Japanese biotechnology R&D is carried out by government research institutes, universities, joint government­private industry research institutes, a few private research institutes, and by private companies. The latter could be considered as the motor of Japanese biotechnology, since they finance the bulk of the total biotechnology R&D in Japan, and carry out most government­initiated R&D in­house, using company staff and resources. Nevertheless, the Japanese government plays an important supportive role.

A survey of industry, university and government officials held at a forum organized by the Japan Bioindustry Association (JBA) in 1993, showed that Japan's strength in biotechnology was considered to be in the detection and separation of micro­organisms, fermentation technology, bioreactors, and the biotechnology applications in electronics, such as biosensors. In the other biotechnological fields Japan was judged to be behind the USA and Europe. According to the forum, the Japanese government should spend more on basic and original R&D. This recommendation supported the trend within the government to shift its emphasis from applied to basic research, a reorientation that started in the late 1980s. More original R&D should be achieved by granting more freedom to researchers at universities and institutes usually heavily controlled by the Ministry of Education, Science and Culture (MESC). Since 1993, some national research institutes have been transformed into "Centres of Excellence" and more institutes will follow. Their new status includes more freedom in decisions regarding staff and research programmes.

Involved ministries
The main ministries in Japan which are involved in R&D promotion and the development of the biotechnology market are the Ministries of International Trade and Industry (MITI), Agriculture, Forestry and Fisheries (MAFF), Education, Science and Culture (MESC), Health and Welfare (MHW) and the Science and Technology Agency (STA). The activities of the ministries are rather autonomous, and cannot be seen as being part of a centrally co­ordinated master plan for the development of biotechnology. STA was established to co­ordinate science and technology development, but lacks sufficient political authority to prevent each ministry from working quite independently.
The total government budget in 1993 was estimated at US$ 1.14 billion, of which MHW alone was responsible for US$ 0.52 billion. The budget for 1995 is planned at US$ 1.8 billion (see table). Of the five ministries, MITI's influence is the largest in spite of having the smallest biotechnology­related budget. This is mainly because of its close relationship with industry. MITI is most enthusiastic about the development of biotechnology, while MESC, MAFF and MHW have a more conservative attitude. MAFF and MHW are closely involved in the safety regulation of biotechnology application in food and plant breeding (see the other article by Commandeur).
MAFF has its own research projects on rice genome, biotechnological procedures for plant breeding, efficient methods for animal genome analysis and utilization of imported genes, and functional products on the base of modified carbohydrates. MAFF controls the Bio­oriented Technology Research Advancement Institution (BRAIN). BRAIN was established in 1986 in order to promote biotechnology­oriented research carried out by the private sector through subsidies, loans, diffusing research information, and making genetic resources stored in the MAFF gene bank available to the private sector.

Biotechnology related budget by ministry (US$ million)    1993 1995* Ministry of International Trade and Industry (MITI) 86.8 100.3 Ministry of Agriculture, Forestry and Fisheries (MAFF) 98.0 115.0 Ministry of Health and Welfare (MHW)  516.7  682.0 Ministry of Education, Science and Culture (MESC)  201.0 598.0 Science and Technology Agency (STA)  243.8 305.0 *Planned budget for 1995 will be passed in Japanese Congress in March 1995.  Sources: Brian Eisenburger and Tokuo Yoshida (1994), Japanese Biotechnology in the Nineties. Tokyo: Royal Netherlands Embassy, pp. 51-52; Mitsuru Miyata, Editor of Nikkei Biotechnology, Tokyo, Japan.

Industry associations
An important feature in the relationship between ministries and private industry in Japan is the existence of a large number of industry associations. These associations act as intermediaries between industry and ministries, apart from stimulating mutual support between their members. The good relationship between these associations and ministries is illustrated by the many 'second careers' that are given to governmental bureaucrats in these associations.
The most important example of these government/private industry links in the field of biotechnology is the Japan Bioindustry Association (JBA). This association is closely linked with MITI and organizes around 190 companies. JBA disseminates information on biotechnology developments (in English in its Japan Bioindustry Letters), and is active in the field of increasing public awareness and consumer acceptance of biotechnology, organizing trade fairs, scientific symposia, and discussions between its members on regulatory issues. It also recommends research priorities for government support to MITI. MHW has a strong relationship with the Japan Health Sciences Foundation (JHSF, including 154 companies), while MAFF works closely with the Society for Techno­Innovation of Agriculture, Forestry and Fisheries (STAFF, including 159 companies).
Besides these "intermediary" associations, a number of organizations for collective research among companies exists. These organizations are used by MITI as vehicles for the implementation of its R&D programmes. The Research Association for Biotechnology, for example, currently participates in several MITI programmes.

Third sector initiatives
Especially local governments use public­private partnerships in research to stimulate the development in their region. Such a so­called 'third sector' activity invites companies to send researchers and to share the available research equipment. These institutes are generally well­funded, and excellently equipped. This approach has resulted in several regional biotechnology research parks. Most of the R&D in biotechnology, however, is concentrated in Tokyo and in Tsukuba, a relatively recent centre for natural sciences located 100 km from Tokyo.
The Protein Engineering Research Institute (PERI) is a "third sector" project of MITI and several private companies. PERI develops basic technologies by studying model proteins. This enables companies to design their own proteins for pharmaceutical and specialty chemicals development. PERI also files patents, for instance regarding thermostability of proteins, and licenses the results.
Osaka Bioscience Institute (OBI) aims to support Osaka's pharmaceutical and food industry. It is funded by the Osaka prefectural government (20 per cent) and 63 Japanese and foreign companies. 40 Institute researchers and 40 researchers from companies are working on molecular biology, enzymes and metabolisms, neuroscience and cell biology.
The Marine Biotechnology Institute (MBI) is an initiative of MITI, local governments and private companies. MBI carries out a significant part of MITI's 8 year US$ 146 million project on fine chemicals from marine organisms. Screening micro­organisms from the ocean is expected to become a important research area in Japan.
The Research Institute of Innovative Technology for the Earth (RITE) is situated in Kansai Science City, affiliated to MITI but mainly funded by private industry. Much of its research is related to Japan's vulnerable position due to its dependence on imported energy, especially oil from the Middle East. Hydrogen might become an alternative fuel, while successful results in atmospheric carbon dioxide fixation in dry areas might be of interest for Persian Gulf countries. Its research includes bioreactors for biochemical production, biological production of hydrogen, biodegradable plastics, and biological CO₂ fixation and utilization, including biological CO₂ fixation in desert areas. Although the basic research might increase knowledge off molecular mechanisms of drought resistance of plants, and off possibilities to genetically increase CO₂ absorption of plants, it is generally doubted whether the ultimate goal of greening deserts is a realistic one.
 

Biotechnology in agricultural research in Japan In Japan, tissue culture is applied in about 150 facilities of propagation of crop seedlings and in plant breeding. New varieties of rice, potatoes, vegetables and fruit trees are developed with the use of embryo culture, anther culture and somaclonal variation. A new fruit, bred between orange (Citrus sinensis) and karatachi (Citrus trifoliata) has been developed by the use of cell fusion. Varieties of tobacco and hiratake (mushroom variety), developed by cell fusion, are cultivated. More than 40 transgenic plants have been developed, half of which are undergoing biosafety tests. These varieties include virus-resistant rice, petunia, tomato, melon, tobacco and potato, low protein rice, low allergen rice, and delayed ripening tomato. In 1992, about 9000 calves were born through embryo transfer. 1000 Calves were born through in vitro fertilization in 1992, while successful experiments of producing clone calves through nuclear transplantation were reported in 1993. Japanese genetic engineering of animals focuses on the development of model animals for pharmaceutical industry, such as the onco-mouse. Life vaccine of swine Aujeszky disease virus developed by means of genetic engineering, and cat interferon produced by silkworm are applied to practical use in Japan. R&D on a rDNA vaccine against cattle leukaemia is in progress. Cell fusion has been applied for the development of rice mold (koji) and yeast for the production of the Japanese spirit (shochu), rice wine (sake) and bread. Fixed enzymes and micro-organisms produce high fructose syrup, cyclo-dextrin (CD) and erythritol in bioreactors.

University R&D
National universities receive almost all of their research funds from MESC. Due to low funding levels, however, their facilities are generally poor compared to US and European universities. In private universities the financial situation is usually even worse. Direct financial contributions by private industry to universities are of limited importance, representing only around 3 per cent of university research budgets. About 80 per cent of these contributions are given as donations without formal contracts. Officially, patents filed by universities relating to research wholly or partly financed by MESC cannot be transferred to companies. However, in general, patents resulting from co­operative R&D, end up with companies through a system of case by case negotiations.
The Tokyo Institute of Technology is the only Japanese university with a separate faculty of biosciences and biotechnology. Its main interest is in the field of thermo­stable micro­organisms. Enzymes in these micro­organisms are expected to have many industrial applications.

Research institutes and organizations
The Japan Research Development Corporation (JRDC) is an organization which operates under the responsibility of STA. It has a special programme on exploratory research (ERATO) and started a system of International Joint Research Projects in 1989. These projects are financed on a 50­50 per cent basis by Japan and a foreign partner country. Some examples of biotechnology projects developed by JRDC are the production of interferon by means of human tissue culture, production of rDNA hepatitis­B vaccine, and a radio frequency hyperthermia system for cancer treatment. In 1991, the Precursor Research for Embryonic Science and Technology (PRESTO) started, which will support innovative individual scientists with research grants of US$ 190,000 per year for a three year period.
STA also supports the Institute of Physical and Chemical Research (RIKEN), one of the most respected research institutes in Japan. RIKEN's biotechnology­related research includes replication of cells and organelles, biodegradable polymers, biopolymers, oligosaccharides and cylo­dextrines. In genebanks in its Life Science Centre in Tsukuba, RIKEN maintains cultured cell lines, DNA clones and DNA libraries, to which researchers from elsewhere also have access. RIKEN also participates in the worldwide Human Genome Project. In the same Centre, at the Plant Molecular Biology Laboratory, gene structures and the regulation of gene expression are studied.
The National Institute of Biosciences and Human­Technology (NIBH) was established from three other MITI laboratories, including the Fermentation Research Institute. The NIBH participates in MITI projects on fine chemicals from marine organisms, energy conversion by photosynthetic micro­organisms, and molecular assemblies of proteins. The institute has a collection of patented micro­organisms. Another project, with the status of "Leading (i.e. exploratory) Technology Research", is the Technology for Preservation and Utilization of Functions of Tropical Organisms project. This project aims at collecting, screening for useful functions or substances, and finally conserving unknown organisms from tropical areas, such as, for example, yeast and bacteria from rainforest soils.
An example of a private research institute is Sagami Chemical Research Centre, financed by contract research and patent fees (40 per cent of its budget). The major part of its research is in organic chemistry applied in pharmaceuticals, agrochemicals, etc. Research at its own financial risk includes marine bacteria producing ingredients for "functional food", and the enzyme used by the private company Tosoh for the production of aspartame (a sugar substitute).
Peter Commandeur

Sources
Large parts of this article are abstracted from: Brian Eisenburger and Tokuo Yoshida (1994), Japanese Biotechnology in the Nineties. Tokyo: Royal Netherlands Embassy.

Robert T. Yuan and Mark D. Dibner (1990), Japanese Biotechnology: A comprehensive study of government policy, R&D and industry. New York: Stockton Press.

Martin Fransman and Shoko Tanaka (1995), "Government, Globalisation, and Universities in Japanese Biotechnology". Research Policy, 24, pp. 13­49.

Dennis Normile (1994), "MITI Ecoprojects Target the Desert ­ And the Home Front". Science, vol.266, 18 November, p. 1188.