Building a human on a chip, organ by organ
Editorial: "The personalised medicine revolution"
Human "organs on chips" could be linked to make the ideal guinea pig, revolutionising the way drugs are tested and cancer is treated
JUSTIN WILLIAMS pokes his brain with a sharp object, then watches what happens through a microscope. He’s studying how it responds to injury, and initial results are already providing new insights. "We’ve found that [immune] cells respond much more quickly than we would have anticipated – we normally think of these cells responding to injury in hours or days, but we see them respond within minutes," he says.
Needless to say, the brain Williams, at the University of Wisconsin, Madison, is needling is not his own. It is a small sample taken from a mouse and held in a "brain-on-a-chip" device: the tissue is suspended between two layers of plastic and surrounded by a nutrient-rich fluid. Williams presented his immune response findings at the International Wyss Symposium on Microfluidics and Medicine in Boston last month.
The brain is just the latest internal organ to be replicated in miniature form. From beating hearts to breathing lungs, livers to fallopian tubes, the list is continually growing. Now Williams and others at last month’s symposium are trying to figure out ways to connect some of these chips together – a step towards creating a body-on-a-chip.
Each micro-organ contains a living core of animal cells sustained by nutrient-rich fluids, and all are revealing how cells respond inside the body in a way that traditional cell cultures cannot.
For instance, when Donald Ingber’s team at Harvard University’s Wyss Institute for Biologically Inspired Engineering created a "breathing" lung-on-a-chip last year, they discovered that it is the breathing mechanism itself – the way cells stretch and contract – that appears to encourage an inflammatory response to potentially harmful nanoparticles produced by the nanotechnology industry (Science, DOI: 10.1126/science.1188302). Studying static cells in a dish would have missed the importance of breathing.
Such organs on chips can be used to model how human organs function and respond to drugs, says Ingber. He thinks that they even have the potential to eliminate the use of animals in drug testing. "Animal testing is expensive and time-consuming, and animals are not always representative of humans."
Williams is not so sure. Even the most sophisticated organ-on-a-chip is unlikely to fully represent how a living organ functions. "So many of the things we like to study from the intact brain of living animals involve the animal’s behaviour," he says. Even a complete brain on a chip cannot replicate this.
Still, Ingber points out that the chips can perform some roles that animal studies cannot. For instance, they could be personalised by building them from an individual’s own cells. In theory, a doctor could send tissue samples to a lab to test a potentially harmful therapy on such a chip before handing out a prescription. This would be especially useful for people with cancer, as the various therapies available can have very different effects on different people, Ingber says. "You could get a quick yes-or-no answer to whether a drug would work or not," he says.
Personalised chips might also speed up clinical trials. "Someday it might be possible to shortcut clinical trials by using chips containing cells from different human populations that are known to respond differently to specific drug classes," Ingber says.
To realise those goals, Ingber and Kevin Kit Parker, also at the Wyss Institute, are going beyond creating versions of isolated organs on chips and beginning to connect them together. At the Society of Toxicology annual meeting in Washington DC earlier in the year, Parker demonstrated his chip version of a beating heart, created by covering a flexible polymer with heart cells derived from mouse embryonic stem cells. The structure is a bit like a Fruit Roll-Up," says Parker. "The engineered muscle is on one side of the polymer."
The heart cells are myogenic – they beat by themselves – just like those in a living heart, and by measuring the degree that the polymer bends, Parker can see if the cells are contracting properly. This makes the model ideal for testing drugs for heart failure – a condition in which cardiac cells often fail to contract strongly enough. "We’re working with a pharmaceutical company to do just that," he says.
Parker’s heart could join up with Ingber’s lung. "We’re trying to mimic natural organ-organ interactions," says Ingber (see diagram). The heart-lung device could be useful for testing the effects of aerosol-based drugs on the heart, as well the cardiac effects of inhaled particles and general air pollution, he says.
"The ultimate test will be if the lung can oxygenate the heart tissues, and we’re still working out how that’s going to happen," says Parker. If his team can figure out how to crack this problem, in theory the heart-on-a-chip could pump a blood substitute to the lung-on-a-chip, which could oxygenate the blood and send it back to the heart, mimicking what goes on in the body.
But once you’ve connected a mini-heart to a mini-lung, why stop there? "Putting other organs on is a big thing that we want to do," says Parker. As for which organ should be up next, "there’s no doubt about it – I want to put a brain on there. "One of the brain regions that Williams has kept alive in chip form is the medulla – a part of the brainstem that is involved in automatic functions, such as breathing. "We’ve found that the tissue will continuously and automatically send out neural signals that would normally cause a person to breathe, even when it’s outside the body," says Williams. His team has already attached electrodes to the nerve roots in the brain sample to tap into those signals. He thinks it would be relatively easy to use them to drive the pump that makes a lung-on-a-chip device "breathe".
Ingber has different ideas about which organs should be next in line for a whole-body model. "The most critical organs would be the kidney, gut and liver, which are all involved in drug metabolism and excretion," he says. Ingber’s team is working on a way to mimic the gut’s microbiome – its bacteria and their environment – on a chip, while different versions of a liver-on-a-chip have been developed by groups at Drexel University in Philadelphia, Pennsylvania, and the Massachusetts Institute of Technology.
Although a sequence of mini organs can never truly mimic an entire body, the human-on-a-chip could provide the ultimate guinea pig. "This is not going to be done overnight," says Parker. "But the rewards – for drug discovery and delivery, and for basic research – would be quite extraordinary."