Each year, the US government spends hundreds of millions of dollars stockpiling countermeasures for potential biological, chemical and radiological warfare agents. For ethical reasons, many of these treatments have never been tested in humans. Now, the US military and civilian science agencies are supporting the development of the next best thing for tests: miniature human organs on plastic chips.
“It’s unethical to expose humans to the kind of radiation that you’d see in a disaster like Fukushima, but you need to be prepared,” says Donald Ingber, a bioengineer at Harvard University’s Wyss Institute in Boston, Massachusetts. With support from the US Food and Drug Administration, he is adapting his ‘bone marrow on a chip’ to study the effects of harmful radiation and experimental remedies.
Other researchers working along similar lines discussed their work on model organs for biodefence applications at a meeting of the American Society for Microbiology (ASM) last week in Washington DC. The hope is that these complex three-dimensional systems will mimic human physiology better than do cells grown in a dish, or even animals.
A common way to form a model organ is to seed cells into channels in a small plastic chip and then feed them with nutrient-rich fluid that flows through the system to mimic blood. The devices can be used individually or connected to other types of organs-on-chips to approximate a biological system, or—eventually—perhaps an entire human body.
The US Environmental Protection Agency plans to announce next month an US$18-million programme to link ‘livers on chips’ with chips that simulate fetal membranes, mammary glands and developing limbs. The ultimate aim is to study how environmental contaminants such as dioxin and bisphenol A alter metabolism in those organs once they have been processed by the liver.
The flexibility afforded by model-organ systems is especially attractive to researchers who are investigating dangerous pathogens, given the expense of animal studies and the security restrictions required. At the ASM meeting, microbiologist Joshua Powell of the Pacific Northwest National Laboratory in Richland, Washington, presented experiments testing the ability of anthrax spores to infect a three-dimensional ‘lung’ grown from rabbit lung cells. The cells sit at an interface between liquid and air, much as in real lungs.
Powell says that the US Department of Homeland Security is interested in using the system to answer questions such as how many anthrax spores are necessary to cause disease in the body.
For some viruses in particular, Ingber says, researchers “have no idea about the mechanism, and they need the mechanism to get new drug targets”. Infecting model organs could allow researchers to watch how gene expression and metabolism change in real time.
This sort of information could also be used to identify an unknown agent during a chemical, biological or radiological attack, by providing baseline data on known agents for comparison. John Wikswo, a physiologist at Vanderbilt University in Nashville, Tennessee, and his colleagues have shown that they can rapidly distinguish poisons such as ricin and botulinum toxin by analysing the metabolic activity of cells (S. E. Eklund et al. Sensors 9, 2117–2133; 2009), and will now apply the model-organs approach.
Researchers have already developed dozens of individual model organs; the next challenge is to hook them together with the eventual goal of forming an entire human body on a chip, says Kristin Fabre, a programme manager at the National Center for Advancing Translational Sciences (NCATS) in Bethesda, Maryland. This would provide a more accurate picture of the effects of a drug, toxin or other agent on human physiology.
Wikswo humorously dubs such a system Homo chippiens—but warns that simulating a human body will not be easy. Among other challenges, the blood substitute that flows between model organs must reach them in the right order and in the right quantity, and carry the right nutrients for each organ.
But plenty of people are trying. An NCATS-funded project aims to hook together at least 4 chips; 11 research teams are participating. The US Department of Defense’s Defense Advanced Research Projects Agency is supporting the development of techniques to link ten organs, and its Defense Threat Reduction Agency aims to build two four-organ systems.
Fabre predicts that some of the systems could be available to academics and industry within five years. She is hopeful that they will prove especially useful in cases in which animals are poor models for human physiology. As researchers inch closer to that goal, she says, “it’s like sci-fi comes to life every day”.
This article is reproduced with permission and was first published on February 17, 2015.