Earl Wilbur Sutherland Jr.

Earl Wilbur Sutherland Jr.(November 19, 1915 – March 9, 1974) was an Americanpharmacologistand biochemist born inBurlingame, Kansas.Sutherland won aNobel Prize in Physiology or Medicinein 1971 "for his discoveries concerning the mechanisms of the action of hormones", especiallyepinephrine,viasecond messengers,namelycyclic adenosine monophosphate,or cyclic AMP.

Earl Wilbur Sutherland Jr.
Sutherland,c. 1970
Born	(1915-11-19)November 19, 1915 Burlingame, Kansas,U.S.
Died	March 9, 1974(1974-03-09)(aged 58) Miami,Florida, U.S.
Alma mater	Washington University in St. Louis(M.D) Washburn University(B.S)
Known for	Epinephrine,cyclic AMP
Awards	Gairdner Foundation International Award(1969) Albert Lasker Award for Basic Medical Research(1970) Dickson Prize(1971) Nobel Prize in Physiology or Medicine(1971) National Medal of Science(1973)
Scientific career
Fields	Biochemistry
Institutions	Vanderbilt University,Case Western Reserve University,Washington University School of Medicine,University of Miami
Doctoral students	Ferid Murad

Early life and education

Sutherland was born on November 19, 1915, inBurlingame,Kansas.The second youngest of six children, he was raised by his mother, Edith M. Hartshorn, and his father, Earl W. Sutherland.Though his father, who was originally fromWisconsin,had attendedGrinnell Collegefor two years, he ultimately led an agrarian lifestyle that took him to bothNew MexicoandOklahomabefore settling down inBurlingameto raise a family. Edith, aMissourinative, had some training in nursing at what was called a "ladies college". To provide for the family, Sutherland's father ran a dry goods store, where he gave each of his children working jobs. Sutherland began fishing at the age of five, and this became a pastime that he enjoyed for most of his life.

As a high school student, Sutherland played and excelled in several sports, includingtennis,basketball,andfootball.

In 1933, at the age of 17, Sutherland enrolled inWashburn CollegeinTopeka,Kansas and began the pursuit of aBachelor of Sciencedegree.In order to pay for tuition, he worked throughout his undergraduate years as a medical staff assistant at a local hospital. Sutherland graduated in 1937, at the age of 21. He was then accepted toWashington University School of MedicineinSt. Louis,where he developed a strongmentorshipwithCarl Ferdinand Cori.In 1942, Sutherland graduated with aDoctor of Medicine.

Career

Academia and research

In 1940, while studying at theWashington University School of Medicine,Sutherland had his first encounter with research as an assistant inpharmacologyin the laboratory of Carl Ferdinand Cori, who won aNobel Prize in Physiology or Medicinein 1947 for his discovery of the mechanism ofglycogenmetabolism.Under Cori's guidance, Sutherland conducted research on the effects of the hormonesepinephrineandglucagonon the breakdown of glycogen to glucose.In 1942, he worked as an intern atBarnes-Jewish HospitalinSt. Louis.

After receiving his medical degree from Washington University in 1942, Sutherland served as aWorld War IIarmy physician. He returned toWashington University in St. Louisin 1945, where he continued to do research in Cori's Laboratory. Sutherland accredits his decision to pursue a research career, as opposed to entering the medical profession, to his mentor Cori.

Sutherland held various teaching titles during his time at the Washington University School of Medicine, including instructor in pharmacology (1945–46), instructor inbiochemistry(1946–50), assistant professor in biochemistry (1950–52), and associate professor in biochemistry (1952–53).

In 1953, Sutherland moved toClevelanda position as a professor of pharmacology and chairman of the department of pharmacology at the school of medicine atCase Western Reserve University.There, he collaborated with Theodore W. Rall, also a professor of pharmacology, who was to become a lifelong research partner. Together, they conducted further research on the mechanism of hormone action at the molecular level.During his ten years at Case Western Reserve University, Sutherland made several ground-breaking discoveries that led to the identification ofcyclic adenosine monophosphate,or cyclic AMP, and its role as asecondary messenger.

In 1963, Sutherland became professor of anatomy atVanderbilt University School of MedicineinNashville.His position allowed him to devote more time to his research. He continued his work on cyclic AMP, receiving financial support from the Career Investigatorship awarded to him by theAmerican Heart Associationin 1967. He held his teaching title atVanderbilt Universityuntil 1973.

In 1973, after spending 10 years atVanderbilt University,Sutherland moved toMiami,where he joined the faculty atMiller School of Medicineat theUniversity of Miamias a distinguished professor of biochemistry.He continued to be involved in novel research aboutadenosine monophosphateandguanosine monophosphate,co-authoring four papers in 1973 alone.

Discovery of cyclic AMP

While working in Cori's laboratory, Sutherland, with the help of his co-workers, made several discoveries concerning the mechanism ofglycogenmetabolismthat, years later, led him to his discovery of the biological activity of cyclic AMP. Cori's laboratory had previously established the basic mechanism of glycogen metabolism, for which they were awarded theNobel Prize in Physiology or Medicine.Sutherland helped to identify the importance ofliver phosphorylase(LP) in the process ofglycogenolysis.Of the three basicenzymesinvolved in glycogenolysis, he found that LP was rate-limiting, meaning that the progression of glycogen metabolism is dependent on this enzyme.LP would become the subject of his research for the next several years, and it was through experimentation on LP andhormoneinteraction that his most renowned discovery was made.

After identifying the importance of LP, Sutherland moved his research efforts to Western Reserve University. There, he worked in collaboration with Ted Rall, Walter D Wosilait, and Jacques Berthet to publish a series of papers in theJournal of Biological Chemistry,"The Relationship of Epinephrine and Glucagon to Liver Phosphorylase", which was released in four parts.These four papers document the purification of LP and the analysis of several of its properties. First, it was determined that the enzymatic activity of LP depends on the addition or removal of aphosphategroup, a process calledphosphorylation.In a later experiment, they demonstrated that more phosphate is taken up in liver slices when epinephrine and glucagon are added, suggesting that these hormones were promoting the phosphorylation of LP, activating the enzyme.The results of a later paper in the series suggested that this phosphorylation and activation of LP was a result of the action of phosphorlyasekinase.This series also investigated the inactivation of liver phosphorylase and characterized an enzyme they initially called LP-inactivating enzyme, which functions by cleaving the phosphate group.This enzyme was later renamed liver phosphorylase phosphatase.These papers also characterized LP in terms of molecular weight and other factors. During their analysis, they found the unexpected result that LP activation increased with the addition of 5-AMP, which is a precursor of cAMP; however, this was not known at the time.

The fourth paper published in this series, "The Relationship of Epinephrine and Glucagon to Liver Phosphorylase: IV Effect of Epinephrine and Glucagon on the Reactivation of Phosphorylase in Liver Homogenates", was published in 1956. In this paper, Sutherland and associates furthered their investigation of epinephrine and glucagon. The key to the success of this experiment was the use ahomogenateof liver cells rather than intact liver cells, as they had been doing in their previous experiments.The general consensus among researchers at that time was that the study of hormones was only possible using intact cells; this was the first instance that a hormone pathway was studied using a cell homogenate. Sutherland and his co-authors were able to observe similar effects in liver homogenate to what was observed in whole liver slices. More importantly, they were able to observe this response in two stages. This stage response was characterized by the particulate fraction producing an unknown heat stable factor in the presence of the hormones epinephrine and glucagon. This factor then stimulates the formation of liver phosphorylase in a fraction of the homogenate where the hormones are not present.This unknown heat stable factor, which was produced in the presence of hormones and ultimately led to the secondary formation of liver phosphorylase, was later termed cyclic AMP.

Even though the discovery of cyclic AMP and the idea ofsecond messengerswere of great importance to the world of medicine, Sutherland's findings were actually achieved through strenuous trial and error. First of all, Sutherland and Ted Rall were convinced that asucrosehomogenate of liver cells was absolutely necessary in order to keep their cells healthy and proliferating.This inference was made by Rall from his experience studyingmitochondria,which responded well to these sucrose homogenates; however, it had nothing to do with what was being studied at the time. It turned out that this sucrose was not necessary for the homogenate and once they set up the experiment without sucrose they were able to see more effective results. Secondly, Sutherland initially believed that there was something vital about the intact cell, and that disrupting its structure would not produce any hormonal effect.However, after some debate, Rall had convinced Sutherland to use liver homogenates. Once they had witnessed nearly a doubling of the rate of LP activation, they knew this belief in that keeping cells intact was crucial to studying the effects of hormones was not necessarily true, at least in this case. Finally, Sutherland had decided to ignore Jacques Berthet's request to conduct the same experiment using proper lab technique, specifically the Lehninger Hard Pour, where the supernatant material was decanted by pouring the liquid into another test tube once the particulate fraction reached the top of the original tube. Berthet not only demanded this step of the procedure be done through careful aspiration, he also critiqued the lack of specificity during centrifugation with respect to suspension height, rpm and time.The willingness of Sutherland and his associates to modify their experimental procedures and mistaken assumptions allowed them to make the discoveries that they made.

Personal life

Sutherland married Mildred Rice in 1937, the same year that he graduated fromWashburn College.In 1944, duringWorld War II,Sutherland was called into service as a battalion surgeon under General George S. Patton, and was later sent toGermany,where he served as a staff physician in a military hospital until 1945.He had two sons and a daughter with Mildred Rice.

In 1962, Sutherland divorced his first wife. A year later, when he became professor of physiology at Vanderbilt University, Sutherland married Claudia Sebeste Smith, the assistant dean at the university, and they were together for the remainder of Sutherland's life.

Awards and achievements

• 1937 – Bachelor of Science fromWashburn CollegeinTopeka, Kansas;
• 1942 – Doctor of medicine fromWashington University School of MedicineinSt. Louis, Missouri;
• 1969 – Torald Sollman Award in Pharmacology |Gairdner Foundation International Award;
• 1970 –Albert Lasker Award for Basic Medical Research;
• 1971 –Nobel Prize in Physiology or Medicine| Achievement Award from the American Heart Association;
• 1971 – Golden Plate Award of theAmerican Academy of Achievement;
• 1973 –National Medal of Scienceawarded by Richard Nixon.

In 1952, Sutherland was awarded theBanting Memorial Lectureshipand, in 1953, was elected as the Chairman of the Case Western Reserve University Department of Pharmacology in Cleveland, Ohio. He was awarded the Career Investigator position at theAmerican Heart Associationin 1967 and was elected as member of theNational Academy of Sciencesin 1973.

Sutherland was also a member of various scientific societies which included the American Society of Biological Chemists, theAmerican Chemical Society,theAmerican Society for Pharmacology and Experimental Therapeutics,theAmerican Association for the Advancement of Science,andSigma Xi. From 1951 to 1956, Sutherland was a member of the editorial board for the Biochemical Preparations Journal. The editorial board of theJournal of Pharmacology and Experimental Therapeuticssought is attention from 1957 to 1958.

Death

On March 9, 1974, Sutherland died of internal bleeding due to surgical complications following a massive esophagealhemorrhage.He was 58 years old.

Legacy

After Sutherland's death, in 1974, theMiller School of Medicineestablished the Sutherland Memorial Lecture. In 1976, Vanderbilt University created the Sutherland Prize which is awarded annually to a faculty member whose work has garnered them national, if not international, acclaim and respect. Recipients are awarded $5,000, and their name is engraved on a silver bowl.Vanderbilt honored Sutherland in 1997 by starting a Sutherland lecture, and again in 2001 in the creation of the Sutherland Chair of Pharmacology. Heidi E. Hamm, a member of the Vanderbilt faculty, was appointed to this position upon its establishment and still maintains this title.

External links

• Earl Wilbur Sutherland Jr.on Nobelprize.org
• Lasker link
• NAS link
• Case-Western link