Enhanced Organoids of the Human Brain to Boost Research on Neurological Diseases

Scientists at Harvard University and the Stanley Institute Psychiatric Research Center at the Broad Institute have made a major breakthrough in the development of the "organoids" of the human brain: miniature 3D tissue cultures modeling the brain cells of one's own brain. patient in a bowl. Their new method, published in Nature, systematically develops the same types of cells, in the same order, as the developing human cerebral cortex. This breakthrough could change the way researchers study neuropsychiatric diseases and test the effectiveness of drugs.

Genetics at the origin of human neurological disease is complex, with large expanses of the genome contributing to the onset and progression of the disease. The study of neurological diseases in other animals offers limited opportunities for relevant discovery, the human brain being quite distinctive.

Organoids are very promising for the direct study of the disease in humans. But until now, they have failed in a very important way.

"We can all use our brain differently, but each of us has the same collection of cell types and basic connections," said Paola Arlotta, lead author, professor of stem cell regenerative biology and the Golub family at Harvard. , and member of the Stanley Center. "This coherence is crucial and, with very few exceptions, it reproduces each time the human brain is formed in the uterus.There are only the smallest differences between us, in terms of types of cells and structures in our brains. "

Until now, this has not been the case with organoids. Although they generate human brain cells, each of them is unique. This means that they can not be used easily to compare differences between diseased brain tissue and control tissues.

"Organoids have dramatically improved our ability to study the developing human brain," Arlotta said. "But until now, everyone has been his own snowflake, creating his own special blend of cell types in a way that could not have been predicted at the outset. this problem."

Building on the pioneering work conducted by stem cell biologist Yoshiki Sasai, the team has created organoids that are virtually impossible to distinguish from each other, even if they have have been grown for more than six months in the laboratory.

In addition, under specific culture conditions, organoids were healthy and able to grow long enough to produce a broad spectrum of cell types that are normally found in the human cerebral cortex.

With these advances, brain organoids can now be used as viable experimental systems to directly study patients' tissue diseases and to compare different effects of drugs on human brain tissue.

The same cells, the same way

The researchers focused on the organelles of the cerebral cortex: the part of the brain responsible for cognition, language and sensations. The cerebral cortex plays a key role in neuropsychiatric diseases such as autism spectrum disorders and schizophrenia.

"We made organoids from multiple lines of stem cells, both male and female, so their genetic origins were different," said lead author Silvia Velasco, a Harvard researcher and Broad Institute researcher.

The tissues of the human brain grow very slowly. In this study, after six months, the organelles were three millimeters in diameter. In the largest monocellular RNA sequencing experiment performed to date in brain organoids, researchers grouped cells according to genes expressed at different stages. Using computer models for analyzing large data, they compared each group to the types of cells that develop in the embryonic cerebral cortex.

"Despite different genetic origins, we found that the same types of cells were made in the same way, in the right order and, most importantly, in every organoid," said Velasco. "We were very happy that this model gave us such consistency."

A new way to investigate the disease

Using the optimized method of this study, researchers could create organoids from stem cells derived from patients, or engineering cells containing mutations associated with specific diseases.

Arlotta's laboratory is currently exploring autism, using CRISPR / Cas9 gene editing techniques to develop brain organelles specific to this disorder.

"It is now possible to compare the control organoids with those we create with the mutations we know to be associated with the disease, which will give us a lot more certainty about the significant differences, the affected cells and the molecular pathways used. uncomfortable, "said Arlotta. "Having reproducible organoids will help us move much more quickly towards concrete interventions, as they will direct us to the specific genetic characteristics of the disease's origin." I plan to be able to pose in the future. much more specific questions about going wrong in the context of psychiatric illness ".

"In a short time, we have gained a remarkable amount of knowledge about the many types of cells in the human brain," said co-author Aviv Regev, a member of the Core Institute and president of the Broad Institute faculty, and co-chair. of the Atlas of Human Cells project. "This knowledge has allowed us to create models of this incredibly complex organ.To overcome the problem of reproducibility opens the door to the study of the human brain in a way that would have been deemed impossible a few years ago. barely."