Tuesday, 4 March 2014

Guest Blogger Professor Phil Ingham FRS

I am delighted to announce that a number of Internationally renowned Scientists have agreed to post a series of Blogs for the UTC.  The first is from Professor Phil Ingham FRS, a geneticist who was born and educated in Waterloo, Liverpool (and is still a keen LFC fan!) but is currently based in Singapore where he is the Toh Kian Chui Distinguished Professor of Developmental Biology and also the Vice Dean for Research at Lee Kong Chian School of Medicine, a partnership between Imperial College, London and Nanyang Technological University, Singapore.

Phil's work on the fundamental pathways that control animal development has been recognized by numerous awards, including the Genetics Society Medal in 2005 and election as a Fellow of the Royal Society in 2002. You may recall in an earlier Blog I mentioned the hedgehog gene. This was discussed originally on the Cancer Research UK site, by their Science Communications team. I will also be posting a follow up interview with Phil later in the year, similar to the one with Rich Roberts.  Here, Phil begins with the background to his work that led to the discovery of an exciting new cancer therapy: it started with fruit flies and zebra fish, model organisms that have been pivotal in identifying the genes that control the complex processes of animal development, many of which when mutated can cause cancer.

"Curiosity in basic biological phenomena with an eye for their relevance to human disease can best define my approach to research over the past 30 years. Genetics is a tremendously powerful discipline because it gives us an entry point to the molecular mechanisms underlying biological processes without any prior knowledge of their molecular basis. The identification of mutations affecting cell division in yeast or the differentiation of the appendages of the fruit-fly, Drosophila, for instance, has provided us with major insights into cell cycle control and the control of embryonic development respectively. As more challenging questions emerge in the Life Sciences, we need to consider increasingly complex model organisms, to investigate the genetic basis of our own physiology.

For this reason, my lab turned to the zebrafish in the early 1990s and cloned the homologue of the Drosophila hedgehog gene from this organism. Hedgehog (Hh) proteins belong to one of the handful of families of signalling molecules that regulate animal development. Dysfunction of the Hh signalling pathway results in severe developmental defects and is associated with a number of different types of tumours in man. Although the pathway is highly conserved through evolution, there are some important differences, particularly between Drosophila (the species in which most is know about the mechanism of Hh signalling), and vertebrates. In my lab, we have used a combination of genetic and proteomic approaches in fruit flies and zebra fish to explore both the conservation and divergence of Hh pathway mechanisms and function. 

These studies paved the way for a drug discovery programme initiated by  a small biotech company in Cambridge Mass in the late 1990s and culminating in FDA approval for the anti-Hedgehog drug  Vismodegib in January, 2012.Vismodegib (pronounced vis-mod-ee-geeb and shown left) also known by its brand name Erivedge (and unhelpfully by the number GDC-0449!) is one of a growing number of “smart” drugs, designed to target specific biochemical pathways that underlie different cancers, in this case, metastatic basal cell carcinomas. These are tumours that start in the skin but spread to another part of the body and are very difficult to remove by surgery. A common feature of these tumours is that they over activate the pathway that is normally controlled by Hedeghog proteins.  Genentech, a pharmaceutical company that has pioneered the development of drugs that target complex biochemical pathways, developed Vismodegib in collaboration with the biotech company Curis Inc.

Another import aspect of my career has been the mentoring of research students and early career scientists (postdocs, or post-doctoral research assistants and fellows, to give them their full title). A large number of both categories of researchers have passed through my own lab over the years, many of whom now occupy very senior positions, for instance as full Professors or Directors of research institutes in countries around the world. 

One of the most challenging but rewarding experiences, was the opportunity to develop a cluster of Developmental Geneticists at the University of Sheffield, an initiative that was eventually awarded Centre status by the Medical Research Council. After moving to Singapore, initially on secondment from the University of Sheffield, I became Deputy Director of the Institute of Molecular and Cell Biology, the oldest biological research institute in Singapore. It was very interesting and exciting experience helping to run an institute in such a vibrant and fast moving country as Singapore, and the experience has set me up well for my latest appointment as Vice Dean of the new Lee Kong Chian School of Medicine (left) where I have full responsibility for the development of its medical research strategy. These are exciting times in medical research with immense problems in health care facing us but enormous opportunities to address them through the application of emerging technologies and the explosion of biological knowledge that has happened over the past three decades. Hopefully, many of you reading this blog will contribute to this effort in the coming years!”


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