by A study published in ‘Cell‘ presents for the first time developing a system to track and measure changes over time in individual cells within the body. The method, called Zman-seq (from the Hebrew word “zman”, meaning “time”), involves labeling cells with different time signatures and tracking them in healthy or pathological tissue. Using this “cellular time machine”, researchers from the laboratory of Gone Amit at the Weizmann Institute of Sciences (Israel) can learn the history of cells and how long each cell has remained in the tissue, ultimately gaining an understanding of the temporal molecular and cellular changes that have taken place within that tissue.
This information, the researchers explain, not only reveals the history of the cells but also serves to advance the development of new therapies for cancer and other disorders.
Single cell technologies, the tools that allow biologists to understand what happens inside individual cells, have come a long way in recent years, largely thanks to the vibrant single cell research community.
With these tools, it is now possible to obtain high-resolution images of how diseases develop and how the body responds to different drugs, identify rare cell populations, decipher which cells interact with each other and how they are spatially distributed in a tissue.
However, all of these big ideas are equivalent to getting a lot of stills from a movie and trying to understand the plot. “Knowing what preceded what is not enough to deduce causality, but without this knowledge, we don’t really have a chance to understand what is the cause and what is the effect,” explains Amit.
The development of new innovative technology began with research. Daniel Kirschenbaum, a postdoctoral researcher in Amit’s lab. Kirschenbaum was born in Hungary and completed his PhD in northeasturopathology in Switzerland, where he studied glioblastoma, the most common and aggressive brain tumor. “We usually think of cancer as cells that grow out of control, but in fact, cancer is also the loss of the body’s ability, and specifically its immune system, to control this growth,” he says. And when he observes tumors, large parts of them are made up of dysfunctional immune cells“which sometimes represent a third or even half of all the cells in a tumor.”
he glioblastoma It is one of the most immunosuppressive types of tumors. “To understand how to beat this cancer, we need to understand what happens to immune cells when they enter the tumor and why they lose the ability to fight the tumor and become dysfunctional,” explains Kirschenbaum. Ideally, we would want to have a little clock in each cell that tells us when it entered the tumor and when the signals and checkpoints that tell it to become incompetent were activated. “It was thought that this time machine to the future was impossible to develop.”
Time Machine
The breakthrough occurred when Kirschenbaum decided to take a surprising approach. “Rather than trying to time cells within the tumor tissue, we decided to try to label the cells while they are still in the blood, before entering the tumor. When using dyes fluorescent different at different times, we can know exactly when each cell entered the tissue and how long it was there, and this reveals the dynamic changes that occurred in the cells in the tissue, for example, what are the different stages in which immune cells develop. “They become dysfunctional within the tumor.”
The challenge was to develop the optimal way to color cells in the blood at specific times, ensuring that the dye does not reach the tissue or stay in the blood for too long, potentially mixing with the next dye. At the same time, the dye had to stay in the cells long enough to measure them.
As part of the study, researchers in Amit’s lab demonstrated that the method allows timing of immune cells in different tissues, such as the brain, lungs and digestive system of animal models.
This explains why therapeutic attempts to harness the immune system to combat glioblastoma are so ineffective.
Wearing Zman-seq, I was able to gain insight into why the immune system is so dysfunctional in the fight against glioblastoma. “For example, we show that immune cells called natural killer cells, which, as their name suggests, are crucial for killing errant cells, become dysfunctional very quickly because the tumor hijacks their death mechanisms, and this happens in less than 24 hours after entering the tumor. This explains why therapeutic attempts to harness the immune system to combat glioblastoma are so ineffective,” explains Kirschenbaum.
Now, researchers are developing ways to block tumor checkpoints that disable the immune system to reactivate the immune system in glioblastoma and other difficult-to-treat tumors.
Additionally, they plan to adapt Zman-seq to study the temporal dynamics of cells throughout the human body. « For example, many cancer patients receive therapy before surgery.. “We want to use the method to stain immune cells in the body during that period so that, after surgery, we can better understand the dynamics of immune cells in the tumor and optimize treatments for patients,” adds Kirschenbaum.
For Amit, “Zman-seq provides the ‘hard facts,’ the empirical measurements that allow scientists to understand the precise order of events that immune and other cells go through when they enter a tumor, and this may lead to completely new thinking.” on how to generate more effective therapies for cancer and other disorders.
