Drawing inspiration from natural sensory systems, an MIT-led team has designed a novel sensor that would detect the identical molecules that naturally occurring cell receptors can discover.

In work that mixes several latest technologies, the researchers created a prototype sensor that may detect an immune molecule called CXCL12, all the way down to tens or lots of of parts per billion. That is a crucial first step to developing a system that may very well be used to perform routine screens for hard-to-diagnose cancers or metastatic tumors, or as a highly biomimetic electronic “nose,” the researchers say.

Our hope is to develop a straightforward device that allows you to do at-home testing, with high specificity and sensitivity. The sooner you detect cancer, the higher the treatment, so early diagnostics for cancer is one necessary area we wish to go in.”

Shuguang Zhang, a principal research scientist in MIT’s Media Lab

The device draws inspiration from the membrane that surrounds all cells. Inside such membranes are hundreds of receptor proteins that detect molecules within the environment. The MIT team modified a few of these proteins in order that they might survive outside the membrane, and anchored them in a layer of crystallized proteins atop an array of graphene transistors. When the goal molecule is detected in a sample, these transistors relay the knowledge to a pc or smartphone.

This kind of sensor could potentially be adapted to research any bodily fluid, comparable to blood, tears, or saliva, the researchers say, and will screen for many various targets concurrently, depending on the form of receptor proteins used.

“We discover critical receptors from biological systems and anchor them onto a bioelectronic interface, allowing us to reap all those biological signals after which transduce them into electrical outputs that could be analyzed and interpreted by machine-learning algorithms,” says Rui Qing, a former MIT research scientist who’s now an associate professor at Shanghai Jiao Tong University.

Qing and Mantian Xue PhD ’23, are the lead authors of the study, which appears today in Science Advances. Together with Zhang, Tomás Palacios, director of MIT’s Microsystems Laboratory and a professor of electrical engineering and computer science, and Uwe Sleytr, an emeritus professor on the Institute of Synthetic Bioarchitectures on the University of Natural Resources and Life Sciences in Vienna, are senior authors of the paper.

Free from membranes

Most current diagnostic sensors are based on either antibodies or aptamers (short strands of DNA or RNA) that may capture a selected goal molecule from a fluid comparable to blood. Nevertheless, each of those approaches have limitations: Aptamers could be easily broken down by body fluids, and manufacturing antibodies in order that every batch is equivalent could be difficult.

One alternative approach that scientists have explored is constructing sensors based on the receptor proteins present in cell membranes, which cells use to watch and reply to their environment. The human genome encodes hundreds of such receptors. Nevertheless, these receptor proteins are difficult to work with because once faraway from the cell membrane, they only maintain their structure in the event that they are suspended in a detergent.

In 2018, Zhang, Qing, and others reported a novel strategy to transform hydrophobic proteins into water-soluble proteins, by swapping out a couple of hydrophobic amino acids for hydrophilic amino acids. This approach is named the QTY code, after the letters representing the three hydrophilic amino acids -; glutamine, threonine, and tyrosine -; that take the place of hydrophobic amino acids leucine, isoleucine, valine, and phenylalanine.

“People have tried to make use of receptors for sensing for many years, but it surely is difficult for widespread use because receptors need detergent to maintain them stable. The novelty of our approach is that we will make them water-soluble and may produce them in large quantities, inexpensively,” Zhang says.

Zhang and Sleytr, who’re longtime collaborators, decided to team as much as try to connect water-soluble versions of receptor proteins to a surface, using bacterial proteins that Sleytr has studied for a few years. These proteins, often called S-layer proteins, are found because the outermost surface layer of the cell envelope in lots of sorts of bacteria and archaea.

When S-layer proteins are crystallized, they form coherent monomolecular arrays on a surface. Sleytr had previously shown that these proteins could be fused with other proteins comparable to antibodies or enzymes. For this study, the researchers, including senior scientist Andreas Breitwieser, who can also be a co-author within the paper, used S-layer proteins to create a really dense, immobilized sheet of a water-soluble version of a receptor protein called CXCR4. This receptor binds to a goal molecule called CXCL12, which plays necessary roles in several human diseases including cancer, and to an HIV coat glycoprotein, which is liable for virus entry into human cells.

“We use these S-layer systems to permit all these functional molecules to connect to a surface in a monomolecular array, in a really well-defined distribution and orientation,” Sleytr says. “It’s like a chessboard where you’ll be able to arrange different pieces in a really precise manner.”

The researchers named their sensing technology RESENSA (Receptor S-layer Electrical Nano Sensing Array).

Sensitivity with biomimicry

These crystallized S-layers could be deposited onto nearly any surface. For this application, the researchers attached the S-layer to a chip with graphene-based transistor arrays that Palacios’ lab had previously developed. The only-atomic thickness of the graphene transistors makes them ideal for the event of highly sensitive detectors.

Working in Palacios’ lab, Xue adapted the chip in order that it may very well be coated with a dual layer of proteins -; crystallized S-layer proteins attached to water-soluble receptor proteins. When a goal molecule from the sample binds to a receptor protein, the charge of the goal changes the electrical properties of the graphene in a way that could be easily quantified and transmitted to a pc or smartphone connected to the chip.

“We selected graphene because the transducer material since it has excellent electrical properties, meaning it will possibly higher translate those signals. It has the best surface-to-volume ratio since it’s a sheet of carbon atoms, so every change on the surface, attributable to the protein binding events, translates on to the entire bulk of the fabric,” Xue says.

The graphene transistor chip could be coated with S-layer-receptor proteins with a density of 1 trillion receptors per square centimeter with upward orientation. This enables the chip to reap the benefits of the utmost sensitivity offered by the receptor proteins, throughout the clinically relevant range for goal analytes in human bodies. The array chip integrates greater than 200 devices, providing a redundancy in signal detection that helps to make sure reliable measurements even within the case of rare molecules, comparable to those that would reveal the presence of an early-stage tumor or the onset of Alzheimer’s disease, the researchers say.

Due to using QTY code, it is feasible to switch naturally existing receptor proteins that would then be used, the researchers say, to generate an array of sensors in a single chip to screen virtually any molecule that cells can detect. “What we’re aiming to do is develop the fundamental technology to enable a future portable device that we will integrate with cell phones and computers, so which you can do a test at home and quickly discover whether it is best to go to the doctor,” Qing says.

The research was funded by the National Science Foundation, MIT Institute for Soldier Nanotechnologies, and Wilson Chu of Defond Co. Ltd.

Source:

Massachusetts Institute of Technology

Journal reference:

DOI: 10.1126/sciadv.adf1402