With Johnson and Johnson, Harvard Spinoff Emulate Unveils New Organs-on-Chips

By Aaron Krol 

June 18, 2015 | Before she came to the Wyss Institute in 2010, Geraldine Hamilton spent over a decade in the pharmaceutical industry working on cell cultures. These masses of dish-bound human cells, extracted from tissue and coaxed to multiply in the lab, are often the first ports of call for potential new drugs. Cell cultures provide the earliest hints of what a compound will do in live human tissue, though experienced drug developers know better than to get too excited when they clear up disease symptoms in a petri dish — the human body does not, in the end, behave much like a mass of cells fed on powdered nutrients.

Hamilton’s job, at pharma companies including AstraZeneca and GlaxoSmithKline, was to create the next generation of cell cultures, new models that might recover a little bit of the complexity of living tissue. Her specialty was “organoids,” three-dimensional cell structures in which a variety of cell types shape themselves into miniature versions of organs. She found the work invigorating, but also a little isolating, with her efforts sometimes getting lost in big pharma’s bureaucracy. “One of the frustrating parts for me,” Hamilton says, “is that over the eleven years I was in the pharma industry, the cell-based systems were not really being used to drive key decisions.”

Then a friend invited Hamilton to meet Don Ingber, who was preparing to run a brand new institute at Harvard. The university had received a massive donation — $125 million, at the time the largest in Harvard history — from Hansjörg Wyss, earmarked for an “Institute for Biologically Inspired Engineering.” The idea was to create a facility where engineers and biologists would work side by side on materials and devices inspired by discoveries in the life sciences. Ingber was to be given charge of a large staff in a lavish new laboratory space, but when Hamilton came to visit, the facility was still under construction; the two scientists toured the grounds together in hard hats.

“It was just meant to be a chat about culture models and in vitro approaches,” says Hamilton. But Ingber admired Hamilton’s depth of knowledge, and Hamilton found Ingber’s ideas about a new type of bioengineered cell model intriguing. “A few hours later,” she says, “I had a job at the Wyss Institute.”

Today, Hamilton is President and Chief Scientific Officer of Emulate, the first for-profit company spun off from the Wyss Institute. Her products are “organs-on-chips,” and as Emulate’s pharma partners are finding, these tiny plastic-cellular hybrids are in many ways more like human organs than any fully biological structures scientists have yet managed to create in the lab.

Achilles’ Heels 

Each of Emulate’s organs-on-chips is only around the size of a rubber eraser, but thousands of human cells live inside the microfluidic channels etched into its polymer frame. The central insight behind organs-on-chips is that you don’t have to recreate whole organoids to capture the natural behavior of tissue. By providing cells with fabricated environments to grow in, and mechanical forces that mimic the real pressures of blood and air flow those cells would feel in the body, you can get a system that is functionally a lot like the real thing.

“Cells have all of the information they need to function properly,” says Hamilton. “You just need to give them the right cues.”

The Wyss Institute spent years creating its first models as proofs of concept, including a Lung-on-Chip and Liver-on-Chip. (See, “Cambridge-Based Emulate Plans to Jumpstart Organ-on-a-Chip Market.”) These models demonstrated that, given the right environment, cells would naturally divide, differentiate, and form complex tissue structures on a tiny scale. At the independent Emulate, however, the plan is to zero in on more advanced models of special interest to pharma customers.

“We have identified what we think are the Achilles’ heels of the pharmaceutical industry,” Hamilton says. Emulate’s value, she believes, is not just in the company’s ability to replace cell cultures with new stand-ins for different tissue types. Instead, she wants to create models for areas of human biology where there is no real incumbent technology (except, perhaps, for animal testing). These include the blood-brain barrier, a huge problem in neurological therapies; liver toxicity, a common class of drug side effects as the liver cleans toxic metabolites from the blood; and inflammation, which is difficult to imitate without a well-developed organ system. For each of these programs, Emulate will partner with pharma companies on design, development, and validation, nurturing new organs-on-chips to the point that they can be used in the drug discovery pipeline.

Johnson & Johnson was the first pharma partner to jump on board, in a collaboration that began a year and a half ago at the Wyss Institute. That partnership has now led to a validated Thrombosis-on-Chip model, which J&J today announced will be used in the company’s early drug-testing pipeline to find out whether candidate molecules might put patients at risk of thrombosis.

Kyung-Jin Jang, a senior scientist at Emulate, holds up a Thrombosis-on-Chip model, co-developed at Emulate and Johnson & Johnson. Image credit: Emulate, Inc. 

Thrombosis, a condition where clots form inside a blood vessel and sometimes lead to heart attack or stroke, is a particularly difficult side effect to explore in the laboratory. There are only two models of thrombosis in regular use, and both are fairly primitive. The first option is simply to measure blood clotting in a test tube, by counting how many platelets form after a drug candidate is mixed into a sample. This is a long stretch from real thrombosis, where the vascular flow of blood cells, immune cells, and the drug itself will affect how clotting impacts the system as a whole.

The second option is animal testing — and because the immune systems of mice and rats are very poor models for human biology in this area, the animals of choice are primates. No one in the industry likes working with primates; the ethical conundrum weighs on researchers, and large, intelligent animals like monkeys and apes are difficult and expensive to keep in captivity.

A Thrombosis-on-Chip was a prime target for Emulate, which already provides blood flow in all its chips and has often worked with immune cells as well. Teams from Emulate and J&J evolved the new Thrombosis-on-Chip from a standard Lung-on-Chip, tweaking the model until they could clearly observe and measure platelets forming clots on the vascular walls. Thanks to the transparent chambers in which blood travels through the chip, users can watch platelet aggregation as it occurs, giving them real-time insights into the process of thrombosis. The researchers have also applied a few select compounds known to cause thrombosis to the chips, finding that they can recreate convincing symptoms inside these polymer microenvironments.

Chips on the Table 

According to Hamilton, a steady process of evolution has been a common theme in Emulate’s development. “Every time we start a new organ system or a new disease model, we can leverage the learnings about the biology and the engineering,” she says. “Our original Lung-on-Chip was actually an alveolus. We have then moved on and created a small airway on a chip, and that small airway allows us to produce models of airway diseases like asthma and inflammation.”

At J&J, leaders on the organs-on-chips project are hopeful that, as these models get progressively more advanced, they will fill more and more niches in the drugs pipeline. At present, J&J will be using the Thrombosis-on-Chip — along with a Liver-on-Chip, which the company also helped to validate — to better characterize existing drug candidates. Later, however, these models could play a role in understanding disease at a functional level, possibly even discovering new drug targets or learning what qualities in potential drugs pose higher risks of thrombosis.

“As it pans out and we get more confident in the pharmacology applications, then I do think we can begin to apply this in other areas of research,” says Dashyant Dhanak, J&J’s Global Head of Discovery Sciences. “If the Liver-on-Chip works out great, we can begin to think about applications in hepatitis. If the lung works out, we can think about COPD [chronic obstructive pulmonary disease] and lung cancer.”

None of the models J&J has helped to develop will be exclusive to the company; Emulate plans to sell all of its organs-on-chips as widely as possible. That goes for other pharma collaborations, too — AstraZeneca and GlaxoSmithKline have both piloted Emulate’s technology, although neither has announced an official partnership. Hamilton expects to make more partnership announcements in the next few months.

Sharing technologies, and the costs of development, across companies is not a common practice in the pharmaceutical industry, although it’s less rare than it once was. With a system like organs-on-chips, however, letting competitors share the fruits of your research is in everyone’s best interest. Organs-on-chips are a very young technology, and no one is yet sure how well they correspond to existing cell and animal models — much less to human biology. For organs-on-chips to become an established platform for testing new drugs, both Emulate and its customers will need huge datasets on their performance, which will be much easier to create if their use cuts across institutions.

“Ultimately, we would love to be seen as a catalyst in this area,” says Dhanak. In time, early investments like J&J’s could build the kind of data-driven support that this new disease model will need to win acceptance from regulators. If the FDA can be convinced that organs-on-chips are meaningful simulations of the human body, the industry may have a chance to start winding down its reliance on animal testing and faulty cellular models. “I think the FDA are open to that,” Dhanak adds. “I think they also want to look at new ways to translate discovery data into clinical data.”

“We’ve gotten a tremendous amount of feedback from the regulatory agencies that they really want to see a broad use and application of this technology,” says Hamilton. “This is really important to generate the data for acceptance. We are working directly with the users to validate the system, so that we can lead and set the standards for what this technology will achieve.”

In the business of big pharma, there’s a lot of pressure in the early stages of the game, when just a small edge picking out the safest, most effective compounds could save months of clinical trials, hundreds of millions of dollars, and possibly even patients’ lives. There’s a fortune waiting for the first company to build a better lab mouse, and Emulate, with its peculiar plastic organs, means to try.