Yellapragada SubbaRow

Indian biochemist

• Born: January 12, 1895; Bhimavaram, India
• Died: August 9, 1948; Pearl River, New York

During the 1930s, Yellapragada SubbaRow determined the roles of phosphocreatine and adenosine triphosphate as the energy “currency” in cells. Later, he helped explain the role of the vitamin folic acid in cell metabolism. He and pathologist Sidney Farber devised a way to apply the folic acid antagonist methotrexate in the treatment of cancer.

Also known as: Yellapragada Subbarao

Primary field: Biochemistry

Specialties: Biochemistry; chemistry

Early Life

Yellapragada SubbaRow was born January 12, 1895, the fourth of seven children to Jagannadham and Venkamma SubbaRow, in Bhimavaram in the West Godavari district of Andhra Pradesh in what was then British India. His father, a member of the sect of Niyogi Brahmins, had served with the government as a member of the revenue service until forced to retire because of illness. As a result, the SubbaRow household was poor.

At the age of fourteen, SubbaRow ran away from home, but was returned by men sent to look for him by his mother. Following the death of his father, SubbaRow completed his secondary education at the Hindu High School in Madras. After twice failing the entrance examinations, he enrolled at Madras Presidency College.

As a college student, SubbaRow was undecided about his career direction. During this era, Mahatma Gandhi was protesting the British presence in India, calling for a boycott of British goods. In solidarity with the movement speaking out against British rule in India, SubbaRow began wearing only traditional khadi dress, and entered the Ramakrishna Mission, a service organization. SubbaRow’s colleagues at the mission encouraged him to enroll in Madras Medical College. SubbaRow decided that the practice of medicine was a good way to serve humanity.

After enrolling in medical school, SubbaRow also married Seshagiri Rao, who grandfather had offered to help fund his work in medical school. SubbaRow planned to continue his studies at the Harvard School of Tropical Medicine, financed by a scholarship established by his older brother Purushottam. After the deaths of two of his brothers from the tropical disease sprue, he opted instead to become a lecturer in physiology at Ayurvedic College in Madras. Having acquired funding help from his father-in-law, SubbaRow enrolled at Harvard Medical School in the fall of 1923.

Life’s Work

After arriving in Boston, SubbaRow took a job as a custodian at Peter Bent Brigham Hospital. As a medical student, he began learning research techniques in tropical medicine. Completing the program in June 1924, SubbaRow joined Harvard’s Department of Biochemistry, where he began working with biochemist Cyrus Fiske. Their first project involved the development of a procedure for measuring the level of phosphorus in a solution. At this time, most chemical quantization consisted of the application of a method of chemical analysis called colorimetry. Otto Folin, chair of the Department of Biochemistry, had developed such methods for measurement of proteins or sugars in solution. SubbaRow and Fiske developed a similar method for analysis of phosphorus. By December of 1924, they had refined the procedure enough to be able to present it to the American Society of Biological Chemists. The Fiske-SubbaRow method was subsequently included in biochemistry textbooks, and SubbaRow and his colleagues used it to explain a part of sugar metabolism: the mechanism by which energy is produced during the conversion of glycogen to lactic acid. The work ultimately led to the discovery of phosphocreatine and adenosine triphosphate (ATP) as sources of energy for muscle.

As an alien working at Harvard during the Depression years, SubbaRow’s chances for promotion were limited. Nonetheless, he continued his research, working on isolating extracts from liver that could be used to treat pernicious anemia. Credit for discovering the role played by vitamin B12 subsequently went to medical researchers George Minot and William Murphy, though at least one pharmaceutical company, Lederle Laboratories in Pearl River, New York, was aware of SubbaRow’s contributions. Harvard recognized SubbaRow’s work by promoting him to associate professor.

In May 1940, SubbaRow joined Lederle as associate director of research, overseeing the development of vitamins and antibacterial compounds such as penicillin. The first antibiotic that SubbaRow’s unit discovered was aureomycin, the first of the tetracycline-like class of antibiotics. SubbaRow also began an investigation into the cause of tropical sprue, the disease that had killed his two brothers. He discovered that a newly recognized vitamin, folic acid, was effective in reversing certain forms of the disease, and he developed procedures for large-scale synthesis of the vitamin. The synthesis of folic acid came to the attention of Dr. Sidney Farber at Children’s Hospital in Boston, who theorized that the vitamin might be of use in treating certain forms of leukemia. Farber’s idea proved wrong; folic acid actually increased the rate at which leukemic cells proliferated. However, SubbaRow and his colleagues had also synthesized modified forms of folic acid—folic acid analogs—which did prove effective in treating leukemia. One of these, methotrexate, became a standard method of treatment in an antileukemic “cocktail.”

SubbaRow died on August 9, 1948. He was fifty-five years old.

Impact

SubbaRow’s research improved understanding of the role played by phosphocreatine and ATP as sources of energy within muscle tissue. The Fiske-SubbaRow method of phosphorus estimation became the standard colorimetric method of analysis for generations of biochemists. SubbaRow’s application of this procedure was critical. While investigating the process by which muscle glycogen was converted to lactic acid, Fiske and SubbaRow discovered the presence of the intermediate phosphocreatine. Further analysis demonstrated that hydrolysis of phosphocreatine released a phosphate molecule that in turn became linked to adenosine, ultimately creating the “energy currency” used by muscles and cells in general, ATP. While it would remain for another generation of scientists to explain precisely how ATP was used, SubbaRow’s discovery laid the groundwork for those future studies.

SubbaRow’s other major contribution during his tenure at Lederle was his development of the first effective drugs for treatment of certain forms of childhood leukemia. The first of the antileukemic drugs, the folic acid antagonist teropterin, proved to exhibit only limited success, despite the publicity associated with its brief effectiveness in treating baseball great Babe Ruth. However, the derivatives aminopterin and amethopterin (methotrexate) proved more effective in treating a variety of cancers. SubbaRow’s relatively early death came as a shock to his colleagues. Nevertheless, his role in the development of the first generation of chemotherapeutic drugs contributed to the belief that cancer could one day be cured.

Bibliography

Mukherjee, Siddhartha. The Emperor of All Maladies: A Biography of Cancer. New York: Simon, 2010. Print. Historical discussion of cancer from the descriptions in ancient Egypt to present-day treatments. Reviews the development of chemotherapy as a form of treatment.

Olson, James. Making Cancer History: Disease and Discovery at the University of Texas M.D. Anderson Cancer Center. Baltimore: Johns Hopkins UP, 2009. Print. Discusses the history and development of chemotherapy. Reviews the work of Sidney Farber and the use of methotrexate.

Skeel, Roland T. Handbook of Cancer Chemotherapy. 8th ed. Baltimore: Lippincott, 2011. Print. Reference work for oncologists. Detailed review of known tumors and chemotherapy treatments.