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Collaborations Cooked Up By Hot Tub

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Japan’s Institute for Advanced Biosciences is stepping out of the box in its approach to metabolomics as well as campus design

By Sara Harris

 

“The most important thing in science is thinking,” says Masaru Tomita, director of Keio University’s Institute for Advanced Biosciences. Good science, he says, will arise from an “environment where you can think well.” If that’s true, then researchers at the IAB, 135 kilometers north of Tokyo, should excel. Intentionally situated near the beach in an area famous for its mountains and hot springs, IAB, which serves as a second campus for the university’s year-old bioinformatics graduate degree program, even has a built-in Jacuzzi bath for its thinkers.

Far from Tokyo’s madding crowds, IAB is breaking new ground in its approach to research as well. It has brought about an unusual pairing of public and private university scientists. And it is unique in Japan for establishing a lab dedicated to metabolomics. The scientists there are fond of calling the institute an “academic venture.”

Academics with an eye toward commercialism is an increasing trend in Japan — the Japanese government has made public a goal of 1,000 new university spin-off companies in the next three years — but the 144-year-old Keio University is especially reputed for its entrepreneurial spirit. A recent survey of venture-minded practices at 357 universities nationwide identified 251 university spin-off venture companies, 26 of which got their start at Keio.

Collaborative Projects

At the IAB, an elite group of researchers from different disciplines and laboratories collaborate intensively, gathering about twice a month to share ideas and coordinate research. Each of five lead researchers does time at the institute’s Yamagata campus and at institutions in Kyoto, Kyushu, and elsewhere and they share a rotating schedule for student lectures.

“For some short but intense period we get together,” explains lead researcher Kazuyuki Shimizu, a biochemical systems engineering expert from Kyushu Institute of Technology. In addition to the bimonthly meetings, the researchers hold planning sessions that span several days at least once a year.

The scientists settled on this mode of collaboration after debating and rejecting full-time residency at the institute as well as Web-based conferencing. “This is very, very important, how the research is being done,” says Shimizu.

One of the institute’s major projects is a five-year, $15 million government-supported exploration of computer-aided design for industrial-use microorganisms. The project-by-project nature of their approach, Shimizu says, means the researchers aren’t necessarily taking their positions at the institute for granted. “If we could find another new, good topic, then we could continue,” he says. For now, though, they are scheduling their work to fit the grant’s five-year timeline.

Much of the project’s progress depends on how precisely and how fast the metabolics team can provide quantitative data of metabolite concentrations and show how, and under what circumstances, different pathways are activated.

Team Metabolome

Shimizu and Takaaki Nishioka, an analytical chemist from Kyoto University and one of the creators of the LIGAND database of enzyme reactions, lead the metabolomics unit. Their team of fewer than 10 is continually refining its methods to narrow in on the goal.

Nishioka’s is partly a quest for speed and volume. Even after building a database that identified the number and kind of metabolites that operate in the cell, the amount of each metabolite remained elusive. He has spent the last two years developing a high-throughput-analysis technique to measure metabolite concentrations. Gas spectrometry and liquid chromatography are de rigueur in analytical chemistry, but they proved too inefficient or imprecise for his purposes.

So he turned to a technique unfamiliar to many of his fellow biochemists. “My idea is: use [capillary electrophoresis],” he says. “This is very suitable for the ionized soluble compounds — this is one reason. The second is very high, good separation — higher than GC or LC.”

It works like this: As the concentration of cells is sent through a capillary, it is subjected to high voltage, which separates the metabolites by molecular weight. The concentration of each metabolite is measured in the mass spectrometer, and the data recorded on a line graph. Each sample takes about 10 minutes to analyze. In an effort to optimize the system, Nishioka and his team have been running about 10 samples a day, although within two or three months he hopes to ramp up to a full-time high-throughput operation, filling orders from other labs as well. Nishioka’s team has measured more than 70 metabolites at IAB.

Single-cell Analysis

His is also, however, a quest for precision within ever-shrinking parameters. While his team is working toward measuring all of the major metabolites, the second goal is to develop techniques that are sensitive enough to analyze a single cell. Nishioka is currently working with researchers at private food companies and other universities to develop single-cell-detection methods, a goal he estimates can be attained in three to four years.

On the other side of the lab, Shimizu cultivates the raw material Nishioka feeds through his specially developed CE-MS measuring device.

Focusing mainly on E. coli, the team also works with yeast, Bacillus subtilis, cyanobacteria, propion bacteria, and other industrially important microorganisms, both wild and engineered varieties.

If Nishioka’s work aims to clarify the operative concentrations of metabolites within the cell, Shimizu’s task is to discover when a certain pathway kicks into action. His team has developed an isotope-labeling technique to trace metabolite activity under varying conditions. “In the organism there are many metabolic reactions taking place at the same time,” Shimizu explained. “So it’s very important to know, in vivo, how the carbon consumed is utilized for metabolic processes. That is the main task.” Researchers label carbon molecules, for example in glucose consumed by the cell, then cultivate the cells under a range of controlled conditions, disrupting them hourly to measure the distribution of metabolites.

They can then trace the isotope-labeled carbon molecules to specific pathways and metabolic products. These data are matched with protein expression data to confirm their findings. In cooperation with IAB’s genome engineering unit, the metabolomics group is generating data on a library of wild and knockout microorganisms in order to delineate the metabolic influence of each gene and to pinpoint the pathways that produce industrially useful metabolites. Their data also form the basis for the in silico cell models being developed in IAB’s third group, the bioinformatics unit.

Coming together across disciplines and institutions, the IAB researchers are breaking new ground. The metabolome unit is using a series of innovative techniques to clarify life’s workings at the most basic level. And together they are introducing a new research model — the academic venture — to an eager Japan.

 

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