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Start with one cell

The long and winding road to doubling the amount of biological material available for research

The field of epigenomics deals with the control of the genetic material and includes cellular control components, including methylation, chromatin and RNA. Methylation is the attachment of a methyl group (hydrocarbon substance) to genes. Unique proteins can bind to this group that block access to the genes, thus silencing them and preventing them from being expressed; Chromatin is a long fiber that consists of proteins and packs the DNA inside; And RNA are molecules that play an important role in the production of proteins according to the information contained in DNA.

These components allow progenitor cells (stem cells) to decide which cell to differentiate into (eg bone cells, cartilage cells, skin cells, nerve cells, muscle cells and more). This differentiation is essential for embryonic development (formation of organs) and tissue regeneration (a field that is also used in regenerative medicine). Disruptions in the differentiation process in the embryonic stage will cause developmental defects, and later disruptions may cause diseases such as cancer.

Dr. Ram Oren from the Institute of Life Sciences at the Hebrew University and his team research epigenomics to deeply understand cellular processes that may go wrong and cause injuries and diseases. "Until now, biological processes have been studied with the thought that they occur in a similar way in all cells," says Dr. Oren, "but today there is a growing understanding that in every biological system there is great intercellular variation. For example, not all embryonic stem cells differentiate in the same way into different organs. In the initial stage of the process, some are still naive (unsorted) and some are already in preparation for differentiation."

To better understand intercellular variation, Dr. Oren and his team - with the help of a research grant from the National Science Foundation - are focusing on developing technologies by which they isolate cells to examine and measure each of them individually. For example, they developed a technology based on creating droplets (using oil and water) and trapping cells (human or mouse, healthy or diseased) in the contents, so that each droplet contains a single cell.

"In order to understand biological processes that are behind the development of diseases, we must examine them at the level of the single cell," says Dr. Oren. "This is the only way we can understand what happens to each of the cells - for example, what does not work in it, how its chromatin functions, how drugs affect it, how it reacts to gene silencing, and why one cell is destroyed and another survives. Using the technology we developed, we can take each cell separately and measure all these parameters and other factors in it."

This is where a difficulty arises: in each such individual cell, the amount of material (such as RNA, DNA and chromatin) is very small and therefore difficult to study. Therefore, in their latest research, which won a grant from the National Science Foundation, Dr. Oren and his team sought to overcome this problem and increase the amount of material in a single cell.

This time, too, they used the droplet technology - they introduced liquid, oil and cells (in one experiment human lung cancer cells and in two experiments mouse embryonic stem cells) - but also added a substance that hardens (peg-dextran). Thus, after a few minutes, the texture of the drops became a gel and they trapped the cells in the contents. After that, the researchers began to grow the trapped cells, which multiplied so that dozens of cells of the same origin were obtained from them; Each cell replicated into more and more cells that resembled it, and the amount of material they contained increased accordingly. "This way we could treat 30 cells, for example, as a single cell because they were very similar to each other, and we were able to measure 30 times as much material," says Dr. Oren.

In this way, the researchers were able to discover findings that they had not discovered before (when examining individual cells). For example, they discovered a group of cells in lung cancer that are less sorted and thus divide and spread faster. In addition, they discovered that the decision of embryonic stem cells to differentiate occurs at a much earlier stage than they thought (the signal for the start of differentiation was already given at the stage when they were single, before they duplicated).

"We have identified a unique group of cells in lung cancer," he says, "and it is possible that in the future we will be able to investigate its characteristics in depth and thus know how to overcome it, and which medicine to use. Thanks to the discovery in the embryonic stem cells, we have a deeper understanding of the differentiation process - which already begins at the RNA level in the cell. It can be concluded from this that the decision on the method of differentiation in laboratory experiments should be made at an earlier stage".

Life itself:

Dr. Ram Oren, 45, married with three children (11, 13, 16), lives in Netaf and likes bouldering (on large rocks). He says that he chose to engage in research, after he had a girl born with a rare genetic disease (a mutation in the GABRG2 gene, which makes her special needs). Today, a project to research the disease is taking place in his laboratory at the same time as the other studies.