Credit: The Wyss Institute at Harvard University

Can Organs-On-Chips Repair The Flawed System Of Drug Discovery?

Reposted from Life Science Leader.

By Trisha Gladd, Life Science Connect Editor

There is an ecosystem of many stakeholders who play a role in the discovery of new drugs, and each of them have a vested interest in making the drug discovery system work successfully and efficiently.  Yet, the realities of a flawed system are evident in the facts and figures.  A Phase 1 clinical trial for one compound can cost close to $15 million and take years to complete. Data published on www.fdareview.org also shows that only about 10 percent of drugs entering Phase 1 trials actually make it to market, which translates to considerable financial losses for those in the other 90 percent.

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Recently, a wide range of these stakeholders – from pharmaceutical companies and academic researchers, to disease foundations and CROs – have signed on to work with Emulate, Inc., a privately held company at the forefront of a new technology, called ‘Organs-on-Chips.’  James Coon, CEO of Emulate, and his team of scientific researchers, designers and engineers are aiming to change the way drug candidates are evaluated in the laboratory by using Organs-on-Chips technology an alternative to today’s cell culture and animal testing techniques.  In the past week, two new collaborators have joined forces with Emulate: a CRO, Covance Drug Development, and a major cancer research center, the Ellison Institute for Transformative Medicine at USC.  This adds to the growing list of partners – including Johnson & Johnson, Merck, the Michael J. Fox Foundation for Parkinson’s Disease, and the government defense agency DARPA – who are putting their hopes and expertise on the line to advance Organs-on-Chips technology into the mainstream of the drug-development process.

Coon says one of the reasons so few drugs make it to market is due to the conventional in vitro models and animal models currently being used by the pharmaceutical industry. To identify viable drug candidates, these models rely on data points from static human cell cultures in plastic dishes that do not represent the broader living biology of human tissues and organ systems, or on studies in animals that do not always directly translate to human biology. Organs-on-Chips technology offers a new approach.  By placing living human cells in an engineered microenvironment that recreates what’s happening within tissue systems, Coon says the technology offers the ability to create the smallest functional unit of a human organ, which gives a biological context that is much more effective at predicting human response than today’s cell cultures or animal testing.

Organs-on-Chip is a technology originally designed by Donald E. Ingber M.D. Ph.D., founding director of The Wyss Institute for Biologically Inspired Engineering at Harvard University, and Dan Dongeun Huh, Ph.D., assistant professor in the department of engineering at the University of Pennsylvania, that combines microfabrication techniques and engineering principals to create living, functioning human organs inside engineered microenvironments. Measuring in a size similar to a AA battery, each chip is made of a clear flexible polymer that contains tiny hollow channels lined by living human cells. Just as if cells from a patient’s body were biopsied and then studied, these translucent devices can be created by scientists to use as a window into the inner workings of human organs.

Since spinning out of The Wyss Institute for Biologically Inspired Engineering in July 2014, Emulate has evolved its Organs-on-Chips technology to become a commercially-viable product platform for use in industry.  By housing the Organs-on-Chips within an automated system Emulate offers a way for researchers and product developers to not only conduct experiments that are predictive of normal human physiology, but they also can create different disease states within the Organs-on-Chips to help determine appropriate therapeutic intervention. This lab-ready automated system includes three components: the Organs-on-Chips, the instrumentation that automates the use of those chips, and the software apps that allows scientists to collect and analyze data.  Because Emulate is integrating their Organs-on-Chips technology into a ‘plug-and-play’ system, end users can easily conduct experiments to meet customized needs within their own labs.

“In collaborations announced over the last year, industry leaders, such as Merck, the Michael J. Fox Foundation and Johnson & Johnson, are recognizing that the Organs-on-Chips technology can be valuable in predicting human response in applications throughout the drug development process and are now engaged in using the technology for a wider range of applications,” says Coon. “This includes early-stage processes, such as discovering new drug targets and understanding disease mechanisms, as well as late-stage testing of the efficacy and safety of new drug compounds.”

How Would Organs-on-Chips Impact The Future Of Animal Testing?

While it seems Organs-on-Chips has the potential to eliminate animal testing, Coon says that, as of right now, that is unlikely. “We live in a world where there is a regulatory system in place that is built around standards using animal testing,” he explains. “As a result, some of our early partners are using Organs-on-Chips to augment their existing pre-clinical models, and over time, we may be able to increasingly replace animals in the development process.” When it comes to the three guiding principles supporting the humane use of animal testing in scientific research—replace, reduce, and refine—Coon says Organs-on-Chips can play a role in each area. “By serving in a role side-by-side with animal testing, the technology can generate human-relevant data that has the ability to guide the refinement of the animal models that are selected for regulatory submissions,” explains Coon. “This could ultimately reduce the ineffective or unnecessary animal studies as well as the number of animals required.”

Consistent with the way new standards are accepted for regulatory filings with FDA and other agencies, the Organs-on-Chips technology will be evaluated for future adoption for regulatory uses as the body of data using Organs-on-Chips continues to grow over time. As of right now, it is a technology that is used part of the R&D process, and continues to be evaluated for adoption as a standard practice for regulatory filings.

Industry Partnerships Drive Commercialization Potential

In 2015, Organs-on-Chips was named the overall winner of the London Design Museum’s Design of the Year award. This marked the first time this award was presented to a product from the field of medicine. Some of pharma’s biggest names also have recognized the potential of this technology. As mentioned, Emulate has entered into a strategic collaboration with Merck. Together, the two companies are working to deploy Organs-on-Chips across certain Merck drug discovery programs with the goal of improving models of human inflammatory diseases and better predicting human response of therapeutic candidates. In addition, Johnson & Johnson Innovation and Janssen Biotech are also in a strategic collaboration with Emulate to use Organs-on-Chips to drive the clinical goals for three Janssen R&D programs.

When it comes to partnerships, Coon says one of the things they have been careful about very early on is not chasing money. “Our goal is to strategically align with companies that help us advance our core business, which is to develop the technology platform, the instrumentation, and the software,” he explains. “All of our partners have brought not just funding but also expertise.,. These partnerships allow us to have the kind of insight that offers a jump-start to move forward in different therapeutic areas we wouldn’t normally have access to.”

Emulate continues to have an active collaboration with The Wyss Institute as well. This includes a $37 million agreement between The Wyss Institute and the Defense Advanced Research Projects Agency (DARPA) to integrate 10 human Organs-on-Chips to study complex human physiology. This project provides foundational research that opened the door for Emulate to envision its overall mission, which is to develop and commercialize the Organs-on-Chips technology into an automated system that is used by industry to emulate human biology, in order to understand how diseases, medicines, chemicals and foods affect human health. “Everything we’ve done with DARPA has given us the insight to not only be able to deliver technically on the science and the biology, but to also scale manufacturing of the chips up and create a stronger foundation for product development,” says Coon.

Emulate is expanding its current product portfolio, which includes Lung-Chip, Liver-Chip, Intestine-Chip and Kidney-Chip, for additional organs such as Skin-Chip, Heart-Chip, Brain-Chip. As the product platform becomes widely adopted and more researchers are using it across multiple industries, Emulate will need to be able to produce millions of chips to move closer to launching Organs-on-Chips as a commercial product. A major step toward the commercialization of Organs-on-Chips was made earlier this year when Emulate secured $28 million of its Series B financing to accelerate its technology into a commercially-available “Human Emulation System.” As stated in a press release on its site, the financing will position Emulate “to accelerate its R&D effort, expedite the launch of its products and expand strategic relationships with industry and academic partners in order to evolve the company towards profitability.”

Since the early stages of research at the Wyss Institute in 2009 to Emulate’s founding in July 2014, experts from design, engineering, medicine, biology, and the physical sciences have shared a common goal of working together to develop Organs-on-Chips to create transformative change. As Emulate continues to advance its product platform, the industry will move closer to a solution that helps develop new therapeutic solutions for patients and offers a less costly way to develop innovative medicines. In addition, the company is also currently working with partners to develop Organs-on-Chips with individual patient stem cells, for use in precision medicine and personalized health applications. Through a focus on improved disease understanding and accuracy of human response, Organs-on-Chips drives efficiency at all levels of drug development and offers possibilities in patient care the industry has yet to see.

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Credit: The Wyss Institute at Harvard University

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From the Wyss Institute press release: "These fluorescence confocal microscopy images show both a high magnification view (left) of a region of the human brain capillary endothelium within the endothelium lined tube (shown at lower magnification at right) that, in combination with surrounding human pericytes and astrocytes, comprise the blood-brain barrier (cell junctions linking adjacent endothelial cells are shown in magenta). " Credit: Wyss Institute at Harvard University

“Blood-brain barrier on-a-chip”

Scientists at the Wyss Institute have created a 3-dimensional in vitro model of the human blood-brain-barrier (BBB)-“on-a-chip.”  The device will make it possible for researchers to test drugs, chemicals, and disease factors that interact with the BBB, without using animals – and in a 3-dimensional environment that mimics that of the human BBB in vivo.

The BBB is a semi-permeable cellular structure that allows some nutrients and substances to enter the blood flow in the brain, and keeps other elements (such as bacteria and potential toxins) out. Because it is so effective, it can also prevent useful treatments from reaching targets in the brain. Researchers need to understand how and why certain substances can pass through the barrier, in part so they can design therapeutic drugs accordingly, and so they can design other substances to prevent neurotoxicity.

From the Wyss Institute press release: "These fluorescence confocal microscopy images show both a high magnification view (left) of a region of the human brain capillary endothelium within the endothelium lined tube (shown at lower magnification at right) that, in combination with surrounding human pericytes and astrocytes, comprise the blood-brain barrier (cell junctions linking adjacent endothelial cells are shown in magenta). " Credit: Wyss Institute at Harvard University

From the Wyss Institute press release: “These fluorescence confocal microscopy images show both a high magnification view (left) of a region of the human brain capillary endothelium within the endothelium lined tube (shown at lower magnification at right) that, in combination with surrounding human pericytes and astrocytes, comprise the blood-brain barrier (cell junctions linking adjacent endothelial cells are shown in magenta). ” Credit: Wyss Institute at Harvard University

To create the device, the Wyss Institute team carved a tiny channel in a polymer chip and filled it with a gel matrix containing human astrocytes, the cells that comprise the extra-tight “barrier” around blood vessels in the brain. Another channel was tunneled through this matrix and seeded with human pericyte cells (contractile cells which control the “gaps” through which substances can enter the neurological bloodstream) and then with human endothelial cells (the cells that line the interior of a blood vessel). The cells “self-assembled” into the same layers and connections they exhibit in blood vessels in vivo.

To test the model, the team introduced a protein known to cause inflammation – one that has been associated with a number of central nervous system diseases and disorders, including Alzheimer’s, multiple sclerosis, and stroke (among others). The in vitro BBB responded by producing protective proteins. The device can thus be used to study neuroinflammation, and to test new treatments.

Read more in the Wyss Institute’s press release.

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Tools for PCR amplification of DNA

Human Toxicology Project Consortium coordinator participates in a TSCA science briefing on Capital Hill

At a recent Capital Hill science briefing organized by the American Chemical Society (ACS) and the American Chemistry Council (ACC), Human Toxicology Project Consortium coordinator Kate Willett joined toxicologists from industry and the EPA to discuss how reforms to the Toxic Substances Control Act (TSCA) can capitalize on scientific advances in non-animal test methods.  Participants explained how technologies such as high-throughput screening, organs-on-chips, and computational modeling will improve the relevance and efficiency of safety assessments, and produce crucial information more quickly. The Royal Society of Chemisty’s Chemistry World covered the briefing.

The experts gathered at the briefing agreed that tremendous advances had been made since the 1970s in understanding how chemicals can interact with biological systems – at the molecular, cellular and organ level. For example, high throughput screening now enables thousands of chemicals to be evaluated in a matter of hours or days….

Kate Willett, a toxicologist at the Humane Society of the US, noted that the critical goal of [TSCA] is to protect human health and the environment. This means a system is needed that can quickly identify potential problems and address them in the most time- and cost-effective way possible.

Willett stressed that any new TSCA reform measure must allow for “the continuing evolution of this science.” Therefore, she said the final updated law should require that all alternative approaches are used before moving to animal testing. “Reducing reliance on animal testing allows more chemicals to be more thoroughly assessed in the most efficient way possible – a win for environmental protection and the industry, and also for the animals that are used in this testing.”

The House and Senate have both passed TSCA reform bills (H.R. 2576 and S. 697) and now must reconcile differences between the two versions.

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Credit: The Wyss Institute at Harvard University

Chipping away at the use of animals to predict human diseases

The Wyss Institute recently announced two new human cell-based inflammatory disease models built on its rapidly expanding “organ chip” platform. Both models could speed the development of treatments for these diseases, and further reduce the use of animals in testing.

Using the “gut-on-a-chip” device first introduced in 2012, Wyss scientists co-cultured human intestinal cells with normal and pathogenic intestinal microbes, producing an in vitro model (viable for up to two weeks) of intestinal inflammation and bacterial overgrowth. These two disease features are present in a number of human intestinal disorders (such as ulcerative colitis and Crohn’s disease). Until now, it has been difficult to reproduce these disorders in the lab in order to test treatments for them. The gut-on-a-chip device “could allow breakthrough insights into how the microbial communities that flourish inside our GI tracts contribute to human health and disease.” The image below, from the Wyss Institute press release, shows how the cells in this microenvironment even reproduce normal peristalsis, the contraction/relaxation cycle of the intestinal walls that moves digested food down the tract.
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The Wyss Institute also used its chip technology to create a human lung “small-airway-on-a-chip.” When the chips are lined with airway cells from patients suffering from such inflammatory disorders as chronic obstructive pulmonary disease (COPD) or asthma, the physiological features of the disease can be observed and tested in vitro. As noted in the Wyss Institute press release, “Demand for such opportunities is especially high since small airway inflammation cannot be adequately studied in human patients or animal models and, to date, there are no effective therapies that can stop or reverse the complex and widespread inflammation-driven processes.”

Watch a video demo of the small-airway-on-a-chip below:

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Organovo's Novogen 3D bioprinter (photo credit: Organovo)

Reading round-up

A few good links to share…

A UCLA scientist is using tiny worms – C. elegans – in a high-throughput, automated format, to screen chemicals for reproductive toxicity.

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Patrick Allard (photo credit: UCLA Fielding School of Public Health)

“With this approach we can now simultaneously screen hundreds of compounds for their toxicity to the reproductive process, which can help to prioritize the chemicals that need further analysis,” Allard said. “Beyond that, once we find compounds that are repro-toxic, we can look further into the stages of reproduction that are affected, and how they are affected.”

Organovo's Novogen 3D bioprinter (photo credit: Organovo)

Organovo’s Novogen 3D bioprinter (photo credit: Organovo)

Chemistry World has a good overview of the growing skin 3D-bioprinting industry, noting that while the initial push is coming from cosmetics companies, “The expertise gained could feed into pharmaceutical research, and even help enable patients’ own cells to be made into almost perfectly compatible skin grafts and eventually replacement organs.”

And in the NIH Director’s Blog, Francis Collins describes NIH-funded efforts to develop neural tissue chips that predict neurotoxicity:

Cultivated neural tissue (photo credit: Michael Schwartz, University of Wisconsin-Madison

Cultivated neural tissue (photo credit: Michael Schwartz, University of Wisconsin-Madison

Each cultured 3D “organoid”—which sits comfortably in the bottom of a pea-sized well on a standard laboratory plate—comes complete with its very own neurons, support cells, blood vessels, and immune cells! As described in Proceedings of the National Academy of Sciences [2], this new tool is poised to predict earlier, faster, and less expensively which new or untested compounds—be they drug candidates or even ingredients in cosmetics and pesticides—might harm the brain, particularly at the earliest stages of development.

Collins also co-authored a Nature commentary summarizing six important lessons learned from Human Genome Project, on its 25th anniversary: embrace partnerships, maximize data-sharing, plan for data analysis, prioritize technology development, address the societal implications of advances, be audacious yet flexible… Read the details here.

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Credit: The Wyss Institute at Harvard University

Alternatives going mainstream

Things are getting interesting when high-tech replacements for animal testing catch the eye of online financial publications like The Economist, Fortune Magazine, Forbes, and CNN Money

Some stories on organs-on-chips and 3D bioprinting from just the last few weeks:

The Economist: Towards body-on-a-chip

Fortune Magazine: This new technology could do away with animal testing

CNN Money: 3-D printers could soon make human skin

Forbes: L’Oreal seeks quantum leap with 3D printed skin

Congratulations to the Wyss Institute, winners of the London Design Museum’s “Design of the Year” award for their organs-on-chips.

Named Design of the Year by a jury chaired by the artist Anish Kapoor, it is the first time the award has gone to a design from the field of medicine, beating off competition from Google’s self-driving car, a project to clean up plastic from the sea and an advertising campaign to convince people to buy misshapen fruit.

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Image attribution: National Center for Advancing Translational Sciences

Have you met “Chip”?

The National Center for Advancing Translational Sciences website has a new interactive feature introducing “Chip,” a handsome collection of 3-dimensional tissue chip devices scientists are working to integrate into a human-on-a-chip. The project is a collaboration between NCATS, DARPA, the FDA, and numerous academic research partners.

Screen shot from NCATS video, "Tissue Chip for Drug Screening"

Screen shot from NCATS video, “Tissue Chip for Drug Screening”

At least a dozen “chip” systems are under development, aiming to model processes in the brain, heart, lungs, kidneys, liver, intestines, muscles, skin, reproductive system, and more. As these fully functional cell, tissue, and organ models are perfected, scientists will be able to use them to test potential drugs or vaccines for their effectiveness or toxicity in humans, with much greater accuracy than animal tests can provide. Currently, over 90% of drug candidates fail in development because drugs that looked promising in pre-clinical (animal) trials turn out to be toxic or ineffective in human trials.

You can read more about tissue chip research in this article from AltTox.org. For more technical information, see the September 2014 issue of Experimental Biology and Medicine, which is devoted to the topic.

And watch this NCATS video, “Tissue Chip for Drug Screening,” for more on this exciting research.

Related posts: Advances in human relevant testing & NIH announces funding for the next phase of its tissue chip for drug screening program

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