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| MEDICAL HISTORY |
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| Year : 2018 | Volume
: 20
| Issue : 2 | Page : 141-144 |
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Unknown facets of “not so well-known scientist” Dr. Y Subbarow: A great scientist, who did not receive the Nobel Prize
Vasant S Dixit
Formerly Director General Medical Services, Indian Navy, New Delhi, India
| Date of Submission | 21-Oct-2018 |
| Date of Acceptance | 01-Nov-2018 |
| Date of Web Publication | 10-Jan-2019 |
Correspondence Address:
Surg VAdm (Retd), AVSM, VSM Vasant S Dixit
G-703, Sterling Terraces, Banashankari, Stage – 3, Bengaluru - 560 085, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jmms.jmms_69_18
Dr. Subbarow (January 12, 1895–August 08, 1948) had obtained admission to MBBS course but was awarded Licentiate of Medicine and Surgery instead of the MBBS degree. He went to the USA in October 1923 where he was admitted to the Harvard School of Tropical Medicine. After receiving a diploma from the school, he became interested in biochemistry. He discovered the function of adenosine triphosphate as an energy source in the cell. Despite the path-breaking discovery, Subbarow was denied tenure at Harvard. Subbarow felt that the giant pharmaceutical firms might offer greater scope for research than universities. Hence, in 1940, he joined the world-renowned Lederle Laboratories as Director of Research and spent the rest of his life in the USA. He would lead some of America's most important medical research during World War II. His output and contributions to human biology and medicine are seminal and phenomenal. His creativity is evident in the trail-blazing discoveries in the fields of biochemistry, nutritional science, pharmacology, microbiology, and oncology. Subbarow had craved for fame but was never in the limelight. He pushed into limelight those whose dedication most nearly matched his own. He was proud of the brilliant members of his research teams. He was quick to share successes with colleagues and was known for his acts of generosity. Subbarow said, “Victories of science are rarely won single handedly. No one man should get the (entire) credit.” Keywords: Estimation of phosphorous in body, Fiske–Subbarow method, Harvard school of tropical medicine, Subbarow
How to cite this article:
Dixit VS. Unknown facets of “not so well-known scientist” Dr. Y Subbarow: A great scientist, who did not receive the Nobel Prize. J Mar Med Soc 2018;20:141-4 |
| Introduction | |  |
Dr. Subbarow [Figure 1] was born in Bhimavaram, a small town in Andhra Pradesh. His childhood was traumatic due to the early death of his father. His mother, Venkamma, was a determined lady. After her husband's death, Venkamma sold her small jewelry so that Subbarow could continue his studies. He passed the matriculation examination in his third attempt and entered Presidency College, Madras. Being spiritually inclined, he spent most of his time at the Ramakrishna Mission. After passing the intermediate examination, he joined the Madras Medical College with the intent that he could serve in Ramakrishna Mission's hospitals after graduation.[1],[2]
While in college, Subbarow started wearing Khadi, following Gandhi's call to boycott British goods. This act incurred the displeasure of his Professor of Surgery and despite his good performance; he was denied the MBBS degree and was awarded the Licentiate in Medicine and Surgery (LMS).[1] Subbarow applied to join Madras Medical Service but was rejected as he did not have a graduate degree. He took up a job as a Lecturer in Anatomy in Ayurvedic College and began to engage in research to put Ayurveda on a modern footing.
A visiting American doctor encouraged him to go to the USA for further studies. He arrived in Boston on October 26, 1923. He did not get a scholarship or an internship because his LMS certificate course did not qualify him for one. In the initial period, Professor Richard Strong helped Subbarow with fees and living expenses. In his spare time, Subbarow supported himself by cleaning hospital bedpans and doing other odd jobs.
| Scientific Career | | |
Estimation of phosphorous in body fluids and tissues
After obtaining a diploma in Tropical Medicine from the Harvard Medical School, Subbarow joined the biochemistry laboratory of Dr. Cyrus Fiske. Here, he devised the now famous “Fiske–Subbarow method” for estimation of phosphorous in body fluids and tissues. This very sensitive procedure became a classic and is taught to biochemistry students even today. It is an important tool to diagnose disorders of the thyroid and renal rickets.
Discovery of the role of phosphocreatine and adenosine triphosphate
Subbarow discovered that adenosine triphosphate (ATP) provided energy for every biochemical process including muscle contractions. Thus, a resting muscle has a higher concentration of ATP than a fatigued muscle.[3] These findings were published in the April 1927 issue of “Science,” which helped Subbarow to demolish the claim that glycogen was the fountainhead of energy required for muscular contraction for which Hill and Meyerhof were awarded Nobel Prize for Medicine and Physiology in the year 1922. The research on ATP earned him a PhD and the work is referenced in biochemistry textbooks.[4] It led to the award of a Fellowship by the Rockefeller Foundation.
Vitamin B12
Subbarow next took up the challenge of pernicious anemia, which afflicted many. He extracted Vitamin B12 from pig liver which proved effective against anemia.[5],[6] This set off a worldwide search for more vitamins, yielding a rich harvest in subsequent years.
Folic acid (Vitamin B9)
In 1931, researcher Lucy Wills made a key observation and found out that folate was a nutrient that was needed to prevent anemia during pregnancy.[4],[7] Bob Stokstad isolated the pure crystalline form in 1943 and was able to determine its chemical structure. Research of obtaining folic acid in a pure crystalline form was done at Lederle Laboratory by the team called the “folic acid boys,” under the supervision and guidance of Dr. Subbarow.[7],[8],[9]
Aminopterin: An antifolate and anticancer drug
Dr. Sidney Farber, a pediatric pathologist, had learned that administration of folates to leukemia patients accelerated the disease. He hypothesized that administration of antifolates might decelerate the disease. Dr. Farber knew that Dr. Subbarow had found antifolates, intermediary compounds, which blocked folate metabolism. Antifolates interrupted normal cell growth in chicks. Dr. Farber chose “aminopterin,” a 4-amino derivative of folic acid which works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. It is an antineoplastic drug with immunosuppressive properties. Dr. Farber first used aminopterin in 1947 on a boy diagnosed with leukemia, and within a month after treatment was started, he improved. Dr. Farber's clinical triumph paved the way to a whole new era of chemotherapy. Aminopterin, the “ first-ever anticancer drug,” was marketed by Lederle Laboratory from 1953 to 1964 for the indication of pediatric leukemia. For this discovery and contribution, Dr. Subbarow can be called the father of targeted cancer chemotherapy.[5],[6],[10]
| Methotrexate | | |
Methotrexate, a compound closely related to Aminopterin, was synthesized by Dr. Subbarow.[6] The drug was less toxic than aminopterin and began to replace it. Methotrexate is mainly used in the treatment of cancer and autoimmune diseases and continues to be on the World Health Organization's list of most important medicines needed in a basic health system.
Chlortetracycline
Penicillin was discovered in 1928. Dr. Subbarow was perceptive to this development and directed research into antibiotics.[11] A well-organized program to screen soil samples brought from all over the world was undertaken. He succeeded in growing mold A-377 resulting in the development of chlortetracycline, a product of an actinomycete, the first of the tetracycline to be identified. Discovery of the drug was disclosed in a symposium held on July 21, 1948, just 2 weeks before Dr. Subbarow's demise.[12] The drug was manufactured by Lederle and named Aureomycin because of the golden yellow color of the substance.[3],[13] Tetracyclines became the most widely used broad-spectrum antibiotics. During this process, polymyxin was discovered which is widely used even today in cattle feed.
Hetrazan (diethylcarbamazine)
Diethylcarbamazine is a synthetic derivative of piperazine, an anthelmintic. The drug is used in the treatment of filariasis in humans, dogs, and cats. The antifilarial action of hetrazan was discovered and described in 1947 by Subbarow et al. while working with cotton rats infected with Litomosoides carinii. Hetrazan is on the World Health Organization's “List of Essential Medicines,” most important medications needed in a basic health system.
| Legacy | | |
Dr. Subbarow led some of America's most important medical research during World War II. He was constantly raising his sights, and his next targets were cures for polio and cancer.
Dr. Subbarow dressed immaculately but led an austere life. He remained a Hindu but supported church charities. Although he made his contributions abroad, they all came from his India-born talents, drives, and inspirations. Although he craved for money and fame during childhood, these mattered little to him in later life. He discovered cures for many killer diseases which brought great relief to millions of suffering people throughout the world. He remained focused on finding cures for dreaded diseases and improve well-being of the humanity.[2],[5],[14],[15]
Dr. Subbarow authored over 100 papers which have been published. There are several unpublished works. The discoveries were fruits of a brilliant, insightful mind. He neither sold his scientific discoveries nor sought patents for any of the products. He shunned interviews to the press, awards, honors, and recognition. He was denied his due, partly because he was selfless.[16],[17] Probably, his reclusive and inhibited nature and pure vegetarianism played a role in him not fully getting assimilated into the American way of life. He remained an Indian citizen even after his entitlement to American citizenship in 1947.
Subbarow's colleague, Dr. George Hitchings said, “some of the nucleotides isolated by Subbarow had to be rediscovered years later by other workers because Fiske, apparently out of jealousy, did not let Subbarow's contributions see the light of the day.”[18],[19]
| Honors and Awards | | |
Despite trailblazing discoveries, the Nobel Prize eluded him. However, in 1950s, Subbarow's colleagues had seen a portrait of him in “Karolinska Institute” in Stockholm, institute which awards the Nobel Prize in physiology and medicine, which so fascinated him during his early years at Harvard.[20],[21]
American Cyanamid honored his memory with a plaque at its research laboratory and inaugurated the Subbarow library. A drug was named Subbaromyces splendens.
Subbarow's birth centenary was celebrated in 1995. India Post released a stamp in his honor, and a bust was erected in the campus of National Institute of Nutrition, Hyderabad.
| Demise | | |
On the morning of Monday, August 9, 1948, Dr. Subbarow was not found at work. His associates felt that his absence was unusual as he was an obsessive workaholic. On opening his apartment, he was found dead of a massive heart attack. He was barely 53-year old.
| Conclusion | | |
Dr. Subbarow was a great innovator and motivator, who led from the front. He was passionate in finding remedies against a whole range of human sufferings. This stemmed from his early experiences in India where poverty and diseases were widespread. Spiritual streak in him must have played a great role in his outlook and engagement. He was interested in research which was evident when he was employed in Ayurveda College soon after obtaining LMS certification. He was fascinated by the healing powers of Ayurvedic medicines and was wanting to put Ayurveda on a modern footing. He carried forward his obsession on joining Lederle Laboratories. As an MD, he motivated PhD's to help alleviate human ailments, and as a PhD, he inspired MD's to help him fashion chemicals to combat specific microbes. Subbarow was a complete scientist – a chemist among chemists and a clinician among clinicians.[22]
The New York Herald Tribune described Dr. Yellapragada Subbarow as “An eminent medical mind of the century.” Doron Antrim, a journalist, wrote in the April 1950 issue of “Argosy” (after the demise of Dr. Subbarow), “You've probably never heard of Dr. Yellapragada Subbarow. Yet, because he lived, you may be alive and well today.”
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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| 12. | Fiske C, Subbarow Y. The colorimetric determination of phosphorus. J Biol Chem 1925;66:375-400. |
| 13. | Bhargava PM. Dr. Yellapragada Subbarow (1895-1948) he transformed science; changed lives. J Indian Acad Clin Med 2001;2:96-100. |
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| 19. | Dashatwar P. Dr. Yellapragada Subbarow (1895-1948). J Assoc Phys India 2015;63:114. |
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| 22. | Farber S, Diamond L, Mercer R, Sylvester R, Wolff J. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (Aminopterin). N Engl J Med 1948;238:787-93. |
[Figure 1]
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