“Returning to the Past: Researchers Pave the Way for the First Technique to Track Temporal Cellular Changes in the Body”

As physicists engage in ongoing debates regarding the possible illusion of time, biologists strongly affirm its crucial role in comprehending life as a dynamic system. Recent advancements have allowed biologists to delve deeper into complex biological systems, employing tools that enable the simultaneous analysis of extensive cellular and molecular data, and the exploration of cellular circuitry underlying diseases. Despite these profound investigations into cellular behavior and interactions, the obtained insights have been limited to individual snapshots, lacking a temporal dimension to reveal the sequence of cellular events within intricate organisms.

In a recent publication in Cell, researchers from Prof. Ido Amit’s lab at the Weizmann Institute of Science have introduced a groundbreaking method, named Zman-seq (derived from the Hebrew word “zman” meaning “time”), capable of monitoring and quantifying changes over time within individual cells within the body. Zman-seq involves the labeling of cells with distinct time stamps, enabling their tracking within healthy or diseased tissues.

This innovative cellular time machine empowers researchers to unravel the cellular history, duration of each cell’s residence in the tissue, and gain insights into the molecular and cellular temporal alterations occurring within that specific tissue. Recent advancements in single-cell technologies, pivotal for comprehending intracellular processes, owe much to the flourishing single-cell research community, with Amit’s lab serving as a pioneering force. These tools now provide the capability to generate high-resolution images depicting disease progression, the body’s response to various drugs, the identification of rare cell subsets, and the deciphering of cell interactions and spatial distribution within tissues.

Nevertheless, despite these critical insights, the analogy to obtaining numerous still-frame images from a movie and trying to comprehend the plot holds true. According to Amit, “Knowing what preceded what is not enough to deduce causality, but without this knowledge, we don’t really have a chance of understanding what the cause is and what is the effect.”

The groundbreaking technology, named Zman-seq (derived from the Hebrew word “zman” meaning “time”), was initiated through the research efforts of Dr. Daniel Kirschenbaum, a postdoctoral researcher in Amit’s lab. Kirschenbaum, originally from Hungary, completed his Ph.D. in neuropathology in Switzerland, focusing on glioblastoma, a prevalent and aggressive brain tumor. Cancer is often perceived as uncontrolled cell growth, but Kirschenbaum emphasizes that it is also a loss of the body’s ability, particularly the immune system, to regulate this growth.

In tumors, a substantial portion comprises dysfunctional immune cells, constituting up to half of all cells in some cases. Glioblastoma, being one of the most immune-suppressive tumors, posed a significant challenge. Understanding the immune cells’ behavior as they enter the tumor and the reasons behind their loss of ability to combat the tumor was crucial.

Kirschenbaum envisioned a “time machine” to track each cell’s entry and activation signals leading to incompetence, previously considered impossible. The breakthrough came by taking an unconventional approach—marking cells while still in the blood before entering the tumor using different fluorescent dyes at distinct time points.

This method allowed the researchers to precisely determine each cell’s entry time, revealing dynamic changes within the tissue. While facing challenges in coloring cells optimally in the blood without affecting the tissue, Kirschenbaum succeeded. The study demonstrated Zman-seq’s ability to measure time in immune cells across different tissues—brain, lungs, and the digestive system—in animal models.

The researchers used Zman-seq to gain insights into the immune system’s dysfunction in battling glioblastoma. Notably, they discovered that natural killer cells, vital for eliminating rogue cells, quickly become dysfunctional within 24 hours of entering the tumor, explaining the ineffectiveness of immune system-based therapies. Members of Amit’s lab, including Dr. Ken Xie and Dr. Florian Ingelfinger, contributed to Zman-seq’s development, with collaborators from various institutions.

The next steps involve blocking immune-disabling tumor checkpoints to reactivate the immune system in glioblastoma and adapting Zman-seq to study cellular temporal dynamics throughout the human body. Amit envisions Zman-seq as a revolutionary method providing empirical measurements to understand the precise sequence of events that immune cells undergo upon entering a tumor. This has the potential to reshape strategies for generating more effective therapies for cancer and other disorders.

This article is republished from PhysORG under a Creative Commons license. Read the original article.