Memorandum by Generation Scotland
1. Generation Scotland welcomes the opportunity
to respond to the House of Lords Science and Technology Committee
Inquiry into Genomic Medicine. We would be pleased to expand on
any of the points outlined in this submission and to assist the
Committee further in its Inquiry.
2. Genome wide analysis of sequence and
copy number variation is now both technically feasible and affordable.
The success of the original Wellcome Trust Case Control Consortium
study of 14,000 cases/controls of seven common diseases is being
followed by a second round of such studies on existing cohorts
and this general approach has now been widely adopted. These early
studies have not only highlighted the potential value of this
research, but also the critical need for replication and validation
at the population level, in cohorts with high quality phenotypic
data. Such cohorts are essential for translating genomic discovery
into health gain. Generation Scotland is poised and positioned
to serve that need.
3. Established in 2001, Generation Scotland
anticipated the ever advancing technological revolution in genomics.
Generation Scotland is funded by the Scottish Government and the
Scottish Funding Council. The founding principle of Generation
Scotland is that a co-ordinated effort of an inter-disciplinary
team of clinicians, scientists, social scientists and lawyers
at the Universities of Aberdeen, Dundee, Edinburgh and Glasgow,
in close collaboration with the National Health Service in Scotland,
would be necessary to create a sustainable genomics research programme
of international standing.
4. Generation Scotland comprises several
large biobank collections: (1) the Scottish Family Health Study
is a high fidelity phenotyped family based cohort (comprising
6,000 and projected to 50,000 recruits). (2) An ancestry cohort
with associated lymphoblastoid cell lines (currently 1,000 recruits,
projected to 2,500); (3) a blood donor DNA database (5,000 recruits);
(4) a proteomics biomarker project; and (5) an extensive public
consultation exercise and ethics/social/legal programme generating
theoretical and practical concepts, such as benefit sharing. Generation
Scotland also has a programme of capacity building in genomics,
mathematical biology, health informatics and related research.
5. The Scottish Family Health Study is explicitly
designed to serve as a platform for gene discovery, for replication
and for validation across a wide spectrum of health domains. Moreover,
the family based structure not only offers substantial advantages
of statistical power over population based cohorts for genetic
studies, but also provides, in the longer term, the exciting opportunity
of transgenerational studies. Demographic, lifestyle and clinical
information, plus blood samples are collected from participants,
along with intensive phenotyping for a number of quantitative
traits that relate to major disease areas, including cardiovascular
disease, obesity, mental health and musculoskeletal disease. Particularly
worthy of mention are the unique mental health and cognitive function
phenotype. Our Phase 1 data suggest 26 per cent of participants
require formal SCID interviews for major mood disorders. "Probands"
are individuals aged between 35 and 65 years, who are recruited
with at least one full sibling and typically more, along with
other first degree relatives. Larger families (particularly groups
of aunts/uncles) are targeted for recruitment, to maximise the
power of the study.
6. Governance has been a key focus. An Advisory
Board Chaired by Lord Sutherland and reporting to the Scottish
Government's Chief Scientist Office, is enshrined in a memorandum
of understanding between the four Scottish Medical Schools and
the NHS in Scotland; an Access Policy is modelled on Wellcome
Trust guidelines and existing funded biobanks; and a dedicated
web site provides information for researchers and the lay public
Unique features of the Scottish Family Health Study include its
family base, the associated phenotype information gathered at
the time of recruitment and the capacity to add further high quality,
lifetime phenotypic information by secure and confidential linkage
to the NHS Scotland electronic health record.
7. An extensive programme of public consultation
has been undertaken through exit questionnaires, public survey,
consultation with Public Partnership Groups and interviews with
participating families. Study documents, procedures, SOPs and
staff training were refined following an initial pilot phase,
taking account of the public consultation, plus advice from the
GS Advisory Board; and international evidence emerging from the
wider ethical, social and legal issues of biobanking. We are also
generating theoretical and practical concepts, such as benefit
sharing, relevant to Generation Scotland and other biobanking
8. Generation Scotland sees knowledge transfer
of genetics into the clinical community as key for the future
adoption of genomic science. The Scottish Genetics Education Network
(ScotGEN) is an extant group of healthcare professionals, university
academic staff and computer scientists involved in genetics education
for nurses, midwives, doctors and other health professionals in
Scotland. Funding in Phase 1 was used to co-ordinate the development
of computer delivered education in genetics for healthcare professionals
in Scotland. Two components were delivered: (i) the mapping of
existing materials to core competencies and specification of work
required; and (ii) design of four teaching modules delivered in
an e-learning format.
9. A secure informatics environment developed
as a service-oriented architecture including re-usable services
and client applications, linking with required NHS systems through
mediating client applications sitting on NHSnet; including electronic
research data capture on phenotypic data and quality management
applications. Written informed consent allows prospective and
retrospective linkage to routine NHS records.
10. Laboratory Integration has been implemented
across the four Scottish academic centres. Key laboratory technologies
have been procured, installed and implemented, including ultra-high
throughput genotyping platforms, capable of supporting genome
wide association studies and an integrated Laboratory Information
Management system, networked across all sites, to manage, govern
and track all biological materials associated with Generation
Scotland projects; a secure database system and Linux analysis
cluster established for genetic analyses.
11. Detailed simulations based upon known
Scottish family demographics and recruited family structures have
been conducted. These confirm the theoretical added power of family
based studies to test quantitative trait hypotheses. They also
provide a clear protocol for optimizing resource allocation in
recruitment of family structures.
We would like to make the following general
comments in response to the questions and issues raised by the
12. POLICY FRAMEWORK
For researchers, the policy framework is complex,
with a large number of bodies, both European and UK, involved
in setting and reviewing policy relevant to issues that impact
upon genomic medicine. This is a congested and rapidly moving
area. The Health Departments and statutory bodies such as the
Human Fertilisation and Embryology Authority play a lead role.
They are supported by numerous Government advisory bodies such
as the Human Genetics Commission. The MRC, post-Alderhey and increasingly,
the Wellcome Trust have taken a lead in policy development around
biomedical research, particularly in the area of access and governance
of bio resources. Other charitable bodies such as the Nuffield
Council on Bioethics have made key contributions as well as professional
bodies including the Academy of Medical Sciences. Internationally,
P3G and HUGO play a major role.
For researchers, translation of policy into
"best practice" that is clearly in the public good is
a key priority. Generation Scotland has therefore been fortunate
to benefit from the Generation Scotland Advisory Board (GSAB).
This is an independent body, accountable to the Scottish Government,
which advises the Generation Scotland Scientific Committee on
policymaking so that Generation Scotland practices and resources
are used to the best advantage of participants and the wider community.
GSAB is chaired by Lord Sutherland of Houndwood.
The five GSAB members were appointed by the
Health Minister on the basis of open competition and following
Nolan procedures on public appointments. Between them they have
an impressive breadth and depth of experience in law, ethics and
What is the state of the science? What new developments
are there? What is the rate of change?
Genomic science is rapidly evolving, with ever
lowering costs, increasing sensitivity and specificity. Whereas
assembling the consensus human genome sequence required international
effort over a decade and at a cost of around $1 per base, or $3
billion total, the next generation genomic technologies promise
whole genome resequencing at around $1,000 total.
Who is taking the lead in the consideration and
co-ordination of research and the development of new technologies?
National funding agencies, such as the NIH,
MRC and Wellcome Trust play a key role, not least in coordinating
major research infrastructure initiatives, such as the HapMap
(an average genetic profile of major ethic groups that can make
population genetic studies more efficient and cost effective),
the 1,000 genome project, which aims to resequence in full the
genomes of 1,000 representative individuals, and the EUCOM and
KOMP projects, which will genetically engineer a mutant mouse
for every gene in the mammalian genome. New technologies are generally
borne in academia, but then rapidly commercialized. Marker leadership
is only assured by innovation. There is a close relationship between
the major genome centres and industry as they serve as the alpha
and beta testing centers for next generation genomics tools.
How effective is the policy and investment framework
in supporting research in this area?
Investment in biobanks is costly and requires
long term investment and is thus not entered into lightly. The
idea however of a "one size fits all" study, is unrealistic
and misses the point and indeed the scale of the opportunity.
The need for multiple themes and rounds of investment is being
recognized, for example by the Wellcome Trust in funding a second
phase of genome wide case-control studies. Whilst supportive in
principle, it is not clear the MRC budget provides the flexibility
and head room to be proactive beyond the UK Biobank and other
How does research in the UK compare internationally?
How much collaboration is there?
The UK was a lead player, technically, scientifically
and financially in the Human Genome Project. The UK has arguably
taken the lead internationally with the UK Biobank and the Wellcome
Trust Case Control Consortium. There is a high level of international
collaboration, through EU Frameworks 5, 6 and now 7. There have
been high level collaborations between the UK (in particular the
Wellcome Trust) and the US (NIH). International organizations
such as HUGO and P3G play their part, but as non-funding agencies,
they have a limited agenda-setting role.
What are the current research priorities?
To identify genetic variants that modify disease
risk across all relevant medical domains of unmet need, including
mental health; to do so at the individual, family and population
level; to translate such genetic information into understand of
the biological underpinning of disease; to use that understanding
as a platform for preventative medicine and rational therapy.
What is the role of industry? How much cross-sector
collaboration takes place?
Industry as a technology provider is essential,
as is a competitive market for the introduction and application
of innovative technologies. The traditional role of industry in
drug target discovery and development has never been under more
pressure than currently as blockbuster drugs inexorably move off
patent. The flow of new molecules to the market place has slowed
despite increasing R&D investment. The "merge-to-survive"
philosophy of recent years has been a sticking plaster on the
problem. Pharma have largely ignored the genomics driven concept
of personalized medicine. Biologics, largely the product of academia
and biotec spin outs, herald a new era, but will depend upon core
pharma "know how" and financial muscle to solve production
and formulation issues and work their way through ever increasing
and costly regulatory hoops. Partnership with healthcare providers
who can provide access to well phenotyped and genetically stratified
patient groups to improve clinical trial efficacy and reduce Phase
2 attrition will be invaluable.
14. DATA USE
We propose that the accurate, reproducible characterization
of phenotypic data and environmental exposures are of equal importance
to DNA sequence data if genomic medical research is to reach its
full potential. The availability of longitudinal datasets that
allow genotypic/phenotypic linkage are key. Scotland has a longstanding,
international reputation in using record linkage of medical records
for epidemiological, genetic and clinical trial research. Compared
with the rest of the UK, data quality is high, the centralisation
of data in NHS Scotland is efficient, and the comprehensive computerisation
of routine clinical data, alongside the mandated use of a unique
patient identifier (the Community Health Index, CHI) for all health
episodes, means that access to data for research is becoming easier
and costs are falling. Building on these strengths, Generation
Scotland has been the catalyst for an informatics work stream
on the quality, quantity and governance of research using electronic
patient records. Developing existing strengths in Scotland and
extending them via the NHS CfH Research Capability Programme will
enable research to achieve its full potential as a "core"
activity for healthcare. This is essential if the United Kingdom
is to keep pace with or even surpass similar research programmes
elsewhere, particularly in Scandinavian countries. Generation
Scotland has therefore brought together leading Scottish groups
in record linkage; epidemiology; social science; legal and ethical
issues; health informatics and clinical trials design and execution.
This has allowed linkage of genomic data to routine clinical data
for studies of pharmacogenetics as well as GWA studies of common
What opportunities are there for diagnostics,
therapeutics and prognosticsnow and in the future?
The promise in this area is very high. Indeed,
it would be an unimaginably wasted opportunity if genomic diagnostics,
therapeutics and prognostics did not become available widely and
quickly. We are already seeing the first offerings in the field,
with biologics matched to genetic tests. Increasingly these tests
will become indirecta "genomic" version of a
blood glucose "dip stick" test, if you likewhere
the test is a measure of a gene product rather than of the genetic
Who is responsible for translation to clinical
Unless there is a radical societal change leading
to Government commissioned (or philanthropic sponsorship of) health
product development, this will remain a complex and uncertain
negotiation between invention and IP protection; clinical need;
willingness to pay; and the need to offer shareholder value.
Given the pace of technological advance, how "future-proof"
is healthcare investment in this area?
As suggested above, by the very nature of the
field, which is currently in R&D and "discovery"
mode, there is no "one size-fits-all" investment. There
is however no obvious challenger to genomic medicine.
How does the UK compare to other countries and
what lessons can be learnt
As suggested above, the UK compares favorably,
but there is no room for complacency. Indeed, as with many previous
examples of UK technology leads, there is a very real danger that
the commercial benefits will fall to others. The level of inward
investment in academic lead R&D is low compared to North America
and to the national level of investment being made by, for example,
Singapore, South Korea and China.
How meaningful are genetic tests which use genome
variation data? What progress has been made in the regulation
of such tests?
As discussed above, genetic tests for common
complex disorders, where risk is shared between multiple genetic
risk factors, will be of a different class and utility from those
that are definitive for rare, single gene, "all or none"
inherited conditions. In the internet era, genetic "testing"
is all but impossible to regulate. That does not mean that there
should not be tight regulation of UK providers, where the emphasis
must be on the underlying evidence base, QA, QC and how the results
should be interpreted.
In what way do genome-wide association studies
contribute to the identification of biomarkers? How is the study
of genetic factors and biomarkers integrated for translational
This has been broadly addressed in the foregoing.
What impact will genomic data have on data emerging
from projects such as UK Biobank, Generation Scotland and other
We have summarized this above for Generation
17. USE OF
Although this research is at a relatively early
stage, it is likely that many diseases (such as asthma, diabetes
and schizophrenia) will be re-classified based on molecular factors
that affect prognosis and response to treatment.
With few exceptions, genetic testing for individualized
medical advice is unlikely to be routinely available for many
years. Any gene that is found to be associated with a clinical
condition (or a response to treatment) needs first to be replicated
in other population-based studies, quantified for its contribution
to the condition in question (alongside other genes and environmental
factors), validated in a clinical setting, and commercialized.
As well as education of the public in the meaning and interpretation
of genetic findings, there must be extensive education of health
professionals. These can proceed in parallel, but are both in
Because of the need for replication, quantification
and validation, there should be regulation of the marketing and
use of genetic testing arising from new research. Without this,
there is considerable risk of producing misleading results and
causing anxiety and mis-treatment.
The results emerging from genetic research will
introduce new concepts of disease and illness, and, eventually,
the possibility of genetic testing and decision-making based on
the results of these. This will be very new to most health professionals.
It will be of a different class to that which currently operates
for highly heritable and disabling disorders for which future
reproductive planning is an important part of the genetic testing.
For the common complex diseases researched through biobanks, genetic
testing will be more about modifying risk of developing symptoms
and of optimizing treatment choice as and when symptoms manifest.
There is little research on the prospective needs for training
and education of health professionals in this area. Such research
as there is suggests a perceived major gap in knowledge and the
ability handle the resultant uncertainty. More research in this
area is needed, urgently.
15 October 2005