Yusuke Himeoka's web page
Research Interest
Past, Current, and (hopefully) Future Projects
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Theory of cell deaths
"What is the difference between the living and the dead state?" is undoubtedly one of the most critical questions in biology.
In recent years, many generic laws have been discovered for the "living" state, specifically,
for the bacterial cells that are growing exponentially. However, there are still many things we do not know about death.
First, do we have any criterion to clearly distinguish between "living" and "dead" states?
For instance, let us suppose we desire to determine whether an E.coli cell is alive or dead. E. coli cells do not age and do not have a life span. Thus, to kill them, we need to impose stress onto the cells through starvation, antibiotics, and so on. The typical cellular response to such stresses is the transition to the dormant state where the cells stop growing, but this does not necessarily mean they are "dead".
Except for the obvious case of cell rupture, to determine whether the cells are alive or dead, we must transfer them to an environment where they can proliferate and see if they start proliferating again.
This method often works, but it is known that cells exposed to stress have a lag time before resuming proliferation. Even in clonal populations, this lag time can vary from a few hours to a few days and even extend to several years. Therefore, to determine the viability of a cell using this method, in principle, it is necessary to wait forever and ever.
Can we somehow determine whether a cell is alive or dead by a method other than "waiting to see if it comes back to life"?
In other words, can we scientifically find the "point of no return"?
Dormant State
There is a state between "alive" and "dead", which is called "dormancy."
Cells transit to the dormant state by exposures to stress such as starvation, antibiotics, pH change, heat shock, etc. In this state, the rate of chemical reactions is much slower, and growth is almost halted, while the rate of death is also strongly suppressed. So, it is literally a "sleeping" state of bacterial cells.
If we continue to stress the cells in this state, they will gradually die, which is (probably) one step before the point of no return mentioned above.
Since antibiotics applications become extremely ineffective on cells in this state, the dormant behaviour is also gathering much attention from pharmaceutical applications. Experimentally, many genes and metabolites associated with the dormant state have been revealed.
Various questions have arisen regarding this dormant state. For example;
・There are multiple ways to induce dormancy, and the genes express differently depending on the induction method. Then, are there distinct dormant states corresponding to the induction method? Or is there a generic law(s) applicable for the states of "sleep", regardless of the induction method?
・Is dormancy a natural property of autonomously proliferating systems? Is the "sleeping" state inevitably accompanied if a system gains the function of proliferating? Or should it be considered a "function" that bacteria have acquired evolutionarily?
・The hibernation in bears and rats and the dry sleep in tardigrades and chironomids have a function similar to dormancy in the sense that they overcome a harsh environment by reducing their activity level. But is this common characteristic more than "somewhat similar"?
We have carried out theoretical research on dormancy and found, for example, that the lag time until growth resumes increases with the square root of the starvation time [1], the evolutionally optimal length of lag time [2], and that the dormant-like behaviour emerge solely from the dynamics of the metabolic reactions even without gene regulation [3].
These are the main areas we are working on now.
[1] YH and Kunihiko Kaneko, Phys. Rev. X, 7, 021049, (2017)
[2] YH and Namiko Mitarai, PLoS Comp. Biol., 17(2):e1008655, (2021)
[3] YH and Namiko Mitarai, bioRxiv (doi:10.1101/2021.07.21.453212), (2021)
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