SIR SHANKAR BALASUBRAMANIAN, who was born in India, came to Britain as a toddler and is now a top chemistry professor in Cambridge, is working on a crucial aspect of cancer research that is likely to touch the lives of millions of people throughout the world if it comes off – and he is reasonably confident there will be major advances in how patients are treated in the next five to 10 years.
Instead of using general chemotherapy which kills both good and bad cells because the chemicals drip fed into patients are so toxic, the idea in future is to devise drugs aimed at combating individual cancers – simply because there are so many of them and each one can be unique. This move towards personalised cancer treatment that is less toxic is what Balasubramanian has been working on for many years now.
“I can’t imagine doing anything else,” he tells GG2 Power List. “The pursuit of ideas each day, each year, is what gets you out of bed in the morning. It’s continuously stimulating. And also working in an environment with students, post-docs and colleagues who are all drawn to that, is very infectious. I love what I do.”
Talking about his work life balance, he added: “I love to spend time with my family as and when I get chance. I have a son, Sachin, who is doing engineering in Birmingham. I have a daughter Sashi who is in the final year of school. My wife Veena is a GP. I live in Cambridge and walk and cycle everywhere. My other main thing is endurance running.”
His formal title is that he is the Herchel Smith Professor of Medicinal Chemistry at the Yusuf Hamied department of chemistry (named after the head of Cipla) at Cambridge University. Balasubramanian, who is 55, is a Fellow of the Royal Society. At Cambridge, he is a Fellow of Trinity College and an Honorary Fellow of Fitzwilliam, his own alma mater where he was an undergraduate and a PhD student for six years.
He was knighted in the New Honours List in 2016 “for services to science and medicine”. And in May 2021, he and another Cambridge chemist, Professor Sir David Klenerman, were named as joint winners of the 2020 Millennium Technology Prize, given for their development of revolutionary DNA sequencing techniques”. It is a prestigious prize, worth one million Euros (£834,000), that is awarded every two years by the Technology Academy Finland.
He also won the 2022 Breakthrough Prize for Life Sciences, shared with Klenerman and Pascal Mayer, for next generation sequencing.
Although the science behind cancer research might seem very complicated to those without an in-depth knowledge of medicine or biology, he explained the principles behind his work – and how the disease occurs when human cells change from what is considered normal.
Once the drivers of change are understood, it is hoped scientists will be better able to devise drugs that can target specific cancers. “Cancer is caused by changes to DNA,” Balasubramanian summed up. “That’s at the root cause of cancer.
And all cancers are not the same.
“The main thing that we’re working on are DNA structures that differ from the Watson Crick double helix,” he went on. “And these DNA structures are four stranded quadruple helix structures called G quadruplex. These are unusual alternative DNA structures, and we’ve shown a form in human cells. We’ve shown that many of these structures form in cancers. We’ve been studying the relationship between these structures and biological mechanisms that drive cancers. That’s fundamental work.”
On using this research to do something “useful”, he said: “We’ve made molecules that combine with these structures and shown that these molecules have anti-cancer activity. So the direction of travel here is we are trying to take everything that we’ve learned and turn this knowledge into the development of cancer therapeutics.”
He contrasted how cancer is treated now and almost indiscriminately, using drugs such as Cisplatin, Carboplatin, Camptothecin. These are the early drugs against cancer. And they do work – but they are basically toxic molecules. Which is why the side effects of these therapies can be hugely unpleasant and debilitating.
“What we have found is a way of targeting structures in DNA that predominate in cancers rather than normal cells. So what this is leading us to believe is it there may be a way of targeting cancer through this approach that has selectivity and tar[1]gets cancers in a way that will not be toxic.”
He injected a note of caution: “We have some way to go. But the science is suggesting that this should be possible. I would hope that in the next five to 10 years, we can actually demonstrate in a clinically relevant setting what the science is suggesting might be possible.
“Indeed, one of our findings and approaches is you can stratify cancers based on the underlying genetics that’s particular to that cancer. You can use that sort of genetic characteristic of a cancer as its Achilles heel.
What we have found is that this approach that we’re adopting works particularly well with certain cancer types that have a certain genetic characteristic. This is part of what we’re hoping to exploit to generate therapies that will be non-toxic. But they’ll be applied in the first instance to particular cancers.”
He predicted: “It’s personalised cancer medicine. That’s the vision of what we want to try and achieve.”
Cancer genome sequencing research, which has been part of his work, “is leading to a better understanding of how to deploy therapeutics against cancer. Some people call this personalised medicine, where a particular cancer with a particular pattern of genetic changes may be more responsive to a certain therapy.
“So the information can be used for therapy selection. I would stress that we are in the early phases of this. And as more and more work is done to sequence tumours, over the next 10 to 20 years, we’ll find out the full extent to which genomic information can be used.
“If you can detect cancer early, the ability to treat it successfully and have a better patient survival outcome is much higher. Anything that can help patient outcomes cannot come soon enough. I think with cancer, we’ve come a long way. And clearly there’s still a long way to go. Certainly we are optimistic that over the next 10-20 years, there will be more transformative change that will translate into patient care.
“One is predisposition. Certain mutations and particular genes can predispose to cancer. So it’s an early warning. The hope is that there may be a new modality for detecting cancer earlier. And prevention is certainly better than cure.”
As someone from a middle class Indian family, Balasubramanian appears to have had a happy childhood growing up essentially in a rural part of northern England but his schooling was not especially privileged.
He did well academically possibly because there was no pressure for him to do so. But there were good teachers around him to nurture his curiosity in science.
As someone who enjoys running, he will appreciate he has travelled a long way from where his life began.
“I was born in Madras, now Chennai, on 30 September 1966. I was nine months old when my parents migrated to the UK in 1967.”
His father Venkataraman Balasubramanian, now retired, worked as an architect, his mother Padma Subramanian in the civil service. Back in India, both his grandparents, S Radhakrishnan and M Venkataraman, had been engineers.
After moving around for a while, his parents settled in Preston Brook, a small village between Warrington and Runcorn in Cheshire. “Where we lived was a working class area where actually many people had to struggle. There wasn’t anything privileged about where we lived.”
It was “very much a rural country area. Which actually, I think, when growing up, is quite a nice environment with not too much going on. I suppose the role that all that played in my personal development is there wasn’t much pressure or expectation in that environment. You found your own path and you drove yourself. I wasn’t too far from Liverpool.
“So I played a lot of football growing up, and that was probably the strongest motivator for a young person then in places like that. Not so much science and education.”
He first went to Daresbury Primary School. “I guess it was renowned because Lewis Carroll was from there.”
He then moved to a comprehensive, Appleton Hall High School. “In all the years I was there, in the school of 1,000 children, I was the only person of colour. Was there racism? Yes. That was part of the environment at that time. I wouldn’t single out the school, though if you’re the only person of colour in an environment, that poses its own challenges.”
Looking back to his formative years, he recalled that “if you were interested in something, there was certainly no barrier if you were finding your own path and driving yourself. It was a school that had some high quality teachers who would spot that and nurture it. I found that a very good environment in which to find myself. I have lifelong friends from my school days that I’m still close with and in touch with even though we’ve all gone in different directions and done different things.”
The school did not send too many of its pupils to university and certainly did not have an Oxbridge tradition. He was the second person from his school to win a place at Fitzwilliam College, Cambridge. That was a turning point in his life.
He went up to Cambridge to read Natural Sciences in 1985. “When I first came to Cambridge, I actually found the environment quite intimidating. It was full of people who exuded confidence and appeared to be better prepared than I was for the Cambridge experience. The first year, finding my feet, was challenging. After the first year, it got easier.”
He stayed on at Fitzwilliam for another three years, completing his PhD in 1991, before going to go to America as a postdoctoral fellow at Pennsylvania State University for two years. He was persuaded to return to Cambridge in 1994, with his own lab at the department of chemistry.
Going to the US was a revelation. “It was my first encounter of America. I’d never been there before. So it was certainly a cultural awakening.
Secondly, I think I was in a very well supported laboratory, led by brilliant scientists. I learnt a lot about how to do science more in the American way.
“It was less conservative than how we do it in the UK. The tempo of research I found to be much faster. At least, in the lab I was in, the ambition was very high in terms of the types of problems that were being worked on.”
Both in his PhD and in America, Balasubramanian was studying “the chemistry and mechanism of how enzymes work – as biological machines. In my postdoctoral year, I worked mainly on two clinically important enzymes. One is HIV-1 Reverse Transcriptase. This is the target for the retroviral therapies. I was working on understanding the mechanics of this enzyme. The other is an enzyme called Phenylalanine Hydroxylase – a mutation in this enzyme leads to a deficiency and childhood developmental condition called Phenylketonuria. I was studying the fundamentals of how they work and the chemistry associated with them.”
Balasubramanian was very lucky to have influenced by three outstanding professors.
His PhD supervisor was Chris Abell. In America, the head of his lab was Stephen Benkovic. And then Alan Fersht persuaded him to come back to Cambridge.
Balasubramanian admitted: “I nearly stayed on in the States.
“The people around me, including the lab director, all strongly advised me to stay on the grounds that American science was fantastic and that ‘you should stay here to do science, not go back to the UK’. I thought I would do that.
“The reason I came back was it was a very senior professor in Cambridge called Alan Fersht – he had taken an interest in my career – persuaded me to come back to Cambridge. So I came back in 1994 to start my own laboratory.”
Balasubramanian appears not to have regretted that decision.