New research at Sheba aims to leverage key mitochondrial differences to control how the immune system functions.
Sheba Medical Center’s Mitochondrial Research Lab has just won a series of prestigious grants for new research that could completely change how cancer treatment works, along with many other immune related diseases besides.
The Mitochondrial Research Lab is the brainchild of Dr. Tal Yardeni, whose body of work focuses on how small differences in the genetic and metabolic function of mitochondria have drastically different effects on immune cells. These differences can regulate how well the immune system can recognize and attack both pathogens and anomalous cellular growths such as cancers.
Unlike other work, which tends to look at metabolic functions in abnormal or compromised immune systems, Dr. Yardeni is examining how the natural differences between mitochondria can lead to drastically different outcomes. She has already proven direct links in animal research, identifying normal variations in mitochondria that can drive differences in immune response, leading to stronger or weaker activity in mice.
The ultimate goal of her research is to develop novel new therapeutic approaches for cancer and all immune diseases, all using a patient’s own immune system, strengthened through targeting their mitochondria.
“We are using cancer as one example,” Yardeni says. “But if we are talking about the immune system, we can also talk about autoimmune diseases, neurodegenerative diseases, any disease that is related to the immune system. This is our focus, to understand the mitochondria signature of each disease, and then to be able to adapt the immune cells of a patient to fight it.”
Other Sheba clinicians and researchers have followed suit, working with Dr Yardeni to understand how mitochondrial function influences the diseases they are working on.
Prof. Yaacov Lawrence is the Chair of The Benjamin Davidai Department of Radiation Oncology at Sheba Medical Center. He uses targeted radiation to kill tumors. This works by shooting a focused beam of X rays at the cancer cells, which causes catastrophic damage to their DNA. The damage prevents the cells from replicating and after several weeks, they die off. The problem is that some cancer cells are remarkably resistant, and are able to sometimes survive such therapies.
“One of my frustrations is that radiation isn’t always as effective as we want it to be,” Lawrence notes. “There are certain cancers where the outcomes are suboptimal. For instance, in pancreatic cancer, we can deliver very high doses of radiation, but the tumor rarely shrinks after treatment. We believe one of the reasons that pancreatic cancer cells are comparatively resistant to radiation is related to their [cellular] metabolism. We have a theory that’s why they are able to survive high-dose radiation therapy.”
Lawrence and Yardeni believe this is directly related to mitochondrial function. The cell’s mitochondria generate energy used to both replicate the cell itself, and critically, to repair damaged DNA. Strong DNA repair can negate the effects of radiotherapy, enabling the cell to survive.
As an oncologist, he sees further possible connections between his clinical work and mitochondrial research. Lawrence believes there is a link between mitochondrial function and apoptosis, predetermined cell death. Apoptosis is a cell’s natural death process, allowing the body to replace old and damaged cells with new ones. The old cell dies off to make room for a new one. However, in cancer cells, the normal apoptosis process is blocked, so cells simply add up instead of replacing the old ones, forming a tumor. The apoptosis process is also how cells with damaged DNA are removed from the body, meaning the process is critical to ensuring radiotherapy success. Finding the mechanism by which mitochondrial metabolism regulates cell death is therefore another key direction to overcoming resistant cancers.
The series of grants secured by the research center will build on this work to find the exact processes and mechanisms that underlie treatment resistance and according to Yardeni and Lawrence will lead to a new generation of cancer therapies.
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