History

Crosstalk: How Two Modest Heroes Won the Battle Against Childhood Leukaemia

Y. Subbarow and Sidney Farber developed a friendship recognising each other to be fellow science warriors, passionate about their research performed in dingy basements against debilitating illnesses.

A scanning electron microscope image of normal circulating human blood. In addition to the irregularly shaped leukocytes, both red blood cells and many small disc-shaped platelets are visible. Caption & credit: Wikimedia Commons

A scanning electron microscope image of normal circulating human blood. In addition to the irregularly shaped leukocytes, both red blood cells and many small disc-shaped platelets are visible. Caption & credit: Wikimedia Commons

“As soon as we touch the complex processes that go on in a living thing … we are at once forced to use the methods of chemistry. No longer will the microscope, the kymograph, the scalpel avail for the complete solution of the problem. … The investigator must associate himself with those who have labored in fields where molecules and atoms, rather than multicellular tissues or even unicellular organisms, are the units of study.” – John Jacob Abel

Sometimes, as fans of the film Kung-Fu Panda know too well, a hero can emerge from the unlikeliest of circumstances.  

Absolutely nothing about Yellapragada Subbarow suggested that he would go on to do great things in science. He was born in 1895 in what was then the Madras presidency into a family of modest means. He somehow completed his matriculation in Madras (in the third attempt), and entered the Madras Medical College thanks to the support of many friends and relatives. Subbarow was greatly influenced by the independence movement in India and adopted traditional khadi clothing (instead of the mandated shirt and trousers) while in medical school.

As a result, he irritated some of his British teachers, who ensured that instead of him graduating with a medical degree, he received a lower licentiate in medicine degree. It’s unclear how Subbarow made his way to America after that but it appears that he did so mostly on hope and a prayer. He reached Boston penniless but completed a diploma at the Harvard University’s school of tropical medicine, and then started as a junior, non-tenured faculty at the institution’s medical school – all while working three shift jobs. At this time, though trained in medicine, Subbarow became fascinated by chemistry and started his work with Cyrus Fiske, a professor at Harvard. Together, they made path breaking discoveries.

A major element in all living cells is phosphorus. Subbarow developed methods by which you could accurately estimate how much phosphorus was present in tissues. This Fiske-Subbarow method soon became the method of choice for all biochemists to detect phosphates. While this in itself was useful, what it enabled him to do was detect and identify new molecules containing phosphorus as well. And it was in 1929 that he would make his big discovery.

Using muscle extracts, Subbarow discovered two molecules named phosphocreatine and ATP (which was found independently by him and other groups). These molecules, as we’d learn, are the energy currency of all living cells. The phosphate bond is a high-energy bond and the energy in it can be stored or released whenever needed in cells. And Subbarow’s find made it straight into the biochemistry textbooks. Any of these discoveries should have made him famous and won him many awards – but didn’t. His boss, Cyrus Fiske, seems to have been a small-minded, insecure scientist. He used Subbarow’s work for great personal gain and asked him to say that he did not make great intellectual contributions to the projects. Subbarow, the prototypical overly modest immigrant, speaking formal English and living in penury, said something to the effect that “Fiske was the mind, and I was the hands”, ensuring that Fiske became chair of the department. In return, Subbarow didn’t even get tenure in the department and lost his temporary research job for added measure.

At this point Subbarow might have gone on to a life of modest obscurity, denied all recognition for his path-breaking work. Yet he was an exceptional scientist, living and breathing the science of chemistry. Denied tenure at Harvard, he was snapped up by industry, which recognised his pioneering talent. He went on to lead one of the most successful chemistry teams in pharmaceutical history at Lederle Labs as director of research. His chemistry team went on to synthesise molecules that would help save tens of thousands of lives. But for that story to become possible, another character was critical.

When Sidney Farber was a 30-year-old pediatric pathologist at Harvard, he would not have dreamt that he would go on to become a storied physician, curing childhood leukaemia and becoming the face of cancer research. Paediatric pathology is hardly the most glamorous of professions in medicine and mostly involves spending long hours late into the night in a basement lab staring at tissue samples, or performing autopsies, but never once seeing a patient. Farber, who was then an assistant professor at Harvard, did this well enough to go on to become the chief of pathology. At this time, he and Subbarow developed a friendship – perhaps recognising each other to be fellow solitary science warriors, passionate about their research performed in dingy basements.

They were outsiders in their own way. Farber was Jewish and grew up with modest means even as he excelled in his studies in upstate New York. He went to Europe to train in medicine in Germany, then returned to Boston and managed to secure a position in Harvard’s medical school. For most Jews at that time, this was a near-impossible task, yet Farber had already demonstrated exemplary abilities. In the course of his research, he authored a textbook on childhood pathology that became an instant classic. Then again, Farber was deeply interested in clinical medicine and was no longer content staring into a microscope. He did the unthinkable and switched fields to start research in clinical medicine, hoping that his background in careful pathological analyses would keep him in good stead.

A visible villain

Childhood leukaemia was a disease that had frustrated doctors for decades: all they had were a spate of symptoms describing it. It was only in the late 1800s that the German polymath Rudolf Virchow, who had been studying a variety of cells from cancers, came up with multiple observations that negated wildly fictitious theories about leukaemia. He realised and proposed that it was the aberrant growth of white blood cells that caused the horrifying disease. As a paediatric pathologist, Farber had stared endlessly at blood cells from patients with leukaemia and observed their relentless proliferation, and had been thinking about finding quelling agents.

In a world before PET scans, it was hard to detect most cancers, yet for leukaemia the problematic cells were visible under a microscope. Farber reasoned that researchers could therefore study ways to stop leukaemia by just using the cells in the blood (and not in a patient), just like biochemists studying single cell organisms like bacteria. He knew about recently discovered antibiotics that could kill bacteria and thought the same concept could work for leukaemia cells as well.

While experimenting with several agents, he became aware of the importance of the vitamin folic acid, present in the blood. In the slave-like textile mills in distant Bombay, many workers – especially women – were affected with anaemia due to poor nutrition. When these workers were given marmite (yeast extracts), they would recover. It was later found that the active agent in marmite was folic acid. Farber figured that treating leukaemia-afflicted cells with the acid would cure them, but to his horror, he found that the compound made the cells grow even faster.

Today, we know that this is because folic acid helps cells make more DNA and RNA, molecules needed for growth. At that time, Farber quickly reasoned that if he could do the reverse and stop folic acid being used by using an ‘anti-vitamin’, perhaps he could cure leukaemia. But where could he get an anti-vitamin that could do this? He then remembered Yella, his old friend at Harvard, who he knew was at Lederle Labs and, most importantly, whom he recognised as the grandmaster of making such compounds.

In the late 1940s, Farber wrote to Subbarow, who immediately and generously sent Farber a range of folic-acid-like compounds that he and his team had painstakingly synthesised for the first time. These were remarkable feats in chemical synthesis, never accomplished before that. Remarkably, Farber’s hunch proved to be right and some of these molecules stopped leukaemia dead in its tracks. Farber had a patient then, a child suffering from the disease. In an era before countless consent forms, approvals and clinical trials, Farber decided to directly treat the child with the compounds Subbarow had sent him. The child was very sick and on the verge of death. Miraculously, once injected with the compound, his white blood cells count started dropping to normal and days later he could walk.

Methotrexate, one of the folate antagonists that Subbarow made in the 1940s, went on to become the first choice drug against leukaemia, saving thousands of lives. It remains widely used to this day. In addition to these enormous contributions, Subbarow and his team also made compounds that treated filariasis, apart from developing other antibiotics. His immense contributions are much better appreciated today, decades after his death in 1948. And somehow this unassuming scientist with a fascination for biochemistry and a relentless quest for discovery helped transform cancer research.

Farber’s and Subbarow’s stories are beautifully described in Siddhartha Mukerjee’s Pulitzer-Prize-winning book The Emperor of All Maladies (2010).

Sunil Laxman is a scientist at the Institute for Stem Cell Biology and Regenerative Medicine, where his research group studies how cells function and communicate with each other. He has a keen interest in the history and process of science, and how science influences society.