In short, scientists managed to genetically remove almost the entire cerebral cortex of rodents and reconstruct this vital area by grafting tissue derived from human stem cells. The procedure, called xenocortication, demonstrated that human cells can occupy almost the entire cranial cavity of the animal, integrating anatomically and functionally into its neural circuits.
Until now, the biggest obstacle in deciphering neuropsychiatric disorders and the mechanisms of brain development has been the lack of living tissue of human origin. Previous attempts to transplant small fragments of human tissue into the brains of mice or rats quickly encountered major structural limitations: the host animal tissue, which develops at an accelerated rate, suffocated the human graft and blocked its expansion.
To solve this dilemma, the research team led by Romanian-born Pașca created a host animal without a neocortex and hippocampus. For the pups to survive this profound anomaly, the researchers devised a care program, relying on highly active surrogate mothers and a high-calorie diet.
In the space left open, the doctors implanted four human cortical tissues each. The human tissue adapted with a success rate of more than 86% and began a spectacular growth phase.
Between the second and third months after the intervention, the volume of the graft increased almost fivefold, according to the article published in Nature.
By the end of the third quarter of life, human cells had come to form almost 92% of the animal’s entire cortical tissue, with an impressive density of approximately 32,000 neurons per cubic millimeter. This led to the appearance of extremely rare neurons, impossible to reproduce in the laboratory.
These include layer-five projection neurons and Von Economo cells, large, elongated neurons naturally present exclusively in mammals with highly complex brains, such as humans or cetaceans, and completely absent in rodents.
The discovery also represents a turning point for the medicine of the future, Dr. Mihail Pautov pointed out on his Facebook page. The xenocortication platform offers scientists the unique opportunity to observe the birth of human neural circuits in real time, study diseases such as autism or schizophrenia directly at the behavioral level, and test new drugs on living, functional human tissue, long before clinical trials begin in patients.
“You cannot take a piece of a living person’s brain to study a disease, because every millimeter there is someone: a word, a memory, a piece of personality. So we have learned about autism or schizophrenia from mouse brains, which do not develop these diseases, and from human brains examined at autopsy, when everything has already ended. It is as if you wanted to find out why an engine breaks down, but you are only allowed to look at another car’s engine, or yours after it has exploded. Sergiu got around this problem,” Dr. Mihail Pautov explained.
In a rare disease, Timothy syndrome, the research team found the exact defect this way and a candidate drug, which is now entering the first human trials.
“Sergiu Pașca graduated from medical school in Cluj and leads the brain organogenesis program at Stanford. He is the highest-ranked Romanian scientist in the diaspora and among the best neuroscientists in the world,” Pautov said.
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