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Wyss Institute 'Organ-on-Chip' to Power DARPA-Funded Microbiome Study, Janssen Drug-Response Testing

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NEW YORK (GenomeWeb) – Two new projects announced last week will showcase organ-on-chip technology developed at the Wyss Institute at Harvard University that has promised to make studies of organ-level function cheaper and more insightful.

Wyss Institute scientists led by Pam Silver and Jeffrey Way announced a $4.7 million Defense Advanced Research Projects Agency (DARPA)-funded project to engineer the human gut microbiome to respond to gastrointestinal illness. Meantime, Emulate, a Wyss spinout that is attempting to commercialize the organ-on-chip, announced a strategic partnership with drug maker Janssen.

"One chip is kind of like one mouse," Jeffrey way told GenomeWeb, except that with the chips, researchers have the added advantage of being able to watch natural processes in real time under a microscope. Additionally, they allow the study of biology at the level of organ function.

Harvard University and Wyss Institute scientist Donald Ingber has been developing the technology for years to improve upon previous attempts to create model systems that mimic human organ function, like 3D cell cultures.

"We call them chips because we use computer microchip manufacturing to form them," Ingber said. "You can envision them as tunnels less than 1 millimeter wide. We put a membrane across it horizontally so it has a top and bottom channel and that membrane has pores we coat with molecules that mediate cell adhesion." It works like an organ because it has cells from an organ and the vessels that supply them. To make a gut, Ingber's lab places epithelial cells on top of the membrane and endothelial cells that line capillary blood vessels on the bottom. "You have a tissue-tissue interface that reconstitutes the function of the gut," he said.

Ingber estimates his lab has developed about a dozen different organs on the chips, including the kidney, liver, eye, bone marrow, and both lung airways and alveoli sacs.

Under the terms of the collaboration with Janssen, Emulate will provide several kinds of those organ chips, including Lung-on-Chip and Thrombosis-on-Chip to evaluate pulmonary thrombosis, the Liver-on-Chip to try to predict drug-induced liver toxicity, and a third undisclosed research program.

Silver and Way's microbiome engineering project is attempting to create a bacterial system to diagnose, report, and even treat pathogen-related gastrointestinal inflammation in humans. Scientists have engineered plenty of clever bacterial systems, Way said, "but nobody feels comfortable releasing these into the environment." He and Silver are trying to engineer a consortium of microbes that will be interdependent on each other and can exist in the human gut but not anywhere else. "If they're in the wrong environment, the bacteria commit suicide," Way added.

Testing whether the bacterial consortia are working will require environments similar to the human gut. "They need a microenvironment to culture the bugs [to be like] something like you'd see inside your gut," Ingber, who is listed on the DARPA grant, said. "We're able to recreate the gut environment under both normal and inflamed conditions, which will help them optimize, design, test, and validate their engineered microbes." Prior to the organ chips, the options were to use mice or 3D cell culture.

Animal testing is expensive and 3D cell culture couldn't support some of the bacteria Way and Silver will need to use.

"If you put bugs in [3D cell culture] they would die in a relatively short time, so you can't have long-term culture and watch how they interact," Ingber said. The cells form a ball, he said, which can't accommodate the flow of materials like the chip can.

For the microbiome study, perhaps the most important feature of the chip is two vacuum channels on either side. The "chips" are actually made of clear, flexible, silicone rubber, so cyclical suction can make the walls of the channel stretch back and forth. In this way, the device is able to recreate peristalsis, the contractions that advance food along its journey through the gut, or the stresses in lungs caused by breathing.

"The physical peristaltic motions and the flow are absolutely critical for these cells to exhibit the structures and functions you see in the human intestine," Ingber said.  The mechanical forces induce the cells to form villi, the finger-like projection of the small intestine, differentiate into all the cell types that make up gut, put out mucus, and even put out enzymes that can metabolize drugs. In short, the motion helps maintain homeostasis, Ingber said.

"Mechanics is intertwined with the chemistry and the genes. It can be an extremely important regulator in development and that's what we see in these chips," he said. "We can bring it all into balance and we keep them alive for weeks and weeks with normal microbes [on them]." Some bacteria won't grow in static culture, but will on the chips, due to the combination of "blood" flow, mucus, and highly differentiated villous epithelium cell layer.

The labs are already collaborating on how to get certain microbes to grow on the chip and to develop fluorescent readouts for their reporter microbes.

Another key feature of the gut that chips can recapitulate is inflammation, which Ingber says can be accomplished in multiple ways, including introducing pathogenic bacteria, or using the devices' microfluidics to release cytokines that simulate inflammation or bacterial endotoxins.

For the microbiome project, Ingber's lab will fabricate the organ chips, but Emulate is trying to develop them for mass production. The company hasn't been able to get to a point where it can sell the chips, but it's "getting close," Ingber said.

If and when the chips make it to market, Ingber sees several applications for them, including as models for inflammatory bowel syndrome and intestinal viruses that can't be cultured, like norovirus. He even envisions multiplexing them with each other through the shared "blood vessel" channel.

But first, Way needs to validate the technology, comparing what happens in the chip and what happens in mice. "We just got this money two weeks ago," he said. "We're still getting a feel for how the chips work," though he added they were "probably pretty realistic."

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