The baby just admitted to the cardiology department at Columbia University Medical Center in New York City was very, very sick. Because of a defect in a gene, his heart didn’t pump correctly. When he was active — when his heart needed to pump faster and stronger — the baby’s heart instead pumped weakly. He was at risk of frequent fainting. As he got older, strenuous exercise might be deadly.
What to do? Experimenting with different drugs and doses on such a young patient could be dangerous, even fatal, explains Gordana Vunjak-Novakovic, a professor of biomedical engineering and medical sciences at Columbia.
Instead, Vunjak-Novakovic’s team works with the stem cells from patients like these to produce an “organ on a chip,” a simplified, beating model of the patient’s own heart, etched into a silicon structure and attached to a source of nutrients. Then they introduce various medications at different doses into the model until they find a regimen that works for a specific disease condition.
“This kind of result makes you happy. It gives you serious hope to understand the pathology of disease, to better determine the drug regimen, and use the platform to develop new drugs,” says Vunjak-Novakovic, who adds that this baby’s treatment was part of a study and that this treatment is probably years from being widely available.
Vunjak-Novakovic voices the general hopes of hundreds of scientists and physicians working around the world to develop “organs on chips,” linked models of various organs, and “organoids,” tiny versions of organs fashioned from stem cells. The first of these systems began to appear just five years ago, but progress and excitement have been building fast as academic researchers construct ever more complex organ models and biotech firms begin to form around these new ideas. The Museum of Modern Art (MoMA) in Manhattan has even acquired several organ chip systems for its permanent collection and displayed them earlier this year.
We need a model to better understand human physiology, something more complex than a Petri dish… using human tissue as the source, not just cells.
The excitement is understandable: These approaches could greatly increase the speed and accuracy of drug testing, a system that most agree is now cumbersome, lengthy, and expensive. These developing technologies allow researchers to study model organs from the individual patient’s cells, for safe and speedy evaluation of the best drug regimens.
Organ models create other new possibilities for researchers: high resolution views of immune cells and drugs as they work in real time within a human organ context and a cost-effective approach for researching rare diseases, which often languish as research subjects because of the difficulty of designing and carrying out research when the disorder might affect only a few dozen, or a few hundred, people at any one time.
Or let’s say you want to figure out how a pesticide might affect humans, cattle, and insects. With organ chip systems, researchers could grow a model of a human gut, a cow gut, and an insect gut, then compare how each reacts to the pesticide. That sort of experiment would be nearly impossible using full-size, living creatures. How would you track the insects? How could you justify dosing humans with pesticides?
To avoid similar issues, the organs on a chip are being used to study the effects of radiation, something you might not want to do with real humans. Or consider the fact that one of the most common, and most dangerous, drug side effects is cardiotoxicity, or damage to the heart. If drugs were first tested on hearts on chips, a lot of patient misery could be avoided.
Or say a pandemic like Ebola or SARS emerges. In that real-world crisis, it’s next to impossible to obtain cultures from patients in the field in an organized way. But what if researchers could build a model of the disease with living cells and then test various drug approaches quickly?
“We need a model to better understand human physiology, something more complex than a Petri dish … using human tissue as the source, not just cells,” explains Kristin Fabre, scientific program manager on the Tissue Chip Initiative, a five-year National Institutes of Health (NIH) program to support research in this area.
Life on a Chip
All these efforts form a natural progression after tissue engineering, which has been around for 25 years. That field has many early successes with growing human cells on “scaffolds” to replace parts of the body that are largely mechanical, like bone, cartilage, or the trachea, or relatively thin, like blood vessels or a bladder.
“What makes an organ different from a tissue?” asks Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering at Harvard University. “It’s two or more different tissues that interface and together create a new function. This is synthetic biology at the organ level.”
Vunjak-Novakovic says her favorite metaphor for organs on a chip is a suburb. “Imagine a set of houses. When you look at them from the outside, they all look the same, but each is very different on the inside. We can customize the interiors of the culture chambers to support different kinds of tissue, and connect them with ‘streets,’ vascular channels through which blood substitute can flow.”
The term “animal on a chip” was first coined in the late 1990s by Michael Shuler, a Cornell professor, when researchers began etching tiny silicon wafers to form small compartments linked by microchannels through which fluid could pass. These systems essentially brought into the physical world the mathematical models that had been used to predict organ interactions. In 2010, Ingber’s team at Harvard produced the first successful organ on a chip, featuring multiple tissues in the form of a lung, and the field has been moving fast ever since. (It was the Ingber Lab’s lung, gut, and liver organs on chips that were displayed at MoMA.)
The NIH tissue chip program has just sent out its second round of funding, supporting 11 research teams around the country who are seeking to build and link models of human muscle, kidneys, brain tissue, heart, skin, blood vessels, and more.
Key issues for all these organ chip researchers are: How complex is complex enough? How simple is too simple? Most researchers are quick to say that all these systems are models. They don’t capture the full complexity of a human organ, with nerves, hormones, immune cells, and everything else.
“If we were able to build a perfect micro human, it would be too complicated for us to understand,” explains John Wikswo, professor of biomedical engineering at Vanderbilt University. “So, instead we build parts of a micro human and study how they interact.”
“We’re trying to look at subsets of organs that form a physiological link,” says Vunjak-Novakovic. “How you build a system depends on what you’re trying to find out. For instance, if you’re testing a drug that affects heart rate, then it’s key that the cells on the chip are beating. If you’re also trying to understand how the liver may metabolize this same drug and change its cardiotoxicity, then the connections between blood, liver, and heart are key for getting a predictive result.”
Kristin Fabre at the NIH says that one of the most difficult things about conventional drug testing is that we still don’t fully understand the intricacies of the human body, including organ-to-organ interaction. “Let’s say you’re studying Drug X. So you give Drug X to kidney cells to see if it works. It looks promising,” Fabre says. “But then, if you connect the liver chip to the kidney, the liver metabolizes Drug X into metabolites A, B, and C. Metabolite B turns out to be toxic to the kidney tissue. That could be missed in current standard models, but quickly discovered by an integrated organ-on-a-chip system.”
In addition, animal models don’t always accurately predict a human response to a certain drug. In other words, what may not be toxic to a mouse may be toxic to a human. Organs on a chip aim to improve testing safety and effectiveness of new drugs.
The physical environment also profoundly affects how organs function. Lung cells grown in a lung on a chip at Ingber’s lab at Harvard don’t absorb airborne particulates when in a static culture. But biochip lung cells that are expanding and contracting, like a real lung, do absorb the carcinogens. No one yet knows why, but everyone agrees that context, both structural and functional, seems to be really important to how organs operate.
Most specialists say that widespread use of these systems is a few years away, but already business is investing in the technology, especially since tests on human organ chips seem to be more relevant than tests on animals like mice. In other words, human chips better mimic human physiology.
Emulate, founded by Harvard professor Ingber, has partnered with Johnson & Johnson to study drugs and toxicity. Hemoshear, founded by two University of Virginia scientists, has teamed with Pfizer to develop several organ systems, including one that mimics blood flow in tissues, trying to predict what sort of blood vessel injuries might be caused by certain drugs. Hepregen, founded by Sangeeta Bhatia, an MIT researcher, has created liver models of humans, monkeys, dogs, and rats, to allow analysis of how the liver processes — and changes — various drugs. Similar biotech firms are starting up around the world. In Europe, big cosmetic companies like L’Oreal hope to replace animal testing with chip models of skin.
Meanwhile, other groups of scientists are trying to get stem cells to self-construct miniature organs. These organoids also can be used to test drugs and to better understand how organs function.
This work is based on the fact that embryonic stem cells are pluripotent. That is, these cells have the potential to change into any kind of cell in the body. This makes it possible to conceive of model organs that aren’t on a chip but are self-constructed.
Sometimes, just placing the cells together in the right environment is enough for them to begin morphing from separate tissues into functional organs. Teams have fashioned a self-organizing micro heart, kidney, pituitary gland, optic cup, even a tiny model of cortical brain tissue.
Others are using bioelectrical messaging and other techniques to drive organoids to become specific organs. “We’re working on understanding the language of how cells coordinate their activity toward a goal. Who’s going to do what? When does it stop?” explains Michael Levin, a principal investigator in the Department of Biology at Tufts University. “If we understand the bioelectrical language of cells, we can issue specific commands that trigger whole patterning programs — a sort of master-regulator function. We give cells the signal and let them do their thing.”
Other teams are using these techniques to model diseased tissue. Last year, a team modeled gastric disease. In 2015, other researchers succeeded in modeling both pancreatic cancer and colorectal cancer.
Wikswo, at Vanderbilt, is working to build a brain on a chip to model the blood-brain barrier. Other groups are building cardiac tissues from patients who have heart abnormalities. Still others are trying to use organoids to understand relatives with different Parkinson’s outcomes.
“Organs on a chip will eventually replace animal models,” says Wikswo. “I think this will be in widespread use within a decade.”