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Earl Wilbur Sutherland, Jr. (1915-1974) was a pioneering American pharmacologist and physiologist who, together with colleague Theodore W. Rall, isolated cyclic adenosine monophosphate (cyclic AMP) in 1956. Following its isolation, he demonstrated the involvement of cyclic AMP in numerous metabolic processes and elucidated the mechanisms and actions of hormones at the cellular level. In 1971 he was awarded the Nobel Prize in Physiology or Medicine for his discoveries concerning the mechanisms of hormone action. However, Sutherland's accomplishments were important for other reasons as well. His discovery that the action of cyclic AMP was a biochemical, rather than a physiological demonstration of receptor activity, was one of the first times receptors were thought of in biochemical terms. When he identified phosphorylase as the rate-limiting step in glycogenolysis, the whole concept of regulatory enzymes was only dimly perceived. After demonstrating the chemical nature of phosphorylase activation, he discovered that the enzyme differed with respect to immunological properties likely the first demonstration of isozymes. Sutherland's many accomplishments can be attributed in large part to his impressive intuition. In the words of Butcher and Robison: It almost seemed at times as if he could peer into a living cell and see exactly the sense of what occurred and why. Everything about living organisms seemed to make sense to him. His incredible intuition was complemented by a highly disciplined and rational mind; he was always dispassionate and unsentimental in his approach to science. A precept by which he lived, and which he often imparted to his colleagues, was that you should never fall in love with your hypotheses and always let nature answer her own questions. Sutherland also possessed a remarkable memory for what he considered important. He could remember minute details, including in some cases the exact numerical results, of experiments which others had done so very long ago that the experiment itself had been forgotten. He was a master of experimental design and had an uncanny knack of perceiving the throat of a problem. He had a fierce sense of independence and constantly strove for total freedom of actions without distractions. He was a strong believer in open scientific communication and honest searching for new truths. In addition to membership in the National Academy of Sciences, Sutherland was a member of the American Academy of Arts and Sciences, Alpha Omega Alpha, and the American Society of Biological Chemistry. In addition to the Nobel Prize, the National Medal of Science and the Lasker Award, Sutherland was awarded the Banting Memorial Lectureship and Medal, the Sollman Award and the Gairdner Award. He was also active on the editorial boards of many journals, including Biochemical Preparations and the Journal of Pharmacology and Experimental Therapeutics. Brief Chronology
Phosphorylase, Epinephrine, Cyclic AMP and Adenyl Cyclase 1940-1974, With Sources and References Following is a summary of Dr. Earl W. Sutherland's major accomplishments with links to selected publications. The complete set of Sutherland's laboratory notebooks are housed in the Archives of the Louis Calder Memorial Library of the University of Miami Miller School of Medicine. The Notebooks are accessible as separate links on this website. Sutherland began his research career at the Washington University School of Medicine in the laboratory of Carl Ferdinand and Gerty Cori in 1940 as a pharmacology assistant. The Coris had established the basic biochemistry of glycogen breakdown, with phosphorylase, phosphoglucomutase and glucose 6-phosphatase being the basic enzymes involved in the production of glucose.[1] Sutherland's first publication was his 1941 letter to the editor of the Journal of Biological Chemistry on the enzymatic conversion of glucose 6-phosphate to glycogen when he was a pharmacology assistant.[2] After receiving his medical degree from the Washington University School of Medicine in 1942 and doing an internship at its Barnes Hospital, he served as an army physician during World World II. When Sutherland returned to St. Louis after the War, Cori convinced him to go into medical research and not enter medical practice, a decision he never regretted. He entered the study of hormone action at the molecular level in 1947 when the prevalent feeling among biologists was that hormone action could not be studied in the absence of organized cell structure. Sutherland's feeling at the time was that since the biosynthesis of urea had been elucidated by studying it first in the whole animal, followed by perfused livers, liver slices and finally cell extracts, the study of hormone action could proceed in an analogous way. Two early avenues were studying other enzymes known to be involved in glycogen metabolism but not yet identified, and determining whether the release of glucose was due to epinephrine increasing its production or causing it to be extruded from the cell.[3] One of Sutherland's first demonstrations was that the release of glucose was the result of increased glucose production.[4] One of his first discoveries was that glycogen phosphorylase was the rate-limiting step in glycogenolysis, perhaps the first demonstration of the important regulatory role of enzymes.[5] He would later demonstrate the chemical nature of phosphorylase activation.[6] This would lead to his discovery that the phosphorylases differed with respect to immunological properties, depending on the type of cell from which it was derived an early demonstration of isozymes.[7] However, in 1951 Sutherland began studying how the hormone epinephrine (adrenaline) signals cells to regulate the degradation of glycogen to glucose in the liver, thereby increasing glucose output into the blood, so that an organism can respond to stress. He worked along side fellow future Nobel Prize winners Edmond Fischer and Edwin Krebs, who demonstrated that adenosine triphosphate (ATP) and magnesium were required for phosphorylase activation. In 1953 Sutherland accepted the position of chairman of the pharmacology department of Case Western Reserve University in Cleveland and was joined by Theodore R. Rall, marking the beginning of a long and fruitful period of collaboration between us.[3] Sutherland and Rall discovered that epinephrine works by stimulating another chemical messenger, the enzyme glycogen phosphorylase, to begin the sugar-releasing process in the cell.[7] This stimulation occurs by means of an intermediary Sutherland called the second messenger, which he identified as a nucleotide and named cyclic AMP.[8-10] As early as 1960, he suggested that cyclic AMP acts as a second messenger for other hormones as well.[11] Sutherland and Rall then found that epinephrine stimulates the cell to form cyclic AMP by a newly discovered enzyme, originally called adenyl cyclase [12] but more correctly named adenylyl cyclase or adenylate cyclase. This stimulation occurs by epinephrine attaching itself to a receptor on the surface of the cell. This attachment leads to the stimulation of adenylate cyclase which is also located on the cell surface. These discoveries demonstrated that it is the hormone epinephrine, released from the adrenal glands during times of stress, that stimulates the production of adenylate cyclase, which induces formation of the nucleotide cyclic AMP in the liver cells. The nucleotide then converts the inactive enzyme glycogen phosphorylase to the active enzyme, which leads to the formation of glucose from glycogen stored in the liver during periods of non-stress. Sutherland and his colleagues also demonstrated that it was the stimulation of adenlylate cyclase, and not the inhibition of phosphodiesterase, the enzyme responsible for catalyzing the breakdown of cyclic AMP, that induced the formation of cyclic AMP. And they identified pyrophosphate as another product in the breakdown of cyclic AMP. As early as 1960, Sutherland suggested that other hormones also do not enter the cell but are caught on the cell surface. This leads to the stimulation of adenylate cyclase on the cell surface which results in the formation of cyclic AMP which, in the cell, then activates or inhibits various metabolic processes. This general hypothesis refuted previously held beliefs and was met with strong criticism. However, during the 1960s decisive proof was obtained by Sutherland and others that a single substance, cyclic AMP, leads to the numerous effects of epinephrine, and at least a dozen other hormones and neurotransmitters utilize cyclic AMP as a second messenger. [13-15] In 1965, Sutherland found that the second messenger cyclic AMP also occurs in bacteria, which up to then were thought to have no need for hormonal effects.[16] This led the way to its effects in unicellular organisms on several regulatory functions which govern the adaptation of the cell to its surroundings. In these instances, cyclic AMP may be regarded as an original primitive hormone. By 1969, sufficient knowledge had been accumulated on the biological role of cyclic AMP [17] and many scientists had become interested in receptors and were studying cyclic AMP. Sutherland's discovery of cyclic AMP paved the way for the fields of second messenger systems, cell signaling, G proteins, and gene expression. Sources Butcher RW, Robison GA. An appreciation of Earl Sutherland. Metabolism 1975 24(3):237-240 Mar. Earl W. Sutherland, Jr. Curriculum vitae. The Nobel Foundation. Karolinska Institutet has decided to award the Nobel Prize in Physiology or Medicine for 1971 to Earl Sutherland for his discoveries concerning the mechanisms of the action of hormones. Karolinska Institutet. Niehoff D. The Language of Life. Washington, DC: John Henry Press, National Academies Press, 2005. pp. 54-57. Kresge N, Simoni RD and Hill RL. Earl W. Sutherland's discovery of cyclic adenine monophosphate and the second messenger system. Journal of Biological Chemistry 2005 280(42):39 Oct. 21. References
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