Wednesday, 15 October 2008

Unpicking the Complexity of Human Disease

Impressive advances in our understanding of the genetic basis of disease were outlined at the 3rd ESF Functional Genomics Conference in Innsbruck, Austria Wednesday, 15 October 2008 The mysteries of the human genome are slowly being revealed – but the more we uncover the more complicated the picture becomes. This was one key message to emerge from the European Science Foundation's 3rd Functional Genomics Conference held in Innsbruck, Austria, on 1-4 October. Functional genomics describes the way in which genes and their products, proteins, interact together in complex networks in living cells. If these interactions are abnormal, diseases can result. "The human genome is just a string of letters which has to be interpreted so that we can understand the function of the genes," said Mike Taussig of Babraham Bioscience Technologies in Cambridge, UK, who organised the conference, which focused on the role of functional genomics in disease. More than 450 scientists from across Europe were told of new developments in research ranging from pinpointing genes involved in diabetes and cancer to using the genetic sequences of different breeds of dog to throw light on human diseases. "What we have tried to do is bring together genome knowledge as it is now, the work which has been done, what it means in functional terms and where it affects our susceptibility to disease," Taussig said. "Conferences like these are important because we try to cover a broad field – there are so many aspects of genomics that it would be impossible to encompass everything in a single lecture. It is very useful for researchers who want to improve their general view of the field, because when you are immersed in one specialty you often do not appreciate how well connected everything is." Dr Patrik Kolar, head of the unit for genomics and systems biology in the European Commission's research directorate, said: "Functional genomics and systems biology is an important and integral part of our health research programme because an understanding of these basic biological processes has huge potential and real applications for understanding disease, and when you understand disease you can design new drugs." "This kind of conference is one of the things that brings together the European community in functional genomics and I am really happy to see that most of the participants are from collaborative projects funded though our Framework programme," Dr Kolar added. Professor Mark McCarthy of the University of Oxford in the UK, who is searching for genes involved in type 2 diabetes, illustrated the unexpected complexity of the role of genes in disease. Here, so-called genome-wide scans, which compare the genetic profiles of healthy people with those who have the disease, have so far revealed around 20 individual gene mutations that can be present in people with type 2 diabetes. However, these variants explain only a small proportion of people's overall susceptibility to the condition. "If you look at the variants we are finding from really large sample sizes, the effects are pretty small," McCarthy told the conference. "For diabetes, weight and age are still better predictors of risk than the gene profile. So, on the one hand we are happy that we have found more signals that we might have imagined, but on the other hand, we are disappointed because we are explaining so little of the variance. There is much work to be done to turn these association signals into function and mechanism." Mutations in cancer genes have also turned out to be far more complicated than people might have first suspected. Professor Mike Stratton, head of the Cancer Genome Project at the Wellcome Trust Sanger Institute in Cambridge, UK, led the team that mapped and identified the high-risk breast cancer susceptibility gene BRCA2. His group is searching for particular types of gene mutations in cancer cells, and is revealing new insights into a class of mutation called rearrangement, where one gene breaks and is fused to another. This rearrangement process could result in the creation of a rogue protein that promotes cancer. Until recently, it has been difficult to study rearrangement mutations because technologies have been lacking. "For many years we have wanted a screen which would allow us to extract rearranged parts of the cancer genome and make a catalogue," Stratton told conference delegates. Techniques have now been developed that are allowing researchers to pinpoint rearrangements and look at them in detail. "New sequencing technologies are enabling us to look at a much larger number of rearrangements, allowing us to do genome-wide screens to identify fusion genes that could be cancer genes," Stratton said. "It turns out there is a lot of complexity in these rearrangements that we would not anticipated before we started." For example it is becoming clear that while there are many more rearrangement mutations than people first thought, the majority of these seem to be effectively harmless, or 'passenger' mutations. The significant mutations are the 'drivers', and these are much more elusive to track down. Meanwhile Dr Kerstin Lindblad-Toh of Uppsala University in Sweden and the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, is analysing gene mutations in different breeds of dog to throw light on human diseases. Because dogs have been reared as distinct breeds with clear isolated populations, it is often easier to detect a genetic flaw than it is in humans, and dogs are susceptible to many similar diseases that occur in man. Professor Olli Kallioniemi's team at the Institute for Molecular Medicine in Finland is working on innovative ways to discover the effects of small strands of RNA, called small interfering RNAs (siRNAs), which can 'silence' genes and are showing promise in the fight against diseases such as cancer. The Finnish researchers have developed new high-throughput techniques for testing thousands of different siRNAs on living cells in one go. "This is a new cell array screening platform which we think has great potential for showing real utility in biological experiments," Kallioniemi told the meeting. Professor Patrik Brundin of Lund University in Sweden leads a team that is learning how best to repair the brain of people with neurodegenerative disorders such as Parkinson's disease, where a part of the brain called the substantia nigra degenerates, leading to slow movement and tremors. Brundin told the meeting that his university has over the past 20 years transplanted brain tissue into 18 patients with Parkinson's, whose condition improved markedly and remained stable for many years. However, certain unexplained side effects have arisen, including uncontrollable movements. "Nigral transplants have clearly worked well in select cases, but the technique needs refinement and is difficult to perform in large series of patients," Brundin said. One key issue is a safe and sustainable supply of tissue, and embryonic stem cells could hold promise. However, Brundin warned that many hurdles remain to be overcome. "Today some people are saying that you can do this with stems cells, but stem cell transplantation to the brain is currently science fiction and should remain so for the moment – there are many challenges before we can do clinical trials." In all, leading scientists, from Europe and the US, gave twelve key lectures at the meeting. In addition, there were more than 40 symposia, with topics ranging from the role of proteins in ageing to new ways to disable viruses that cause influenza. ......... ZenMaster


For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

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