1.  SUMMARY

  1.1  Following adoption of the Japanese government's 1999 "Basic Strategy towards the Creation of Biotechnology Industry" the government has sought to expand the breadth of activity through new initiatives aimed at consolidating work within the area of genome exploration and pushing forward into the period of post genome sequencing.

  1.2  Underpinning the new drive is the Japanese Government's "Millennium Projects" initiative with its priorities of analysing full length cDNA and undertaking SNPs research; the results of which will supplement the databases of earlier initiatives, including amongst others GenomeNet and the DDBJ (DNA Database of Japan).

  1.3  As part of the effort to fully exploit genetic information, Japan is actively seeking to expand its collections of human cells, genes and tissues and to exploit the resources of historical collections. Associated with this expansion is increased emphasis on the key issue of consent and anonymity. Both the Ministry of Health and Welfare (MHW) and the Council have produced guidelines for Science and Technology. A "Basic Law for Personal Data Protection" is currently under discussion.

  1.4  Although none of the public databanks are understood to contain information from which DNA profiles could be generated, measures to prevent linkage of data with individuals have not to date been universally employed and some databases with the ability to generate DNA profiles do exist.

  1.5  The exact reason(s) for assembly of the latest databases is not entirely clear. The databases will benefit studies of gene function, studies of drug response, prediction of side-effects, and the study of the Japanese population's genetic characteristics. Whether or not use of the data will eventually extend to the development of new drugs is a point for discussion.

  1.6  MHW considers ethical issues to be amongst the main constraints to development. Discussion of hereditary diseases is anathema to the Japanese.

  1.7  To date the majority of databases are the responsibility of government and have been assembled with public money. There is however some private activity, such as that of the Japan Pharmaceutical Manufacturers Association and its 43 member companies.

  1.8  In the post-sequencing era, researchers are well aware of IP value accrued through the identification of useful genes and those causing disease. Rights to the IP will be shared between the government and all those having had an input, including, where appropriate, universities, research institutes and companies.

  1.9  Human genetics research in Japan is currently in a transitional stage and wide-ranging decisions on ethics and the acceptability of working practices are currently under discussion. Few principles have been fully determined and little information is available on the current profile of Japanese activity.

2.  INTRODUCTION

  2.1  The Japanese Government's 1999 "Basic Strategy towards the Creation of Biotechnology Industry" expects Bioinformatics to play a major role in the post genome sequencing period. Since its adoption, the government has sought to expand the breadth of activity through new initiatives aimed at consolidating work within the area of genome exploration and pushing forward into the period of post genome sequencing. Ranging from work relating to SNPs through to Genome information on Protein Structures and Protein Analysis and Function, initiatives are encompassing both public and private sectors.

  2.2  A number of the current bioinformatics activities, such as GenomeNet and DDBJ (DNA Database of Japan) are clearly the product of earlier initiatives. Yet there is no doubt that under the latest initiative, bioinformatics has been a major beneficiary of additional resources and increased attention, in anticipation of post genome sequencing activity.

  2.3  Underpinning the new bioinformatics drive is the Japanese Government's "Millennium Projects" initiative with its priorities of analysing full length cDNA and undertaking SNPs research. In support of this work, five government ministries proposed the building of four new databases, encompassing "Healthy SNPs and Polymorphism Networks", "Biological System Information Integrated Database" (including non-human), "Disease SNP database" and a "Comprehensive Database" for the private sector. Along with the development of these and other new databases, Bioinformatics in Japan, as in Europe and the US, is evolving to take account of the new challenges involved in "post genomic informatics".

  2.4  As part of the effort to fully exploit genetic information, Japan is actively seeking to expand its collections of human cells, genes and tissues and to exploit the resources of historical collections. Driven by the Government's Millennium Project, consideration of the degree to which information in current and future databases can/should be linked with individuals has precipitated guidelines from both the Ministry of Health and Welfare and the Council for Science and Technology. Although these set the parameters for future information collection, they are not retrospective. Measures to prevent linkage of data with individuals have not to date been universally employed and some databases with the ability to generate DNA profiles do exist. These are, however, as far as can be ascertained, principally restricted to research institutes and to the hospitals with which they are collaborating and are neither made generally available nor integrated into broader databases.

  2.5  None of the public databanks are understood to contain information from which DNA profiles could be generated. In the main, profile generation should only be possible where donors have made a request to be informed of the outcome of the research. Many of the databanks containing linkable data are in the public sector (University/hospital/research institute). However, before data is passed to central databanks, any opportunity for linkage is removed.

  2.6  Human genetics research in Japan is currently in a transitional stage and wide-ranging decisions on ethics and the acceptability of working practices are currently under discussion. Few principles have been fully determined and little information is available on the current profile of Japanese activity. Enquiries by the leading practitioners, in the Human Genome Diversity Forum, into the range, diversity and application of databases in Japan proved inconclusive and much additional work is required before a reliable picture can be produced.

  2.7  Within these limitations the following provides an outline of the major genetic databases under consideration or construction and through examples gives an insight into the activities of the estimated 40 to 50+ centres with privately constructed databases.

3.  CURRENT ACTIVITIES

  3.1  By no means have Japan's efforts in Bioinformatics only just materialised. A number of databases have been developed and operated since the early part of the 1990s when Monbusho set up the Human Genome Project; the foundation of today's much expanded activity. These databases include:

3.2  GenomeNet

  Since 1991, the Ministry of Education have, as part of their Human Genome Project "Genome Science", undertaken Genome Bioinformatics Research. Led by Professor Minoru Kanehisa, the GenomeNet Database has been developed and jointly operated by the Institute of Chemical Research (ICR) of the University of Kyoto, the Human Genome Centre, University of Tokyo and the Japan Advanced Institute of Science and Technology in Hokuriku. It provides an integrated database search facility and access to the Kyoto Encyclopaedia of Genes and Genomes (KEGG), with services for base arrangement analysis, including homology search, protein motif search, pathway search and other analytical tools.

3.3  Kyoto Encyclopaedia of Genes and Genomes (KEGG)

  Constructed by Professor Kanehisa's group, KEGG contains comprehensive data on metabolic Pathways, Enzyme Reaction Compounds (LIGAND), Inter-reaction amongst molecules (BRITE) and Gene and Genomes catalogues. From an early stage KEGG aimed to undertake the analysis of interactions among genes and proteins. New funding from the Science and Technology Agency (STA) and Japanese Society for the Promotion of Science (JSPS) will facilitate a scaling up of activity in readiness for post-sequencing genome analysis. Additional information on KEGG can be found at http://www.genome.ad.jp.

3.4  Laboratory of Genome Database

  Led by Professor Takagi of the Human Genome Centre, as part of the GenomeNet activity, work is ongoing into (1) the investigation of database technologies such as deductive, object-orientated databases that are suitable for complex and huge genome-related data; (2) Re-arrangement, re-organisation and integration of databases; (3) Development and construction of database tools, based on new database technologies and networks and (4) Providing supporting services by developing specialised databases and software tools for the operation of GenomeNet.

3.5  DNA Databank of Japan (DDBJ)

  Funded by the Ministry of Education, DDBJ, the sole DNA data bank in Japan, began its activities in 1984 at the Ministry's National Institute of Genetics (NIG). It had been collaborating internationally with the European Bioinformatics Institute responsible for EMBL databases and with the National Centre for Biotechnology (NCBI), responsible for GenBank databases in the US. Information on links to other databases developed by NIG, other Japanese institutes and foreign organisations may be accessed at http://www.ddbj.nig.ac.jp.

3.6  KDRI-DB Kazusa DNA Research Institute

  KDRI-DB is a collection of biological information mainly derived from the sequencing data from the research institute. Genome sequences include human, full-length cDNA data.

3.7  RIKEN Genome Science Centre (GSC), Science and Technology Agency

  "Human Genome Research Group"/"Protein Research Group". Having, along with the US and UK, completed sequencing chromosome 21 and 22 genes, the Human Genome Research Group are currently working on chromosomes 11 and 18. The recently established "Howdy" database has been developed to retrieve human genome information from different data sources that are available to the public. At the same time, Dr Shigeyuki Yokohama has started work on building a "Protein Folding Catalogue/Encyclopaedia" using NMR.

3.8  PRF/LITDB and PRF/SEQDB, Protein Research Foundation

  The Protein Research Foundation funds the Protein Research Institute in Osaka University and holds Japan's major peptide sequence database.

3.9  Private Sector

  Unlike US genomic venture firms, there is little known of the current databases compiled by private sector companies, outside of two compiled by Otsuka Pharmaceutical Co Ltd's Tokushima Genome Research Institute, who in collaboration with Professor Yusuke Nakamura's group of the Institute of Medical Science, University of Tokyo, have produced open access databases, including "GENOTK", a human cDNA database.

4.  NEW INITIATIVES

  4.1  Following commencement of Japan's Bioinformatics research in 1991, the country is now entering a new phase in its commitment to this discipline. A raft of new initiatives is either underway or in the final stages of planning. These include:

—  "New Development of Genome Information Science" Monbusho.

—  RIKEN's Genome Science Centre.

—  Single Nucleotide Polymorphisms Project.

—  The Bioinformatics Research Centre, MITI.

4.2  "New Development of Genome Information Science"

  4.2.1  Succeeding the "Genome Science" initiative, Monbusho has this year started a "Specially Promoted" informatics orientated research programme, led by Professor Takagi of the Human Genome Centre, University of Tokyo. Work is focused in the following four areas:

—  Advanced Database Systems and Systemisation of Biological Knowledge.

—  Knowledge Discovery from Databases.

—  Genome Information on Protein Structures; and

—  Modelling and Simulation of Gene Networks.

  4.2.2  Alongside this programme Monbusho and the Japan Society for the Promotion of Science will, under the leadership of Professor Kanehisa, be developing a "Biological Systems Database and Genome Information Science" programme, aimed at taking a central role in the "Academic consortium of bioinformatics".

4.3  RIKEN Genome Science Centre

  4.3.1  The RIKEN Genome Science Centre is due for completion in October this year. Emphasis will be given to five main areas, including the Human Genome (Chromosome Nos 11 and 18). From this year, a sixth group, "Genome Information Science", will be set up to undertake research into the areas of:

—  "Gene Network Modelling";

—  comparative expression research focusing on colour, hand, foot and internal organs; and

—  signalling transaction mechanism modelling research for effective molecular analysis of proteins.

  4.3.2  This group will be responsible for bioinformatic analysis of all data produced by the Genome Science Centre.

5.  PLANNED DATABASES UNDER THE MILLENNIUM PROGRAMME

5.1  SNPs Single Nucleotide Polymorphisms

  The Millennium human genome research programmes focuses on the analysis of human complementary DNA (cDNA) and single nucleotide polymorphisms (SNPs). The Japanese healthy SNPs database is the only one already being constructed and opened to the public. Professor Y Nakamura, Director of the Human Genome Centre (HGC) of the Institute of Medical Sciences, Tokyo University (IMST) is undertaking the project in collaboration with the Japan Science and Technology Corporation (JST), an organ of the Science and Technology Agency (STA). Other databases being planned are listed below.

5.2  Normal SNPs

5.3  Disease SNPs database being planned

  Myocardial Infarction, chronological joint rheumatoid arthritis and osteoarthritis are also the target of work at RIKEN. The numbers of samples collected are 650, 311 and 194 respectively. From 2001, Diabetes and interferon's side effects work will commence. Osaka University, IMSUT and Kyushu University will collaborate with the centre.

5.4  Drug responder SNPs

  There are two major initiatives to study Japanese drug responder SNPs; one by the National Institute of Health Sciences (NIHS), MHW and the other by the "Pharma SNPs Consortium" (PSC); involving 43 Japan Pharmaceutical Manufacturers Association (JPMA) member companies.

  5.4.1  National Institute of Health Sciences (NIHS), MHW project involving drug categories and their metabolic action points, including cytochrome p540 and transporter related molecules and receptors.

  5.4.2  The "Pharma SNPs Consortium" (PSC) was set up in September 2000 to investigate SNPs within the Japanese population, to determine individuals differences and thereby facilitate the production of tailor-made pharmaceuticals with less side effects. Forty three Japanese pharmaceutical companies will participate in the project, which will start from October, collecting blood samples from a target number of 1,200 volunteers. Research themes include: the identification of SNPs involved in pharmaco-kinetics, frequency and functional analysis and standardisation of sample donation. A database will be built to accommodate research results and after filing of patents, the data will be open to the public. The research period will be for three years with a total investment of 1 billion Yen. PSC has commissioned the work to Professor Y Nakamura of IMSUT.

6.  OTHER HUMAN RELATED GENETIC DATABASES

  6.1  Some other human-related databases are:

—  Osaka University—BodyMap (Human and Mouse Gene Expression Database).

—  Otsuka GEN Research Institute, Otsuka Pharmaceutical—Human cDNA Database.

—  Kazusa DNA Research Institute—HUGE: Human Unidentified Gene-encoded large proteins.

6.2  Keio Mutation Database (KMDB)

  Keio Mutation Database (KMDB) is a database of mutations in human disease-causing genes, which was constructed by Professor Nobuyoshi Shimizu's group. As of July 2000, KMDB accommodates mutation data for 64 different genes involved in 72 different diseases of the eye, heart, ear, brain, auto-immunity and syndrome (Table 1).

7.  HUMAN CELL, GENE AND TISSUE COLLECTIONS

  7.1  There are three kinds of collections; namely:

(1)  Public banks which distribute samples to researchers.

(2)  "Private collections" among researchers of universities and medical research institutes who have been pooling samples while undertaking research programmes funded by Monbusho and the Ministry of Health and Welfare (MHW). They don't distribute their samples beyond their groups or institutes.

(3)  Envisaged massive "collections" obtained through clinical practices by hospitals, which are not formally available for medical research unless patients give their consent for the use of medical research.

7.2  Principles governing the collection of samples

  Following an increasing awareness of patients' rights over the last several years, "informed consent" has been introduced. The MHW in May this year introduced guidelines governing the way in which research under the human genome projects was to be undertaken and in June the Council for Science and Technology (CST) announced the "Fundamental Principles of Research on the Human Genome". Both require strict adherence to good practice during the collection of human tissues.

7.3  How to deal with existing collections

  7.3.1  Many samples collected before the introduction of the MHW guidelines are now being considered for use in genetic studies. The question therefore is how should these be treated within the context of the new guidelines?

  7.3.2  These materials have been assigned to one of the following three categories, dependent upon the level of consent given at the time the samples were obtained. Alongside each category are conditions to be met before the sample can be used in genetic research.

  7.3.3  How this will work in practice is yet to be seen; particularly in respect of the ethical committees granting permission to use materials for which consent has not been given. To do so may give rise to the risk of public opposition and an aversion to providing samples for research.

7.4  Public cell, gene and tissue banks in Japan

  The major public bank in Japan is the Japanese Collection of Research Bioresources (JCRB). This comprises cell and gene banks, operated by the National Institute of Health Sciences (NIHS) and the National Institute of Infectious Disease (NIID) respectively. Both institutes belong to the Ministry of Health and Welfare (MHW).

  7.5  Since 1995, with NIHS and NIID acting as master banks, MHW's Japan Human Science Foundation (JHSF) has distributed samples. Of the cell and gene collections, roughly 59 per cent of the cells are human derived cells and 55 per cent of the genes of human derivation. Those using the banks must follow sound ethical principles in conducting their research.

  7.6  In response to a MHW report in May this year, Japan's biomedical research infrastructure is to be consolidated, with JHSF setting up the Health Science Research Resources Bank (HSRRB) in Osaka. This will be the first public tissue bank in Japan. Tissues within HSRRB will be confined to those removed during operations. Conditions to be met include:

(1)  The institutional ethical committees of donor organisations must approve the taking of samples.

(2)  Full information should be provided to donors, including the intention to put the sample into the HSRRB and to use the sample in private sector research.

(3)  Donor institutes should anonymise samples (Fig 1).

  7.7  RIKEN Gene Bank (Tsukuba), set up 1987, is another major bank, including a human Cell Bank, human DNA Bank and Bio Info Bank.

  7.8  Other banks include:

Medical Cell Resources Bank Institute of Development, Ageing and Cancer, Tohoku University, http://www.idac.tohoku.ac.jp/idac/HomePages/ccr/—Set up in 1984 as a Tumour Bank, based on knowledge accumulated by Professor Yoshida and Professor Sato under Monbusho 10-year cancer research programme.

Institute for Fermentation, Osaka (IFO), http://village.infoweb.or.jp/—Set up in 1994 under the auspices of Monbusho. Animal cell and micro-organisms cell lines, of which 47 per cent is human derived.

Hayashibara Fujisaki Cell Centre, http://cellbank.nihs.go.jp/jtca/book/—Set up in 1985. Specialising in human leukaemia, lymphoma.

7.9  Private collections by medical research institutes and university research groups

  It is difficult to identify which groups have what kinds of human tissue collections potentially available for genetic research. For the past 20+ years genetic studies have been conducted mainly in Japanese universities. Some collections related to genetic study may have until recently been known only to the scientists. Whilst these are currently kept by individual researcher groups, there is a prospect in the long term of integration into public tissue banks in order to consolidate resources. Examples of such banks are thought to include:

The National Children's Hospital "Tonsil Lymph Tissue Bank"—Xeroderma Pigmentosum.

Dr Furuichi and Dr Makoto Goto—Werner's syndrome genes, causing early ageing.

Professor Katsushi Tokunaga, Tokyo University—Sample collections for Japanese population HLA study.

Professor Tsuji, Niigata University—Brain specimens.

National Centre of Neurology and Psychiatry—Centre's "Child Brain Bank" keeps about 1,200 brain specimens, 50 Alzheimer disease patients' brain specimens, and 700 DNA samples of Alzheimer patients.

National Cardiovascular Centre Research Institute—Blood samples.

National Cancer Centre—Cancer related tissues.

National Children's Medical Research Centre—Samples involved in allergy.

7.10  Anonymity

  7.10.1  In meeting the requirements of MHW's guidelines, research organisations are required to safeguard information with the potential to link donors to research data generated from donated samples. Donors also have an opportunity to withdraw their consent for use of donated samples, or resultant research data, at any time. Upon transferring research data to the central data bank, the linkage between the donor of the sample and the research data generated from the sample will be irrevocably broken. At the time of providing consent, the donor is made aware that once within the central data bank, the data can no longer be linked and cannot therefore be withdrawn.

  7.10.2  The guidelines provide for two stages in anonomysing donor data. In the first stage, samples taken and used in research by the medical institution remain linkable to the donor (Figure 2). Managers appointed to supervise the protection of donor information provide each sample with a unique bar code, containing donor information. Details of the coding are kept on a stand-alone workstation, protected by fingerprint operated mouse controls and a hard disc drive password entry system. Paperwork relating to the donors is kept in a high security safe. The bar-coded sample is then passed (along with the age of the donor) to the research team. The adequacy of this level of security is currently under debate.

  7.10.3  At the conclusion of the research (second stage), and at the point of transfer of research data to a central database, the data along with the age of the donor is fed into an online computer connected to the central database (Figure 2). Linkable now only by age and under normal circumstances amongst an array of data for similar aged donors, the data and donor should no longer be unequivocally linkable. Transfer to the central database further diminishes the probability of being able to link data to the sample donor.

  7.10.4  All MHW national research institutes are required to follow this procedure.

  7.10.5  Under conditions yet to be fully determined and with the agreement of the Research Institute ethical committee, Director Generals of the Institutes have the authority to link research data to the sample donor. However, in the event that confidentiality is broken in a way judged not to be acceptable, the public funds supporting the research may be withdrawn from the Institute and legal proceedings instituted against those considered responsible.

  7.10.6  It is accepted by MHW that there is value in certain circumstances (when disease related) in being able to link research data to the sample donor; the value varying dependent upon which disease is involved. Determining the best ways of exploiting these benefits whilst still retaining the principles of consent is currently being considered. Where the disease is a hereditary one and beneficial medical intervention is not possible, a decision on whether or not to permit linkage under these circumstances is also currently under consideration by MHW.

  7.11  It is broadly accepted that it is difficult to construct patient linkable databases in Japan, principally due to the fear of discrimination and sensitivity to information linking the patient to genetic diseases. Linkable information is also recognised to be of limited value where additional essential information such as environmental conditions is not routinely collected.

8.  OTHER ASPECTS

8.1  Reasons behind data assembly

The exact reason(s) for assembly of some of the databases is not entirely clear. Views to some extent differ between those constructing the databases and between these groups and the MHW. What is agreed is the benefit that the databases will have in studies of drug response and prediction of side-effects and in the area of gene function and the study of the Japanese population's genetic characteristics. Whether or not use of the data from the Millennium project will eventually extend to the development of new drugs, is a point for discussion. In the case of the JPMA database (one of the very few private databases), both the side effects resulting from the level of drug metabolising enzymes and the identification of target drugs will form the focus of the database assembly. The MHW suggested that the information collected as part of the Millennium projects might ultimately feed into drug development work, but that this was not the present focus. Others expressed doubts of extending the scope and suggested that the schemes were not drawn up in a way that would readily connect to drug discovery.

8.2  Constraints to development

  MHW considers ethical issues to be amongst the main constraints to development. Historically, discussion of hereditary diseases has been shunned by Japanese society. The prospect of compiling databases containing information of this type is therefore anathema to many Japanese.

  8.3  Consciousness of the potential effects that information on hereditary disorders might have on prospects for employment, marriage and insurance, is likely to dissuade many prospective donors from giving consent. To address this, MHW is currently working on how to best protect private information and how to legislate in support of this.

  8.4  Integration of research across the responsibilities of the Japanese Ministries is not fully developed. In circumstances where hospitals are likely to have insufficient patients for a satisfactory association study and study methods between researchers varies considerably, useful comparisons of research data will be difficult to make.

  8.5  The ability to fund consolidation of medical infrastructures, to provide genetic counselling and to meet the stringent standards of informed consent will require considerable additional funds. Providing the funds may produce strain on budgets.