Today, new pharmaceuticals are approved by a process that culminates in human clinical trials. The clinical trial is a rigorous process from development of the active molecule to animal trials before the human ones, costing billions of dollars and requiring many years. Patients participating in the trial are exposed to side effects, not all of which will have been predicted by animal testing. If the drug is successful in trial, it may receive approval, but the time and expense are present regardless of the trial outcome.

But what if there were another, safer, faster, and less expensive route to approval? Instead of requiring years of “ex vivo” and animal studies before human testing, what if it were possible to test thousands of new molecules on billions of virtual patients in just a few minutes? What would be required to demonstrate such a capability? At the very least, the virtual patients must mimic the physiology of the target patients, with all of the variation that actual patients show. The model should encompass circulatory, neural, endocrine, and metabolic systems, and each of these must demonstrate valid mechanism–based responses to physiological and pharmacological stimuli. The model must also be cost efficient, simulating weeks in a span of seconds.

Such simulations are called computational cognitive architectures, although the current ones actually lack a comprehensive representation of human physiology. A truly comprehensive system would make it possible to model conditions, symptoms, and even drug effects. To order reach this brave goal, every tiny detail of the human body needs to be included in the simulation from the way our body reacts to temperature changes to the circadian rhythms of hormone action.

HumMod is a simulation system that provides a top–down model of human physiology from organs to hormones. It now contains over 1,500 linear and non–linear equations and over 6,500 state variables such as body fluids, circulation, electrolytes, hormones, metabolism, and skin temperature. HumMod was based on original work by Drs. Arthur Guyton and Thomas Coleman in the early 1970’s.

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HumMod is not the only effort in this area. The Avicenna project, partially funded by the European Commission, aims to construct a roadmap for future “in silico” clinical trials, which would make it possible to conduct them without actually experimenting on people. Other projects use real models instead of computational ones. A liver human organ construct, a physical object that responds to toxic chemical exposure the way a real liver does, was designed at the Gordon A. Cain University. The goal of the five–year, $19 million multi­institutional project is to develop interconnected human organ constructs that are based on a miniaturized platform nicknamed ATHENA (Advanced Tissue–engineered Human Ectypal Network Analyzer) that looks like a CPR mannequin.

It would then be possible to test molecules without risking the toxic effects on humans, and to monitor fluctuations in the thousands of different molecules that living cells produce and consume. The beauty of this project is its plan to connect their working liver device to a heart device developed by Harvard University. If successful, they hope to add a lung construct in 2015 that is being developed at Los Alamos, and a kidney designed by the UCSF/Vanderbilt collaboration by 2016, thus building the first physiological model of a human being piece by piece.

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