MRC Toxicology Unit
Unit profile from the MRC Network publication issued Summer 2004
The Hodgkin Building, Leicester
The MRC Toxicology Unit is one of the MRC's longest standing research centres. It was conceived during the Second World War by a few enlightened people who foresaw that industrial, technical and medical developments might expose people to new kinds of potentially hazardous chemicals, with unpredictable consequences. The Unit was originally sited at Porton Down in 1947 under the Directorship of John Barnes, with Norman Aldridge as the only member of staff. In 1950 it moved to Carshalton, where it flourished as the world's leading centre for toxicology research and inspired other countries to create similar establishments.
The Unit's success was largely due to Aldridge's realisation that studying how chemicals exerted their effects at all levels, from the whole animal right down to individual molecules, would help scientists to understand the toxicity of related compounds and allow them to make generalisations about the underlying biological processes. This pioneering multidisciplinary approach aimed at investigating fundamental mechanisms reaped rewards over the following decades and led to understanding of the toxicity of environmental pollutants including pesticides and solvents. These successes stimulated demand for studies into the toxicology of specific compounds, for example to establish reference values for risk assessment, and a gradual shift towards more applied research.
In 1991, the Unit was transferred to purpose-built premises at the University of Leicester to strengthen its academic ties and enhance both basic and applied strands of research. While it continued to assess the dangers and effects of environmental chemicals including organophosphate pesticides, it also pursued new lines of fundamental research such as genetic susceptibility and mechanisms of cell death, and the toxicology of various drugs including certain anti-cancer agents.
Major restructuring in 2001 saw the arrival of the Unit's current Director, Professor Pierluigi Nicotera, with a vision to revitalise toxicology to reflect its origins as a mechanistic science. He believes that over the years the application of toxicology to advance biomedical science has become neglected at the expense of meticulous cataloguing of the toxic effects of particular compounds on diverse biological processes, often driven by social and political pressures.While acknowledging that this work is important, Professor Nicotera thinks it is better left to dedicated businesses and government agencies, and that the Unit should focus on answering fundamental questions that can help to solve a variety of health problems. He told Network, "Diverse organisms from the fruit fly and nematode worm right up to humans often show common patterns of responses to toxins and injury. By studying these interactions within individual cells and organs we can gain fundamental insights into the underlying biology that can help us understand the potential adverse effects of a wide variety of substances. As well as revealing the mechanisms of known toxins, this knowledge can be extrapolated to other human health problems and could be valuable in anticipating and assessing risks, giving us the flexibility to react quickly to emerging health threats."
Matters of life and death
Cell dysfunction and death are central to both toxicology and human disease. Research into the causes and mechanisms involved is the common thread running through all of the Unit's research. Its scientists are looking at how cells, tissues and simple organisms react to different types of injury triggered by toxic agents as well as by endogenous molecules. The research falls into three broad areas: cell injury in the nervous and immune systems, mechanisms of cell death and resistance in cancer, and common patterns of gene and protein activity in toxicity and disease.
Neuronal connections in the cerebellum
Cell death has important implications for all these areas, but for different reasons. Mature nerve cells are long-lived, stable and generally irreplaceable once they die. Nerve cell depletion due to disease or toxic agents severely impairs brain and nervous system function. For example, excessive cell death plays a role in neurodegenerative diseases, including Huntington's and Alzheimer's. Research into preventing cell death may therefore provide valuable clues to treating these devastating conditions and other neurotoxic syndromes. Cancer and some diseases of the immune system, on the other hand, often result from a failure of cells to die at the end of their natural life. Learning how to re-activate or trigger cell death in cells that are proliferating uncontrollably could help to develop anti-cancer drugs. Understanding the complex feedback systems that balance cell proliferation and cell death, and predicting the overall consequences of alterations in these processes are key goals of much of the Unit's research. The effect of drugs on cell death regulation is also part of these studies. Cholesterol-lowering statin drugs have neuroprotective properties, and Toxicology Unit researchers are investigating the underlying mechanisms and the possible side-effects of long-term statin treatment. One group is conducting research, in the lab and in patients, into the effects of statins in the immune system. Another is investigating the modulation of cell death regulatory proteins by statins in neurodegenerative disease and stroke.
Apoptosis breakthrough
This year, research led by Deputy Director Professor Gerry Cohen achieved a fundamental breakthrough in the understanding of apoptosis. The process is dependent on a cellular structure called the proteasome, which controls cell fate by regulating the balance of short-lived intracellular proteins. Normally, proteins that are no longer needed are tagged to mark them out for destruction by the proteasome. But in apoptosis, enzymes called caspases are released and prevent the proteasome from recognising the markers. As a result the cells own apoptosis-promoting proteins accumulate and eventually trigger the in-built cell death programme. Professor Cohen told Network, "This new research takes us a step closer to understanding how cells die. The challenge now is to use this knowledge to work towards finding new drugs and treatments for the many common diseases and conditions which occur when cell death goes wrong."
Well connected
The Unit's links with the University, local hospitals and research groups world-wide are vitally important to its success. There are close ties with the university departments of pharmacology, biochemistry, pathology, genetics, and several Unit staff have honorary university appointments. The Units teams work side-by-side with university research groups in areas of shared interest, promoting a mutually beneficial two-way exchange of expertise in molecular biology and toxicology. And with five clinicians including the Director on the staff, the Unit has the expertise necessary to recognise potential clinical applications arising from its research. Research into the causes of chronic lymphocytic leukaemia in collaboration with the University Hospital of Leicester NHS Trust has led to the development of a new drug treatment, which the Unit is planning to test in clinical trials working with the University and industry. Professor Nicotera also emphasises the importance of maintaining links with the public – for example, the Unit is holding a public open day this summer which will include demonstrations of its research.
Back to the future
Three years after Professor Nicotera's arrival, the Toxicology Unit is in good shape to continue its distinguished tradition of world-leading research. Under his leadership the Unit has expanded to 115 staff, and has become a major and internationally respected centre for studies related to cell death. Professor Nicotera told Network, "We have made substantial progress over the last three years, and good cohesiveness and interaction between our research groups is already bearing fruit. Several teams are close to making new fundamental contributions." With a creative, attractive and well-resourced research environment, a critical mass of talented researchers and a string of major publications in the pipeline, there is a tangible air of excitement about the Unit's prospects for the future.