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| My encounter with molecular biology |
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I enrolled in the University of Tokyo's Science I course in 1962. I had thought about studying astronomy or architecture. The dramatic encounter that changed my mind occurred during the school's Komaba Festival during the fall of my freshman year. People came into the dormitories during the festival, and it got very noisy. I was a dorm student, and I wanted to find a quiet place to take a nap, so I went to find a lecture. I found Prof. Fujio Egami's Genetic Code and Prof. Kazutomo Imahori's Double Helix. They were so fascinating, I listened to them spellbound. I realized immediately that DNA was a substance containing information that was the background for living creatures, and I could apply the concept in which the structure of living creatures was written in code.
I plunged into the study of biology and took the biochemistry course. My university days coincided with the height of student activism. I conducted research in genetic transformation and DNA repair using a phage, but I was confused. I wondered if people would be unable to conduct multicellular research into activity on the molecular level, even if we took a lot of trouble to do so. Kenichi Matsubara gave me a lot of good advice, and he told me about Prof. Itaru Watanabe. I went to see him right away. |
Though microbiology is an imported discipline, we talked about conducting uniquely Japanese research in the field using unique Japanese materials. I immediately began investigating whether an experimental system in microbiology using silkworms would be successful. I learned the ABCs of silkworms at an agricultural testing station and quickly understood how difficult they were to breed.
Finally, the breeding management system got on track, and I made every effort to watch silkworm activity in the cocoon. Ultimately, I was not able to quantify their activity. Using the technique of their parallel, mosaic-like eggs, I created a chart for forecasting their procreation.
In 1977, I met Dr. Tatsuji Nomura, the head of the Central Laboratories for Experimental Animals. Experimental animals in those days had symptoms that resembled human illnesses, but the causes were for the most part different. They would not be useful in studying human illness. We could not look for an animal to use as a human illness model, because none existed. Therefore, we had to create our own specimens.
The concept became clearer as the two of us discussed this over many hours. We decided later on a method for using mice. During the 80s, it was difficult to obtain mulberry leaves because the sericulture research station had closed. Therefore, we began trying to raise mouse embryos outside the body, and we saw their potential for use in experiments for gene manipulation. To observe gene function in a body, not a cell, and introducing the technology for transferring DNA, it is essential for mammals to have the technology to raise embryos from inside the body outside the body.
I had long wanted to understand human beings using basic biological principles, so I thought the time had come to conduct research using the transgenic mouse as a model for people. Based on my experience with silkworms, I thought it was necessary to accurately learn the breeding management system for mice and the experimental technology. Therefore, I went to study at the Jackson Laboratories, the premier site for mouse research.
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| Upper left: The silkworm's mosaic-like eggs, which come from the different-colored embryo. Right: The trace of the larva mosaic Lower left: Creating differnt mosaics, we developed a chart to forecast silkworm procreation. |
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The full-scale operation of embryological
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After returning to Japan, I devised a system for creating transgenic mice with Minesuke Yokoyama. To raise embryos taken from the ovarian duct, it was necessary to begin with the basics, such as what to do about the water and air used. Next was the technology. If the embryo was removed from the body, raised, and then returned to the womb, it should be born normally. At that time, however, our birth rate was 50%. Even Yokoyama, who was very skilled at this, could achieve only 70%. To increase this to 100%, we even brought a protractor to determine the angle of the glass tube to increase our accuracy.
We finally reached 100% at about the third week, I think. We returned 12 embryos to the body and all 12 were born. This had set the standard for both breeding management and technology, so with the variant shiverer mouse, which shows violent trembling symptoms of intention tremor, we investigated whether the symptoms would disappear by introducing in the variant the myelin basic protein (MBP) gene that it lacks. This was a major project that merged genetic engineering with embryological engineering.
We were able to restore the trembling three months later. This time, we tried to reverse the process and introduce the MBP gene antisense into the wild type creature and control the original function. When we did so, the mouse that had been born trembled. We were excited at this development. We had inserted a gene and controlled the function of the original gene.
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 Misbehaving and tearing a shoji circa 1944 |
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 I've loved model airplanes since I was small. |
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 With friends from Komaba Dorm in my second year at university (Fourth from left in back row) |
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 During my doctoral studies, using the blackboard in a debate with younger student Yasutake (left) |
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 In 1974, a discussion in a Keio seminar room (back)
I like having dialogues
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 In 1981, with Dr. Sidney Brenner, who came to visit the Watanabe Laboratories at Keio University
(Katsuki at front row center, Prof. Itaru Watanabe at the upper right)
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 In 1982, in front of the Jackson Laboratories where I studied
(Prof. Tatsuji Nomura at left, Katsuki at right)
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 In 1988, Dr. Tonegawa visited the Central Laboratories for Experimental Animals (Katsuki is at right) |
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 In front of a microscope at the Central Laboratories for Experimental Animals |
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 Third dan in GO! (Katsuki is in the foreground) |
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Upper: Placing a fertilized egg in the mouse with the pipette at the left. Also inserting DNA solution into the nucleus by using a thin glass tube (right).
Lower: Trembling caused by antisense (above) and a transgenic shiverer mouse whose tremors have stoped (below). |
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& Latter, we adopted the knockout mouse technology that had been developed, and we made the embryonic engineering of mice in Japan a reality. We felt we had to have the technology to do real science. Previously, we wanted to know about human central nerve genes, but couldn't study them, but we can conduct research now using mice. This has finally gotten started in the network I'm part of. We're confident we have contributed to clearing up various questions one person cannot handle working alone. Working with people whose objectives are entirely different from mine, our aim has been to make overall progress. I think we have conducted research that overlaps our individual interests.
(Text: SICP)
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| A fire broke out at the Jackson Laboratories in 1989, destroying valuable mice. Dr. Katsuki made a poster to collect funds for rebuilding, raising \24 million. The poster still hangs today at the Jackson Laboratories. |
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Biohistory Jyournal, Winter, 2003
