1.  As the UK's principal public-sector funder of genetics research relevant to human health, MRC welcomes the opportunity to contribute to the Committee's inquiry.

  2.  Human Genetic Databases play an important role in medical research and will do so increasingly over the coming years. The major benefits of knowledge of the human genome sequence for public health will come from the discovery of genetic factors predisposing people to develop the common, multi-factorial diseases of later life, and those affecting an individual's response to treatment of such disorders. Knowledge will allow the possibility of more effective use of existing treatments and also the development of new treatments and interventions to prevent the progression of disease. Databases bringing together health information and genetic information are one of the key tools we can use to make these advances.

What current projects involve collecting genetic information on people in the UK?

  3.  We believe that policy on the operation of human genetic databases needs to reflect a broad definition of research in this area, that includes not only collection of genetic sequence information, but also collections of human biological samples and tissue that could be suitable for genetic analysis.

  4.  A survey of MRC and Cancer Research Campaign-funded scientists in 1998-99 suggested there are well over 300 collections of cell or tissue samples in use, within this research community alone. Many were developed with support from more than one funder, and are likely to have been counted in the estimates submitted by the Wellcome Trust and other charities. The diseases addressed included cancer, heart disease, asthma, diabetes, dementia, stroke, Parkinson's disease, malaria, HIV, influenza and many others. Most of the existing collections are small: two thirds involve samples from 500 people or less, and only five exceeded 10,000 samples. DNA sequence information from these samples is invariably accumulated in the course of research.

  5.  The collections and their uses are very diverse. Some collections of tissue samples are used purely for studies of the physical, molecular and cellular processes involved in the disease. Those used in genetics research could be grouped as follows:

Research to identify genes involved in disease

  6.  Collections of tissue or DNA from people with and without a particular disease can be used to identify the gene or genes key to processes underlying the disease. Sometimes the comparison of samples from ill and healthy people—or whole families—is the first and most important method of identifying the genes involved. More often, a number of approaches are pursued, and the collections may be used to test ideas about genes identified through animal studies, or more basic studies of variations in the properties of molecules or cells. Most common conditions, such as hypertension, cancer and mental illness, are influenced by variations in many different genes, each modest effect located in different parts of the genome: in these cases, research studies require greater numbers of samples than when the disease is caused by a single gene of large effect.

  7.  Example: the "BRIGHT" study is a major UK collaborative study, co-ordinated from Glasgow University, which aims to identify the main genes affecting the risk of hypertension. Volunteers from 1,500 families nation-wide have been recruited through MRC's General Practice Research Framework, and the genetic analysis is being carried out at the Wellcome Trust Centre for Human Genetics in Oxford.

Research into gene/environment interactions

  8.  To gain a full understanding of the causes of common diseases, research needs to address genetic factors and external factors, such as diet, lifestyle, and environment, in parallel. The effects of diet on health may be strongly influenced by an individual's genetic make-up; conversely, when it is discovered that a variation in a particular gene may predispose to disease, the best preventative measures may prove to be a dietary or lifestyle change, rather than drug therapy or regular check-ups. Such data collections usually need to be large, and to collect detailed information about people's health, lifestyle and medical care over a long period of time.

  9.  Example: the Avon Longitudinal Study of Parents and Children (ALSPAC), now in its ninth year, was specifically designed to analyse this interplay between genes and environment in areas such as childhood, infection, allergy, asthma, growth and development. The project is based on information about 14,000 children born in 1991 and 1992, and their parents. Information is derived from the analysis of questionnaires completed by their parents, measurement of the environment in the home, non-genetic assays of biological samples, and tests at age seven and eight, as well as analysis of DNA. Over 127,000,000 items of information are already on the main database, and some 70 research papers have been based on the survey.

Collections linked to evaluations of medical treatments

  10.  Patients participating in clinical trials are being asked for samples for genetic studies in a few cases at present, but we expect that such samples will increasingly be used to analyse the genetic influence on disease progression and the response to treatment. A current example is the collection of samples from adult patients with leukaemia entered into MRC-sponsored clinical trials. Analyses of the DNA and RNA, linked to knowledge about clinical outcomes and response to treatment, have already allowed identification of mutations associated with differences in prognosis in different patients. This research will allow therapy to be tailored to specific tumour types, and already allows identification of patients with a poorer prognosis, in whom more aggressive therapy might be appropriate.

  11.  As well as the scientific diversity, it is also important to recognise the different contexts in which the collections are assembled. The relationship between the individual and the collection is as important as the nature of the science in determining the ethical issues that need to be considered in each case. Some depend on healthy people providing samples and information about their life and medical history through altruism, sometimes on many occasions over the years. Others are based on samples given by patients and their families, sometimes in the hope that the research results may directly benefit them in their lifetime. Whereas others may be collections of anonymous samples linked only to basic information about the diagnosis of the person from whom they came.

Are there collections of material (eg tissue samples) that could be used to generate databases of DNA profiles?

  12.  It is technically possible to extract DNA from most recent collections of human tissues (including blood) that have been stored for research, and from archives of samples taken for routine diagnosis. Whether it is acceptable and worthwhile doing so depends on the sample's size and storage, the quality of the accompanying information about the donor's health, and the nature of the agreement with the original donor about how the sample should be used. In most existing collections, the donor consented to the sample being used only for a specific project or line of research.

  13.  Current MRC guidelines stipulate that old samples taken for routine clinical purposes, where the individual was not asked to consent to research, can normally only be used for research if anonymised, and with the approval of an ethics committee.

What is the genetic information that is being collected? How is it being stored?

  14.  Most newly established collections of material for genetic analysis are based on samples of blood, from which white cells are extracted and frozen (mature red cells do not contain chromosomes). Either DNA can be extracted from the white cells, and used until the supply runs out, or the sample of cells can be immortalised (ie changed so that they divide and reproduce indefinitely) to provide a larger supply, though this is a costly procedure. For some research, such as work on gene mutations in cancer cells, samples of frozen tissue are needed.

  15.  The nature of the genetic analysis varies: in some studies, the aim is to gather information about the likely position within the genome of genes that appear to influence particular diseases, as a prelude to more detailed work to identify the gene and sequence it. When research explores the links between known genes and health, the study might typically involve analysis of samples of DNA or RNA to detect variations in the code of anywhere from one to 20 genes, out of the 100,000 or so genes that a person has. New technology is beginning to allow larger scale analyses, however, that might allow analysis of the key variations in hundreds of genes at a time from each person.

What other projects are about to start? Why are these genetic databases being assembled?

  16.  Genetic databases and collections have a central place in MRC's strategy for developing the research skills and resources to apply advances in genetics to better understanding, prevention and treatment of common, complex diseases. MRC's plans reflect the following principles:

—  the UK's strengths in population based research and clinical trials, the almost universal population coverage by the NHS, and the UK's strengths in genetics, mean we are well placed to play a leading international role in large studies of common diseases;

—  as the UK's principal public sector funder, MRC has a special responsibility to develop resources, such as large collections, that individual research centres or small charities could not;

—  collections of samples donated through public goodwill should be developed in a co-ordinated way, and access and sharing of collections must be managed to maximise the scientific return and reflect the wider public interest;

—  the ethical codes governing the use of collections should be transparent and as consistent as possible across the UK.

Custodianship

  17.  To clarify the standards that MRC-funded research must meet, and to help build a wider ethical consensus across the various different stakeholders in the UK, MRC has prepared draft guidelines on the use of human tissue and biological samples in research (Annex A) (not printed), which will be finalised at the end of this year. A separate guide on general aspects of the use of personal data in medical research will be published on 5 October 2000.

  18.  The guidelines underline researchers' responsibilities to ensure optimum use is made of human tissue collections. MRC expects all those holding collections to co-operate with reasonable and ethical requests from other research teams for access to the collection, and, for newly funded collections, will only release funds once clear plans for managing access to the collection have been agreed.

  19.  To help make best use of existing collections, MRC, with the Cancer Research Campaign, will be making details of over 300 collections available on the Internet based on information derived from the survey mentioned in paragraph 4. However, the consent given by the donors will in many cases limit the new uses to which these collections can be put.

  20.  Next year, MRC expects to commit funds to establish national DNA banking facilities, to provide central and secure storage for DNA samples, to facilitate sharing of samples and data for use in medical research within the original terms of the participant's consent.

Patient-based collections

  21.  In many cases, identifying the many genes involved in common diseases, and their relative importance, requires more fully characterised collections of samples and medical data than exist already. In the 1998 Comprehensive Spending Review, MRC bid successfully for additional funds to develop new DNA collections. As part of this initiative, we invited proposals for large-scale collections on the Web earlier this year of samples from patient cohorts or case-control studies.

  22.  Priority has been given to collections relating to common diseases of public health importance, and where sample collections are not already available. The call generated considerable scientific interest; out of 155 outline applications, 27 research groups were invited to submit full proposals, and funding decisions will be taken in October. This call complements the Wellcome Trust's recently advertised Functional Genomics Development Initiative.

The proposed UK population biomedical collection (UK PBC)

  23.  In May 1999, following preliminary discussions within MRC and the Wellcome Trust, the Council and the Wellcome Trust jointly organised a workshop, with representatives from other major UK research funders, to consider whether the UK would benefit from one or more new collections, large enough not only to help identify genes, but also to analyse the interplay between different variants of important genes and individual lifestyle and environment factors in the development of common complex diseases. The workshop concluded that a large, long-term collection would provide opportunities for advancing understanding of health and disease that could not be achieved in other ways. In the UK and world-wide, most existing collections are too small to allow statistically meaningful research, do not have enough high quality health information, have too little DNA left, or are not based on full consent for this sort of research.

  24.  Following further analysis, a Working Group involving MRC, the Wellcome Trust and the Department of Health recommended establishing a long-term study of about 500,000 volunteers, aged 45 to 64, and representative of the UK population. MRC Council supports this proposal, which has also been agreed in principle by the Wellcome Trust. Firm plans for the study are still being developed, but the expectation is that it would involve each volunteer providing a blood sample via their GP from which DNA would be extracted. In addition to a detailed interview to establish the individual's agreement to participate, basic measurements (height, weight, blood pressure, lung function, etc) would be made and participants would complete a questionnaire about their medical history and lifestyle. With the participants' consent and involvement, follow up data on their health and lifestyle would be collected over the succeeding years, and the results of genetic analyses carried out on all, or subsets of, the volunteers by separate research groups would be held centrally, so that the collection would become a much more valuable resource with time.

  25.  The 45 to 64 age group was chosen for the survey because this is the stage in life when the major diseases of adult life become common: the sample size is expected to be around 500,000 so that within a few years of the start it should be possible to undertake meaningful research into significant numbers of ill people, in many different disease areas.

How do the organisations involved see their responsibilities regarding privacy, consent, future use, public accountability and intellectual property rights?

Consent and ethical guidance

26.  In 1998 MRC decided that additional guidance was required on the ethical, legal and management issues relating to the use of samples of human tissue (including DNA) in research, recognising that such samples would be increasingly important in understanding the function of human genes and translating that knowledge into benefits for health. A Working Group including researchers, ethicists, and lay members, and representatives of the Department of Health and other funders developed new guidelines, with widespread consultation with research and consumer groups. These were published as an interim version for further public consultation in November 1999 (Annex A) [Not printed]. The revised version will be available by the end of this year. They have been broadly welcomed and endorsed by other organisations such as the Wellcome Trust and the Cancer Research Campaign.

  27.  The law on ownership of samples of human tissue is unclear in the UK. The MRC guidelines highlight the need for secure and responsible custodianship of samples and the data associated with them, and recommend that in most instances formal responsibility for custodianship should rest with institutions rather than individual researchers. They highlight the importance of obtaining proper informed consent from donors, and detail issues that must be addressed in the consent process to ensure that participants have a full understanding how any planned and future research using their sample might affect their interests. The guidelines recommend a two-stage consent process, first consent for the experiments immediately planned, and second for a broader (but limited) range of possible future experiments. Consent must always be obtained for genetic research, and any secondary use of samples must be approved by an ethics committee, which must decide whether the use proposed is within the terms of the consent given by the donors or whether new consent is required. However, genetic tests of known clinical predictive value should never be done on samples that can be linked to individual donors without their express consent.

  28.  The responsible use of old sample collections presents difficult issues. Such collections can be very valuable or impossible to replicate, but often consent for secondary use was not obtained and it can be impractical or impossible to approach the original donors for further consent. The MRC guidelines recommend that old collections can be used for secondary research if the samples are anonymous to the researchers, and if the rationale of the research is approved by a suitable ethics committee.

Privacy

  29.  Databases of genetic information can be anonymised, but for much medical research, including that on the genetic factors affecting disease risk or response to treatment, it must be possible to link individual data to names, contact addresses, or other information that can identify individuals in order that the database can be updated with follow-up surveys about people's health and lifestyle from time to time. However, there is no need for any more than a few people to have access to this identifiable information. For databases used by several research teams, the majority of researchers should only have access to anonymised data. The MRC guidelines stress that any researcher with access to identifiable data must have a formal duty of confidence to research participants.

Public accountability and supervision

  30.  There are a range of mechanisms in place to ensure public accountability for medical research involving human participants and materials, including genetic databases. As well as consenting to participate at the outset, generally (excepting anonymous databases) any individual is entitled to ask to withdraw from any research project at any time and for data on them to be removed. Individuals participating in research should also be told who to contact if they have any complaints about their treatment, and how to take the complaint further if necessary.

  31.  All research involving human participation or materials is already reviewed by independent Research Ethics Committees. The Department of Health's proposals to strengthen research governance should help ensure that, even where a project has no external funder, there are local mechanisms for supervising the quality and conduct of the work.

  32.  Special governance arrangements are felt to be necessary for the proposed UK population biomedical collection, not least because of its scale and the longer lines of communication between researchers and participants. Detailed plans for a management structure are still being developed and consulted upon, but the funders expect that it will be appropriate to form an independent body, with lay and public representation, to oversee custodianship of the DNA samples, management of the collection, application of the ethical codes, the principles guiding priority-setting, the quality of information available to participants, and the handling of complaints. Members of this overseeing body would be recruited through public advertisement.

  33.  The UK PBC can only be formed if the initiative enjoys widespread public support: without volunteers, the research cannot proceed. Arrangements for public consultation and feedback are therefore central to the initiative, and the consultation has to be a genuinely two-way process, with the aim of developing the sort of collection that the public will support. MRC and the Wellcome Trust have already commissioned a preliminary study to explore perceptions of the use of biological samples in research. The executive summary of the report, from Cragg Ross Dawson Ltd, is at Annex B. [Not printed]

  34.  Further consultations are planned over the coming months both with the public and with primary care practitioners.

Commercial use and intellectual property rights

  35.  While some research using genetic databases will point towards possible new public health measures, other research will identify genes important in disease and help clarify their role, providing new targets for drug design. The UK PBC may also contribute to pharmacogenomics—ie establishing how genetic variations make different individuals respond differently to drugs or other treatments—knowledge that is potentially of great economic importance to the health service and to industry.

  36.  Attitudinal research carried out thus far suggests that participants in the UK PBC will need to appreciate that the knowledge gained will often be used by industry in developing new treatments, and that this is one of the expected benefits. At the same time, they will want assurances that decisions about the management and use of the collection are being made in the public interest, rather than in the interests of industry alone.

  37.  The exact terms of engagement whereby industry, or academic groups funded largely by industry, will be able to analyse samples or data in UK PBC, are still under discussion. However, the principles are likely to be that:

—  industry will not provide core funds for the creation of the collection;

—  industry users will be expected to meet the full costs of survey work or analysis needed for their projects;

—  since DNA samples are a finite resource, and there is also a need to limit the volume of surveys which participants are involved in, a basic prioritisation system will need to be established to ensure all studies—from academia and industry—are well designed;

—  to ensure all the knowledge gained is available for use in the public interest, all users will be expected to add their results to a central database after a set period of time.

  These basic principles will be developed further in discussion with industry at workshops later this year and in the spring.

  38.  Intellectual property arising from research using samples of human tissue is expected to be protected by academic or industry researchers in the normal way. Where sample collections are established as shared resources, the Funders may act to ensure that IPR arising from use of the UK PBC data is handled centrally and exploited effectively, with the ultimate aim of ensuring that potentially beneficial new treatments or diagnostic tests are developed and made available for the public good as soon as possible.

What practical considerations will constrain developments? (The comments below reflect the factors which could constrain development of the proposed large UK biomedical and large patient collections. All are being actively addressed by the funders and further details can be provided as required.)

Development of databases of human genetic variation

39.  Although the sequence of the human genome is almost complete, there is currently insufficient information available on the extent of sequence variation between different individuals. The availability of a public database of single nucleotide polymorphisms (that is, individual bases within the human genome sequence at which variation is known to occur) will simplify the search for genes in which variation is associated with the development of disease. MRC strongly supports the principle that such information, along with all basic DNA sequence information on humans and other organisms, should be placed in the public domain, as free and equal access by all researchers will speed up the translation of such basic knowledge into improvements in human health.

Genotyping technology

  40.  To realise the benefits of this approach, improvements in the technology to identify genetic mutations are required, in order to increase the speed and decrease the cost of genotyping, and to allow accurate results to be obtained with smaller amounts of DNA. Using currently available technology it is not feasible to screen thousands of individuals for hundreds of thousands of possible mutations, so attempts to find genes related to disease must rely on a targeted approach. The amount of DNA available also constrains the amount of genotyping that can be done on a single sample; work is ongoing to develop the technology for whole genome amplification by the polymerase chain reaction, but currently expansion of an individual DNA sample requires the creation and maintenance of transformed cell lines, which is both expensive and time consuming. Developments in statistical methodology and the recruitment and training of bioinformaticians are also required for analysis of the very large amounts of data produced.

Public and professional support

  As discussed above, the development of collections of genetic and health information depends on widespread public support.

  41.  Since recruitment for UK PBC will be through general practices, the initiative also depends on the support and expertise of general practitioners and other practice staff. In addition, a large number of research nurses will need to be recruited and trained to carry out the initial interviews and assessments of the 500,000 volunteers.

Availability of NHS records

  42.  A current constraint for studies following up large numbers of individuals to study the effects of genetic variables on disease is the cost and time involved in obtaining the information on clinical outcomes. It would be significantly more efficient if it were possible to obtain such information from data collected by the NHS in the course of the research participants' normal clinical care, rather than through questionnaires completed by participants and their doctors. This would of course require the participants' informed consent, and very careful measures to protect confidentiality.

  43.  Currently such an approach is constrained by the uneven quality of the data recorded and the lack of comprehensive electronic health records. In planning the UK PBC, one option that will be assessed will be the collection of data on health outcomes through the electronic health records increasingly being kept in General Practices.

How are activities to be funded?

  44.  It is currently assumed that MRC and the Wellcome Trust will be partners in funding the setting-up of the resource, and will provide the majority of the necessary funds, although it is hoped that the Department of Health, the Scottish Executive and other charities may also contribute.

  45.  The establishment of DNA banking facilities and assembling large collections of samples for patients with particular diseases will be funded by the MRC, in some cases the funding is in partnership with medical research charities. However, these resources are intended for use by all bona fide researchers and it is envisaged that funding for research using the samples will come from multiple sources. For example it is likely that a number of disease related research charities would fund programmes of work based on these resources.

How are activities in the area of genetic databases developing in the future? What advances in sequencing, screening and database technology are they anticipating?

  46.  The key technological and scientific developments that will shape future use of DNA databases are:

—  advances in the speed and affordability of genotype analysis (ie identification of genetic variations in specific genes in individuals);

—  advances in the quality of electronic health records;

—  advances in the ability to transfer and link health records between centres securely;

—  development of new mathematical/statistical tools, and software, for analysis of large databases;

—  expansion of the UK's pool of skilled personnel in health informatics and bioinformatics.

What lessons should be learnt from genetic database initiatives in other countries?

  47.  The key lessons are that:

—  large collections will only win widespread support if they are publicly accountable, and managed for the public good;

—  the public needs to be engaged in discussion about the aims, safeguards, and ownership of a survey at an early stage, and the dialogue needs to continue throughout the initiative;

—  participation in genetic surveys should be based on consent, opt-in rather than opt-out, which can be withdrawn at any stage;

—  plans should take account of the need for genetic counselling or confirmatory tests if and when results are fed back;

—  there need to be clear, visible boundaries between medical and forensic databases;

—  collections need to be linked to high quality health and lifestyle information if the genetic factors influencing health are to be fully understood.