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Gene regulation, Human Genetics, Technology

CRISPR computers: how to program a cell

Inside every cell in your body, a complex network of signals are constantly being sent, received, interpreted and acted upon. These signals tell the cell how and when to perform its particular specialised task, in concert with all the other cells surrounding it. Understanding how these networks operate is critical to developing a full understanding of biological systems, but until recently, scientists have lacked tools with sufficient precision to probe these networks accurately. In this blog post, Quentin Ferry (a DPhil student in Tudor Fulga’s lab at the MRC WIMM) describes their latest research, recently published in Nature Communications, in which they have developed new molecular tools that allow rewiring of cellular signalling networks with unprecedented precision.

Cells are complex computational machines that can probe, adapt to, and influence their environment in astonishing ways. The sophisticated set of behaviours that they are capable of is the product of biological programs encoded in the intricate interactions that exist between DNA, RNAs, and proteins.

Our growing understanding of the inner working of the cell, namely in-depth characterisation of these biological parts and the way they interact, has made it possible to start to tinker with the set of naturally evolved cellular programs as well as modify them to encode completely new functions and behaviours.

Along with artificial intelligence, this relatively new field, called synthetic biology, has been held by many as one of the transforming disciplines of the 21st century. The ability to reprogram living systems as bio-computers will be instrumental to both furthering our understanding of biological systems as well as providing solutions to looming medical, economic and environmental problems ahead.

To accomplish this, scientists in the field are trying to build a repository of standardised biological parts, which, very much like the syntax used to code computer software, can be assembled to encode a desired cellular program.

Central to all programming languages, “IF/THEN statements” are used to dictate how the system should behave when a given condition is met. Similarly, synthetic biologists are working towards creating molecular switches inside cells, which will enable them to program conditional behaviours (e.g. IF the cell is cancerous, THEN terminate it).

In a recent study by our lab at the MRC WIMM (published in Nature Communications) we describe how, by adapting the revolutionary CRISPR genome engineering tool, we have developed a platform to create molecular switches inside cells.

The clustered regularly interspaced short palindromic repeats (CRISPR):Cas9 system has been widely used by biologists as molecular scissors to edit genomes. More recently, the system was repurposed to create CRISPR-based transcription regulators (CRISPR-TRs), which can be used to activate or repress the expression of any gene in a given cell.

While a valuable addition to the synthetic biologist toolkit, this system is limited by the fact that it does not allow to dynamically switch genes ON and OFF on demand. Rather, CRISPR-TR will lock the gene it controls in one of the two states as soon and as long as it is present in the cell.

To address this limitation, we have re-engineered the system to create inducible CRISPR-TRs which only exert their effect in the presence of a particular inducer, making it possible to code programs of the kind: IF a particular inducer is present, THEN turn ON or OFF a specific target gene.

Using this new technology to precisely orchestrate the expression of multiple genes in living cells, the group demonstrates how cells can be reprogrammed to exhibit specific behaviours conditioned on either internal signals generated by the cell, or external input molecules delivered by researchers.

Together with the vast repertoire of CRISPR-based molecular tools, this innovative approach will allow scientists to probe the complex signalling networks inside cells with unprecedented precision, and could be used to manipulate these circuits for therapeutic purposes.

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