PROF SIR SHANKAR BALASUBRAMANIAN’s cutting edge research at Cambridge University potentially affects millions of cancer sufferers. As cancer patients know, normal chemotherapy drugs are very toxic in that they weaken the immune system and indiscriminately kill both diseased and healthy cells.
Balasubramanian is the Herchel Smith Professor of Medicinal Chemistry at the Yusuf Hamied department of chemistry at Cambridge. What he and his team are trying to do is to understand how drugs affect the DNA with a view to developing safer targeted treatment.
By way of background, he said to GG2 Power List: “There are many different types of cancer. And, of course, each person has a unique genome. The cancer occurs within a unique genome context. So there is uniqueness to every cancer. By that token, cancer certainly isn’t just one disease.”
One report pointed out: “Many life-saving drugs directly interact with DNA to treat diseases such as cancer, but scientists have struggled to detect how and why they work – until now.
“In a new paper in Nature Biotechnology, researchers in the Balasubramanian group describe a new DNA sequencing method which can detect where and how small molecule drugs interact with the targeted genome.”
The report likened Balasubramanian’s breakthrough as “lifting the veil”.
“The powerful new method, called Chem-map, lifts the veil of this ‘genomic black box’ by enabling researchers to detect where small molecule drugs interact with their targets on the DNA genome,” the report said.
It added: “Millions of cancer patients annually receive treatment with genome-targeting drugs, such as doxorubicin. But despite many decades of clinical use and much research, the molecular mode of action with the genome is perhaps surprisingly still not well understood.”
Balasubramanian, who is leading the research, was quoted as saying: “Chem-map is a powerful new method to detect the site in the genome where a small molecule binds to DNA or DNA-associated proteins. It provides enormous insights on how some drug therapies interact with the human genome, and makes it easier to develop more effective and safer drug therapies.”
Balasubramanian founded Cambridge Epigenetix in 2012.
According to another report, “researchers at Balasubramanian Group spin-out Cambridge Epigenetix have found a new way to sequence genetic and epigenetic information in the same work flow, which could help detect diseases like cancer.
“Cambridge Epigenetix continues to conduct research in collaboration with Balasubramanian, and is at the forefront of developing technology which will enable a new generation of diagnostic and therapeutic innovations that offer hope for many patients living with life-threatening diseases.”
Balasubramanian was born in Madras (now Chennai) on 30 September 1966, and was brought to Britain when he was nine months old. He grew up in Preston Brook, a small village in Cheshire, and attended Daresbury Primary School followed by Appleton Hall High School. He read the Natural Sciences Tripos at Fitzwilliam College, Cambridge, where he also did his PhD. After two years in America as a postdoctoral fellow at Pennsylvania State University, he was persuaded in 1994 to return to Cambridge where he set up his own lab in the department of chemistry.
And this is where the latest exciting discoveries have been made.
Balasubramanian told Power List: “I’ll just say two things. One was a breakthrough in relation to one of my companies called Cambridge Epigenetix.
“This new breakthrough is a sequencing chemistry that identifies the epigenetic characteristics of DNA. And the reason why it’s important is it gives a more comprehensive readout of the information stored in DNA than you get with standard sequencing. And we think this is going to be important for revealing previously invisible information about biology and about disease states.”
He continued: “Now, the other noteworthy thing is a lot of drugs that are used for antiviral therapy and also anti-cancer chemotherapy act by the drug literally contacting the DNA of cells and impairing the ability for those cells to replicate the DNA.
“The very first anti-cancer drugs acted like this, and many of the ones that are still used today also act like this. Now, to really understand what’s going on, you need to have a method of measuring how and where these drugs interact with the DNA in different cell types and disease cell types.
“And there hasn’t been a way to do that,” he summed up. “So we developed and just recently published a paper that describes a sequencing method, but it’s a sequencing method that reveals all the drug/DNA interaction sites.
“We’ve demonstrated, for example, with a known drug commonly used in chemotherapy, exactly where it binds and interacts with DNA in cells. And we also explained how co-administration of that with a different drug augments its ability to kill cancer cells.”
He emphasised: “One of the articles written about this work describes it as lifting the veil off the black box. What it does is it reveals information about how certain classes of drugs act, which was previously not measurable. And so why is this important? It’s important because to really understand how drugs act or to improve drugs or even develop completely new ones, you need to be able to measure the mechanism going on. This is important because for quite a large number of classes of drugs, we should now be able to see what’s going on.”
He agreed he was working towards developing effective targeted drugs. “In chemotherapy, drugs are, of course, toxic systemically and they can weaken the immune system and they can also target all cells. And so being able to see which targets the drug is actually hitting, literally at the molecular level, is a step towards building understanding and optimising drugs to minimise general toxicity. You move towards drugs that can act without these side effects.
“Once you can see what’s going on, you’ve got a rational basis for retuning drugs or developing drugs that work in the way that you want and don’t work in ways that you don’t want. If you can’t see it, you’re working in the dark. So I’m very optimistic.”
On time scale, he acknowledged: “Difficult to say. Moving from scientific discovery to real world translation takes time. But if there are opportunities to re-examine existing, approved drugs, and get more information that allows us to have a better understanding of what situations in which to use them, then, in principle, there may be ways of either adjusting existing drugs or repositioning them. By that I mean, using existing drugs in different ways, or different combinations. Now, that is relatively a faster route than developing completely new drugs because they’ve already been approved to pass through safety trials.
“Earlier diagnosis, more refined diagnosis, more detailed characterisation of a disease state or a specific cancer means there’s better information to go on as to what is the problem. More judicious choice of what drugs to develop, or what drugs to use, and indeed, what combination of drugs to use, will, in time, lead to better opportunities for patient care.
“There are, of course, many advances that have happened and are happening in parallel. The ones from my lab are just a minuscule representation of the sort of things going on in the world. So really the holistic embracing of all of that will, I think, have the potential to make a big change.”
