User:R1237h/Orly Reiner

Orly Reiner is a professor of molecular genetics and molecular neuroscience at the Weizmann Institute of Science, serving as the head of the Bernstein-Mason Professorial Chair of Neurochemistry and Head of the M. Judith Ruth Institute for Preclinical Brain Research. Her research deals with brain development, with the aim of understanding the molecular, cellular and developmental mechanisms that cause brain disease. The research includes modeling with mice and organoid models of the human brain using human stem cells.

Academic Career
Orly Reiner completed her Bachelor's degree in field crops at the Faculty of Agriculture at the Hebrew University in 1978. In 1985 she received her Master's degree in Microbiology, also at the Faculty of Agriculture at the Hebrew University. Her thesis dealt with the subject of the oxygen attraction mechanism of the soil bacterium Azospirillum brasilense, under the guidance of Prof. Jacob Okun. Reiner completed her Doctorate in molecular genetics in 1990 at the Weizmann Institute of Science. Her thesis dealt with the structure and control of genes involved in Gaucher's disease, a lysosomal storage disease under the guidance of Prof. Mia Horowitz.

Between 1990 and 1993, Rainer went on a three-year postdoctoral fellowship at the Baylor College of Medicine in Houston, Texas, under the guidance of Prof. Thomas Caskey, after which she returned to the Weizmann Institute as Senior Scientist in 1993. In 2002, she was appointed as a Associate Professor at the Weizmann Institute and in 2010 she was appointed as a full Professor at the same institution.

Research
During her post-doctorate, she isolated and identified the LIS1 gene as a gene involved in Lissencephaly, a rare syndrome, one in 30,000 births, characterized by the paucity of folds characteristic of the shape of the brain and causes death at a young age. This ground-breaking research was published in Nature in 1993 and received wide acclaim. In a series of studies in her laboratory at the Weizmann Institute, she found how the protein affects cell properties, in combination with other proteins, some of which are also involved in developmental brain diseases. The mutations that cause smooth brain syndrome are in one allele of the gene, so patients have about half the amount of the protein. Rainer prepared mouse models in the laboratory, which helped to understand how a small amount of the LIS1 protein disrupts the course of normal brain development. The absence of the protein causes the death of the fetus at a very early stage - before, or during implantation in the uterus. There are usually two copies (alleles) of each gene, one from the mother and one from the father. Sometimes there is an excess or a lack. Unlike in most cases, where a lack of a gene is not harmful, in the case of the LIS1 gene, a lack of one copy causes a smooth brain, while an excess causes delays in the development processes (developmental delay). In collaboration with Prof. James Lupski's group, they were able to show that an increase in the amount of protein causes developmental problems in the brain, both in humans and in mouse models. This work was published in Nature Genetics in 2009.

In further studies using mouse models, they were able to track migrating nerve cells, understand basic processes in brain development, and understand what goes wrong when there are changes in the genes that control these processes. Prof. Reiner's research on fetal neurons revealed that certain diseases may have two opposite causes: overproduction or underproduction of the enzymes responsible for connecting the fatty acid, which controls the speed of migration of nerve cells to the outer layers of the brain. Other studies have found that the innate immune system has a specific role in fetal brain development, causing neurons to migrate from the place of origin to target areas in the brain. If the system does not function properly, brain development can be impaired, which can cause neurodevelopmental disorders such as autism and mental retardation. This work was published in Nature Communications.

In the last decade, her group began using organoid models from human stem cells, which mimic developing brain tissue. Her research on the cortical folds published in Nature Physics (English) in 2018, described a unique system that makes it possible to study initial stages of human brain development in the laboratory (organoids) while overcoming nutritional limitations by growing them in the form of a thin and round structure that wraps an internal space, A structure reminiscent of a pita shape. The structure enables proper feeding of the cells and real-time simulation of the growth process and the development of the folds necessary for the proper development of the brain, using a physical model. The study verified the model by comparing it to organoids in which the LIS1 gene with a mutation that causes smooth brain syndrome was implanted. Atomic force microscopy helped prove that the mutant cells are less rigid than the normal cells, which allow the formation of folds. This discovery may help in the understanding of diseases such as epilepsy and schizophrenia. One of the factors affected by LIS1 activity is the production of extracellular proteins, Extracellular Matrix (ECM). A study she recently published in Nature Communication showed that LIS1 binds to RNA and hundreds of proteins in the cell and affects gene expression control at the level of transcription, splicing, binding to microRNA, translation, and more.

Prof. Rainer has published over a hundred articles.