At the end of the 20th century, science and technology made immeasurable strides in the field of life sciences. The declaration of the completion of the Human Genome Project was hailed as a monumental achievement for humanity, comparable to the moon landing during the space program. Over the course of the 20th century, we battled numerous diseases, contributing to advancements in medicine and the development of drugs such as antibiotics.
However, the environmental changes brought about by the evolution of civilization have created even more intractable diseases. Humanity now lives in a world far removed from nature, one largely crafted by the constructs of civilization.
Understanding the genome is vital for advancing drug development aimed at treating these diseases and conditions. While this holds significant importance, modern life sciences have also uncovered another critical challenge: understanding mechanisms that prevent disease. Analysis of cellular mechanisms through studies on gene expression and protein functions has implications not only for the life sciences surrounding the human body but also for industries such as food production, agriculture, forestry, livestock, marine science, and environmental preservation. Today, the global biotechnology market is united in its effort to employ scientific tools to create new industries.
Now, 24 years into the 21st century, cellular and tissue sciences are evolving toward unraveling signaling pathways and advancing regenerative medicine. True regenerative medicine is the science of understanding the body’s self-repair mechanisms, bridging medicine and health in entirely new ways. Another area of significant development lies in the information revolution that has become a part of our daily lives.
The IT revolution brought us mobile phones and accelerated the field of bioinformatics, where biological simulations are conducted on computers. Today, we are witnessing the emergence of IoT (Internet of Things) and further infrastructure revolutions. These advancements are poised to evolve into medical sciences dedicated to maintaining health and are undoubtedly contributing to a sense of a “smaller” planet as human connectivity grows each year.
However, there are still countless unknowns, including phenomena such as human energy, sleep, thoughts, and emotions. The terms “analog” and “digital,” born in the 20th century, remind us that to thrive in the 21st century, we must re-evaluate the balance between these two realms. By doing so, we can strive to use science to create a more hospitable and sustainable Earth for future generations.
Departure from Classical Biotechnology
Looking back at Japan’s bioindustry, the nation has long been a land of rice, miso, soy sauce, and sake, with fermentation technologies leading the way in maintaining the unique characteristics and traditions of its food culture. Japan’s classical biotechnology involves a historical legacy of utilizing microorganisms to develop food products. Notably, after World War II, the first global industrial success using a bioreactor was achieved by Nitto Chemical (now Mitsubishi Rayon) with its process engineering for microbial production of acrylonitrile. However, as plant biotechnology advanced and genetic recombination technologies evolved, Japan left its citizens with a lingering sense of “danger” regarding genetic modification. This period, marked by public apprehension, hindered the full appreciation of the importance of biosciences compared to the rest of the world.
In the recent post-genomic era, protein technologies have become indispensable. The know-how to leverage traditional protein technologies derived from fermentation with cutting-edge technologies is essential. Building upon Japan’s historically advanced analytical and measurement technologies and the craftsmanship inherent in its industries, the nation is poised to create new markets for advanced bio-related instruments. This era will contribute not only to cutting-edge medical applications but also to preemptive health science—a field focused on maintaining health before illness occurs. Furthermore, advancements in food science and sports science will lead to significant innovations in health science, fostering global alliances between domestic companies and researchers, ultimately positioning Japan as a leader in the field.
However, this classical biotechnology powerhouse found itself lagging behind Western industry-academia collaborations following the national project to develop human genome decoding methods in the 1980s. This divergence marked a turning point, leaving Japan significantly distanced from the ambitious plans of Europe and the United States.
The Era of Exploring Biomolecular Mechanisms
In the summer of 1987, I traveled to the outskirts of Boston for training on a DNA synthesizer. At the time, Millipore Corporation, where I worked, was expanding its business by acquiring Waters Corporation. Shortly thereafter, it entered the biosciences market by acquiring several small venture companies and forming the in-house venture called the Milligen Division. The first product released by this division was a DNA synthesizer. At the time, there were about three domestic and five international companies developing DNA synthesizers, and Millipore entered the market as a latecomer.
The laboratory adjacent to Millipore’s headquarters in Bedford, Massachusetts, left a vivid impression on me as a dreamlike space entirely different from the atmosphere of Japanese companies. In the lab, the DNA synthesizer was the size of a refrigerator, operated by an Apple II computer with a green screen, and the computer even “spoke” the letters A, C, G, and T. Dr. Alex Bonner, the development manager at the time, explained, “We’ve lent a demo unit to MIT, where it’s collecting data. There are many Japanese researchers there; let me introduce you,” and kindly escorted me.

This led me to the laboratory of Nobel Prize laureate Susumu Tonegawa, where I had the privilege of learning the mechanism of solid-phase DNA synthesis from Dr. Yotaro Takagaki, one of the professor’s key associates. At the time, methods were being developed to synthesize DNA monomers sequentially on a modified solid-phase substrate, which was also being adapted for peptide synthesis and protein sequencing. Solid-phase methods had the advantage of being easily automated, driving intense competition among companies to develop surface chemistry modifications and reaction protocols. The transition from phosphotriester methods to methoxyamidite methods, and later to the beta-cyanoethyl amidite method, marked a significant evolution. Patent disputes, such as those involving the Koster patent from the University of Hamburg and the foundational Caruthers patent in the US, were hot topics during this pioneering era of bio-tools.
Back then, a single cycle of DNA synthesis took 17 minutes, and contract synthesis costs were as high as 5,000 yen per coupling. These were still considered groundbreaking advancements. Today, with synthesis costs dropping to well below 100 yen per coupling, it highlights the rapid progress in the field. In peptide synthesis, the industry was shifting from the hazardous tBOC batch solid-phase method, which used hydrogen fluoride, to the milder Fmoc column solid-phase method. Advances in HPLC column separation technology also paralleled developments in solid-phase synthesis, accelerating biotechnology with similar principles of precision separation and reaction management.
Initially, protein sequencers used solid-phase immobilization of peptide fragments obtained from enzymatic protein digestion to determine amino acid sequences via Edman degradation. However, the need for higher sensitivity posed challenges in impurity removal. This led to innovations using gas-phase reagents for N-terminal Edman degradation, which spurred the creation of automated systems. Dr. Mike Hunkapiller and his team at Applied Biosystems (now part of Thermo Fisher Scientific) pioneered gas-phase protein sequencers, dominating the market and rendering liquid-phase systems obsolete within a year.
Reflecting on those days, I believe American companies genuinely strived to understand the real needs of their users (researchers) and designed equipment to meet those needs. In contrast, Japanese companies often prioritized hardware development as analytical instrument manufacturers, without fully aligning with the application-oriented needs of users. This approach, particularly in the biosciences market, remains a visible aspect of Japanese corporate culture and technical development even today.
Japan’s Genetic Analysis Projects
The invention of the Polymerase Chain Reaction (PCR) method in the late 1980s revolutionized DNA science. One of the most significant advancements was the development of DNA sequencers, devices designed to read DNA base sequences. By amplifying DNA fragments, even minute samples could be increased in quantity using PCR. Initially, DNA sequencers relied on the Maxam-Gilbert chemical method developed in the late 1970s. However, the introduction of the Sanger method, a dideoxy sequencing technique using enzymes, coupled with the emergence of PCR, catalyzed groundbreaking innovations.
These methods were also being developed in Japan. In the 1980s, HAYASHIBARA Biochemical Laboratories hosted the world’s first Genome Science Forum in Japan. In 1987, Professor Akimitsu Wada, then Dean of the Faculty of Science at the University of Tokyo, published a paper in Nature, stating:
“Just as nations compete to build large telescopes, the 21st century will see countries constructing genome centers as symbols of their power and knowledge.”
This paper, written three years before the US formally embarked on its Human Genome Project, highlighted the labor-intensive, manual nature of genetic decoding at the time.
Professor Wada foresaw a future where centers equipped with automated decoding devices would unlock the secrets of life. However, despite leading a world-first development project for such devices, Japan lacked the infrastructure to capitalize on its innovations, and no patents were secured. As Wada later reflected, “Only the US and UK reacted to our work. Now, the US leads the world in this field,” underscoring the critical importance of foresight.
DNA sequencers utilizing the Sanger method began to integrate multi-channel capillary electrophoresis, significantly enhancing detection capabilities. Innovations like horizontal laser detection, stemming from Japanese university inventions and Hitachi’s engineering, drove product development. During this time, the Ministry of International Trade and Industry (MITI) spearheaded a collaborative industry-academia initiative, involving private companies such as Hitachi, Seiko Electronics, Fujifilm, Mitsui Information Development, and Tosoh Corporation, to develop human genetic analysis techniques. This ambitious project focused on automating the Maxam-Gilbert method, attracting international attention. Japanese advancements included high-capacity gel electrophoresis plates, film-based gel materials, and robotics for automation. However, with the advent of the Sanger method, these five years of development ultimately succumbed to overseas competition.
Notably, many components and substrates incorporated into these automated devices were of Japanese origin. Yet, the final product brands were “Made in the USA.” The development of DNA sequencers with capillary electrophoresis advanced rapidly in the US. Applied Biosystems (ABI) later partnered with Hitachi, outsourcing manufacturing to the Japanese company. The resulting co-branded DNA sequencers dominated the market, yet few consumers were aware of this collaboration. As a result, the narrative that “the US triumphed in biotech while Japan fell behind” became widespread.

In the late 1990s, as a board member of the NPO Genome Bay Tokyo Council, I attended an industry-academia-government conference. During the meeting, a government official expressed skepticism: “Even if we allocate a budget, won’t it just be used to purchase US-made products again?” To my astonishment, no one challenged this statement. I promptly responded, “What exactly do you mean by that? What are you referring to? Do you know that more than half of the components inside these devices are Japanese-made?” My remarks were met with silence, and the meeting ended without further discussion. This incident revealed the limited understanding of Japan’s upper echelons regarding the nation’s contributions to biotechnology.
(To be continued…)

Mr. Hisashi Iwase
Life Science Innovation Advisor at the Japan Analytical Instruments Manufacturers’ Association (JAIMA),
and President & CEO of BioDiscovery Inc. Born in 1951, Tokyo.
Graduated from the Department of Industrial Chemistry, College of Science and Technology, Nihon University.
Mr. Iwase’s extensive career in managing and marketing analytical and bioscience instruments includes
positions at Merck Japan, Waters Japan, Millipore Japan, PerSeptive Biosystems Japan, Applied Biosystems,
Varian Technologies, and Agilent Technologies. In 2001, he established BioDiscovery Inc., and since 2013,
he has served as a Life Science Innovation Advisor for JAIMA.