New DNA computer stores long-term cellular memory.

The ability to process and store information in living cells, also known as biocomputing, is essential for developing next-generation therapeutics and for capturing events within the body. A computation is the execution of an algorithm, a list of instructions that takes an input, processes it, and produces a result. In DNA computing, input is represented using the four-character genetic alphabet, adenine, guanine, cytosine, and thymine, rather than the binary alphabet used by traditional computers. However, DNA computational technology has only been able to capture and record a limited number of molecular events in the body, meaning they cannot be used over long periods of time. Now, a study from researchers at MIT programs human and bacterial cells to keep a record of complex molecular events over a long length of time. The team state their DNA-based Ordered Memory and Iteration Network Operator (DOMINO) could one day track the changes which occur from generation to generation as cells differentiate, or create sensors that could detect, and possibly even treat, diseased cells. The opensource study is published in the journal Molecular Cell.

Previous studies show that existing biocomputers have limited recording capacity and are challenging to scale. Recent studies from the group developed a technique which placed new DNA sequences into predetermined locations in the genome in bacterial cells. In 2016, they developed a memory storage system based on CRISPR, a genome-editing system that consists of a DNA-cutting enzyme called Cas9 and a short RNA strand that guides the enzyme to a specific area of the genome. This CRISPR-based process allowed the researchers to insert mutations at specific DNA locations, however, the mutational outcomes were not always predictable, limiting the amount of information that could be stored. The current study uses a variant of CRISPR that can precisely edit DNA bases, to store complex memories in the DNA of living cells, including human cells.

The current study attaches a version of the CRISPR-Cas9 enzyme to a recently developed base editor enzyme, which converts the nucleotide cytosine to thymine without breaking the double-stranded DNA. Results show guide RNA strands, which direct the base editor where to make this switch, are produced only when certain inputs are present in the cell. Data findings show when one of the target inputs is present, the guide RNA leads the base editor either to a stretch of DNA that the researchers added to the cell’s nucleus, or to genes found in the cell’s own genome, depending on the application; measuring the resulting cytosine to thymine mutations determines what the cell has been exposed to.

The lab state that they used DOMINO to create circuits that perform logic calculations, including AND and OR gates, which can detect the presence of multiple inputs; and circuits that record a cascade of events occurng in a certain order, similar to an array of dominos falling. They go on to add that their DNA computer can be used to record the intensity, duration, sequence, and timing of many events in the life of a cell, such as exposures to certain chemicals; this memory-storage capacity can act as the foundation of complex circuits in which one event, or series of events, triggers another event, such as the production of a fluorescent protein.

The team surmise they have developed a DNA computer which extends the utility of molecular recording beyond DNA write-only applications and enables long-term recording and monitoring of in vivo molecular events. For the future, the researchers state these new ‘living sensors’ may one day be able to sense pathogens and toxins in the body.

Source: Massachusetts Institute of Technology

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