Wellcome Trust Biocentre
University of Dundee
Victoria Cowling graduated from Emmanuel College, Cambridge University with a BA in Natural Sciences. She performed her doctoral research with Julian Downward and Gerard Evan at Cancer Research UK laboratories in London, investigating the biochemistry of caspase activation during programmed cell death. She was a postdoctoral researcher with Michael Cole at Princeton University and Dartmouth College, USA. As a postdoc Dr Cowling investigated the role of c-Myc oncogene in breast cancer, identifying c-Myc as a key regulator of Wnt signalling in epithelial cells. She also discovered that c-Myc oncogene upregulates formation of the methyl cap on mRNA, a process critical for gene expression.
Dr Cowling received a MRC Career Development Award in 2007 which allowed her to intiate a research group at the College of Life Sciences, University of Dundee. The Cowling lab investigates how gene expression is regulated and restricted during cell proliferation, and the mechanisms by which gene expression becomes deregulated in hyperproliferative states. Their current focus is the cellular synthesis and regulation of the mRNA methyl cap. Dr Cowling's group determined that upregulation of methyl cap formation is critical for c-Myc to drive protein synthesis and cell proliferation, and that inhibition of cap methylation is synthetic lethal with c-Myc deregulation. Dr Cowling's group is now developing therapeutic strategies to inhibit methyl cap formation with the aim of inhibiting hyperproliferation.
Dr Cowling's group has recently discovered a novel activator of the human cap methyltransferase, called RAM (RNMT-activating mini-protein), which is essential for formation of the methyl cap and gene expression. RAM evolved in vertebrates whereas the cap methyltransferase enzyme is found in all eukaryotes. RAM may have evolved either to increase the general efficiency of cap methylation or to select specific transcripts for enhanced translation. Currently, the lab is investigating the mechanisms by which the cell communicates with RAM and the enzymes that form the methyl cap, and whether they can be targetted therapeutically. Structural studies are being performed to determine how RAM activates the cap methyltransferase.
Dr Michael Eddleston
Clinical Pharmacology Unit, University/BHF Centre for Cardiovascular Science, University of Edinburgh
Dr Eddleston obtained his first degree in medical sciences from the University of Cambridge before going to the Scripps Research Institute, La Jolla, to do a PhD on the brain’s astroglial response to infection. The work was then actually written up in Cambridge over one year, giving him a Cambridge PhD. He then went to Oxford to do his clinical medicine studies; there he met Prof David Warrell who sent him to work on snake envenoming in Sri Lanka. Exposure to self-poisoned patients during a year off medical school writing an Oxford handbook resulted in a long lasting fascination with pesticide and plant poisoning in rural Asia. After basic medical training, a Wellcome Trust Career Development Fellowship allowed him to return to Sri Lanka where he studied the clinical presentation, treatment and prevention of pesticide self-poisoning. He is now a Scottish Senior Clinical Research Fellow at the University of Edinburgh and Honorary Consultant Physician in the National Poisons Information Service, Royal Infirmary of Edinburgh.
The overall aim of his work is to halve suicidal deaths from pesticide poisoning, and thereby substantially reduce global suicides. Agricultural pesticide self-poisoning kills over 250,000 people each year. The World Health Organization now recognises pesticide poisoning to be the single most important means of suicide worldwide. Organophosphorus (OP) insecticides are responsible for about 2/3 of these deaths. Although the most toxic Class I OP compounds are slowly being withdrawn from agricultural practice, the less toxic Class II compounds will remain in use for many years to come. Unfortunately, these Class II insecticides still kill many people, with case fatalities often over 20%.
Dr Eddleston’s work addresses this problem via multiple approaches. Public health studies have determined the effect of past and future pesticide bans; an ongoing 162 village cluster randomised controlled trial in Sri Lanka will determine the cost-effectiveness of improving storage in rural Asian households. Clinical trials have assessed the effectiveness of several interventions - unfortunately, none have been found to markedly improve outcome. Novel antidotes are being tested in a minipig model of OP pesticide poisoning. The lab is also setting up a mouse model of OP pesticide poisoning in which it will be possible to study the mechanism of neuromuscular junction failure that occurs in many OP poisoned patients, causing them to spend many days and week being ventilated. Better understanding of this problem could result in new treatments that may save tens of thousands of lives every year.
Dr Rob Klose
Department of Biochemistry
Oxford University
Dr Klose graduated with an honours degree in Biology from the University of Waterloo in Canada. After graduating he carried out his PhD studies as a Wellcome Trust Prize Student at Edinburgh University in the lab of Adrian Bird. His PhD work was focused on understanding how DNA methylation signals are interpreted by the methyl CpG binding protein MeCP2. Following his PhD studies Rob moved to University of North Carolina at Chapel Hill where he carried out Post-doctoral training as a Canadian Institutes of Health Research Post-doctoral Fellow in the lab of Yi Zhang. His post-doctoral work led to the characterization of novel histone lysine demethylase enzymes involved in regulation of gene expression. In 2008 Rob was awarded a Wellcome Trust Research Career Development Fellowship to set up his independent research group in the Department of Biochemistry at Oxford University. In 2011 Rob was selected as an EMBO young investigator.
The DNA information in a cell in compacted and organized into a structural unit called chromatin which is composed of DNA and histone proteins. Recently it has become clear that the histone component of chromatin can profoundly impact how the DNA information is recognized and utilized. In Oxford, Rob’s research team are focussed on understanding how the structure and modification of chromatin impact gene expression. In particular, they focus on understanding how highly specialized regions of the vertebrate genome, called CpG islands, are used to modulate gene expression and transcriptional networks. CpG islands are poorly understood DNA encoded elements found near the promoter of most genes. Rob’s team recently made the important discover that CpG islands are directly recognized by a class of DNA binding proteins that recruit histone modifying enzymes to specifically alter chromatin architecture around gene promoters. This work was a significant conceptual advance as it demonstrated that CpG islands are actively interpreted and indicated that their function is tightly coupled to chromatin modification. Building on this discovery the Klose lab is now dissecting mechanistically how CpG island chromatin architecture impacts gene regulation through the use of cutting edge genomic and proteomic techniques. Understanding how CpG islands function in normal cells has important biomedical implications as CpG island processes are perturbed in many human cancers and diseases.
