Interview with Fiona Marshall

Scientific Life: TrendsTalk

Interview with Fiona Marshall Heptares Therapeutics Ltd, Biopark, Welwyn Garden City, Hertfordshire, UK

Dr Marshall is a cofounder and Chief Scientific officer of Heptares Therapeutics Ltd, a G-protein-coupled receptor (GPCR) drug discovery company that uses a novel structure based drug discovery approach utilizing stabilized receptors (StaRs). She has a B.Sc. in Biochemistry from Bath University and a Ph.D. in Neuroscience from Cambridge. She has over 20 years experience in genomic-based drug discovery with particular expertise on GPCRs. She spent 12 years at GlaxoSmithKline, where she held a number of senior positions including Head of the Department of Molecular Pharmacology. Her group was responsible for the discovery of the GABAB receptor heterodimer, the identification of RAMPs, the cloning of the CGRP and adrenomedullin receptors, the identification of the nicotinic acid receptor and the deorphanization of GPR41 and 43. She was Director of Discovery Pharmacology, Europe, for Millennium Pharmaceuticals and then spent several years as an independent consultant to a variety of Venture capital and biotech companies. She is currently Chair of the CRUK Drug Discovery Committee and Vicechair of the Wellcome Trust Seeding Drug Discovery Committee. Did you always want to be a scientist? Yes, I was born and spent my early years in Africa where I saw firsthand the amazing diversity of life on our planet. On moving to England I focused on science at school. I was not a polymath; in fact I was the only person at school who was in the top set for all the science subjects and the bottom set for all the arts subjects. In later years I have tried to redress this balance and now enjoy the arts and literature. I have always wanted to understand exactly how things work. When learning to drive a car I first had to understand how a combustion engine worked. Being good at science I was expected to do Medicine, however, I opted for a degree in Biochemistry and moved onto Neuroscience so I could try and get some insight into how the greatest machine on earth, the human brain, actually works. Tell us about a particular exciting moment in your scientific career so far? The discovery that the GABAB receptor could only function as a heterodimer of two subunits. This was the first clear demonstration of GPCR heterodimerization. The first evidence for this came from yeast two hybrid studies, where using the C terminal tail of the GABAB1 as bait we pulled out the GABAB2 subunit from a screen on brain cDNAs. This resulted in the instant realization that the two could function as a heterodimer. We then planned the experiments required to demonstrate that this was the case. The key experiment involved injecting the cDNA of the subunits alone or in combination into Xenopus oocytes. Only when expressed together did we see the massive

change of current in response to application of GABA, the benefit of electrophysiology being the instantaneous result. At Heptares, there is great excitement every time we get a new GPCR structure. I do not sleep well on the nights the crystallographers go to the synchrotron and I leap up the next morning to check emails to see if the latest crystals have diffracted to the required resolution. Seeing the structures with the ligand bound helps us to design better drugs, this is the reason we founded Heptares. Do you have any scientific heroes? My scientific heroes who have had a major influence on my career are firstly the drug discovery team at Glaxo in Ware during the 1980s and early 1990s. This was my first job in Pharma where I was given a real training in what drug discovery was all about. Pat Humphrey and Mike Tyers studied the role of serotonin in disease which led to the discovery of two innovative medicines, Sumatriptan and Ondansetron. I cannot have a career in GPCRs without mentioning Robert Lefkowitz. Roberts’ laboratory has been responsible for some of the most important discoveries in GPCR research: his work on the cloning of the adrenergic receptors encouraged me to move from studying biology at the cellular level to molecular pharmacology. Finally, Richard Henderson at the Laboratory of Molecular Biology in Cambridge, who was a co-founder of Heptares, has led the field of membrane protein structure determination. Working with Richard moved me even further from studying biology at the level of the protein to the atomic level. All my scientific heroes share three characteristics. They have a lifelong passion for their areas of research, they have persevered on difficult problems until they have found answers, and most importantly, they have been hugely supportive mentors of scientists who have been fortunate enough to work in their laboratories. Pharmacology is an area of science where women are still greatly outnumbered by men. Why do you think this is? There is no reason why women cannot be very successful pharmacologists. I have never encountered any hurdles through being a woman; in fact the opposite is true. Being female makes you stand out and I have no doubt that I have been invited to join various committees or speak at conferences because the organizers thought they should have at least one woman there. The problem is that science is all consuming, it cannot be done nine to five; you have to eat, sleep and breathe your work. It involves a lot of travelling to conferences and visiting collaborators or business partners. Through bad planning my daughter happened to be born the same week as the annual American Neuroscience meeting. This meant I missed her first four birthdays. Of 413

Scientific Life: TrendsTalk course she did not mind as I simply moved her ‘birthday’ to another date. Once she got older and realized, I stopped attending the conferences. Additionally, it is difficult to take a career break, science moves on very quickly and there are always people waiting to take your place. In my view, the reason for the small numbers of women in pharmacology is because most women do not want to make sacrifices in their family life for the sake of their careers. How did you and your colleagues decide to focus work at Heptares on GPCR drug discovery? GPCRs are expressed on all cell types and regulate every aspect of our physiology. They enable one to see, taste and smell. They regulate appetite, breathing, sexual cycle, mood and thought processes. They represent one of the most important classes of proteins for drug discovery. Unfortunately, drug discovery at GPCRs over the last 10 years has had a very poor success rate with many drugs failing during development due mainly to failures in getting sufficient target engagement with a safe molecule. The aim of Heptares has been to apply structure and fragment based methods which have been used for soluble enzyme targets to GPCRs. This enables the design of highly optimized drug candidates which bind with high efficiency and selectivity to the target GPCR. This has required use of the StaR technology to produce large quantities of functional purified GPCR proteins. Much discussion about partnerships in drug discovery has focused on the idea of partnerships between academia and large Pharma companies. How do you see Heptares fitting in with these sorts of relationships? Pharma are increasingly interested in partnerships with academia, particularly to access novel areas of disease biology, and many academics are now involved in drug

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discovery to turn their fundamental research into therapeutics. However, the challenge remains to find drugs for many disease relevant targets, which are resistant to ‘classical’ approaches. Hence, there is an opportunity for a company such as Heptares, which has unique expertise in the discovery of drug candidates for GPCRSs, to help translate some exciting academic findings into therapies. To this end Heptares is actively involved in partnerships with both academia and Pharma. We fund academic collaborations in the areas of GPCR molecular pharmacology and structural biology and we have extensive partnerships with Pharma companies including Takeda, Astra Zeneca and Shire. We are also involved in collaborations across the European Union which bring together academia, Pharma and biotech companies working on GPCRs. If you were to imagine a ‘Set of Golden Rules’ for successful scientific research, what would they be? First, get the best possible team together to solve the problem. Ideally, this should be interdisciplinary combining biophysics, mathematics and chemistry with molecular and clinical science. High quality science can no longer easily be done by a single person in isolation. Choose an important scientific question and design smart experiments. Do not be constrained by current thinking, dogma or be afraid to take a high risk approach. Use the best technologies available to you to answer the question. Do not use high throughput methodologies for stamp collecting, but instead, use computational models to integrate the output with biological and chemical data to accelerate hypothesis driven science. Such strategies apply to basic academic research, as well as drug discovery. 0165-6147/$ – see front matter http://dx.doi.org/10.1016/j.tips.2012.05.006 Trends in Pharmacological Sciences, August 2012, Vol. 33, No. 8