucocorticoid-responsive gene by a chimaeric receptor. Nature. 325 75–79.

Leid, M., Kastner, P., Lyons, R., Nakshatri, H., Saunders, M., Zacharewski, T., Chen, J.Y., Staub, A., Garnier, J.M., Mader, S., and Chambon, P. (1992). Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 68, 377–395.

Bourguet, W., Ruff, M., Chambon P., Gronemeyer H., and Moras, D. (1995). Crystal structure of the ligand binding domain of the human receptor RXRD. Nature. 375, 377–382.

Chambon, P. (1996). A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954.

Ronald Evans

Acceptance remarks, 2004 Lasker Awards Ceremony

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nature Medicine Essay


It is a great pleasure to be here! I wish to thank Joe for his elegant overview and Mike for your warm and personal comments about our discoveries. I was even beginning to like the guy you were talking about.

I am truly delighted to be the recipient of the 2004 Lasker Award. I want to thank the distinguished jury for this honor. The vetting process is extremely rigorous — I knew this when they asked for dental records. I am greatly honored to be included in the select group of physicians and scientists who have won this prestigious award. I wish to heartily congratulate my co-recipients, Elwood Jensen and Pierre Chambon.

At times it seemed that our work was everything, enveloping us in a surreal world of complex ideas and swirling emotion. It was like we had fallen into that magical tunnel described by Lewis Carroll depositing us at the entrance to Wonderland… an entrance that was sealed and could be unlocked only by asking the right question.

Science is about asking the right question — as I tell every one who joins my lab, "if you want a big answer you must ask a big question." I have had the good fortune to work with a remarkable cadre of people, my "comrades in science," some of whom are sitting at my table, who were not afraid ask and work on the big questions.

The idea of asking questions takes me back to the time I first met Francis Crick. It was said Francis' great gift was asking the right question. I remember at Salk when I first went to his office to discuss my work. An office first occupied by the famed Jacob Bronowski with a framed picture of Charles Darwin adorning the wall, with Francis sitting in Shakespearean mode at his desk, I began to wonder "Lord, why am I here? And how can I get out?" Those were my first questions. Realizing I was nervous, Francis asked his first of many questions: "Ron, would you like some cinnamon toast? And perhaps some tea?" "Kathleen," he said, "some cinnamon toast and tea for Ron." Deceptively simple, but it settled me down and was a brilliant start to a 26-year-long relationship.

So what are the next questions? For us, we ask how our studies of transcriptional physiology can help to understand human development and control human disease. Biomedical research can only be pushed forward by the next generation and it is my hope to encourage the spirit of young people to pursue science and bring their energy and enthusiasm to help answers to these questions.

Finally, in addition to the idealistic aspects, science is a grueling and competitive discipline and I want to thank my wife, Ellen, for unflagging emotional support, advice and love. I also acknowledge my daughter, Lena — as of three weeks ago a freshman at Columbia — who spackles me with style and gives me perspective on what life is all about.
My thanks to you all for sharing this special day.

I end on the note that this week in 1687, Sir Isaac Newton published his theories of gravitation in the "Principles" — so all of you may be comforted by the knowledge that what stood up will now sit down.

Thank you.

Key publications of Ronald Evans

Hollenberg, S., Weinberger, C., Ong, E.S., Cerelli, G., Thompson, E.B., Rosenfeld, M.G., and Evans, R.M. (1985).Primary structure and expression of a functional human glucocorticoid receptor of cDNA. Nature. 318, 635–641.

Giguere, V., Ong, E.S., Segui, P., and Evans, R.M. (1987) Identification of a receptor for the morphogen retinoic acid. Nature 330: 624–629.

Mangelsdorf, D.J., Ong, E.S., Dyck, J.A., and Evans, R.M. (1990). Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 345, 224–229.

Kliewer, S.A., Umesono, K., and Evans, R.M. (1992). Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone, and vitamin D3 signaling. Nature. 355, 446–449.

Heyman, R.A., Mangelsdorf, D.J., Dyck, J.A., Stein, R.B., Eichele, G., Evans, R.M., and Thaller, C. (1992). 9-cis-Retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 68, 397–406.

Mangelsdorf, D.J. and Evans, R.M. (1995). The RXR heterodimers and orphan receptors. Cell. 83, 841–850.

Elwood Jensen

Acceptance remarks, 2004 Lasker Awards Ceremony

Nature Medicine Essay


First, I can say that I am thrilled to be here, not only by the enjoyment of this festive occasion but also by the opportunity to join the impressive group of scientists who have received Lasker Awards in the past. When I was growing up, one of the adages to which we were exposed was "you are known by the company you keep." When one surveys the amazing list of Lasker Laureates, one must agree that, at least by this criterion, the five scientists who are being honored today seem to have heeded this admonition.

To have the opportunity, as well as the obligation, to sit down and reflect on how we came to do the research being recognized today is of immense value in planning future activities. As explained in more detail in my article entitled "From Chemical Warfare to Breast Cancer Management" in the October issue of Nature Medicine, of which you have received a copy, my path was rather indirect. Having majored in chemistry at Wittenberg College in Ohio, I had already begun graduate training in organic chemistry at the University of Chicago when World War II came along. Although I had a private pilot license and wanted to join the Air Force, they would not accept contact lenses, so I spent the war on a project in the Department of Chemistry, synthesizing new and more effective poison gases while finishing my graduate studies and flying for the Civil Air Patrol on the weekends. Many of these toxic agents were quite formidable and actually put me in the hospital on two occasions, so I was glad that we did not need to drop them on the baby in Göttingen who 40 years later was to become my wife. So Peggy can be here today to help us celebrate.

The poison gas studies stimulated my interest in biology and medicine. But when the war was over, I had a family and was a bit too old to begin four years of medical school. So I had to settle for a one-year Guggenheim Fellowship to learn steroid hormone chemistry at the Swiss Federal Institute of Technology in Zürich. While in Switzerland, I had the opportunity to climb the Matterhorn, which, as a novice, was the most difficult physical challenge of my life. More important, I learned the concept of 'alternative approach' from the fact that the Matterhorn was the last major peak in Europe to be climbed, simply because people had always tried it from the Italian side, which looks much friendlier than the sheer northeast face usually seen in photographs. An Englishman named Edward Whymper decided to test the "impossible" northeast face, found it relatively easy, and, in July 1865, he and his party were the first to reach the top. As explained in the Nature Medicine article, two of our most important contributions, discovery of steroid hormone receptors and preparation of the first antibodies to them, depended on approaches different from what other laboratories were using.

Finally, during the past few weeks we have had a wonderful opportunity to learn more about the Lasker Foundation and what they have done and continue to do in supporting and stimulating biomedical research. This is an inspiration to all of us, as well as a cause for strong optimism for the future.

Key publications of Elwood Jensen

Jensen, E.V. and Jacobson, H.I. (1960). Fate of steroid estrogens in target tissues. In Biological Activities of Steroids in Relation to Cancer, G. Pincus and E.P. Vollmer, eds., Academic Press, New York, pp. 61–174.

Jensen, E.V. and Jacobson, H.I.. (1962). Basic guides to the mechanism of estrogen action. Rec. Prog. of Hor. Res. 18, 387–414.

Jensen, E.V., Suzuki, T., Kawashima, T., Stumpf, W.E., Jungblut, P.W., and DeSombre, E.R. (1968). A two-step mechanism for the interaction of estradiol with rat uterus. Proc. Natl. Acad. Sci. USA. 95, 632–638.

Jensen, E.V. and DeSombre, E.R. (1973). Estrogen-receptor interaction: Estrogenic hormones effect transformation of specific receptor proteins to a biochemically functional form. Science. 182, 126–134.

Jensen, E.V., Block, G.E., Smith, S., and DeSombre, E.R. (1973). Hormonal dependency of breast cancer. Rec. Res. Canc. Res. 42, 55–62.

Jensen, E.V., Greene, G.L., Closs, L.E., DeSombre, E.R., and Nadji, M. (1982). Receptors reconsidered: a 20-year perspective. Rec. Prog. Hor. Res. 38, 1–34.

Interview with Pierre Chambon, Ronald Evans, and Elwood Jensen