Fishing for chemical answers to biological questions
04 July 2011
James K. Chen talks to Michael Smith about chemical biology, his love for the outdoors and fly fishing
When did you decide to go into chemical biology?
It was when I was an undergraduate, during a lecture given by Stuart Schreiber at Harvard University. He was talking about his work on the immunosuppressive compound FK-506. His laboratory had found that FK-506, and another molecule called cyclosporin, inhibited the activity of calcineurin, a serine/threonine protein phosphatase. These studies were important because they implicated a role for calcineurin in T cell function and provided new insights into how T cell receptor signalling is transduced from the cell surface to the nucleus. After that lecture, I immediately knew that this was the kind of research I wanted to do. I loved organic chemistry, but I was more interested in answering the questions of biology. Using a small molecule to gain insight into a complex biological process was exactly what I wanted to do.
What happened next?
I became a graduate student with Stuart Schreiber and I ended up working in his lab for seven years. This was longer than you'd normally expect for a graduate career, but I was having a lot of fun and wasn't in a hurry to leave. There, I worked on two projects. One was looking at the molecular recognition properties of Src homology 3 domains, which are polypeptide modules common in many cell signaling proteins, including some involved in cancer. I was interested in the types of peptide sequences that bind to these domains. My other project was studying the immunosuppressive compound myriocin to understand how it acts. Myriocin is a natural product, and after isolating the compound from fungal cultures, we synthesized derivatives that enabled us to identify binding proteins in cytotoxic T cells. We found that it bound to serine palmitoyltransferase, which is the enzyme that catalyses the first committed step in sphingolipid biosynthesis. Working in Stuart Schreiber's lab was great because I gained experience in synthetic chemistry, cell biology and biochemistry and so received a good grounding in the fundamentals of each of those fields.
At end of my graduate career, I realised the biological area that I was most interested in was developmental biology or, in other words, explaining how patterns arise. For example, why do we have five fingers on each hand? Why do we have two eyes in the right place? In a sense, these are basic questions that a child would ask, and that's the fun of science. If the question you're trying to answer is one that you know a six year old would ask, then that's really fundamental and exciting! At first, I had to learn some developmental biology. I was fortunate to have the chance to take an embryology course at the Marine Biological Laboratory in Woods Hole, Massachusetts, for six weeks over one summer. I was immersed in the field of developmental biology, and I learned to work with different model organisms. It was six weeks out of the lab and I was grateful that Stuart let me do it.
I then did a post doc with Philip Beachy, who was at the Johns Hopkins School of Medicine at the time. His laboratory studies the Hedgehog signalling pathway, which is one of the key processes that enable an embryo to develop properly. The Hedgehog gene was originally identified in fruit flies, where its loss gives rise to unusually round, bristled embryos (hence the name Hedgehog). Phil was studying a small molecule called cyclopamine that he thought was inhibiting this vital pathway, but he didn't know how. This was a perfect situation for me coming from a chemical biology lab with my experience in small molecules, synthesis and cell biology. My post doc work showed that cyclopamine targets a transmembrane protein called Smoothened, which is one component in the Hedgehog pathway. I then discovered other molecules that modulate the activity of this protein. That was my introduction to developmental biology, in a very biochemical and signal transduction-focused kind of way.
And what made you decide to work on zebrafish?
I wanted to work with a living organism for my research and zebrafish seemed ideal. They are a good model system for studying the effects of chemical reagents on biological processes. Zebrafish embryos are transparent, so you can observe effects on individual cells at each stage of development. They're cheap to grow and maintain, and their embryos are relatively easy to culture. You can grow them in 96-well plates, an ideal format in which to treat them with small molecules. Another feature is that you can inject the embryos directly with chemical compounds. This is important, since not all small molecules are membrane permeable and injection gets around this problem. For example, we frequently use synthetic oligonucleotides called morpholinos, which bind to RNA within the cell and modulate gene expression. They are great chemical tools but don't easily cross the membrane barrier, so having the option of injecting them directly into tissues is essential.
What can chemistry bring to developmental biology?
Chemistry can bring an understanding of biological mechanisms at the molecular level. It enables us to learn what is biologically interesting with molecular clarity. At the technology level, chemistry can help us to break through the natural system, for instance, chemists can make a molecule that doesn't exist in nature and see the effect it has on a biological system. Chemical technology can break the bounds of biology.
What advice would you give to a chemist who is considering moving into biology?
A key difference between the two disciplines is the degree and level of focus - chemists tend to focus on techniques and they want to understand a system in terms of the simplest model possible; it's a reductionist approach. With biology, you almost need peripheral vision - the system you're trying to understand is like a forest, with complexity at many different levels and you have to be aware of it all. Often the simplest answer is not the correct one. Also, there's a lot to learn, but it's like learning a new language - if you immerse yourself in it, in time, you can know as much about your particular field as your biology colleagues do.
If you weren't in this field, where would you have ended up?
I think I would have still been a developmental biologist, but any area of developmental biology is interesting to me. My interest isn't focused on one particular organism; rather, it's all about answering the key question: how does pattern form from nothing? It's about basic architecture. Of course, developmental biology is also related to cancer biology, since many embryonic signalling pathways are dysregulated in tumours, but primarily my interest is fundamental rather than applied.
When you're not doing science, what do you enjoy doing?
One thing I like to do is run; I normally do a half marathon every three months or so. Also I love fly fishing - it's my passion. Once a year, I meet up with some old friends from our grad school days and we go fly fishing together. It's a great way to catch up and enjoy nature at the same time. I love the outdoors so I enjoy anything that gets me out of the office into the natural world.
Link to journal article
Characterization and development of novel small-molecules inhibiting GSK3 and activating Wnt signaling
Hanbing Zhong, Haixia Zou, Mikhail V. Semenov, Deborah Moshinsky, Xi He, Haigen Huang, Song Li, Junmin Quan, Zhen Yang and Shuo Lin, Mol. BioSyst., 2009, 5, 1356
Chemical technologies for probing embryonic development
Ilya A. Shestopalov and James K. Chen, Chem. Soc. Rev., 2008, 37, 1294
Genetic approach to evaluate specificity of small molecule drug candidates inhibiting PLK1 using zebrafish
Hanbing Zhong, Shengchang Xin, Yanqiu Zhao, Jing Lu, Song Li, Jianxian Gong, Zhen Yang and Shuo Lin, Mol. BioSyst., 2010, 6, 1463
Also of interest
16 June 2008
Ilya Shestopalov and James Chen look at how chemistry can be used to probe the earliest processes of life
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