Takehiko Kitamori Professor, Department of Applied Chemistry, School of Engineering, The University of Tokyo, Japan Project Leader, Micro Chemistry Lab, Kanagawa Academy of Science and Technology, Japan (2024)

I live deep in the centre of Tokyo with my precious wife Hatsumi. Our university is located in the same town, Hongo, and my office is less than 17 min walk from the house, thus I walk to the office everyday. The place where we live is rather calm and green for Tokyo, but the house is very small as you may imagine. I moved here several years ago to survive the unbelievably busy life I lead. I stay in the office until midnight almost everyday. Some people envy our typical urban life in Tokyo, but we dream of living in the countryside with my family and hopefully a cat after getting over these terribly busy days. I try to spend at least the whole of Sunday with my wife to go shopping, to drive in the countryside, and to enjoy cooking or eating out. I believe I manage to achieve this rather well through significant efforts though the situation is far from ideal.

I was born in 1955 in Tokyo, and grew up with a younger sister in Saitama prefecture. The name of the town today is Toda City and it borders Tokyo. Whilst we were growing up we watched the rapid change from pastoral scenery into an industrial town. I don't remember when I began hoping to be a scientist, but I clearly remember the picture book biography of Madame Curie, and I wrote in a graduation yearbook at primary school that “my hope is to be a physicist” although I didn't know what a physicist actually was. I was devoted in tennis when I was a junior high school student. I was in rather delicate health until I took up tennis, but I ended up tough in both body and spirit in the process of winning second and third place in City Tournaments. I have been learning to play the piano since childhood, and was gradually immersed in music when I was a high school student. (Why can music move people?) Actually, I strongly desired to specialize in music at university, but my master told me “Even Herbert von Karajan learned in an institute of technology, and you must learn science at university because you are good at mathematics and physics”, so I did as she recommended in 1976. However, I continue to play the piano although it is very difficult for me to find the time now. I sometimes enjoy playing piano and violin duets with Professor Edward S. Yeung of Iowa State University who is a famous and active analytical chemist. A Japanese TV station has filmed our duet in a scientific program for the younger generation to introduce the life of scientists. I learned through music that complete mastery of basic and common skills and knowledge is indispensable producing unique or original ideas.

My major subject as an undergraduate at The University of Tokyo was physics. The main subject was to look for solid evidence of “one photon two electron excitation” by using high-energy photons from synchrotron radiation (SR). The SR facility of the day was very primitive, and the research staff and students were responsible for taking care of everything including the beam line, spectrometer, electronics, data processor, and even assembling the photomultiplier. This practical experience was invaluable for later work on instrumentation. I helped out at my father's garage in those days and had the opportunity to modify a tired old car into a low-budget rally machine. We enjoyed the mechanics as well as the sports driving. This hobby helped me to deal with mechanics and electrical engineering principles later.

After graduation, my career is quite unique for a professor. I didn't progress to graduate school, but went to work directly for Hitachi Ltd. in 1980. My research career was incubated in this company. A few years later during this Hitachi period, I changed my speciality from physics to chemistry, as described below. During a research collaboration, I moved from Hitachi to The University of Tokyo and became a Professor of Chemistry as a result. I did not even dream of teaching chemistry when I was a student and young scientist.

Hitachi period and Dr of Engineering work

Simulation and experiments for revealing the behaviour of radioactivity or charged particles in a nuclear power plant or fusion chamber was the first main theme in the Energy Research Laboratory of Hitachi Ltd. However, programming calculation codes based on complicated but well known equations of fluid dynamics didn't sustain my research curiosity and creativity for long, although nuclear technology and computational physics were the most popular technologies for young scientists a quarter century ago in Japan. I was therefore happy to accept a change of speciality when the lab was short of staff for analytical chemistry and was encouraging applicants. Thus I changed my research activities to focus on analytical chemistry.

The first job I held in the analytical section was water analysis from a nuclear power plant, and the main analyte was cobalt which is the main factor of radioactivity in nuclear power plants. I began with the ABC of wet analysis not guided by a textbook but by experience on the job. However, working with concentrations at the part-per-trillion (ppt) level, 1 mm/25 rounds of earth in other words, was still very difficult even after my long term apprenticeship at the discipline. Therefore, I proposed developing laser spectrometry to do the job to the director of the analytical laboratory. Fortunately, the proposal was adopted and I devoted my time to develop laser induced photoacoustic spectrometry for liquid samples, and eventually heavy metal ion analysis in water at sub-ppt level was achieved.1 Photoacoustic spectroscopy is one category of photothermal spectroscopy in which thermal phenomena induced by heat energy from non-radiation relaxation processes of molecules is utilized in highly sensitive measurements. The thermal lens microscope which is our original and most powerful research tool is also another category of photothermal spectroscopy. In the case of photoacoustic spectroscopy, the photothermal phenomenon is acoustic emission by thermal expansion of a sample irradiated by chopped laser light. And my PhD thesis of Dr of Engineering given by The University of Tokyo in 1988 is entitled “Basic Theory of Photoacoustic Spectroscopy for Liquid and Its Application to Analytical Chemistry and Spectroscopy.” I developed instrumentation and theory of photoacoustic spectroscopy2 which was inchoately applied to liquid phase, and applied to ultra sensitive analysis,1 immunoassay,3etc.4 Nano-particle nucleate laser breakdown was found in the process of studying photoacoustic signal generation from turbid solution by increasing the intensity of the excitation laser,5 and the finding opened spectroscopy6,7 and analysis8 using breakdown plasma. It goes without saying that those works formed the basis of the invention of the thermal lens microscope.

The University of Tokyo and KAST

My study of photoacoustic spectrometry proceeded through collaboration with Professor T. Sawada of The University of Tokyo. This joint research between the university and the company triggered my transfer to the university. The laboratory unit of Japanese universities is call a “Kohza”, the meaning of which is nearly same as professorship chair or cathedra, and Kohza has quite a unique and large construction. Typically, a Kohza possesses one full professor, one associate professor or lecturer, and two research associates who are almost same as assistant professors. I was invited to join the Department of Applied Chemistry of The University of Tokyo by Professor Sawada as research associate of his Kohza, and moved from Hitachi in 1989. I continued to study photothermal phenomena and their application to spectrometry, especially, to instrumentation for ultrasensitive and ultratrace analysis, and I was promoted to lecturer in 1990, to associate professor 1991, and to full professor in 1998. Therefore, I have had my own Kohza since then.

	Plate1 Research staff, post doctorates and students in Professor Kitamori’s groups at University of Tokyo, KAST and his Research Project groups.

During this period, serendipity and luck led me to develop the thermal lens microscope (TLM) which is our most powerful detector, and then the TLM later led us to microchip technology. One day in 1991, Mr Sakae (a technician of our department) and I picked up a very old optical microscope from the University Hospital. We used the microscope for developing laser microscopic analysis based on a new idea for photothermal phenomenon for microparticles.9 When we applied this method to liquid samples we were surprised to find that the method was quite sensitive.10 We couldn't believe that the effect measured was the thermal lens effect which is one of photothermal phenomena, because chromatic aberration between the excitation and probe beams is indispensable for thermal lens measurements, and it is impossible for a modern optical microscope for which chromatic aberration is well compensated to realize TLM, this is commonsense knowledge within the field. In fact, I didn't use the words TLM in the title of the first two papers,9,10 and we used “photothermal microscopy with excitation and probe beams coaxial” and “Coaxial beam photothermal microscopy” instead. Later, a student from our labratory reported that the microscope possessed chromatic aberration running to 2.2 µm, and we were very surprised to learn this. We reinvestigated the characteristics of the developed microscope from every view point of optics and thermal lens effects, and proved that this was a true thermal lens effect measured under an optical microscope, and we named it the “thermal lens microscope”.11 In all honesty, it still took a few years to convince reviewers to recognize and accept this. The microscope was forty years old (Fig. 1) at that point, it had a slight but sufficient chromatic aberration for TLM measurement. Once the principle was revealed to be a true thermal lens effect, it was easy to optimize TLM optics and obtain maximum sensitivity, and we could demonstrate sub-yocto mol, that is sub-single molecule level determination of non-fluorescent molecules.12

	Fig. 1 Thermal lens microscopes

Development of the TLM was epoch making and a part of my laboratory turned towards microchip technology and science. The space between an objective lens and the sample stage of the optical microscope is usually very narrow. Thus, it was impossible to insert a sample cell in the space, and therefore we used glass slides fabricated a thin channel and covered with a cover slip instead of a cuvette. We were already fabricating a microchannel on a glass chip, we tried to evolve the simple I-shape channel to a Y-shape channel, and attempted to detect the result of chemical reactions after developing TLM.13 Next, we found micro solvent extraction was also successful by using the Y-shape channel.14 I was reassured at that point that we could integrate chemical processes freely by combining basic chemical operations such as mixing, extraction, phase separation and other various kinds of so called unit operations in chemical engineering.

I applied this concept of integrating chemical processes onto a microchip to the project of Kanagawa Academy of Science and Technology (KAST) in 1997, and that concept was fortunately adopted. Our first five year project “Integrated Chemistry Project” launched in 1998, the same year that I was promoted to full professor. This occasion was quite timely for me to expand my activities to chemistry in micro space. We developed a library of micro unit operations (MUOs) of liquid/liquid, liquid/solid, and even liquid/gas operations (see Fig. 2), and a method of continuous flow chemical processing (CFCP) enabling the connection of MUOs in arbitrary combination in serial and parallel was established.15 TLM also flourished to give knowledge of molecular behaviour in micro space and for creating MUOs and CFCP as well as providing an ultra sensitive detector for widespread use in microchip technologies. Surface modification methods were also important for controlling microfluids and the chemical and biological characteristics of microchannels. Therefore, we could construct our original methodology for integrating microchemical and bio systems on chip by using MUO, CFCP and TLM, and we developed over eighty kinds of microsystems covering analysis, bioassay,16 diagnosis,17 synthesis,18 cell biology,19 physical chemistry,20 micro and nano fluidics,21etc. These works were summarized in a review article.22 Recently, even TLM was integrated onto a micro glass rod by gradient optics technology, and we named it the μ-TLM device. Thereby, some micro chemical and bio systems have been already integrated with an ultra sensitive detection device on chip (Figs. 3 and 4).

	Fig. 2 Micro unit operations

	Fig. 3 3D integrated microchemical system in a microchip

Though there were a lot of troubles and difficulties, embarking on my career as professor was quite smooth. If KAST had not adopted our proposal, we couldn't have established our methodologies and I couldn't have expanded my research activity. I would therefore like to acknowledge the Chairman of KAST of the time, Dr S. Nagakura who is Professor Emeritus of The University of Tokyo and is now President of The Japan Academy.

	Fig. 4 µ-TLM on a chip

University–industry–government cooperation

During these five years, we could promote the usefulness of microchip technology not only for industrial application but also for basic research as a novel tool. Therefore a variety of research projects were organized and launched. These projects consisted of collaboration among universities, companies, and governments. The budget for more than ten projects exceeds one million Euro per year.(Fig. 5) I myself manage four of them. However, I clearly separate the basic research activities within the university and industrialization projects carried out outside of the university.

	Fig. 5 National research projects in Japan involving Professor Kitamori’s group.

These projects are roughly categorized into two groups. One category is aimed at practising and industrializing the technology, and the other one is developing new horizons for sciences. There are two ministries governing industry and agriculture that are responsible for the application side, and another ministry governing science and education is responsible for basic research projects. Nano-technology is political terminology, but the recent current trends for “nano and bio” pushes the “micro” chemical and bio technology in Japan. The distinct direction for Japan is that the goal is not limited to biotechnology, e.g. gene technology and proteomics but also covers chemical and biological production. Even for analytical applications, their subject is miniaturizing total systems including sample preparation for analysis. For these final destinations, general methodologies are expected to be a basis for industrial technologies. As far as the science is concerned, these novel miniaturised tools are revealing many characteristic phenomena which occur only in micro and nano spaces, and they are providing the most basic and important knowledge for applications.

This area is a typical multidisciplinary field, and collaboration between the academic disciplines is indispensable. We established a small academic society “The Society for Chemistry and Micro-Nano Systems (CHEMINAS)” in 2000 where scientists and engineers from chemistry, analytical chemistry, biochemistry, chemical engineering, MEMS, micro machine, biology, medicine, pharmaceutical science, and others are gathering. The membership of this society is now approaching three hundred. Publication of the society journal, two domestic meetings, one international meeting International Symposium on Microchemistry and Microsystems (ISMM), and other irregular events are the main annual activities of the society. I was president of CHEMINAS for the 2002 and 2003 financial years.

Along these lines, activity in this field in Japan has been very energetic. I believe that the mutual understanding among university, industry, government, and also the interdisciplinary academic fields is quite important. We are establishing very desirable and constructive relationships between these groups.

Research philosophy and conclusion

I believe creativity and originality are the most humanlike activities. Highly creative and original music moves people, and creative and original science and technology always opens the next page of human life and reveals the nature of the world. But stunted music, science and technology never moves people and does not benefit society. Creativity and originality must be supported by a steady base and must be logical. The base depends on the quality of training and experience of individual scientists. I was lucky enough to experience both academia and industry, and learned the labour pains of creation and the struggle of growing commercial products, respectively. They are both difficult, requiring a frontier spirit, while the difficulties are quite different and incomparable. I also experienced both physics and chemistry, and I am aware of the differences in the ways of thinking within these disciplines. Throughout my career, my ideas and inspirations have all been multidisciplinary and my instrumentation skills tools for realization, and fortunately, these fit well in this field. I would like to recommend younger people to learn and experience many things and remove the wall of accomplished concept. In addition, cooperation and collaboration are also indispensable, because the experience of the individual person is limited. I am always very happy to meet people and to know their way of thinking, culture and their respectful creativity and originality through effective collaborations.

Conclusions

I am still travelling the road to my goals, but I must be grateful to all the staff, students, and their families and of course my own wife, because we have been able to participate in the frontier of novel science and technology. We are merely at a milestone and the gong for next round is dinging. I will continue to strive with my best efforts to move forward in the hope of opening new horizons of science and industry with my great crew.

References

1. Takehiko Kitamori, Kazumichi Suzuki, Tsuguo Sawada, Yohichi Gohshi and Kenji Motojima, Determination of Sub-ppt Amount of Cobalt by Extraction and Photoacoustic Spectrometry, Anal. Chem., 1986, 58, 2275CrossRefCAS.
2. Takehiko Kitamori, Masaaki Fujii, Tsuguo Sawada and Yohichi Gohshi, Optimal Geometrical Conditions of Photoacoustic Signal Detection with Cylindrical Direct Coupling Cell for Liquids, J. Appl. Phys., 1985, 58, 268CrossRefCAS.
3. Takehiko Kitamori, Kazumichi Suzuki, Tsuguo Sawada and Yohichi Gohshi, Photoacoustic Immunoassay Using Sensitivity Size Dependency for Determination of Turbid Solutions, Anal. Chem., 1987, 59, 2519CrossRefCAS.
4. Takehiko Kitamori and Tsuguo Sawada, Novel Analytical and Chemometric Applications of Photothermal Spectroscopy, Spectrochim. Acta Rev., 1991, 14, 275SearchPubMed.
5. Takehiko Kitamori, Kenji Yokose, Kazumichi Suzuki, Tsuguo Sawada and Yohichi Gohshi, Laser Breakdown Acoustic Effect of Ultrafine Particle in Liquids and Its Application to Particle Counting, Jpn. J. Appl. Phys., 1988, 27, L983CAS.
6. Masato Nakamura, Takehiko Kitamori and Tsuguo Sawada, Highly Anisotropic Light Emission from Laser Breakdown of Microparticles in Water, Nature, 1993, 366, 138CrossRef.
7. Hiroharu Yui, Takehiko Kitamori and Tsuguo Sawada, Spectroscopic Analysis of Stimulated Raman Scattering in the Early Stage of Laser-Induced Breakdown in Water, Phys. Rev. Lett., 1999, 82, 4110CrossRefCAS.
8. Takehiko Kitamori, Tetsuya Matsui, Masaharu Sakagami and Tsuguo Sawada, Laser Breakdown Spectrochemical Analysis of Microparticles in Liquids, Chem. Lett., 1989, 2205CAS.
9. Masaaki Harada, Kouji Iwamoto, Takehiko Kitamori and Tsuguo Sawada, Photothermal Microscopy with Excitation and Probe Beams Coaxial under Microscope and Its Application to Microparticle Analysis, Anal. Chem., 1993, 65, 2938CrossRefCAS.
10. Masaaki Harada, Masashi Shibata, Takehiko Kitamori and Tsuguo Sawada, Application of Coaxial Beam Photothermal Microscopy to Analysis of a Single Biological Cell in Water, Anal. Chim. Acta, 1995, 299, 343CrossRefCAS.
11. Kenji Uchiyama, Akihide Hibara, Hiroko Kimura, Tsuguo Sawada and Takehiko Kitamori, Thermal Lens Microscope, Jpn. J. Appl. Phys., 2000, 39, 5316CrossRefCAS.
12. Manabu Tokeshi, Marika Uchida, Akihide Hibara, Tsuguo Sawada and Takehiko Kitamori, Determination of Sub-Yoctomole Amounts of Non-Fluorescent Molecules Using a Thermal Lens Microscope: Sub-Single Molecule Determination, Anal. Chem., 2001, 73, 2112CrossRefCAS.
13. Kiyoshi Sato, Manabu Tokeshi, Takehiko Kitamori and Tsuguo Sawada, Integration of Flow Injection Analysis and Zeptomole-Level Detection of the Fe(II)-o-Phenanthroline Complex, Anal. Sci., 1999, 15, 641CAS.
14. Kiyoshi Sato, Manabu Tokeshi, Tsuguo Sawada and Takehiko Kitamori, Molecular Transport between Two Phases in a Microchannel, Anal. Sci., 2000, 16, 455CAS.
15. Manabu Tokeshi, Tomoko Minagawa, Kenji Uchiyama, Akihide Hibara, Kiichi Sato, Hideaki Hisamoto and T. Kitamori, Continuous Flow Chemical Processing on a Microchip by Combining Micro Unit Operations and a Multiphase Flow Network, Anal. Chem., 2002, 74, 1565CrossRefCAS.
16. Yuki Tanaka, Kiichi Sato, Masayuki Yamato, Teruo Okano and Takehiko Kitamori, Drug Response Assay System in a Microchip Using Human Hepatoma Cells, Anal. Sci., 2004, 20, 411CAS.
17. Kiichi Sato, Manabu Tokeshi, Tamao Odake, Hiroko Kimura, Takeshi Ooi, Masayuki Nakao and Takehiko Kitamori, Integration of an Immunosorbent Assay System: Analysis of Secretory Human Immunoglobulin A on Polystyrene Beads in a Microchip, Anal. Chem., 2000, 72, 1144CrossRefCAS.
18. Yoshikuni Kikutani, Takayuki Horiuchi, Kenji Uchiyama, Hideaki Hisamoto, Manabu Tokeshi and Takehiko Kitamori, Glass Microchip with Three-Dimensional Microchannel Network for 2 × 2 Parallel Synthesis, Lab Chip, 2002, 2, 188RSC.
19. Eiichiro Tamaki, Kiichi Sato, Manabu Tokeshi, Kae Sato, Makoto Aihara and Takehiko Kitamori, Single Cell Analysis by a Scanning Thermal Lens Microscope with a Microchip: Direct Monitoring of Cytochrome-c Distribution During Apoptosis Process, Anal. Chem., 2002, 74, 1560CrossRefCAS.
20. Akihide Hibara, Masaki Nonaka, Manabu Tokeshi and Takehiko Kitamori, Spectroscopic Analysis of Liquid/Liquid Interfaces in Multiphase Microflows, J. Am. Chem. Soc., 2003, 125, 14954CrossRefCAS.
21. Akihide Hibara, Takumi Saito, Haeng-Boo Kim, Manabu Tokeshi, Takeshi Ooi, Masayuki Nakao and Takehiko Kitamori, Nanochannels on a Fused-Silica Microchip and Liquid Properties Investigation by Time-Resolved Fluorescence Measurements, Anal. Chem., 2002, 74, 6170CrossRefCAS.
22. Takehiko Kitamori, Manabu Tokeshi, Akihide Hibara and Kiichi Sato, Thermal Lens Microscopy and Microchip Chemistry, Anal. Chem., 2004, 76, 53ACrossRefCAS.