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Aiming to understand ‘genome instability’ observed in cancer cells
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The main theme of Professor Shimizu’s research can be summarized as follows: Elucidation of “genome instability” for clarification of human cancer and application of study results to bio-pharmaceutical manufacturing.
The genome indicates the entire genetic code and is regarded as something like the identity of living organisms.
According to Professor Shimizu, ‘In cancer cells, the genome, which is normally stable, can no longer remain stable and becomes destabilized. “Genome instability,” characterized by loss, growth and deformation of genes, is a very important concept in the field of cancer cell research.’
Professor Shimizu is interested in the system that protects genomes. More specifically, he attempts to understand the mechanism involved in the increase and decrease of gene numbers. |
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‘Gene numbers in a given cell should be consistent. To maintain this consistency, a large variety of smart mechanisms are active in the living body. In cancer cells, however, these mechanisms do not work normally and gene amplification occurs. Bad genes, once amplified, may decrease in number, and cancer cells may be normalized later. A long time ago, our research team discovered this phenomenon, which triggered the development of this research.’
Once genes are amplified, they are localized to one of the following structures in a cell: the extrachromosomal genetic elements called as double minute (DM) and a portion of chromosome arm named as homogeneously staining region (HSR).
‘Because amplified genes are localized mainly to DM in cancer cells in a body, we examine these DMs in detail.’ |
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Engagement in unique research to clarify the behavior and the elimination mechanism of extrachromosomal genetic elements
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The discovery that prompted Professor Shimizu to launch this research can be summarized as follows.
Once the number of intracellular copies of cancer genes amplified on DM-type micronuclei decreases, cancer cells lose malignant phenotype and differentiate.
Professor Shimizu explains: ‘In other words, cancer cells can be normalized if DMs may be eliminated from the cells efficiently. This rationale can be applied to human cancer treatment.’
He found that these DMs had quite unique intracellular behavior, and came to understand that these DMs could be released selectively from the cells depending on the conditions.
More surprisingly, in his research process, he discovered a unique gene amplification method. |
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‘I conducted an experiment to examine what might happen after insertion into a human cancer cell of a plasmid (a DNA molecule for gene delivery) with a special structure. In this experiment, the number of such plasmids increased tremendously in human cancer cells.’
On the basis of this experimental result, Professor Shimizu’s research team believed this technique should be quite useful in reproducing gene amplification. This experimental technique was named ‘initiation region (IR)/matrix attachment region (MAR) gene amplification method,’ following the name of the structure of the plasmid.
Professor Shimizu says confidently, ‘We are proud to have established an absolutely unique research field on the basis of dynamics of extrachromosomal genetic elements.’ |
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Contributing to society through application of the ‘IR/MAR gene amplification technology,’ leading to further development
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The gene amplification method described above has been utilized fully in Professor Shimizu’s subsequent studies. His studies have gradually moved close to elucidation of various mechanisms and have achieved significant results in the process of elucidation.
‘We promote application of the gene amplification method not only to such a basic research field but also to recombinant protein-based pharmaceutical manufacturing technique.’
According to Professor Shimizu’s explanation, protein-based pharmaceuticals, which are classified as biopharmaceuticals, are effective therapies for rheumatism and cancer with limited adverse effects. These pharmaceuticals should be administered to patients in large quantities. The conventional technique based on animal cell cultivation has a difficulty in applying pharmaceutical manufacturing because it requires great expense for equipment and culture media.
He says, ‘In this situation, our “IR/MAR gene amplification method” has attracted attention. This technique enables increased production of protein per cell.’
Attention should be directed to the fact that Professor Shimizu played a pioneering role in establishing an experimental system that is related not only to the biological aspect of cancer but also to bio-pharmaceutical manufacturing. There are many researchers who specialize in one of these fields, but only few specialize in both of them. |
At the end of this interview, Professor Shimizu gave the following message to the young researchers responsible for the next generation.
‘Our research project has been promoted in the world’s best laboratory because the basic aspect and application of our research have both been highly appreciated. The best part of research is the joy of discovering something that was not previously known to anybody. I would like young researchers to experience this joy.’ |
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| Noriaki Shimizu |
Professor, Laboratory of Biological Chemistry
April 1, 1983-November 30, 1988: Researcher, Central Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd.
April 1, 1994-September 30, 1995: Visiting Scientist, the Salk Institute for Biological Studies
December 1, 1988-March 31, 2005: Instructor, Assistant Professor and Associate Professor, School of Integrated Arts and Sciences, Hiroshima University
April 1, 2006-January 31, 2008: Associate Professor, School of Applied Biological Science, Hiroshima University
February 1, 2008-: Professor, School of Applied Biological Science, Hiroshima University
Posted on Nov 17, 2014
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