There is little doubt that Japan has missed the genomics revolution, but there seems to be a widespread belief among Japanese scientists and industrialists that the country is in a much better position to capitalize on structural genomics. The Japanese government has made large increases in funding for structural genomics explicitly to help the Japanese pharmaceutical industry enter the post-genomics age.

But industry spokespeople say that it is not yet clear to many companies how they will benefit from the new efforts. Future success in applying structural genomics and high-throughput structure-determination technologies to drug development will depend on cooperation between the public sector, specialized biotechnology or software companies and the pharmaceutical industry.

Online success: Japan's SPring-8 synchrotron facility has attracted unprecedented interest. Credit: RIKEN

Research on protein-structure determination is rapidly emerging as a major priority in post-genomics research in Japan. The organizers of an industry consortium to build and operate a beamline dedicated to protein-structure determination at Japan's SPring-8 synchrotron radiation facility were amazed earlier this year when 21 companies joined. Toshikazu Miyagishima, manager of the healthcare information division at Tanabe Seiyaku and chair of the Japan Pharmaceutical Manufacturers Association's R&D committee, says he expected fewer than a dozen.

The unexpectedly large number of participants illustrates the rapid surge of interest in structural genomics and protein-structure determination in the Japanese pharmaceutical industry, says Miyagishima. The new beamline will provide companies with access to some of the most advanced instrumentation for structural genomics presently available.

Web links

SPring-8 → http://www.spring8.or.jp

RIKEN → http://www.riken.go.jp

Japan Biological Informatics Consortium → http://www.jbic.or.jp

TARGET IDENTIFICATION

Most companies in Japan say they plan to use high-throughput structure-determination methods to investigate favourite drug targets, and only a few companies say they will attempt to investigate new targets, which is a much more demanding task. This seems to confirm the observation, made by many industry analysts, that only a handful of pharmaceutical companies in Japan can support full-scale drug-development programmes based on structural genomics.

Shape of things to come: structural genomics is a major focus at RIKEN's Genomic Sciences Center. Credit: RIKEN

Structural genomics tends to be seen as just another tool to add to most companies' existing repertoire of research techniques, rather than a fundamentally new approach. In particular, smaller pharmaceutical companies will use structural-genomics tools initially to narrow down the number of leads, to refine lead compounds already under development, or to re-evaluate compounds that had dropped out at a late stage of the drug-development process. But several pharmaceutical companies are cooperating with RIKEN, the Japanese Institute of Physical and Chemical Research, in an international effort to determine 3,000 new protein structures.

Although industry remains sceptical about large-scale efforts to determine thousands of new protein structures, structural genomics has rapidly emerged over the past two years as a major recipient of funding in the life sciences and biotechnology in Japan. Structural genomics is a major research focus at the RIKEN Genomic Sciences Center (GSC), Japan's foremost genomics research centre, and the Japan Biological Information Research Center (JBIRC), a new centre for structural genomics funded by the Ministry of Economy, Trade and Industry (METI), which opened its doors in April.

The structural-genomics initiative at RIKEN consists of two large projects — the structurome project and the protein-fold project. Both efforts are funded at around US$5 million to $7 million per year over several years, with additional funding provided for instruments and facilities. The structurome project, located at RIKEN's Nishi-Harima Research Center, is an effort to determine the structure of all proteins of the extremophile bacterium Thermus thermophilus. Although the structurome project will mainly use X-ray crystallography for structure determination, the protein-fold project at the GSC has been intimately linked since its inception to GSC's large new nuclear magnetic resonance facility. Research activities under the protein-fold project will focus on structure determination of mouse and plant proteins, using complementary DNA libraries developed by scientists at the GSC.

INFORMATION INITIATIVES

Research at the JBIRC will focus mostly on human transmembrane proteins, which are not typically a focus of structural-genomics projects — membrane proteins are difficult to obtain in sufficient quantities and do not crystallize easily. At its completion, the JBIRC expects to host some 100 full-time researchers in three divisions, specializing in structural genomics, functional genomics and bioinformatics. An overall budget of ¥3.5 billion (US$32 million) per year for a seven-year period was approved by METI. But although the JBIRC is part of METI's National Institute for Advanced Industrial Science and Technology, most of the funding comes from the New Energy and Industrial Technology Development Organization, a METI funding body. As a result, only some 20 of the positions available at the JBIRC confer government official status, and for the remaining positions only temporary contracts will be available.

To aid interactions with industry, management of the JBIRC has been entrusted to the Japan Biological Informatics Consortium (JBiC), an industry organization with some 83 corporate members from the life sciences and information-technology industries. Although the JBIRC plans to hire new staff over the next few months, some of the positions available will also be filled by scientists from JBiC member companies or universities. But filling the new positions is likely to take more time than initially expected — for the centre's director, Yoshimasa Kyogoku, this is an unusual situation. “At the university we used to have a large number of students. Here we have plenty of funding, but as yet only limited staff,” he says.

One of the goals behind setting up the JBiC was to jump-start an indigenous bioinformatics industry. But even today the Japanese market for computational tools or databases in structural genomics remains dominated by US and European companies, although several start-up companies in Japan — including PharmaDesign and Protein Express — now offer software products and services for structure prediction, structure databases or rational drug design. Large information-technology companies, such as NEC, have also announced their intention to accelerate the development of high-performance systems and software tools for knowledge-based protein-structure prediction or molecular-dynamics simulations for drug-development applications such as the 'virtual screening' of compounds.

Larger pharmaceutical companies such as Yamanouchi and Eisai say that they plan to increase investment in genomics and post-genomics research significantly over the next few years — and research on protein structure is rapidly emerging as a major focus at many companies. Other companies are also gearing up activities in protein engineering, structural genomics and proteomics.

Even outsiders such as the consumer electronics company Sanyo and the automotive company Honda have started to hire scientists with a background in biotechnology, genomics or protein engineering.

Specialized recruiters say employment opportunities for scientists with a background in protein expression, structure determination, protein bioinformatics or rational drug design are likely to increase over the next few years, but that this may not always mean permanent employment. In trying to catch up in the genomics field, many pharmaceutical companies in Japan have started to hire more mid-career scientists or have contracted specialized staff through temporary employment or staff-outsourcing agencies, such as Hitec. And, especially in Japan, temporary employment is still considered second-rate.