From DNA to mountain climbing. Shankar Balasubramanian talks to Alison Stoddart about his research and other interests.

Shankar Balasubramanian is a chemical biologist at the University of Cambridge, UK, and he is a member of the editorial board for Chemical Communications. His research uses the principles of chemistry and molecular biology to study nucleic acids.

 

How would you define chemical biology?

Identifying an important problem that is fundamentally routed in biology and addressing it with an approach that is intellectually chemical. The view that you just have to synthesise molecules is a disservice to chemists as it removes the intellectual aspect. Last year's Nobel laureate in chemistry, Roger Kornberg, did some brilliant work on the x-ray crystallography of polymerase - he didn't synthesise any molecules but he was thinking on the molecular level, as a chemist.

What are telomeres and why are they interesting?

Telomeres are protective DNA structures at the end of linear chromosomes in the human genome. When cells divide, the telomeres get progressively shorter. And when they get very short, the cells stop dividing and a number of things can happen, including programmed cell death. If telomerase, the enzyme responsible for their synthesis, extends the telomeric length then the cells keep dividing. Telomerase is activated in cancerous cells, so the cells replicate rapidly and indefinitely. So understanding the fundamentals of this mechanism, which is critically linked to why cells live and why cells are cancerous, is important. The potential to interfere with these processes may be a pathway to therapeutics.

In terms of therapeutics, what are the possibilities?

At present, these are not proven therapeutically but there are interesting possibilities. If you can inhibit the action of telomerase in cancer cells, you could inhibit their proliferation. Another area is in tissue replacement - it may be possible to selectively activate telomerase with a drug and regenerate tissue by stimulating cells to divide. This could regenerate tissue in the treatment of neurodegenerative diseases and tissue trauma. The key question is: will a chemical agent that interferes with telomerase be selective? Understanding the details of how this molecular machine works could provide clues on how to approach these applications.

What is the hottest thing you are working on?

The possibility of small molecule gene regulators is a significant holy grail. If you can do that there are many diseases that are caused by an imbalance in the expression of genes or could be tackled by tinkering with the expression of certain genes.

We are aiming to influence gene expression using small molecules. Telomeres have unusual sequences; they are G [guanine] rich and can fold into 4-stranded structures called G quadruplexes. Agents, either synthetic molecules or proteins, that selectively bind to quadruplexes interfere with the mechanism of telomerase-mediated telomere extension and the folded state of the telomere. We have found molecules that can bind in this way and these are attractive anticancer therapeutics.

Together with Stephen Neidle, at the University of London, UK, we have used informatics to identify sequence motifs that fold into 4-stranded structures and found that they are prevalent in the human genome. We are exploring a hypothesis that links these sequence motifs, and the formation of the quadruplex, to gene expression. If you can stabilise the structures, you can affect the expression of selected genes. We have found synthetic molecules that can stabilise a particular quadruplex and shown, on the cellular level, that you can influence the expression of a particular gene. There is the possibility of small molecule gene regulators.

What inspired you to become a scientist?

I had a very inspiring headmaster at primary school - whose name was Brian Leich. He was creative and intellectually provocative; he made us think. Also, I had excellent science teachers who collectively made science stimulating. What is needed today is more stimulating science teachers in schools.

What is the secret of successful research?

Choosing the right research problem is critical. Choose a long term and stimulating research problem and play to your strengths. I have a talented team of researchers, who have a range of expertise, including bioinformatics, molecular biology and synthetic chemistry. We approach problems in multidisciplinary teams and have excellent collaborators. Most of all, if the science is stimulating, bright talented people just get even more motivated.

Recently, you climbed Mount Kilimanjaro. Why did you do it?

I did it to celebrate my 40th birthday with a couple of friends. One of them suggested we should go to a beach somewhere. But my wife said 'Why don't you climb Mount Kilimanjaro?' It was new and different, and a worthy challenge.

Is day-to-day life like climbing a mountain?

Climbing is not an intellectual challenge but it requires a certain kind of mental discipline. In particular, climbing the last metres to the summit was challenging - the oxygen was thin and I was tired. If you thought too far ahead you would stop. Once you commit to certain problems, you just have to push yourself one step at a time and there are some aspects of research that are like that.

What's the biggest research problem you have overcome?

In 1997, David Klenerman and I thought of a new way to sequence DNA. We believed it could enhance the rate and cost of whole genome sequencing by a rate of about 5 orders of magnitude. It was a major, interdisciplinary project that required organic chemistry, enzymology, physical chemistry, programming and engineering so we set up a spin-out company called Solexa. Ten years later, the latest commercial system is able to sequence more than one billion bases in one run and could resequence the human genome for $100 000. This is a real product that does more than we dreamt the concept would do. I hope it revolutionalises human genetics. As a scientist, you want to make a difference, so maybe it will.

If you were not a scientist what would you do?

It was my teenage ambition to be a professional footballer and play for Liverpool. One turning point in my career was at the end of my undergraduate years - I had the option to set up a chain of wine bars in the Ohio valley, it was appealing to go into business and be an entrepreneur but I decided to do a PhD instead. It might have been even more fun, I would definitely have been invited to more parties!