Advances in the Field of : A Demographic Analysis

A Research Thesis Presented to

The Faculty of the Department Adelphi University

By Pari Waghela

In Partial Fulfillment of the Requirements

for the M.S. Degree in Biology

Date: 1/14/2021

Advisor: Dr. Tandra Chakraborty

Thesis Committee: Dr. Andrea Ward

Dr. Deborah Cooperstein

Acknowledgement

I want to express my gratitude to my thesis advisor, Dr. Tandra Chakraborty, Chair and Professor of the Biology Department of Adelphi University. The doors of her office were always open whenever I had doubts and queries regarding the thesis and the courses that I found extremely difficult to understand. Her vision, motivation, and faith in my work deeply inspired me. She has always guided me to the right path of my career, and this would not be possible without her guidance and support. I am extremely grateful for the opportunity offered to me.

I would also like to thank my committee members, Dr. Andrea Ward, Associate Dean for Student

Success Strategic Initiatives, Adelphi University and Dr. Deborah Cooperstein, Professor at

Biology, College of Arts and Sciences and Vice President for Collective Bargaining American

Association of University Professors, Adelphi Chapter, Adelphi University. I have gratefully indebted them to her for their precious comments on this thesis.

I am extremely grateful to my parents, Rakesh Waghela (Father) and Mittal Waghela (Mother), for their love, prayers, and sacrifices to educate and prepare me for my future. I am very much thankful to Pratham Waghela (brother), for understanding and support me throughout my education. This accomplishment would not have been possible without them.

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ABSTRACT

Endocrine glands are the ductless glands of the endocrine system that directly secrete their products, , and blood. Once released into the bloodstream, they travel to their target organ or tissue, which has receptors that recognize and react to the . Endocrinology is growing daily, upcoming with new hormones and hormone-like factors being discovered regularly, and these discoveries have been influential in medical science. The first in and was awarded in 1909. Since then, around 23 Nobel Prizes have been awarded to the different Nobel Laureates that had discoveries directly or indirectly linked to Endocrinology.

However, we have a moderate nearness about the Nobel Laureates that have positively contributed to Endocrinology, and they are addressed as a scientist or distinguished lecturers. The research in this article will discuss the contribution of each Nobel Laureates in the field of Endocrinology.

With the help of the custom world map tool, the distribution of each Nobel Laureate in the World and within the US is obtained and distinguished. Therefore, this paper will introduce the discovery and the achievements of the Nobel Laureates. It will also reflect the distribution of Nobel laureates worldwide- discoveries and inventions, distribution of renowned universities with the number of winners, GDP influence on these discoveries, and ethnic representation.

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TABLE OF CONTENTS

Introduction ...... 5

The Nobel Prize for 1909 was awarded to ...... 7

The Nobel Prize for 1923 was jointing awarded to Frederick Grant Banting and John James

Rickard Macleod ...... 10

The Nobel Prize for 1939 was awarded to Adolf Friedrich Johann Butenandt and Leopold

Ruzicka ...... 14

The Nobel Prize for 1947 was divided, one half jointly to Carl Ferdinand Cori and Gerty

Theresa Cori and the other half to Bernardo Alberto Houssay...... 18

The Nobel Prize for 1950 was awarded to Edward Calvin Kendall, Tadeus Reichstein and

Philip Showalter Hench ...... 23

The Nobel Prize for 1955 was awarded to Vincent du Vigneaud ...... 28

The Nobel Prize for 1958 was awarded to ...... 31

The Nobel Prize for 1964 was awarded jointly to Konrad Bloch and ...... 34

The Nobel Prize for 1966 was awarded equally to Peyton Rous and Charles Brenton Huggins

...... 38

The Nobel Prize for 1970 jointly awarded to , and

...... 42

The Nobel Prize for 1971 was awarded to Earl Sutherland ...... 45

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The Nobel Prize for 1977 was divided, one half jointly to and Andrew V.

Schally and another half to Rosalyn Yalow ...... 47

The Nobel Prize for 1982 jointly to Sune K. Bergström, Bengt I. Samuelsson and John R.

Vane ...... 52

The Nobel Prize for 1985 jointly to Michael S. Brown and Joseph L. Goldstein ...... 56

The Nobel Prize for 1986 was awarded to Stanley Cohen and Rita Levi-Montalcini ...... 59

The Nobel Prize for 1994 was awarded jointly to Alfred G. Gilman and ...... 62

The Nobel Prize for 2000 was awarded jointly to , and Eric R.

Kandel...... 67

The Nobel Prize for 2010 was awarded to Robert G. Edwards...... 73

Distribution of Nobel Prizes in the Field of Endocrinology by Country ...... 76

Distribution of Nobel Prizes in the field of Endocrinology within ...... 78

Women in Science ...... 80

Ethnic Representation ...... 82

References...... 84

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INTRODUCTION

The Nobel Prize is considered the World's most prestigious award. The Nobel Prize is awarded to

'those who, during the preceding year, shall have conferred the greatest benefit on mankind.' Alfred

Nobel was known for his great invention of dynamite, smokeless gunpowder, and a blasting cap.

He was a Swedish engineer, , and industrialist. He signed his last will in 1895 about passing down all of his "remaining realizable assets" to series of annual awards. Moreover, because of his will, the Nobel Prizes are awarded every year. Around 603 Nobel Prizes have been awarded between 1901 to 2020. The youngest Nobel Prize was awarded to Malala Yousafzai at 17 for her discoveries and justifications on Peace in 2014. With modern technologies, hormones and hormone-like factors are getting developed regarding helping the Endocrinology department of medical science grow faster. Endocrinology has consistently had a solid appearance at the Nobel

Prizes. The Nobel Laureates who have worked in endocrinology have also worked on other medicine areas, such as the immune system and nerve signaling (Shampo et al., 2012). In the last century, endocrinology has proved to be the one branch that has excelled in innovations. Women researchers have accomplished a moderately more grounded nearness in endocrinology. Two winners have declined the Nobel award, Jean-Paul Sartre, who was awarded the 1964 Nobel Prize in literature. He consistently received a denial from all official honors; therefore, he considered declining the Nobel Prize. Furthermore, Lê Ðức Thọ declined the 1973 Nobel Prize jointly with

US Secretary of State Henry Kissinger, who negotiated the peace agreement for Vietnam.

However, Lê Ðức Thọ said he was not in the position to accept the Nobel Award due to the current situation in Vietnam. The Nobel Prizes in Physiology or Medicine, Chemistry, and have been awarded to at least 33 distinguished researchers who were directly or indirectly involved in research into the field of endocrinology. With Nobel Prizes awarded all over the World to different

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Nobel Laureates, the United States has the highest number of Nobel Prizes. Many studied have been performed to analyze the distribution of the Nobel Prize in the United States (Shampo and

Kyle, 2001). Women are less likely recognized in medicine, and only three women have received

Nobel awards in the field of endocrinology. Therefore, this paper will introduce the discovery and the achievements of the Nobel Laureates. It will also reflect the distribution of Nobel laureates around the World- discoveries and inventions, distribution of renowned universities with the number of winners, and the influence of GDP on these discoveries. It will also describe the .

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THE NOBEL PRIZE FOR 1909 WAS AWARDED TO EMIL THEODOR KOCHER

Emil Theodor Kocher

Prize motivation: "for his work on the physiology, and

surgery of the gland."

Born: 25 August 1841, Berne,

Died: 27 , Berne, Switzerland

Affiliation: Berne University, Berne, Switzerland

Photo from the Nobel Foundation archive.

Kocher was born on August 5, 1841, in , Switzerland, the eldest of five children. He finished his medical studies in 1865 and started practicing surgery. Kocher was engrossed in research and published much experimental and clinical work in various surgical fields. Kocher was born on August 5, 1841, in Bern, Switzerland, the eldest of five children. He finished his medical studies in 1865 and started practicing surgery. Kocher was engrossed in research and published much experimental and clinical work in various surgical fields. He then spent a long time in Europe and , learning from pioneers such as Paget, Lister, Pasteur, Virchow, von

Langenbeck, and Billroth. Amongst them, Billroth and Lister had a significant impact on Kocher.

Billroth was considered one of the best thyroid in Europe and had performed 20 thyroidectomies by 1869. A thyroidectomy is a surgical procedure to remove all or part of the thyroid gland and treat the thyroid gland's diseases. In 1866, Kocher returned to Switzerland and worked as an assistant to Dr. Lücke, a surgery professor at the . Seven years

Page | 7 later, Lücke left his post, and Kocher was appointed full professor of surgery at the young age of

31. He stayed there and was active there until his death on July 27, 1917.

Theodor Kocher was the first to receive the Nobel Prize "for his work on the physiology, pathology, and surgery of the thyroid gland." In Switzerland, iodine deficiency was endemic, and many of Kocher's patients suffered from large goiters. In 1872, Kocher performed his first thyroidectomy using Billroth's vertical incision technique before splitting the capsule and ligating the major arteries. Sadly, they noticed profuse bleeding in the vascular gland, and the mortality rate was up to 40 percent. Moreover, it was then Kocher decided to abandon this technique. With this research background, several researchers decided to work upon the same experiment and reported their work. Also, other complications were recognized, specifically damage to the recurrent laryngeal nerve, causing hoarseness. It was essential to preserve this nerve. The complications of tetany and hypoparathyroidism were not understood. However, compared to

Billroth, Kocher had an impeccable and precise operating technique and worked in a relatively bloodless field. Probably because of this, he had fewer problems with postoperative tetany. Als, well-known to all thyroid surgeons, is the "Kocher incision," a transverse, slightly curved incision about 2 cm above the sternoclavicular joints.

In 1874, one of Kocher's patients, an eleven-year-old girl, successfully removed her thyroid gland and was expected. However, later, she became exhausted, and no signs of the initiative. Also, she had an idiotic appearance compared to her sister, which stimulated Kocher to investigate all his patients further. Almost all his patients, especially children, had this common symptom of hyperthyroidism: "Cachexia Strumipriva." However, Kocher did not understand that this was due to removing the thyroid gland but ascribed it to tracheal injury. These data made Kocher decide not to remove the whole gland in his future patients. When he died in 1917, more than 7,000

Page | 8 thyroid operations had been done in his clinic. The mortality decreased steadily from 14% in 1884 to 2.4% in 1889 and 0.18% in 1898.

The contributions of Theodor Kocher still today have a significant impact on thyroid surgery.

Theodor Kocher was a world leader in the surgical revolution in the last third of the nineteenth century.

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THE NOBEL PRIZE FOR 1923 WAS JOINTING AWARDED TO FREDERICK GRANT BANTING AND JOHN JAMES RICKARD MACLEOD

Frederick Grant Banting

Prize motivation: The discovery of

Born: 14 November 1891, Alliston, Canada

Died: 21 February 1941, Newfoundland, Canada

Affiliation: University of Toronto, Toronto, Canada

Photo from the Nobel Foundation archive.

John James Rickard Macleod

Prize motivation: The discovery of insulin

Born: 6 September 1876, Cluny, Scotland

Died: 16 March 1935, Aberdeen, Scotland

Affiliation: University of Toronto, Toronto, Canada

Photo from the Nobel Foundation archive.

Frederick Banting was born on 14 November 1891 on a farm in Ontario, Canada. Two childhood incidences motivated him to choose medicine as a carrier. The first was two men collapsing off a roof they were working on during construction. Banting quickly got the doctor from the to town with the presence of mind, and this action n left everyone shocked. The other one

Page | 10 was about his closest friend Jane. She was very energetic and charming until when she started losing weight and complained about her constant thirst. A few months later, Jane passed away due to mellitus. Banting wondered why it is so difficult to cure this and the pointless deaths.

John James Macleod was born on 6 September 1876 in Cluny, Scotland, and died on 16 March

1935, Aberdeen, Scotland. He was selected as a Professor of Physiology at the University of

Toronto, Canada, in 1918, and he was interested in carbohydrate and specifically in

Diabetes. He has also published around 37 research papers on and around 12 papers on experimentally produced glycosuria.

Diabetes Mellitus is known to be the World’s oldest disease. The term ‘diabetes’ means ‘to pass through’ in Greek. It explains to donate a large amount of water consumed and the urine produced in Diabetes. Later the Romans added the term ‘Mellitus,’ which means ‘as sweet as honey’ when they saw that the urine of diabetic patients was sweet. It was a challenge to detect Diabetes in children with a less remote past, and most survived only a year after being diagnosed. Banting’s desire to become a doctor conflicted with his family. However, he transferred from his theology college to the University of Toronto Medical School in Canada. He was employed as a Professor at the University of Western Ontario. He was lecturing related to the pancreas, and with that, he started reviewing all the information he knew about the glands. With a little information out there, it was known that various juices are produced by the pancreas and flow through the tubes into the intestine that helps in the breakdown of food. Till the end of the 19th Century, in

Institute, the authorities of Diabetes, Dr. Joseph Freiherr Von Mering and Dr. Oscar Minkowski, depicted that the pancreatectomized dogs also had similar features to that of human Diabetes. A pathologist at the John Hopkins University, Eugene Opie, studied an essential relation between

Diabetes and the destruction of the Islets of Langerhans.

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Dr. Moses Barron described an autopsy report of a patient suffering from pancreatic stones and was obstructing the pancreatic ducts. One night, all these thoughts came into his head, and in a notebook, he scribbled “Diabetes [sic]. Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate, leaving islets. Try to isolate the internal secretion of these to relieve glycosuria [sic].”

Therefore, Banting decided to turn these thoughts into fruition. The results of the previous experiments and the healthy pancreas extracts were given to people with Diabetes with no improvement. Banting worked on the next step; he prepared a purified extract from only the islet cells. He later approached John Macleod since he wanted to work in a laboratory. Initially,

Macleod disagreed with Banting’s theory; however, he was convinced and allowed him to use the laboratory. In May 1921, Banting started working with a 21-year-old medical student, Dr. Charles

Herbert Best. He was doing his master’s thesis with Macleod. There was a sickly dog named

Marjorie, who had his pancreas removed a few days before the experiment. A few weeks later, the pancreatic ducts were tied off, and the atrophied pancreas was released, from which an extract was prepared that was then injected into Marjorie. An hour later, dogs’ demeanors were not as it was observed and noticed earlier. Marjorie could raise its head, stand, and also wagged its tail. Dog’s blood sugar level was drastically decreased. This dramatic reversal was possible due to islet cells extracted, and it was named ‘isletin’ by Banting.

Unfortunately, this joy of success did not last any longer because the blood sugar drop was impermanent. Very soon, Banting realized that this problem a considerable amount of extract is required and examined a report showing a higher amount of islet cells in the pancreas of fetal and newborn animals than an adult pancreas. With the help of Professor JP Collip, a biochemist joined the research group. The extract of islets that were obtained and were safe to be injected into humans. This non-toxic and effective material was named ‘isletin.’ Banting and Best presented the

Page | 12 first findings in dogs in November 1921. The first paper was published in February on ‘The

Internal Secretion of the Pancreas,’ which illustrated that insulin could abolish ketosis in the of diabetic dogs and stimulate glycogen formation. This massive clinical publication, ‘Pancreatic extracts in the treatment of diabetes mellitus,’ was mentioned in the ‘Journal of the Canadian

Medical Association’ in March 1922.

The data included the results of the diabetic patients on insulin treatment under the supervision of

Professor D Graham in Toronto General Hospital by WR Campbell and AA Flecther. Moreover, this data demonstrated that ‘the insulin reduced blood sugar to average values, abolished glycosuria and acetone bodies in the urine and produced general clinical improvement in human patients with severe Diabetes. The paper also demonstrated a case report of a 14-year-old boy,

Leonard Thomson, who was treated with the pancreatic extracts with dramatic and immediate success.

The exact details on the contribution of Macleod are still an ongoing topic for debate. According to Banting, Macleod had no part in the initial experiments and was not involved until returning to the University from Scotland. Macleod claimed that he guided Banting and Dr. Best from the start.

There was great aggression between the two men since Banting felt that Macleod took more credits than he essentially deserved. Furthermore, this bitterness was in their head when both of them were awarded the Nobel Prize for the discovery of insulin. Banting was furious because Dr. Best was not mentioned in the Nobel Prize. However, Banting decided to credit Dr. Best publicly and share half of his prize money. Macleod also chose to share his prize money with Dr. Collip.

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THE NOBEL PRIZE FOR 1939 WAS AWARDED TO ADOLF FRIEDRICH JOHANN BUTENANDT AND LEOPOLD RUZICKA

Adolf Friedrich Johann Butenandt

Prize motivation: "for his work on sex hormones."

Born: 24 March 1903, Bremerhaven-Lehe,

Died: 18 January 1995, Munich, Germany

Affiliation: University, Berlin, Germany

’ Photo from the Nobel Foundation archive.

Leopold Ruzicka

Prize motivation: "for his work on polymethylenes and terpenes."

Born: 13 September 1887, Vukovar, Austria-Hungary

Died: 26 September 1976, Zurich, Switzerland

Affiliation: Swiss Federal Institute of Technology, Switzerland

Photo from the Nobel Foundation archive.

Adolf Butenandt was a German Businessmen born on March 24, 1903, in Bremerhaven-Lehe in northwestern Germany. After his early education, he entered the University of Marburg, where he studied biology and chemistry. Soon after receiving his bachelor's degree, he started with his postgraduate work at the University of Göttinge. In 1927 he received Ph.D. on his thesis

Page | 14 concerning "chemistry of rotenone, a compound used in insecticides." Leopold Ruzicka was born on September 13, 1887, in a small town on the Danube in Croatia. His father was Croatian, and his mother was of German descent. With frequent riots in his home country, he moved to Germany and studied at the Karlsruhe Institute of Technology. He finished his laboratory courses in less than two years and moved forward with his doctoral work on ketenes. In 1910, he received his doctorate, and he joined as an assistant at the Swiss Federal Institute of Technology in Zurich

(ETH). By 1916, Ruzicka wanted to research his own choice, and he was pleased to work on the laboratory bench from morning tonight.

Significantly less was known about sex hormones. The only hormones known were thyroxine, insulin, and adrenaline. was a scientific assistant from 1927-1930 at the Institute of Chemistry in Göttingen. Butenandt was supplied with dark brown syrup that was extracted from a pregnant woman's urine. A crystalline substance was isolated from the extract and was named 'progynon' in the first paper by Butenandt. It was then changed to 'folliculine' that indicates its sources: the ovarian follicles. Many various names were suggested for this hormone until the term 'oestrone' was internationally accepted at the League Nations conference in 1935 in

London. Estrone is one of the hormones responsible for the functions and sexual development in females. And this work was vital in the development of the birth control pill. Accidently, similar research was performed simultaneously by Edward A. Doisy (1893-1986), an American

Biochemist.

However, now the race was amongst the two for the prize, and the one to receive should obtain the oestrone's chemical structure. Butenandt and other research groups from the US and Britain accepted the challenge. For the structural studies, Butenandt further isolated oestrone and the

Page | 15 related hormone oestriol from 1000-2000 liters of urine.

Figure 1: Butenandt’s degradation experiments (Akhtar, M., & Akhtar, M. E et., al 1998).

The mutual relationship between oestrone and oestriol was defined by Butenandt's degradation experiments and by establishing that these sex hormones contain the carboxylic ring system of cyclopentanophenanthrene. This data, along with the knowledge of the structure of other degradation products, led Butenandt to propose the four-ring structure of oestrone (Akhtar, M., &

Akhtar, M. E et al.,1998). With his fine work on oestrone, he was appointed to the Biochemical

Department's headship at the University of Gottingen, and this position further encouraged him to work on . Therefore, two years later, by working with another chemist, Butenandt also isolated androsterone, a male hormone. It was obtained by 15 milligrams of crystalline substance from 3,960 gallons of male urine.

Further research demonstrated that male hormones are not only similar to that of oestrone, but they are closely related to steroids. Leopold Ruzicka then illustrated that cholesterol could be transformed into androsterone. Based on this work, they synthesized testosterone, the hormone responsible for the development of masculine characteristics. Butenandt successfully isolated another female hormone, progesterone, by using the extracts from sow ovaries. After 20 years of

Page | 16 research, in 1958 and 1959, Butenandt and his co-workers purified the sexual attractant of the silk moth Bombyx mori and also determined the chemical structure of that substance, now known as a pheromone.

Leopold Ruzicka is also known as the Lord of the Carbon Rings, and he was at the forefront of hormone research in the World. All his life, he was interested in the chemical process of .

He was a Professor of Organic Chemistry and has also worked in an analytical laboratory. Ruzicka had a partnership with perfume manufacturers Chuit, Firmenich, and Naef. After working on the natural odors from 1916 to 1924, his interest developed in researching other large ring molecules like steroids and hormones. Ruzicka investigated polyethylenes and terpenes; these are the chemical names for the odorous substances that are produced by animals and plants. During his research, he could identify the chemical structures of civetone and machine, odors from the skin glands of civet cats and musk deer.

Furthermore, he achieved great success in synthetically producing these substances in the lab that caught the Swiss perfume company's interest. He identified that these substances contained rings of seventeen and fifteen carbon atoms, respectively. His discovery created an impression in organic chemistry because, during those times, it was believed that the molecules having rings of more than eight carbon atoms are unstable and therefore did not exist. This discovery of Ruzicka was a heroic one and was achieved during a time of significant experimental challenges. After a few decades, started using the advanced version of analytical methods such as X-Ray analysis and spectroscopy with his findings.

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THE NOBEL PRIZE FOR 1947 WAS DIVIDED, ONE HALF JOINTLY TO CARL FERDINAND CORI AND GERTY THERESA CORI AND THE OTHER HALF TO BERNARDO ALBERTO HOUSSAY.

Carl Ferdinand Cori

Prize motivation: "for their discovery of the course of the

catalytic conversion of glycogen."

Born: 5 December 1896, , Austria-Hungary

Died: 20 October 1984, Cambridge, MA, USA

Affiliation: Washington University, St. Louis, MO, USA

Photo from the Nobel Foundation archive.

Gerty Theresa Cori

Prize motivation: "for their discovery of the course of the catalytic

conversion of glycogen."

Born: 5 December 1896, Prague, Austria-Hungary

Died: 20 October 1984, Cambridge, MA, USA

Affiliation: Washington University, St. Louis, MO, USA

Photo from the Nobel Foundation archive.

Gerty Theresa Cori

Prize motivation: "for their discovery of the course of the catalytic

conversion of glycogen."

Born: 5 December 1896, Prague, Austria-Hungary Page | 18

Died: 20 October 1984, Cambridge, MA, USA

Affiliation: Washington University, St. Louis, MO, USA Bernardo Alberto Houssay

Prize motivation for his discovery of the part played by the

hormone of the anterior pituitary lobe in the metabolism of

sugar."

Born: 10 April 1887, ,

Died: 21 September 1971, Buenos Aires, Argentina

Affiliation: Institute for Biology, Buenos Aires, Argentina

Photo from the Nobel Foundation archive.

Carl Cori was born on December 5, 1896, in Prague, Czechoslovakia. He was a son of a

Zoology Professor at the University of Prague. He has served in the Austrian army on the Italian front since his education was interrupted during World War I. During that time, he was appointed to the ski corps, a bacteriological laboratory, and a hospital for an infectious disease during his military service. However, in 1918, he returned to the university and received his MD from the

German University of Prague in 1920, and at the same time, he met Gerty when they were students and got married. She was born on August 16, 1896, in Prague, Czechoslovakia. She was the third woman to receive the Nobel Prize after and her daughter Irene Joliot-Curie. Her early education was from private tutors and, she graduated from a private school for girls in 1912 in

Prague. She started her education at the German University of Prague, where she met Carl. Gerty and Carl immigrated to the United States and initially obtained positions at the New York State

Institute for the Study of Malignant Disease in Buffalo in 1922 and became US citizens in 1928.

She was appointed as a biology chemistry professor at Washington University School of Medicine in St Loui,s and Carl were selected as a pharmacology professor. The Coris directed their Nobel

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Prize-winning work in St Louis on the metabolism of glycogen. Bernardo A. Houssay was born on April 10, 1887, in Buenos Aires, Argentina. From the very beginning, youthful Houssay showed great enthusiasm in academics, and his abilities allowed him to receive scholarships at a very early age. Within months, he matriculated from a bachelor's degree to pharmacology at the University of Buenos Aires. After his graduation, he was appointed as a Professor of Physiology at the

University's School of Veterinary Medicine.

From the beginning, when the Coris moved to Buffalo, they were interested in carbohydrate metabolism in malignant as well as normal tissue. During the initial years in Buffalo, they focused their research on the metabolism of carbohydrates in tumor cells. They additionally worked on the impacts of ovariectomy on the growth of tumors. They investigated how glycogen was broken down and resynthesized in the body. Glycogen is the carbohydrate that is stored in the liver and muscles. Two decades earlier, Otto Meyerhof, a German Biochemist (1884-1951), demonstrated glycogen's conversion to lactic acid in a moving muscle, but no details were provided about the conversion. The Cori ester is the activated intermediate phosphate, and the Coris discovered it in 1936. They also confirmed that the conversion of glycogen into glucose is the very first step.

The laboratory at Washington University was under contract with the Office of Scientific Research and Development to study the effect of toxic gases on enzyme systems, and Carl was assigned the responsibility. In 1942, The Coris achieved the test-tube synthesis of glycogen by isolating and purifying enzymes held responsible for catalyzing the glycogen-Cori ester reaction. The Cori cycle was formulated by demonstrating the interconversion, stating that glycogen in the liver is converted to blood glucose, which later is reconverted to glycogen in muscle, where its breakdown to lactic acid causes muscle contraction by providing energy. By studying the impact of hormones

Page | 20 on carbohydrate metabolism in animals, the Coris proved that epinephrine further induces the formation of a phosphorylase enzyme that favored conversion of glucose to glycogen and that the removal of sugar from the blood is due to insulin. A few years later, after his wife's death, he was working as a visiting professor of at Harvard University School of Medicine. During that phase of time (1984), he was able to purify glucose-6-phosphate and studied its role in regulating blood glucose in diabetic patients. Carl has published more than 200 scientific articles and was honored by societies and institutions around the World.

Bernardo Houssay took part in taking care of patients suffering from acromegaly symptoms, a noncancerous tumor that mostly affects adults. The patient was found to have a pituitary tumor, and therefore, Houssay was keen to learn about it in depth. He learned the physiologic activity of the pituitary glands and also got accustomed to the methods on how to harvest the tissue, analyze it, and also isolate the physiologically active components. He described this work as his doctorate thesis, for which he was awarded the University of Buenos Aires' prestigious Faculty of Medical

Science Award. His journey to the Nobel Prize took place right at this moment. In 1919, a 32-year- old transformed the Physiology Department at the University of Buenos Aires into an extremely active center of research. Houssay studied in-depth about human physiology of the respiratory, endocrine, and circulatory systems, and immunology and neurology.

Following the finding of insulin by , Charles Best, and other researchers in 1921,

Houssay further investigated this hormone and included carbohydrate metabolism. However, during this time of his investigation, it was believed that the dogs that have gone through the pancreatectomy were more prone to hyperglycemia, i.e., the lack of insulin production; therefore, these animals seemed to develop diabetes mellitus. More critical, Houssay found that these animals that had undergone hypophysectomy experienced the complete opposite effect, and that was; they

Page | 21 were more susceptible to hypoglycemia. This observation and investigation concluded that there is one or more than anti-insulin in the adenohypophysis, diabetogenic principles. Houssay worked on pancreatectomized dogs, and they were mainly known as 'Houssay dogs'; in them, he noticed that the diabetic state was highly enriched on the removal of the adenohypophysis (Tan, S. Y., &

Ponstein, N. et al., 2016). Toads have a very favorable anatomic accessibility and the east of selectively extracting the anterior pituitary tissue.

For this reason, Houssay also used toads for his experiment. After he injected the anterior pituitary extracts into the euglycaemic toads that lacked the hypophysis and the pancreas, hyperglycemia was supervened. After receiving all this data, Houssay concluded that the carbohydrate metabolism is not entirely dependent on the insulin action itself and the interplay and feedback of insulin and additional hormones produced in the anterior pituitary. Due to Houssay's discovery, we now know that growth hormone is considered a critical hormone. However, a thyroid-stimulating hormone, adrenocorticotropic hormone, and other hormones play some vital roles in stabilizing the human body's metabolic activity.

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THE NOBEL PRIZE FOR 1950 WAS AWARDED TO EDWARD CALVIN KENDALL, TADEUS REICHSTEIN AND

Edward Calvin Kendall

Prize motivation: "for their discoveries relating to the hormones of

the adrenal cortex, their structure and biological effects."

Born: 8 March 1886, South Norwalk, CT, USA

Died: 4 May 1972, Princeton, NJ, USA

Affiliation: , Rochester, MN, USA

Photo from the Nobel Foundation archive.

Tadeus Reichstein

Prize motivation: "for their discoveries relating to the hormones

of the adrenal cortex, their structure and biological effects."

Born: 20 July 1897, Wloclawek,

Died 1 August 1996, Basel, Switzerland

Affiliation: Basel University, Basel, Switzerland

Photo from the Nobel Foundation archive.

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Philip Showalter Hench

Prize motivation: "for their discoveries relating to the hormones

of the adrenal cortex, their structure and biological effects."

Born: 28 February 1896, , PA, USA

Died: 30 March 1965, Ocho Rios, Jamaica

Affiliation: Mayo Clinic, Rochester, MN, USA

Photo from the Nobel Foundation archive.

Edward Kendall was born on March 8, 1886, in South Norwalk, Connecticut. His father was a dentist, and he was the third of eight children. He went to Franklin Elementary School in

South Norwalk for his early education. He then enrolled himself at Columbia University in New

York City. He received his BS degree in 1908 and MS degree in 1909, both Columbia. In 1910, he received his Ph.D. degree with a thesis on the kinetics of pancreatic amylase. While working at

St. Luke's Hospital, Kendall discovered his interest in the thyroid gland and researched thyroid hormone in thyroid gland extract. On February 1, 1914, he joined the Mayo Clinic in Rochester,

Minnesota, as Biochemistry. However, his early research was concerned with the effects of the active constituent, i.e., thyroxine, of the thyroid gland (Shampo, M. A., & Kyle, R. A. et al., 2001).

Philip Showalter Hench was born on , 1896, in Pittsburgh, PA. He was also highly known as a clinician, a teacher, and a medical historian. In 1916, he graduated in arts from

Lafayette College in PA. He also worked in the Medical Corps during World War I in 1920 medicine. Before joining the Mayo Clinic in 1923 as a Fellow of the Mayo Foundation in

Rheumatic disease, he was an intern at St. Francis Hospital, Pittsburgh, PA. Reichstein was born

Page | 24 on July 20, 1897, in Włocławek, the Polish Province of Kujawy. His parents were truly Polish, and therefore they named their son after a Polish National here, Tadeusz Kościuszko. They later settled in Zurich, and Tadeusz had a private tutor. He became a Swiss citizen in 1914, and during that time, he was studying Chemistry at the Technical University in Zurich. He was a very bright student, and in 1920 he completed his undergraduate studies. In 1922, he received his doctorate research on aromatic substances in coffee and chicory under Professor (1881-

1965). He later received the Nobel Prize for discoveries in the field of macromolecular chemistry.

Reichstein was an author or a co-author of 635 papers, and the last paper was published at the age of 97. He presented himself as "a Swiss of Polish-Jewish descent" but was known as a World

Citizen with his scientific achievements.

The effectiveness of steroids for topical use mainly depends on their chemical structure and base. Natural and therapeutic steroids are often used for therapeutic purposes. Topical steroids are mainly for their anti-inflammatory and anti-proliferation activity to treat various skin conditions, including psoriasis and atopic dermatitis. In 1934, Reichstein started his research on hormones of the adrenal cortex. During 1931, the main details about these hormones were known, but what remained a mystery was the active substances. Reichstein and many other researchers took these as a challenge and started working on identifying and synthesizing these substances for commercial purposes. In 1936, the first paper was published on this subject, and it was due to using chromatography for isolating and identifying new substances by Reichstein.

Moreover, in the time span of the next ten years, he could isolate and elucidate the chemical structure of 29 pure substances from the extract, and all of these were derivatives of steroids, including corticosterone and hydrocortisone. The era in dermatology began when Marion

Sulzberger (1895-1983) and Victor Witten (1916-2007) used hydrocortisone as a topical treatment.

Page | 25

The first success by Reichstein was marked in 1937 when he produced deoxycorticosterone, an asteroid that had one less oxygen atom at the 11 positions of the sterane rings. This substance proved to be useful in Addison's disease by regulating electrolytes and water levels. Reichstein isolated deoxycorticosterone from adrenal cortex extract and named it "A substance." With a great passion for Botanics, he turned his research to plant steroids because the cardiac glycosides have a genin part and a steroid structure. However, the search was based on discovering the substance having oxygen atoms at the 11 position of the sterane ring, and they were finally found in

Strophanthus seeds. Furthermore, this discovery was important because it could be further used for commercial production.

However, in the late 1920s, Edward Kendall and other researchers working together discovered thyroxine and its role in the physiologic condition. This discovery led them to the structurally undefined substance glutathione, which plays a crucial role in enzyme activation and oxidation. In the 1930s, Kendall isolated 28 various corticoids or cortical hormones from the .

Amongst these, only six were active, so in 1935 he named these compounds as A, B, C, D, E, and

F. Reichstein and Edward both worked on isolating the same substances but in a different organization. Kendall believed that his "compound A" (II-dehydrocorticosterone) was the one.

However, the Germans were using Kendall's "compound A" and constant research efforts to find different ways to synthesize it. Merck and Co, in the United States, finally found a way for synthesizing . They came to know that about 575kg of bile can produce 1000mg of cortisone. An American rheumatologist at Mayo Clinic, Philip Hench, observed that pregnancy and jaundice caused remission of arthritis patients' pain. Kendall and Philip together determined that adrenocortical hormones triggered the remission. Moreover, this further made the arthritis patient the best for the first clinical trials with steroids. On September 21, 1948, a 29-year-old

Page | 26 woman who was utterly bedridden was administered the first cortisone, and surprisingly, after a couple of days, she went shopping by herself. This moment marked the beginning of steroid treatment in medicine.

Kendall's and Hench's contributions played an important role because they used adrenocortical hormones not for using them as missing hormones but for treating a disease that had no relation to the adrenal glands' functioning. At the same time, Reichstein's contribution was identifying and isolating the hormones and elucidating some of the many stages in their synthesis.

Page | 27

THE NOBEL PRIZE FOR 1955 WAS AWARDED TO VINCENT DU VIGNEAUD

Vincent du Vigneaud

Prize motivation: "for his work on biochemically important

sulphur compounds, for the first synthesis of a polypeptide

hormone."

Born: 18 May 1901, , IL, USA

Died: 11 December 1978, White Plains, NY, USA

Affiliation: , Ithaca, NY, USA

Photo from the Nobel Foundation archive.

Vincent du Vigneaud was born on May 18, 1901, in Chicago, Illinois. He was the son of a designer and inventor of machines. In 1923, he received his bachelor's degree, and in 1924, he received his master's degree, and both were in Chemistry at the University of Illinois at

Champaign-Urbana. He worked as an assistant biochemist at the Graduate School of Medicine at the University of , and at the same time, he also worked in the chemistry laboratory at the Philadelphia General Hospital. In 1927, he received his Ph.D. in chemistry. For three years, he studied in Germany as well as London, UK. In 1930, he returned to the United States and joined the Department of Physiological Chemistry at the University of Illinois at

Champaign-Urbana. For eight years, he was a professor and a chair of the Biochemistry

Department at the George Washington University School of Medicine in Washington, DC, until he became head of the Department of Biochemistry at Cornell University Medical College in

New York City. While studying organic chemistry, his primary interests were sulfur-containing

Page | 28 compounds that eventually gave results for a better understanding of the pituitary gland and the development of the therapeutic and diagnostics tool for diseases related to the pituitary. His interests led to the discovery of the synthesis of the first polypeptide hormones: vasopressin and .

Du Vigneaud developed his interest in chemistry from a very young age. During the early days of his bachelor's, he realized his interest in biological compounds' chemistry. His mentors from the University of Illinois recommended him to Professor Murlin for his doctoral degree at the School of Medicine, New York. In November 1927, his thesis work on "The Sulfur of Insulin" was published in the Journal of Biological Chemistry. With a constant interest in chemistry, he decided to continue working on the chemistry of insulin. He was first known by his peers after receiving an award in 1937 for his work on "The chemistry of biologically significant sulfur compounds, and really for the synthesis of glutathione" from the Chemical

Society of Washington. Since he was offered a professorship position in biochemistry in

Washington, DC, at the George Washington University School of Medicine, he worked there for

6 six years and later moved to Cornell Medical College. The research group he was working with,

George Washington University, joined Cornell's research group and worked together. Therefore, at Cornell, he continued his work on insulin and the posterior pituitary hormones, and he also had special knowledge in biochemistry.

He discovered the structure of biotin (vitamin H), determined the transmethylation of homocysteine and choline, and determined the mechanism of transsulfuration of methionine to cysteine (Ottenhausen, M., Bodhinayake, I., Banu, et al., 2016). During the Cold War, there was great importance on scientific research, especially in medicine and chemistry. Therefore, post-war, he continued his work on one of the posterior pituitary hormones: oxytocin. He had developed

Page | 29 certain methods of his own while working at George Washington University, so after isolating and purifying oxytocin, he used glutathione synthesis methods to synthesize oxytocin. The methods were; initial protection of the sulfur groups using benzyl groups and subsequent removal of the benzyl groups using sodium and liquid ammonia. This effort made the breakthrough by marking the first synthesis of a polypeptide hormone. He was awarded several times at Cornell, such as the

Mead Johnson Award and the Osborne and Mendel Award in 1943, the Nichols Medal in 1945, the from the American Public Health Association in 1948, the Nobel Prize in 1955, and the Gibbs Medal in 1956. Furthermore, in 1955, he received a Nobel Prize for his "work on biochemically important sulfur-containing compounds," especially "the first synthesis of a polypeptide hormone." On December 12, 1955, Du Vigneaud gave his Nobel lecture, and in that he mentioned that the synthesis of the sulfur-containing oxytocin "was the culmination of many experiences along a trail of research stemming from my original interest in sulfur and insulin."

His research prolonged the medical treatment options available for the posterior pituitary disease and marked the route for clinical trials by using hormone therapy. However, oxytocin is most used for the labor induction and prevention of postpartum hemorrhage. Vincent du

Vigneaud's deep-rooted commitment to the organic chemistry of sulfur-containing mixes was the spotlight that drove him on a path to the revelation that had a broad and dependable effect all through various fields of medication.

Page | 30

THE NOBEL PRIZE FOR 1958 WAS AWARDED TO FREDERICK SANGER

Frederick Sanger

Prize motivation: "for his work on the structure of proteins,

especially that of insulin."

Born: 13 August 1918, Rendcombe, United Kingdom.

Died: 19 November 2013, Cambridge, United Kingdom.

Affiliation: , Cambridge, United

Kingdom

Photo from the Nobel Foundation archive.

Frederick Sanger is also known as an English Biochemist and Molecular Biologist. He was born on August 13, 1918 in Rendcombe, Gloucestershire, in southwestern England. He died at the age of 95 on November 19, 2013 in Cambridge, United Kingdom. He was twice winner of the

Nobel Prize in Chemistry, the first one in 1958 for his work on the structure of the insulin molecule and the 1980 award for determining the base sequence of nucleic acids. The 1980 Nobel Prize was shared between Sanger, Paul Gilbert and . Sanger was a son of a local and that motivated him to choose biology and aimed for a career in scientific research. From the year

1932 to 1936, he attended the Bryanston School in Blandford in Dorset. Later he got a place in St.

John’s College, Cambridge and during those times his interest started building in biochemistry and he believed that he could develop a more scientific basis to understand different problems related to medicine. During the phase of World War II, he chose to engage himself in antiwar hard work and contributed in social relief work and also in hospitals.

Page | 31

In 1939, he received his bachelor’s degree but remained in Cambridge during World War

II and worked on his doctorate degree. Professor A. Neuberger was his research advisor and he explained that the main problem England was facing at that time was lysine metabolism therefore,

Professor A. Neuberger encouraged him to work on that and especially the nutritional value of potatoes. However, 1943 he received his doctorate degree in biochemistry for his thesis on investigating the metabolism of amino acid lysine. A protein chemist, Professor A. C. Chibnall that recently received a place in F. G. Hopkins as Head of the Biochemistry Department offered

Sanger a space to work according to his freedom. And just within a year, he received a Beit

Memorial Fellowship for Medical Research award. For 10 years, Sanger continuously worked on developing the structure of the bovine insulin molecule. And by the year 1955, he established the exact order of all the amino acids of the molecule. Fluorodinitrobenzene (FDNB) was a newly discovered colored reagent and Sanger made a beneficial use of it by using it to tag and identify the termini of insulin’s two chains; phenylalanine and glycine. Sanger was able to generate various number of peptides by using partial acid hydrolysis and enzymatic digestions with different proteases, and those peptides having amino-terminal were tagged with 5,5’-dithiobis-2- nitrobenzoic acid (DTNB) and they were separated by a complete new techniques those times, which is now used for every research, electrophoresis and paper chromatography. After many years of efforts, but by following all the methods, Sanger successfully deduced the amino acid sequence of two insulin chains. And what took many years to solve the mystery was which cysteins were involved in the single intra-A chain disulfide bond and in the two disulfide bonds linking the

A and B chains. However, by the year 1955, the entire sequences of the insulin A and insulin B chains were known and also determined the linkages that held these two chains together.

Page | 32

It is essentially difficult to overestimate the effect he has had on present-day modern genetics and molecular biology, with significant outcomes to all of the existence sciences. Apart for the Nobel Prize he received in 1958 for this discovery, he also received many other Prize and honors, including the Corday-Morgan Medal and Prize of the Chemical Society (1951), the

Gairdner Foundation Annual Award (1971 and 1979), the William Bate Hardy Prize of the

Cambridge Philosophical Society (1976), the Copley Medal of the Royal Society (1977), the

Wheland Award (1978), the Horwitz Prize (1979), and the Lasker Award (1979).

Page | 33

THE NOBEL PRIZE FOR 1964 WAS AWARDED JOINTLY TO KONRAD BLOCH AND FEODOR LYNEN

Konrad Bloch

Prize motivation: "for their discoveries concerning the

mechanism and regulation of the cholesterol and fatty acid

metabolism."

Born: 21 January 1912, Neisse, Poland.

Died: 15 October 2000, Burlington, MA, USA.

Affiliation: Harvard University, Cambridge, MA, USA.

Photo from the Nobel Foundation archive.

Feodor Lynen

Prize motivation: "for their discoveries concerning the

mechanism and regulation of the cholesterol and fatty acid

metabolism."

Born: 6 April 1911, Munich, Germany

Died: 6 August 1979, Munich, Germany

Affiliation: Max-Planck-Institut für Zellchemie, Munich,

Germany Photo from the Nobel Foundation archive.

Konrad Emil Bloch was a German-American Biochemist. He was born on January 21,

1912, in Neisse, a small town in Germany. He died on October 15, 2000, in Burlington, MA, USA.

He received his early education in Neisse and entered Technische Hochschule in 1930. He

Page | 34 graduated in 1934 with a degree in chemical engineering. To avoid the environment created by

Adolf Hitler (1889-1945), Bloch moved to Switzerland and studied the biochemistry of phospholipids in tubercle bacilli. He stayed in Switzerland until 1936, when he moved to the

United States and got admitted into Columbia University, where he received his Ph.D. Feodor

Felix Konrad Lynen was born on April 6, 1911, in the Schwabing district of Munich, Germany.

He was the seventh child, and his father was a great Professor of Mechanical Engineering. He showed a great interest in chemistry since he was a child by playing with a few experiments in his parent's house's loft area. Therefore, he started studying Chemistry at Munich University. In the early 1920s, he received his Ph.D. for working "On the Toxic Substances in Amanita." On the fruition of his doctoral theory, Lynen got familiar under his direction with natural chemistry's dynamic field.

Cholesterol contains 27 carbon atoms in each molecule and is found in animal cells. It plays a vital role in cell regulation, stabilization of cells' membranes, and a precursor to cortisone, bile, and all the steroid hormones. It is produced by the intestinal and liver cells. It is also ingested into the diet.

However, Bloch accepted the Columbia research team's position that was led by Rudolf

Schoenheimer. Scheonheimer, with his associate, David Rittenberg, had developed a technique by using radioisotopes as traces to flow the path of specific molecules in cells and living .

Moreover, this method was useful, especially in studying the biochemistry of cholesterol. Bloch and Lynen studied the biochemistry of cholesterol by using the technique developed in

Schoenheimer's lab that used radioisotopes.

Schoenheimer died in 1941; after his death, Rittenberg (his associate) and Bloch continued their research on cholesterol biosynthesis. The experiment was performed with rats in which they

"tagged" acetic acid (a 2-carbon compound) with radioactive carbon and hydrogen isotopes. After

Page | 35 performing this research, they were able to understand that acetate is a major component. This marked the beginning of Bloch's contribution to the Nobel Prize. However, in 1954 he got a position in the Department of Chemistry at Harvard University as a Biochemistry Professor.

Furthermore, throughout his period as a Professor, he continued to solve the mystery about the origin of all 27 carbon atoms in the cholesterol molecule. Eventually, they discovered that acetate's

2-carbon molecule is the origin of all carbon atoms in cholesterol. Bloch's research could explain the significance of acetic acid as a building block of cholesterol and proved that cholesterol happens to be a vital component of all cells of the body. The conversion of acetate into cholesterol requires 36 individual steps; one step involves transforming acetate molecules into hydrocarbon

(that is mainly found in of sharks in a huge amount). According to Bloch's plan for the research, he wanted to inject radioactive acetic acid into dogfish (a shark type). However, he also wanted to remove squalene as an intermediate role in cholesterol biosynthesis. Unfortunately, the dogfish died in confinement, and therefore he obtained squalene by injecting the radioactive acetate into the rat's liver. This experiment proved that squalene is one of the means in the biosynthetic transformation of acetic acid into cholesterol. Bloch and his co-researchers also discovered the other steps involved in converting acetate into cholesterol.

Lynn was attracted by "activated acetic acid," so he started working on converting acetic acid into citric acid- the reaction at the center of the aerobic breakdown of carbohydrates. Heinrich Wieland and Lynen both worked together on this project. Moreover, Wieland made an eye-catching observation; when you shook the yeast cells along with oxygen for many hours that had already used up oxidizable substances and by the addition of acetic acid to the "depleted" yeast, it was just ready to oxidize it following a few hours and could subsequently utilize for energy production.

However, it was still not determined what exactly happened inside the reaction vessels. Many

Page | 36 experiments resulted in disappointment. An American biochemist Franz Lipmann made the breakthrough because, in 1947, he had already isolated an unknown coenzyme from a pigeon-liver extract. It was able to transfer the acetyl groups; he chose to name it "coenzyme A." Therefore, the experiments with acetyl coenzyme A from the boiled extracts of yeast demonstrated Lynen correct.

And in two months, he confirmed his assumptions into experiments and was able to publish in

Angewandte Chemie. This clarification on the structure of "activated acetic acid" brought Feodor

Lynen an international clarification. Lynn and Bloch were researching different places; they discovered that mevalonic acid is converted into isoprene (chemically active), a hydrocarbon type.

And this is further converted into squalene; squalene is also transformed into lanosterol, and eventually, cholesterol is produced.

In 1964, Bloch and Lynen won the Nobel Prize together for their discoveries concerning the

"mechanism and regulation of the metabolism of cholesterol and fatty acids." The Swedish biochemist Sune Bergstrom who also won a Nobel Prize, commented, "The importance of the work of Bloch and Lynen lies in the fact that we now know the reactions that have needs to study concerning inherited and other factors. We can now predict that through further research in this field, we can expect to be able to do individual specific therapy against the diseases that in the developed countries are the most common cause of death."

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THE NOBEL PRIZE FOR 1966 WAS AWARDED EQUALLY TO PEYTON ROUS AND CHARLES BRENTON HUGGINS

Peyton Rous

Prize motivation: "for his discovery of tumour-inducing

viruses."

Born: 5 October 1879, , MD, USA

Died: 16 February 1970, New York, NY, USA

Affiliation: , New York, NY, USA

Photo from the Nobel Foundation archive.

Charles Brenton Huggins Prize motivation: "for his discoveries concerning hormonal

treatment of prostatic cancer."

Born: 22 September 1901, Halifax, Canada

Died: 12 January 1997, Chicago, IL, USA

Affiliation: University of Chicago, Ben May Laboratory for

Cancer Research, Chicago, IL, USA Photo from the Nobel Foundation archive.

Peyton Rous is also known as the father of the tumor virus. He was born on October 5,

1879, in Baltimore, MD, USA. He received his Bachelors's in 1900 and a master’s degree in 1905 from John Hopkins University. He also received an internship offer from John Hopkins, and he worked there for a short period of time. After that, he started working in research at the University

Page | 38 of Michigan. He worked in Europe after receiving a fellowship offer. He then returned to the

United States to take up a grant offered by the Rockefeller Institute for Medical Research to pursue research on lymphocytes. Charles B. Huggins was born on September 22, 1901, in Halifax,

Canada. He died at the age of 95 years. He completed his BA in 1920 from Acadia University and received his MD in 1924 from Harvard University, Boston, MA. He was the William B. Ogden

Distinguished Service Professor Emeritus of Surgery at the University of Chicago Medical Center.

Initially, there were eight faculty members in the department, and he was the last survivor of them, who died at the age of 95.

Tumor viruses belong to the six distinct families of animal viruses, and they are capable of directly causing cancer in experimental humans or animals. Biologic standards for a causal relationship of viruses with tumors include the presence of the virus in tumor tissues, viral presence, and the presence of virus before disease onset, the location of the virus at appropriate sites, and prevention of disease by prevention of viral infection. Peyton performed a series of experiments, and in 1909 his research studied the transmission of spontaneous cancerous tumors in chickens. He prepared a cell-free filtrate from a malignant sarcoma that was isolated from a chicken leg. It was further injected into the healthy hens, this way Rous discovered that the recipients that were injected developed the same tumors as the donors. This tumor could be further transmitted either by direct injection or through injection into the fertilized eggs, indicating that a

‘virus’ was the agent that was responsible for the transmission. Other different tumors were transmitted similarly with comparative loyalty in delivering tumors of the donors in the recipients.

However, by using mice Rous’ efforts were displayed whether tumors were transmitted in mammals until 1932, his Rockefeller colleague and his friend, Richard Shope, asked if he could work on the benign papillomas that were very commonly found in the wild rabbits that showed to

Page | 39 be transmissible by cell-free extracts. Despite providing evidence for Rous’s viral theory of cancer, many medical researchers refused to accept this theory. They argued with Rous that he had discovered a strange condition concerning birds and benign tumors, instead cancer. Furthermore, by 1950, this research in virology marked the beginning as the central element of the theory of cancer origins. Rous also influenced medical research through his position as long-time co-editor of the Journal of Experimental Medicine.

Prostate Cancer is one of the main reasons for death in the male in the United States. The prostate is a sex accessory gland present in all-male mammals, and it contributes secretions to the ejaculate during intercourse. The normal growth and development of the gland depend on the requirement of androgenic hormones. To better understand if prostate cancers were responding to the manipulation of the sex steroids hormone levels, Huggins used the blood biomarkers of disease activity. Many Huggins patients asked him about the purpose and function of the prostate, so by late 1930, Huggins and his students studied the relation between the function of the prostate gland and the endocrine system. Until then, the metastatic pain was reduced by a large dose of alkaloids and radiation of nerve roots. In 1951, he demonstrated that breast cancer was like prostate cancer, dependent on hormones, and advanced breast cancer can be possibly influenced by positive hormonal manipulation. Nevertheless, only 30 to 40% of women with breast cancer showed a positive response to this treatment. Therefore, after searching for a method that predicted positive response, he convinced Elwood Jensen, his colleague at the Ben May Laboratories in Chicago, to develop a technique that could identify estrogen receptors. Today, breast cancer classification as estrogen- negative or positive, an important prognostic and therapeutic marker marked the history. Later the Ben May Laboratories at the University of Chicago, with Huggins' help, contacted Ben May. After many years of decisions, Ben May agreed to support the Ben May

Page | 40

Laboratory for Cancer Research. Huggins was the first director of Ben May Laboratory in 1951, but Elwood Jensen succeeded him in 1969. Now this laboratory is known as the Ben May Institute for Cancer Research. In 1966, Dr. Huggins was known amongst the scientific world when he received the Nobel Prize for Physiology and Medicine, jointly with the virologist Peyton Rous.

Huggins' work influenced many other scientists to continue their research related to the behavior of cancer cells. Furthermore, his discovery opened a new era for rational chemotherapy of malignant disease through manipulation of endocrine regulation.

Page | 41

THE NOBEL PRIZE FOR 1970 JOINTLY AWARDED TO BERNARD KATZ, ULF VON EULER AND JULIUS AXELROD

Sir Bernard Katz

Prize motivation: "the humoral transmitters in the nerve

terminals and the mechanism for their storage, release and

inactivation."

Born: 26 March 1911, , Germany

Died: 20 April 2003, London, United Kingdom

Affiliation: University College, London, United Kingdom

Photo from the Nobel Foundation archive.

Ulf von Euler

Prize motivation: "the humoral transmitters in the nerve

terminals and the mechanism for their storage, release and

inactivation."

Born: 7 February 1905, Stockholm, .

Died: 9 March 1983, Stockholm, Sweden.

Affiliation: Karolinska Institutet, Stockholm, Sweden

Photo from the Nobel Foundation archive.

Page | 42

Julius Axelrod

Prize motivation: "the humoral transmitters in the nerve

terminals and the mechanism for their storage, release and

inactivation."

Born: 30 May 1912, New York, NY, USA.

Died: 29 December 2004, Rockville, MD, USA.

Affiliation: National Institutes of Health, Bethesda, MD, USA.

Photo from the Nobel Foundation archive.

Bernard Katz was a German-born British physician and biophysicist and was known for his work on nerve physiology. He was born in Leipzig, Germany, on March 26, 1911 and died on

April 20, 2003, in London, United Kingdom. Ulf von Euler was a Swedish psychologist and pharmacologist. He was born on February 7, 1905, in Stockholm, Sweden, and died on March 9,

1983, in Stockholm, Sweden. His work on made his outstanding. Julius Axelrod was an American biochemist. On May 30, 1912, he was born in New York, NY, and died on

December 29, 2004, in Bethesda, MD, the United States. The discovery by Katz, Euler, and

Axelrod has given a special understanding based on the working of and effector organs and nerve terminals. Neurotransmitters carry out the transmission between the nerve cells. Katz,

Euler, and Axelrod's independent discoveries had contributed to finding a solution for the main question about neurotransmitters, their storage, release, and inactivation.

Katz's discovery was related to the mechanism concerning the release of the transmitter acetylcholine from the nerve terminals at the nerve-muscle junction, under the influence of the nerve impulses. These nerve impulses are essential for the understanding of cholinergic Page | 43 transmission. They are also important for knowing the synaptic transmission between the nerve cells in the central . Euler discovered that noradrenaline plays a critical role in serving as a at the sympathetic nervous system's nerve terminals. He also discovered this substance's storage in the nerve granules within this particular system's nerve fibers.

Axelrod's discoveries focused on the mechanisms that regulated the formation of the transmitter in the nerve cells. Including that the mechanisms involved in the inactivation of noradrenaline under the influence of the enzyme that was discovered by him. The discoveries made by Euler and

Axelrod helped us build our basis of understanding the transmission in the CNS (central nervous system) and its pharmacology and also increased our knowledge about the transmission in the sympathetic nervous system. In a concise and significant manner, the three Nobel Laureates have presented the basic data regarding the chemical and the physical mechanisms of synaptic transmission. Their discoveries have taught us basic knowledge about the messages mediated between the nerve cells.

Their discoveries concerning these regulatory mechanisms in the nervous system are fundamental in neurophysiology and neuropharmacology and have greatly stimulated the search for remedies against nervous and mental disturbances (Julius Axelrod - Jewish Virtual Library)

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THE NOBEL PRIZE FOR 1971 WAS AWARDED TO EARL SUTHERLAND

Earl W. Sutherland, Jr.

Prize motivation: "for his discoveries concerning the

mechanisms of the action of hormones."

Born: 19 November 1915, Burlingame, KS, USA.

Died: 9 March 1974, Miami, FL, USA.

Affiliation: , Nashville, TN, USA.

Photo from the Nobel Foundation archive.

Earl W. Sutherland, Jr. was born on 19 November 1915, Burlingame, KS, USA, and died:

9 March 1974, Miami, FL, USA. He started working on this about twenty years before receiving the Nobel Prize. Epinephrine is a hormone as well as a neurotransmitter, and the adrenal glands produce it. Epinephrine is released into the bloodstream under a condition like stress. At the start,

Sutherland discovered that epinephrine demonstrations by initiating the enzyme (phosphorylase), which prompts the formation of glucose from glycogen. Sutherland explained that this activation took place by an intermediate and named this intermediate as “secondary messenger,” and it plays a major role in the mechanism of epinephrine and other hormones. And this recently named

“secondary messenger” proved to be a nucleotide; hence he named it cyclic adenosine phosphate.

The inactive phosphorylase is converted to an active enzyme by the nucleotide on cyclic AMP formation in the liver cells. He discovered that it was the enzyme adenyl cyclase by which the hormone stimulates the cell to cyclic AMP formation. He explained his results, and they were that epinephrine is attached to a receptor on the cell surface. The epinephrine attachment stimulates the Page | 45 enzyme adenyl cyclase, which then forms cyclic AMP, and when the phosphorylase is activated, cyclic AMP exerts its effect in the cell. And the effect of many other hormones is similar to this action. Sutherland first hypothesized that many hormones do not enter the cell and are stuck on the cell surface. Many scientists did not believe that cyclic AMP- a single molecule can have specific effects initiated by different hormones. With the mechanism of cyclic AMP action by

Sutherland, a large number of polypeptide hormones exert their effect similar to epinephrine.

Later, he also discovered that cyclic AMP also occurred in bacteria. Therefore, cyclic AMP is known as an original “primitive hormone.”

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THE NOBEL PRIZE FOR 1977 WAS DIVIDED, ONE HALF JOINTLY TO ROGER GUILLEMIN AND ANDREW V. SCHALLY AND ANOTHER HALF TO ROSALYN YALOW

Roger Guillemin

Prize motivation: "for their discoveries concerning the peptide

hormone production of the brain."

Born: 11 January 1924, Dijon,

Affiliation: The Salk Institute, San Diego, CA, USA

Photo from the Nobel Foundation archive.

Andrew V. Schally

Prize motivation: "for their discoveries concerning the

peptide hormone production of the brain."

Born: 30 November 1926, Wilno (now Vilnius), Poland.

Affiliation: Veterans Administration Hospital, New Orleans,

LA, USA.

Photo from the Nobel Foundation archive.

Page | 47

Rosalyn Yalow

Prize motivation: "for the development of

radioimmunoassays of peptide hormones."

Born: 19 July 1921, New York, NY, USA.

Died: 30 May 2011, New York, NY, USA.

Affiliation: Veterans Administration Hospital, Bronx, NY,

USA.

Photo from the Nobel Foundation archive.

This Nobel Prize is divided between two discoveries, one to Roger Guillemin and Andrew

Schally for their discoveries concerning "the peptide hormone production of the brain" and another half to Rosalyn Yalow. Yalow, the American medical physicist, was born on July 19, 1921, in The

Bronx, New York, United States, and died on May 30, 2011, in The Bronx, New York. She was the second woman and the first American-born woman to be awarded the Nobel Prize in physiology or medicine. Numerous hormones in our body belong to a group of peptide hormones produced by the thyroid gland, the hypophysis, the gastrointestinal tract, the placenta, and other tissues. There were no specific procedures to measure the number of peptide hormones in the blood, but the discoveries of Yalow had a contribution to this. Yalow and her coworker Solomon

Berson found that the patients that received the polypeptide hormone insulin injection developed antibodies against the hormone. Later it was discovered that with the addition of insulin labeled with radioactive iodine, the insulin antibodies formed a soluble complex. Besides non-labeled insulin to the mixture, it was able to displace the labeled insulin bound to the antibody. But it can be depicted in another way like "the percentage binding of labeled insulin to the antibodies is a

Page | 48 function of the total insulin concentration in the solution." And this leads to the start point for the radioimmunological determination of insulin. The radioimmunological assay known as RIA was described in many papers during 1950 and 1960, and by combining RIA with immunology, isotope research, physics, and mathematics, it received importance.

Even 10-20 pg of insulin could be detected due to the sensitivity of RIA. Also, ACTH less than 1 pm was determined. Due to RIA, there has been a huge development in hitherto closed areas of research. There are enormous numbers of producers that are similar to that was RIA, and they are the ligands methods used for the determination of peptide hormones, hormones not being peptides, peptides not being hormones, viruses like particles, enzymes, antibodies, different kinds of drugs and many more. Yalow's discoveries were not restricted to radioimmunoassays. Yalow, along with her coworkers, with the help of radioimmunoassays, could elucidate the physiology of the peptide hormones insulin, ACTH, growth hormone and enhanced little on the pathogenesis of diseases that were caused by abnormal secretion of similar hormones.

Therefore, diabetes got importance and had a place in research. Yalow's contribution had a huge impact and gave new outlooks on the causes of diseases in the whole field of medicine.

However, the discoveries by Guillemin and Schally are concerned with a different section of peptide hormone medicine and physiology. Many hormones in the body secreted by the pituitary gland get transported along with the blood to almost all the hormone-producing glands in the body.

For the production and stimulation of hormones, specific functions are stimulated. For a long period, it was already known that the CNS was able to modulate the endocrine functions that the brain stem – the hypothalamus – behaved as an intermediary in this whole process. Here and there, data was passed to the hypophysis, which, by the method of its particular hormones, moved the data to the next endocrine organs. And in the early 1930s, it was discovered that these small blood

Page | 49 vessels connecting the hypophysis with the hypothalamus would contribute to the transportation of information from the brain to the hypophysis. And by the end of the 1950s, Guillemin and

Schally worked separately in their laboratory. They extracted some compounds from the hypothalamus of pigs and sheep while administering to pituitary tissue that released their hormones. The extract is made; the pituitary releases ACTH, another Thyroid Stimulating

Hormone (TSH), and the last one FSH and LH, i.e., the gonadotrophic hormones. And these substances were termed as "releasing hormones or factors," RH or RF by Guillemin and Schally.

The one promoting the arrival of TSH, along these lines, was called TSH-RF or TRF.

In 1969, the nature of these hypothalamic factors was determined. Guillemin worked with 5 million hypothalamic fragments of sheep, whereas on the other hand, Schally worked with the same number of fragments, but they were from pigs. But their focus and concentration were just one releasing factor, 'TRF.' After many years of struggle, these two groups determined a difficult race, and that was by standing there one day with 1mg of a pure substance that had only one single mode of action; it released TSH from the hypophysis. And this was 'TRF.' A few months later, the structure of TRF was recognized. It is a minimal peptide that is composed of three amino acids in a particular manner. And in the same year, Guillemin's group synthesized the TRF. The way was paved. In two years, LH-RH was isolated and sequenced, and synthesized, initially by Schally and later by Guillemin.

These Nobel Laureates made the discovery; Guillemin and Schally built the pillars for modern hypothalamic research. The experiments from the field of animal research were then moved to humans and introduced into clinical work. After this discovery, many new peptides were isolated from the hypothalamus, somatostatin, which brings in the decrease of the production of pituitary growth hormone, and it is known to be the first inhibitor of pituitary function. The

Page | 50 significant discoveries made in 1977 by the Nobel Laureates in Physiology or Medicine led to a huge development by researching their fields.

Page | 51

THE NOBEL PRIZE FOR 1982 JOINTLY TO SUNE K. BERGSTRÖM, BENGT I.

SAMUELSSON AND JOHN R. VANE.

Sune K. Bergström

Prize motivation: "for their discoveries concerning prostaglandins

and related biologically active substances."

Born: 10 January 1916, Stockholm, Sweden

Died: 15 August 2004, Stockholm, Sweden

Affiliation: Karolinska Institutet, Stockholm, Sweden

Photo from the Nobel Foundation archive.

Bengt I. Samuelsson

Prize motivation: "for their discoveries concerning

prostaglandins and related biologically active substances."

Born: 21 May 1934, Halmstad, Sweden

Affiliation: Karolinska Institutet, Stockholm, Sweden

Photo from the Nobel Foundation archive.

Page | 52

John R. Vane

Prize motivation: "for their discoveries concerning

prostaglandins and related biologically active substances."

Born: 29 March 1927, Tardebigg, United Kingdom

Died: 19 November 2004, Farnborough, United Kingdom

Affiliation: The Wellcome Research Laboratories, United

Kingdom Photo from the Nobel Foundation archive.

Sune K. Bergström was born on 10 January 1916, Stockholm, Sweden died on 15 August

2004, Stockholm, Sweden. He was a Swedish biochemist and appointed to the National

Foundation of Board of Directors in Sweden. Later, he received the Louisa Gross Horwitz Prize together with Bengt Samuelsson from Columbia University. Bengt Ingemar Samuelsson was born on 21 May 1934. He is a Swedish biochemist. He has several Membership, Honors, and Awards.

John Robert Vane was born on March 29, 1927, in Tardebigge, the United Kingdom died on

November 19, 2004, in Kent, United Kingdom. He was an English Pharmacologist; he was famous for understanding aspirin's pain relief mechanism, and his work led to new treatments for heart and blood vessel disease and the introduction of ACE inhibitors.

Prostaglandins are a group of physiologically active lipid compounds found in nearly almost all the tissues in humans and some animals. They protect the cells against any sudden changes in the body. Prostaglandins are formed from arachidonic acid; it is a saturated fatty acid. Arachidonic has the enzymatic ability to form prostaglandins. When the tissue's function is confused during trauma, stress, the release of prostaglandins takes place, maintaining the normal function of tissues.

Sune Bergstrom has a major contribution to the study of prostaglandins. Bergstrom, along with his

Page | 53 co-worker, purified two prostaglandins PGE and PGF, explained their chemical structure, and explained that prostaglandins are formed from unsaturated fatty arachidonic acids. The presence of fatty acids in the body showed the fundamental importance of several processes in the healthy and diseased body. Therefore, Bergstrom's discoveries were focused on the importance of unsaturated fatty acids in body cells. Samuelsson, a co-worker of Bergstrom, was a leading scientist in biochemistry in 1965. The credit for the prostaglandin tree and its branches is shared with us due to Samuelsson (Figure 2). He also explained biochemical processes by which different prostaglandins are formed. Due to his discoveries, it is now possible to separate two different branches in the tree. The stable prostaglandins and the unstable thromboxanes and prostacyclin are formed by the cyclic endoperoxides that constitute an important branching point. The other branch is Leukotriene A, and it consists of other short-living branches of leukotriene B, C, and D.

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Figure 2: Prostaglandin tree and its branches.

John Vane has made fundamental contributions in the discovery of prostacyclin and its biological significance. His major contribution was in explaining that aspirin and allied anti-inflammatory drugs block the prostaglandins' synthesis, and similar characteristics were found in steroid hormones. In the diagrammatic presentation, it is explained that steroids inhibit the formation of endoperoxides and leukotrienes from arachidonic acid, whereas aspirin only blocks endoperoxides. Aspirin is the most frequently used drug throughout the world, and the discovery of aspirin's mode of action is of great importance and significance.

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THE NOBEL PRIZE FOR 1985 JOINTLY TO MICHAEL S. BROWN AND JOSEPH L. GOLDSTEIN

Michael S. Brown

Prize motivation: "for their discoveries concerning the regulation

of cholesterol metabolism."

Born: 13 April 1941, New York, NY, USA.

Affiliation: University of Texas Southwestern Medical Center at

Dallas, Dallas, TX, USA

Photo from the Nobel Foundation archive.

Joseph L. Goldstein

Prize motivation: "for their discoveries concerning the regulation

of cholesterol metabolism."

Born: 18 April 1940, Sumter, SC, USA.

Affiliation: University of Texas Southwestern Medical Center at

Dallas, Dallas, TX, USA.

Photo from the Nobel Foundation archive.

Michael Brown was born on 13 April 1941, New York, NY, USA. He graduated from the

University of Pennsylvania in 1962 and received his M.D. from the University of Pennsylvania

School of Medicine in 1966. And Goldstein was born on April 18, 1940, in Sumter, South Carolina.

Page | 56

Brown and Goldstein shared the Nobel Prize for their studies related to cholesterol metabolism regulation were performed at the University of Texas Southwestern Medical Center at Dallas,

Texas. Cholesterol is a waxy, fat-like substance present in all our tissues, produced by the body.

The two main sources of cholesterol are the liver and the diet. The cholesterol particles are packed into particles, and lipoproteins transport these packed cholesterol particles into the bloodstream and the lymphatic fluids. Lipoproteins are classified as Low-Density Lipoproteins (LDL), Very

Low-Density Lipoproteins (VLDL), and High-Density Lipoproteins (HDL). They are separated based on densities. Generally, LDL transports the cholesterol into the bloodstream.

Brown and Goldstein studied that familial hypercholesterolemia (FH) exists in various forms and is inherited as a monogenic trait. Individuals carrying mutant genes in double dose, i.e., homozygotes, are severely affected. They discovered that cholesterol in LDL is taken up from the blood by the specific receptors-LDL receptors. And the conclusion to this was Fibroblasts from

FH patients did not inhibit as they lacked the LDL-receptors. In further studies, Brown and

Goldstein showed that the cell surface's LDL receptors are known as the coated pit. It invaginates and pinches off to form a coated vesicle, and these coated vesicles, if fused, form an endosome.

This whole process was termed “receptor-mediated endocytosis.” Brown and Goldstein discovered a new way of regulating cholesterol metabolism, and this discovery led to new ideas for the treatment of cholesterol. They studied that during low cholesterol (LDL) available in the blood circulation, the cells increase the number of LDL-receptors on their surface, leading to decreased

LDL concentration in the blood. With modern technologies, Brown and Goldstein discovered that the nature of the LDL receptor is a glycoprotein. It consists of 839 amino acids, of which 767 are localized on the cell surface, 22 within the membrane 50 inside the cell in the cytoplasm (fig. 3).

Some LDL receptors are defective; LDL is bound to the receptor, but the LDL-receptor complex

Page | 57 is not internalized, or the LDL binding is poor.

Figure 3- LDL receptors, one from normal patient and two from abnormal. (Nobel prizes medicine press release

1985).

Also, the analysis showed variation in the location of the protein part of the glycoproteins.

In patient 1, out of 50 amino acids in the cytoplasm, only two are present, and in patient 2, out of

50 amino acids, only 6 (correct) and 8 (wrong) amino acids are present. Patients 1 and 2 are unable to complete the internalization.

Brown and Goldstein have introduced new fundamentals to treat cholesterol concerning the LDL receptors. Milder heterozygous form of FH can be treated with drugs like cholestyramine and mevinolin, increasing the number of LDL-receptors. With missing LDL receptors, a severe homozygous form of FH therapeutics is not an option. They are suggested for liver transplantation.

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THE NOBEL PRIZE FOR 1986 WAS AWARDED TO STANLEY COHEN AND RITA LEVI-MONTALCINI

Stanley Cohen

Prize motivation: "for their discoveries of growth factors."

Born: 17 November 1922, Brooklyn, NY, USA

Died: 5 February 2020, Nashville, TN, USA

Affiliation: Vanderbilt University School of Medicine, Nashville,

TN, USA

Photo from the Nobel Foundation archive.

Rita Levi-Montalcini

Prize motivation: "for their discoveries of growth factors."

Born: 22 April 1909, Turin, Italy

Died: 30 December 2012, Rome, Italy

Affiliation: Institute of Cell Biology of the C.N.R., Rome, Italy

Photo from the Nobel Foundation archive.

Rita Levi-Montalcini was an Italian Nobel laureate. She was awarded the 1986 Nobel Prize together with Stanley Cohen for the discovery of nerve growth factor (NGF). Stanley Cohen was born on 17 November 1922, Brooklyn, NY, USA. He was awarded the Nobel Prize in Physiology

Page | 59 or Medicine in 1986 for the isolation of nerve growth factor and the discovery of epidermal growth factor. He died in February 2020 at the age of 97.

The pattern of cellular growth was already known, but due to the discovery of nerve growth factors (NGF) by the Italian developmental biologist Rita Levi and American biochemist Stanley

Cohen, it was possible to explain how the growth and differentiation of a cell are regulated. The nerve growth factor is a protein that promotes the development of the sensory and symptomatic nervous systems and is required for the maintenance of sympathetic . In 1952, Rita Levi transplanted tumors from mice to chick embryos, and they induced potent growth of chick embryo nervous system, especially sympathetic and sensory nerves. The outgrowth did not require direct contact between the tumor and the chick embryo; hence Rita concluded that the nerve growth- promoting factor has a discriminatory action on various types of nerve cells. Therefore, to confirm the action of NGF in different extracts, Rita prepared a sensitive cell culture with one billionth part of one gram of NGF in one ml of the cell culture. And within a few minutes, the nerve cells began to grow out from the ganglion.

The American biochemist Stanley Cohen at St. Louis purified the contents of the nerve growth-promoting factor, and they contained nucleic acids as well as proteins. In order to determine the active components between protein and nucleic acids, Stanley added snake venom into the culture, but surprisingly snake venom contained more nerve growth-promoting factor activity than the tumor itself. And he confirmed this by adding only snake venom into the culture; it induced a massive growth of just sympathetic nerves. Stanley was able to produce antibodies against NGF with the help of snake venom and salivary extracts from the male mouse. Cohen noticed the aggressive opening of the mouse eyelids and its tooth eruption. And the explanation for this is that the salivary gland contained another growth factor apart (EGF) from NGF, and

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Cohen named it as epidermal growth factor because it was able to stimulate the proliferation of epithelial cells in the cornea and skin. Later, Cohen, along with his co-workers, discovered that

EGF itself could stimulate glucose and amino acid transportation and initiation of DNA. For EGF to act, the presence of specific binding sites on the surface of target cells is required.

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THE NOBEL PRIZE FOR 1994 WAS AWARDED JOINTLY TO ALFRED G. GILMAN

AND MARTIN RODBELL.

Alfred G. Gilman

Prize motivation: "for their discovery of G-proteins and the role of

these proteins in in cells."

Born: 1 July 1941, New Haven, CT, USA

Died: 23 December 2015, Dallas, TX, USA

Affiliation: University of Texas Dallas, Dallas, TX, USA

Photo from the Nobel Foundation archive.

Martin Rodbell

Prize motivation: "for their discovery of G-proteins and the role

of these proteins in signal transduction in cells."

Born: 1 , Baltimore, MD, USA

Died: 7 December 1998, Chapel Hill, NC, USA

Affiliation: National Institute of Environmental Health Sciences,

Research Triangle Park, NC, USA Photo from the Nobel Foundation archive.

Alfred G. Gilman was an American pharmacologist, born on July 1, 1941, and died on December

23, 2015. Gilman attended and Case Western Reserve University, where he

Page | 62 studied under Nobel Prize recipient Earl W. Sutherland. Martin Rodbell, an American biochemist, was born December 1, 1925, in Baltimore, , the U.S., and died December 7, 1998. The

1994 Nobel Prize for Physiology or Medicine to discover natural signal transducers called G- proteins that help cells in the body communicate with each other was shared between Gilman and

Rodbell.

G proteins are named G-proteins because they bind the (GTP). G proteins are also known as guanine nucleotide-binding proteins. They are a family of proteins that act as molecular switches inside cells and transmit signals from various stimuli outside a cell to its interior. Cells communicate through hormones and various signals released from nerves, glands, and other tissues.

Chemical signals released from glands, nerves, and other tissues attach to receptors on the cell surface. Now, these receptors transmit the signals to the interior of the cell. This is called communication between cells, whereas the transduction of signals in cells was unclear until Alfred

G. Gilman and Martin Rodbell made their discoveries.

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Figure 4: Transduction of a message from the exterior to the interior of the cell.

Martin Rodbell showed in 1971, explained that the transduction of a message from the exterior of the cell to its interior. He emphasized how this requires the cooperation of three functional units:

1. A discriminator (receptor) that recognizes different extracellular signals (first messengers).

2. A transducer that requires GTP.

3. An amplifier that generates large quantities of a second messenger.

Source: Physiology or Medicine 1994 - Press release - NobelPrize.org.

He demonstrated that signal transduction through the cell membrane involves few cooperative actions of different functional entities along with his coworkers. When a chemical signal binds to its receptor in the cell membrane, the receptor determines which signal molecules it will bind its functions. The amplifier generates huge amounts of the intracellular “second messenger.” Rodbell the first one to realize that the receptor/discriminator was distinct from the amplifier. But his outstanding discovery demonstared a seperate transducer function. However, his major discovery

Page | 64 was the demonstration of a separate. It provides a link between the discriminator and the amplifier and plays a key role in signal transduction. Rodbell found that the transducer was driven by guanosine 5′-triphosphate, GTP, an energy-rich compound.

Alfred G. Gilman was working at the and decided to contribute to Rodbell’s discoveries; therefore, he determined Rodbell’s transducer's chemical nature.

Figure 5: Various lukemia cells with altered genetic makeup to identify and demonstrate G-proteins. (Nobel prizes medicine press release 1994).

Gilman used various leukemia cells with altered genetic setup. He found that one mutated leukemia cell possessed a normal receptor and a normal amplifier that generated cyclic AMP as a second messenger. But the cell failed to respond normally. Normal leukemia cells respond with a normal biological response to the appropriate first messenger (Figure 5). And it was because these mutated

Page | 65 cells lacked the transducer function. In 1980, he and his coworkers discovered that a protein in normal cells that, when transferred into the cell defective cell membrane, restored its function. The function could be restored by G-protein derived from another tissue such as the brain. This is how the “” was discovered, and due to Gilman and Rodbell, several laboratories started working in this area.

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THE NOBEL PRIZE FOR 2000 WAS AWARDED JOINTLY TO ARVID CARLSSON, PAUL GREENGARD AND ERIC R. KANDEL

Arvid Carlsson

Prize motivation: "for their discoveries concerning signal

transduction in the nervous system."

Born: 25 January 1923, Uppsala, Sweden

Died: 29 June 2018, Gothenburg, Sweden

Affiliation: Göteborg University, Gothenburg, Sweden

Photo from the Nobel Foundation archive.

Paul Greengard

Prize motivation: "for their discoveries concerning signal

transduction in the nervous system."

Born: 11 December 1925, New York, NY, USA

Died: 13 April 2019, New York, NY, USA

Affiliation: Göteborg University, Gothenburg, Sweden

Photo from the Nobel Foundation archive.

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Eric R. Kandel

Prize motivation: "for their discoveries concerning signal

transduction in the nervous system."

Born: 7 November 1929, , Austria

Affiliation: Göteborg University, Gothenburg, Sweden

Photo from the Nobel Foundation archive.

Arvid Carlsson was born in Uppsala, Sweden, both of his parents were highly educated.

After performing a series of experiments in the 1950s, Arvid Carlsson showed that plays an important role in the brain as a transmitter itself.

The Human brain has more than a billion nerve cells, and they are connected through a complex network of nerve cells. The signal from one brain cell is transmitted to another with the help of different chemical transmitters. Just like this, the nerve cells in our brain have contacts with such other nerve cells. A high concentration of dopamine was found in the basal ganglia; it has a major role in controlling motor behavior.

Carlsson performed an experiment where he used reserpine and introduced it to animals, and they could not perform any physical movements. Later they were treated with L-dopa precursor of dopamine, which is then transformed into dopamine in the brain. And on the other hand, the animal we're given the precursor of transmitter serotonin. Therefore, the results were observed as the animals who received L-dopa resumed their normal motor movement, and the ones who received serotonin did not normalize the brain cells. Today, L-dopa is the most important for the treatment of Parkinson's disease. It is possible because Carlsson realizes that the symptoms of Parkinson's

Page | 68 and the symptoms caused by reserpine were similar Parkinson's patient has a low concentration of dopamine in the basal ganglia. Apart from his contribution to Parkinson's disease, he also showed that antipsychotic drugs, mostly used against schizophrenia, affect synaptic transmission by blocking dopamine receptors. Depression is one of our most common diseases, but Carlsson's contribution had great importance to this. He has also contributed to the development of selective serotonin uptake blockers.

Figure 6: Chemical transmitters help in transmitting messages with the help of different chemical transmitters.

Chemical transmitters send messages from one nerve cell to another is transmitted. (figure

6). This takes place at synapses; they are the specific point of contact between two nerve cells.

Dopamine, the chemical transmitter, is formed from the precursor's tyrosine and L-dopa and stored

Page | 69 in the nerve ends. For Parkinson's disease's therapeutics, L-dopa is subjected, which later converts to dopamine, in the brain.

Paul Greengard received the Nobel Prize for discovering the effects of dopamine, noradrenaline, and serotonin. Transmitters such as serotonin, dopamine, noradrenaline, and certain neuropeptides transmit their signals, commonly known as slow synaptic transmission. The longevity of the change in the working of the nerve cell is from seconds to hours. Therefore, this type of signal transmission is responsible for several basal functions in the nervous system and is important for, e.g., mood and alertness. The slow synaptic transmission has the ability to control fast synaptic transmission, which enables, e.g., speech, movements, and sensory perception. He also showed that slow synaptic transmission involves protein phosphorylation (chemical reaction). This indicates that phosphate groups are coupled to a protein so that the protein's form and function are altered. Signals by transmitters like dopamine, noradrenaline, serotonin, and certain neuropeptides are transmitted by slow synaptic transmission. Such signal transmissions are responsible for basal functions in the nervous system and are important, e.g., alertness and mood.

Paul Greengard explained that slow synaptic transmission involves protein phosphorylation, a chemical reaction. This indicates that phosphate groups are coupled to a protein so that the protein's form and function are altered. Greengard also showed while dopamine stimulates a receptor, it causes an elevation of a second messenger, cyclic AMP, in the cell. It activates a Protein Kinase

A, which can add phosphate molecules to other proteins in the nerve cell. Greengard's discoveries regarding protein phosphorylation have increased our understanding of several drugs' mechanisms of action, specifically affecting proteins' phosphorylation in different nerve cells.

Eric Kandel studied learning and memory in mammals. He investigated an experimental model, the nervous system of a sea slug, Aplysia. It has few nerve cells (around 20.000), most of them are

Page | 70 large. It has a protective reflex that protects the gills, which can be utilized to study basic learning mechanisms. He found that certain types of stimuli resulted in an amplification of the sea slug's protective reflex. This strengthening of the reflex remained for weeks and remained as a source to learn. He later could explain that this learning was due to an amplification of the that connects the sensory nerve cells to the nerve cells that activate the muscle groups that give rise to the protective reflex. initially showed that weaker stimuli give rise to short-term memory, which lasts from minutes to hours. This "short-term memory" mechanism is that ion channels are affected so that more calcium ions can throw oneself into the nerve terminal. This will kindle an increased quantity of transmitter release at the synapse and thereby amplifies the reflex. This change is due to the phosphorylation of certain proteins utilizing the molecular mechanism described by Paul Greengard. A more powerful and long-lasting stimulus will result in the form of long-term memory that lasts up to weeks. The powerful stimulus will give rise to increased messenger molecule cAMP levels and so-as-to . The cell nucleus receives these signals and causes a change in several proteins present in the synapse. Some proteins will have more formation, whereas; some will have low formation. The result is that the synapse shape can increase and thereby create a long-lasting increase in synaptic function. Eric

Kandel thus demonstrated that short-term memory and long-term memory in the sea slug at the synapse. In the 1990s, he has also carried out studies in mice. He has shown that the same type of long-term changes of synaptic function noticed during learning in the sea slug can also be applied to mammals.

The rudimentary mechanisms that Eric Kandel has disclosed are applied to humans as well. Human memory is known to be "located in the synapses," and changes in synaptic function are central

Page | 71 when different memories are established. It is now practicable to study how complex memory images are stored in our nervous system and how they can recreate earlier events' memory.

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THE NOBEL PRIZE FOR 2010 WAS AWARDED TO ROBERT G. EDWARDS.

Robert G. Edwards

Prize motivation: Development of in vitro fertilization.

Born: 27 September 1925, Batley, United Kingdom

Died: 10 April 2013, Cambridge, United Kingdom

Affiliation: University of Cambridge, United Kingdom

Photo from the Nobel Foundation archive.

Robert G. Edwards, a British scientist, was born in 1925 in Manchester, England. He graduated in Biology from the University of Wales in Bangor and began his elementary research on the mechanism of fertilization in the 1950s. He then received his Ph.D. in 1955 with a thesis on

"Embryonal development in Mice." He was granted the 2010 Nobel Prize for "developing in vitro fertilization (IVF) therapy."

Infertility is a medical condition that prevents pregnancy, and 10% of the world's population has been affected by this condition. This is a great disappointment for couples and is also psychological trauma. Today, it can be possible due to the discovery of IVF. IVF is a medical procedure by which an egg is fertilized by sperm in a test tube or elsewhere outside the body.

In the early 1950s, Edwards brought together all his ideas about implementing fertilized human egg cells in cell culture dishes. This effort finally received success when the world's first "test-tube baby" was born on 25 July 1978. IVF is a therapy when sperm and egg cells meet outside the body.

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Since other scientists gave birth to rabbits' offspring by fertilizing egg cells in the tubes and then adding the sperms, Edwards chose to implement similar strategies to treat human egg cells. But it was found that human eggs have a unique lifecycle than those of rabbits. Then Edwards, along with co-workers, studied the maturation of human eggs, the role of hormones in their maturation, and point the eggs are susceptible to fertilizing sperms. Even after all this research and success, there was a significant problem, and the eggs did not develop after a certain single cell division.

He detected that this was due to the maturation of eggs in the ovaries before they were removed for IVF.

Patrick Steptoe, a gynecologist, used laparoscopy, a technique that was completely controversial and new at those times in medical science. Edwards and Steptoe together worked and brought IVF from theoretical to practical and proved it an experimental overview. With the help of a laparoscope, Steptoe extracted the eggs from the ovaries and put them in the cell culture with the addition of sperms. The fertilized eggs then divided and formed embryos. Even though the studies were promising, the medical Research Center decided not to fund the project anymore, but later it was funded through a private source.

In 1977, Leslie and John Brown visited the clinic after nine years of failed attempts to have a child.

They carried out IVF, and when the fertilized eggs were developed into the embryo with eight cells, it was implanted into Mrs. Brown. Later on, a completely healthy baby, Louise Brown, was born through a cesarean after full-term pregnancy on 25 July 1978.

Brown Hall clinic in Cambridge was established in 1988 by Edwards and Steptoe, and today, due to them, IVF is renowned in the world. Around half of all the children are born after IVF in the world at that time. IVF has gone under certain improvements now. Around 20 to 30% of fertilized eggs lead to the birth of the child. It includes some complications like premature birth, but that is

Page | 74 very rare (Nieschlag and Nieschlag et al., 2017). Long-term studies show that IVF is as healthy as other children. Today, Robert Edwards's efforts bring joy to all the infertile people around the world.

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DISTRIBUTION OF NOBEL PRIZES IN THE FIELD OF ENDOCRINOLOGY BY COUNTRY

The Nobel Prize is considered a Global honor. The first award was distributed in 1901, and since then, the number of awards has been increasing every day. Individuals from 30 or more countries have contributed to the Nobel Prize. In 104 years of its reality, the Nobel Prize has been granted to near 1,000 laureates.

Table 1: Distribution of Endocrinologists who have received Nobel Prizes throughout the World in Numbers.

The graph above indicates that the Nobel Prizes are distributed throughout the World among different countries. Some endocrinologists have received the Nobel Prize, and considering the distribution, eight countries have received the awards. The United States has 19 awards, which is the highest number of Nobel Prizes in Endocrinology and the total number of Nobel Prizes that are distributed throughout the World. The second highest country to receive the Nobel Prize in

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Endocrinology is Sweden, with five awards. The United Kingdom has 4 Nobel awards, whereas

Switzerland has three, and Germany and Canada have 2 Nobel Prizes. Italy and Argentina have 1

Nobel Prize. The United States has 383 Nobel Laureate, following the United Kingdom with 132

Nobel Laureate.

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DISTRIBUTION OF NOBEL PRIZES IN THE FIELD OF ENDOCRINOLOGY WITHIN UNITED STATES

According to this study, the United States has known to be the country with the highest number of Nobel awards considering all the fields. The map below highlighted the distribution of

Nobel Prizes within the states of America.

Figure 7: World Map of the United States highlighting the distribution of Nobel Prizes in each state.

Although the United States has the highest number of Nobel Prizes throughout the World, even in the field of endocrinology United States has the highest number of awards. With the distribution of Nobel Awards in the United States, 12 states have received awards. It includes

Minnesota, Illinois, New York, Massachusetts, Missouri, Tennessee, Louisiana, Texas, Florida,

California, Maryland, and North Carolina. This data represents that the distribution of Nobel awards has been distributed all over the United States. The map was customized using the

“Simple Maps” tool that helps in building customized maps. Page | 78

Gross Domestic Product

The substantial historic investment in academic freedom, primary science for the researchers, and the patience in the results led the United States with the highest number of Nobel

Awards. The secrets to achieving the Nobel award are always correlated with the efforts put in the past. Eight out of eleven Nobel awards are affiliated with the American Institutions, but many have immigrated to the United States and are not born here. At least one American is given out the

Nobel Prize since 1935; it does not include the years 1940 and 1942 because no prizes were announced. The United States has sent a significant amount on basic research encouraging the scientist to learn more about their goal instead of directly applying the research of their goal. This funding and academic freedom, which are not common in all countries. It is not a coincidence that gets the breakthroughs but studying basic science and winning the Nobel Prize together makes the breakthrough. America’s Nobel success comes from the stories of immigrants. Many countries are encouraging researchers from different parts of the World, like South Korea and Singapore. These countries are building up their universities equivalent to the universities in the U.S., but they are not enough. The United States has a unique way of embracing each student’s talents and putting them up across different universities. America is highly known for its research excellence. If we had to categorize their own, the U.S.-born Nobel laureates have received the highest number of awards, and the second is the immigrants from various countries that lived and received the award in the U.S.

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WOMEN IN SCIENCE

Women and Science, these two words are not always studied together, and that is because they are not thought to be compatible enough. Women serve as role models to other girls when they achieve the highest levels in medicine, sports, science, and politics. But are they equally represented as men? Many factors are holding back representing women in labs, classrooms, and on the ground.

However, the distribution of women in STEM (science, technology, engineering, and mathematics) has increased drastically within the last 20 years, and these approaches have been increasing every day (Lunnemann et al., 2019). In the workplace, women often experience male dominance, and therefore they feel isolated and more susceptible to different forms of harassment.

With fewer female colleagues, women are less likely to build a relationship around the workspace that includes working at a company or a laboratory and as a professor; this makes them feel less empowered than men, and they consider themselves a minority. In medicine, about 12 women have been awarded the Nobel Prize and count for 6% of the total Nobel Awards in Medicine.

Rosalyn Yalow was the first woman in physics awarded the Nobel Prize in 1977, and until today, there are only three women Nobel Winners in physics.

On the other hand, Marie Curie was the first woman to study physics as a major at Hunter College.

Her achievement was a great discovery for the treatment of diabetes. Although there were a lot of issues, her discovery made a huge breakthrough. Similar to her, Rita Levi-Montalcini received the

Nobel Prize in 1986. Her father was against women's education, but she convinced him that she should get a medical education to get enrolled in medicine. She successfully contributed to the field of neurobiology. After facing so many obstacles in her career, she ensured that the scientist can access equipment, support, and funds. Gerty Theresa Cori was also awarded a Nobel Prize, but her prize was shared with her husband. They worked together at Buffalo, and later, she joined

Page | 80 him as a research associate. Rita Cori and her husband Carl Cori have contributed equally to the

Nobel Prize and are known for their discoveries.

Women contribute equally as men do, yet we have a handful of Nobel prizes distributed to women.

Rosalyn Yalow and Rita-Levi experienced denial from families and parents to study medicine.

However, they convinced their parents of their capability and proved it by receiving the Nobel

Prize with all their will and dignity. When an individual says 'Nobel Laureate,' the picture that comes to mind is an old white male with facial hair because 97% of Science Nobel Laureates have been men. And this encourages every individual out there to consider Nobel Laureates as men.

There is a huge gender gap in recognition, citation, and awards. And therefore, men consider citing their references about 56% of the time. Even after recognizing women's recognition, we can see that their last name calls men, but their first name generally refers to females. Women have limitations while entering the Nobel Prize base because there are other responsibilities a woman tends to fulfill. But a woman Nobel laureate is less likely to get married (63 vs. 97%) and have children (55 vs. 86%) than their male colleagues (Lunnemann, P., Jensen, M. H et al., 2019). All the findings conclude that there should be nothing in the way of women getting awarded a Nobel

Prize and recognized equally as men.

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ETHNIC REPRESENTATION

A statistic from 2017 shows that only one-third of the United States population is white, but more than half of the Nobel scientists are white (National Center for Science and Engineering Statistics).

There are not enough minority professors in elite universities where the Nobel laureates come from, and these things have not changed over the years. Many factors are related to this; scarcity of mentors and role models, poverty, and lack of family background. It is also the same for women.

Only three women out of 213 physics Nobel laureates, and this is highly disappointing. Black

History Month is a very tender reminder that there are more than 930 Nobel Laureates, but only

14 are a minority, and none of them in science. Unfortunately, no minorities have been awarded the Nobel Prize in the field of endocrinology. The main reasons behind this are due to the limited option offered to minorities to opt for a career in science or equivalent field and are less likely to progress in scientific careers. To be elected as a Nobel Laureate, an individual should be a professor of a leading institute or become a principal investigator.

However, minorities have a difficult time being elected as a professor and do not reach up to the

Nobel Prize level. The youth who attend pre-school and school consider the professors their role models; however, the schools lack minority professors. Therefore, the student does not have a role model and will not opt for studying master's or Ph.D. Even if a student gets into a master's or an equivalent program, they face many hard times making classmates or consulting the professors.

Therefore, we can conclude that the problem lies in the roots like there is decreased awareness in educating minorities, considering them compatible with the rest of the races. Many universities do not consider hiring professors from minorities will eventually lead to a smaller number of role models for the students belonging to the minority group. The actions taken to overcome the problems lying in the roots should include organizations having diversity in the workplace and

Page | 82 encouraging the minorities to contribute to the organization and other groups taking their concerns seriously.

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