This capsule of glowing E. coli will probe your gut for signs of trouble

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Whether you go in from above or below, probing the inner workings of our innards is a tricky task. Our intestines are an extensive, inaccessible tangle of tubes, full of dark tucks and turns. But with a new ingestible capsule, researchers hope to shed light on the depths of our perplexing plumbing—quite literally.

The capsule contains living bacteria engineered to sense specific molecular signs of gut troubles and, when those molecules are present, the bacteria glow. The illuminating biological sensors are paired with low-power microelectronics within the pill. This includes photodetectors, a microprocessor, and a wireless transmitter. In all, this ingestible micro-bio-electronic device, or IMBED, is designed to painlessly drift through our ductwork, probe for trouble, and relay findings wirelessly in real time as it takes its excursion through our entrails.

“Basically, our vision is that we want to try to illuminate and provide understanding into areas that are not easily accessible,” Timothy Lu, a biological and electrical engineer at MIT, said in a press briefing. Lu and electrical engineer Anantha Chandrakasan (also at MIT) led a team of researchers developing the IMBED.

As a proof of concept, the team started with an IMBED that can detect intestinal bleeding. Currently, catching this problem in the upper digestive tract requires endoscopy—threading a long, flexible tube with a little camera on the end down your throat, through your stomach, and into the upper section of your small intestines. Its not the most pleasant experience. As an alternative, the researchers built a 10 millimeter by 30 millimeter IMBED with custom genetic circuitry and tested it in pigs. Their results were published this week in Science.

Living gadgets

The prototype IMBED contains a harmless strain of Escherichia coli called Nissle 1917, which has been used as a probiotic for gut inflammation. Lu, Chandrakasan, and the team engineered the E. coli to carry a synthetic genetic circuit that would allow the bacteria to sense heme, a compound in red blood cells that would be released if those cells ruptured in the intestines.

The circuit contains three genetic components swiped from other bacteria. The first is a gene that encodes a transporter protein from a different E. coli strain. The transporter protein sits on the cells outer membrane, snags heme from the environment, then drags it into the cell. The second part is a regulator protein from a Lactococcus species. This regulator essentially controls whether specific genes are turned on or off depending on the presence of heme within the cell. The team engineered this regulator to control the third and final part of the genetic circuit, which is a set of genes that encodes a luminescence system—resulting in a bioluminescent enzyme called luciferase—from Photorhabdus luminescens.

So, basically, when theres heme in whatever environment the bacteria find themselves—lets say the intestines—the transporter drags the heme into the cell. There, it interacts with the regulator, which switches on the activity of the luminescence system. Then, the bacteria glow.

  • Capsule for sensing biomarkers in vivo with whole-cell bacterial sensors and wireless electronic readout.
  • Cross section, electrical system diagram, and front- and back-side photos of the device. PDMS, polydimethylsiloxane.
  • Mobile phone and 900 MHz wireless receiver dongle used for visualizing IMBED measurement results and logging them to the cloud.
  • Application software displaying IMBED measurement results to the user on a mobile phone.

Within the capsule, the bacteria sit in little compartments with only a heme-permeable membrane separating them from the outside. This keeps the bacteria in (although theyd be harmless if they got out), while allowing heme to wander in with the bacteria, where the transporters can drag it into the bacterial cells.

If the bacteria start glowing, the photodetectors that sit just below the bacterias compartment are activated. The luminescence is converted to digital code with a low-power luminometer chip, and the signal is transmitted wirelessly to an external receiving device. The system is powered by an internal button-cell battery, and the capsule is likely to be pooped out well before the battery poops out (likely months beforehand). The researchers also created an Android app that receives the data in real time and produces handy readouts of blood levels.

Bowel gazing

After the prototype passed lab testing—suggesting it worked the way they expected—the team tried it out in pigs. They placed the capsules in pigs stomachs, with or without blood, then watched. The capsule picked up a strong blood signal within an hour and by two hours achieved full detection. The team concluded that the IMBED could sensitively and specifically detect small amounts of blood in the intestines.

  • Schematic of the experimental flow, which consisted of blood administration in neutralization solution, capsule deposition, and wireless transmission to a commercial receiver connected to a laptop or a cellular phone.
  • Representative endoscopic image.
  • X-ray image that illustrates the location of the device in the stomach at the conclusion of our two-hour experiments, just before device removal.
  • Kinetic response of blood sensor IMBED in a porcine model of gastric bleeding. IMBEDs deposited in gastric cavity can rapidly discriminate between pigs administered blood versus buffer control. Error bars denote SEM for six IMBED experiments (three animals on different days, two capsules per animal). *P < 0.05, Students t test.
  • Receiver operating characteristic (ROC) of IMBED sensing over time. Perfect detection is achieved at t = 120 min. AUC, area under the curve.

The success is just a first baby step. The engineers are working to optimize the device further. They think they can get it down to about a third of the size before moving to human testing. And, the team stresses, this is just the first iteration of an IMBED. They have plans to create more synthetic genetic circuitry to detect all sorts of biological markers of gut troubles.

“These biosensors are really modular,” team member and biological engineer Mark Mimee of MIT emphasized in the press briefing. By exploiting other microbes genetics and even evolution, theyre optimistic that they can create IMBEDs to detect “conceivably any sort of biomarker.”

To make the point, they already created IMBEDs with E. coli carrying genetic circuits to detect other biomarkers. Namely, they created biosensors for thiosulfate, a sign of gut inflammation, and acyl-homoserine lactone, a molecule that certain bacteria—some pathogenic, some not—use for sensing.

Though the devices are years from clinical trials, let alone hitting the market, the team is optimistic about the future of IMBEDs. And they arent setting their sights low. “This integration of biological engineering and semi-conductor electronics offers opportunities to transform diagnosis, management, and monitoring of health and disease,” they conclude.

Image credit Mimee et al, Science.

Science, 2018. DOI: 10.1126/science.aas9315 (About DOIs).

Original Article

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