Back to the beginning

E. K. BROWN/EPA/CORBIS

Over the past few decades, Osaka University immunologist Tadamitsu Kishimoto has pulled off what most would consider an extraordinary success in translational science. Throughout the 1970s and 1980s, he pieced together the function of interleukin-6 (IL-6), a key molecule for stimulating the immune response. The result was the IL-6-inhibiting drug tocilizumab, approved by the science ministry for treatment of Castleman's disease in 2005. Later, rheumatoid and juvenile idiopathic arthritis were added to the list of indications. Other countries have approved or are considering indications as well. And clinical trials focused on pancreatic cancer are expected to start this month in Japan. Analysts say it could reap US$2 billion per year in total profits as its indications expand. Already the drug has brought millions of dollars to Kishimoto, who owns most of the patents.

Unfortunately for Osaka and its research community, such success stories are rare. Despite the region's long-standing reputation as a locus for biomedical research, many of the companies that made Osaka famous in the late nineteenth century as a pharmaceutical base, such as Tanabe (now Mitsubishi Tanabe Pharma) and Takeda, have moved their main research laboratories to the Tokyo area. There, they can plug into the growing bioscience prowess of many universities and research centres in the area and forge closer connections with federal drug regulators and other key government agencies. Even the research wing of the company that developed tocilizumab, Chugai Pharmaceutical, is based in the Tokyo area. And many Western drug companies have stopped doing research in Japan, including Pfizer, GlaxoSmithKline and Novartis.

But Kishimoto, who is donating all his profits from tocilizumab to a Kishimoto Foundation that will support research at Osaka University, sees potential for the region and for new discoveries. "I want to support the immunological sciences in Osaka," he says, adding that the area's researchers could some day generate another discovery similar to his own.

Nor have other biomedical scientists and policy-makers lost faith in Osaka as a drug-manufacturing base. Programmes such as the government-led National Institute of Biomedical Innovation (NIBIO), set up in 2005, offer opportunities to bridge the gap between basic science and drug discovery. "The idea is that we will get some companies to move their research arms to Osaka, or at least get some biotechs starting up," says Koichi Yamanishi, director of NIBIO, which is based near Osaka University's campus.

The health ministry is investing an annual ¥13 billion (US$140 million) in NIBIO to carry out research in bioinformatics, proteomics and immunological regulatory mechanisms. Since 2008, it has been heading two 'super special consortia', large-scale collaborations among institutes throughout Japan. In one, the institute characterizes and standardizes dozens of induced pluripotent stem (iPS) cells that it hopes will become the foundation for national guidelines on the use of iPS cells for toxicological and clinical research. The other, headed by Yamanishi, aims to develop new adjuvants and novel vaccines against multiple infectious diseases.

NIBIO is also charged with amassing, distributing and ensuring the quality of other resources for clinical studies including cultured cells from patients, cynomolgus monkeys and mice. "These are things that neither universities nor industry want to do, and that's been part of the problem," says Yamanishi.

IFREC (above) is the latest stage in Osaka's biomedical history.OSAKA UNIVERSITY

NIBIO resources are shipped nationwide, so companies might not feel the need to rush to Osaka. But there are other reasons, according to the pharmaceutical company Shionogi, which was founded in Osaka in 1878. In 2007, the company set up a ¥5-million programme funding university researchers, starting with ten collaborations and adding five more in 2008. This March, it invested ¥400 million in a molecular imaging centre on the Osaka University campus. A collaboration with the university's graduate school of medicine, the centre will include cutting-edge positron emission tomography equipment with a self-shielded cyclotron, which produces radioactive isotopes that can be used for tracers within the body without the need for a thick vault to block extraneous radiation. Osaka University's expertise in imaging will make drug discovery more efficient and boost the success rate of clinical trials, says molecular biologist Tsuneaki Sakata, a deputy general manager at Shionogi's strategic planning division. Shionogi is, however, one of a few drug companies keeping its research in Osaka. The city's biomedical hopes increasingly ride on biotechnology.

Japan's most prominent biotech, AnGes, is at a crossroads. Founded by Ryuichi Morishita, a professor in the department of clinical gene therapy at Osaka University, AnGes has been developing a hepatocyte growth factor plasmid, Collategene, since 2001. This is intended to treat peripheral arterial disease, a narrowing of the arteries that increases the risk of heart attack and stroke. Observers have long kept an eye on AnGes as a leader in Japanese biotech. The moment of truth is near. The company has been awaiting the results of a regulatory review by the Japanese government of a drug application submitted for Collategene in March 2008. AnGes is now revising its phase III clinical trial application in the United States to meet demands for additional information from the US Food and Drug Administration.

Local government support could nurture successful new biotechs, says Morishita. Two years ago, the governor of the prefecture of Osaka established a biotech strategy team to find ways to support businesses in the region. So far progress has been slow, but the team has set up a US$10-million biotech venture fund.

Sosho, another biotech firm spun off from Osaka University, finds other advantages to operating in Osaka. It has succeeded in crystallizing some of the most difficult-to-crystallize proteins, and subcontracting this service is its core business. Recently its crystallization and analysis of a protein in HIV led to proposals of a possible catalytic mechanism for the virus and, potentially, new therapeutic targets (M. Adachi et al. Proc. Natl Acad. Sci. USA 106, 4641–4646; 2009).

Sosho's president, Hiroaki Adachi, values proximity to Spring-8, among the world's most powerful synchrotron light sources, in nearby Hyogo prefecture, where the crystallized proteins can be analysed. The area's entrepreneurial atmosphere is also useful, he finds. Sosho, for example, has linked up with Osaka-based PharmAxess, which carries out analysis of proteins, to create a one-stop service.

A pharmaceutical renaissance may seem a distant hope, given the disappearance of some research arms of some Japanese firms from Osaka and the exodus of Western drug companies from Japan. Still, biotechs and the basic research that underpins them could flourish (see 'Building a better research institute in Japan'). If Kishimoto gets his way, resident researchers might replicate his success. Or it could at least be a stepping stone along the way. "I want people to be able to say 'I did a postdoc at Osaka'," he says, "and have it be recognized around the world."

Building a better research institute in japan

Traditionally, Japan has had difficulty establishing cutting-edge, scientifically nimble institutions that attract international talent. Osaka University's Immunology Frontier Research Center (IFREC), founded in October 2007, could turn out to be a notable exception.

One of five World Premier Institutes selected by Japan's science ministry, IFREC opened its first building this August. It will receive another US$20 million from a stimulus package for a second building as well as US$10 million every year for operating expenses and salary. Already IFREC has enviable expertise. Institute director Shizuo Akira had been the most cited scientist in the world for two consecutive years for helping to unravel the complexities of the innate immune system (see Nature 450, 475–477; 2007). Other famous Japanese scientists on the roster include Tadamitsu Kishimoto and Shimon Sakaguchi, who has pioneered efforts to understand how an immune system restrains itself to prevent autoimmune disease and allergies.

But plenty of foreigners have joined as well. So far, about 40% of IFREC's postdocs come from outside the country — a figure almost unheard of in Japan. Only two of its 21 principal investigators are foreign, though. That's a far cry from the 30% Akira hopes for. "It's hard especially for those with families, so it's probably more attractive for young singles," he says, alluding to language and cultural adjustments. He notes that one married candidate had just dropped out at the last minute. Still, Akira refuses to lower the bar. "A lot of others, we can tell, just failed in the United States, so they thought they would try here. We reject them right away."

Akira has started a junior principal investigator programme to recruit young scholars who can take independent positions. The institute offers salaries in the ¥8-million (US$87,000) range and guarantees three years of research funds, enough to cover a postdoc and a technician, so that researchers do not have to worry about grant applications. The centre also has the ability to adjust salaries, a rarity in Japan. It took a large chunk of IFREC's budget to land Sakaguchi, who brought his whole team with him.

Those IFREC seeks are scientists with backgrounds in imaging, bioinformatics and systems biology. Akira says these skills could enable one to see the entire immune response rather than just the fragmentary pieces perceived in most studies to date. IFREC's Masaru Ishii, for example, is developing a two-photon microscopy system that can image living tissue up to depths of 2 millimetres, to look at bone homeostasis. "We want people who can discover things that have never been thought of before, not just confirm," Akira says.

D.C.