Technion Stem-cell Researcher Becomes First Israeli Scientist to Win Prestigious Prize

Prof. Yaron Fuchs’ breakthrough cell research wins him American Association for the Advancement of Science prize for regenerative medicine and cell therapy

Asaf Ronel
Asaf Ronel
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Prof. Yaron Fuchs at the Technion, March 7, 2019.
Prof. Yaron Fuchs at the Technion, March 7, 2019. Credit: Nitzan Zohar / Technion Spokesperson
Asaf Ronel
Asaf Ronel

When does a cell decide to die? Every second, an average of a million cells in our bodies kill themselves. But adult stem cells, which are found in various tissues and are characterized by their ability to develop into different types of cells have been thought of in recent years as being almost immortal because of their ability for infinite cell division.

These characteristics have awarded stem cells great scientific interest for a long time, and this has led to a great deal of scientific and medical benefits. But these cells can, and sometimes must, die too, and the question of what causes an almost immortal cell to commit cellular suicide has received almost no attention until recently.

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Prof. Yaron Fuchs, who heads the laboratory of stem cell biology and regenerative medicine at the Technion – Israel Institute of Technology in Haifa focuses his research precisely on these questions: When, why and how do stem cells decide to kill themselves. Adult stem cells need to be especially resilient because of their longevity, says Fuchs, whose research is on apoptosis, a form of programmed cell death in multicellular organisms. But if something bad happens to them, you need to have a mechanism to kill them as fast as possible otherwise there is a reasonable chance that they will develop into cancerous growths, he told Haaretz.

Fuchs’ discoveries so far, along with the great potential of his ground-breaking research, have made him the first Israeli scientist to win the American Association for the Advancement of Science prize for regenerative medicine and cell therapy. In an article published in the prestigious journal Science, published by the AAAS, Fuchs presented his discoveries about the therapeutic promise of apoptosis and the factors involved in cellular suicide of stem cells. The article discusses the scientific and medical potential of future research on the question, whether for healing wounds and for tissue regeneration or for finding new techniques for fighting cancer. Because of the durability of adult stem cells, Fuchs says he expects to find that their mechanism for apoptosis is different than in regular cells.

Mechanism of cellular suicide

To understand the mechanism of cellular suicide in stem cells, Fuchs focused initially on a tissue with a large number of adult stem cells: the hair follicle. The first discovery in the context of this research, made by Prof. Sarit Larisch of the University of Haifa, was the function of a protein called ARTS in the apoptosis of stem cells. “If the gene that is responsible for creating this protein is deleted, the stem cells of the hair follicle stop killing themselves; as a result their number rises significantly, to about double the original,” Fuchs says. That caused wounds inflicted on mice in the course of the research to heal at an accelerated pace 10 times the normal rate. No less important, scarring was significantly reduced.

From hair follicles, Fuchs and his team went on to study the effect of the protein on stem cells in the intestinal epithelium, the single-cell layer that lines both the small and large intestine. Epithelial cells line the surfaces of the body and its organs, and their stem cells are constantly dividing in order to repair damage to the lining. Fuchs says their research showed that deleting the gene responsible for ARTS in the epithelium helped animals to recover from a variety of diseases and injuries characteristic of the intestines, including damage to the tissue as a result of cancer treatments.

The next breakthrough that took place in the laboratory in the Technion challenged one of the most fundamental assumptions in the study of apoptosis for many years. Fuchs explains that one of the main ways for scientists studying cellular suicide to identify the process was by measuring a protein called caspase-3. The assumption was that it plays a role in the process of programmed cell death. But in the laboratory, he says, it was discovered that in many cells with caspase-3, no signs were found indicating progress of the process of apoptosis. In fact, some cells with the protein continued to divide.

In an article published a few months ago, Fuchs and his colleagues presented the two different scenarios in which the function of caspase-3 is reversed. The protein acts like scissors in the cell. In one situation, it travels through the cell and cuts anything in its path, thereby encouraging cell death. But in the second scenario, the cutting operation focuses on cutting the control that inhibits the operation of another protein, called YAP. Caspase-3 can liberate YAP, which then enters the cell nucleus and affects the expression of genes that promotes cell division. “When YAP gets out of control, it promotes the development of cancerous growths, including melanoma,” Fuchs says.

He says that understanding the interaction of these two proteins could make cancer treatments significantly more effective. “This discovery... sheds light on standard-of-care cancer treatments like radiation and chemotherapy, which intentionally accelerate caspase-3 activity to execute tumor cell apoptosis,” Fuchs says.

Earlier research showed that when there is a high concentration of the protein, the prognosis for recovery declines. And so, by understanding the dual role of caspase-3, the scientist and his colleagues came to an understanding of this seeming contradiction. “When you try to extinguish one fire, you ignite another,” he says, adding that his laboratory is now working on showing how inhibiting the protein’s operation in human melanoma cells significantly delays the development of the cancerous cells.

An additional area of research for Fuchs, together with Herman Steller and Ainhoa Perez-Garijo of New York’s Rockefeller University, undermined a long-standing basic scientific assumption about apoptosis, according to which cellular suicide was a discrete process that did not affect other cells. “We discovered that when cells suicide, they release signals into their environment,” Fuchs says. He adds that there is a signal that encourage nearby cells to proliferate and a signal that encourages them to kill themselves. “Each cell reacts differently to the mixed message,” the researcher explains. Healthy cells aren’t affected by the suicidal instruction, and respond to the signal that stimulates proliferation, while the suicide signal induces cells that are in bad shape to kill themselves.

This discovery explains, among other things, why malignant growths respond to treatments that are meant to kill them by accelerating their growth rate instead: It’s because the dying cells transmit signals encouraging the healthy cancer cells around them to divide more quickly. This discovery, too, Fuchs hopes, will lead to new treatments. His lab is working on showing how “they can promote tissue regeneration by strengthening the positive signals and promoting the death of cancer cells by reinforcing the negative signals.”

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