Yellapragada Subbarow

Yellapragada Subbarow
Born	12 January 1895 Bhimavaram, Madras Presidency, British India (now in Andhra Pradesh, India)
Died	8 August 1948 (aged 53) New York, United States
Nationality	Indian
Fields	Biochemistry
Institutions	Lederle Laboratories, a division of American Cyanamid (Acquired by Wyeth in 1994, now Pfizer)
Alma mater	Harvard Medical School Madras Medical College
Known for	Discovering the role of phosphocreatine and adenosine triphosphate in muscular activity; synthesis of folic acid; synthesis of methotrexate; discovery of diethylcarbamazine
Influenced	Benjamin Minge Duggar George H. Hitchings

Yellapragada Subbarow (12 January 1895 – 8 August 1948) was an Indian biochemist who discovered the function of adenosine triphosphate as an energy source in the cell, and developed methotrexate for the treatment of cancer. Most of his career was spent in the United States. Despite his isolation of ATP, Subbarow was denied tenure at Harvard^[1][2] though he would lead some of America's most important medical research during World War II. Subbarow died in the United States.^[3] Subbarow is also credited with the first synthesis of the chemical compounds folic acid and methotrexate.

Subbarow's colleague, 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."^[4] A fungus genus was named Subbaromyces in his honor.^[5][6] Writing in the April 1950 issue of Argosy, Doron K. Antrim observed,^[7] "You've probably never heard of Dr. Yellapragada Subbarow. Yet because he lived you may be alive and are well today. Because he lived you may live longer."^[8]

Early life and education

He was born in Bhimavaram, Madras Presidency, now in West Godavari District, Andhra Pradesh in India. He passed through a traumatic period in his schooling at Rajahmundry (due to the premature death of close relatives by disease) and eventually matriculated in his third attempt from the Hindu High School, Madras. He passed the Intermediate Examination from the Presidency College and entered the Madras Medical College where his education was supported by friends and Kasturi Suryanarayana Murthy, whose daughter he later married.

Following Gandhi's call to boycott British goods he started wearing khadi surgical dress; this incurred the displeasure of M. C. Bradfield, his surgery professor. Consequently, though he did well in his written papers, he was awarded the lesser LMS certificate and not a full MBBS degree. Subbarow tried to enter the Madras Medical Service without success. He then took up a job as Lecturer in Anatomy at Dr. Lakshmipathi's Ayurvedic College at Madras. He was fascinated by the healing powers of Ayurvedic medicines and began to engage in research to put Ayurveda on a modern footing. The promise of support from Malladi Satyalingam Naicker Charities in Kakinada, and financial assistance raised by his father-in-law, enabled Subbarow to proceed to the U.S. He arrived in Boston on 26 October 1922.

Career in United States

After earning a diploma from the Harvard Medical School he joined Harvard as a junior faculty member. With Cyrus Fiske, he developed a method for the estimation of phosphorus in body fluids and tissues. He discovered the role of phosphocreatine and adenosine triphosphate (ATP) in muscular activity, which earned him an entry into biochemistry textbooks in the 1930s. He obtained his Ph.D. degree the same year. He joined Lederle Laboratories, a division of American Cyanamid (now a division of Wyeth which is owned by Pfizer), after he was denied a regular faculty position at Harvard. At Lederle, he developed a method to synthesize folic acid, Vitamin B₉,^[9] based on work by Lucy Wills to isolate folic acid as a protective agent against anemia. After his work on folic acid and with considerable input from Dr. Sidney Farber, he developed the important anti-cancer drug methotrexate - one of the very first cancer chemotherapy agents and still in widespread clinical use.^{[10][11][11][12]} Subbarow also discovered the basis for hetrazan which was used by the World health Organization against filariasis.^[13] Under Subbarow, Benjamin Duggar made his discovery of the world's first tetracycline antibiotic, aureomycin, in 1945. This discovery was made as a result of the largest distributed scientific experiment ever performed to that date, when American soldiers who had fought all over the world were instructed at the end of WWII to collect soil samples from wherever they were, and bring the samples back for screening at Lederle Laboratories for possible anti-bacterial agents produced by natural soil fungi.^[2]

Publications

• Angia, R.B.; Boothe, J.H.; Hutchings, B.L.; Mowat, J.H.; Semb, J.; Stokstad, E.L.R.; Subbarow, Y.; Waller, C.W.; Cosulich, D.B.; Fabrenbach, M.J.; Hultquist, M.E.; Erwin, K.U.H.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1946). "The structure and synthesis of the liver L. casei factor". Science 103 (2683): 667–669. doi:10.1126/science.103.2683.667.
• Angier, R.B.; Boothe, J.H.; Hutchings, B.L.; Mowat, J.H.; Semb, J.; Stokstad, E.L.R.; SubbaRow, Y.; Waller, C.W.; Cosulich, D.B.; Fahrenbach, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1945). "Synthesis of a compound identical with the L. casei factor isolated from liver". Science 102 (2644): 227–228. doi:10.1126/science.102.2644.227. PMID 17778509.
• Angier, R.B.; Mowat, J.H.; Boothe, J.H.; Waller, C.W.; Semb, J.; Hutchings, B.L.; Stokstad, E.L.R.; Subbarow, Y. (1948). "The preparation of 2-amino-4-hydroxy-6-keto-5,5-dichlorodihydropyrimidine". Journal of the American Chemical Society 70 (3): 1274–1275. doi:10.1021/ja01183a502.
• Angier, R.B.; Stokstad, E.L.R.; Mowat, J.H.; Hutchings, B.L.; Boothe, J.H.; Waller, C.W.; Semb, J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1948). "Synthesis of pteroylglutamic acid. III". Journal of the American Chemical Society 70 (1): 25–26. doi:10.1021/ja01181a008.
• Angier, R.B.; Waller, C.W.; Boothe, J.H.; Mowat, J.H.; Semb, J.; Hutchings, B.L.; Stokstad, E.L.R.; Subbarow, Y. (1948). "Pteridine chemistry. I". Journal of the American Chemical Society 70 (9): 3029–3031. doi:10.1021/ja01189a058.
• Angier, R.B.; Waller, C.W.; Hutchings, B.L.; Boothe, J.H.; Mowat, J.H.; Semb, J.; SubbaRow, Y. (1950). "Pteroic acid derivatives. VI. Unequivocal syntheses of some isomeric glutamic acid peptides". Journal of the American Chemical Society 72 (1): 74–77. doi:10.1021/ja01157a021.
• Baker, B.R.; Querry, M.V.; Bernstein, S.; Safir, S.R.; Subbarow, Y. (1947). "Biotin. IV. A second synthesis of 2-(Œ¥-carboxybutyl)-thiophane-3,4-dicarboxylic acid". Journal of Organic Chemistry 12 (1): 167–173. doi:10.1021/jo01165a021.
• Baker, B.R.; Querry, M.V.; McEwen, W.L.; Bernstein, S.; Safir, S.R.; Dorfman, L.; Subbarow, Y. (1947). "Biotin. VI. Synthesis of biotin and epiallobiotin". Journal of Organic Chemistry 12 (1): 186–198. doi:10.1021/jo01165a023.
• Bernstein, S.; Binovi, L.J.; Dorfman, L.; Sax, K.J.; Subbarow, Y. (1949). "7-Dehydrocholesterol". Journal of Organic Chemistry 14 (3): 433–446. doi:10.1021/jo01155a015.
• Bernstein, S.; Sax, K.J.; Subbarow, Y. (1948). "7-Dehydrocholesteryl chloride and bromide". Journal of Organic Chemistry 13 (6): 837–842. doi:10.1021/jo01164a009.
• Boothe, J.H.; Mowat, J.H.; Hutchings, B.L.; Angier, R.B.; Waller, C.W.; Stokstad, E.L.R.; Semb, J.; Gazzola, A.L.; Subbarow, Y. (1948). "Pteroic acid derivatives. II. Pteroyl-γ-glutamylglutamic acid and pteroyl-γ-glutamyl-γ-glutamylglutamic acid". Journal of the American Chemical Society 70 (3): 1099–1102. doi:10.1021/ja01183a068.
• Boothe, J.H.; Semb, J.; Waller, C.W.; Angier, R.B.; Mowat, J.H.; Hutchings, B.L.; Stokstad, E.L.R.; Subbarow, Y. (1949). "Pteroic acid derivatives. III. Pteroyl-γ-glutamylglutamic acid and pteroyl-γ-glutamyl-γ-glutamylglutamic acid". Journal of the American Chemical Society 71 (7): 2304–2308. doi:10.1021/ja01175a010.
• Boothe, J.H.; Waller, C.W.; Stokstad, E.L.R.; Hutchings, B.L.; Mowat, J.H.; Angier, R.B.; Semb, J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1948). "Synthesis of pteroylglutamic acid. IV". Journal of the American Chemical Society 70 (1): 27–28. doi:10.1021/ja01181a009.
• Fiske, C.H.; Subbarow, Y. (1927). "The nature of the "inorganic phosphate" in voluntary muscle". Science 65 (1686): 399. doi:10.1126/science.65.1686.401. PMID 17807679.
• Fiske, C.H.; Subbarow, Y. (1929). "Phosphorus compounds of muscle and liver". Science 70 (1816): 381–382. doi:10.1126/science.70.1816.381-a.
• Harned, B.K.; Cunningham, R.W.; Halliday, S.; Vessey, R.E.; Yuda, N.N.; Clark, M.C.; Hine, C.H.; Cosgrove, R.; Subbarow, Y. (1948). "Studies on the chemotherapy of filariasis. VI. Some pharmacopynamic properties of 1-diethylcarbamyl-4-methylpiperazine hydrochloride, Hetrazan". The Journal of Laboratory and Clinical Medicine 33 (2): 216–235.
• Hewitt, R.I.; Kushner, S.; Stewart, H.W.; White, E.; Wallace, W.S.; SubbaRow, Y. (1947). "Experimental chemotherapy of filariasis. III. Effect of 1-diethylcarbamyl-4-methylpiperazine hydrochloride against naturally acquired filarial infections in cotton rats and dogs". The Journal of Laboratory and Clinical Medicine 32 (11): 1314–1329.
• Hewitt, R.I.; Wallace, W.S.; White, E.; SubbaRow, Y. (1947). "Experimental chemotherapy of filariasis. I. Experimental methods for testing drugs against naturally acquired filarial infections in cotton rats and dogs". The Journal of Laboratory and Clinical Medicine 32 (11): 1293–1303.
• Hewitt, R.I.; White, E.; Wallace, W.S.; Stewart, H.W.; Kushner, S.; SubbaRow, Y. (1947). "Experimental chemotherapy of filariasis. II. Effect of piperazine derivatives against naturally acquired filarial infections in cotton rats and dogs". The Journal of Laboratory and Clinical Medicine 32 (11): 1304–1313.
• Hultquist, M.E.; Germann, R.P.; Webb, J.S.; Wright Jr, W.B.; Roth, B.; Smith Jr, J.M.; Subbarow, Y. (1951). "N-heterocyclic benzenesulfonamides". Journal of the American Chemical Society 73 (6): 2558–2566. doi:10.1021/ja01150a042.
• Hultquist, M.E.; Kuh, E.; Cosulich, D.B.; Fahrenbach, M.J.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M.; Angier, R.B.; Boothe, J.H.; Hutchings, B.L.; Mowat, J.H.; Semb, J.; Stokstad, E.L.R.; SubbaRow, Y.; Waller, C.W. (1948). "Synthesis of pteroylglutamic acid (liver L. casei factor) and pteroic acid. II". Journal of the American Chemical Society 70 (1): 23–24. doi:10.1021/ja01181a007.
• Hutchings, B.L.; Stokstad, E.L.R.; Bohonos, N.; Sloane, N.H.; SubbaRow, Y. (1948). "The isolation of the fermentation Lactobacillus casei factor". Journal of the American Chemical Society 70 (1): 1–3. doi:10.1021/ja01181a001.
• Hutchings, B.L.; Stokstad, E.L.R.; Mowat, J.H.; Boothe, J.H.; Waller, C.W.; Angier, R.B.; Semb, J.; SubbaRow, Y. (1948). "Degradation of the fermentation L. casei factor. II". Journal of the American Chemical Society 70 (1): 10–13. doi:10.1021/ja01181a004.
• Kushner, S.; Dalalian, H.; Cassell, R.T.; Sanjurjo, J.L.; McKenzie, D.; Subbarow, Y. (1948). "Experimental chemotherapy of tuberculosis. I. Substituted nicotinamides". Journal of Organic Chemistry 13 (6): 834–836. doi:10.1021/jo01164a008.
• Little, P.A.; Oleson, J.J.; SubbaRow, Y. (1948). "The effect of nutrition on the tumor response in Rous chicken sarcoma". The Journal of Laboratory and Clinical Medicine 33 (9): 1139–1143.
• Little, P.A.; Sampath, A.; SubbaRow, Y. (1948). "The use of antagonists of pteroylglutamic acid in controlling Rous chicken sarcoma". The Journal of Laboratory and Clinical Medicine 33 (9): 1144–1149.
• McKenzie, D.; Malone, L.; Kushner, S.; Oleson, J.J.; SubbaRow, Y. (1948). "The effect of nicotinic acid amide on experimental tuberculosis of white mice". The Journal of Laboratory and Clinical Medicine 33 (10): 1249–1253.
• Mowat, J.H.; Boothe, J.H.; Hutchings, B.L.; Stokstad, E.L.R.; Waller, C.W.; Angier, R.B.; Semb, J.; Cosulich, D.B.; SubbaRow, Y. (1948). "Erratum: The structure of the liver L. casei factor (Journal of the American Chemical Society (1948) 70, (14))". Journal of the American Chemical Society 70 (12): 4275. doi:10.1021/ja01192a622.
• Mowat, J.H.; Boothe, J.H.; Hutchings, B.L.; Stokstad, E.L.R.; Waller, C.W.; Angier, R.B.; Semb, J.; Cosulich, D.B.; SubbaRow, Y. (1948). "The structure of the liver L. casei factor". Journal of the American Chemical Society 70 (1): 14–18. doi:10.1021/ja01181a005.
• Mowat, J.H.; Gazzola, A.L.; Hutchings, B.L.; Boothe, J.H.; Waller, C.W.; Angier, R.B.; Semb, J.; Subbarow, Y. (1949). "Pteroic acid derivatives. IV. Pteroyl-α,γ-glutamyldiglutamic acid". Journal of the American Chemical Society 71 (7): 2308–2310. doi:10.1021/ja01175a011.
• Mowat, J.H.; Hutchings, B.L.; Angier, R.B.; Stokstad, E.L.R.; Boothe, J.H.; Waller, C.W.; Semb, J.; Subbarow, Y. (1948). "Pteroic acid derivatives. I. Pteroyl-Œ±-glutamylglutamic acid and pteroyl-α,γ-glutamyldiglutamic acid". Journal of the American Chemical Society 70 (3): 1096–1098. doi:10.1021/ja01183a067.
• Safir, S.R.; Bernstein, S.; Baker, B.R.; McEwen, W.L.; Subbarow, Y. (1947). "Biotin. IX. A synthesis of dl-dehydrobiotin". Journal of Organic Chemistry 12 (3): 475–482. doi:10.1021/jo01167a017.
• Safir, S.R.; Kushner, S.; Brancone, L.M.; Subbarow, Y. (1948). "Experimental chemotherapy of trypanosomiasis. II. The preparation of compounds related to p-phenylenediguanidine". Journal of Organic Chemistry 13 (6): 924–932. doi:10.1021/jo01164a024.
• Sanders, M.; Subbarow, Y.; Alexander, R.C. (1948). "An effective antiviral synthetic". Texas reports on biology and medicine 6 (3): 385–395.
• Semb, J.; Boothe, J.H.; Angier, R.B.; Waller, C.W.; Mowat, J.H.; Hutchings, B.L.; Subbarow, Y. (1949). "Pteroic acid derivatives. V. Pteroyl-α-glutamyl-α-glutamylglutamic acid, pteroyl-γ-glutamyl-α-glutamylglutamic acid, pteroyl-α-glutamyl-γ-glutamylglutamic acid". Journal of the American Chemical Society 71 (7): 2310–2315. doi:10.1021/ja01175a012.
• Stewart, H.W.; Turner, R.J.; Denton, J.J.; Kushner, S.; Brancone, L.M.; McEwen, W.L.; Hewitt, R.I.; Subbarow, Y. (1948). "Experimental chemotherapy of filariasis. IV. The preparation of derivatives of piperazine". Journal of Organic Chemistry 13 (1): 134–143. doi:10.1021/jo01159a018.
• Stokstad, E.L.R.; Hutchings, B.L.; Mowat, J.H.; Boothe, J.H.; Waller, C.W.; Angier, R.B.; Semb, J.; SubbaRow, Y. (1948). "The degradation of the fermentation Lactobacillus casei factor. I". Journal of the American Chemical Society 70 (1): 5–9. doi:10.1021/ja01181a003.
• Stokstad, E.L.R.; Hutchings, B.L.; SubbaRow, Y. (1948). "The isolation of the Lactobacillus casei factor from liver". Journal of the American Chemical Society 70 (1): 3–5. doi:10.1021/ja01181a002.
• Subbarow, Y.; Dann, W.J. (1938). "The inactivity of β-aminopyridine in blacktongue". Journal of the American Chemical Society 60 (10): 2565. doi:10.1021/ja01277a506.
• Subbarow, Y.; Dann, W.J.; Meilman, E. (1938). "The effect of β-aminopyridine in experimental blacktongue". Journal of the American Chemical Society 60 (6): 1510–1511. doi:10.1021/ja01273a505.
• Subbarow, Y.; Hastings, A.B.; Elkin, M. (1945). "Chemistry of Anti-Pernicious Anemia Substances of Liver". Vitamins and Hormones 3 (C): 237–296. doi:10.1016/s0083-6729(08)61114-0.
• Subbarow, Y.; Hitchings, G.H. (1939). "Pantothenic acid as a factor in rat nutrition [9]". Journal of the American Chemical Society 61 (6): 1615–1616. doi:10.1021/ja01875a522.
• Subbarow, Y.; Jacobson, B.M.; Prochownick, V. (1936). "Studies of the pernicious anemia principle in liver. III. The isolation and properties of a substance with primary therapeutic activity". Journal of the American Chemical Society 58 (11): 2234–2236. doi:10.1021/ja01302a044.
• Subbarow, Y.; Rane, L. (1939). "Pantothenic acid as a growth factor for the Dochez NY5 strain of hemolytic Streptococcus [10]". Journal of the American Chemical Society 61 (6): 1616. doi:10.1021/ja01875a523.
• Waller, C.W.; Hutchings, B.L.; Mowat, J.H.; Stokstad, E.L.R.; Boothe, J.H.; Angier, R.B.; Semb, J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1948). "Synthesis of pteroylglutamic acid (liver L. casei factor) and pteroic acid. I". Journal of the American Chemical Society 70 (1): 19–22. doi:10.1021/ja01181a006.

References

1. Mukherjee, Siddhartha (16 November 2010). The Emperor of All Maladies: A Biography of Cancer. Simon and Schuster. p. 31. ISBN 978-1-4391-0795-9. Retrieved 6 September 2011. Quote: "Any one of these achievements should have been enough to guarantee him a professorship at Harvard. But Subbarow was a foreigner, a reclusive, nocturnal, heavily accented vegetarian who lived in a one-room apartment downtown, befriended only by other nocturnal recluses"
2. Pushpa Mitra Bhargava (2001). "History of Medicine: Dr. Yellapragada SubbaRow (1895-1948) - He Transformed Science; Changed Lives" (PDF). Journal of the Indian Academy of Clinical Medicine 2 (1,2): 96_100.
3. Yellapragada SubbaRow Archives OnLine
4. The Hindu : Discoverer of miracle medicines - Y. Subba Row (1895-1948)
5. MycoBank, retrieved 26 December 2015
6. Hesseltine, C.W. (1953), "Study of Trickling Filter Fungi", Bulletin of the Torrey Botanical Club 80 (6): 507–514, doi:10.2307/2481965, JSTOR 2481965 page 511
7. "Miracle man of miracle drugs: Dr Yellapragada SubbaRow". Retrieved 10 March 2014.
8. Dr. Yellapragada SubbaRow (1895-1948): The man and the method by Kapur, S. & Gupta, S. P. K. in Indian Journal of Experimental Biology, 36(11):1087-92
9. Farber, S; Cutler, EC; Hawkins, JW; Harrison, JH; Peirce Ec, 2nd; Lenz, GG (1947). "The Action of Pteroylglutamic Conjugates on Man". Science 106 (2764): 619–21. doi:10.1126/science.106.2764.619. PMID 17831847.
10. Farber et al.'s article, published in the New England Journal of Medicine in 1946, noted Dr Subbarow's work as a foundation for this landmark paper. The paper remains one of the earliest top-cited research articles and is a classic in the field of medicine.
11. Farber, Sidney; Farber S; Diamond LK; Mercer RD; et al. (1948). "Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin)". N. Engl. J. Med. 238 (23): 787–93. doi:10.1056/NEJM194806032382301. PMID 18860765.
12. Miller, DR (2006). "A tribute to Sidney Farber-- the father of modern chemotherapy". British journal of haematology 134 (1): 20–6. doi:10.1111/j.1365-2141.2006.06119.x. PMID 16803563.
13. WHO Report on Global Filaria Control 2002