Answers in the genes
27 June 2011
Alexandra Blakemore, Imperial College London and Andrew Read, St Mary's Hospital, Manchester, assess future research and policy directions for human genetics in the UKů
The UK punches well above its weight in genetics research. One-third of the Human Genome Project was the work of the Wellcome Trust Sanger Institute near Cambridge. Its completion in 2003 triggered a step change in the rate of human genetics research: the 'reference human genome sequence' provided an essential basis for understanding how our genome works, and documenting and interpreting the genetic differences between individuals.1
Historically, there have been two different strands of genetics research: the study of families with 'simple' diseases caused by single gene changes, such as cystic fibrosis or haemophilia, and population-based studies of more subtle genetic phenomena affecting the way our bodies work, in order to identify the genetic factors that contribute to common 'complex' disorders, such as obesity, hypertension and diabetes. It is becoming clear that such complex disorders represent not single entities, but instead, a collection of different pathogeneses with similar clinical endpoints (high BMI, blood pressure or blood sugar, respectively). We are now finding that when investigated closely, complex disorders include many hidden cases of 'simple' disorders. In the example of severe childhood obesity, we already know that there is a clear genetic cause of disease in about one in 20 cases.2 These individuals and their families are affected by genetic mutations with effects every bit as strong as those causing cystic fibrosis, and deserve the same level of sympathetic, specialised professional treatment and genetic counselling service. It is clear that many other inherited causes of obesity remain to be discovered, and that there are similar, very strong genetic effects hidden among sufferers of other complex disorders.
The British Society for Human Genetics has a particular interest in translational research. This is an area where the UK has special advantages. As an integrated nationwide healthcare system, the NHS allows access to patients and high-quality data on a scale unmatched elsewhere. A network of integrated NHS regional genetics centres covers the whole country. While their primary role is in diagnosis, counselling and, increasingly, management of families affected by genetic disease, they are also at the forefront of research into the thousands of rare genetic diseases that collectively affect a substantial part of the population. In addition, as more and more simple genetic causes of common complex conditions are discovered, the need for genetic counselling services will increase. Identifying the genes involved and understanding how their malfunction produces disease may provide a shortcut to effective treatment. Sometimes the disease turns out to involve a biochemical pathway that has already been effectively targeted in an apparently unrelated disease. In some cases, this has allowed an effective drug to be identified without all the cost and time required to develop a new drug.
Genetic factors may also critically affect how patients respond to treatments, such as drugs and other interventions. For example, in a case of severe obesity, knowledge that the patient has an unavoidable genetic appetite dysregulation might guide the choice of weight-loss surgery options to ensure maximum benefit. In addition, new drugs directly acting on the product of the most commonly altered gene in severe obesity (called MC4R) are in development: genetic information on this gene may allow us to assess whether a particular patient is likely to respond well to these new drugs and/or guide dosage.3 Genetic factors are also known to play an important role in the response to several existing drugs, such as warfarin and many psychiatric drugs.4
Thus, genetics research is relevant not only to the many overtly genetic diseases. Virtually every other disease that affects humanity depends on an interplay between a person's individual genetic constitution and external factors – infections and harmful chemicals, and also dysfunctional lifestyles. Identifying the genetic variants that make people susceptible or resistant to environmental insults is a major drive in genetics research. The UK Biobank has collected baseline data and biological material on half a million adults aged 40-69, and through the NHS, will be able to follow them prospectively for the rest of their lives. This provides unrivalled opportunities to identify interactions between genes and life events that will steer future public health policies. How far analysis of the general population for common gene variants would allow long-term predictions for individuals is very controversial. Early predictions that such research would quickly move healthcare from a 'diagnose and treat' to a 'predict and prevent' model proved naive. That vision remains, but is now more relevant to the analysis of strong genetic effects – in particular subgroups of patients rather than at the level of the whole population. To this end, separate clinical biobanks targeting specific diseases will be a key resource.
New technologies are now opening the way to a world in which DNA sequence data is available almost without limit.5 Although we are not quite there yet, it will not be long before documenting a person's complete DNA sequence will be a routine task. In both research and genetic services, the emphasis has moved from sequencing DNA to interpreting the sequence. The genome of an average healthy person will typically show three million differences from the 'reference human sequence'. What do these changes mean for the person's individual characteristics and for their health risks? What do they mean for a person with a disease? In cancer, the cells of a tumour have often acquired a hundred thousand or more genetic changes as the tumour developed from a normal cell of the patient. How many of those changes are 'passengers', incidental changes that are irrelevant to the pathological process, and how many are 'drivers', changes that helped the tumour develop, and that might be targets for drug treatment?
All these new directions push bioinformatics to the fore. Bioinformatics is the key infrastructure for virtually all current genetic research. Progress depends crucially on high-level skills in extracting meaning from the terabytes of raw data produced by a single run of a current state-of-the-art DNA sequencing machine. It is imperative that the UK trains sufficient numbers of scientists with the necessary skills, and provides career opportunities that retain them in this country. Our current career structure for scientists is remarkably wasteful, with the vast majority of postdoctoral researchers unable to find suitable jobs, and being forced to leave the profession. This is particularly damaging to the career prospects of female scientists since the 'squeeze' occurs at around the time that many are contemplating having families and career re-entry is rarely possible.
In summary, progress in preventing and treating disease must depend on understanding the enemy, and genetics research is a key part of that. Treatment of several cancers and leukaemias has already been revolutionised by such understanding. Specific driver mutations in the patient's tumour are identified, and a drug prescribed that specifically counteracts the effect of that mutation. Individual-specific prescribing ('personalised medicine') is likely to extend to many other areas of medicine. Developing effective drugs is a task for the pharmaceutical industry; the underlying research is being driven not only by large collaborative DNA sequencing projects in facilities such as the Wellcome Trust Sanger Institute, but also by smaller research groups undertaking detailed investigations of particular families. The next challenge will be to integrate the various existing genetic databases to allow systematic analysis of all available data on the implications of particular DNA changes, followed by distillation of this information to make it accessible and useful for clinicians at the point of care. Our final challenge will be to upgrade the training of existing and new clinicians to cope with the expected tsunami of new genetic information and also to find ways of communicating the genetic findings to patients in a way that supports the highest quality healthcare.
1 'A vision for the future of genomics research', F Collins et al, Nature (2003) 422, 835-847
2 'A new highly penetrant form of obesity due to deletions on chromosome 16p11', R Walters et al, Nature (2010) 463, 671-675
3 'Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response', P Roubert et al. Journal of Endocrinology (2010) 207, 177-183
4 'Pharmacogenomics and Individualized Drug Therapy', M Eichelbaum et al. Annual Review of Medicine (2006) 57, 119-137
5 'Sequencing technologies – the next generation', M Metzker, Nature Reviews Genetics (2010) 11, 31-46