A huge collaborative project led by Los Alamos National Laboratory (LANL) and Vanderbilt University is bringing together human surrogate organ constructs married with highly sensitive ion-mobility mass spectrometry in a bid to revolutionize the way that compounds are screened.
Scientists from several different institutions are working together in the hope of developing a benchtop human, called Homo minitus, where miniaturized heart, lung, liver and kidney constructs are brought together and interconnected in a project called ATHENA (Advanced Tissue-engineered Human Ectypal Network Analyzer). It is hoped that eventually Homo minitus will be able to mimic the way that multiple human organs respond to novel drugs and chemicals, providing far more information than an animal model can.
The current system for drug development first involves studies on cells in tissue culture followed by tests in non-human animals. By law, no drugs are allowed to enter human trials without first being tested in animals for possible adverse effects. If approved, the novel compound may then proceed into phase I clinical trials on humans, but astonishingly around 40% of trials fail in this stage, costing billions each year. This is because what happens in an animal does not necessarily mirror what may happen in a human due to physiological differences, therefore unexpected toxic effects may appear.
Although synthetic livers are currently being tested in the hope of reducing the need for animal testing, this is the first project aimed at connecting numerous different organ constructs in order to give a much more comprehensive picture on how a compound interacts with the body and produces side-effects. Senior scientist Rashi Iyer from LANL said "By developing this 'Homo minitus' we are stepping beyond the need for animal or Petri dish testing: There are huge benefits in developing drug and toxicity analysis systems that can mimic the response of actual humans."
The scientists are not aiming at developing exact organ replicas; instead they have been miniaturizing them in such a way that will retain their functional capacity and key features necessary to behave in a manner similar to that of actual human organs. If successful, the organs will ultimately be hooked up via a blood surrogate in a way that imitates actual bodily connections. It is hoped that this system could also be used in the field of toxicology, since a huge percentage of the tens of thousands of chemicals used in commerce are untested, and even those that have been tested have not been extensively investigated for long-term chronic effects.
Researchers from Vanderbilt University led by Professor John Mc Lean combined this miniature organ system with an ion-mobility mass spectrometer, enabling the detection and identification of the thousands of molecules that living cells produce, allowing them to monitor fluctuations in what is both consumed and produced in response to compounds being tested.
The first results to be reported from this system were in a presentation by Professor John Wikswo, which described the surrogate liver developed by a team of scientists also at Vanderbilt University. A small perfusion device was created, only a few inches in size, that was capable of keeping human liver cells alive for extended periods. They tested the effects of different dosages of the well known liver toxin acetaminophen. They found that the liver cells responded in the same way as a normal liver by first forming metabolites, then tryptophan levels began to increase as the cells became compromised. "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," said Wikswo.
The next stages of the project will hopefully involve hooking up the heart developed in Harvard to the liver, followed by the lung developed at LANL and the kidney from the University of California San Francisco and Vanderbilt University.