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Cambridge-Based Emulate Plans to Jumpstart Organ-on-a-Chip Market


By Aaron Krol 

July 30, 2014 | The organs-on-chips approach to preclinical testing took another step forward this week, with the launch of Emulate, a Cambridge-based startup building pocketsize models of human organs. Although Emulate only recently completed its $12 million Series A funding round, it enters the market with a deep IP portfolio, several large industry partners, and an end-to-end platform for using its chips in the lab, thanks to a five-year incubation at Harvard’s Wyss Institute for Biologically Inspired Engineering.

The concept of organs-on-chips is a young one — the phrase itself only entered the lexicon around 2008 — but it has quickly sparked the imagination of pharma scientists and basic researchers. The idea promises a happy medium between cell cultures and living animals, the flawed models that still dominate the early stages of drug testing. Like a cell culture, an organ-on-a-chip uses real human biology, in the form of thousands of human cells grown together in a fabricated microenvironment. Like an animal, it has functioning, interconnected tissue, with different cell types playing their unique roles in the model organ, and mechanical engineering filling in for forces like blood flow and air exchange. In this way, an organ-on-a-chip can help reveal the system-wide effects of a compound, without wandering too far from human drug response and toxicology.

And unlike other futuristic twists on preclinical testing, such as hyper-realistic computer simulations or free-living organoids, the organ-on-a-chip has seemed nearly within reach for as long as it’s been talked about. The microfluidics techniques needed to miniaturize the systems already exist, and culturing the cells in small tissue layers doesn’t require any novel biology. Working prototypes of Emulate’s own chips appeared as early as 2010, when Wyss Institute scientists published the design of their first lung-on-a-chip in Science.

Organs-on-chips have inspired such enthusiasm that there is already competition to be the first to market with a scalable system. Seattle-based Nortis, which has been working on novel preclinical models since 2007, has promised a commercial product by the first quarter of next year. In Europe, MIMETAS already sells “organs-on-chips” in the form of microfluidic plates with 3D cultures of interrelated cell types*.

Emulate’s launch is particularly noteworthy, however, because of the measures the company has taken to create a built-in market for its technology. Behind the scenes, Emulate’s founders have spent years paving a path to widespread acceptance of organs-on-chips by both drug industry leaders and the FDA, whose trust in the models is essential for their success. The Wyss Institute has also left its new spinout with a plug-and-play architecture of hardware and software around the chips, an attractive feature for a technology that very few labs have experience working with.

That level of preparation makes it a little easier to get swept up in Emulate’s high expectations for its system. “Our feeling is that this will have a profound effect across preclinical development, and even into the clinic,” CEO James Coon tells Bio-IT World. “It’s really going to change how we look at developing therapeutics. At a fundamental level, it gives such a greater understanding of human biology.”

Anatomy of a Chip 

Every organ-on-a-chip has a different design, reflecting the need to mimic higher-level organ functions like breathing or peristalsis. Still, says Coon, “there’s a consistent theme for each of the different organ systems.” Embedded in each chip are two main compartments, one to represent the organ itself, and another to represent blood flow. Both are populated with human cells; the blood chamber can even contain functioning immune cells, which in early Wyss experiments were shown to attack invasive bacteria just like in a living body.

Separating the compartments is a microscopic membrane, made from a silicone-based organic polymer, and coated on both sides with a protein matrix such as collagen. The membrane acts like a capillary wall, allowing regular flow of blood cells in and out of the tissue to deliver nutrients — along with any compounds being tested. The entire system, which can contain tens of thousands of cells once fully populated, is around the size of a memory stick.

Lung Chip 

A Wyss Institute lung-on-a-chip. Image credit: Emulate 

Unique design challenges emerge once the engineers try to make the system behave like an organ, and not just a tissue culture with a blood supply. Here, though, the cells will do some of the work themselves, if treated appropriately. In the lung-on-a-chip, for instance, Emulate etches two chambers into the chip beside the cell compartments. Acting on these chambers with a vacuum stretches the membrane between the compartments, much like breathing stretches lung tissue in the body. Given that mechanical stimulus, says Coon, “cells start to behave like they would in the human body. They start forming cilia, which are directional just like in the body. They do mucus and particle clearance. If you give them high-level cues, you get, on a cellular level, the performance you would expect.”

This level of cellular function is invaluable in drug testing, helping to simulate the movement and metabolism of compounds through an organ, something that typical cell cultures are poorly equipped to predict. It also makes for better models of disease. By tweaking the mechanical cues to the lung-on-a-chip, Emulate can create proxies for conditions like asthma and chronic obstructive lung disease.

In addition to the lungs-on-chips, Coon describes Emulate’s liver, intestine, and skin models as “well-advanced.” Also in the pipeline are eyes- and kidneys-on-chips, as well as a model of the blood-brain barrier, a notorious labyrinth for pharmacokinetics. (A blood-brain barrier will reportedly also be an early part of Nortis’ product line, reflecting the huge industry interest in a better model for this molecular bottleneck.)

It’s not clear when each of those chips will be ready for mass production and sale, but there’s a real advantage to having so many organ models already moving forward. Emulate plans to string its organs-on-chips together, taking aim at the biggest asset of animal testing: the ability to foresee unexpected toxicology and side effects in distant organ systems.

“We can integrate these organs,” says Coon. “We can look at what would happen if you were to give a drug orally, and have it go into the gut, and then to the liver, and then to the heart… It gives us a lot of flexibility.” Connections can also be drawn at a smaller scale; rather than condensing many cell types into one lung-on-a-chip, for instance, Emulate can link a series of chips that represent the different lung cell types found from the upper respiratory tract down through the small airways.

The company is already speaking publicly about a human-body-on-a-chip in which every major organ system is represented. The concept is still in early development, but the Emulate platform is modular enough that each new chip brings it tangibly closer.

Organs in the Lab 

Officially, Emulate is less than a week old, but its core team has been together much longer. Coon came to the Wyss Institute more than two years ago to fill the experimental role of “entrepreneur-in-residence,” with the specific responsibility of nurturing the organs-on-chips program into an independent company. He joined Geraldine Hamilton, who had taken a leading role in the project since 2010, and Don Ingber, the Institute’s director, scientific founder of Emulate and an early champion of the organ-on-a-chip concept, as well as a dedicated team of scientists and lab technicians. Emulate’s scientific staff is drawn almost entirely from the ranks of that team; Hamilton is moving to the company as President and CSO, and Ingber will continue to participate as head of the scientific advisory board.

The Wyss Institute’s program was well-funded, with over $40 million in grants from organizations like DARPA and the FDA, and had already led to several major publications before Coon became involved. Coon’s task was to take the scientific successes of Hamilton’s team, and present them to potential funders and business partners, making sure Emulate would have a sound commercial footing when it branched off from academia.

Thanks to those efforts, at least two of the top ten pharma companies, GlaxoSmithKline and AstraZeneca, have already used Emulate’s chips for small-scale projects. Members of GSK and the Wyss Institute worked together on a preclinical study in 2012, published in Science Translational Medicine, which offers a good overview of how organs-on-chips might be used in drug testing. The study, of a compound meant to prevent pulmonary edema brought on by cancer treatment with interleukin-2, used early lungs-on-a-chip. When given interleukin-2, the cells in the chip started to leak fluid into the artificial airways, and clots of the blood protein fibrin formed on the cellular matrix — two telltale symptoms of pulmonary edema. GlaxoSmithKline went on to successfully clear up the symptoms with the experimental compound GSK2193874.

Even in this quite basic study, the Wyss Institute could show some clear advantages over other preclinical models. Unlike a cell culture, the lung-on-a-chip could develop physical, tissue-wide disease symptoms; and unlike in animal testing, those symptoms could be observed directly in real time. The study was also a validation of the model’s ease of use in preclinical trials. “We could treat [our chip] in a clinically relevant fashion with the same treatment regimen you’d see in the clinic, get the same adverse side effects, and then were able to come in with a novel therapeutic and reverse that,” says Coon.

AstraZeneca, meanwhile, has found a more creative use for organs-on-chips. In a partnership with the Wyss Institute announced in October, the company began designing organs-on-chips with animal cells in place of human cells. Those animal chips will soon be tested side by side with the standard human chips, with the goal of spotting differences in drug responses between the two models. By comparing the two types of organs-on-chips, AstraZeneca hopes to nail down where animal models correctly mimic human toxicity, and where animal anatomy is simply too different to be predictive.

Coon says that kind of outside-the-box project is typical of the applications he has discussed with potential partners. “Industry is not just slotting us in as another toxicity or safety testing tool, but using us as an early model to understand how organs function, how human health functions, how disease functions, and look at new therapeutic targets and mechanisms of injury and disease,” he says. “If you start with better input at an early stage of development, and you keep applying better models throughout development, when you get to the clinic you have a much better chance of success.”

Selling the Concept 

Emulate’s shift to a commercial company comes with $12 million in new funding. The Series A is led by NanoDimension, a San Francisco-area seed fund, and also includes investments from Cedars-Sinai Medical Center and Hansjörg Wyss, the major benefactor behind the Wyss Institute.

Besides setting up Emulate with its own office and laboratory space, and hiring the company’s first employees, that financing will mainly be dedicated to scaling up manufacturing. So far, the Wyss Institute has partnered with Sony DADC to build its silicone chips, and Cedars-Sinai is providing many of the primary cells. Those relationships seem likely to continue under Emulate, but another aspect of the business requires new manufacturing partners.

One of the big selling points of Emulate’s technology is its instrumentation, a benchtop device the chips are physically plugged into. “The instrument does everything,” says Coon. “It maintains the chip. It does all the microscopy, so you can do constant visualization of your chip looking at different cell biology changes. It does all your sampling, so it has a robotics system to introduce drugs or pull samples from the chip. And we have a bunch of other endpoints that we’ll be announcing in the coming year.” The company now needs to create a pipeline to build that instrument in bulk, as it searches for customers willing to take a chance on organs-on-chips in their own laboratory space.

Emulate also provides the software for working with its system — both on the front end, programming experiments, and on the back, analyzing data. With a consolidated, push-button platform, Coon hopes it will be easier to translate the industry’s frustration with current preclinical models into early adoption of organs-on-chips.

One wildcard in the acceptance of organs-on-chips is the FDA, who will ultimately judge whether they provide convincing enough data to move therapeutics from preclinical to clinical trials. The FDA’s funding of work at the Wyss Institute, however, is an encouraging sign, not only for Emulate, but for any company exploring new preclinical models. Emulate’s founders have had a rare opportunity to introduce their technology to regulators at a very early stage, and hope to establish a basic level of comfort with their chips among the stakeholders in drug development.

It helps that the weaknesses of traditional testing have been weighing on the industry for so long. “There is a groundswell of interest across the whole industry to replace animal testing,” says Coon. “That’s driven by the lack of predictability. As we move more and more toward personalized medicine, and biologics, and things that are very human-centric, it’s difficult to have animal models that are effective.”

Emulate has not yet announced any customers, or even a timeline for the release of its products, so it’s far too early to know whether the company will be the first to break through with this technology. Certainly the industry’s natural caution will remain a barrier to the widespread use of organs-on-chips for years to come — and rightly so, given the high stakes of drug testing. Partners will demand to know how well the chips align with true human biology when it comes to compounds that are already well understood, a validation process that Emulate is still pursuing. But whatever the company’s fortunes, its forebears at the Wyss Institute have already made their impact in bringing the organ-on-a-chip model closer to realization. 


 

 


 

 

*8/1/2014: An earlier version of this article stated that the MIMETAS organs-on-chips “do not try to recapitulate tissue function.” However, as a MIMETAS representative has since pointed out to me, although MIMETAS does not use mechanical forces to mimic high-level functions like breathing the way Emulate does, the company very much aims to recreate organ-like biological systems by growing different cell types in co-cultures. MIMETAS chips include both 3D cultures of cells from the specific tissue of interest, and boundary tissue like vasculature connecting them. 

 


 

 

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