The Genomics Revolution: Promise and Reality
Thursday, 03 March 2016
Professor Zosia Miedzybrodska, Clinical Director Medical Genetics Services, NHS Grampian.
Notes for Society Meeting 3rd March 2016
The President welcomed the company to the meeting. He spoke about the recent letter sent to members highlighting the importance of the Society in supporting local medical heritage, and encouraging recruitment of new members as an important part of continuing this function. Two relevant forthcoming events were described: the James Petrie Memorial Lecture during the RCPE symposium in Aberdeen on 30th March and the Society’s Heritage Evening to be held on 14th April. He then drew attention to the Society’s desire to recruit new members of Council (nominations by 5th May), the Famous for Five Minutes concert on 14th May, and encouraged members to enrol for the golf tournament. He finally drew to our attention a forthcoming lecture by Sir Paul Nurse to be streamed from the Francis Crick Institute on the evening of 30th March.
He then introduced the evening’s speaker, Professor Zosia Meidzybrodska, Clinical Director of the Medical genetics Service, NHS Grampian to give her lecture entitled ‘The Genomics Revolution: promise and Reality’.
Professor Meidzybrodska described her own progression from trainee in obstetrics and gynaecology to her senior career in genetics via a PhD project on a direct mutation test for cystic fibrosis. She told the audience how she had initially found genetics confusing and, as an introduction and reminder of the relevant terminology, shared with us a five minute animation on how the human genome works, which can be viewed at https://unlockinglifescode.org/media/animations/659#660 .
Professor Meidzybrodska emphasised the importance of remembering the ongoing and ubiquitous interplay between genetics and environmental influences which must always be borne in mind when considering any genetic factors in disease. This was illustrated by reference to the difference between relatively simple and rare, single gene mutations that cause specific conditions where environment is less important, and relatively common diseases with multifactorial genetic and environmental drivers.
She explained that 1-2% of the human genome codes for over 20k proteins (collectively called the exome) while the remaining 98+%, comprises introns which may effect the activity of the genome without carrying specific protein codes. An overview of the types of errors and rearrangements and translocations in the human genome was given and the crucial realisation that many of these may have no functional or pathological significance was stressed.
It was suggested that Clinical Geneticists deal mainly with the uncertainty that lies between genetic ‘errors’ and clinical consequences. This will remain a major challenge since ever-evolving technology allows increasingly extensive genetic arrays to be analysed on a single sample. The enormous amount of data generated gives considerable difficulties in terms of data storage and even greater challenges in trying to decipher the clinical consequences of any variation seen. In addition, larger and larger reference data sets are always needing to be gathered to define ‘normality’ and hence permit meaningful comparison between this and any new analysis of an individual genome (or exome) so that the anticipated clinical significance of apparent variations, or ‘abnormality’ therein can be meaningfully assessed.
The audience were informed that a very valuable national genetics network has been in operation in Scotland for the past 28 years based in the four main cities with some routine work being carried out in all, while particular areas of special interest have a single centre focus with that laboratory operating as a national centre for the particular condition. This helps Scotland to keep pace with clinical advances while limiting costs of establishing ‘everything everywhere’. In any event, there has been a huge increase in genetic analysis done in the past 15 years, perhaps even trebling in the past three. Much of the challenge of meeting this demand has been the result of increased automation and efficiency but the co-operative national network certainly also helps.
Some of the challenges of commercial interests in genetic analysis, particularly prevalent in the United States, were also described whereby multiple analyses are offered directly to the public by profit-making companies which are neither fully regulated, nor have any responsibility for ongoing management of the, often numerous, potential ‘abnormalities’ that their tests can detect. There are also scenarios where such commercial tests may give false reassurance since even sophisticated analysis methods do not accurately detect all kinds of genetic variation – for example, the multiple repeat anomaly that characterises the genetic aberration in Huntingdon’s Disease.
Continuing with analytical uncertainties associated with this condition, the Professor described some recent work showing that the abnormal gene in Huntingdon’s, first detected more than 20 years ago, still presents difficulties with interpretation. While it is usually accepted that an error comprising at least 40 repeats is required to produce clinical Huntingdon’s Disease, it has been shown that 4% of the population in Northern Scotland have 37-39 repeats and the potential implication of this for clinical outcomes is difficult to predict; is such a situation really a near miss or does it have, perhaps albeit moderate, clinical consequences?
Similarly, genetic analysis of tumour cells holds out some promise for determining relative susceptibility of particular tumours to particular therapeutic interventions. However, once again, the issue of trying to determine which genetic variations are clinically important in cancer management is far from clear and such concerns are amplified when one realises that there are commonly multiple genetic ‘errors’ in malignant cells which, furthermore, may be patchy in nature.
The presentation concluded with news of a major Scottish initiative, the Scottish Genome Project, which was launched on the day prior to the talk, represents another national, government-supported collaboration whereby whole genome analysis will be carried out on a number of patients across Scotland. Patients recruited from genetic clinics will be required to have 2 further family members agreeing to genome analysis, and will require to remain under prolonged surveillance as clinical outcomes will be prospectively monitored and related to recorded genetic parameters. Whether such a broad approach to laboratory enquiry in potentially genetically determined disease will, in fact, prove as fruitful as most enthusiastic estimates remains to be seen – and there will be considerable risks of turning up a lot of potential genetic ‘anomalies’ which cannot be readily analysed or usefully explained. The Aberdeen laboratory has been asked to particularly focus on rare inherited diseases within the national project.
There followed a lively question and answer session covering a broad range of issues raised in the talk. The President proposed the vote of thanks and the meeting adjourned.