The Royal Society of Edinburgh

Bruce Preller Prize Lecture Our Genetic Inheritance: for better or for worse, in sickness and in health 1 December 2008 Professor David Porteous Medical Genetics Section, University of Edinburgh Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine Report by Jennifer Trueland
Delivering the Bruce Preller Prize Lecture, Professor David Porteous set out his vision of how the new genetics has the potential to transform our health. He spoke about the Generation Scotland project, where volunteer families are helping to build up a picture of the importance of genetic history. And he made particular reference to how mental health problems can be addressed through genetics. Professor Porteous lecture added grist to the mills of those who want to blame their parents for everything but quickly made it clear that its not all mum and dads fault. Family history has an important role in determining our health, he said, but it isnt the whole story. Theres a balance, of nature and nurture. Our genetic inheritance probably accounts for about half our risk of developing a given disease, but other factors, including lifestyle, environment and what we do for a living, account for the other 50 per cent. In the Bruce Preller Prize Lecture, Professor Porteous set the scene by showing that we are living longer than ever before. From the situation early in the last century, where only a very few people reached what we would now call a ripe old age, were heading for a time where the number people in their 60s and 70s outstrips those in any other age group. This ageing population brings with it a growth in chronic disease. The west of Scotland has a particularly grim tale to tell in that respect, with high rates of heart and lung disease and cancer. Nature and nurture have roles to play in whether we succumb to these diseases. Professor Porteous described the role of the genetic dice, which determines our genetic likelihood of developing disease. Our greater understanding of DNA the stuff of life has revolutionised our understanding of our genetic inheritance. From the solving of the structure of DNA in 1953 to the mapping of the human genome in 2003, our knowledge of this area has moved on tremendously in the last few decades. What we have learned, among many other things, is that were all pretty much 99.9 per cent the same; its that 0.1 per cent which accounts for individual variation and whether were at risk of getting diseases. The hunt for genes implicated in disease has also moved on apace. More than 2,400 genes for single gene disorders such as cystic fibrosis have been found. These tend to be rare, however, affecting only small numbers of people. In the same period, more than 100 genetic risk factors have been found for common disorders, including cancer and mental illness. These affect far more people and rates will continue to rise as populations age. The technology has moved on so much that it has become cheaper, less labour-intensive and much quicker to sequence or read human genomes. We are almost at the point where an individual can get an entire genetic printout for $1,000, with results on the same day. Advances have moved hand-inhand with computer technology, however, which is essential for storage of information, for example. Professor Porteous showed a slide which gives a vision of a future where patients receive medicine which is personalised to them, depending on their genetic make-up. This should revolutionise

treatment and help move away from the current system which means that only 30 per cent of people benefit from the drugs they are prescribed, with 10 per cent suffering serious adverse effects. Having outlined the current position and the potential benefits of genetic research, Professor Porteous went on to describe Generation Scotland, a pioneering, family-based study which aims to cast new light on how and why we develop diseases. Generation Scotland - www.generationscotland.com involves all four Scottish medical schools and is supported by a number of other organisations including Scottish Enterprise and the Scottish Government. Scotland is a good place for such a study, he said, partly because of our high levels of ill-health, but also because the population is relatively stable and supportive, which makes family-based research possible. Scotland also punches above its weight academically and has a strong background in clinical and other research. The NHS, with disease registers and cradle-to-grave health records is also a valuable resource. Those taking part in the research are all volunteers. The process involves filling out questionnaires about the history and health of individuals, as well as clinical testing to build up a biological picture. The aims include identifying genetic risk factors, understanding the origins of disease, devising new approaches to treatment and prevention, finding new (cheaper and better) medicines and making better use of existing treatments. As an example of the huge potential benefits of using genetics to help solve health problems, Professor Porteous looked specifically at mental illness. Around 450 billion people 10 per cent of the global adult population are affected by mental disorder and in the UK it is estimated that one in four will experience mental illness during their lifetime. Mental ill health is a huge burden, both personally and globally, in terms of years lost to disability and its use of NHS resources, yet there are no laboratory tests to diagnose it. Drugs such as anti-depressants and anti-psychotics have been great steps forward and do save lives, said Professor Porteous, but arent good enough. Some people dont respond, or respond badly and there are significant side-effects. A new approach is needed. He looked particularly at schizophrenia, explaining that the biggest risk factor for developing the condition is a family history of it. Professor Porteous described research he conducted in Scotland with colleagues, which has identified genes implicated in schizophrenia. The most important of these is DISC1. Those with a damaged version of that gene have a ten-fold raised risk of schizophrenia or bipolar disorder and also are at more risk of major depression. Although the research was dismissed at first, it has since been backed up by studies worldwide and has provided valuable information about the biology behind the conditions. It appears that DISC1 is active at the point of our brain where connections are made and where learning and memory take place. In other words, damage to the DISC1 gene suggests our memories work in a disrupted way. Professor Porteous described DISC1 as the conductor in an orchestra of the brain: if it isnt working, the music wont sound the same. The hunt is now on to find other leading players, such as the first violin, or other genes which are involved in the pathway. Some promising genes have already been found. Professor Porteous widened his orchestra analogy to the rest of the mind and body, describing mental and physical health as a long orchestral performance played out by nature and nurture. There is hope, he said, and work being done through Generation Scotland and elsewhere is helping to make his vision of the next generation of predictive and preventative medicine a reality. Questions Asked whether it was possible to have schizophrenia but not have a damaged DISC1 gene, Professor Porteous said that it was. Indeed, estimates of how many people with schizophrenia have a damaged DISC 1 gene range from two to 30 per cent. Likewise, people with the damaged gene do not necessarily develop the condition. The importance of DISC 1, he said, was that it identified a biological pathway. Around 50 other genes linked biologically to DISC1 had been found, and the discovery gave more of an idea of what to look for.

Asked about relevance to the animal kingdom, Professor Porteous said that animals were, in general, still under evolutionary pressures whereas mankind had escaped that. This means that mankind is living with the consequences of its history. For example, in the past it might have been useful to have a gene which enabled you to survive famine, but in an age where there is plentiful food, this trait might lead to diabetes. Domesticated animals are the exception, he added. One member of the audience described herself as a first generation immigrant to Scotland and asked if that would rule her out of the Generation Scotland study. Professor Porteous said that it was open to all-comers, but that they had to have first degree relatives in Scotland who could attend the clinical research centres. She also asked whether there would be single genes implicated in other diseases, such as cancer. Professor Porteous said that some genes had already been identified, such as the BRAC 1 and 2 breast cancer genes, but they accounted for a very small number of cases. He said the jury was out on other conditions it could be that we are just not good enough yet at diagnosing different forms of heart disease, for example, so there could be a gene or genes implicated in a small subset of patients. Another question, from someone who described himself as a punter, concerned whether one would inevitably get a disease if the gene for it was damaged. Professor Porteous said that the good news was that it wasnt inevitable, because other factors such as lifestyle also come into play. If we can identify the early signs of a condition, it might be possible to prevent it. Vote of Thanks Professor Ian Deary from the University of Edinburgh thanked Professor Porteous for a lecture which he called accessible and visionary. It brought out both the importance of the issues and the need to engage with and involve many groups, including families and the public generally.

Opinions expressed here do not necessarily represent the views of the RSE, nor of its Fellows The Royal Society of Edinburgh, Scotlands National Academy, is Scottish Charity No. SC000470