Royal Society of Chemistry: November 9, 2017

Blavatnik Awards recognize groundbreaking cancer researcher

Dr Alan Healy, post-doctoral researcher at Yale University, has been named a Finalist in the 2017 Blavatnik Regional Awards for Young Scientists. Alan has been recognised by the Blavatnik Family Foundation, in association with the New York Academy of Sciences, for developing the first synthetic route to producing colibactins – bacterial compounds linked to colorectal cancer formation.

We caught up with Alan to find out how the award will help him to expand his research and fulfil his ambitions of setting up his own research group.

Alan grew up on the west coast of Ireland in the small town of Doonbeg. “It’s become quite infamous now because it’s a Trump International Golf course,” explains Alan, “That’s the landmark that people recognise.

“I think my interest in science came from my home; my father was part of the medical profession and when we were growing up we discussed science around the dinner table. I was interested in medicine but saw that going into drug discovery and development could have the potential to have a greater impact and affect more people’s lives.”

Opportunities overseas

Alan studied medicinal chemistry at Trinity College Dublin but cites the six months he spent at the Consejo Superior de Investigaciones Científicas (CSIC) in Madrid, for his final year research project, as the pivotal experience that led him to pursue a career in research.

“It was a very important experience; at that point I’d had no practical research experience outside of undergraduate labs. I worked for Dr Christophe Dardonville, a really great mentor, who nurtured a highly stimulating and educational research environment in a great institute. I was really grabbed by the applied nature of the research, developing new compounds to target Human African Trypanosomiasis (HAT) and malaria.

“It was a very positive first experience of research and was really what prompted me to go down the path of a more academic, research-based career. The opportunity to experience a different culture and observe how scientists from around the world approach and think about science is really important for a young scientist.”

On returning from Madrid, Alan was accepted onto a Cancer Research UK fellowship to do a combined MSc and PhD in anti-cancer research. He did his master’s degree in biomedical science at the University of Edinburgh and then moved to the University of St Andrews for his PhD with Professor Nicholas Westwood. He enjoyed the experience so much that he recently returned to St Andrews to get married.

Synthesising a ‘black box’

The majority of Alan’s PhD had focused on medicinal chemistry, developing functional small molecules for different applications, but towards the end, he shifted his focus to natural product chemistry. “It was a great learning experience, I was given the latitude to start new research tracks and develop as an independent scientist.

“I looked at a few labs in the US that were undertaking natural product chemistry research with a translational focus. The opportunity here [at Yale University] really appealed to me because I have a joint position – I’m in the Department of Chemistry and also the Chemical Biology Institute, working with Professors Seth Herzon and Jason Crawford. This brought the aspects of a very strong organic chemistry lab, in combination with biochemistry; I really like that interplay.”

Alan’s research aims to aid our understanding of the human microbiome – all of the microorganisms that live in or on the human body. In the last decade or so, there has been increasing interest in the effects that these microorganisms – specifically gut bacteria – have on human health.

“There is a rapidly growing body of research that links the bacteria in your gut with the development of cancer, neurological disorders, obesity, heart problems, and even how your body responds to the medicine that you take. However, it is still very challenging to establish causal relationships between the change in the composition of your gut bacteria and the development of disease,” explains Alan.

Alan’s research is focused on a select strain of E. coli (a bacterium found in our gut) that produce a small molecule shown to damage the DNA of mammalian cells, and has been strongly linked to the formation of colorectal cancer. The molecule is produced by the bacteria in vanishingly small quantities, and the human gut is such a complex environment, that so far, no one has been able to isolate the complete toxin to study it. Alan has designed a synthetic method to produce molecules that he believes are the basis for the toxin, using a process that mimics the way the bacteria produces it.

“The role of small molecule toxins produced by the gut microbiome in human health is still a “black box”, but our multi-disciplinary approach to this challenge is beginning to shed light on it. By unravelling how the bacteria produces the colibactin molecule and its role in colorectal cancer formation, we can then begin to ask the question if we can inhibit its production or function; and thus potentially prevent cancer formation. Another exciting aspect is, whenever you get molecules that are really potent at killing cells, is there a way of modifying them so that you can target them selectively towards cancer cells? We are beginning to explore this possibility using antibodies and tumour targeting peptides.”

Risks rewarded

Designing a synthetic pathway for a molecule that doesn’t even have a confirmed structure, has been a challenge, but Alan explains it’s this complexity and novelty that also keeps him motivated.

“When I started on the project it was very risky in a lot of ways; natural product chemists rarely make compounds in cases where the structure has not been elucidated. But by taking on that challenge, we’ve been able to reveal a huge amount about how these molecules function and provided key insights into how they are produced by the bacteria. The molecules themselves are really interesting, they are obsessively engineered; for every part of the molecule you can nearly see the evolution that’s gone into developing its precise function. It’s the applied nature of the research and the opportunity to work between two groups (although we’ve now expanded to a consortium of four different groups working together on this) doing the cancer biology and the chemistry that has been the most rewarding. Being able to interact with scientists from diverse disciplines and thinking about how we develop this further as therapeutics, has been really interesting.”

Celebrating the science and the scientist

Alan believes that stepping back and keeping the big picture in mind is key to staying motivated. Acknowledgement from the Blavatnik Regional Awards is further confirmation that the risks are worth it, and Alan hopes it will help him to take the project even further. “Recognition by the award is a validation for both the risk we took with this project and the importance of carrying out research at the interface between disciplines. We’re looking at one particular strain of bacteria that produces one molecule but ideally I’d like to expand this; there’s huge diversity of microbial ecosystems that produce natural products. Significant technological advances now allow us to predict that vast untapped resources of natural products exist, but they are very challenging to isolate and hence study. One very enabling technology to do this is chemistry, but we need to have a very general and widely applicable platform. Traditionally, in chemistry, it’s all about engineering and designing a synthetic route to make one molecule. This would often take years, and a lot of man power and resources to develop, but what I think is really needed is a very general biomimetic platform, something that you could even potentially begin to automate, where you can target a whole range of these predicted molecules and then study their molecular function.

“That’s why the award is very important because it is an ambitious goal, and trying to convince people in the future or funding bodies that it’s a worthwhile goal, recognition like this helps with that.”

As a Finalist, Alan was honoured at the New York Academy of Sciences gala dinner on 6 November.

“It’s really great to be a Finalist, it’s a highly recognised award and they go the bit extra to recognise the scientists. They came to Yale for an interview and to film me working in the lab. They celebrate the science and the scientist.”

Future plans and Brexit challenges

Alan is currently on a two-year Charles H Revson senior fellowship, that will allow him to start developing his own research in Professor Herzon’s lab. His long-term goal, is to eventually establish his own research group, building on his award-winning work, back in the UK. But the ongoing complications of Brexit are an ever-present concern.

“Brexit is really a big factor that’s looming over science in the UK. So while I’m very keen to move back and contribute to science in the UK, it’s definitely a concern. I’m an Irish citizen, which means I may be welcome; but it’s not fully clear. Loss of scientific funding – the ERC (European Research Council) is one of the biggest funders, particularly for people trying to develop new labs, could be one of the big downsides of Brexit. Science is very global; I’ve taken advantage of that. I’ve carried out research in Dublin, Madrid, Edinburgh, St Andrews, and now New Haven, and I’ve worked with fantastic people from around the world. You need to be part of a bigger scientific community with access to funding and excellent scientists. The UK will really struggle without it. The US has some fantastic funding opportunities here, such as the fellowship I’m on now. It’ll be very difficult to try and go back and set up a meaningful, impactful research lab if there are not good sources of both research funding and of students and scientific talent. So that’s definitely something that’s concerning.

“I have received a lot of support and encouragement to apply for positions in the US, but I was trained by Cancer Research UK – they funded both my Masters and PhD, and I was educated in Ireland and the UK so I’d like to be able to return and contribute to science there. The independent fellowship that I have is for two years so I’m going to use that time to develop my own research program but also hopefully travel to the UK to present my research and investigate the opportunities that are there.”

 

http://www.rsc.org/news-events/profiles/2017/nov/alan-healy/