89th Congregation (2020)
Professor Sir Shankar BALASUBRAMANIAN
Doctor of Science
Professor Sir Shankar Balasubramanian was born in 1966 in Madras, now known as Chennai, in India. His parents moved to the UK the following year, and their infant son went with them. They settled just outside Runcorn in Cheshire, now all administratively part of the Liverpool City Region; this is where he grew up. Many will have envied him: Liverpool was the city to be in that year in Britain. The Liverpool Beat could be heard worldwide, and The Beatles released their most iconic album, Sergeant Pepper’s Lonely Hearts Club Band. One of its two most ground-breaking tracks was ‘Lucy in the Sky with Diamonds’, whose contextual mood derived from a chapter in Lewis Carroll’s Alice Through the Looking Glass. Carroll’s name is usually associated with Oxford, but he was actually born right in the vicarage at Daresbury, mere yards from Daresbury primary school, which is where Professor Balasubramanian began his formal education. He and his family were making their new lives against a distinctively inventive background.
From Daresbury he went to Appleton Hall High School and from there to Fitzwilliam College Cambridge where from 1985–1988 he read Natural Sciences as an undergraduate, taking a first-class degree – inevitably, as we are all tempted to say, with the clarity of vision that hindsight confers on us. He stayed on to take a PhD, in Enzyme Chemistry supervised by Professor Chris Abell. That is a very significant step for the way that his career developed. Enzymes are biological molecules that act to catalyse reactions. They are molecular enablers – facilitators if you will – which speed up chemical reactions between other molecules (without being consumed themselves: they are always ready for more…).
We depend on them utterly. Almost all the metabolic reactions within the individual cells of which we are built rely on enzymes. Otherwise those reactions would be too slow to support life. Here is an extreme example: there is an enzyme which enables a process that would otherwise take millions of years to happen in thousandths of a second. This makes them great targets for drugs – whether health-giving or toxic. Cyanide snuffs us out so rapidly by acting on an enzyme, cytochrome c, to block a key oxygen metabolism pathway in the cell. Fortunately, our honorand is no poisoner; his studies of enzymes are distinctly benevolent. He has used them to provide keys to enable us to understand our own genetic make-ups – and I use the plural to mean not just yours or mine; I am also referring to the different expressions of genes within each of us. How did he do this?
Dr Balasubramanian – as he was by 1991 – made a move reciprocally matching the one that Professor Harvey Lodish had made exactly a quarter of a century earlier. He crossed the Atlantic from East to West – though this is the one time that our honorand escaped Cambridge of one kind or another. His postdoctoral fellowship took him to Pennsylvania State University where he spent two years with Stephen Benkovic. This extended his work in enzymes; the most highly cited of their resulting joint publications focussed on an enzyme derived from the human immunodeficiency virus (HIV). But, despite the appeal of Pennsylvania, Cambridge enjoys an undoubted magnetism (honesty compels me to admit that it is detectable even in Oxford). The award of a Royal Society University Research Fellowship – at that time a relatively new scheme aimed at giving formative, research independence to the UK’s most promising young scientists – represented a wonderful way to return there. 1994 found him back in Cambridge once more; and I do mean once more. He has been there ever since.
Cambridge is, of course, the place where the structure of DNA was solved. That fundamental discovery offered a key, in principle, to an extraordinary, virtual landscape of possibilities; but to realise those possibilities – even to see, let alone to sculpt, that landscape – we needed to find practical ways to read genetic codes; finding ways to manipulate them followed. A critical first step was taken in Cambridge when Frederick Sanger showed a practical way to read – or sequence – DNA. Sanger’s methods led to a Nobel Prize (his second), and made the Human Genome Project possible. That monumental work took more than 13 years and cost over US$3 billion. It started in 1990 and was deemed to have concluded (with at least a good draft specification) in 2003. But, while this huge, international project was going on, other work in Cambridge was already laying the ground for a radical change of speed. Having returned to Cambridge and taken up a Fellowship at Trinity College – following in the footsteps of Sir Isaac Newton – Professor Balasubramanian was working with Professor Sir David Klenerman on DNA polymerase. You will at once realise that this has something to do with DNA. Polymerases are enzymes that enable the formation of polymers – large molecules that are constructed by connecting together the same smaller molecules over and over again. This work led to the discovery and eventual application and commercialization of a new way to sequence DNA.
Moore’s Law suggests that computing power doubles every 18 months. But the deployment of this new sequencing method produced far more dramatic changes. Something that had very recently taken a massive, extended, international programme to do could now be done for less than a millionth of the original cost, and a million times faster. The increase in raw computing power is of course part of that, but we would have to have lived a lot longer than we have for Moore’s Law to have been able to make this gigantic difference. What mattered was the new method that Professor Balasubramanian had worked out.
Dominus illuminatio mea. Oxford University’s centuries-old motto means the Lord is my light. But many scientists and clinicians today might say Illumina dominus meus: Illumina is my Lord, because that is the name of the company that provides the fast, sensitive and reliable but, crucially, affordable DNA sequencing on which they – and, increasingly we – depend. Balasubramanian and Klenerman’s work is Illumina’s core technology. Without it much of modern pre-natal diagnostic testing or cancer diagnostics would not be possible. This is an immense contribution both to science and to welfare, and you might think that I would have to stop at this point, with a well-rounded concluding phrase. But there is more.
Our genes are all in our DNA; they make us what we are and they determine what we can pass on to our descendants. And yet our different component parts really are different – skin, liver, teeth, guts, taste buds, hair and brains: all these different bits are constructed from the same DNA. This is possible because, during development, the basic genes themselves are turned on or off by further mechanisms. Those higher order switches can include environmental events or drug treatments, and at least some of the resulting changes in gene expression, as well as the genes on which they operate, can be passed on to our descendants, dialling up or down expression of particular genes in our children and even our children’s children. They are called epigenetic changes and add a new complexity to understanding inheritance. They are not in the genes themselves but in the genes’ abilities to exert their effects, rather like a voiceover constantly commenting on the message conveyed by the fundamental structure of the DNA. Wittgenstein once asked, ‘if a lion could talk, could we understand him?’ (The best answer is, ‘No’.) So it is with the genes encoded in our DNA, unless we understand epigenetics as well as genetics. You will therefore understand why, not content with what he had achieved in conventional DNA sequencing, Professor Balasubramanian turned his attention to epigenetic sequencing. And, knowing even the little that I have been able to tell you, you will be unsurprised – though impressed – to hear that by 2012 he had revolutionised this field as well. That too has led to the formation of a company that makes the method available to the wider world outside academia, where basic biologists use it – as, too, do clinicians. Ideas that have real consequences are surely the most valuable of ideas, and the promise of personalised medicine with all its potential benefits leans heavily on the application of Professor Balasubramanian’s ideas.
Many honours and distinctions have rightly been accorded to him: ours is one voice among many. We can recognise this by using the title conferred upon him in 2017: Mr Chairman, it is my privilege to present to you Professor Sir Shankar Balasubramanian, illuminator sequentiae who has used fluorescence to shine a light on our inheritance, for the award of Doctor of Science, honoris causa.
This citation is written by Professor Nicholas Rawlins