Remembering the forgotten Indian biochemist who made pioneering contributions to cancer treatment

In May 1948, Gobind Behari Lal, a science writer and the first Indian to win a Pulitzer, wrote in his column about a patient at New York’s Harlem Hospital. The patient, afflicted with cancer of the oesophagus, had been treated with a new drug, Teropterin, which had considerably alleviated his pain.

The drug, synthesised by pioneering biochemist Yellapragada Subbarow and his colleagues was a “chemical relative of synthetic folic acid”, a vitamin used in treating certain forms of anaemia. Lal’s conclusion was that Teropterin temporarily arrested the cancer, and “Subbarow would use this new knowledge to develop new far-reaching cancer treatments”.

Two years later, in February, another article by Lal and Paul Murphy recounted the case of an eight-year-old boy affected with leukaemia. Beginning December 1947, the child had been administered the drug Aminopterin, after which the cancer cells showed obvious signs of remission. Seven months later, he developed a bacterial infection that was successfully treated with the new antibiotic Aureomycin.

Like Teropterin, Aminopterin and Aureomycin too were developed by Subbarow and his team at Lederle Laboratories, a pharmaceutical laboratory owned by the American Cyanamid Corporation. In the 1940s, their work was trailblazing, promising an exciting new stage in the quest for the medicinal conquest of cancer. By the time Lal and Murphy’s article appeared, however, Subbarow had been dead two years. Aged just 52 when he suffered a cardiac arrest on August 9, 1948, Subbarow had been working then on a polio drug, popularly called Darvisul.

Young Runaway

Yellapragada Subbarow was born on July 1, 1896, in Bhimavaram, in the West Godavari district of present-day Andhra Pradesh. His early life was filled with disquiet and adversity, as shown by Sikharam Prasanna Kumara Gupta’s 1987 biography, In Quest of Panacea, Raji Narasimhan’s related work, and a website dedicated to spotlighting Subbarow’s life and work.

Subbarow was the fourth of seven children. His father, Jagannadam, who worked in the tax department, had to retire early because of ill health. It was left to his mother, Venkamma, whose presence in his early life was by turns overwhelming and dominating, to run the household. It didn’t help that young Subbarow showed little interest in studies. He once ran away from home with a cousin, intending to travel to Benares to sell bananas to pilgrims, but a boatman alerted his mother. When he failed his matriculation twice, his mother sold her jewellery to send him to Madras (now Chennai), where he enrolled at the Hindu High School at Triplicane. He was drawn at this time to the Ramakrishna Mission, with its principles of asceticism and unconditional service to humankind.

In 1915, he began attending the Madras Medical College. Money was a problem, however. Sometimes when he could not pay the fees, support was provided by his roommate and later by Suryaprakasa Rao (whose granddaughter, Seshagiri, Subbarow would marry in 1919). An American doctor working in India, John Fox Kendricks, encouraged Subbarow to travel to the US for research. But there were personal setbacks. A sudden illness later diagnosed as “tropical sprue” killed two of his brothers and almost debilitated him. For a while, he taught at the Madras Ayurvedic College and compiled a compendium on ayurvedic treatments. But he realised that for more serious research, he needed to go to the US.

With great difficulty, Subbarow secured some money – a loan from his in-laws and assistance from a charity – that just about covered his travel costs. Once at Harvard, studying for a diploma in tropical medicine, he had to work several hours every day as a porter, clearing bedpans and urinals, at Boston’s Brigham Hospital. A year later, in 1924, he got the diploma and enrolled at Harvard Medical School’s chemistry department.

Tipping Point

This was the beginning of a landmark career in medicine and health. With his supervisor, Cyrus Fiske, Subbarow – called Yella by friends – worked to measure phosphorus in tissues and body fluids, a method soon named the Fiske-Subbarow method. As the story goes, at the time of publishing the research, Subbarow insisted his name follow Fiske’s in the proper alphabetical order. It was a mark of gratitude and a measure to ensure that Fiske got the tenure he wanted.

Soon after came the discovery of phosphocreatine in 1927 and identification of Adenosine Triphosphate in 1929, the chief energy source in the cell. Subbarow was awarded his PhD that same year.

In the meantime, there were personal sorrows and upheavals. A son born to Seshagiri and him did not survive beyond his first year. And while he had promised his wife he would return to her in Madras, he never did. Subbarow, a junior faculty member at Harvard, took to working weekends at Lederle Laboratories. It was a punishing schedule, as a friend, the pastor Gordon Torgersen, wrote later. In 1942, he moved permanently to Lederle, located at Pearl River in New York State, to head its research department.

By this time, the pharmaceutical company Eli Lilly had been selling a concentrated form of vitamin B12 as the treatment for pernicious anaemia. So Subbarow focused on the anaemia caused by folate deficiency.

In 1945, he began the synthesis of folic acid from scratch. This brought up surprising results. The variants of folic acid, including anti-folates, which closely mimicked natural molecules, could bind themselves to the cell and thus block any toxic action. Sidney Farber, pathologist and Harvard professor, had been studying causative developments, especially that between folic acid and certain cancers. Teropterin, which Lal wrote about, was the first anti-folate or antagonist to folic acid that appeared ameliorative.

Oral Medicines

Subbarow and his team took the research a step further, and developed Aminopterin. Farber tried this on his young patients at Boston’s Children’s Medical Center and it yielded impressive result. Soon a more developed version, Amethopterin (Methotrexate), was created. Its dosage could be adjusted, helping mitigate Aminopterin’s toxicity. Methotrexate became the drug of choice for many cancers, and later for psoriasis, rheumatoid arthritis and for resolving cases of ectopic pregnancy.

During the Second World War, Subbarow’s research led to diethylcarbamazine, an orally administrable drug for filariasis, a mosquito-borne illness that was tormenting soldiers in the Pacific.

The adventure with Aureomycin progressed simultaneously. Subbarow had invited the well-known University of Missouri professor Benjamin Duggar to join his laboratory to study the moulds that appeared in soil samples so as to isolate the fungi that could treat bacterial infections. One sample from Missouri yielded the promising gold coloured mould (sample A-3777) that treated with corn steep liquor led to the medicine Aureomycin. Louis Tompkins Wright, a noted African American surgeon and rights activist, first tried it for treating venereal disease at Harlem Hospital and found remarkable success. Unlike penicillin and streptomycin that were injectable, Aureomycin was an oral medication. It looked so promising that later that year, thieves broke into a Boston medicine warehouse to steal it. Tetracyclines, of which Aureomycin was the first, have since helped combat many serious bacterial illnesses.

Research Genius

After Subbarow’s sudden death in August 1948, his funeral services were held at the Emmanuel Baptist Church in Ridgewood, New Jersey. For some years, he had been involved with the church. This, like his involvement with the Ramakrishna Mission, seemed to arise from his desire to help his fellow man and his recognition of human limitations. As he remarked once, as a scientist, “we only prolong life, we don’t deepen it”.

His death was mourned not just by the scientific community but by others too. Among them were the people he knew at the bowling alley at the YMCA in Nyack, a New York suburb, which he used to frequent at a less busy period of his life. In its obituary, the New York Herald Tribune wrote, “Few laymen knew directly of Subbarow’s work… but many advances in modern medicine stand as a monument to his genius and countless thousands will benefit for years to come from investigations he set in motion and supervised.” The pastor Gordon Torgersen’s sermon titled “There are Giants on Earth” moved two members of the Emmanuel Baptist Church to pay off its long-standing mortgage in Subbarow’s name. The commemorative plaque still stands.

A plant set up by Lederle (now part of Pfizer) in Gujarat’s Valsad district in 1953 was inaugurated by US ambassador George Allen in the presence of Subbarow’s mother, Venkamma. In 1995, the Indian postal department issued a stamp in his name. Siddharth Mukherjee’s 2010 Pulitzer-winning book Emperor of All Maladies gives Subbarow his due place as a trailblazing researcher in the world’s quest to find a cancer cure: “Yella was a pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.”

This is the fourteenth part in a series on early Indians who blazed a trail in other parts of the world. Read the rest of the series here.