Professor Alan Clarke
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.