Professor John Todd, Wellcome Trust Diabetes and Inflammation Laboratory, University of Oxford
MRC INTEGRATIVE EPIDEMIOLOGY UNIT (IEU)
Friday, 10th March, 2017
16.00 – 17.00 - Room OS6 – Oakfield House
Professor of Precisioin Medicine, University of Oxford
Director JDRF/Wellcome Trust Diabetes and Inflammation Laboratory
Wellcome Trust Centre for Human Genetics
"Polygenes to clinic"
The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, just recently moved to the University of Oxford, is researching the causes of the autoimmune disease type 1 diabetes (T1D) in order to treat and prevent the disease by modulating the causative pathways. We achieve this by linking genetic determinants of disease with phenotypes and pathways in cells and in patients, using a wide range of molecular, metabolic and immunological approaches.
Genetics: Identification of T1D genes and their pathways is essential for understanding the biology underpinning disease susceptibility. We are integrating the latest and emerging genomics data - genetic variation, RNA gene expression, methylation, transcription factor binding sites and chromatin phenotypes – to better define the T1D causal genes. For example, identification of contacts between promoter and enhancer sequences is providing major insight to causal gene identification (ImmunoBase; http://www.immunobase.org; CHiCP; http://www.chicp.org; https://www.ncbi.nlm.nih.gov/pubmed/27863249).
Phenotypes and mechanisms: Identify aberrant cellular interactions and pathways caused by susceptibility genes that mediate a loss of immune tolerance to insulin-producing beta cells culminating in their destruction. These will provide potential targets for therapeutic intervention, as demonstrated by our work in the IL-2 pathway (https://www.ncbi.nlm.nih.gov/pubmed/27727279). This knowledge will contribute to understanding cell interactions altered by disease genes, an essential step for prioritizing potential immune-modulating agents to be investigated in experimental studies in T1D patients. Our interests also include the genetic vulnerability of the pancreatic islet beta cells as a major pathway in diabetes (https://www.ncbi.nlm.nih.gov/pubmed/27120442).
Experimental medicine: Our hypothesis is that determination of the optimal dosing regimen of a potential therapeutic in terms of its molecular and cellular responses in vivo will greatly improve the likelihood of a beneficial outcome in future clinical trials. We are testing the utility of this approach in the ongoing investigation of the effects of ultra-low doses of IL-2 in patients with T1D (https://www.ncbi.nlm.nih.gov/pubmed/27727279), and will consider and evaluate other potential therapeutics.
Primary prevention: We will participate in an RCT, POINT, to test the possibility that improving tolerance to the primary autoantigen in T1D during the first few months of life can prevent or delay the development of anti-islet autoimmunity (https://www.ncbi.nlm.nih.gov/pubmed/27069865).
John Todd FRS, FMedSci, FRCP Hons, PhD is Professor of Precision Medicine at the University of Oxford (until recently Professor of Medical Genetics at the University of Cambridge), Director of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (DIL) in the University’s Wellcome Trust Centre for Human Genetics, and a Senior Investigator of the National Institute for Health Research. Todd researches type 1 diabetes (T1D) genetics and disease mechanisms with an aim of clinical intervention. Previously, Todd was Professor of Human Genetics and a Wellcome Trust Principal Research Fellow at the University of Oxford. Todd helped pioneer genome-wide genetic studies, first in mice and then in humans. He then went on to study the associations between mapped genomic disease-associated regions and phenotypes by founding and deploying the Cambridge BioResource. His research in genetics and diabetes has received several awards and prizes. In the latest phase of his research, to translate basic genetic and immunological knowledge to treatment and prevention, the DIL has now completed its first mechanistic, statistically adaptive, drug dose-finding trial in T1D patients, establishing new and effective methods of trial design, governance, conduct and patient recruitment. This design and analyses have revealed several previously unknown effects of interleukin-2 (IL-2) on the human immune system, providing key information on the future possibility of using subcutaneous administration of ultra-low doses of IL-2 to preserve pancreatic islet beta-cell function to treat and prevent T1D. Todd has supervised 29 PhD students with three in progress. h-index 93, total citations over 36,000.