Research in “minority biology,” a new field studying what will be brought about by minority molecules and molecular individuality
Do you know the academic discipline known as “minority biology”? This is a research area that explores life phenomena in which a small number of molecules—neither a single molecule nor large number—function in a cooperative manner. Associate Professor Yuichi Togashi has been conducting this research with his attention focused on “minority” since he was a graduate school student.
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What inspired him to pursue this area were the results of a simulation he had carried out to write his master's thesis. Dr. Togashi recalls: “It was such a long time ago. In the spring of 2000, while I was struggling to come up with an abstract chemical reaction model, I became increasingly confused. To extricate myself from the confusion, I dared to build an extremely simple model. Then, I obtained strange results, in which I saw the figures changing suddenly and dramatically. Since I had also written the simulation program by myself, I first attributed these results to a bug in the program. However, when I checked the program over and over again, I realized they were not wrong.”
He therefore came to realize that the presence of even a single molecule can make a significant difference in the results. This finding marked the starting point for him to undertake research into the area of “minority.”
He says: “Activities of organisms are primarily based on chemical reactions, so they can be considered within the framework of chemistry. In biochemistry, the rate of chemical reaction is thought to depend upon the concentrations of substances such as enzymes involved in the reaction, considering the enormous number of molecules, as defined by Avogadro's number—1 mole ≈ 6×1023 molecules. This is a kind of common knowledge that is described in any textbook.”
However, Dr. Togashi and his colleagues cast doubt on what constitutes the precondition for such common knowledge in the first place. He explains: “As for ‘concentrations,’ which I mentioned earlier, when the concentration of a substance is considered, it is assumed that there are a lot of the same molecules within a certain range. Usually we are not aware of such a precondition. This is true in the case of in vitro chemical reaction, but we have begun to understand that this precondition does not actually hold in a cell.”
Among biomolecules, there are some that define the properties of a cell, despite a very limited number (only one or two) of the same molecules being present in each cell, as exemplified by DNA. Also, in the case of some biomolecules, it is thought that each molecule has its own individuality. In addition, catalysts, such as enzymes, can be involved in chemical reactions many times over, without undergoing change, even if there is only one molecule present.
Dr. Togashi says: “When the number of molecules is small and their individuality is evident, the concept of continuous ‘concentrations’ breaks down—such interesting phenomena have been newly observed.” In this way, “minority biology” has theoretically shown diverse phenomena arising in reaction systems including various minority molecules, and has been making further experimental verifications.
Fig 1: Example of the effects of small numbers exhibited in a simple chemical reaction model
As shown in the left figure, we consider the reactions of Molecules A and B in accordance with Rules 1 and 2. Let us assume that the volume of the container containing these two types of molecules is proportional to the total number of molecules (i.e., the total “concentration” is the same in all containers), and that the contents are well mixed. As illustrated in the left figure, under Rules 1 and 2, Molecules A and B are interchangeable. (Here, we will not go into the details, but assumed values are assigned to the constants k and u, which determine the rate of reaction.) For this reason, you can intuitively presume that A and B will have a half-and-half ratio.
In fact, according to the conventional way of thinking based on “concentrations” (rate equation), the ratio of A to B will become closer to half and half, even if the reaction begins with any ratio. On the other hand, the right figure shows the results when each and every reaction is simulated. When there are a large number of molecules (indicated by the gray line), the ratio is mostly half and half, whereas when there are a small number of molecules, the ratio tends toward the extremes–either all A or all B (as indicated by the red dotted line. Note, however, that in actuality the numbers of molecules are always integers, so they are always depicted with ● [black dots]).
Moving to Hiroshima University to pursue DNA research—Studying “minority” means investigating digital nature
Dr. Togashi specializes in computer simulations and theoretical biophysics. You may find it difficult to imagine how computer simulations are linked to biology, etc. In answering such questions, he gives the following explanation.
“Nature and organisms are frequently discussed as analog entities. For example, when counting people, no one would say ‘1.5 people’ or ‘0.5 people.’ To give another example, since a distance always exists between people, one seat cannot be shared by 0.3 people and 0.7 people. So to speak, the conventional theory of chemical reaction assumes a world where such a situation is possible. However, if there are small numbers of molecules, and each of them is regarded as an individual entity, we should assume that these molecules are digital entities, whose number is expressed as an integer. In other words, addressing the issue of ‘minority’ means investigating digital nature.”
Dr. Togashi originally wanted to create a computer, and this desire motivated him to become a researcher. Ever since he was a kindergartener, he has been familiar with computers. At the age six, he first wrote a computer program. He says: “My pursuit of theoretical studies may reflect my own desire to view things from a higher perspective. My mother still tells me that, in my childhood, I used to climb trees but was unable to climb down. Even now, when I go out somewhere, I often climb a tower or church steeple to look over the townscapes and take photographs.” As such, his unchangeable research objective is to achieve a great ambition: to invent a computer that surpasses existing ones, which were originally created by Alan Mathison Turing and John von Neumann.
“I have long been interested in the way organisms perform information processing, and have striven to learn from organisms about the principles of a new information processing mechanism that is different from digital computers,” says Dr. Togashi. It is therefore a great paradox that he has come to realize that digital numbers are all the more important for organisms.
In 2014, he moved his research base to Hiroshima University, which appointed him as a member in charge of mathematical modeling and computer experiments at the Research Center for the Mathematics on Chromatin Live Dynamics. This research facility is led by Professor Shinichi Tate of the Graduate School of Integrated Sciences for Life.
He says that he decided to come to Hiroshima University because “DNA is the most extreme example of minority molecules.”
Chromosomal DNA is thought to be a medium in which information on the base sequence A, T, G and C is described. Actually, however, it is not merely a tape, and its folding pattern determines how the information is used. In a sense, DNA itself is part of an information processing machine. Here, it is not appropriate to think of the relationship between a tape and a computer, or between a tape and a head. Instead, you can imagine that the tape functions as a computer. Usually only one or two molecules of exactly the same DNA exist. We can therefore cite DNA as the most extreme example of minority, in the sense of belonging to a realm regulated by small numbers of molecules. In addition, since proteins working on DNA include those whose number is very small, DNA is considered to be a system that involves all the issues relating to state, shape and small number.
The abovementioned framework is still well-supported. As in the case of the “minority biology” project implemented between 2011 and 2016, various initiatives are under way, with researchers from many different fields working in concert as an interdisciplinary team.
Seeking to discover a new information processing system by learning from organisms, as a pioneer of a new field
“I have been conducting research, while paying attention to what would happen if a given situation were specified, and what the results would be if such a situation were to occur. However, biologists have continuously told me: ‘No, such a situation will not arise in biology,’” says Dr. Togashi.
Nevertheless, as research has made progress, they have made various findings. Taking a type of molecular motor as an example, its direction of travel is reversed between when a single molecule works alone and when several molecules are combined to function in a cooperative manner. “Minority biology” is still in the stage prior to its establishment as an academic discipline. However, Dr. Togashi expresses his intention to continue expanding the scope of this research to cover diverse areas to explore the significance of “smallness in number” for the systems of life. He will also promote collaboration with a wide variety of researchers to advance theoretical studies regarding small numbers of factors that control life systems.
What is interesting about this research?
“Simulation can be placed somewhere between pure theory and experiment, and this methodology enables us to reproduce what will occur if a particular hypothesis is adopted, in a visible manner,” says Dr. Togashi.
He adds: “You may think we are simply reproducing the movement of molecules accurately. There’s more to it than that. In creating a mathematical model, we extract a specific part of what is actually occurring, refine it into a form that allows us to develop concrete ideas, and examine the ideas through manual calculation and simulation methods. First, the extracting process is challenging but intriguing to me. Next, I also find it interesting to observe how the molecules behave, since sometimes their behavior turns out to be completely different from what we expected.”
Furthermore, he points out that research into minority has great potential for development, saying: “This kind of discussion may also be applied to fields other than molecules. For example, the effects of small numbers can be considered at a cellular or individual level, as in the case of molecules. In this respect, I expect that minority research may be applied to studies regarding individuals within a group, ecosystem or society, thereby developing into different layers. These represent future challenges to be addressed by minority biology, and I look forward to taking on such challenges.”
It is said that recent booms in artificial intelligence (AI), deep learning and machine learning are largely brought by the presence of a neural network, which is a mathematical model that imitates the functions of the human brain. Likewise, his research into exploring digital nature may achieve an amazing breakthrough someday. With this expectation in mind, Dr. Togashi says he will continue to work on this research. He also invites young people to conduct research together with his team.
“For theoretical research, human resources are indispensable assets. My laboratory will address various themes, while valuing the ideas of individual members. I believe it is not merely a dream for students to become pioneers by pursuing their research activities here. We hope ambitious students will join us.