Animal toxicity studies in pharmaceuticals and cosmetics had already been controversial, not least because animal models can utterly fail to predict the human reaction to certain drugs or chemicals. Then the European Union completely banned animal experimentation in the development of cosmetics. Now an Israeli-German team is working on a breakthrough technology that could please Big Pharma, Cosmetics Giants and animal lovers as well: "livers on a chip" for early-stage testing on human cells. (Later-stage testing will still probably be done on actual people.)
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The technological breakthrough was creating tiny livers, less than a millimeter in diameter, from human liver cells. These micro-livers survived for more than a month, something of a breakthrough in itself.
Because they were creating exogenous systems, not ersatz animals, the scientists realized they could embed highly sensitive nanotechnological sensors in the tissue.
"Essentially we are building bionic organs on a chip,” explains Prof. Yaakov Nahmias, director of the Alexander Grass Center for Bioengineering at the Hebrew University of Jerusalem.
Why liver cells, not, say, kidney or skin cells? Because our livers metabolize the drugs we take. Before a drug is marketed, the manufacturer needs to prove that the drug does not harm the body and/or the liver (at least beyond reasonable levels). “Drug-induced liver injury” is one of the most common reason a drug fails clinical trials or gets withdrawn, explains Nahmias.
In short, drug companies need to see how drugs in development affect the liver – so having a wee one on a chip, rather than a live one in a rabbit or rat, is useful. Though it bears saying the team doesn't anticipate marketability before 2017.
"Nobody put sensors inside liver tissues before," said Nahmias, "This enabled high sensitivity measurement of cell respiration in real time, so we could detect minute changes in metabolism."
For whom the penicillin tolls
Why replace lab rats with high-tech and presumably expensive bionic nanotechnology?
Leaving animal rights aside, one problem with animal models is that different species may react in different ways to the same drug.
A classic example is that the Valium that soothes your nerves can kill your cat, in high doses (through liver failure!). Chocolate will charm the kids but will damage the dog, and penicillin may save your life, but administer it to your hamster and he's toast.
More? Aspirin will ease your suffering but cause severe birth defects in rodents. And conversely, thalidomide had tested completely safe in animals, yet caused severe birth defects in humans throughout the 1950s.
That is because, briefly, different species have different bodies – we're not even affected by the same bacteria and other germs. Our cats don’t get our colds. What is a medical researcher, or lipstick maker, to do in order to test products to make sure they're safe for humans?
One idea is to test drugs on human cells grown in the lab. At least it's the same species.
But keeping cells alive outside the body isn't so simple. Also, isolated cells don't behave as they would in our bodies, where they're part of a bigger, infinitely complex system. However, the liver-on-chip device created by scientists the Hebrew University and the Fraunhofer Institute for Cell Therapy and Immunology in Germany does mimic human physiology, the scientists say.
Meanwhile, Tylenol toxicity
In fact, thanks to the teeny sensors in their weeny livers, the scientists also achieved a scientific breakthrough. While testing the abilities of their liver-on-chip device to detect human toxicity, they discovered a previously unknown mechanism of acetaminophen (Tylenol) toxicity.
"We used our new technology to look at the toxicity of acetaminophen (Tylenol) and other drugs," Nahmias told Haaretz. "We showed that acetaminophen caused direct damage to cellular metabolism, by targeting the mitochondria, a small organelle in the cells responsible for generating energy. Our discovery explains why acetaminophen sometimes damages kidney and skin. It was not possible to get this type of information from animal experiments." Now, thanks to the livers on a chip, we know.
“This is a fascinating study,” commented Prof. Oren Shibolet, Head of the Liver Unit at the Tel-Aviv Sourasky Medical Center and an expert on drug-induced liver injury. “We knew that acetaminophen can cause nephrotoxicity as well as rare but serious skin reactions, but up until now, we didn’t really understand the mechanism of such an effect. This new technology provides exceptional insight into drug toxicity, and could in fact transform current practice.”