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In conversation with Professor John Todd

Updated: May 10, 2021

Jia Jhing Sia speaks to Professor John Todd about the developments in personalised medicine both at a biomedical research and therapeutic level.


Ox Pers Med J 2021; 1(1): 22-23


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#diabetes #probiotics #autoimmunediabetes


Professor John Todd is a Professor of Precision Medicine at the University of Oxford. Professor Todd is the Director of the Wellcome Centre for Human Genetics and JDRF/Wellcome Diabetes and Inflammation Laboratory. He is also the Co-chair of the Centre of Personalised Medicine Steering Group in Oxford.


OUPM: Thank you so much for giving us some of your time Professor Todd, could you begin by briefly telling us about your research and how it relates to personalised medicine?

Professor Todd: Our aim is to treat and prevent type 1 diabetes. It is typically diagnosed in early childhood or adolescence and has lifelong implications such as blindness, kidney failure, neuropathy and cardiovascular disease. It is caused by a complex interaction of genes and environmental factors acting especially in the first year of life leading to the body’s own immune system destroying the cells in the pancreatic islets that produce insulin. The only current treatment, now for 100 years this year, is to inject insulin every day for the rest of the person’s life. Our group takes a unique approach to treating and preventing type 1 diabetes because we aim to understand the genetics of the disease and the relevant pathological mechanisms. By doing so, we are then able to treat the disease using drugs with a mode of action specific for the disease mechanism. This is our personalised or precision medicine approach for type 1 diabetes.


In the early 1990’s, my co-director Linda Wicker, and I discovered that subtle deficiencies in the Interleukin-2 (IL-2) pathway predisposed type 1 diabetes in many patients. Thus, we proposed using Aldesleukin (a recombinant human IL-2 drug) to compensate for the IL-2 pathway deficiency as a treatment for type 1 diabetes. The first two clinical trials were conducted in Cambridge to determine the dose and dosing regimen in patients with type 1 diabetes. Currently, we are running the third trial (ITAD – IL-2 Therapy for Autoimmune Diabetes) in Oxford with children who have been recently diagnosed with type 1 diabetes. We started the double-blinded trial in the first lockdown and currently only have 8 children left to recruit for the trial. I’m very excited and impatient for the outcome of this trial because the results will help to implement IL-2 therapy for children and young adults who have signs of autoimmunity but are not yet diagnosed with the disease, and consequently prevent progression and diagnosis of this common (1 in 350 children) and serious disorder.


In another exciting, ongoing trial, we are trying to promote immune tolerance to insulin (which is the primary autoantigen in type 1 diabetes) by giving children daily oral insulin over three years. In this trial, we screened pregnant mothers and genotyped the babies at birth to determine if they have a high genetic risk for type 1 diabetes. Here, we tested for 47 single nucleotide polymorphisms (SNPs) that determine type 1 diabetes risk. If the new-born child was found to be in the high-risk category, we asked their families if they would like to have the child randomised into the trial. This week, the trial, called POInT, completed recruitment across five countries, where over 1,050 children were randomised to daily oral insulin or placebo, a magnificent achievement.


I’m also currently planning another trial to investigate the use of probiotics in the primary prevention of type 1 diabetes. This follows a huge amount of literature linking type 1 diabetes and gut dysbiosis (bacterial imbalance in gut microbiome) as microbiome dysbiosis is established as one of the many causal factors of the disease. The trial involves giving probiotics to pregnant mothers with type 1 diabetes as well as their new-born babies. By giving the probiotics to the mothers, gut dysbiosis can be prevented in their babies as the mothers will be able to donate the commensal probiotic bacteria to their babies. I’m also very excited about this as we’ve been working on it for 3 years together with Dr Marcin Pekalski in the group. We are currently seeking for funding to carry out the trial. I’ve termed it PEaCH (Probiotic Enhancement of Childhood Health) as the trial also has implications for other diseases such as eczema and childhood obesity and neurological conditions.


OUPM: What are the challenges that your team is facing and how are you overcoming them?

Professor Todd: The pandemic has definitely been a major challenge as some hospitals have paused recruiting patients for trials. However, we have managed to ensure that the children in the ITAD trial were still able to receive their Il-2 or placebo syringes twice a week thanks to the dedicated nurses who delivered the syringes to the families’ homes. This ensured that everything could continue smoothly, accurately. I’m also very grateful for my highly professional clinical trials team led by Claire Scudder and Sylvia Kopijasz and our marvellous chief and principal investigators for both the trials, Professors Paul Johnson, Manu Vatish and Matthew Snape and Dr Rachel Besser.


OUPM: It’s so amazing to hear of all the work that you are doing! Could you next describe how you became interested in Type 1 diabetes and personalised medicine?

Professor Todd: Following my PhD in Biochemistry at Cambridge University, I completed a post-doctoral fellowship in human genetics and immunology in Hugh McDevitt’s lab in Stanford. There, I met John Bell in 1984 and we immediately hit off. In 1986 (1), we discovered the single most important genetic determinant of type 1 diabetes – position 57 of the beta chain of the HLA-DQ molecule, which impacts the susceptibility and resistance to developing type 1 diabetes. This discovery helped to launched my career. The mechanism behind how position 57 affects type 1 diabetes is still a mystery but with major advances in single cell sequencing technology for T cell receptor antigen sequencing over the last four years and careful clinical collections over many years, we are beginning to unravel the mechanisms underlying how the amino acid Aspartic acid at position 57 protects from type 1

diabetes.


I committed myself to combatting type 1 diabetes with my knowledge on the genetics of the disease. To this day, I thrive on discovery – from my students, colleagues, postdocs or anyone really. When you’ve felt the flow of adrenaline as the first human in history to discover something, you’ll realise that such discovery moments, although rare, are addictive and you’ll rush to confirm your results and replicate them. Both my love for discovery and patient benefit in type 1 diabetes drives me every day.


OUPM: In your opinion what do you think is the most exciting current development in personalised medicine?

Professor Todd: Following Jennifer Doudna’s humbling and inspiring CPM seminar on CRISPR-Cas9 technologies, I believe that CRISPR opens up a whole new revolution in gene therapy towards a more precise form of disease prevention and treatment. I can’t imagine what healthcare is going to look like in 20 years’ time. Some of the current challenges are in ensuring that the gene edits are delivered to the right cell type (which Jennifer addressed in her last part of her seminar) as well as providing these technologies to countries that have poorer economies. With efforts such as those by Jeremy Farrar (Director and CEO of the Wellcome Trust) to increase the accessibility of these technologies, I think we can say that what has happened in the last year will definitely be in the top three highlights of this century.


The Oxford Personalised Medicine Journal would like to thank Professor Todd for his time, and for his honest and interesting answers to our questions.


REFERENCES

  1. Todd, J.A., Bell, J.I. & McDevitt, H. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987). https://doi.org/10.1038/329599a0

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