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Researchers have coaxed mouse brain cells to produce self-assembling protein chains that can record information, or “memories”, about the hidden processes taking place within the cells. Once fully formed, these biological black boxes can be easily read using a light microscope, potentially revolutionizing how scientists study cellular processes and the diseases that affect them.
Cells are hubs of constant activity, performing the crucial daily tasks that keep organisms alive. This activity is coordinated by specific “cellular events”, such as the expression of certain genes or the triggering of cellular pathways, a series of interactions between molecules in a cell that lead to a specific product or a change in a cell. But understanding exactly how these cellular events unfold can be challenging.
By imaging the proteins, RNA or other molecules created during these events inside the cells, scientists have learned how most cellular events work. However, this method provides only a brief snapshot of the event. And while these snapshots can be stitched together to form a loose picture, researchers are likely to miss much of what is really happening.
In a new study, published January 2 in the journal Nature biotechnology (opens in a new tab), researchers have genetically altered mouse neurons to create physical timelines of these events. It hacked brain cells continuously produced identical fluorescent protein subunits, which naturally assemble themselves into a long chain. When important cellular events—such as a specific gene being turned on—occurred, an alternative subunit was produced by the cells instead and was added to the chain in place of the normal recurrent subunit. This allowed the researchers to go back and look at the chains to see exactly when these cellular events occurred.
“It is not only a snapshot in time, but also records past history,” study lead author Changyang Linghu (opens in a new tab), a cell biologist at the University of Michigan, said in a statement. “Just like how tree rings can permanently store information over time as the tree grows.”
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During the new experiments, researchers grew cultures of the genetically altered mouse neurons in petri dishes. The hacked brain cells were able to produce two protein subunits: HA, which was continuously produced by the cell, and V5, which was produced instead of HA every time a gene called c-Fos – which is activated in neurons when memories are formed in mice and people — was turned on.
Each of the two subunits, which are not produced by normal mouse neurons, had a uniquely colored fluorescent antibody attached via a short peptide known as an epitope tag, which makes it easy to differentiate under a microscope. The HA subunit had a blue tag, and the V5 antibody had a pink tag. The resulting chains therefore looked like long, blue lines, with the occasional pink part sprinkled in each time the c-Fos gene was activated. This allowed the researchers to count how often the c-Fos gene was activated and how long elapsed between each activation.
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In principle, if the same method were applied to human neurons, it could allow researchers to see how and when people form new memories, which could be used to study neurological conditions such as dementia. However, this study is only a proof-of-concept, and it will take years, if not decades, before the protein chains can be used in a clinical setting.
In addition, the team believes that this method could eventually be used in all types of cells to create timelines of when several different genes are activated. Additional subunits could also be produced for other cellular events, potentially revealing the hidden inner workings of almost all cell types and how they interact with each other, which could be a game-changer in medicine, the researchers said.
However, there is a major limitation to memory chains: They can grow only as long as the cell is wide. Once the chain hits the inside of the cell wall, there is nowhere left for it to go and it will begin to become tangled and unreadable.
During the experiments, the researchers created memory chains over the course of about two days before they hit the cell wall. Microscope images were taken just before this happened to preserve the data.
In theory, the rate at which the subunits are added to the chains can be slowed so that the end chain is still the same length, but it takes longer to form, which in turn could allow the researchers to record more specific events, Linghu said. But doing so would reduce the accuracy of the timeline because there would be more uncertainty about exactly when the event occurred, he added.