Arrays of synthetic cell-like capsules, or protocells, made of proteins and polymers can communicate with each other via chemical signals and perform molecular computation thanks to DNA logic gates entrapped inside them. This is the new finding from researchers in The Netherlands and the UK who say that the circuits might serve as molecular biosensors for diagnosing disease or in therapeutics applications, such as to control drug delivery.

DNA computers work using programmable interactions between DNA strands to transform DNA inputs into coded output, explain Stephen Mann of the University of Bristol and Tom de Greef of Eindhoven University of Technology, who led this research effort. These devices operate very slowly, however, since they work in biological environments where they rely on random diffusion to interact with each other and execute a logic operation.

If these DNA strands were assembled inside capsules that could transmit DNA input and output signals to each other, this would increase operating speed. Such encapsulation would also protect the entrapped DNA strands from being degraded by enzymes in blood or serum, for example.

BIO-PC

Mann and de Greef and colleagues have now made such a system using a platform known as “biomolecular implementation of protocellular communication” (BIO-PC). This is a programmable messaging system based on protein microcapsules called proteinosomes containing molecular circuits that can encode and decode chemical messages from short single-stranded nucleic acids.

The proteinosomes are permeable to short single-stranded DNA (containing less than 100 bases), which makes them ideal for protocellular communication, say the researchers. The molecular complexes inside the proteinosomes can work as signal processors, such as logic gates, and contain two different DNA strands tagged with fluorescent labels (so that the researchers can track the activity of the DNA). The proteinosomes themselves are sandwiched between pairs of small pillars in a microfluidic device.

“An incoming DNA strand with the correct sequence can bind with one of the gate’s DNA strands,” explain Mann and de Greef. “This displaces the gate’s other DNA strand. The ejected strand then leaves the protocell and acts as the input signal for a second protocell containing a different gate.”

Towards disease detection

By carefully tailoring the protocells, the DNA gates and the signals transmitted between them, the researchers say they are able to construct a range of different circuits. These include logic gates like AND and OR, and a feedback circuit in which the output strand from one group of protocells deactivates the fluorescent tag in another group. Some protocell circuits can even amplify signals as they transmit them, they explain.

The team, reporting its work in Nature Nanotechnology, says that it is now further developing its DNA circuits into a system that could diagnose disease by detecting tell-tale patterns of microRNAs (which help regulate gene expression). “We’re currently working with Microsoft to build a DNA computer that can do microRNA processing from human blood using this technology,” says de Greef. “I think a DNA computer could eventually do this fully autonomously.

“Microsoft has also been working on storing large quantities of data within DNA using the molecule’s sequence of bases to encode this data, he says. “We hope to integrate this approach with our DNA computing technology.”