Nobel Laureate: Earl W. Sutherland, Jr.

 

The Nobel Prize in Physiology or Medicine 1971.

"for his discoveries concerning the mechanisms of the action of hormones"

Earl W. Sutherland, Jr. (1915-1974) received the Nobel Prize in Physiology or Medicine for his work on the mechanism of action of hormones, particularly epinephrine. Sutherland was very much influenced by Carl Cori [Nobel Laureates: Carl Ferdinand Cori and Gerty Theresa Cori] who worked on the pathways of glycogen breakdown and glucose synthesis in mammalian liver cells. Sutherland is responsible for discovering how the hormone epinephrine regulates glycogen synthesis [Regulating Glycogen Metabolism]. Along the way, Sutherland discovered the second messenger cyclic AMP (cAMP), which was Monday's Molecule #39.

The presentation speech was delivered by Peter Reichard of the Karolinska Medico-Chirurgical Institute. Note the opening line that refers to Monod's famous quote"What is true of E. coli is also true of the elephant." It was 1971 and Chance and Necessity had just come out. For years scientists had thought that the action of hormones demonstrated that so-called "higher" organisms used higher-level processes to regulate metabolism. Hormones needed whole tissues and organs to show an effect. What Sutherland proved was that hormones work at the cellular and molecular level just like the molecules that regulated activity in bacteria.

Your Majesty, Your Royal Highnesses, Ladies and Gentlemen,

What applies to bacteria also applies to elephants. This free quotation after the French Nobel prize winner, Jacques Monod, illustrates with some exaggeration one important principle of biology: that of the identity of the fundamental life processes.

Yet one need not be a Nobel prize winner to know the difference between bacteria and an elephant. The latter is not only much larger. The decisive difference lies in the fact that bacteria are unicellular organisms and that all the functions of life are contained in a single cell. In higher organisms on the other hand, there occurs a division of labor between different types of highly specialized cells. Nevertheless, the elephant must function as an integrated unity. The cells in the different organs must be coordinated in such a way that they rapidly adapt to the changing requirements of the environment.

The hormones form part of such a coordinating system. Among other things, the difference between a bacterium and an elephant lies in the fact that the latter - as well as all of us here - for the sustainment of his life is completely dependent of the proper function of hormones, while bacteria can do without them.

What then is the function of hormones? Ever since the first hormone was discovered about 70 years ago this has been a central theme of research for many scientists. This question is also of considerable medical importance. Many diseases are hormone diseases, amongst them diabetes. In spite of this the mechanism of hormone action remained a complete mystery until recently. The answer did not come until Earl Sutherland started his investigations on the function of the hormone epinephrine.

This hormone is produced in the adrenal glands and is transported to different organs of the body by the blood. It is formed in increased amounts during stress and adapts the individual to new situations. One of its important functions lies in the liberation of glucose inside the cells for the production of energy. Epinephrine serves as a chemical signal, as a messenger, which is sent out from the adrenals to activate different organs essential for the defense of the individual.

Sutherland investigated the effect of epinephrine on the formation of glucose in liver and muscle cells. He discovered a new chemical substance which serves as an intermediate during the function of the hormone. This substance is called cyclic AMP. It transmits the signal from epinephrine to the machinery of the cell, and Sutherland therefore called it a "second messenger". Furthermore, Sutherland made the important discovery that cyclic AMP is formed in the cell membrane. This means that epinephrine never enters the cell. We may visualize the hormone as a messenger which arrives at the door of the house and there rings the bell. The messenger is not allowed to enter the house. Instead the message is given to a servant, cyclic AMP, which then carries it to the interior of the house.

Sutherland suggested already around 1960 that cyclic AMP participates as a second messenger in many hormone mediated reactions, and that its effect thus is not limited to the action of epinephrine. First this generalization was not willingly accepted by the scientific community, since it was difficult to visualize how a single chemical substance could give rise to all the diverse effects mediated by various hormones. By now Sutherland and many other scientists have provided convincing evidence, however, that many hormones exert their effects by giving rise to the formation of cyclic AMP in the cell membrane. Sutherland had discovered a new biological principle, a general mechanism for the action of many hormones.

How can one then explain the specificity of different hormones? A good part of the explanation lies in the fact that different cells in their membranes possess specific receptors for various hormones. The different messengers thus must find their way to the right door in order to deliver their messages.

Cyclic AMP was discovered in connection with investigations concerning the function of hormones. It came therefore as a big surprise when Sutherland in 1965 reported that cyclic AMP also occurred in bacteria which apparently had no use for hormones. It was soon found that cyclic AMP was produced by other unicellular organisms, too. In all these cases cyclic AMP was shown to have important regulatory functions which aid the cells in their adaptation to the environment. Maybe we can look upon cyclic AMP as the first primitive hormone, regulating the behaviour of unicellular organisms. We then may look upon the true hormones of higher organisms as components of an overriding principle which was added during the course of evolution. Thus the difference between uni- and multicellular organisms does not, after all, appear to be so great, and with respect to cyclic AMP we can turn around Monod's dictum and say that what applies to elephants also applies to bacteria.

Dr. Sutherland,

Hormones were known in biology and medicine for a long time. The mechanism for hormone action remained a mystery, however, until you discovered cyclic AMP and its function as a second messenger. In recent years it has become apparent that cyclic AMP also serves as an important regulatory signal in microorganisms, and that its action thus is not limited to the function of hormones. When you discovered cyclic AMP you discovered one of the fundamental principles involved in the regulation of essentially all life processes. For this you have been awarded this year's Nobel prize in physiology or medicine. On behalf of the Karolinska Institute I wish to convey to you our warmest congratulations, and I now ask you to receive the prize from the hands of his Majesty the King.