Biocomputation made easy by a new method in cracking up proteins

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Most functions in biology are carried out by proteins, which is why researchers often look for ways to tinker them.

Often, biologists control proteins by breaking them up into two smaller pieces. Either piece is inactive, and by gluing them back into one piece, researchers can recover the original function. “It takes two to tango” – this binary property is the key to implementing logic behaviour in living cells. 

As easy it sounds, one cannot break a protein in an arbitrary manner. Snap at the wrong point and the glues cannot fit in, and the pieces will be ruined. To complicate matters, proteins come in all shapes and sizes, and so do the molecular glues, which are known as inteins. It is difficult and not always reliable to predict how or where to take a protein apart. 

Researchers at the University of Edinburgh and Microsoft Research Cambridge collaborated to come up with an efficient solution to this complex problem. It uses a natural randomizer, a transposon, to “carpet bombs” all possible break locations. Then, the ones that “hit” the sweet spots will pass the screen and remain. Therefore, researchers no longer need to rely on intuitions or educated guesses. 

As a side benefit, undesirable and strongly leaky activities of the original protein can be tamed, once they are broken and reassembled. With this, researchers can achieve better control over the on-off states.  

The new method facilitates work towards large scale genetic circuits, and in turn makes living cells easier to engineer for many applications in biotechnology and biomedicine including producing high value biologics and detecting and treating diseases in the future. 

Publication link:

Ho T, Shao Y, Lu Z, Savilahti H, Menolascina F, Wang L, Dalchau N and Wang B, “A systematic approach to inserting split inteins for Boolean logic gate engineering and basal activity reduction”, Nature Communications, 2021, 12, 2200  https://doi.org/10.1038/s41467-021-22404-9 O