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Engineered proteins can record cellular "memories"

As cells perform their daily functions, they turn on various genes and cellular pathways. A research team led by the Massachusetts Institute of Technology (MIT) has now managed to coax cells to inscribe the history of these events in a long protein chain which can be then studied using a light microscope.

According to the experts, cells programmed to produce these chains incessantly add building blocks encoding particular cellular events. Later, these ordered protein chains can be labeled with fluorescent molecules which the scientists can use to reconstruct the timing of the events. This method could help clarify the steps that underlie processes such as memory formation, responses to drug treatments, or gene expression.

“There are a lot of changes that happen at organ or body scale, over hours to weeks, which cannot be tracked over time,” explained study senior author Edward Boyden, a professor of Neurotechnology at MIT. However, if the newly developed technique could be extended to function over longer time periods, it could be also used to study temporal phenomena such as disease progression or aging.

To study the functions of biological cells, scientists usually image proteins, RNA, or other molecules from inside the cells. Unfortunately, most current methods for doing this offer only a glimpse of a single moment in time, or don’t function properly with large populations of cells.

“Biological systems are often composed of a large number of different types of cells. For example, the human brain has 86 billion cells,” said study lead author Changyang Linghu, an assistant professor of Cell and Developmental Biology at the University of Michigan. “To understand those kinds of biological systems, we need to observe physiological events over time in these large cell populations.”

To achieve this, the scientists recorded cellular events as a series of protein subunits continuously added to a chain, by using engineered protein subunits that can assemble into long filaments. Then they designed a genetically encoded system in which one of these subunits is continuously produced inside cells, while another is generated only when specific events occur. Each subunit contains an “epitope tag” – a short peptide that can bind to a different fluorescent antibody that can help scientist later on visualize the tags.

“We’re hoping to use this kind of protein self-assembly to record activity in every single cell,” Linghu said. “It’s not only a snapshot in time, but also records past history, just like how tree rings can permanently store information over time as the wood grows.”

This approach could detect and record a variety of temporally extended cellular events, including the progression of a disease or a drug treatment, as well as processes related to growth or aging. In future research, the scientists aim to extend the recording period so that longer temporal events can be recorded and analyzed.

“The total amount of information it could store is fixed, but we could in principle slow down or increase the speed of the growth of the chain. If we want to record for a longer time, we could slow down the synthesis so that it will reach the size of the cell within, let’s say two weeks. In that way we could record longer, but with less time resolution,” he concluded.

The study is published in the journal Nature Biotechnology.

By Andrei Ionescu, Staff Writer

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