Winter 2007 Newsletter

Mark Johnston

THRT George Duncan Memorial MSc Studentship

Dr Michael Wormstone, UEA

This prestigious studentship will be carried out by Mark Johnston, a recent UEA graduate, who will be investigating the role of histamine in posterior capsule opacification (PCO). This condition results from robust lens cell growth leading to light scatter following cataract surgery. Histamine is typically released from storage cells (mast cells) in response to immunological challenge, but it can also be released independently of an immune response; such stimuli can include chemical and mechanical trauma e.g. surgery. Importantly, the human lens exhibits histamine receptors and whole lens culture experiments have identified signalling responses following histamine addition. Activation of Histamine receptors is also reported to promote proliferation in other cell types. Therefore the likelihood of elevated histamine levels post-surgery, the presence of responsive receptors and a putative role in proliferation provide a rational basis to study histamine effects on lens cell function with respect to PCO. Mark will carry out a more robust analysis of receptor expression and determine the functional effects of histamine using an inhibition approach (of the 3 receptor types). This work will therefore determine if histamine signalling could promote PCO and whether suppression could be of therapeutic benefit.

Elsevier/OCDEM Junior Research Prize

DPhil Student Jenny Collins

Jenny Collins is a second year DPhil Student funded by The Humane Research Trust and is based at the Oxford Centre for Diabetes, Endocrinology & Metabolism. 

St Mary’s Update

As the name implies, infection with so called high-risk types of the human papilloma virus (HPV) increases the risk of developing certain types of malignancy.  Cervical cancer is the most common although some types of oral cancer are also known to be related to infection with HPV. The way the virus causes these effects is poorly understood and one of our main goals is to increase understanding of the complex interplay between the virus and the human host. This should not only help to develop effective antiviral therapies but should also provide new understanding of how cancer is caused. To this end, THRT Student Wilawan Bunjopol has been working on a human protein which we have shown is a newly discovered target of the E6 protein from high-risk HPV. She is currently investigating how E6 alters the behaviour of this protein and how this can produce changes that may lead to the development of cancer. The most interesting and unique feature of her work is that E6 has been previously shown to cause some of the same pre-cancerous changes but by a totally different mechanism. These findings highlight a very important aspect of how such viruses work. They do not usually rely on one means of achieving a specific goal but rather have built-in alternatives. Basically viruses use both belt and braces to achieve the end result and we are currently carrying out experiments to prove this hypothesis. If these are successful this will be a major contribution to the understanding of how these organisms subvert cellular growth control to promote malignant transformation. It also illustrates a significant obstacle to the development of targeted antiviral therapies. For example, if a drug is used to block one specific effect of the virus, this may not produce a curative response as the virus may have other means of producing the same effect.

Dr Eric Hill

Neurotoxicity Testing

Drs Mike Coleman and Eric Hill Aston University

Every year thousands of new chemicals are manufactured for a variety of purposes and they are entering our bodies through our diets, in the air we breathe and in our water supply. The testing processes for some of these chemicals can be surprisingly cursory and usually take place in animal models which bear no real relation to man. There is also increasing concern that chemicals in the environment are affecting foetal development; indeed, changes in human fertility have been linked with increased levels in the environment of various products of the petrochemical and plastics industries. The European Union (EU) has recognised that to test all these new chemicals, as well as older ones, is a huge but necessary undertaking. They have enacted what has become known as REACH legislation: this stands for Registration, Evaluation, Authorisation and Restriction of Chemicals. To its credit, the EU has realised that testing thirty or forty thousand chemicals in the next few years is impossible through the use of live animal studies and this decision is welcome. However, the methods that the EU wish to adopt to evaluate the toxicity of these chemicals are still based on the use of modified animal cell systems which still require the suffering of animals. This is partly because of political pressures to start some form of testing to reassure the public. However it is also true that the development of viable alternatives which use human cellular systems in this area is still in its infancy. In order to rectify this situation, The Trust recently supported Dr. Eric Hill at Aston in  a two-year postdoctoral fellowship that laid the foundations of a new test system that uses human teratoma cells. These cells are capable of mimicking some of the development processes of human embryos although they are not sourced from human embryos and are completely free from the associated ethical problems. These teratoma cells can be induced to become human neuronal and astrocytic cells, the main cell types in our brains. Dr. Hill has developed a system whereby the process where human neurones and astrocytes develop at the embryonic stages can be modelled in the laboratory. To date, he has shown that this model detects known human teratogens, that is, chemicals which damage the unborn. The current project is aimed at developing and building on this work. Dr. Hill will use the latest techniques known as microarrays, which amplify the effects of toxins on specific genes which are expressed as the human cellular system he has designed ‘develops’ in the laboratory. It is intended that the effects of various known teratogens on gene expression will pinpoint the developmental stages where these toxins damage human gene expression. It is not enough to know whether an agent is toxic to human embryonic development, it is essential to know precisely which genes are being damaged at this, the most crucial stage in human development. The Trust is in the forefront of the race to develop human cellular models to solve a human problem, that is, our inability to prevent the proliferation of toxins in our environment. Once it is known how these chemicals affect our gene pool, we can prevent the release of more genotoxins and perhaps devise methods to prevent the effects of current toxins. It is also vital that these new methods are developed to provide the regulatory authorities of the EU real, viable and relevant alternatives.

Stress, Cataract and Myotonic Dystrophy

Dr Jeremy Rhodes

Myotonic dystrophy (DM) is an incurable inherited disease and is the commonest muscular dystrophy of adult life worldwide. It is also one of the most variable of all disorders not only affecting muscles, but also multiple organs of the body, and is associated with a number of seemingly unrelated clinical features including: muscle function and muscle wasting, heart problems, diabetes, hair loss and cataracts (a clouding of the lens).

It has been suggested that most studies investigating DM have been carried out on tissues of the body that are too complex to see clearly the underlying mechanisms of the disease. In addition a number of transgenic animal models of DM have been engineered none of which, truly reflect the characteristics of the disease as seen in humans. The human lens provides an ideal system to study DM as it has a well defined cell organisation and exists in isolation from other tissues. Moreover, the lens is highly sensitive to DM; in fact early onset of a characteristic colourful cataract is a hallmark of the DM in affected families. Another major benefit is that clinically pure samples of lens cells can be obtained for analysis after cataract surgery.

We have used these samples to create cell lines from both patients with DM and non-DM patients. Using these cell lines, we have recently discovered that DM lens cells die more quickly than normal cells and this could contribute not only to cataract but many other symptoms of DM as well. This finding is significant as other researchers have already noticed that there is a greatly reduced cell density in the lenses of DM patients. We now have new results which indicate that increased cell death in DM could be due to a fault in the place where cells produce and process new proteins. This region is called the endoplasmic reticulum. The faulty endoplasmic reticulum can initiate a chain of events which ultimately leads to the death and elimination of the faulty cells. In this project it is our intention to identify the main route by which the faulty cells are eliminated and, using drugs and the latest molecular techniques, try to block the process and prolong the life of the cells. To achieve this we will measure the amounts and activities of the most likely candidates in these pathways using the latest molecular and cell biological tools available.