Whether you go in from above or below, examining the inner workings of our guts is a difficult task. Our intestines are an extensive, inaccessible tangle of tubes, full of dark folds and curves. But with a new ingestible capsule, researchers hope to shed light on the depths of our mind-boggling plumbing — quite literally.
The capsule contains live bacteria that are designed to detect specific molecular signs of gut problems and when those molecules are present, the bacteria glow. The illuminating biological sensors are linked to low-power microelectronics in the pill. This includes photo detectors, a microprocessor and a wireless transmitter. All in all, this recordable micro-bioelectronic device, or IMBED, is designed to painlessly float through our channels, search for problems and wirelessly relay findings in real time as it travels through our guts.
“Basically, our vision is that we want to try to illuminate and provide insight into areas that are not easily accessible,” Timothy Lu, a biological and electrical engineer at MIT, said in a news conference. Lu and electrical engineer Anantha Chandrakasan (also at MIT) led a team of researchers that developed the IMBED.
As a proof of concept, the team started with an IMBED that can detect intestinal bleeding. Currently, trapping this problem in the upper digestive tract requires endoscopy: a long, flexible tube with a small camera at the end through your throat, through your stomach, and into the upper part of your small intestine. It’s not the most pleasant experience. Alternatively, the researchers built a 10 by 30 millimeter IMBED with modified 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 intestinal inflammation. Lu, Chandrakasan and the team have the E coli to carry a synthetic genetic circuitry that allows the bacteria to detect heme, a compound in red blood cells that would be released if those cells ruptured in the gut.
The circuit contains three genetic components wiped from other bacteria. The first is a gene that codes for a transport protein from another E coli deformation. The transport protein sits on the outer membrane of the cell, chops haem from the environment and then drags it into the cell. The second part is a regulatory protein of a Lactococcus types. This regulator essentially determines whether specific genes are turned on or off depending on the presence of heme in the cell. The team developed this regulator to control the third and final part of the genetic circuitry, a set of genes that codes for a luminescence system — resulting in a bioluminescent enzyme called luciferase — from Photorhabdus luminescens.
So basically, if there’s heme in whatever environment the bacteria are in — let’s say the gut — the transporter drags the heme into the cell. There it interacts with the controller, which turns on the activity of the luminescence system. Then the bacteria glow.
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Capsule for detecting biomarkers in vivo with whole cell bacterial sensors and wireless electronic readout.
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Cross-section, electrical system diagram and photos on the front and back of the device. PDMS, polydimethylsiloxane.
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Mobile phone and 900MHz wireless receiver dongle used to visualize IMBED measurement results and log them in the cloud.
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Application software that displays IMBED measurement results to the user on a mobile phone.
Inside the capsule, the bacteria reside in small compartments with only a heme-permeable membrane separating them from the outside. This keeps the bacteria in (although they would 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.
When the bacteria begin to glow, the photodetectors located just below the bacteria compartment are activated. The luminescence is converted into digital code with a low-power luminometer chip and the signal is sent wirelessly to an external receiving device. The system is powered by an internal coin cell battery and the capsule will likely be pooped out well before the battery runs out (probably months in advance). The researchers have also created an Android app that receives the data in real time and makes useful readouts of blood levels.
gut staring
After the prototype passed lab tests — suggesting it worked as they expected — the team tried it out on pigs. They placed the capsules in pig stomachs, with or without blood, and watched. The capsule picked up a strong blood signal within an hour and reached full detection after two hours. The team concluded that the IMBED could sensitively and specifically detect small amounts of blood in the gut.
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Schematic of the experimental flow, which consisted of blood administration in neutralizing solution, capsule deposition, and wireless transmission to a commercial receiver connected to a laptop or cell phone.
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Representative endoscopic image.
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X-ray illustrating the location of the device in the stomach at the end of our two-hour experiments, just before the device is removed.
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Kinetic response of blood sensor IMBED in a porcine model of gastric bleeding. IMBEDs deposited in the gastric cavity can quickly distinguish between blood-administered pigs and buffer control. Error bars indicate SEM for six IMBED experiments (three animals on different days, two capsules per animal). *P < 0.05, Student's t-test.
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Receiver operating characteristic (ROC) of IMBED detection over time. Perfect detection is achieved at t = 120 min. AUC, area under the curve.
Success is just a baby’s first step. The engineers are working on further optimizing the device. They think they can cut it down to about a third of its size before moving on to human testing. And, the team emphasizes, this is just the first iteration of an IMBED. They have plans to make more synthetic genetic circuits to detect all kinds of biological markers of gut problems.
“These biosensors are really modular,” MIT team member and biological engineer Mark Mimee emphasized in the press conference. Taking advantage of the genetics and even the evolution of other microbes, they are optimistic they can create IMBEDs to detect “probably any kind of biomarker.”
To make the point, they’ve already made IMBEDs with E coli with genetic circuitry to detect other biomarkers. They created biosensors for thiosulfate, a sign of intestinal inflammation, and acyl-homoserine lactone, a molecule that certain bacteria – some pathogenic, some not – use for detection.
Although the devices are years away from clinical trials, let alone hitting the market, the team is optimistic about the future of IMBEDs. And they don’t set their sights low. “This integration of biological engineering and semiconductor electronics offers opportunities to transform diagnosis, management and monitoring of health and disease,” they conclude.
Image credit Mimee et al, Science.
Science2018. DOI: 10.1126/science.aas9315 (About DOIs).