A new method called Zman-seq, reveals the history of cells and may advance the development of new therapies for cancer and other disorders. Researchers from Ido Amit’s lab at the Weizmann Institute of Science report they managed for the first time to develop a method for tracking and measuring changes over time on in single cells inside the body.

The new study is published in Cell in an article titled, “Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.”

The method, called Zman-seq (from the Hebrew word zman, for “time”), consists of labeling cells with different time stamps and tracking them in healthy or pathological tissue. Using this cellular time machine, researchers can get to know the cells’ history and how long each cell had stayed in the tissue, ultimately achieving an understanding of the molecular and cellular temporal changes that had taken place within that tissue.

“Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology,” the researchers wrote. “Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma.”

The development of the new technology started with the research of Daniel Kirschenbaum, PhD, a postdoctoral researcher in Amit’s lab. Kirschenbaum was born in Hungary and did his PhD in neuropathology in Switzerland, where he studied glioblastoma, the most common and aggressive brain tumor. “We usually think of cancer as cells growing out of control, but in fact, cancer is also the loss of the ability of the body, and specifically of its immune system, to control this growth,” he said. “And when you look at tumors, large parts of them are composed of dysfunctional immune cells, which sometimes make up one third or even half of all the cells in a tumor.”

Glioblastoma is one of the most immune-suppressive types of tumors. “Ideally, we’d want to have a little clock on each cell telling us when it entered the tumor and when the signals and checkpoints that instruct it to become incompetent are activated. This back to the future time machine was thought to be impossible to develop.”

The researchers decided to try to mark the cells while they are still in the blood—before they enter the tumor. By using different fluorescent dyes at different time points, they are later able to know exactly when each cell entered the tissue and how long it had been there.

The challenge, Kirschenbaum added, was to develop the optimal way to color the cells in the blood at specific time points, making sure the dye does not reach the tissue itself or stay too long in the blood, potentially mixing with the next dye. At the same time, the dye had to stay on the cells long enough for them to be measured.

Using Zman-seq, Kirschenbaum and his colleagues were able to gain insights into why the immune system is so dysfunctional in battling glioblastoma. “For example, we showed that immune cells called natural killer cells, which, as their name implies, are crucial to killing rogue cells, become dysfunctional very quickly because the tumor hijacks their killing mechanisms—and this happens within less than 24 hours after their entry into the tumor. This explains why therapeutic attempts to harness the immune system for fighting glioblastoma are so ineffective,” Kirschenbaum said.

The researchers in Amit’s lab are now developing ways to block the immune-disabling tumor checkpoints in order to reactivate the immune system in glioblastoma and other hard-to-treat tumors. In addition, they plan to adapt Zman-seq to the study of temporal dynamics of cells throughout the human body. “For example, many cancer patients are getting therapy before surgery. We want to use the method to color immune cells in the body during that period so that after the surgery, we can better understand the dynamics of immune cells in the tumor and optimize patient treatments,” added Kirschenbaum.

“Until today, there were quite a few different methods trying to analyze single-cell data and arranging them along a time axis according to different parameters. But these approaches were all somewhat arbitrary in choosing what are the sequence of events,” Amit said. “Zman-seq supplies the ‘hard facts,’ the empirical measurements enabling scientists to understand the precise order of events that immune and other cells are going through when they enter a tumor, and this may lead to a completely new thinking on how to generate more effective therapies for cancer and other disorders.”

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