Professor Sir Shankar Balasubramanian, Co-founder of Cambridge Epigenetix and pioneering researcher, shares his perspectives on Chairing the company’s Scientific Advisory Board (SAB), his research and the opportunities that lay ahead in the field of epigenetics.
The Cambridge Epigenetics Scientific Advisory Board
I am delighted to Chair the Cambridge Epigenetix SAB. It is a privilege to work alongside world-renowned scientists and original thinkers such as Professor Anjana Rao, Professor Jay Shendure and Professor Wolf Reik. Their ground-breaking research has helped to shape the field of epigenetics and epigenomics, and their contribution to the SAB will be a highly valued strategic resource for the company.
The founding scientific vision for Cambridge Epigenetix was built on research from my laboratory, which focuses on the chemistry of nucleic acids and the structure of DNA and RNA. We invent methods for detecting and decoding chemical modifications in DNA to gain a better understanding concerning the role of these modifications in living cells or systems, and their contribution to human disease and dysfunction. These modifications are fundamental to the function of DNA.
Pioneering approaches to DNA sequencing
My involvement with genetic and genomic sequencing began in 1998 when I developed a new way of decoding DNA alongside my colleague Professor David Klenerman. This led to a spin-out company called Solexa (subsequently acquired by Illumina) and the technology is now the most widely applied method of genome sequencing across the world.
Our inspiration was to gain an understanding of the genetic basis underpinning human characteristics, including disease and predisposition for disease. Over the past 20 years we have worked through from ideas, inventions and technologies to application.
Today, our primary driver remains the understanding of human health; whether it is improving detection and diagnosis or choosing an appropriate therapeutic agent for a given condition. There is currently a huge global effort concerning genetics and personalised medicine, particularly in the treatment of cancer and rare diseases. It is wonderful to see how this is developing and to know that we initiated the technology associated with this research.
Epigenetics: a new dimension to genomic research
My initial interest in epigenetics was ignited in 2009 when Professor Anjana Rao’s lab published the discovery of 5-hydroxymethylcystosine (5hmC) as a new base modification in human DNA. At this stage, 5-methylcytosine (5mC) had already been identified. My colleague, Professor Tony Green, from the Department of Haematology at Cambridge University, challenged me to identify an approach to detecting 5hmC using chemistry techniques. We developed oxidative bisulfite sequencing (oxBS-Seq) and I became aware that the potential for the DNA alphabet was much greater than I had previously understood.
We also examined the role of 5-formylcytosine (5fC), in collaboration with Professor Wolf Reik; mapping the positioning of 5fC during early mammalian development and demonstrating that this modification alters the physical properties of DNA. It was initially believed that 5hmC and 5fC were intermediates, but we have shown that these modifications can be stable, suggesting a greater functional purpose.
This dynamic reprogramming of DNA through chemical modification is a hugely exciting area of science with the potential to provide a completely distinct dimension to the study of genetics and genomics.
Research challenges and perspectives on the future
There are considerable opportunities to discover how we can best utilise epigenetic tools, methods and concepts to make an impact on human health.
As new modifications are discovered, e.g. N6-Methyladenosine (m6A), there are technical challenges in detecting and measuring them; accurately placing them within the context of the genome and identifying their position or changes in their position. Once technologies are available, we need to develop formats and workflows that enable seamless implementation of these tools in different contexts.
Making accurate measurements using precious, and often very small, clinical samples can be difficult. Different formats of clinical sample (e.g. blood, urine, saliva, formaldehyde fixed tissue) can present a challenge when conducting epigenetic measurements. Practical solutions that enable implementation of research techniques in these scenarios are important.
Personalised healthcare: an important role for epigenetics
Epigenetics has a significant role to play in the developing area of personalised medicine, including detection and diagnosis. There are already drugs in use that target epigenetic machinery, particularly in the field of oncology. This may extend to routine monitoring of health in the future. If we are able to identify practical and predictable approaches to measuring, monitoring and re-programming our epigenome in a defined way, we may be able to move towards a future where control of your epigenome leads to better health. This is clearly a long-term vision, but conceptually very exciting.
Opportunities for Cambridge Epigenetix to support research
DNA sequencing has become hugely democratised over the past 10 years. These techniques have expanded beyond the domain of geneticists and are commonly used in most life science research laboratories. Industry partners could play a role in making epigenetic analyses as routine as DNA sequencing through provision of information and access to data. This would be incredibly empowering for life science researchers and represents an important opportunity for Cambridge Epigenetix.
Processing and interpretation of sequence-based data are absolutely critical in our research. The analyses often require bespoke thinking. Bioinformatics expertise is a vital element of our research and we are lucky to have 4 bioinformaticians within my academic research group, but not all researchers have access to the same level of bioinformatics resources. This is another area that would benefit from industry support. Companies such as Cambridge Epigenetix could reduce the burden of these analyses through provision of specialised bioinformatics support.
Advice for young researchers
My advice to any new scientific researcher: be bold, think your own thoughts and create your own pathway. Explore your chosen scientific area to define a research question that is interesting, important and worthy of focusing on for at least 10 years.
Recommended reading – research papers of interest
- Raiber EA et al. Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma. Genomic Medicine 2017;2:6. doi:10.1038/s41525-017-0007-6.
- Iurlaro M et al. In vivo genome-wide profiling reveals a tissue-specific role for 5-formylcytosine. Genome Biology 2016;17:141. doi: 10.1186/s13059-016-1001-5.
- Bachman M et al. 5-Formylcytosine can be a stable DNA modification in mammals. Nat Chem Biol. 2015;11(8):555-7. doi: 10.1038/nchembio.1848.
- Booth MJ et al. Chemical methods for decoding cytosine modifications in DNA. Chem Rev. 2015;25;115(6):2240-54. doi: 10.1021/cr5002904.
- Raiber EA et al. 5-Formylcytosine alters the structure of the DNA double helix. Nat Struct Mol Biol. 2015;22(1):44-9. doi: 10.1038/nsmb.2936. Epub 2014 Dec 15.
- Bachman M et al. 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat Chem. 2014;6(12):1049–1055. doi: 10.1038/nchem.2064.
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