Harvard-rejected Indian, old physiologist & Black surgeon made US’ ‘most versatile antibiotic’

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The three men who were ultimately responsible for the next drug breakthrough were quasi-outcasts; one a foreigner barred by U.S. immigration from becoming an American citizen, another judged too old by colleagues, and the third a black surgeon at a time when the medical profession was nearly all white.

Lederle’s chief of research was an Indian-born physiologist and physician, Yellapragada SubbaRow. He was one of seven children from a poor family in Bhimavaram, an eastern Indian city best known as a major Hindu pilgrimage site. At thirteen, SubbaRow ran off to become a banana trader to the visiting pilgrims. His father, a tax collector, found and brought him home.

When his father died when SubbaRow was 18, he ran away again, this time to become a monk. This time his mother found him and ordered him back to school. Local charities at first helped him afford Madras Medical College. But lack of money was always a problem. When he was 24, he wed the 15-year-old granddaughter of a respectable merchant as part of an arranged marriage. His father-in-law paid for the last two years of tuition.
SubbaRow was at school when the movement for Indian independence from Great Britain gained momentum inspired by Gandhi. He refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College. Instead, he joined a local Ayurvedic College as an anatomy lecturer. While he was there an American doctor on a Rockefeller scholarship working on an anti-hookworm campaign in India, encouraged SubbaRow to apply to the Harvard School of Tropical Medicine.

Harvard considered his Ayurvedic work disqualifying and rejected him. In 1922, he tried again, but withdrew his application in order to help his mother and siblings after two brothers died from Tropical Sprue, a rare infectious digestive disease. Not dissuaded, he applied again the following year. This time he emphasized his anatomy training. Harvard accepted him.

SubbaRow was 28 when he left behind his wife, who was pregnant with their first child, and emigrated to the U.S. (his child, a son, died of a bacterial infection before he was one years old; not only did SubbaRow never see his child, he never again saw his wife). He was ineligible for a scholarship at the School of Tropical Medicine because his Indian degree did not meet Harvard’s standards. The same was true when he tried getting an internship at Boston hospitals. He finally landed some odd jobs at one of them. Between his studies and the little sleep he got, he managed to start repaying his father-in-law for the loans. Industrious and hardworking, he earned his diploma in Tropical Medicine in 1924 and started on his PhD in biochemistry at Harvard Medical School.

In 1929, he co-authored his first scientific paper about his discovery of a simple color test to determine the amount of phosphorus in biological tissue. The following year he was the first Indian in Harvard history to earn a biochemistry PhD and began working as a teaching fellow at Harvard Medical School. Although it was common for a scientist of his talent to use research assistants and collaborate with peers in the lab, Harvard directed that he work alone. Although he made advances in phosphorus compounds connected to RNA synthesis, he was not allowed to publish his results. In 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard.

Denied tenure and tired of his second-class status at Harvard, in May 1940, he accepted an offer to become Lederle’s Associate Director of Research at their Pearl River, New York lab. When the previous director retired at the end of that year, SubbaRow became the chief.

SubbaRow had joined the pharma industry just in time to be part of the penicillin project. He was Lederle’s representative when dealing with the government or other pharma companies. Although the penicillin work left little time in the laboratory, he was the first researcher to synthesize amethopterin, a chemical analogue of folic acid. The research was prompted by a study that showed children with leukemia got significantly worse when fed a diet rich in folic acid. Scientists like SubbaRow wondered if an analogue that was hostile to folic acid might have the opposite effect. Sidney Farber, a pathologist at Boston’s Children’s Hospital, made a breakthrough with SubbaRow’s analogue, developing in a few years the first effective chemotherapy agent.

In 1942, SubbaRow hired someone who would play a critical role in the postwar discovery of the next broad-spectrum antibiotic. That was 70-year-old Benjamin Duggar, a plant physiologist, who had been forced to “retire” by the University of Wisconsin as he was “too old” that his specialty was not what they needed. SubbaRow saw experience in what others judged “too old” and he thought that in Duggar he might have found Lederle’s “antibiotic hunter.”

At Lederle, coworkers came to know the Alabama native as amiable and eccentric. He went to the lab every day, slowly but methodically sifting through soil samples looking for antibiotic producing fungi. At his suggestion, Lederle requested the Army have soldiers returning home bring a small amount of soil from some of the places they had served. By 1944, a small shack outside the lab held thousands of such samples from more than 20 countries on three continents. Duggar sometimes isolated antibiotic organisms from the samples. He and SubbaRow would carry out the tests to see if they had any effect in petri dishes on a broad range of bacterial pathogens.

Some days Duggar stayed away from the soil and instead reverted to the professor he had been for many years. He’d stop by the lab but only to give a lecture to his younger colleagues. Most evenings Duggar left no later than 5:30 so he could play golf at a country club before it got dark. A chain smoker, Duggar also spent his free time tending to a makeshift garden he had created near an abandoned stable. He shared little about his personal life with coworkers.

One day in 1945, while extracting molds from soil samples sent to him from a dormant hayfield on the University of Missouri, he noticed one was an unusual gold-color. Duggar had isolated hundreds of what he called “ultra-molds” during his three years at Lederle. Somehow, he had a hunch that this one was special. With SubbaRow overseeing his work, Duggar tested the mold he had labeled A-377. To the elation of the Lederle lab, A-377 proved effective in halting the growth of both Gram-positive and Gram-negative bacteria, including the microbes responsible for bubonic plague, tuberculosis, typhus, and Rocky Mountain spotted fever. They had discovered the first broad spectrum antibiotic since streptomycin.

Although SubbaRow and Duggar put it on a fast track, that did not translate into much speed given Lederle’s small staff and limited resources. It took three years of additional testing, until 1948, before Duggar was confident enough with his finding to publish a paper about it. There, he dubbed the antibiotic organism he discovered Streptomyces aureofaciens, the “gold maker.” Lederle executives liked that so much they gave the drug its brand name, Aureomycin (Aureo is Latin for gold). Duggar’s paper notified Lederle’s competitors that they lost the race to find the first postwar broad-spectrum antibiotic.

Before there could be certainty that Aureomycin was a wonder drug, Duggar had developed a process to produce substantial quantities of a purified version for human testing. One of Lederle’s shortcomings was its failure to have an exclusive arrangement with a top testing hospital or school. SubbaRow and Duggar picked New York’s Louis Tompkins Wright to run clinical tests on the most important drug in Lederle’s history. A decade earlier Life had dubbed Wright the “most eminent Negro doctor in the U.S. . . [the] surgical director of Harlem Hospital, [and] only colored Fellow of American College of Surgeons.”

A lower caste Indian who was rejected for tenure at Harvard had selected the son of a Confederate officer and doctor, and together they picked the most famous black doctor in America — the son of a slave who had himself become a doctor —to conduct the clinical trials.

Lederle Laboratory’s SubbaRow and Duggar probably cared little about Wright’s trailblazing when it came to race and medicine. They chose him to conduct Aureomycin’s clinical trials because they considered him eminently qualified. He had by then published nearly 90 papers in leading scientific journals, 35 of them about antibiotics. And Wright, who had just returned to work after a three-year leave of absence to recuperate from a severe bout of tuberculosis, was enthusiastic about undertaking the trials. He had long been interested in LGV, a sexually transmitted infection of the lymphatic system. Aureomycin was his chance to discover whether there was a drug to help patients with the painful, chronic condition. Over two months in the spring and early summer of 1948 Wright conducted the first human experiments.

Lederle’s drug destroyed the chlamydia bacteria responsible for the disease. It was also effective on a nasty viral variant of pneumonia. Wright uncovered few side effects and certainly nothing toxic. His report to Lederle was that their drug was ready for public release. By the time Aureomycin was ready to go on sale in December 1948, Lederle’s chief of research, Yellapragada SubbaRow, was not alive to savor it.