Childhood home videos can be heartwarming, hilarious, or downright embarrassing. But the tapes contain an invaluable resource: snippets of a child’s journey as they learn to navigate the world. Sure, photos can also capture a first birthday or a first fall off a bike too — but rather than a movie, they’re single snapshots in time.
Scientists have long sought to embed DNA “camcorders” into cells to capture their history. Like kids, cells grow, diversify, and mature as they interact with the environment. These changes are embedded in a cell’s gene activity, and by reconstructing them over time, scientists can infer a cell’s current state — for example, is it turning cancerous?
The technology “would deepen knowledge about developmental and cancer biology that could be translated into therapeutic strategies,” said Dr. Nozomu Yachie and colleagues at the University of British Columbia.
The problem? The recording process has, to date, been comprised only of single snapshots and has destroyed the cell, making it impossible to track its growth.
Now, a team led by Dr. Seth Shipman at the UCSF Gladstone Institute engineered a biological recorder — dubbed Retro-Cascorder — that, like an old school camcorder, can capture a cell’s gene expression history on a DNA “tape,” for days at a time. Thanks to CRISPR, these “tapes” are then integrated into the cell’s genome, which can be read at a later date.
The resulting data isn’t exactly America’s Funniest Home Videos. Rather, it’s more of a ledger that documents multiple biological signals and neatly stores them in chronological order.
“This new way of collecting molecular data gives us an unprecedented window into cells,” said Shipman. Aside from eavesdropping into a cell’s developmental history — for example, how it diversified from a common stem cell — adding Retro-Cascorder could transform normal cells into living biosensors that monitor for pollution, viruses, or other contaminants, all the while testing DNA’s ability as a reliable data storage device.
The Rise of DNA Tapes
Why track a cell’s history?
Imagine a cell as a child. Starting from a fertilized egg, it grows, changes its outward appearance — into a skin cell or a neuron, for example — and for reproductive cells, passes on genetic information to its kids. A cell’s journey through life isn’t set by its genetics alone — rather, how its genetic instructions are carried out depends on interactions with both its cellular neighbors and the outside world: diet, exercise, stress, and anything its human host experiences.
These nature and nurture prompts trigger a cell to activate a certain pattern of genes — a process dubbed gene expression. All of our cells harbor the same set of genes; what makes them different is which ones are turned on or off. Gene expression is massively powerful: it can change a cell’s identity, function, and ultimately, the biological processes that govern life.
It’d be great to have a peek inside their inner workings.
One way is the snapshot approach. Using “omics” technologies — that is, analyzing millions of cells at the same time for gene expression, metabolism, or other states — we can get a high-resolution snapshot of a group of cells at a particular time. While powerful, the process destroys the sample. The reason is because reading the gene expression information stored within the cells, a method dubbed RNAseq, requires breaking down the fatty, bubbly envelope of the cell to access and extract the molecules. Imagine pointing the James Webb Telescope at any point in space, knowing that the telescope will obliterate anything it sees — yeah, not great.
DNA tapes take a different approach. Like a video editor, they “tag” a cell’s events with a barcode made up of DNA letters — a bit like a timestamp. Shipman is no stranger to using DNA as a storage device. Back in 2017, working with synthetic biologist Dr. George Church at Harvard and team, they encoded a digital movie into the genome of living bacteria using CRISPR.
A DNA Diary
The new study had a relatively simple goal: like a motion-tripped camera, start recording any time a particular gene turns on.
To design Retro-Cascorder, the team turned to an enigmatic genetic element, retrons. These are little chunks of bacterial DNA that flummoxed scientists for decades, before realizing that they form part of a bacteria’s immune system. Back in 2021, study co-author Church transformed retrons from a weird bacterial quirk into a gene editing tool that can screen millions of DNA variations, and follow their effects, at the same time. Crucially, they realized that retrons can be used as tags to timestamp a particular genetic change in time.
Here, the team began by engineering retrons to produce specific DNA tags — like printing a series of barcodes to mark packages. The tags are linked to DNA promotors, which, like a traffic light, give the cell the okay to turn on a gene.
Once a gene turns on, the retron automatically generates a unique barcode that certifies its activity. It’s a multistep process: the tag, originally encoded in DNA, is first transcribed into RNA by the cell, and then rewritten back into DNA “receipts” by retrons.
Think of a restaurant cash register. That’s the equivalent of printing out one order, at a certain time, with one receipt.
After verifying the technology works as expected, the team then turned to making “movies” of a cell using retron-based tags. It’s not a video in the traditional sense: the team still had to analyze the barcodes at the end of a recording session — around 24 hours — for playback, which destroys the cells.
Keeping track of gene expression changes in one snapshot in time is relatively simple. Keeping track of the same changes throughout a day is far more difficult. To build a “memory” of sorts for the recorder, the team turned to CRISPR-Cas. Here, CRISPR arrays act as the diary, whereas retrons as like daily entries. The DNA receipts, generated by retrons, are incorporated into a CRISPR array. Like cassette tapes, they contain data followed by spacers, like a black screen, to help separate events. As new information is added, previous spacers shift further away from the nearest entry, making it possible to decipher a timeline of events.
Cells with the ability to use CRISPR to write genetic data “can progressively record cellular events… into DNA tapes,” said Yachie.
In a proof-of-concept, the team introduced Retro-Cascorder into Escherichia coli (E. Coli), the lab’s favorite bacteria, through genetic engineering. Incorporating the new construct was a breeze for the bug, and a good sign for the scientists, as it suggests little stress or toxicity to the cells.
They then turned on either or both DNA promotors using chemicals, like clicking “record” on a Walkman. Over 48 hours, the system recorded gene expression changes as expected into the CRISPR array. After further digging into the sequence of CRISPR arrays — that is, reading them back afterward — they found that the cell’s history progressed as expected.
An Entire History of You
The new DNA tape is like recording little snippets of a movie through time. But it’s weirdly edited. While the Retro-Cascorder can tell the sequence of gene activations, it can’t pinpoint the timelapse between two adjacent events. Like in a home video, a clip of a dance rehearsal followed by a dinner might be on the same day; or years apart.
But compared to previous attempts, the tape is a technological leap, with better signals, longer recording duration, and better playback.
“This is not a perfect system yet, but we think it’s still going to be better than existing methods, which only enable you to measure one event at a time,” said Shipman.
The race for the perfect cellular documentarian is on, and most have CRISPR at their center. To Yachie, one way is to replace good-ole’-CRISPR with base editors or CRISPR prime, both of which cause less damage to the cell’s genome. The biological “VCR” —which reads back a gene’s recorded expression — also needs an upgrade, potentially powered by better computing prowess.
When more perfected, DNA recorders could help us track the developmental trajectory of mini-brains and other organoids, study cancer cells as they evolve, monitor for environmental pollutants in cells — all without putting lives at stake.
Image Credit: Immo Wegmann / Unsplash