Synthetic biology on a piece of paper: Brighter future for disease diagnostics?

ebola blotter paper
A synthetic gene circuit printed on a piece of paper. Image: Wyss Institute

If prevention and cure are the two arms of healthcare, diagnostics is the body that connects them.

To treat a disease, you have to identify it first. Though we have come a long way in the field of diagnostics, doctors continue to primarily use the array of symptoms a patient presents with along with tests that could take anywhere from days to weeks to diagnose a health problem, like an infection. A simple bacterial culture test for example, could take a week for results to arrive.

But what if we could diagnose faster? It would be better for the patient and for the healthcare system as a whole. Surely with advancing technology, we can and should do better than a week for a bacterial culture.

Can synbio help diagnostics?

While synthetic biology is a broad and diverse field, one of its goals is to engineer biology much in the same way that we are able to create electronic circuits. To do that researchers are trying to break down complex and unpredictable biological systems into simpler components—biological bricks so to speak that are more reliable for use in building synthetic gene circuits not so different from electronic ones. Popular Science‘s Francie Diep describes a gene circuit:

A gene circuit works a bit like an electronic one, only all its components are biological. Gene circuits include dozens of genes, plus the proteins needed to read those genes. Together, the genes and proteins perform a task.

A gene circuit that senses a bacterial or viral pathogen, for example, could involve a protein that binds specifically to the pathogen (serving as the ‘input’ signal) which would in turn activate a gene that will produce a colored protein that serves as a visible ‘readout’. Synthetic gene circuits have been used to build biosensors to detect a wide range of molecules including DNA, RNA and proteins.

Imagining the applications for synthetic biology based diagnostic tests is not hard, as they would allow us to create cheap, accurate and efficient molecular tests that could dramatically reduce the time to diagnose diseases. The impact of such a test is particularly relevant considering the current Ebola epidemic that has devastated several African nations (more on that later).

But what’s the catch? Why aren’t these tests available yet? A significant hurdle is that these sensors need the cellular machinery to make the circuit work, similar to how an electronic sensor might need a power source to function. Therein lies the challenge. To make a viable diagnostic biosensor using synthetic biology would mean transporting the cells or cellular extracts (containing the genetic circuit) wherever you needed to perform the test. This brings with it a host of challenges including maintaining a ‘cold-chain’ (transporting and storing the reagents under refrigeration) and loss of biological activity of the reagents over time and with changing storage conditions. Moreover this would make it impractical for the test to be used in regions with poor healthcare infrastructure.

Biological litmus test

A 2014 study published in the journal Cell (paywall) shows that researchers have been able to work through the challenge, using a very simple approach.

The team that published the work, based at Boston University and Harvard’s Wyss Institute borrowed an idea from another research group at Harvard that had successfully used a technique known as ‘freeze-drying’ to preserve biochemical systems on a piece of paper and combined it with their synthetic gene circuit system. Though freeze drying is commonly used to preserve the activity of proteins, the researchers weren’t sure if the entire cocktail of proteins and genes would retain is activity. Surprisingly it did and was fully functional.

To experiment with some use case scenarios, the researchers used the test to detect synthetic viral RNA fragments that matched the RNA of the Ebola virus. By designing DNA segments that bound to the viral RNA and activated production of the colored readout protein, the test detected the presence of the synthetic RNA in as little as 30 minutes. What’s more, it cost only around $20 to produce. Predictably though, while the paper showed that the test could also detect glucose molecules effectively, the ability to test for Ebola caught the media’s fancy.

Paul Fremont, a biologist who was asked to comment on the research described the test quite elegantly as “going back to a biological version of litmus.”

The idea of paper-based gene circuits is still in its early stages, as the researchers themselves point out. The detection levels are not high enough to be used in the field. And using cellular extracts is a tricky factor in itself because the extracts contain lots of proteins that may interfere with the efficiency of detection. Nevertheless, it is an extremely promising technology and one that we should keep our eyes on in the near future.

Arvind Suresh is a science communicator and a former laboratory biologist. Follow him @suresh_arvind

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