Heroes in endocrinology: Nobel Prizes

The Nobel Prize in Physiology or Medicine was first awarded in 1901. Since then, the Nobel Prizes in Physiology or Medicine, Chemistry and Physics have been awarded to at least 33 distinguished researchers who were directly or indirectly involved in research into the field of endocrinology. This paper reflects on the life histories, careers and achievements of 11 of them: Frederick G Banting, Roger Guillemin, Philip S Hench, Bernardo A Houssay, Edward C Kendall, E Theodor Kocher, John J R Macleod, Tadeus Reichstein, Andrew V Schally, Earl W Sutherland, Jr and Rosalyn Yalow. All were eminent scientists, distinguished lecturers and winners of many prizes and awards.


Introduction
Among all the prizes awarded for life achievements in medical research, the Nobel Prize in Physiology or Medicine is considered the most prestigious.
The Swedish chemist and engineer, Alfred Bernhard Nobel (1833-1896), is well known as the inventor of dynamite and the owner of the company Bofors, which manufactured armaments. Disappointed by the public image of him as 'the merchant of death', Nobel sought to alter the negative perception of his legacy by leaving his fortune to be used posthumously for the establishment of the Nobel Prize Trust. The award of prizes for preeminence in five individual fields: physical science, chemistry, medicine or physiology, literature and peace. Given his penchant for the development of inventions related to war and death, it is paradoxical that Alfred Nobel had also an active interest in medical research. In fact, the award for Physiology or Medicine was the third prize defining his will of 1895 where he proposed the establishment of the concept of recognising global merit.
The Nobel Prize in Physiology or Medicine is awarded annually by the 50 voting members of the Nobel Assembly at the Karolinska Institutet in Stockholm (Sweden) (1,2).
In 1901, the first prize was awarded to the German physiologist Emil A von Behring (3,4). This award heralded the first recognition of extraordinary advances in medicine that has become the legacy of Nobel's prescient idea to recognise global excellence. It is noteworthy that the First Nobel Prize in Physics of the same year was awarded to Wilhelm C Röntgen for the discovery of X-rays. This advance presaged the subsequent application to the field of medicine and laid the basis for the development of the interdisciplinary application of science.
In the years that have elapsed since the initiation of the concept, the Nobel Prize has also been awarded to several distinguished endocrinologists. Their achievements and lives are briefly reviewed in this text, and summarised in Table 1.

Theodor Kocher
Emil Theodor Kocher was born on 25 August 1841 in Bern (Switzerland) and schooled in Burgdorf (Switzerland) and Bern. He undertook his doctorate studies in Bern under the leadership of Michael Anton Biermer and in 1865 obtained his Doctorate 'summa cum laude unanimiter'. Thereafter, Kocher joined the staff of the German surgeon C A Theodor Billroth who was at that time Professor and Director of the University Surgical Hospital and Clinic in Zurich (Switzerland). Kocher then travelled Europe and consorted with many of the famous surgeons of his time. From 1865 to 1867, he worked with Bernhard R K von Langenbeck, Director of the Clinical Institute for Surgery and Ophthalmology at the Charité, Berlin (Germany), before in 1867 visiting London (UK) to undertake further study with Sir Henry Thompson, Professor of Clinical Surgery, and Sir John Eric Erichsen, Professor of Surgery, at the University College Hospital. In 1867, he also travelled to Paris to meet with the surgeon Auguste Nélaton, the chemist Auguste V L Verneuil and the chemist and microbiologist Louis Pasteur. His (sponsored) travels gave him exposure to diverse scientific concepts and also enabled him to acquire and develop many novel surgical techniques. In 1867, he returned to Bern where he prepared for his 'habilitation' and was granted the 'venia docendi'. At this time, he was appointed assistant to Georg A Lü cke, whom he succeeded in 1872 as Ordinary Professor of Surgery and Director of the University Surgical Clinic at the Inselspital Bern. In 1869, he married Marie Witschi-Courant (1841-1921) and the couple had three children.
In his lifetime, Kocher established himself as a legendary teacher and clinician authoring almost 250 medical papers and textbooks while training an entire generation of surgeons. He served in 1900 as the mentor of Harvey W Cushing, the founder of neurosurgery and the pioneer of the evolution of pituitary surgery and pituitary disease. Cushing worked for several months in the laboratory of Kocher and addressed the problem of the regulation of cerebral vascular perfusion (6). Kocher achieved pre-eminence for his advances in endocrine surgery, especially by reducing the mortality of thyroidectomies from as high as 75% to below 1%!! So effective was his surgical resection of goitre, however, that the complete extirpation of all thyroid tissue carried its own consequences. Thus, in 1882, the Swiss cousins and surgeons Jacques-Louis and Auguste Reverdin first reported that myxoedema occurred as a delayed complication of total thyroidectomy (7,8,9,10,11,12). This adverse effect was unmanageable until 1953 when thyroid hormone replacement therapy became available (13,14,15). As a consequence of these observations, Kocher also came to the conclusion that a complete removal of the thyroid was not to be recommended and reported this to the German Surgical Society in 1883 (11,16,17,18,19). Nine years Wilhelm C Rö ntgen X-rays after a total thyroidectomy in a young female, Kocher had noted very substantial changes as compared with her younger sister, who in the past had closely resembled her. He reported: 'whilst the younger sister has now grown up to a blossoming young woman of very pretty looks, the sister operated on has remained small and exhibits the ugly looks of a semi-idiot'. Kocher immediately reviewed all goitre patients he had operated on and noted considerable differences between those in whom he had undertaken a partial thyroidectomy and those in whom he had performed a total thyroidectomy. While partially thyroidectomised patients were generally in good health and 'very happy with and grateful for the success of the operation', only two of the total thyroidectomised patients showed improvements.
Kocher was an innovative administrator as well as surgeon and was responsible for the modernisation of the Inselspital 1884-1885 and Rector of the University in 1878 and in 1903. In addition to these University activities from 1905, he owned a small private clinic called 'Ulmenhof' where he treated many wealthy and famous patients.
On the evening of 23 July 1917, Theodor Kocher performed his last emergency operation. Feeling unwell thereafter, he retired to his bed where he lost consciousness and died 4 days later on 27 July 1917, aged 75 years (20).

The Nobel Prize in Physiology or Medicine 1923
The Nobel Prize in Physiology or Medicine 1923 was awarded to Frederick Grant Banting and John James Rickard Macleod 'for the discovery of insulin'. In the beginning of the 20th century, several distinguished scientists including the German pathologist Bernhard Naunyn, the Lithuanian internist Oskar Minkowski, the English physiologist Sir Edward A Sharpey-Schafer and the American pathologist Eugene L Opie all addressed issues of metabolism, especially glucose homoeostasis. In this respect, the focus was the identification and isolation of a pancreatic agent, later named 'insulin' and its involvement in the regulation of blood glucose levels. A critical experimental problem was the difficulty of extracting insulin from the pancreas before its enzymatic degradation. In 1920, Frederick Banting approached John J R Macleod, Professor of Physiology at the University of Toronto, and suggested to him an approach for the isolation of insulin from the pancreas. Macleod provided him laboratory space, experimental animals and the assistance of one of his students, Charles H Best, who worked as a demonstrator. Banting and Best isolated insulin from the pancreas and successfully reduced the blood glucose levels in a diabetic dog, whose pancreas had been surgically removed (21,22 (21,22). Although all members of the team were listed as publication co-authors, the relationship between Banting and Best on one side and Macleod on the other rapidly deteriorated, the former group being of the opinion that their contributions in the discovery of insulin far outweighed those of Macleod. Much controversy emanated from the identification of insulin and, although a variety of versions regarding the saga exist, all concur that considerable acrimony was felt by all parties involved. The Nobel Prize committee further accentuated the tension by ignoring the contributions of Best and Collip with the result that Banting shared his Prize money with Best and Macleod provided half his award to Collip. The issue was further inflamed by the lack of recognition provided to the Romanian physiologist Nicolae C Paulescu (1869-1931) who had 8 months before Banting and Best's paper reported the discovery of a pancreas extract (named: 'pancrein'), which lowered the blood glucose concentration (23 Houssay's main contribution was on the experimental investigation of the role of the anterior pituitary in the metabolism of carbohydrates, particularly in diabetes mellitus. He demonstrated the diabetogenic effect of anterior pituitary extracts and showed that the severity of diabetes decreased after anterior hypophysectomy (29,30). These discoveries were instrumental in initiating research into the mechanistic basis of hormonal feedback mechanisms. Bernardo Houssay was widely acclaimed as a scientist and his contributions led to the award of numerous prizes ranging from that of the National Academy of Sciences, Buenos Aires, in 1923 to the Dale Medal of the Society of Endocrinology (London) in 1960. He died at the age of 84, on 21 September 1971 (31,32,33,34,35,36,37).

The Nobel Prize in Physiology or Medicine 1950
The Nobel Prize in Physiology or Medicine 1950 was awarded jointly to Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench 'for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects'.

Edward Kendall
Edward Despite his original seminal work on thyroxine, Kendall was mostly recognised for the isolation, identification and purification of several adrenal steroids (40,41,42). One of these isolated steroids was designated 'compound E' by Kendall and subsequently became better known as 'cortisone' (40,41,42). In studies in collaboration with Philip S Hench, cortisone proved to be a very effective drug in the treatment of rheumatoid arthritis. After retirement in 1951, Edward Kendall (43) became a Visiting Professor at Princeton University in Princeton, New Jersey (USA), remaining in Princeton until his death on 4 May 1972 at the age of 86 years (44,45).

Tadeus Reichstein
Tadeus Reichstein was born on 20 July 1897 in Wloclawek (Poland) (German: Leslau) and spent his early years in Kiev (Ukraine). His early schooling was in Jena (Germany) and thereafter from 1916 to 1920 he was educated at the Federal Institute of Technology in Zurich (Switzerland), where he obtained his PhD in 1922 and acquired Swiss citizenship. In 1922 in Zurich, he began the analysis of the chemical compounds that provide coffee and chicory their distinctive aromas (46). In 1927, he married the Dutch Lady Henriëtte Louise Quarles van Ufford (1898-1993). They had one daughter. Two years after their marriage (1929), Reichstein was appointed lecturer in organic and pharmaceutical chemistry at the University of Basel (Switzerland) and in 1933, he synthesised vitamin C (ascorbic acid) using a specific chemical procedure which was subsequently referred to as the 'Reichstein process'. In 1938, he became Professor in Pharmaceutical Chemistry and Director of the Pharmaceutical Institute in Basel (1938)(1939)(1940)(1941)(1942)(1943)(1944)(1945)(1946)(1947)(1948)(1949)(1950) (44,48,49).

Philip Hench
Philip Showalter Hench was born on 28 February 1896 in Pittsburgh, Pennsylvania (USA). He received his undergraduate education at Lafayette College in Easton, Pennsylvania. In 1920, he was awarded a MD degree from the University of Pittsburgh having initially studied in the Medical Corps of the United States Army and the Reserve Corps. In 1923, he became a Fellow and thereafter in 1926, Head of the Department of Rheumatic Diseases at the Mayo Clinic, Rochester, Minnesota (USA). Hench focused his interest on arthritis and was one of the early observers of the fact that rheumatoid arthritis followed a milder course during pregnancy and jaundice (50,51) and concluded that this phenomenon was due to a specific chemical compound (which later became known as 'steroid'). Hench married Mary Genevieve Kahler

The Nobel Prize in Physiology or Medicine 1977
The Nobel Prize in Physiology or Medicine 1977 was divided between Rosalyn Yalow 'for the development of RIAs of peptide hormones' and the other half jointly to Roger Guillemin and Andrew Victor Schally 'for their discoveries concerning the peptide hormone production of the brain'. before becoming a secretary for Rudolph Schoenheimer, a leading biochemist at Columbia University's College of Physicians and Surgeons. Thereafter, she became the secretary to Michael Heidelberger, immunologist at Columbia University, who hired her as she studied stenography. Sussman subsequently graduated from Hunter College (New York) in January 1941 (3) and moved as the only female teaching assistant in physics to the College of Engineering of the University of Illinois at Urbana-Champaign. In 1943, she married Aaron Yalow (1920Yalow ( -1992. They had two children. In 1945, Rosalyn Yalow earned her PhD in nuclear physics and acquired a position as the only woman assistant engineer at the Federal Telecommunications Laboratory in New York. In 1946, she returned to Hunter College to teach physics to returning war veterans, maintaining this responsibility until 1950. In 1948, Yalow joined the Bronx Veterans Administration Hospital (VAMC), New York, as a parttime consultant to assist Bernard Roswit, Chief of the Radiotherapy Department, to establish a radioisotope service and initiated research projects with him. In the Bronx VAMC, she met the internist Dr Salomon  (68,69,70,71).

Roger Guillemin
Roger Charles Louis Guillemin was born on 11 January 1924 in Dijon (Bourgogne, France), undertook his undergraduate work at the University of Burgundy and received an MD degree from the Faculté de Médecine of Lyon in 1949. During the Second World War, he was active in the French resistance (for this heroism he was decorated with the 'Ordre national de la Légion d'honneur' in 1973). In 1951, he nearly died of tuberculous meningitis, but recovered and married his nurse, Lucienne Jeanne Billard. Later she became a famous professional harpsichord player. They became American citizens in 1965 and they had six children.
In His research team focused on unravelling the hypothalamic biochemical regulation of anterior pituitary function and secretion. Independent of, and also in competition with, the research group of Andrew Schally, Roger Guillemin and his co-workers discovered the following hormones: thyrotrophin-releasing hormone (TRH), growth hormone-releasing hormone (GHRH) and somatostatin (72,73,74,75,76,77). In addition to hormonal structure function investigation, Guillemin addressed the subjects of activins, inhibins and fibroblast growth factor (FGF). Guillemin (81). Andrew Schally has won many prizes and was awarded many honorary doctorates an MD honoris causa from the Jagiellonian University in Cracow, Poland.

Other Nobel Prizes
Other Nobel Prizes in Physiology or Medicine, or in Chemistry for research into areas closely related to endocrinology were as follows:

The Nobel Prize in Chemistry 1939
The Nobel Prize in Chemistry 1939 was divided equally between Adolf (Friedrich Johann) Butenandt  'for his work on sex hormones' and Leopold Ružička (1887-1976) 'for his work on polymethylenes and higher terpenes'.

The Nobel Prize in Chemistry 1955
The Nobel Prize in Chemistry 1955 was awarded to Vincent du Vigneaud  'for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone'.

The Nobel Prize in Chemistry 1958
The Nobel Prize in Chemistry 1958 was awarded to Frederick Sanger (1918-2013) 'for his work on the structure of proteins, especially that of insulin'.

The Nobel Prize in Physiology or Medicine 1964
The Nobel Prize in Physiology or Medicine 1964 was awarded jointly to Konrad (Emil) Bloch  and

The Nobel Prize in Physiology or Medicine 2000
The Nobel Prize in Physiology or Medicine 2000 was awarded jointly to Arvid Carlsson (1923), Paul Greengard (1925) and Eric (Richard) Kandel (1929) 'for their discoveries concerning signal transduction in the nervous system'. Arvid Carlsson discovered that dopamine is a transmitter in the mammalian brain.

The Nobel Prize in Physiology or Medicine 2010
The Nobel Prize in Physiology or Medicine 2010 was awarded to Sir Robert (Geoffrey) Edwards (1925-2013) 'for the development of IVF'.

Declaration of interest
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.