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."
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.”