New worlds: Simulation on microchip offers insight into dynamics of cellular function
Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity.
By JUDY SIEGEL-ITZKOVICHA laboratory assistant(photo credit: DANIEL K. EISENBUD)
Organ-on-a-chip technology, which uses microchip-manufacturing methods for arranging living cell cultures to simulate the physiology of tissues and organs, is poised to replace drug toxicity testing in animals. However, it so far has shown few advantages over traditional methods and animal experiments.Now, researchers from the Hebrew University of Jerusalem describe a new generation of “liver-on-chip” devices, in which the researchers add glucose and lactate micro-sensors, allowing them to measure minuscule changes in central carbon metabolism in real time (seconds to minutes). The platform is uniquely able to monitor metabolic changes indicating damage to the mitochondria (powerhouses of cells), damage occurring at drug concentrations previously regarded as safe, said the study’s lead author, Prof. Yaakov Nahmias, who is director of the university’s Alexander Grass Center for Bioengineering.Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity. However, current methods to evaluate mitochondrial activity still rely on traditional tests called end-point assays, which provide limited prognostic information.The chip is composed of submillimeter human tissues that the authors characterize as “bionic,” as they contain optoelectronic sensors for oxygen and are maintained under conditions simulating the human physiological environment. The platform includes a computer-controlled switchboard and permits the automated measurement of glucose and lactate using clinical-grade micro-sensors.The sensor-integrated platform permits realtime tracking of the dynamics of metabolic adaptation to any type of mitochondrial damage for over a month in culture.The study recently appeared in the Proceedings of the National Academy of Sciences.“Central carbon, or glucose and amino acid metabolism, is by far the most important source of energy and materials for our cells,” said Nahmias. “It is the backbone of cellular function.” German physiologist Otto Warburg recognized the importance of changes in central carbon metabolism to cancer development back in 1924, and more recent studies tied alterations in this pathway to the emergence of stem cells. “This metabolic pathway is very sensitive, and any toxic damage will either directly or ultimately lead to changes in glucose metabolism,” he added.This approach already enabled Nahmias and his team to identify a new mode of acetaminophen (Tylenol) toxicity last year, suggesting the drug could directly block respiration in the kidneys and skin.In the current research, the team used an array of micro-sensors to measure small changes in metabolic fluxes. In other words, the sensor-integrated “bionic” micro-livers actively told researchers how they change their metabolic pathways (what they “eat,” “digest” and “spew out”) when exposed to new drugs. This allows researchers to identify new causes for “idiosyncratic toxicity,” one of the biggest problems in drug discovery and the main cause for post-market drug withdrawal.Idiosyncratic toxicity occurs without obvious reason to about 1:100,000 in the population, requiring new warning labels or complete withdrawal of the drug (costing billions).
The researchers tested the new technology on troglitazone (Rezulin), an antidiabetic and anti-inflammatory drug which was removed from the US market 16 years ago due to severe drug-induced liver injury, costing Pfizer Inc. over $750 million in lawsuits.The results showed that even at low troglitazone concentrations previously regarded as safe, in which traditional tests don’t reveal any damage to the cells, the new liver-on-chip technology was able to detect mitochondrial stress that forces the liver to increase its reliance on glucose metabolism.By revealing the dynamics of cellular adaptation to mitochondrial damage, this novel organ-on-chip technology permits detection of chemical toxicity before any effects on cell or tissue viability can be observed.Yissum, the technology transfer company of the Hebrew University, has recently filed two provisional patent applications covering the promising liver-on-chip technology that will be the basis of a company to be established together with Nahmias. This new company will provide diagnostic and prognostic analysis for pharmaceutical and cosmetics companies to help define drug safety and screen out idiosyncratic drug toxicity.