Tributes to leading cancer researcher

Chancellor, Professor Sir Martin Evans reflects on Professor Alan Clarke’s life and work.

The sudden and untimely death of Alan Clarke on 28 December 2015 has taken from us a friend, an eternally upbeat individualistic colleague and a superb scientist, teacher and leader. Alan was always seen in T-shirt and jeans, he had no truck for formality and a suit was for him a foreign garment. A slightly gruffly dismissive manner concealed great friendliness, humanity and intellect. It also concealed a driven, if not Stakhanovite leader in research.

He was a PhD student in my lab in Cambridge at a very exciting time when embryonic stem (ES) cells were first discovered and characterized; but his own research project predated this. On his move to a postdoctoral position in Edinburgh, however, he was able to combine ES cell culture experience with the interests around him.

He was instrumental in the first targeting of a mouse chromosomal gene (HPRT) in ES cells and its germline transmission and went on to be pivotal in the creation of numbers of targeted mouse mutations including proto-oncogenes and tumour-supressor genes.

He started to concentrate on mouse models of human tumourigenesis models for both Retinoblastoma, and the Li-Fraumeni syndrome. The creation of these models and their subsequent use again gave rise to a series of seminal and highly cited papers, which, for example, defined the requirement for p53 in aspects of both embryonic development and spermatogenesis. 

The influence of Professor Andrew Wyllie in the Edinburgh Experimental Pathology department who had discovered the extreme importance of control of cell death in tumour biology may have been instrumental. Alan started to address the in vivo mechanisms by which mutations in key genes lead to cancer development and the importance of their bearing on programmed cell death. He pursued the hypothesis that p53 normally drives the death of cells bearing DNA damage, and that when p53 is non-functional these cells persist with the potential to become the founder cells of tumours. He was able to demonstrate by using genetic models in mice how loss of this function led to a greater predisposition to cancer particularly thymomas and intestinal tumours.

Using his mouse models, he was able to rigorously test the hypothesis that cancer arises due to a failure to engage a cell death pathway.  Alan showed increased cancer founder cell survival, compromised cell death responses and altered mutation incidence in mice with mutant p53 and mismatch repair pathways. 

Many mutations in important genes lead to embryonic lethality or have effects in multiple tissues - so precluding focused studies in adult tissues. Alan therefore began to develop new mouse models based around the use of the Cre-Lox system to deliver gene mutations that were both tissue specific and stage-specific, because the mutation was only activated in specific places and times. The first of these was the creation of mice that would allow the deletion of genes specifically within the lactating mammary epithelium. This strategy allowed an assessment of the role of Stat3 in cell death in the mammary gland, and the modelling of tumourigenesis in the mammary epithelium, for example following loss of function of the Wnt pathway component Apc. More recently, he was one of the pioneers of using such genetically engineered models to assess novel therapeutics, for example in testing the efficacy of Parp inhibitors with a specific aim of speeding the use of these reagents into the clinic. Subsequently he used even more refined methods which allow timed induction of the desired genetic change in precise locations.

The more controlled approaches Alan used allowed him to gain unique insights into the earliest stages of tumour development. For example, he defined many of the cellular and molecular events that occur immediately following mutation of key tumour related genes in the intestine, such as Apc, Ki-Ras and Pten. He also used this approach to identify and validate several potential new therapeutic targets, including methyl binding proteins and DNA damage markers. This approach also gave invaluable insights into normal stem cell function within the intestine and, remarkably, allowed a definition of the cell of origin of tumours within the intestine.

He became a cancer researcher not from a clinical perspective but from a fundamental approach to the understanding of genetic, cellular and tissue mechanisms coupled with a strong personal commitment to future clinical progress.

Convinced of his star quality I was absolutely delighted in 2000 to be able to attract Alan to Cardiff to the newly developing School of Biosciences and indeed he proved a key appointment that greatly contributed to its development and success over the intervening years.  His research output blossomed even further, he was a great research mentor both to his own PhD students, Research Assistants and Postdocs and became  Head of Research providing a huge input into advice to less (and more) experienced academics on grants. He also took on much of the task of preparing the School’s submission to RAE2008 and REF2014, as well as serving on the REF2014 Biological Science national panel. Always reluctant to suffer fools gladly or to subscribe to organisational nuisance and paperwork, Alan nevertheless was generous in his personal scientific advice and his help was greatly appreciated by numerous students and more junior staff many of whom I am sure have been launched on their successful careers as a result his training.

Alan was well connected and active internationally and served for instance on the scientific committee of Worldwide Cancer Research from 2005 to 2008 and chaired it until 2012.

It was Alan’s leadership that helped establish a number of important Cardiff initiatives, including the Wales Gene Park and the Wales Cancer Partnership. He led Cardiff University to found the European Cancer Stem Cell Research Institute (ECSCRI) and as its Director was in its first few years able to very firmly establish its reputation in the field, recruiting a cadre of outstanding young Fellows. ECSCRI clearly encompasses his vision of a strong research focus combining fundamental study with translation to practical progress and it is now leading this burgeoning field. Alan was also Director of the Cardiff Cancer Research UK Centre.

Professor Sir Martin Evans FRS FMedSci
Chancellor, Cardiff University

Tributes

Professor Andrew Wyllie, Emeritus Professor of Pathology, Cambridge University recalls:

Alan joined the CRC group in the Department of Pathology in Edinburgh in the early 1990s, as a post-doc working with Martin Hooper on the (then new) technology of gene targeting. He quickly demonstrated his remarkable technical skills, his love of science, and his astonishing capacity for work. The whiteboard in his office swiftly filled up with simultaneous ambitious projects - completed, attempted and contemplated. Amongst these was the effect of selective deletion of a gene that still holds fascination for many in cancer science - p53. Alan's short paper in Nature of 1993, in which deletion of p53 was shown to influence the ability of cells to initiate apoptosis, has been cited in the international literature over 2,000 times. He continued to develop cleverly designed animal models of human disease, and demonstrated important new insights into the organisation and regulation of cells in normal and neoplastic tissues. Moreover, he was a delightful colleague, inspirational, thoughtful, cheerful, "can do" and often very amusing. It was clear even from these early days that he was destined to contribute to the highest ranks of cancer science.

Professor Jim Murray, Head of the School of Biosciences, Cardiff University comments:

Alan was a scientist with a genuine international reputation, and he was instrumental in building our research success in the School of Biosciences as Director of Research and a member of the Executive Team of the School. His wise words and sensible, pragmatic approach were always central to making the right decision. He was at the height of his career and his loss is felt keenly across the field, but particularly by the many students, researchers and staff to whom he was a mentor within both the School and the European Cancer Stem Cell Research Institute which he founded and led.

Dr Owen Sansom, Beatson Institute for Cancer Research, University of Glasgow writes:

I worked for Alan in both Edinburgh and Cardiff and would have happily stayed working for Alan for my whole career. He was a great mentor, very insightful, he asked key scientific questions and importantly was brilliant at designing ways to answer them. He could reduce a problem to its components amazingly quickly as you would struggle to keep up. But more than that Alan was a wonderful person, funny, enthusiastic, patient and supportive.

Dr Lee Parry, European Cancer Stem Cell Research Institute, Cardiff University adds:

Alan was a true scientist, in his own words what he loved most about his work was the opportunity for “discovering something genuinely new”.   Despite being extremely modest and humble Alan failed to disguise his great pride in establishing the ECSCRI, listing it alongside making the first gene targeted mouse as his proudest accomplishment.   As he put it the “the big difference ECSCRI made is that you can see it very clearly that people interact and integrate more. The different groups that we've got here are definitely more open to simple interactions and discussing things with each other”.  At ECSCRI he took a great interest in supporting new researchers and fostering their ideas as they attempt to establish themselves in the scientific world.  It greatly pleased him that the first experimental anti-cancer stem cell drug emerged from ECSCRI within a couple of years of its opening. 

Alan acted as an information hub for so many researchers effortlessly linking together basic scientist with clinicians.  Aside from his primary focus on bowel cancer he had an extensive portfolio of research into many different cancers.  His easygoing manner fostered strong collaborations with major pharmaceutical companies which allowed Alan to use his animal models to test the ability of their drugs for treating cancers with particular mutations.  His work using olaparib in breast cancers with BRCA mutations helped olaparib on its way to clinical trials.  Some of his latest work investigates the potential for cutting edge nano-technology to directly target tumour cells with agents that will target the genes he identified as playing key roles in the very earliest stages of bowel cancer.  He wanted to try to prove that the particular genetic changes he was looking at would be good targets for new prognostic indicators and new cancer therapies.   

He was interested in tackling cancer from all angles.  Due to the limitations of animal models for drug discovery he saw the need for better models and was pioneering the use of patient stem cells to grow 3D “mini-organs” or cancers that could be used for research and bring routine personalized medicine closer to reality.  His work at ECSCRI also incorporated trying to understand the links between diet and bowel cancer.  Alan loved good food and wine despite the knowledge that an estimated 47% of bowel cancer could be prevented by healthy lifestyle choices.  He had active research programs with Tenovus and the World Cancer Research Fund investigating how dietary components, e.g fibre and fruit, gut bacteria and the products they produce influence the bowel cells to prevent or promote cancer.   

He was a central figure in cancer research within Wales and the UK, a collaborator, scientist, mentor and friend.  In his absence there will be many a toast raised to him at meetings and conferences, ideally with a glass of the Lagavulin whisky he so enjoyed. He will be greatly missed.

Sir Terry Matthews, KBE, FREng, FIEE

I had the privilege of working with Professor Alan Clarke in my role as Patron to the European Cancer Stem Cell Research Institute, a pioneering institute and global leader in cancer research - the creation of the institute is a huge testament to Alan’s academic brilliance, profound foresight and commitment to undertaking science that would have a transformational and positive impact for cancer patients worldwide.  One of Alan’s invaluable strengths was his ability to articulate highly complex, academic principles into layman’s terms – and therefore to making science accessible for all.  His death is a great loss.