Research

The research programme of the ISB focuses on identifying and managing the health effects of radiation exposure.

Exposure to ionizing radiation is required during many medical procedures, both to diagnose and to treat disease. The art of the clinician is in balancing the potential benefits against possible harmful effects when using radiation. Whilst good clinical practice ensures that no unnecessary exposures are made, there are possibilities to increase the effectiveness of the exposures and to restrict the exposure of critical tissues.

However, a number of critical issues must be resolved before these goals can be achieved.

Research question 1: What emergent chronic health effects of radiation (therapy) do we not yet know about, and what is their cause?

Problem: Emergent pathophysiologies. The development of late health effects is a concern for long-term cancer survivors treated with radiation therapy who represent the largest and most important group of radiation-exposed people. The same concerns exist for individuals exposed to lower doses of radiation in the workplace, from diagnostic imaging and from environmental releases. Whilst a focus has always been on cancer as a late health effect the appearance of non-cancer diseases of the heart and immune system is now established. Evidence is growing for radiation-induced increases in metabolic disease /diabetes, cognition and vascular diseases outside the heart.

ISB Research: Using in vitro and in vivo models we aim to identify the pathogenic mechanisms responsible for these non-cancer effects. We postulate that damage to the endothelial cell system, to mitochondria and to the integrity of stem cells all contribute to the development of these chronic diseases.

Research question 2: Are radiation-induced health effects at different doses due to a cellular DNA damage response, a tissue level stress response, or a mixture of both?

Problem: Mechanisms of radiation-induced health effects.   The way in which radiation causes long-lasting damage to health has been assumed to be due to a combination of cell killing and the accumulation of mutations in the DNA. This hypothesis can no longer be upheld which may lead to a fundamental new evaluation of risk estimation and optimization procedures in all medical applications of radiation.  Indeed, our studies on the effect of different radiation doses show a discontinuous response in transcription and translation.  The effects at lower doses indicate that an inflammation/stress type response predominates, whilst at higher doses the response is that of stress plus DNA damage.

ISB research:  Our experimental approach is to use in vitro and in vivo (both animal and clinical) models to define the interactions between radiation and the non-coding transcriptome, the DNA methylome and the chromatin histone epigenome, as well as the proteome and exosome. Our long-term goal is to create a predictive systems model of dose-dependent responses, in particular at the individual level where genetic variation/mutation can alter the response.  The basis of this model will be that effects of radiation at the tissue level involves an orchestrated response of multiple cells in exposed and non-exposed tissues.

 Research question 3: Can we modulate the radiation response to sensitize tumours to radiation, and does this spare normal tissue?  

Problem:  More effective radiation therapy: Radiation therapy is extraordinarily effective in the control of cancer. The normal cells that surround a tumour are sensitive to radiation. Therefore the radiation applied to the tumour must be restricted by the need to preserve adjacent tissues. Minimizing local damage by technical means has proven very effective, but biological approaches to improve effectiveness are in their infancy. Additional problems are the acquisition of resistance to radiation during treatment, and unpredictable hypersensitivity of some patients, leading to cessation of treatment.

ISB research:  We propose that differentially modulating the radiation responses of tumour and normal tissues will provide an effective way to increase individual therapy success. We are developing small molecule drugs, lentiviral vectors and engineered exosomes to influence the radiation response.