Professor Emeritus, The University of Tokyo
President, Yokohama Science Center, Special Advisor, RIKEN Genomic Sciences Center and Executive Director, Ochanomizu University
Life process from the viewpoint of physics
—Interface between life and engineering—
Living organisms have a hierarchical structure that consists of molecules, metabolic networks, cells, tissues, organs, individuals, and populations. Prof. Wada has unraveled life processes by studying the various physical properties of macromolecules, including DNA and proteins, that are involved in transmission, recording and expression of genetic information within a cell using innovative methods based on his novel ideas and tools. His studies have been based on the perspective of how living organisms utilize physical and chemical principles for their existence.
After graduating from the department of chemistry, Prof. Wada started investigating the properties of internal rotation of small molecules, such as dichloroethane, using a variety of physical methods. From there, his interests shifted to conformational changes in polymers, and he began to study helix-coil transitions of proteins in Prof. Paul Doty’s lab at Harvard University, where biological macromolecules were being researched. Prof. Wada’s interest in “the relationship between living organisms and physical properties” increased in one of the most advanced research environments in biophysics.
Several years after returning to Japan, Prof. Wada was invited to join the Department of Physics, Faculty of Science at The University of Tokyo, where he started researching the physical properties of DNA and proteins. He wondered, for instance, how the physical properties of DNA support its biological functions under the restriction of genetic information. One of his answers was the “close relationship between genetic information, i.e. base sequences, and the stability distributed along a DNA double helix”. The DNA double helix is made up of alternately and regularly aligned deoxyribose and phosphoric acid. The four bases responsible for genetic information are linked to deoxyribose and G (guanine)-C (cytosine) and A (adenine)-T (thymine) base pairs are formed to maintain the double helix structure. In G-C rich regions, the bonding is stronger, and the double helix is more stable than in A-T rich regions. Prof. Wada discovered that the double helix structure of individual genes is uniformly stable, in other words, a gene has a homostabilizing propensity. “When DNA is replicated, the double helix must unwind smoothly into its genetic units. Therefore, the stability of the double helix should be uniformed within the genetic units: genes. The stability as a physical characteristic is related to genetic information,” says Prof. Wada.
Prof. Wada wondered how the double helix of genetic units maintains uniform stability without the genetic information changing. He looked for the answers in the redundancy of the “codons,” or arrangements of three bases that specify the same amino acid. For leusine, which is an amino acid, the first and the second bases of the codon have to be C and T, respectively. However, the third one can be T, C, A or G. He says, “The stability may be adjusted by using weak A-T base-pairing or strong G-C pairing at the codon’s third letter without changing the protein’s amino acid-sequence. Thus, living organisms utilize the flexibility in the third position without changing the genetic meaning.” It was remarkable to determine the relationship between the physical properties of DNA and the strategy for extending life. The originality of his research is appreciated again 20 years after publication.
Prof. Wada developed a high-speed and automated DNA base-sequence analyzer. In the early 80’s, he thought that decoding a large amount of base sequences was necessary for further DNA research, and therefore, decoding DNA base sequences automatically for much faster analysis was indispensable. His idea was published in the magazine Nature in 1987, where research involving human genome project was reported: his idea led to progress in human genome projects worldwide. Fully automated DNA analyzers currently being used are what he pictured in the article and partially utilize the technology he developed. One DNA analyzer can decode one million base pairs in a day.
Prof. Wada has been trying to determine the principles and strategy for designing living machines. He compares living organisms, which are naturally engineered machines, to artificial machines. “The design of artificial machines is based on the principles of physics and chemistry and accumulated engineering knowledge. Biomachines are based on the capacity for survival in a fickle global environment,” says Prof. Wada. Bionanotechnology applies the principle of “strategy of life” to engineering. He says, “Biomachines make use of nanometer-size spaces effectively while engineered machines utilize micrometer-size spaces at best. Biomachines have evolved over 3.6 billion years; there is so much to learn from their strategy for survival on the Earth.
