Mark Butler talks to Elinor Richards about Singapore, sponges and scuba diving               

Mark Butler is director of natural product chemistry at MerLion Pharmaceuticals, Singapore. His interest lies in the role of natural products in drug discovery. He has written a recent review on natural product derived compounds in clinical trials for Natural Product Reports and is currently co-editing a book for the RSC entitled Natural Product Chemistry for Drug Discovery.

What inspired you to become a chemist?

I enjoyed science at school and studied mathematics with chemistry and physics in my first year at the University of Melbourne. Although maths was my initial focus, in the second year I became attracted to the practical and social aspects of chemistry, especially marine chemistry.

What attracted you to the field of natural products in drug discovery? 

You feel like you're doing something useful. It's a really challenging subject - something I didn't know when I got into it. My honours degree was in analytical chemistry with a marine focus. Then I got a scholarship that allowed me to choose any field for my PhD - I decided on marine natural products. That's when I started working on marine sponges and was able to discover a lot of interesting chemistry. I would also go out on fishing boats and scuba dive to collect samples. 

During my postdoctoral work with Bob Pettit at Arizona State University, US, I started to work exclusively on bioassay-guided isolation. Then, in 1994, I started work at the Griffith University and AstraZeneca joint venture in Australia, focusing on natural products in drug discovery. In 1999, I moved to Singapore to lead the natural product chemistry group at the Centre of Natural Product Research (CNPR), which was part of the Institute of Molecular and Cell Biology and affiliated with GlaxoSmithKline. In 2002, CNPR privatised to become MerLion Pharmaceuticals, where I work today as director of natural product chemistry.

Do you go scuba diving to collect samples now?

When I worked at Griffith University, I went out on a few trips but I haven't been out collecting samples since I've been in Singapore. I do go diving but just for pleasure.

What's your most exciting discovery to date?

Identifying many novel natural products from cold water sponges from southern Australia and Antarctica during my PhD. Before this time, most compounds had been isolated from tropical sponges.

What are you currently working on?

Natural product lead discovery. Identification of potential anti-infective candidates is our main role, but I'm also involved in some aspects of clinical drug development.

What's hot in natural products at the moment?

Big developments don't occur often. People come up with good ideas, but progress is in small increments. Advances in instrumentation, however, are significant. In particular, structure elucidation on small amounts of compound has become more accessible. With the right equipment you can now analyse structures with just 10 micrograms of compound, so it's pretty cutting edge. The hot area is the elucidation of the biological mechanism of action of natural products. A compound that may not have an interesting structure from a medicinal chemistry viewpoint may have interesting biological activity; this can help develop a whole new area. It also can potentially help to find out if compounds are non-specific or have any toxic liabilities.

Cutting edge natural product research, though, involves up to date equipment and close interactions with biologists (microbiologists, molecular biologists, taxonomists, pharmacologists etc.) and other branches of chemistry (synthetic and medicinal, X-ray etc.) - this doesn't come easily.

You lead a research team. How do you get the best out of your team? 

Being knowledgeable about the field so that you can give good advice, as well as being fair but firm when needed. In my team, I allow people the freedom to develop an ongoing interest in any aspect of our work. This allows people to enrich their skills and keeps the job interesting and challenging. 

What are the best and worst parts of your job? 

The best part of the job is the discovery of novel compounds, especially if the compound possesses really interesting biological activity, and interacting with colleagues at work and conferences. The worst part is the difficulty in finding novel natural products that have the drug-like properties. Even if you get a compound with biological activity, sometimes the compound is not druggable and can't be progressed.

Do you work in collaboration with any other teams, and if so, what are the advantages of these collaborations?

Internally, the natural product chemistry group liaises with the biology, bioprocessing, medicinal chemistry and IT groups and externally with collaborators and contract research organisations. All of these collaborations are important for the discovery and devolvement of natural product-derived pharmaceuticals. I also have an adjunct position in the chemistry department at the National University of Singapore, where I have an ongoing collaboration with Dr Martin Lear on the synthesis of new potential antimalarial agents. 

MerLion has an agreement with the National Parks Board of Singapore. What is this about and what are the benefits of the agreement? 

The agreement allows MerLion to access Singapore's diverse plants, animals and micro-organisms. The benefit for us is being able to access local biodiversity, while the benefit for the board would be a share in potential future royalties. MerLion has a commitment to the Convention on Biological Diversity by recognising the sovereign right of signatory countries to ownership of the organisms collected, stored and identified by MerLion's scientists. 

What's the future for natural product research in Singapore? 

Like many other universities around the world, universities in Singapore have no natural product research programmes at the moment. Currently, research is only undertaken at MerLion and some polytechnics. This trend seems paradoxical given the ongoing interest in biodiversity and climate change and the urgent need for new antibiotics.

We are seeing a push back towards natural products, but I would have expected the area to be much better funded. It's an easy topic to dabble in, but to become an expert takes many years and good funding. People have simplified things in the pharmaceutical industry, for example, Lipinski's rule of five [a method used by many to evaluate druglikeness, or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans]. Success in drug discovery requires the use of multiple approaches. In the end, you've just got to use the right tools and I think that people are finding that now there's a lot more interest in natural products, just as much as there is in screening synthetic libraries. It cannot be said that natural products are great for everything, but likewise, one cannot say that synthetic chemical libraries have utility for all targets either - you need a balance.

If you could be at a dinner party with any scientists in history, who would be there and why? 

It would be interesting to have dinner with some famous chemists in the natural products field. I would invite John Faulkner (Scripps Institution of Oceanography, 1942-2002), a pioneer of marine natural products research I knew, who passed away too early, Robert Burns Woodward (Harvard, 1917-1979, Nobel prize in 1965 for natural product synthesis) and James Robert Price (CSIRO Division of Organic Chemistry, 1912-1999), one of the leaders of the Australian phytochemical study from the 1950s.

When you aren't at work, what are your pastimes? 

Spending time with my family, being involved with the local Australian football team (Singapore Wombats), scuba diving and holidays in the region. 

If you weren't a scientist, what would you be? 

Science has been such a large part of my life; it's difficult to imagine not working in the area. I'm interested in property, so maybe I'd renovate houses or work in real estate. If I wanted to stay in a related field, I'd probably choose to be a patent attorney.