Ribosomes, pictured here, synthesize proteins by translating messenger RNA (mRNA) into amino acid chains. Credit: Christoph Burgstedt/Science Photo Library
Researchers have engineered a time capsule for cells, capable of collecting and storing mementos of past activity.
The cellular storage units, called TimeVaults, could help unlock secrets to cancer-drug resistance and stem-cell biology, and more broadly how past events shape a cell’s future. The findings were published today in Science1.
TimeVaults are made from mysterious cell structures called vaults, which have been modified to collect and store the molecular products of gene transcription, known as messenger RNA (mRNA) molecules.
“This is a major step towards a longstanding goal in the field: being able to continuously record transcription in human cells,” says Randall Platt, a biological engineer at the Swiss Federal Institute for Technology in Zurich. “I anticipate that TimeVaults will allow us to observe facets of biology previously inaccessible to us.”
Cell recorders
Cells change constantly. Researchers tend to study their dynamics in two ways. One method is to watch them live under a microscope, where a limited number of types of molecules can be tracked for days with fluorescent tags. Another way is in test tubes at a single time point, usually the end of an experiment, where mRNA molecules can be measured and compared with those in other cells to reconstruct the past.
Over the last decade, researchers have developed a bevy of ‘cell recorders’ — many using CRISPR gene editing — to create an indelible genetic ledger of transient events, such as the activity of a particular molecular pathway over time. This ledger can then be read by genome sequencing to identify the edits at a later point, 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 and genome biology at Harvard University in Cambridge, Massachusetts.
In search of an unbiased way of recording of a cell’s lifetime, Chen and his colleagues found inspiration on YouTube. A student in his lab came across a profile of Leonard Rome, who goes under the name of Vault Guy. Rome is a cell biologist at the University of California, Los Angeles, and host of an educational YouTube channel about mysterious, barrel-shaped cellular organelles called vaults. In the 1980s, Rome co-discovered vaults, which are present in the thousands in most mammalian cells. Yet their function has remained unknown ever since.
To turn vaults into time capsules, Chen’s team reengineered a vault protein in such a way that it recognizes and links to a molecular hallmark of mRNA molecules, thereby capturing the mRNA inside the vault. The production of this protein — the equivalent of hitting the ‘record’ button — is triggered by treating cells with a drug and stopped by withdrawing the drug.
With these modifications, the TimeVaults captured a small fraction of all of the mRNA molecules produced by a human cell line over a 24-hour window, and stored them for at least a week, Chen’s team found. The researchers found no sign that cells with TimeVaults behaved differently because of their cargo, nor that the barrel-shaped structures changed shape or size once filled. “They are incredibly happy,” Chen says.
Practical applications
Chen’s team is just beginning to play around with their invention. In the Science paper, Chen’s team used TimeVaults to understand — and overcome — pernicious cancer cells known as persisters. These cells lack genetic mutations that evade targeted cancer drugs, yet somehow survive drug treatment.