OOne of the longest-standing questions in biology is how a living thing, which begins as an embryonic clump of unitary cells, transforms over time into an organism with diverse tissues, each with its own unique patterns and properties. The answer would explain how a leopard gets its spots, a zebra its stripes, trees their branches, and many more mysteries of pattern evolution in biology. For more than half a century, the preferred explanation has been an elegant model based on chemical signals proposed by mathematician Alan Turing, which has achieved many successes.
But a growing number of scientists suspect that Turing’s theory is only part of the truth. “In my opinion, we were blind to how widely it should be applied just because of its beauty,” said Amy Shyer, a developmental biologist at Rockefeller University. In her opinion, physical contraction and compression forces that act on cells during growth and division could also play a central role.
And now she has proof of it. In a publication in cell In May 2022, Shyer, her co-senior author and developmental biologist Alan Rodrigues, and their colleagues showed that mechanical forces can induce embryonic chicken skin to form follicles for feather growth. Just as surface tension can draw water into spherical beads on a glass surface, the physical stresses within an embryo can create patterns that guide growth and gene activity in developing tissues.
As an organism grows and develops, the cells in its tissues pull and push against each other and the supporting protein scaffold (extracellular matrix) to which they are intricately connected. Some researchers have suggested that these forces, coupled with changes in cell pressure and stiffness, could guide the formation of intricate patterns. However, no studies to date have been able to separate the action of these physical forces from the chemical stew in which they simmer.
extract a pattern
At the Rockefeller University Morphogenesis Laboratory, which they co-direct, Shyer and Rodrigues removed the skin from a chicken embryo and dissected the tissue to pull the cells apart. Then they put a drop of the cell solution in a Petri dish and let it grow in culture. They watched as the skin cells self-organized into a ring at the bottom of the dish — like a 2-D version of the ball of cells that the embryo normally becomes. Pulsing and contracting, the cells pulled on collagen fibers in the extracellular matrix they had built up around them. Over 48 hours, the fibers gradually twisted, bunched up, and then pushed each other apart, forming bundles of cells that became feather follicles.
“This was such a clean, simple setup that you could see a nice pattern and check it quantitatively,” said Brian Camley, a biophysicist at Johns Hopkins University who wasn’t involved with the study.
Later, by adjusting the rate of cell contraction and other variables, the researchers showed that physical tension in the embryonic mass directly affected the pattern. “I think the biggest surprise was the way the cells interacted with the extracellular matrix in this very dynamic way to create these patterns,” Rodrigues said. “We realized that it’s a reciprocal dance between the two of them.”
“This suggests that contractility may be sufficient to drive pattern formation,” Camley said. “This is a really new, must-have piece.”
Mechanics first, genes later?
The mathematician D’Arcy Wentworth Thompson suggested as early as 1917 that physical forces could guide evolution. In his book About growth and formThompson described how torsional forces control horn and tooth formation, how eggs and other hollow structures are formed, and even the similarities between jellyfish and liquid droplets.
But Thompson’s ideas were later eclipsed by Turing’s explanation, which was more easily linked to the emerging understanding of genes. In a 1952 paper, The Chemical Basis of Morphogenesis, published two years before his death, Turing suggested that patterns such as spots, stripes, and even the sculpted shapes of bones in the skeleton were the result of a swirling gradient of chemicals , called morphogens, which interacted with each other as they spread unevenly in cells. As a molecular blueprint, the morphogens would initiate genetic programs that led to the development of fingers, rows of teeth, or other parts.
Turing’s theory was popular among biologists for its simplicity and soon became a central tenet of developmental biology. “There’s still a strong molecular and genetic view of most of the mechanisms in biology,” Rodrigues said.
But something was missing from this solution. If chemical morphogens drive development, Shyer says scientists should be able to show that one precedes the other—chemicals first, then pattern.
She and Rodrigues were never able to show this in the lab. In 2017, they took small slices of chicken embryo skin and watched closely as the tissue bunched together to form a follicle. At the same time, they tracked the activation of the genes involved in follicle formation. They found that gene expression occurred around the same time the cells were clustering — but not before.
“Instead of ‘first gene expression, then mechanics,’ it was like the mechanics were creating these shapes,” Shyer said. They later showed that even removing some of the gene-regulating chemicals didn’t disrupt the process. “That opened a door to be like, ‘Hey, there might be something else going on here,'” she said.
The active soft matter of biology
Shyer and Rodrigues hope their work and future research will help elucidate the role of physics and how it interacts with chemicals and genes during development.
“We realize that all of molecular gene expression, signaling, and the generation of forces involved in cell movement are simply inseparably coupled,” said Edwin Munro, a molecular biologist at the University of Chicago who was not involved in the study.
Munro believes the role of the extracellular matrix is more important than scientists currently realize, although recognition of its more central role in development is growing. For example, recent research has linked forces in the extracellular matrix to the development of fruit fly eggs.
Rodrigues agreed. “It’s like the cells and the extracellular matrix are forming a material on their own,” he said. He describes this coupling of contractile cells and extracellular matrix as “active soft matter” and believes this points to a new way of thinking about the regulation of embryonic development by extracellular forces. In future work, he and Shyer hope to elucidate more details about the physical forces involved in development and to merge them with the molecular perspective.
“We used to think that if we just looked at the genome with more and more depth and rigor, all of this would be clear,” Shyer said, but “the answers to the important questions may not lie at the genome level.” as if developmental decisions are made by the interplay of genes and their products inside cells, but the emerging truth is that “decision making can take place outside the cell, through the physical interactions of cells with each other.”
Leading image: Isolated embryonic chicken skin cells self-organized in a laboratory dish. Over 48 hours, the force of the cells pulling against each other caused them to cluster into follicles for feather growth. Credit: Karl Palmquist.
This article was originally published on the quantum abstractions to blog.