ATHENA "desktop human" for drug and toxic agent screening gets a liver
A five-year, US$19 million multi-institutional effort is working on developing a "desktop human" that could reduce the need for animal testing in the development of new drugs. The "homo minitus" is a drug and toxicity analysis system that would comprise four human organ constructs interconnected to mimic the response of human organs. The project has now reported success in the development of its first organ construct, a human liver construct that responds to exposure to a toxic chemical much like a real liver.
The miniaturized platform being developed through the Advanced Tissue-engineered Human Ectypal Network Analyzer project (ATHENA) will see each organ component shrunk to the roughly the size of a smartphone screen, with each of the components connected by tubing infrastructure that mimics the way the real organs are connected in the human body by blood vessels. The entire "ATHENA" body would be compact enough to fit on a desk or bench.
"By developing this 'homo minutus,' we are stepping beyond the need for animal or Petri dish testing," says Rashi Iyer, a senior scientist at Los Alamos National Laboratory (LANL), the lead laboratory on the project that is supported by the Defense Threat Reduction Agency (DTRA). "There are huge benefits in developing drug and toxicity analysis systems that can mimic the response of actual human organs."
With around 40 percent of pharmaceuticals failing their clinical trials and with the effect of thousands of chemicals on the human body simply unknown, Iyer says that the ultimate goal of the project is to, "build a lung that breathes, a heart that pumps, a liver that metabolizes and a kidney that excretes." The researchers say that combining these components together would provide a more accurate way of screening new drugs for potency and potential side-effects than current methods.
This week, the project's co-principal investigator, John Wikswo from the Vanderbilt Institute for Integrative Biosystems Research and Education at Vanderbilt University, which is collaborating on the project, presented details of the successful development and analysis of a liver human organ construct.
"We spent a bit of time analyzing the challenges in building miniature human organ constructs, and we believe we’ve figured out how to capture the key features we need," said Wikswo. "There are a lot of trade-offs, and we’re not trying to build an exact replica of a human liver, but an in vitro model that allows us to measure human liver responses to drugs and toxins that cannot be replicated by a layer of cells growing on plastic."
After starting out with a patient-support liver bioreactor with the same volume as a human liver, the ATHENA team scaled it down to a four-layer, three-dimensional device with a volume of only one-tenth of a milliliter.
"The cell mass of the final design was optimized based on metabolic performance and enzyme release and cell structures now resemble native human liver tissue," says Katrin Zeilinger, the head of the Bioreactor Group and her colleagues at the Berlin-Brandenburg Center for Regenerative Therapies (BCRT), which is developing the liver construct.
Unlike other research projects developing human organ constructs and organ-on-a-chip devices that have reported tracking the variations in concentrations of a few well-known chemical compounds that are expected to change, the ATHENA team is also claiming to be the first to successfully monitor the fluctuations of the thousands of different molecules the living cells produce and consume.
This was achieved by connecting the organ platform to an ion mobility-mass spectrometer that is able to detect and identify minute quantities of thousands to tens of thousands of different biological molecules simultaneously. The researchers have used this capability to monitor the liver cells' response to different dosages of a well-known liver toxin, the drug acetaminophen.
"We could actually see what the acetaminophen is doing to the liver cells," says Wikswo. "In the beginning we saw an increase in the drug and its metabolites. Then, over the next 24 hours, we recorded a steady increase in tryptophan as acetaminophen began to interfere with normal liver metabolism. After that we saw decreased production of bile acid, a clear indication that something was going very wrong with the liver, as expected when exposed to seriously high doses of acetaminophen, and a decreased ability to detoxify penicillin."
Iyer says that the rich level of detail provided by coupling the ATHENA organ platform with mass spectrometry technology proves the approach provides a more sensitive and effective method for screening both new drugs and toxic agents than is possible with current techniques.
The ATHENA team plans to connect the liver device to a heart device developed at Harvard later this year. This will be followed by the lung construct being developed at LANL being hooked up in 2015, with the kidney being developed at Vanderbilt University and the University of California, San Francisco (UCSF) to be connected in 2016.
Sources: LANL, Vanderbilt University
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