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Tissue Engineering

Donald Ingber is leading efforts to develop organ-on-a-chip devices to replace animal tests

Widespread adoption of the chips will require mass production and finding the right questions to ask with the devices

by Celia Henry Arnaud
June 24, 2018 | APPEARED IN VOLUME 96, ISSUE 26

 

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Credit: Wyss Institute at Harvard University

Donald Ingber—founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University—remembers the first time he heard of an organ on a chip. He was at a meeting, and a former postdoc he comentored with George Whitesides, Shuichi Takayama at the University of Michigan, presented something called a “lung on a chip.” The chip had channels with branches the size of small airways. Takayama flowed droplets through the channels to mimic mucus plugs. He played a recording of the chirping sound the chip made.

“It was exactly the noise I was trained as a med student to listen for through a stethoscope,” Ingber recalls. “It’s called a crackle. You listen for that to see if people have pneumonia.”

Vitals

Hometown: East Meadow, N.Y.

Education: B.A., M.A., M.Phil., Ph.D., and M.D., Yale University

Professional highlights: Authored more than 450 publications and 170 patents, founded five companies, and has been an invited speaker at more than 500 events worldwide. Member of the National Academy of Medicine, National Academy of Inventors, American Institute for Medical & Biological Engineering, and the American Academy of Arts & Sciences. Named one of the top 20 translational researchers worldwide in 2012 by Nature Biotechnology and a Leading Global Thinker of 2015 by Foreign Policy magazine.

Hardest part of designing a new organ on a chip: Obtaining the correct set of functional human cells

Organ chip not yet made that you most want to make: Lymph node chip (but we are almost there)

That chip had no cells on it, but it sparked inspiration in Ingber. Months later, in September 2007, when Ingber hired Takayama’s grad student, Dan Huh, as a postdoc, the two set out to build a living lung on a chip containing actual lung cells.

Ingber’s plan was to take advantage of the laminar flow in microfluidic chips to deposit a layer of extracellular matrix—biomolecules that support cells in tissues—at the interface between two fluids and make an artificial basement membrane—a molecular scaffold for epithelial cells that separates them from underlying connective tissue.

“We made some headway, but it was never robust,” Ingber says. “We then explored doing it the other way around—put a membrane in the channel and coat that membrane with matrix. That’s how it got to be a living lung on a chip,” he says.

And that lung on a chip was just the beginning. Ingber and his colleagues have mimicked key functional units of more than 10 human organs as well as mouse, rat, and dog organs.

“One of the reasons we’ve been so successful with the organs on chips is that we set recapitulation of physiological and pathophysiological function as the benchmark,” Ingber says. “We’re not building a system like a hammer and trying to find nails. We try to mimic real, organ-level structures and functions and learn what the real problems are.”

We’re not modeling the whole organs. We’re modeling key functions of them.

They published that first lung chip in Sciencein 2010 (DOI: 10.1126/science.118830), and it caught the attention of the Defense Advanced Research Projects Agency. DARPA announced it was seeking a system incorporating 10 organ chips that could be used to evaluate medical countermeasures, such as those for exposure to chemical or biological weapons, for which human trials would be impractical or unethical.

Putting together the proposal for that grant was hard, Ingber says. “With DARPA, you have to write a science fiction story, and then you have to make it real,” he says. “If you shoot for the impossible, you can often go beyond what you think is possible.”

DARPA gave the Wyss team a $37 million grant. DARPA specified 10 physiological systems—cardiac, urinary, liver, gastrointestinal, nervous, respiratory, circulatory, immune, reproductive, and integumentary (skin, hair, nails, etc.)—but left it to the team to decide what aspect of each system to include.

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Ingber has a strict definition of what constitutes an organ on a chip. “An organ is two or more tissues that come together and new functions emerge,” he says. “People put cells in microfluidics and call it an organ on a chip. That’s not an organ on a chip; it’s a tissue on a chip. That’s perfectly useful for some things. We do it sometimes.” But it’s not an organ on a chip, he says.

“We’re really doing functional units,” Ingber says. “It’s very important to realize we’re not modeling the whole organs. We’re modeling key functions of them. You have to design them for the functionality you’re interested in.”

What’s needed now is to get organ chips into the hands of more researchers to confirm the robustness of the approach for mimicking organ function, Ingber says. “That requires commercialization and mass manufacturing of chips,” he says. Part of the challenge of mass production is achieving consistency from chip to chip, he adds. “Even in my lab, when different grad students and postdocs made chips, they’d sometimes get different results.”

Ingber helped found the company Emulate to make the chips more uniform and more widely available. He currently chairs Emulate’s scientific advisory board and holds equity in the company. Ingber also points out that other companies are making different versions of organs on chips that also look promising.

The organ chips won’t replace the 96-well plates used for conventional assays that toxicologists or drug developers run. The chips are too expensive and too hard to use to replace those kinds of assays, and it takes a long time—weeks in some cases—to have the organ chips ready for one experiment.

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Credit: Wyss Institute at Harvard University
The lung on a chip contains a vascular channel through which a blood-mimicking medium flows (red) and airway channels through which air flows (blue), each lined by living human cells. Connecting the chip to a pump can imitate the physical forces that breathing exerts on lung tissue.

From an equipment standpoint, the organ chips are ready to go. But they won’t really take off in labs until people identify the right questions to ask with the devices. Chip companies “have to collaborate with pharmaceutical, biotech, food, and chemical companies,” Ingber says, “because they understand the key problems and questions in their fields.”

A prime application that Ingber is targeting is using organs on chips as replacements for animal models, which tend not to be good stand-ins for humans.

For example, animal models of injury induced by exposure to γ radiation don’t do a great job mimicking what happens to humans exposed to radiation. Wyss scientists have a grant from the U.S. Food & Drug Administration to develop human lung, intestine, and bone marrow chips that can be used to model injury as well as to develop γ radiation countermeasures. The researchers have been able to mimic human responses to radiation, such as loss of intestinal villi and increased intestinal permeability, using a human gut on a chip. They are now modeling fibrosis in the lung and suppression of blood cell formation with other human organ chips. “Amazingly, the three different organ chips display different sensitivities to radiation exposure that precisely match those previously observed in humans,” Ingber says.

In another example, researchers from Wyss and Emulate worked with scientists at the pharmaceutical company Janssen to address a problem for which there weren’t good animal models. The company had an antibody that showed no toxicity in animals. But in human trials, multiple people died of blood clots in their lungs. The researchers developed a chip that recapitulated the problems in the human trials.

“Here’s a situation where there is no animal model to go back and figure out which other drug in your chemical pipeline you move up,” Ingber says. “I hope that if this company can discover another active drug in their pipeline without toxicity in this model that they will go to FDA saying, ‘We would like to use this chip model instead of an animal model.’ ”

The chips have succeeded in areas beyond just science and engineering. They’ve also received accolades from the design community. One of the devices from Ingber’s team is even part of the permanent collection at the Museum of Modern Art in New York City.

“We were nominated for multiple international design awards out of the blue,” Ingber says. Ingber and Huh’s lung on a chip was a finalist for the 2011 Index: Award, which is given by the Danish nonprofit Index: Design to Improve Life. The human organs on chips system was awarded the Design of the Year and Product Design of the Year awards in 2015 by the Design Museum of London.

“The design community has moved to be focused on how design impacts the world to make it a better place,” Ingber says. Designers really focus on finding the simplest way to produce an impact, he adds. And that’s what his team did: “We distilled this complex organ to its minimal features.”

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