A Former Hospital Porter and a Forgotten Giant of Cancer Research

We owe thanks to a forgotten Indian immigrant who began his working life as a hospital porter, later became a biochemist, and revolutionized treatment for leukemia, still the most common pediatric cancer.

Dr Yellapragada SubbaRow is also known for developing a powerful, inexpensive treatment for leukemia and other diseases, methotrexate, earning him the name “the (Real) Father of Chemotherapy.” He also became known for other scientific achievements.

Born in southeastern India, SubbaRow nearly succumbed to a tropical disease that also took his two older brothers. He did not apply himself to his schoolwork until around the time his father died. Later, as an immigrant in the United States, he spent years facing prejudice. At 53, a blood clot took his life.

Yet, unfortunately, in scientific terms, SubbaRow achieved many triumphs despite the dozens of obstacles he faced and the fact that many people still do not know him today. During US National Cancer Research Month, we revisit his extraordinary life and work to remember him, remind others of him, and appreciate his achievements.

Dr Yella, Folic Acid, and the Transformation of Oncology

SubbaRow receives little recognition beyond a group of Indian-born doctors keeping his legacy alive in journal articles, presentations, and Pulitzer Prize-winning books.

Among them is author and oncologist Siddhartha Mukherjee, who chronicled SubbaRow's achievements in the No. 1 New York Times bestseller “The Emperor of All Maladies: A Biography of Cancer” (The Emperor of All Diseases).

As Mukherjee wrote, SubbaRow was “a pioneer in many ways, a physician who became a cell physiologist, a chemist who accidentally entered biology.”

(According to Indian tradition, SubbaRow is the doctor's given name and Yellapragada his surname. However, the medical literature uses SubbaRow, with some variations in spelling. His friends also called him “Yella,” as Mukherjee wrote.)

After enduring a difficult childhood and youth, he survived religious turmoil, childhood rebellion, and a failed arranged marriage. He had a child, but lost the baby in infancy. Leaving everything behind, SubbaRow arrived in the United States in 1923.

He was not admitted to Boston Medical School. For a time, he worked as a porter and night attendant at Brigham and Women's Hospital in Boston, changing sheets and cleaning toilets. The culture shock of performing these tasks must have been especially jarring for a poor but proud high-caste Indian Brahmin.

SubbaRow was admitted to Harvard Medical School, also in Baston, and became a young faculty member. Mukherjee writes that, as an outsider, SubbaRow was “reclusive, nocturnal, and heavily accented”. He was so different that academic advancement seemed impossible. Despite his pioneering biochemical research, Harvard did not allow SubbaRow to continue in a further permanent position.

In the early 1940s, he joined Lederle Labs, a pharmaceutical company in New York (later acquired by Pfizer). Folic acid was the vitamin whose synthesis he worked on. Eventually, he obtained an antivitamin similar to folic acid. But what use would there be in stopping the body from absorbing folic acid?

Many Discoveries, but No Funding or Fame

SubbaRow was no stranger to breakthroughs in biological research. He had previously discovered phosphocreatine and ATP simultaneously, both crucial for muscle contraction. However, author Gerald Posner wrote in “Pharma: Greed, Lies and the Poisoning of America” that “Subbarow had to deny his major role in the discovery of the phosphorus-related color test in 1935, and the honor instead went to a coauthor being considered for promotion to a full professorship at Harvard.”

Kirtan Nautiyal, an oncologist in Houston, honored SubbaRow in a paper published in 2018, saying: “His instinct to push himself into the background irreparably sabotaged his own career.”

Nautiyal also wrote that SubbaRow and his team developed “the first effective treatment for filariasis, which causes elephantiasis in the lower legs and genitals of millions of people, mostly in tropical countries .” “Ten years later, he produced polymyxin, the first effective treatment against the class of bacteria known as Gram-negatives, and aureomycin, the first broad-spectrum antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

SubbaRow's discovery of a folic acid antagonist likewise remained largely unheard of. However, it was first recognized that folic acid made childhood leukemia worse rather than better, and the possibility emerged that this process could potentially be reversed.

The Rise of Methotrexate and Success in Leukemia

Mukherjee recounted in his book:

“Sidney Farber, a pathologist in Boston, was desperate to help Robert Sandler, a 2-year-old with leukemia. Farber contacted his former colleague SubbaRow and requested some aminopterin, an early version of methotrexate that SubbaRow had developed with his team. Farber injected Robert with this substance, and within 3 days, the boy's white blood cell count began falling—rapidly. His bleeding stopped, he began eating, and he once again looked almost the same as his twin brother.”

There had never previously been success in treating leukemia. Unfortunately, however, this treatment worked only temporarily. Like the other children treated with this drug, Robert relapsed and died within months. But Farber “saw an open door” —a chemical had been used to treat cancer, and the chemotherapy era began. Thus, one of the most important steps toward using chemicals correctly had been taken.

Methotrexate, an anticancer agent synthesized by SubbaRow, would become the starting point for leukemia treatment and, in 1970, when combination chemotherapy was developed, would usher in long-term remission (a disease-free period) in acute lymphoblastic leukemia.

Methotrexate was also used for other cancer types. According to a history of methotrexate written by the US National Cancer Institute, “Previous assumptions that cancer was almost always fatal were overturned, and the previously nonexistent field of medical oncology was formally established in 1971.” Yet this account, too, made no mention of SubbaRow.

Gone, but His Legacy Lives On

Both in biographies and in his own words, SubbaRow emerges as irritable in personal relationships, ambitious, and a workaholic. Before completely severing ties in the early 1930s, he wrote to his wife in India, “It is not pleasant that you ask in every letter when I will return .” “I will come as early as possible… I do not want to write anything more.”

His biography describes SubbaRow as follows: “He was deeply determined to devote all the time allotted to him on earth to finding treatments for the diseases afflicting humanity.”

Nevertheless, SubbaRow's research team was devoted to him, and he had many reasons to be tough, including the prejudice and isolation he faced in the United States and, before that, in British-ruled India.

The SubbaRow described in Mr Posner's book had heeded the call of Indian independence activist Mohandas Gandhi even as a young medical student. “He rejected the British surgical gown issued to him at school and instead wore traditional, simple cotton Khadi. This act of defiance cost SubbaRow the university degree required for entry to the State Medical School.”

SubbaRow faced humiliation even in his final year: in his landmark 1948 study of aminopterin as a leukemia treatment, his colleague Farber also failed to give him credit. As Yaddanapudi Ravindranath, a pediatric hematologist/oncologist at Wayne State University in Detroit, put it, “an astonishing omission”. In an interview, Ravindranath said, “As far as I know, Farber spent the rest of his career apologizing and trying to make up for it.”

A Short Career and a Lasting Legacy

SubbaRow died suddenly in 1948 at just 53. Ravindranath said that “many people think SubbaRow would have won a Nobel Prize if he had lived a little longer.”

Like SubbaRow, Ravindranath was born in Andhra Pradesh, near Chennai, formerly known as Madras. Ravindranath, who made breakthroughs in his own research on methotrexate and leukemia, said, “As a compatriot, in a way I am carrying on his legacy, and I am openly proud of him .”  

Nearly 75 years after SubbaRow's death, Indian-born doctors such as Ravindranath continue to honor him in writing, trying to ensure he is not forgotten. Methotrexate remains a crucial treatment for leukemia and a range of other diseases, including psoriasis.

Recognition of “Yella” may have come late, but he was later offered immortality through the Lederle Laboratory research library bearing his name. As a stone plaque commemorating him as a scientist, teacher, philosopher, and philanthropist reads: “Science merely prolongs life; religion deepens it.” In any event, SubbaRow was a man of science and faith who believed in science.