Continuing our series of articles on Great British bioscience pioneers, we profile Professor Shankar Balasubramanian FRS. His research at the interface between biology and chemistry led to the invention of the Solexa sequencing method – one of the main 'next generation' technologies that has made it possible for labs around the world to sequence whole genomes in a matter of hours and for a fraction of the cost.
How did your bioscience career first begin?
During my late high school years I wasn't sure whether I was headed for a future in science or medicine (or football).
I went on to study Natural Sciences at Cambridge, which taught me to think about science in a broad sense; I specialised in Chemistry. I stayed on at Cambridge to pursue a PhD on the mechanism of an enzyme-catalysed reaction supervised by Professor Chris Abell.
My interests in the chemistry-biology interface were further stimulated by a two-year SERC-NATO Postdoctoral Fellowship at Pennsylvania State University in the lab of Professor Steven Benkovic. I was excited by the attitude towards science and the great sense of opportunity in the USA, and so I was tempted to stay there. However, Alan Fersht persuaded me to return to the UK and I took up a position as a Royal Society University Research Fellow.
This marked the start of my independent research career within the Department of Chemistry in Cambridge at the age of 27, coincidentally around the same time, 1994, that BBSRC was formed. I pursued a number of disparate directions at the start of my independent career, perhaps reflecting many ideas for 'small' projects. The main research area that has evolved in my lab is the structure, function and chemistry of genomic DNA.
What are you working on now?
I am currently interested in two aspects of nucleic acid structure and chemistry. The first concerns four-stranded G-quadruplexes. We now have reasonable evidence that such structures form in the genomic DNA of human (and other) cells and that their formation is dynamically coupled to DNA replication and transcription.
The future goals are to better understand where in the genome such structures form and to more deeply elucidate how they are linked with the biology of cells. Given the associations with cancer (and cancer genes), G-quadruplexes are also an interesting class of molecular targets for small molecule intervention and we have already demonstrated that they can be 'drugged' with synthetic small molecules in human cells. I also predict that G-quadruplexes exist within the RNA of cells and we are just beginning a programme of research to explore this RNA structural motif.
The other main area of interest in my lab is naturally occurring modifications to DNA bases. While the epigenetic DNA modification 5-methycytosine has been known and studied for decades, the recent observation of the enzyme-generated oxidised derivatives 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine in human DNA has invigorated this field.
While it is clear that such intermediates constitute a metabolic pathway leading to demethylation, it is also emerging that these 6th, 7th and 8th DNA bases may be directly involved in mechanisms that regulate genome function. To address the role(s) of these 'new' base modifications, my lab has invented chemistry to decode the modifications at a single base resolution in a way that is scalable to whole genomes. I am primarily interested in understanding the function of these chemical modifications in normal biology and disease and also have half an eye on the other chemically modified bases that (might) exist in nature.
What advances have you seen in your chosen field in the last 20 years?
Speaking as a card carrying organic chemist, I would say there has been a major cultural shift that has led/allowed chemists to more easily consider addressing questions of importance to the life sciences. Today, I (and many of my colleagues) would be referred to 'chemical biologists' in recognition of our focus at the interface between these two disciplines. I regard this as a very positive advancement that is shaping more and more young chemists to think more broadly about science and to be hypothesis driven, whilst maintaining their core strength in chemistry.
In terms of methodological advances, there have been huge strides in the analytical capabilities that we now have access to via ultra-sensitive mass spectrometry, high field NMR spectroscopy, single molecule spectroscopy and DNA sequencing – all of which my lab uses on a fairly routine basis.
What are the five key bioscience milestones that you've been part of and when did these occur?
- 1997 together with David Klenerman, I invented a method for sequencing DNA, scalable to human (and other) genomes. This was commercialised via Solexa Ltd, which we founded, then Illumina Inc., and is now being widely used for large scale genome sequencing and also for routine molecular and cell biology studies
- 2007 demonstration that a natural RNA G-quadruplex in a 5'UTR could modulate translation of the mRNA
- 2012 invention of a chemical method for sequencing 5-hydroxymethylcytsoine and 5-methylcytosine at single base resolution in genomic DNA
- 2012 demonstration that G-quadruplex structures exist in human, cellular genomic DNA
- 2014 visualisation and chemical targeting of RNA G-quadruplexes in the cytoplasm of human cells
How has BBSRC supported you throughout your career?
My very first grant was a project grant from BBSRC in 1995, which ultimately led to the genesis of our invention of Solexa sequencing. I have since received continuous funding from BBSRC, including a career development fellowship.
Whilst I am very fortunate to now have programme funding from Cancer Research UK, the Wellcome Trust and the ERC to support established ideas, each of those programmes started with an exploratory idea that was funded either by a project grant or studentship from BBSRC. It has, therefore, been of vital importance to my research to have a source of funding to try adventurous, new ideas that will either fail or grow into something much bigger. In the life sciences, BBSRC is the major source of funding for such ideas in the UK. It is essential to support blue skies research in this way to maintain a vibrant and innovative science base in the UK.