Archive of Analytical Instruments that Unravel Life：Part 4 Capillary DNA sequencer

Archive of Analytical Instruments that Unravel Life

Part 4
Capillary DNA Sequencers

ABI, which held a leading position in the global DNA sequencing market, recognized the potential of a Japanese technology that applied capillary tubes to electrophoresis, enabling high-throughput analysis of multiple samples. At the time, ABI’s own development efforts were focused on capillary gel array systems, in which grooves were formed in slab gels to perform electrophoretic separation.

The original concept of DNA sequencing based on capillary electrophoresis was developed by Dr. Hideki Kambara of Hitachi, Ltd. The technology was further strengthened by the four-color fluorescence detection method developed by Prof. Yuzuru Fushimi, then at Saitama University. This innovation made simultaneous detection of the four DNA bases possible and became one of the essential technologies for automated DNA sequencing.

Prof. Fushimi filed a patent application for the four-color fluorescence method on April 9, 1983, preceding similar applications in the United States. However, Japan’s Science and Technology Agency questioned whether a technology developed with government funding should be patented. As a result, the application was suspended and ultimately withdrawn in January 1984 before it was ever published. Looking back, this remains one of the most regrettable episodes in the history of Japanese life science innovation.

Glass capillary tubes were used for electrophoresis, but because laser excitation was required for fluorescence detection, the glass itself interfered with sensitivity by refracting the laser beam. Consequently, obtaining sufficiently high detection sensitivity proved extremely difficult.

Dr. Kambara had already demonstrated a highly sensitive detection method by irradiating slab gels from the side with a laser. Building on this experience, he combined specially designed capillary tubes with a side-illumination laser system known as the sheath-flow method. In addition, he developed a technique that allowed the separated DNA fragments to be irradiated immediately after leaving the capillary, before diffusion could occur, thereby achieving dramatically improved detection sensitivity. This became one of the key technologies developed by the Japanese research team.

At that time, ABI’s development team had already envisioned combining capillary electrophoresis with four-color fluorescence detection. However, they had not yet found a practical solution for achieving the required level of sensitivity. Dr. Kambara’s sheath-flow cell technology, utilizing direct side laser irradiation, therefore represented an extremely attractive breakthrough for the company.

Michael Hunkapiller, one of the founders of ABI, quickly approached Hitachi with a proposal to introduce this technology. The two companies agreed to establish a strategic alliance for joint development. This collaboration rapidly accelerated advances in DNA sequencing technology and played a significant role in the progress of large-scale genome analysis, including the Human Genome Project.

In the late 1990s, as the International Human Genome Project was gathering momentum, ABI and Hitachi jointly developed the Model 3700 DNA Sequencer, which offered high-throughput processing of multiple samples. Released in 1998, the instrument sold in remarkable numbers.

By that time, ABI had been acquired by PerkinElmer and, following a corporate restructuring, had become PE Biosystems. Dr. Craig Venter, who had left the publicly funded U.S. Human Genome Project, established Celera Genomics as a venture company under PE Biosystems. Celera devised an extraordinary plan: to operate 500 Model 3700 DNA Sequencers and complete the sequencing of the human genome ahead of the international public-sector project.

As described in the previous section, the cooperation of Dr. Kambara of Hitachi was indispensable to the technological development of ABI’s Model 3700 DNA Sequencer. Much of the development and manufacturing of the instrument was carried out at Hitachi’s Naka Works. The same was true of the Model 3730 DNA Sequencer, commercialized in 2002 under the product name PRISM 3730 DNA Analyzer.

In fact, these instruments carried both the ABI—or PE Biosystems—logo and the Hitachi logo. I sometimes wonder how many life science researchers were aware of this fact.

Before the completion of the draft human genome sequence was announced in 2001—the complete sequencing of the human genome was declared in 2003—I had several opportunities to visit Celera Genomics.

Dr. Craig Venter would often arrive at the company wearing shorts and flip-flops, accompanied by two Labrador retrievers. Next to the laboratory containing 500 Model 3700 DNA Sequencers was an operations room that looked like the control room of a spacecraft. Outside stood an uninterruptible power supply system as large as a convoy truck of the kind used to cross the American continent.

I was also involved in inviting Dr. Venter of Celera Genomics to Japan for the first time, where he delivered a lecture at Yasuda Auditorium of the University of Tokyo. I still remember seeing him sitting beside the fountain outside the auditorium, dressed in a suit and an unfamiliar tie, looking somewhat uncomfortable as he studied a notebook.

PROFILE

Hisashi Iwase

Advisor for Life Science Innovation, Japan Analytical Instruments Manufacturers’ Association (JAIMA),
and President & CEO of BioDiscovery, Inc.
Born in Tokyo in 1951. Graduated from the Department of Industrial Chemistry,
College of Science and Technology, Nihon University.
He has extensive experience in the management and marketing of analytical and bioscience instruments
at Merck Japan, Waters Japan, Nippon Millipore, PerSeptive Biosystems,
Applied Biosystems, Varian Technologies, and Agilent Technologies.
He founded BioDiscovery, Inc. in 2001.
Since 2013, he has also served as Advisor for Life Science Innovation at JAIMA.

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