A Bioelectronic Sensor with Great Reception

The detection of proteins and other biomolecules is a tricky business, yet detecting the presence or abundance of these molecules is essential for the early detection of many cancers and other diseases. A sensor must have very high levels of sensitivity and specificity to detect molecules that may be present in very low concentrations and difficult to differentiate from related biomolecules in the same sample. Given these tight constraints, and the fact that our best efforts to build fully synthetic sensors have not been sufficiently successful in detecting these nanoscale molecules, the most common approaches involve the use of biological molecules in the sensing devices.

Such devices typically rely on the use of either antibodies or short strands of DNA or RNA. These molecules can certainly provide the sensitivity and specificity needed to get the job done, but they each come with their own set of limitations that can limit their use in practical applications. Production of antibodies is challenging, and maintaining consistency across batches can be problematic. This can introduce many problems and lead to incorrect conclusions being drawn. Nucleic acids, on the other hand, can be quickly broken down by body fluids, greatly limiting the conditions under which they can be employed.

Another option that has been explored is the use of the receptors that poke out of cellular membranes. Identical copies of these receptors can be produced in vast quantities, and they are stable in biological fluids. However, these molecules are accustomed to being firmly planted in a cell membrane, and they are not happy when they are removed. Upon separation, they will quickly lose their structure (and therefore, function) unless they are immersed in detergents.

The reason for this is that cellular receptors have hydrophobic amino acids within their bases to help them remain securely planted in the cell wall. A group of MIT researchers realized that by replacing these hydrophobic amino acids with hydrophilic substitutes, the receptors would be able to maintain their structure without being embedded in a cell wall. This key finding was the first in a string of innovations that led them to the development of a practical bioelectronic sensor that can accurately detect signs of cancer and other diseases.

But first, they needed to get these trillions of receptors under control so that they could be put to use. They did so by creating sheets of crystalized S-layer proteins sourced from bacteria and archaea cell envelopes. Other proteins, like cell receptors, are easy to anchor to these S-layer protein sheets. The only thing left to do was build in a method to sense when target molecules have bound to the receptors.

The crystallized sheet of S-layer proteins, with receptors in tow, was attached to a chip with graphene-based transistor arrays. When a molecule binds with a receptor, the charge of the molecule changes. This change alters the electrical properties of the graphene in a quantifiable way that can be measured by an external device, like a computer or a smartphone. Taken together, this series of innovations yielded a chip with one trillion receptors per square centimeter that can produce reliable measurements of even very rare molecules.

The research team created a prototype sensor in the course of their work that can recognize the immune molecule CXCL12. It was shown to be capable of detecting the target even when it was present in only tens of parts per billion. They noted that this first step could one day lead to the development of a tool that can sniff out difficult to detect cancers. And on the topic of sniffing, this technology could be useful in many application areas, like in super-sensitive electronic noses, for example.

At this time, the team is still working to further refine their technology. One of the researchers involved in the work noted that they ultimately “...hope is to develop a simple device that lets you do at-home testing, with high specificity and sensitivity. The earlier you detect cancer, the better the treatment, so early diagnostics for cancer is one important area we want to go in.”