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Winter Newsletter 2006
HIV drug could be used to prevent cervical cancer Drs Ian and Lynne Hampson, University of Manchester
Following on from the work that was presented at The HRT Secretaries Conference in 2004, Drs Ian & Lynne Hampson at St Mary’s Hospital in Manchester have made significant progress towards the development of a topical treatment against the human papilloma virus (HPV) which is responsible for pre-cancerous and cancerous disease of the cervix as well as other human malignancies. In the UK 50,000 women undergo surgery to remove pre-cancerous lesions every year. Instead they may be able to apply a simple cream or pessary to the affected area. The discovery may be even more significant in developing countries which lack surgical facilities and where HPV related cervical cancer is one of the most common forms of cancer in women. The new treatment is based on a type of drug known as a protease inhibitor that is given orally to treat HIV. It was found that this drug can selectively kill cultured HPV infected cervical cancer cells and, since it is already available as a liquid formulation, it is possible it may work by direct application to the cervix. The research, funded by The Humane Research Trust, has been published in the September issue of the journal Anti-Viral Therapy (2006; 11(6): 813-825) and was also presented at the International HPV meeting in Prague on 5th September. It is very exciting to find such a significant new use for this HIV drug which is already licensed and approved for oral administration. This means that it will not require the extensive animal testing that is necessary before any new drug is licensed for use in humans. Current research is focused on understanding how the drug kills HPV infected cells and exploring the means of delivering this drug directly to the affected tissue. It should then be possible to move to a clinical trial in humans. If this proves successful we could see the treatment available fairly rapidly. Although there has been a great deal of publicity given to clinical trials of anti HPV vaccines, these are a preventative and not a treatment. Since millions of women are already HPV infected this means that the virus will be a major problem for many years. A non surgical therapy will have significant advantages – better preservation of reproductive function, the potential for use in resource poor settings such as underdeveloped countries and it may appeal more to women than surgery. This work has attracted a great deal of international press coverage. Most notably on the 24th August it was the lead story on BBC News online:- (see http://news.bbc.co.uk/1/hi/health/5282206.stm) and it was given live coverage on the 31st August, Radio 4 Women’s Hour. If you have internet access the broadcast can be heard again on:- (see http://www.bbc.co.uk/radio4/womanshour/listenagain/2006_35_thu.shtml) More than 500 world-wide web sites are carrying this story and it was given front page coverage in the London Evening Standard. If anyone with internet access would like to see the scale of coverage put the search terms:- ‘Hampson, HIV Cervical Cancer’ into Google. Finally we are very grateful for the strong support we have had from The Humane Research Trust who exclusively funded the development of this work.
Tetraspanin proteins can act as ‘Giant killers’ Dr Peter Monk, University of Sheffield All animals are communities of individual cells that must work together in a regulated fashion to ensure survival and reproduction. When regulation fails, perhaps due to age, infection or a genetic mutation, the consequences are serious: inflammatory diseases, for example, occur when cells of the immune system are active at the wrong time and in the wrong place. The tetraspanins have been identified as a family of proteins that facilitate communication between cells and regulate cell movement and cell fusion (where single cells join together e.g. in fertilization of eggs by sperm). The tetraspanins also have roles in susceptibility to virus infections, the spread of cancer and in inflammatory conditions such as arthritis.
The HRT have funded a new study to produce smaller versions of the tetraspanin molecules that mimic the activity of the whole protein but are more suitable for development as therapies to treat illnesses such as AIDS and those caused by giant cells. Small versions of the tetraspanin proteins, or “peptides”, will be synthesized in the laboratory and PhD student, Rachel Hulme, will test their activity on human cells donated by consenting volunteers or on cell lines grown in tissue culture. The overall aim of this work is to find the ideal peptide ‘shape’ and use this to make totally synthetic molecules with a similar shape that could be developed as new therapies to help fight disease. Moreover, this work will demonstrate that such research is possible without recourse to animal experimentation.
Conference report: Digestive Diseases Week (Los Angeles) May 20-25, 2006 Alyson Parris is a PhD student funded by The Humane Research Trust at the University of East Anglia The Digestive Disease Week is the premier educational forum for digestive disease researchers, both academic and clinicians, with over 16 000 delegates from the USA, UK and Europe and at least 40 other nations in attendance. This year, the Digestive Diseases International meeting was held in Los Angeles, California from May 20-25th. Conferences are an extremely important event in the calendar and provide a forum for the international research community to present and discuss the latest research findings. I attended the conference with Dr Mark Williams, the Head of the Gastrointestinal Research Laboratory at UEA. Our research is funded by the Trust and studies the physiology of the human colonic epithelium in health and disease. We had the privilege of presenting two aspects of our work in two different formats. On the first day of the conference Mark presented a talk in the plenary session, which is typically reserved for research deemed by the organisers to be of the highest quality. Over 500 fellow researchers were in the audience for this presentation. I was able to attend the research conference by virtue of a travelling bursary from The HRT, and on the second day I presented a poster entitled “Human Colonic Crypt renewal ex-vivo”. Poster sessions are an alternative mechanism to disseminate research findings. On this occasion they were held in a hall the size of an aircraft hanger and comprised hundreds of posters on display. Apart from Mark’s talk, my poster presentation was the only work that used live tissue derived from the human colon to study its property of perpetual renewal. Unlike when giving a relatively short talk to an impersonal audience, a poster presentation allows the presenter to discuss the research findings ‘one-to-one’ with fellow researchers from around the globe. My poster generated a phenomenal amount of interest, and I was able to engage in dynamic discussion for a large portion of the day. The highlight was when Professor Hans Clevers, the world leader in the field of intestinal stem cells and cancer, spent one hour at my poster discussing my work. All these discussions provided valuable input into the future direction of our work, and I derived an immense amount of confidence and sense of achievement. On the remaining days of the conference I attended 17 talks in abstract plenary sessions and research forums, including a “state of the art” lecture, and a “sunrise” (7am!) session. I also spent about two hours per day viewing posters and talking to their presenters. Highlights were the presentations by two ‘guests of honour’; Professor Clevers (mentioned above), and Professor Barry Marshall, who won the Nobel Prize in Physiology or Medicine in 2005 for his work on digestive ulcers. These presentations were of the highest quality and will stay in my mind forever. The meeting was wide ranging and intense over several days and the experience has developed my scientific thinking further. Having already attended the Chicago meeting last year (DDW 2005) I found that I was much more confident in speaking to other authors at their posters this year. The presentations I attended were extremely useful for my education as a scientist, widening my knowledge around the research field I am directly involved in. They also demonstrate how research questions are posed and experiments designed to test research hypothesises, and how research data is interpreted and presented. Perhaps most significantly, the experience demonstrated the rigour required to defend the work under questions posed by your audience and peers. The usefulness and value of the intact human tissue model that I work with was continually reinforced, and I was struck by the potential that our model has to explore many research questions in the future. To conclude, the opportunity of attending an international scientific conference again as a delegate and poster presenter has been a valuable influence on my development as a scientist. I am grateful to the HRT Trustees and fundraisers for their generous ongoing support. Dr Mike Coleman Aston University
The consequences of damage to many organs in the body can be serious, but often these organs can recover in time. The brain, however, is unable to repair itself, so damage caused by a drug or toxin will be irreversible. To predict and prevent possible neurological damage by a new drug or pollutant, the experimental usage of human cellular systems is essential for relevance to man. The Humane Research Trust began its sponsorship of the Mechanisms of Toxicity Group at Aston in September 2002, supporting a project carried out by Ph.D. student Tom Zilz aimed at developing new techniques to study neurotoxicity using human cell lines isolated from human cancers and studying the effects of various neurotoxins. Tom found some food colourings showed significant toxicity in this line that may be linked with DNA damage. He also adapted a relatively new technique known as flow cytometry to examine the difference between different toxins in this system. The HRT also supported a project carried out by Ph.D. student Ray Ransley, which is aimed at using technology developed by NASA scientists that was aimed at growing small human tissues in conditions similar to those weightless conditions encountered in space. This work is progressing towards a model of human tissues that studies the effects of toxins on how cells bind and hold each other together. As a direct consequence of this work, a postgraduate project was supported by The Trust (carried out by Dr. Eric Hill) which has also used this NASA technology to replace animal-based tests to predict toxic effects on the human embryo. This project does not involve human embryonic cells, but rather a cell line that can be instructed chemically to grow in a similar fashion to a human embryo in three dimensions. This work has already shown that it does detect known human embryotoxins. In 2004 Liz Woehrling, also funded by The HRT, began her Ph.D. project based on forming human neurones and astrocytes in a co-culture, which mimics the anatomical reality of our brains. This work has recently come to fruition and Liz has shown that this co-culture model behaves like a faithful model of human brain tissue. The model caught the interest of the 14th International Workshop on Toxicology (INVITOX) and she was invited to write a paper for a Special Issue on new methods to be published in 2007. The Trust has recently agreed to support the further development of the co-culture technology by Liz allowing her to develop her career towards postdoctoral work. Throughout the period that the Group have been associated with The Trust, complex and demanding ‘drawing board’ ideas have became a reality which we hope will ultimately replace animal test systems used in the European Union and the USA in the future detection of toxic drugs and chemicals. Our achievements so far would never have come about with the financial support of The HRT.
As our work funded by The Trust is published in scientific journals, scientists around the world can access our methods and results, as well as exchanging ideas on how to design new human-based models. We were contacted by a group in Argentina who were interested in our methods in furthering their own research with an anti-inflammatory drug known as dapsone. One of the group based in Rosario (about 400 miles from Buenos Aires) Dr. Luis Maria Veggi, came to work in our laboratory for three months sponsored by the Royal Society. Dr. Veggi had to date used animal models and he quickly learned to replace these animal studies with our methods and he has enthusiastically transplanted these methods to Argentina, where he is now working with human cellular systems. Over the past four years, our gratitude to The Trust, its members, supporters and contributors remains without measure and we recognise that The HRT is a national and world force in the long-term struggle to replace inadequate animal models with relevant and beneficial and more humane human-based systems. Glaucoma Research at the University of East Anglia Dr Julie Sanderson, University of East Anglia The question of why retinal cells die in patients with glaucoma is of key importance in developing therapies to treat this disease. By understanding the mechanisms involved we move towards a new era of therapeutics for glaucoma, where disease mechanisms are treated directly, rather than therapies to reduce the risk factors. The Humane Research Trust has funded a new and exciting project at the University of East Anglia, which will use human tissue models to investigate molecular mechanisms underlying glaucoma. The research will be carried out by PhD student, Peter Sidaway. Peter joined the Norwich Eye Research Group in October, having gained a first class honours degree in Pharmacology from the University of Newcastle. He will be working with Dr Julie Sanderson, Lecturer in Pharmaceutical Cell Biology at the University of East Anglia and Mr David Broadway, consultant ophthalmologist at the Norfolk and Norwich University Hospital. The work will be carried out in The Humane Research Trust Laboratory, headed by Professor George Duncan.
Glaucoma is a debilitating disease, which ultimately causes blindness. Once vision has been lost it cannot be regained and it is the major cause of irreversible blindness worldwide. The reason why vision is lost in glaucoma is because certain nerve cells in the retina die. The retina is the light-sensitive part of the eye and these nerve cells usually take visual information from the retina to the brain. Without them the patient will become blind. Most people, when they think of glaucoma, think about an increase in pressure in the eye and, in fact, increased pressure is the major risk factor for this disease. However, it is important to note that some patients loose their vision due to glaucoma even though the pressure in their eyes is normal. Currently all medicines used to treat glaucoma act by lowering the pressure in the eye. In many patients, this does not prevent loss of their sight. At UEA, they are interested in looking for new ways to treat the disease. A major area of interest is to look for medicines that stop the nerve cells from dying. This is called “neuroprotection” and is also an area of interest in other diseases such as Alzheimer’s disease and stroke. In this project, Peter will investigate reasons why the nerve cells die, identifying targets to interfere with this process, and hence prevent cell death. All these experiments will be carried out using human retinal tissue culture techniques developed by Dr Sanderson to maintain human retinal nerve cells alive in the laboratory. Dr Sanderson said “We’re very pleased be given this opportunity. Thanks to funding by The Humane Research Trust we are in a unique position worldwide to carry out this research using human retinal cells. We hope this will research will contribute to the development of novel therapies to stop people becoming blind as a result of glaucoma”.The Humane Research Trust Inter-Laboratory Exchange Bursaries
We are pleased to announce a new initiative by The Trust – ‘The Humane Research Trust Inter-Laboratory Exchange Bursaries’. Contacts between people are a key part of medical research, including visits to other teams at other centres to study different methods, ideas, skills, technologies etc. The Trust has therefore established a formal bursary scheme to facilitate such exchanges. The Trust is using the proceeds from the sale of ‘actually it’s love’, a gift to us from ROC, to make a special ‘ROC Award’ to the team at St Mary’s Hospital, whose current success is reported elsewhere in this newsletter. St Mary’s will use this additional grant to purchase new equipment. Copies of this excellent book are still available from our latest catalogue priced at £3.99 including P&P.
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Until recently, most studies on tetraspanins have used antibodies (produced in animals) or genetically modified animals. In a previous HRT-funded studentship, we demonstrated that an alternative approach, using proteins derived from tetraspanins but made in bacteria, could be employed to investigate the biological functions of this important group of molecules. We were able to show in the laboratory that such proteins could interfere with the infection of human cells by the AIDS virus, HIV-1, and prevent the formation of so-called “giant cells”. “Giant cells” are formed when white blood cells involved in the immune response, which normally protect us against infection, join together. This appears to give them an enhanced ability to kill and limit the spread of certain microbes, such as those that cause TB. However, when the immune system goes wrong, giant cells can form that contribute to chronic inflammation, damaging the body’s own tissues and organs. Giant cells are associated, for example, with Crohn’s disease (chronic inflammation of the bowel) and with some types of arthritis, heart disease and cancer. They also form in response to the presence of foreign bodies, and may contribute to the rejection of surgical implants e.g. artificial hips. A type of giant cell is also involved in bone development, and their over-activity can result in osteoporosis. Although rather controversial, it has even been suggested that the white blood cells that form giant cells can fuse with cancer cells, and that this may contribute to cancer spread. Therapies able to inhibit cell fusion and the formation of giant cells might therefore have uses in treating many types of disease.
