This story is from February 21, 2018

Scientists get peek into physics of 'brain folds'

Scientists get peek into physics of 'brain folds'
JAIPUR: Researchers at the Weizmann Institute of Science in Israel have found a way to track how the brain of human babies emerges from the womb “wrinkled like a walnut”. The research, published in journal Nature Physics, describes the method used for growing tiny “brains on chips” from human cells, which aided in tracking the physical and biological mechanisms underlying the wrinkling process.

A report on website Science Daily explained that tiny brains grown in the lab from embryonic stem cells, so-called organoids, were pioneered in the last decade by Yoshiki Sasai in Japan and Juergen Knoblich in Austria.
Orly Reiner of Weizmann Institute’s Department of Molecular Genetics said her lab, along with many others, embraced the idea of growing organoids. However, the sizes of the organoids they obtained were far from uniform. With no blood vessels, the insides did not have a steady supply of nutrients and started to die. The thickness of the tissue got in the way of the optical imaging and microscope tracking.
The researchers then developed a new approach to growing organoids -- one that would enable the group to follow their growth processes in real time, by limiting their growth in the vertical axis. This gave researchers a “pita”-shaped organoid -- round and flat with a thin space in the middle.
“This shape let the group to image the thin tissue as it developed and to supply nutrients to all the cells. And by the second week of the tiny ‘brain’s’ growth and development, wrinkles began to appear and then to deepen, Science Daily reported.
A physicist, Eyal Karzbrun, is part of this group of researchers. “He naturally turned to physical models for the behavior of elastic materials to understand the formation of the wrinkles,” Science Daily explained.

“Folds or wrinkles in a surface are the result of mechanical instability -- compression forces applied to some part of the material. So, for example, if there is uneven expansion in one part of the material, another part might be forced to fold in order to accommodate the pressure. In the organoids, the scientists found such mechanical instability in two places: the cytoskeleton -- the internal skeleton -- of the cells in the center of the organoid contracted, and the nuclei of the cells near the surface expanded. Or, to think of it another way, the outside of the ‘pita’ grew faster than its inside.”
The website explained that while this achievement was impressive, Reiner was not convinced that wrinkles in the organoids were really modeling the folds in a developing brain. The group grew new organoids, this time bearing the same mutations carried by babies with smooth brain syndrome. Reiner had identified this gene -- LIS1 -- back in 1993, and has continued to investigate its role in the developing brain and in the disease, which affects one in 30,000 births, the website report said.
“Among other things, the gene is involved in the migration of nerve cells to the brain during embryonic development, and it also regulates the cytoskeleton and molecular motors in the cell.
“The organoids with the mutated gene grew to the same proportions as the first group, but they developed few folds and the ones they did develop were very different in shape from normal wrinkles. Working on the assumption that differences in the physical properties of the cell were responsible for these variations, the group investigated the organoid’s cells with atomic force microscopy,” the report said.
The website report mentions that the scientific community had been showing interest in the new approach to growing organoids even before this paper’s publication. “It is not exactly a brain, but it is quite a good model for brain development,” Reiner says, “We now have a much better understanding of what makes a brain wrinkled or, in cases of those with one mutated gene, smooth.”
This research shows potential to unravel secrets behind brain disorders like microcephaly, epilepsy, and schizophrenia.
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