The Nobel Prize in Physiology or Medicine 1988
Sir James W. Black, Gertrude B. Elion, George H. Hitchings
Presentation Speech by Professor Folke
Sjöqvist of the Karolinska Institute
Translation from the Swedish text
This year's Nobel Prize in Physiology or Medicine has been awarded for the discoveries of important principles for drug treatment which have been applied successfully to the treatment of a wide variety of serious illnesses. Sir James Black's findings have made possible the development of new and improved agents for the treatment of angina pectoris, myocardial infarction, high blood pressure and peptic ulcer. In Sweden alone, approximately half a million people were treated in 1987 with the types of drugs which resulted from his research. Gertrude Elion's and George Hitchings' research has led to drugs effective against such widely differing conditions as leukemia, rejection of transplanted organs, gout, malaria and bacterial and viral infections. The drugs which have resulted from the discoveries of this year's prizewinners are now well-proven medications which have stood the test of time over the past 15-35 years, and which remain today front-line agents for the treatment of a wide spectrum of illnesses. They also appear in the World Health Organizations's list of so-called "Essential Drugs", which denotes those medicines which should be available worldwide in order that the goal of "Health for All by the Year 2000" can be realized.
In a letter to a close friend, written a few months before his death in 1896, Alfred Nobel wrote, "My heart trouble will keep me here in Paris for another few days at least... Isn't it the irony of fate that I have been prescribed nitroglycerin to be taken internally! They call it Trinitrin, so as not to scare the chemist and the public". By the latter remark, Nobel was referring to the use of nitroglycerin as an ingredient of dynamite. Nitroglycerin reduces the pain of angina pectoris by dilating the cardiac blood vessels and thereby increasing the supply of oxygen to the heart. Sir James Black was the first to recognize that an alternative therapeutic strategy for angina would be to use a drug which decreases the heart's requirement for oxygen. He therefore focused his attention on the specialized binding sites, the so-called b-receptors, on heart-muscle cells to which the stress hormones adrenaline and noradrenaline bind and thereby increase the workload and oxygen demand of the heart. The stress hormones are the keys, and the receptors are the "locks" which have to be opened in order for this biological process to occur. In 1962, Black was successful in developing clinically useful compounds which blocked specifically the effect of stress hormones on the heart by inhibiting their binding to receptors. These compounds functioned simply as false keys in the locks. Patients treated with such agents, the so-called b-receptor blocking drugs, were able to increase their physical effort without over-exerting heart function and experiencing chest pain as a result. Subsequently, it was found that these same compounds could he used in the treatment of high blood pressure and in reducing fatalities resulting from myocardial infarction.
Sir James Black also developed a fundamentally new approach to the treatment of peptic ulcer. A formerly widely used diagnostic test of a patient's susceptibility to develop peptic ulcer was to administer histamine, which is a powerful stimulant of gastric acid secretion. Black raised the question of why the so-called antihistamines failed to inhibit this production of' gastric acid, despite the fact that they successfully blocked the allergic reactions mediated by histamine. The explanation proved to be that histamine present in the stomach acts upon a quite distinct family of receptors from those blocked by the antihistamines. Through altering the chemical structure of the histamine molecule, Black succeeded in developing false keys for this new type of receptor, and produced compounds which almost immediately stopped the production of gastric acid (1972). These so-called histamine-2 receptor blockers proved to be highly effective in the treatment of peptic ulcers, and decreased the need for surgical intervention in patients suffering from this disease.
While Sir James Black worked with the structure of the exterior of cells, Gertrude Elion and George Hitchings studied the nucleus and its genetic content, the nucleic acids. During the early 1950's they published the hypothesis that, with the aid of drugs, it should be possible to, selectively inhibit the synthesis of nucleic acids used by e.g. cancer cells and bacteria, without simultaneously impeding the growth of normal cells. In these days our knowledge of how nucleic acids were synthesized within the cell was very limited. However, it was known that cells used certain simple building blocks in the manufacture of their nucleic acids. Elion and Hitchings studied how false building blocks, the so-called antimetabolites, could be used to interrupt cellular growth. Asearlyas 1951, they discovered a compound, 6-mercaptopurine, which was used successfully in a hitherto incurable form of leukemia. Through a simple chemical alteration of the 6-mercaptopurine structure, they developed another drug, azathioprine (1957) which inhibited the property of white cells to reject transplanted organs. Twenty years later, one of the world's leading transplant surgeons asserted that, as a result of the discovery of this immunosuppressant drug, 20 000 individuals had been able to receive a new kidney. Furthermore, a new strategy for the treatment of gout with allopurinol was developed by Elion and Hitchings in 1963.
Hitchings and co-workers also developed the anti-malarial drug pyrimethamine (1950) and the anti-bacterial agent trimethoprim (1956). An important observation of theirs was that the effects of both of these drugs were enhanced by sulfonamides, which led to the use of the trimethoprim-sulfa combination in the treatment of severe bacterial infections, such as those encountered in AIDS patients, and also in an important antimalarial preparation. A subsequent outcome of Elion's and Hitchings' research programme was the successful development of the first effective antiviral drug, acyclovir, which is used against infections caused by e.g. the herpes virus. The virus-infected cell is tricked into transforming acyclovir into a compound which inhibits cell growth and thereby suppresses the ability of the virus particle to reproduce. Only cells infected by the virus are attacked.
Through their research efforts, Black, Elion and Hitchings succeeded in developing a rational approach to the discovery of new drugs, based upon basic scientific studies of biochemical and physiological processes. As a result, a new era in drug research was born which offers promise for the development of new therapeutic strategies for the treatment of illnesses against which existing drugs are either unsatisfactory or simply do not exist.
Dr. Black, Dr. Elion and Dr.
On behalf of the Nobel Assembly of the Karolinska Institute I would like to congratulate you on your outstanding accomplishments and ask you to receive the Nobel Prize in Physiology or Medicine from the hands of His Majesty the' King.
From Nobel Lectures, Physiology or Medicine 1981-1990, Editor-in-Charge Tore Frängsmyr, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1993
Copyright © The Nobel Foundation 1988
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