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“Glowing Proteins” That Can Help Solve Medical and Energy Problems and Revolutionize the Society of the Future

Looking at intracellular structures with the use of glowing proteins

What are these “glowing proteins” which enable imaging of life phenomena? Professor Nagai explained, “One type are fluorescent proteins (FP) that emit light when irradiated with photostimulation light. The other are luminescent proteins (LP) that emit light through oxidation catalysis reaction of a light-emitting compound (luciferin). Fireflies light up because of this system.”

Currently, the Nagai Laboratory is studying both FPs and luminescent proteins (LPs). “Our great achievement is the development of the ultramarine fluorescent protein Sirius with the shortest wavelength.” The maximum spatial resolution (the ability to differentiate between two objects that are relatively close together) is in principal approximately a half of the wavelength. Thus, with the use of Sirius, intracellular structures are visible through a general optical microscope.

Success in hybridization and multicoloring

Prof. Nagai also developed Kohinoor, a fast-switching, positively photoswitchable FP. With the use of Kohinoor, clearer images have become available than with the use of Sirius. It has enabled super-resolution imaging with capabilities close to that of an electronic microscope. However, imaging with FPs required ultraviolet (UV) light irradiation in order to make them glow in the cell.

“UV light causes damage to cells, phototoxicity. So, we thought that the use of "LPs responsible for the bioluminescent properties of fireflies and Renilla (a type of glowing coral), which does not require UV irradiation, would allow us to realize long-term imaging that does not damage living cells.” However, the brightness of LPs, less than one thousandth of that of fluorescent proteins, was not enough for imaging.

“Thus, we made fusion proteins by joining LPs extracted from Renilla and a highly efficient FP (Venus) that we had previously developed. As a result, energy that LPs obtained through chemical reaction was transferred to Venus by Förester resonance energy transfer (FRET), which increased the efficiency of converting excitation energy into light. This led to our successful development of LPs that glowed yellowish-green more than 10 times brighter than before. We called it a ‘Nano-lantern’, reminiscent of a light source on a nano-scale.”

Because tumors in ambulatory mice marked with Nano-lanterns can be observed in real time, it is expected that Nano-lanterns can be used for diagnosis and treatment of cancer. Prof. Nagai continued, “In order to understand complex life phenomena, simultaneous quantification of gene expression and cell geometry is important.” Following FPs, he also succeeded in making multicolor Nano-lanterns.

Save the earth from global warming through glowing street trees

In addition to the field of medicine, Professor Nagai, currently, attempts to address global environmental and energy issues by using glowing proteins -- a grand project ‘Glowing Street Trees.’ “If trees with leaves emitting light are planted as street trees, for example, along the Midosuji Boulevard, it will significantly reduce energy costs. If we spread trees with glowing leaves to the world, it may be possible to prevent global warming by reducing CO2.”

However, the Cartagena Act that regulates the spread of genetically modified plants for protecting biodiversity is a barrier to this project. Somei-Yoshino, a flowering cherry cultivar, is not able to multiple by its own seeds due to the self-incompatibility. Self-incompatibility prevents self-fertilization; interactions between pollen and pistil does not lead to fertilization. “If we adopt self-incompatibility to genetically modified plants, we may be able to prevent spread of genetically modified plants and clear the act.” he said.

Treasure troves ought to be in left field

Throughout the interview, Professor Nagai appeared to be really enjoying his research. “I was influenced by science historian Thomas Kuhn’s The Structure of Scientific Revolutions. He mentioned that the history of science is not the accumulation of facts, but a series of revolutionary changes. That made me pursue not ordinary science as puzzle-solving, but revolutionary science that causes paradigm shifts. To do that, we have to find and study ‘oddities’ that other people have never thought of. If you study while thinking that way, you’ll definitely enjoy yourself.” (Laughs)

In the research world as well, following trends is a matter of common occurrence and there are many existing research projects on similar themes. Believing that treasure troves ought to be out in left field, Prof. Nagai has devoted himself to his own research. Although there is a risk, he continues, “I want to continue to present results that will amaze the world without quitting.”

An "outside-of-the-box" idea

As a researcher, he cherishes interactions with people. In order to "have a wide range of knowledge such as in physics, chemistry, biology, engineering, and humanities and keep his eyes open for new things,” he holds a Mongolian BBQ party at the Institute of Industrial Science and Technology with over 150 people every year.

He also plans to open a salon in his lab in March this year so that they can discuss while eating and drinking. “Researchers should not be shy. They must doubt common wisdom and proactively interact with people who have ‘crazy ideas.”

• Takeharu Nagai

A 1992 graduate of the College of Biological Sciences, University of Tsukuba, Prof. Nagai completed the Master Course at the Graduate School of Agriculture of the same university in 1994 and the Ph. D. Course at the Graduate School of Medicine, University of Tokyo in 1998. After serving as a special postdoctoral researcher at RIKEN and a researcher at JST Sakigake (PRESTO), he became professor at the RIES, Hokkaido University in 2005. He started at his current position as professor at the Institute of Scientific and Industrial Research, Osaka University in 2012. Prof. Nagai has been presenting new accomplishments one after another in the field of bioimaging.

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