Interview with a corporate partner

How we used chromosome engineering technology: Part 1

Kazuma Tomizuka

Group Manager and Manager of the Drug Discovery Technology Research Institute,
Research Functions Unit,
Research & Development Headquarters,
Kyowa Hakko Kirin Co., Ltd.

Manager of the Drug Discovery Technology Research Institute, Research Functions Unit, Research &Development Headquarters, Kyowa Hakko Kirin Co., Ltd.

Visiting Professor, Tottori University Chromosome Engineering Research Center
Doctorate (Life Sciences)
Born in 1964.
Joined Kirin Company, Limited after obtaining a Master’s degree from the Kyoto University Faculty of Science. Held various positions before assuming his present post in 2014, such as researcher at the Central Laboratories for Key Technology, research student at the National Center of Neurology and Psychiatry, Senior Researcher and Group Manager at the Pharmaceutical Research Laboratory, and VP and CSO of Kyowa Hakko Kirin California.

The technology is not only interesting and intensely challenging, but is also extremely useful

What research were you conducting before you met Dr. Oshimura?

Around 1990, we were trying to enter the field of antibody drug development that was not yet well-established. However, the monoclonal antibody (mAb) that we were targeting as a potential antibody drug could only be obtained from mice at the time,
meaning that it would be considered a foreign substance by the human body and create safety problems that would be a major challenge for clinical application. One solution to this problem was to create a human mAb. Naturally, many groups were already competing to develop such technology. Using conventional methods, it was not possible to insert “complete human antibody genes” into mice, which is what would be required to achieve sufficiently potent antibodies. We tried to overcome this problem by developing completely novel technology. My boss, Isao Ishida (currently a professor at Teikyo Heisei University) wanted to attempt the audacious idea of “carefully manipulating a cluster of genes large enough to enable observation with chromosomes as a ‘microscope’ and putting an entire human chromosome containing a complete antibody gene into a mouse.” We thus launched a project to develop human antibody-producing mice in 1992.

What motivated you to pursue chromosome engineering collaboration?

We tried a number of techniques to transfer human chromosomes into mice, but all our attempts gave negative results, and the two-year deadline that was given for this project was rapidly approaching. Our last hope was the globally unique chromosome transfer technology developed by Dr. Mitsuo Oshimura at Tottori University. In 1993, we visited his laboratory with a feeling that we were grasping at straws. All experts in this field knew that mice with chromosome abnormalities were not viable, and Dr. Oshimura was initially surprised by our incredible suggestion to transplant human chromosomes into mice. He said that, while it would be a major challenge, the prospect was very interesting as success would result in vitally useful technology, and that he would be glad to work with us. We then launched our collaboration. This visit during which Dr. Oshimura’s unique chromosome transfer technology, his strong interest in the challenge ahead, and our intentions to develop human antibody-producing mice all came together may be considered the catalyst for open innovation, in today’s terms.

What have you accomplished using artificial chromosomes (chromosome engineering technology)?

Our collaboration with Tottori University proceeded without a hitch, resulting in success after success at a far greater pace than we expected. By the second year of our collaboration, we had successfully created a mouse containing a human chromosome fragment and had applied for a patent. What surprised us was that the human chromosome fragment was passed on to subsequent generations of mice. Mice usually have 40 chromosomes, and we are able to create mice with 41 chromosomes including the human chromosome we had transplanted. These results were not only published in the prestigious science journal Nature Genetics, but were also covered by media outlets such as the Washington Post and New York Times, astonishing people around the world. We later used this technology to create human antibody-producing mice.

What do you like about chromosome engineering technology?

One of the things that I feel is very important when conducting research is to “learn from the wisdom and design of living things.” Cloning technology to artificially splice gene fragments, and vector technology to transplant those spliced segments into the desired host, dramatically accelerated the progress of biotechnology. Nevertheless, we still lacked the ability to manipulate huge genes such as human antibody genes. Chromosomes are natural vectors that contain all of the wisdom of living things, and the use of chromosomes made it possible for the first time to transplant complete human antibody genes. A major problem with chromosome vector systems is low cell transplantation efficiency. We used the “chromosome transfer method (microcell mediation)” developed by Dr. Oshimura to achieve a sufficiently high transplantation efficiency--a truly significant accomplishment. Treating cells with a certain chemical agent creates a “particle (microcell)” containing a chromosome. This can be considered one example of utilizing the wisdom of living things. At any rate, we were lucky that Dr. Mitsuo Oshimura, who is a leading expert in this unique technology, lives in Japan and kindly accepted our proposal. As a result, we were able to create technology that may be genuinely considered “made in Japan.”

How will you be able to use this technology in the future?

The first example of industrial application of chromosome engineering technology was the human antibody-producing mouse, but it is clear that the potential of this technology does not stop there. For example, there is an urgent need for development of technology to increase clinical prediction performance in pharmaceutical development, and the demand for experimental animals such as transgenic mice containing other human genes in addition to antibody genes will continue to soar. Researchers at Tottori University have already successfully created a humanized P450 drug metabolizing enzyme model mouse using this technology. The University has also succeeded in creating a trans-chromosomic model mouse for Down syndrome carrying human chromosome 21. In the field of regenerative medicine that is currently garnering much attention, we can expect an increase in the use of chromosome vectors carrying a huge human gene or, for example, that are capable of refined gene expression control. In a more familiar area, these characteristics of chromosome vectors will likely become useful in building cell systems for drug screening. One issue is that chromosome transfer technology is not readily accessible for general researchers, and proactive activities are needed to spread this technology. I am sure that the value of general-purpose technology will rise as it becomes more widely used among researchers.

The value of general-purpose technology will rise as it becomes more widely used among researchers.