What kind of research do you do and what is the goal of your research?

 

We utilize bioimaging technology to visualize signaling, which constitutes the basic framework of biological phenomena. Our goal is to understand the mechanism underlying the origins of life on the basis of the achievements of our research. Our motto is "seeing is believing.” Bioimaging is a powerful tool through which we can simultaneously "visualize" molecular dynamics as an elementary process, as well as a whole-cell behavior as an integrated phenomena (see figure bottom right). We aim to understand the functions of cells, particularly functions at the tissue or whole-organism level by unraveling piece by piece “the mechanism of life” from a microscopic view.

Visualization of Ras Activation Responding to Environmental Changes
Ras activation in living cells was imaged using a FRET biosensor. Red shows areas with high activity, and blue shows areas with low activity. You may notice that the cells that responded to the environmental changes display significant morphological alterations, and Ras is highly activated in such areas.

Microscopy for Bioimaging
An inverted microscope (an upside-down version of standard, upright microscope) is a core component, which is equipped with a camera to acquire images and a computer to control the system, etc. as a set (the room light is turned on to take this photo; however, actual observations are conducted in total darkness).

The human body consists of 60 trillions of cells. When viewed from a long-term perspective, these cells appear to maintain a stable, unchanging state (steady state). Observed under a shorter period, however, these cells are under constant change. Since the changes are kept within a certain, but limited range, they can be stable in a steady state as a result. For example, epidermal cells in skin, which cover the surface of the body, are continuously replaced through the turnover, with all epidermal cells being replaced by new cells within approximately four weeks. In addition, when cells detect a change emerges in their circumstances (environmental change), they display various behaviors in response, and eventually take actions to restore to their initial states. One example of this is the process of wounds healing. Such mechanism to maintain a state of living organisms within a certain range is called homeostasis. For the execution of homeostasis, it is important that each individual cell detects environmental changes precisely, as well as responds to the change appropriately. Moreover, rather than each cell behaving randomly, all cells need to work in cooperation in order to benefit the whole tissue or living organism. Intercellular and intracellular signaling forms the foundation for such environmental change detection, response induction, and cooperative activities with other cells. The accuracy of the control of signaling is the critical factor for cells to develop accurate physiological functions.
Basic elements for signaling are proteins that are expressed in cells. Ions, lipids, etc. are also involved. A series of proteins and other molecules react in orderly cooperation in response to external stimuli. The theme of our research is to visualize secrets of how such coherency is established in cells through the use of bioimaging, and then to unveil its mechanisms by microscopic observation. Our dream is for our laboratory to achieve outcomes that will change content of textbooks.

 

What was the trigger to begin your current research?

After graduating from the Hokkaido University School of Medicine, I entered the Hokkaido University Graduate School of Medicine and began studying diagnostic pathology. However, I was not content studying subjects that did not move. Part-way through my doctoral program, I began studying under Dr. Michiyuki Matsuda (currently a professor at Kyoto University) at the Research Institute, International Medical Center of Japan, and encountered bioimaging research using living cells. Since that time, I have dedicated myself to the research of Ras protein signaling through bioimaging. In addition, I am seeking out methods of helping patients by applying bioimaging clinically.

 

What instruments and technology do you use for your research?

I currently use bioimaging technology called fluorescence protein and Förster resonance energy transfer (FRET) to visualize cell signaling and to analyze its role in cell physiological functions. 

Visualization of Drug Efficacy in Living Leukemia Cells
We introduced a FRET biosensor of the target molecule of the drug into leukemia cells from patients and imaged the drag efficacy. Cells that turned blue quickly are the cells with high drug efficacy. Individual cells are shown to display different responsiveness.

Images are acquired by observing cells transfected with fluorescent biosensors under a fluorescent microscope (upper right figure). The resulting images were then analyzed by a computer, producing images like the ones in the figure on the right, or on the previous page.
Bioimaging technology is useful not only for basic research, but also clinically. We succeeded in determining the effectiveness of therapeutic drugs for each individual patient cell through bioimaging (see figure on right). Thus, it is now possible to "see the future" of how a patient's disease will progress through therapy.