By Andy G. Smith PhD, DSc; George Skalka; Melissa Lennartz-Walker, DPhil; and Anne E. Willis OBE, PhD, for the MRC
The Medical Research Council (MRC) in the UK was created in 1913, and through intra- and extramural funding has supported many advances that have led to paradigm shifts in medical sciences. These include:
- the structure and sequencing of DNA and proteins;
- key aspects of the cell cycle, apoptosis, mitochondrial function, and transgenic mice;
- monoclonal antibodies; and
- nuclear magnetic resonance (NMR) imaging.
The MRC is associated with 29 Nobel Prizes.
The Toxicology Unit of the MRC was originally established in 1947 at Porton Down Chemical Defence Establishment and then Carshalton near London. It is currently based in the University of Leicester and will relocate to the University of Cambridge in 2020. The Toxicology Unit has made major contributions to the science of toxicology in both traditional areas and evolving concepts. Its original remit was for experimental investigations of toxicological problems of industrial hazards, and early work was concerned with beryllium, dinitro-ortho cresol, and the new organic phosphorus compounds used as insecticides. Later, major contributions included the cytotoxic and cancer-causing mechanisms of aflatoxin and pyrrolizidine alkaloids; the discovery and carcinogenicity of alkylating agents, such as dimethylnitrosamine and diazomethane; and the consequences of 06 methylation of guanine. Important studies demonstrated the neurotoxicity of alkyl lead and tin compounds, as well as synthetic pyrethroids and the phenomenon of “ageing” in the covalent binding of some organophosphorus pesticides to a neuropathy target esterase. Some of the first experimental investigations of dioxins, cadmium, and mercury toxicities were initiated in the unit.
In the 1950s, a unit mission statement was “to increase knowledge of normal physiological processes by studying the mechanism of disturbances produced by both physical and chemical injury.” Approaches focused on neuronal and mitochondrial toxicity and control and disturbances of iron metabolism and haem synthesis of cytochrome P450 in models of human drug-triggered clinical disorders. This included the demonstration of the suicidal inactivation of cytochrome P450 during the metabolism of drugs and chemicals. The development of sensitive chromatographic and mass spectrometric methods enabled the detection and quantitation of haemoglobin and DNA adducts in biomonitoring of human exposures to alkylating agents and to endogenous metabolites.
In 1993, the Toxicology Unit was relocated to the University of Leicester and undertook new major mechanistic studies on the risk to patients in prophylactic treatment by tamoxifen and elucidating intrinsic and extrinsic pathways of apoptosis and how these might be important in the development of chemical-induced disease and cancer. Subsequent strengths have been the mechanisms of neuronal injury and cell death, particularly in models of stroke, and the roles of p63 and p73 of the P53 family in clinical and toxicological disorders.
Under the vision of the present director, Anne E. Willis, OBE, PhD, (2010–), the mission of the MRC Toxicology Unit is to deliver field-changing mechanistic insights into toxicology and disease. This is achieved by pursuing an integrated scientific program using unbiased systems approaches to examine the effects of exposure to chemicals, radiation, and external biological agents. Toxicology research in the unit impacts major areas of socio-economic importance—namely drug development and diseases that result from exposure to both endogenous toxic agents and environmental hazards. A lack of understanding of off-target effects contributes to adverse drug reactions and severely hampers new drug development. Through the MRC’s mechanistic research, the unit has generated novel information that enhances successful drug design and has developed predictive adverse outcome models that can be shared with industrial partners. In addition, researchers have gained a greater understanding of a number of diseases that result from toxic injury and have provided innovative therapeutic avenues for translation of the discovery science into a clinical setting (e.g., in the development of drugs that can be utilized in dementia treatment).
Beyond focusing on the basic science of toxicology, the Toxicology Unit has been successful in addressing major public health concerns. For example, through hazard mechanisms studies to compare the consequences of exposure of carbon nanotubes with asbestos, MRC data show that there is a related molecular signature associated with exposure to these agents, which results in the development of mesothelioma.
Galvanising the translation of mechanistic insights into drugs that can directly benefit the public, a number of industry partnerships have been developed. Notably, the unit supports pre-PhD students and postdoctoral researchers working in partnership projects with a number of companies, including AstraZeneca, GlaxoSmithKline, and GE Healthcare. This has been an important factor in keeping the research within the unit relevant to clinical and industrial issues. Staff within the unit contribute to numerous expert and regulatory committees for both the UK and Europe. The unit is very active in a number of outreach initiatives both locally and across the UK.
The relationship between the MRC and SOT has been long standing. The MRC has sponsored a basic science lecture at the SOT Annual Meeting since 1995. Speakers in this series have included some of the most influential biomedical scientists of the last few decades, including a number of Nobel Prize recipients—usually with links to the MRC. Together the MRC, a publicly-funded organization, and SOT are united in their objective to tackle problems pertinent to public health and highlight the impact of basic science upon toxicology research.
Professor Andy Smith is the director of the MRC Integrative Toxicology Training Partnership. George Skalka is a PhD student, and Melissa Lennartz-Walker, DPhil, is a postdoctoral researcher. Anne E. Willis is the director of the MRC Toxicology Unit and is a programme leader, whose group is studying post-transcriptional control of gene expression following toxic injury.