Ribosomes, pictured, make proteins by translating messenger ribonucleic acid (mRNA) into chains of amino acids. Credit: Christoph Borgstedt/Science Image Library
Researchers have designed a time capsule for cells, capable of collecting and storing mementos of past activity.
Cellular storage, called TimeVaults, can help unravel the secrets of cancer drug resistance, stem cell biology, and, more broadly, how past events shape a cell’s future. The results were published today in sciences1.
TimeVaults are made of mysterious cell structures called vaults, which are modified to collect and store the molecular products of gene transcription, known as messenger RNA (mRNA) molecules.
“This is a big step toward a long-term goal in this field: the ability to record transcription continuously in human cells,” says Randall Platt, a bioengineer at the Swiss Federal Institute of Technology in Zurich. “I expect TimeVaults will allow us to observe aspects of biology that were previously inaccessible.”
Cell recorders
Cells are constantly changing. Researchers tend to study their dynamics in two ways. One way is to view them directly under a microscope, where a limited number of types of molecules can be tracked for several days using fluorescent markers. Another method is to use test tubes at a single point in time, usually the end of the experiment, where mRNA molecules can be measured and compared to those in other cells to reconstruct the past.
Over the past decade, researchers have developed an array of “cellular recorders” — many of which use the gene-editing technology CRISPR — to create an indelible genetic record of transient events, such as the activity of a particular molecular pathway over time. This ledger can then be read by genome sequencing to determine the point of subsequent modifications, creating a timeline of cellular events.
But these have a downside: Researchers have to decide in advance which events they want to monitor, says Fei Chen, who studies single-cell biology and genomics at Harvard University in Cambridge, Massachusetts.
Searching for an unbiased way to record cell lifespan, Chen and his colleagues found inspiration on YouTube. In his lab, a student found a profile of Leonard Roma, who goes by the name Vault Guy. Roma is a cell biologist at the University of California, Los Angeles, and hosts an educational YouTube channel about mysterious, barrel-shaped cell organelles called vaults. In the 1980s, Rome participated in the discovery of vaults, which are present in the thousands in most mammalian cells. However, its function has remained unknown since then.
To turn the vaults into time capsules, Chen’s team re-engineered the vault protein in such a way that it could recognize and bind to the distinct molecular feature of mRNA molecules, thus capturing the mRNA within the vault. Production of this protein – the equivalent of pressing the “record” button – is stimulated by treating the cells with a drug, and stopped by withdrawing the drug.
With these modifications, TimeVaults captured a small fraction of all the mRNA molecules produced by a human cell line over a 24-hour period, and stored them for at least a week, Chen’s team found. The researchers found no sign that cells containing TimeVaults behave differently due to their load, nor that the barrel-shaped structures change shape or size once full. “They are very happy,” Chen says.
Practical applications
Chen’s team has just begun trialling their invention. in sciences In a paper, Chen’s team used TimeVaults to understand and defeat malignant cancer cells known as persisters. These cells lack genetic mutations that avoid targeted cancer drugs, yet somehow survive drug treatment.