Memorandum by the ESRC Centre for Genomics
in Society (Egenis)
Egenis carries out a wide range of research
on the interpretation and implications of contemporary biosciences.
Specific areas of expertise relevant to the preparation of this
evidence are the philosophy of biology, especially emerging areas
of genomic and post-genomic science, regulation of biomedical
technologies with a special focus on stem cells, and the use of
family histories in the clinical management of common polygenic
disease.
What is the state of the science? What new developments
are there? What is the rate of change?
1. We must begin this response by expressing
some doubts about what is meant by "genomic medicine".
This would most naturally be taken to refer to systemic interventions
in overall genomic function, but as yet no therapies of this kind
exist. The term "genomic" might be taken to contrast
with more traditional genetic medicine, involving the diagnosis,
prediction, and treatment of monogenic diseases, but these might
also be thought of as encompassed by the broader term "genomic".
It is common to understand the investigation of multifactorial,
polygenic disease as genomic and we shall comment below on some
research here in this area. Given that this includes the common
killer diseases in the West (cardiovascular disease, cancer, diabetes)
this is presumably an area that deserves serious attention. Anticipated
developments such as the use of RNAis to block transcription of
specific regions of the genome would probably be considered genomic.
2. The science in this area is developing
at an extraordinary rate which, we suppose, provides a strong
reason for interpreting the term "genomic" in as broad
a way as possible so as to encompass developments that are as
yet difficult even to foresee. A general trend in those developments
is a move away from a vision as the genome as a code or program
intrinsically containing the future development of the organism,
but rather to see the process of development as involving constant
two-way interaction between the genome and other elements of the
cell and even of the wider environment. The "central dogma"
that proposed one way causal processes running from DNA to RNA
to proteins is in terminal decline if not quite yet dead. One
area that is opened up by this recognition of constant two-way
interaction is the possibility of epigenomic medicine, for example
medical intervention directed at dysfunctional methylation patterns
in the genome, increasingly implicated in cancer aetiology. A
second possibility that can be anticipated partly as a result
of this general reform of our understanding of the genome is the
eventual application of systems biology based insights to medicine.
And third, following on developments such as the human microbiome
project (http://nihroadmap.nih.gov/hmp/),
we anticipate medical implications for the increasing understanding
of the symbiotic relations between humans and ectosymbiotic microbes.
These include increasing awareness of the ways that humans and
microbes mutually modulate gene expression, and therefore should
surely be seen as a potential expansion of genomic medicine.
3. We assume that stem-cell based therapies
would be included under the genomic rubric, since one interpretation
of the central challenge in this area is the attempt to elicit
specific patterns of genomic expression appropriate for specialised
cell-types in unspecialised cells (or cells rendered effectively
unspecialised). Moreover the spontaneous rearrangements of genomes
observed in cultured cells are phenomena with wide implications
not only for medical applications of stem cells but even for general
understanding of life processes. Stem cell research has been constituted
as an emergent scientific field of inquiry connected to hopes
of biomedical innovations that will lead to the cure of major
degenerative diseases. While the transplantation of haematopoietic
stem cells has become a routine treatment in blood disorders such
as leukaemia in the last 30 years, stem cell science is still
in its early stages as regards the development of treatments for
major diseases such as diabetes, cardiovascular diseases and neurodegenerative
diseases. To date no clinical research has of yet been carried
out with cells derived from human embryonic stem cells while tissue
engineering uses of adult stem cells have only recently moved
into the clinical trial stage, eg trials with autologous bone
marrow stem cells for cardiac repair.
4. A very wide range of medical and other
issues are raised by the growing storage of human genomic and
genetic data. We cannot comment in detail on these here, but will
mention some specific issues under the heading of regulation and
translation.
5. Although all these are areas under active
investigation at Egenis it is too early to predict in any detail
the impact of such scientific developments on medical practice.
None of the possibilities mentioned in paragraph 2 yet exist as
part of medical practice, though in each case there are strong
arguments for anticipating that this will change over the next
few years or decades. We mention them to emphasise the fast-moving
and open-ended nature of the science and the need that any general
account of the state of this science should be as broadly conceived
as possible to make room for these as yet undeveloped, but potentially
very powerful, medical technologies.
POLICY FRAMEWORK
6. Although there is no particular body
dealing with genomic medicine, the existing regulatory and advisory
bodies (especially within the DH) inevitably enter and regulate
the field locally, through, eg, cancer, heart disease, and epidemiology
regulations. This leads to a complex and fragmented regulatory
landscape. While it provides flexibility, it also enables a "pick
and choose" policy, which can result in legal uncertainty
and inconsistent patients' protection.
7. Direct-to-consumer genomic tests are
inadequately regulated by existing legislation on quality and
safety of diagnostic devices. The risk of adverse psychological
effects on the individual and, very importantly, family members
needs to be addressed. This has been confirmed by in the Draft
Additional Protocol to the BioConvention on genetic testing for
health purposes.
8. Legislation is desirable concerning biobanks
(genetic data banks) setting up general rules regarding consent,
privacy issues, benefit sharing, funding and management. Crucially,
genomic studies are never restricted only to genetic/genomic data,
but encompass medical and other data. Reconciliation between data
protection legislation and provisions on biological material is
required. This also raises very wide-ranging issues of potential
genetic discrimination in health and life insurance and employment,
especially due to the limited scope of the definition of genetic
testing and the lack of clarity with regard to what is understood
by genetic data.
Note: paragraphs 9-13 are specifically addressed
to stem cell medicine.
9. Because of ethical problems connected
to the sourcing and therapeutic use of stem cellsespecially
human embryonic stem cellsand the assurance of the quality
and safety of stem cell technologies in human application, a complex
and intersecting set of regulatory mechanisms and authorities
apply to them in the UK. These include the Human Fertilisation
and Embryology Authority (HFEA), the Medicines and Health Care
Products Regulatory Agency (MHRA), the Human Tissue Authority
(HTA) and the NHS research governance frameworkand their
regulatory responsibilities following the transposition of European
regulation into UK law. As with other biotechnology-based medicinal
products, advanced therapy medicinal products now fall under the
centralised authorisation procedure of the European Medicines
Agency (EMEA).
10. In broad terms, the three UK regulatory
authorities have remits with regard to the regulation of tissues
and cells and on the basis of the transposition of the EU tissue
and cells framework into the UK regulatory system. In accounting
for the special status that was accorded to the embryo in the
HFE Act 1990, research on and use of embryos and gametes falls
within the remit of the HFEA as competent authority under EU law,
which also regulates fertility treatment. The regulation of the
procurement, donation, processing, storage and distribution of
tissues and cells for human application of all other tissues and
cells now falls within the remit of the HTA. If cells and tissues
are classified as a medicinal product, they fall under the licensing
conditions of the MHRA as competent authority. In this case the
HTA will only be responsible for the procurement, donation and
testing of cells, while the manufacture, storage and distribution
will come within the remit of the MHRA. By contrast, if tissue
or cell treatments are not classified as medicinal product, the
manufacture, storage and distribution will remain within the remit
of the HTA. Final market authorisation of medicinal products containing
cells or tissues will be granted through the EMEA.
11. While this may be seen as a flexible
system allowing for the tailoring of requirements to the specific
stem cell treatments under consideration, it is equally in danger
of inconsistencies and the creation of friction through the potential
creation of overlaps as well as the integration of expertise when
it comes to assessing particular treatments from the point of
procurement through to application in patients. Currently, there
exists some regulatory uncertainty as to the division of responsibilities
between the HTA and the MHRA. The translation of regulatory boundaries
in terms of institutional boundaries of the two regulatory authorities
raises tensions insofar as the requirements of manufacturing,
storage and distribution may have implications for the way in
which material is procured and the testing requirements that might
apply before further processing.
12. Given the complexity of tissue and cell-based
treatments, it is highly desirable that expert oversight reaches
across the entire process from ethical procurement to the manufacturing
and distribution of particular treatments/product groups rather
than being centred on one or particular steps in the authorisation
chain. Overall, in light of the fact that multiple regulatory
authorities have remits within this area and current regulatory
uncertainties among the authorities in this area, it needs to
be assured that a regulatory process is put in place which defines
the responsibilities and points of contact between the HFEA, the
HTA, and the MHRA as well as associated bodies such as research
ethics committees and GTAC (as the national ethics committee which
advises upon the carrying out of trials on gene therapy).
13. The development of stem cell therapies
is dependent upon the collaboration of scientists working in the
bio-sciences (molecular biology, biochemistry) and medical scientists.
With regard to the translation of technologies from the laboratory
to the clinic, preliminary findings suggest that this exchange
is dependent upon social factors which facilitate this exchange,
and suggest that the extent to which resources are available for
clinicians in engaging in translational research within the NHS
and the incentives present to do so across different levels of
training need to be addressed in furthering translational research.
What opportunities are there for diagnostics,
therapeutics and prognostics, now and in the future?
14. It is important to distinguish between
the opportunities for diagnostics, therapeutics and prognostics
in monogenic conditions and more common, complex polygenic conditions
(eg coronary heart disease, most cancers, diabetes). The possibilities
for screening for monogenic conditions is high (indeed it already
occurs); there is only one or a few genes to locate and their
penetrance (ie the extent to which they will cause the given disease)
is very high. This makes genetic screening, coupled with standard
treatment, cost-effective but only applicable to the small number
of people affected by monogenic diseases. The opportunities for
genomic medicine as applied to common, complex diseases such as
coronary heart disease and diabetes are different. Although advances
in genetics have led to the discovery of some genes linked to
diabetes and coronary heart disease, there are no clinically validated
genetic tests currently available. This is because such diseases
are the product of far more complex gene-gene and gene-environment
interactions which at present are not well understood (over 250
genes may be associated with cardio-vascular disease [CVD], for
example). In relation to CVD, tests have been developed for a
handful of "best-known" markers (mutations connected
with LDL metabolism, blood pressure, homocysteine) but it is not
clear they are the most significant or best predictors (except
for monogenic familial hypercholesterolaemia). It is also arguable
they offer no current benefit over and above existing tests (eg
cholesterol, BP, HDL/LDL ratio) and interventions are generally
the same (Mediterranean diet, statins and blood pressure modification).
This has not stopped companies entering into the market offering
tests such as Cardio for heart disease (eg GeneticHealth in the
UK). However, the predictive value of such tests is likely to
be very low, and so are not justifiable either in terms of NHS
cost or clinical utility.
15. In the absence of any clinically valid
genetic tests for CHD and diabetes suitable for widespread use,
there has been a resurgence of interest in using family history
as a "proxy" for genetic risk. Family history also encapsulates
other factors which are transmitted from generation to generation,
such as lifestyle behaviours and environment, is cheap and can
be delivered by in primary care. Its use is advocated in the National
Service Framework for diabetes and coronary heart disease in the
UK.
16. If family history is to be used as an
"alert" or "risk marker" for common and complex
diseases, it needs to be planned and implemented at central level
within the NHS if it is to deliver. Research conducted at Egenis
(in conjunction with the University of Nottingham) on behalf of
the Department of Health indicates several key features of current
practice which could be improved:
(i) Health professionals need very clear guidelines
on what constitutes a "positive" family history of common
and complex diseases (and therefore indicative of genetic/familial
risk).
(ii) Having identified familial risk, health
professionals need guidance/training on how best to communicate
this information as the different understandings of GP/nurse and
patient can lead to mis-communication.
(iii) The lack of standardization amongst recording
systems used by GP practices makes recording and using family
history/genomic information currently difficult (our ongoing study
found as many as eight different systems being used, all with
different family history criterion).
It is important to note that genomic medicine
does not have to be operationalised using high tech and expensive
processes to have considerable clinical utility.
Note: References in support of empirical claims
made in this evidence are on file and available on request.
15 April 2008
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