Understanding “life” through the lens of physics and statistics

What is life?

What is this thing with its exquisite appearance, extraordinary abilities even at a cellular level, and mind-boggling diversity from bacteria to human beings that we call “life”?

“Some people believe that there is life only when there is an ability to self-replicate, while others believe that there is life only when there is an ability to move voluntarily. I believe that understanding the movements and patterns of living things and how they arrange spontaneously to form order will lead to uncovering the essence of life.”

Associate Professor Sugimura's research aims to unravel the mysteries of life by understanding the shapes and patterns of cells from a physics perspective. The mechanical forces that trigger deformations and movements are key. Sugimura's approach is groundbreaking in the field of biology because it layers statistics on top of mechanics and geometry.

“If we want to understand shapes and patterns, it is quite natural to consider the mechanical forces that trigger deformation and motion. For example, a tent cannot stand by simply having sticks and a piece of cloth. A tent will stand only when there is a balance of forces between the sticks, the cloth, and the ground. In other words, looking at living organisms through the lens of mechanics is very natural. In fact, examining the shapes and patterns of living organisms from a mechanical point of view dates back more than a century. However, molecular biology began to spread in the middle of the 20th century, and as higher organisms became the main object of study from the 1980s, research about genetics took center stage. Consequently, the “physics approach” began to fade away.”

Another obstacle was the lack of mechanical measurement technology for microscopic objects such as cells. This, however, began to change around 2000. The rapid progress of live imaging technology (Dr. Osamu Shimomura won the Nobel Prize for isolating GFP, a green fluorescent protein used in live imaging) enabled the observation of cells in their "alive" state, making it possible to visualize the process of cell shape change in real-time. This, Sugimura says, renewed the researchers' interest in the mechanics behind cellular deformation.

“Since the late 2000s, various new in vivo force measurement techniques have been developed, such as the FRET tension sensor (a sensor that measures intramolecular tension) and the oil droplet method (which measures local stress based on the distortion of oil droplets embedded in the tissue), kick-starting a rapid scientific advancement. Our lab published one such method in 2012 called "Bayesian Force Inference" (a method that quantifies the forces acting on cells by statistically inferring them from images). I would say that our attempt to understand living organisms using statistical methods incorporating physical laws was probably very innovative at the time.”

Another marvel of life

Some readers may wonder about the significance of studying the forces that shape cells in the age of widespread genome sequencing.

“DNA merely encodes the sequence of proteins and determines when they are expressed. So, we need to think about how that DNA information is converted into shapes and patterns via mechanical or other ways. In the example of a tent, DNA can prepare the sticks and the cloth, but it does not code how the sticks and the cloth are to be balanced to form a tent. So that step has to be clarified by the laws of physics.”

This is precisely where another marvel of life is hidden.

In the epithelium of the stomach and small intestine, many cells are arranged in a regular and orderly honeycomb-like hexagonal shape called a hexagonal lattice. This structure makes the tissue strong and stable. Sugimura successfully clarified the physical mechanisms of how the hexagonal lattice forms in the epithelial cells in the wings of fruit flies.

“We have been trying to understand the geometrical and mechanical aspects of the phenomenon using laser-induced tissue injury and Bayesian force inference methods. But the simple fact is that the hexagonal latticework is merely the arrangement of cells in a comfortable direction where the forces are balanced. The cells themselves are not “counting” the number of vertices. They are just moving in line with the balance of forces.”

Her recent work on cell junction (the adhesive part on the surface of a cell) exchange during cell rearrangement is another discovery of mechanical forces that influence cell shape and patterning.

“There are three types of cellular changes in multicellular deformation and pattern formation: changes in the number of cells (cell proliferation), changes in the shape of cells, and changes in the arrangement of cells (cell rearrangement). Understanding the latter is very important for understanding the shape and pattern of tissues.”

Cell rearrangement, which occurs when cells exchange cell junctions with neighboring cells as if they were rotating (but in fact, they are not), proceeds in three steps. First, the cell junction contracts, then it gets exchanged. Finally, the newly formed junction elongates. The mechanisms of the first and third steps had already been known, but those of the second step, the exchange, were not understood at all. Sugimura's challenge was to solve this mystery.

“Using a high-resolution microscope, we could visualize events in which cells exchange junctions, clarifying many things that had been baffling before. It is difficult to explain the mechanisms here in an easy-to-understand way, but it’s not the cell junction itself that has the property of changing from vertical to horizontal. The mechanics and signaling of the cell are coupled with the geometry of the cell junction, and it naturally switches to the correct direction as it contracts and elongates. That is what we found.”

And here is the marvel mentioned earlier.

“The strangest thing about this kind of multicellular ordering is that the cells only have local information. Yet, the whole is arranged into an ordered shape or pattern.”

Wanting to do research that expresses nature

When building a house, workers stack the bricks according to a blueprint, checking the number and position of each one. In multicellular tissue, however, the “house” is built by the bricks arranging themselves without external supervision. Cells only have local information, that is, information about the cells next to them. And yet, it looks as if someone, just like a site supervisor, was giving instructions to each cell from a bird's eye view of the whole, creating a large and orderly formation. Of course, there is no supervisor. Our bodies are also growing and forming in this self-organizing way. That is the most mysterious thing of all.

“This strongly suggests that regardless of how complicated an organism's form or pattern is, processes are broken down into tasks that individual cells can easily perform.”

Sugimura believes that mechanics and geometry are crucial to these tasks.

“The complexity of living organisms is astonishing, and there are many things that make me think, "Phenomena like sound reception in hair cells are too good to be true (laughs)." To me, it’s fascinating to try to figure out how simple tasks can give birth to such complexity. You want to find the simple rules hiding within. When we were researching the hexagonal lattices and the cell junction exchange, we found that it was important to couple geometry with quantities borrowed from physics. Looking for ways to abstract mechanisms common to multiple life phenomena is a fundamentally physics-minded approach.”

Nevertheless, some might be surprised by the juxtaposition of geometric images with things that are rather soft and fluid, like organisms.

“Even soft objects, such as biological tissue, will always have the curvature. Geometric properties and information are internal to everything. Geometry covers properties like curvature and not just rigid arrangements like tiles. Therefore, it can apply to both solids and fluids.”

Sugimura says that until now, they have targeted phenomena with relatively few active elements. However, they would like to take up the challenge of more active elements.

“For example, cells actively exert force when they divide. In the future, I would like to conduct research on shape and pattern formation that includes such active forces. I would also like to develop technologies specifically for this purpose.”

Sugimura also says that she is a little different from other biologists.

“I think a lot of researchers aim to create something new or explain a certain phenomenon. But in my case, it is a little different. I have the desire to express nature in some way. People who want to unravel nature will come up with more questions and perhaps more research results. I have made peace with that. I might be an outlier, but I just want to keep doing research that expresses nature in some way.”

A soccer girl who likes science

She was in junior high school when she decided to pursue a career in science.

“I read a lot of books and liked catching insects, but I already had a vague sense of wanting to express the world. I thought I had no talent for writing, however. It was conducting an experiment in a class in junior high school that made me truly fall in love with science. We were in groups of four, but the other three girls were completely uninterested, so I had to do all the thinking, experimentation, and report writing by myself. It was a lot of fun (laughs). I became interested in biology in my first year of high school. I happened to pick up an introductory molecular biology book during summer break. It featured a story about how, for example, three nucleotides are used to code a single amino acid. This made me realize there was an underlying logic behind organisms and that changed my view of biology. That was when I decided I wanted to understand living things from a physics perspective. At that time, I was also interested in architecture and design, but I thought that the mystery of “life” was the most intriguing question of them all. So, I'm not quite the type of person who became a biologist because of her love for animals."

Sugimura says that she was always obsessed with soccer which she played from her early years in kindergarten until the summer of his senior year in high school (except for in junior high school because there was no soccer team). Most of the time, she was playing as a forward, but "it did not suit my personality. I preferred being a central midfielder and orchestrating the game,” she adds.

Does the position of a central midfielder sound like giving her the role to manipulate the "forces and geometry,” the very elements, of a soccer game?

She has the following message for women who aspire to become researchers in the natural sciences.

“I hope you will continue to do what you love. I hope the people around you will not restrict you from doing what you want. Japan is not harnessing the talents of half of its population, a luxury the country does not have. We need to change the environment so that women are free to pursue their interests. I would like to urge society to make proper use of the talents of half of its population and involve them in the production of knowledge.”

Well, does Professor Sugimura enjoy her job?

"Yes, I'm doing what I wanted to do when I was 16," she smiles.

laboratory: http://www.koolau.info/about.html

※Year of interview: 2023
Interview・Text: Minoru Ota
Photography・ Video: Junichi Kaizuka

SUGIMURA Kaoru

Associate Professor, Department of Bioinformatics and Systems Biology, Faculty of Science, The University of Tokyo

She graduated from the Faculty of Science at Kyoto University in 2001, and from the Graduate School of Science at Kyoto University in 2006. After working as a JSPS Research Fellow and a RIKEN special postdoctoral researcher, she became an assistant professor in 2011 and an associate professor in 2017 at Kyoto University. She became an associate professor at the Department of Bioinformatics and Systems Biology, Faculty of Science, the University of Tokyo in 2021.