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Going deeper into the roots of the diseases

Researchers have built cellular models of genetic diseases such as fragile X syndrome and found the mechanism that causes them

Embryonic stem cells. Illustration:
Embryonic stem cells. Illustration:

Pluripotent stem cells ("multipotent") are cells that can differentiate into any cell in the body, therefore they have the potential to regenerate and heal damaged tissues and organs (regenerative medicine).

What is the question? How do you build disease models to develop ways to cure them?

Prof. Eran Mashorer from the Department of Genetics and the Edmond and Lili Safra Neuroscience Center (ELSC) and Prof. Nissim Benvanisti from the Department of Genetics at the Hebrew University, Prof. Shulamit Levenberg from the Faculty of Biomedical Engineering at the Technion and Prof. Ohad Birak from the Faculty of Health Sciences at Ben Gurion University and from the Institute of Human Genetics at the Medical Center Soroka develop models of genetic and brain diseases, based on pluripotent stem cells, to understand their mechanisms and discover ways to cure them. "It is often difficult to understand what is happening in the brains of patients with these diseases, and even if it is studied in mice, it is difficult to extrapolate from this to humans. That's why we build models of human cells where we model the diseases in a dish. This way we can learn a lot about their pathology (among other things about the expression of genes and proteins in them) and test substances that reduce or cure them", explains Prof. Meshorer.

In their latest study, which won a grant from the National Science Foundation, the researchers built cellular models of genetic diseases such as Fragile X and Huntington's syndrome. Fragile X syndrome is the most common hereditary cause of developmental intellectual disability and autism. It is caused by a mutation in the FMR1 gene (Fragile X Mental (Retardation on the X chromosome which causes it to be silenced. Normally this gene codes for FMRP - a protein essential for the development of the brain). Huntington's is a neurological disease characterized by motor disorders (annoying involuntary movements that can lead to instability, falls and injuries), cognitive (such as decreased memory and concentration) and psychiatry (such as severe depression and psychosis). It is caused by a mutation in the gene responsible for coding (producing) a protein called huntingtin - which plays an important role in the activity of brain cells and is necessary for their metabolism, their development and communication between them.

For the purpose of building the models of the diseases, the researchers produced pluripotent stem cells from skin samples taken from the patients, reprogrammed them (an artificial soaking process in which a certain genetic program is expressed) and thus could turn them into any type of cell they wanted. In this case they decided to make nerve cells (neurons) and brains (miniature versions of the brain that contain many types of neurons) from them. This is how they created models of the diseases. At the same time, neurons were isolated from the patients' skin samples and the mutation was corrected using CRISPR genetic editing technology. In this way, they created two systems with a similar genetic background - of sick (with mutation) and healthy (without mutation) neurons - and were able to compare them.

In this way, among other things, they created an authentic model for fragile X syndrome, in which the mutation causes the duplication of nucleotides that make up the DNA, and therefore the FMR1 gene undergoes methylation (the attachment of a methyl group to the DNA molecule) and its expression is silenced. They marked the gene with fluorescence methods and saw that in the diseased neurons there was no light because it was not expressed and in the healthy neurons there was a green light.

The researchers found two substances. One causes demethylation of the genetic material, and the other opens the chromatin of the gene, and together they cancel the silencing of the gene and cause its expression.

Following this, substances that stimulate the gene were applied to the diseased neurons (which were located in the libraries of substances that affect the chromatin - the DNA and the substances accompanying it - in the cell). This is how they found two substances - one causes the demethylation of the DNA and the other opens the chromatin of the gene and together they cancel the silencing of the gene and cause its expression. This could be seen when the garden was re-marked and glowed green. According to Prof. Mashorer, "the hope is that it will be possible to test these substances in experiments with patients with the syndrome so that they will encourage the expression of the gene and lead to a cure." 

In another part of the study, the researchers damaged each of the genes in the genome that code for proteins (about 18,000 in number) using CRISPR technology to understand which of them are involved in the silencing of FMR1 and to identify substances that would damage them. This experiment is still ongoing.

Life itself:

  • Prof. Nissim Benvanisti, director of the Azrieli Center for Stem Cells and Genetic Research at the Hebrew University, married, father of three and grandfather of three, lives in Jerusalem.
  • Prof. Eran Mashorer, 52, married + three (22, 20, 13) + a cat and a dog. Lives in Neve Ilan. likes to ride a bike, run, play the guitar and cook.
  • Prof. Shulamit Levenberg, 53, married + six children (27, 26, 24, 20, 17, 14), lives in the heritage settlement. She likes to read, travel in nature and ride a bike ("but I really don't reach Eran's level").
  • Prof. Ohad Birak, geneticist, doctor and researcher. Married to Prof. Ruth Birak and father of Jonathan and Michael. Lives in Rehovot and travels every day to Be'er Sheva. Plays the piano and composes.

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