Ashley Jean Yeager Freelance Writer GEN
Slides of Cells Can Mimic Human Tissues Better Than Animal Models but Still Have Development Challenges, Scientists Say
Developing drugs isn’t easy or cheap.
Even after extensive testing in cell cultures and animal models, drugs can fail miserably in clinical trials. In fact, less than one out of every 10 drugs moved to the clinical-trial stage gets FDA approval. And, should a drug make it to market, it will have been in the making for more than a decade carrying a price tag of more than a billion dollars.
Organ-on-a-chip—miniaturized versions of the brain, heart, liver, and other vital tissues—offer an enticing alternative. With the technology, researchers aim to cut the cost and time of drug development in half, Danilo Tagle, Ph.D., associate director for special initiatives at NCATS, the National Center for Advancing Translational Sciences, told GEN. The ultimate goal is to develop a body-on-a-chip system that would replace drug screening in cell culture, animal models, and even the need for humans in Phase II and Phase II clinical trials. All of those tests would be done on the chip. Then, if a drug passes, it would move right to Phase III clinical trials.
Realizing that goal is 10 to 15 years away, or longer. But researchers have been making progress. In 2012, teams of scientists started publishing landmark papers on organ-on-a-chip technology, and since then, they have developed single-organ systems for the brain, fat, skin, blood vessels, lungs, heart, muscle tissue, and much more. These systems mimic the human body, receiving fresh flows of blood and nutrients, so they work as they would in the body.
Right now, researchers are currently using single- and multiorgan chips to test drug compounds that have already shown to be safe and effective or toxic in humans. These tests, Tagle explains, build confidence in the technology, proving it is as reliable or better than the current gold standard—cell cultures and animal models. Most of the compounds tested in the organs-on-a-chip have responded just as researchers predicted. The chips reveal the efficacy and toxicity of a drug just as a petri dish of cells or a mouse or rat would, or possibly even better.
But, the research has provided some surprises along the way, discoveries that could shape the development of drugs in the future.
Beating and Breathing
At his Wyss Institute lab at Harvard, bioengineer Kevin Parker, Ph.D., has been working on a heart-on-a-chip, and his colleague, Donald Ingber, M.D., Ph.D., has pioneered the development of the lung-on-a-chip. Their research has revealed “fundamental knowledge gaps in organ physiology,” Parker told GEN. Studying their heart chip, he and collaborators realized that what they had learned in physiology textbooks about how the organ pumps is flawed. “Turns out we don’t understand muscular pumps,” he says, adding that this lack of understanding could be why it has been so difficult to treat heart disease.
The same could be true for lung conditions. In 2012, Ingber and colleagues published a paper in Science Translational Medicine describing a lung-on-a-chip where human pulmonary epithelial and endothelial cells experienced air and fluid flow along with mechanical strain, which mimicked motions of normal breathing. When the cells were exposed to interleukin-2 (IL-2) to simulate treatment of human cancer patients, the “lung” responded with increased vascular leakage, leading to pulmonary edema or swelling of the lungs. Cancer patients can experience this swelling when undergoing treatment. The experiment, however, revealed that the edema developed even though there were no immune cells circulating in the chip. This single-organ experiment suggested that damage to the lung itself was at the root of the edema, not signals from the immune system, as researchers had thought.
It was a surprising bit of physiology, a discovery that suggests “we tend to make things more complicated than they need to be,” Tagle says. Single-organ chip studies will be key to resolving that lack of understanding of how cells talk to each other and respond to foreign substances such as bacteria and drugs.
Already those kinds of results are emerging. In May, an organ-on-a-chip spin-off company of Wyss called Emulate in partnership with pharmaceutical company Merck presented data on what they called asthma-on-a-chip. When the researchers infected the “lung” with human Rhinovirus, which has been linked with asthma exacerbation, the cells responded with a pro-inflammatory response. Using a selective CXCR2 antagonist drug agent, the team showed it could curb innate inflammatory cell infiltration to the lungs.
Parker calls the single-organ drug screening a work in progress. Multiorgan chips being the ultimate goal.
Single-organ chips are good for testing the efficacy of drugs or how cells respond to, say, a food additive or a cosmetic component. But true tests of toxicity come when more than one organ is integrated onto a chip, Tagle says. His vision, along with many others, is to see a body-on-a-chip.
With multiple organs represented, researchers can determine whether a drug’s metabolites harm any or all of the cells types, Cornell biomedical engineer Michael Shuler, Ph.D., tells GEN. Researchers can also test chronic versus acute dosing of drugs and monitor how all tissue types respond. Essentially you could watch how the body responds to a drug.
Development of single- and multiorgan chips is a “hot area,” Shuler says. He is principal investigator of Hesperos, LLC, which is designed to develop the organ-on-a-chip technology and distribute it to pharmacology companies for testing drug candidates. Emulate has a similar mission. The company’s CSO, Geraldine Hamilton, Ph.D., wrote in an email to GEN that the current challenge and opportunity for the organ-on-a-chip technology is the translation into a lab-ready system that encompasses tests with multiple organs and that can be used by any researcher.
“We want to pilot-proof the technology,” Tagle says. That means a researcher would have a tabletop platform where he or she essentially presses a button and receives readouts on a particular drug candidate. To get to such a point requires standardization, which is why Tagle has drive the development of organ-on-a-chip testing centers. They will reproduce the chips, experiments, and data already published by researchers and companies working on the technology to create the baseline for what companies will need to submit to the FDA to show efficacy and safety of a drug.
Right now, NCATS is focused on the preclinical space, where researchers screen and test efficacy and toxicity of drugs, Tagle says. But down the line, using induced pluripotent stem cells, researchers could generate many types of cells in the body, essentially giving you an individual on a chip. With thousands of these “body” chips, drug developers could run Phase I and Phase II clinical trials without exposing actual people to drugs only tested in model animals. Replacing people with chips at these early stages would mitigate the risks of harmful exposure to drugs that currently happens now, Tagle says. Human subjects would not be given any medication until Phase III in a drug trial.
There’s promise, but there’s work to do, Parker says.