KOMM: IdentiPhy - In Silico Tools for Improved Drug Testing in Microphysiological Systems

Medical treatment using safe and effective drugs gives society an amazingly powerful means to manage and cure a host of diseases and conditions. Past successes promise an even better future, where new drugs are available to treat many more common afflictions, from Alzheimers to heart failure, cancer to diabetes. Bringing such new promising drugs forward from discovery to use is often hampered by problems with side effects these drugs may have on the human body. These problems are all too frequently not found in current testing regimes, and history is full of mistakes where drugs were deemed safe in animal testing, only to fail in human populations, mistakes that have come at great expense and that have cost many lives. This challenge has been seen clearly in these past two years, with a rush to bring new medicines to help in the pandemic, some of which have had cardiac side effects that needed to be studied and managed in the clinic on patients. Clearly, better early understanding of toxicity of compounds in humans is needed, to replace and augment the patchwork of our current methodology. The introduction of human induced pluripotent stem cells has provided such hope. These cells give the ability to grow functional human tissue that can be used directly for drug testing, and is truly a paradigm shift that stands ready to completely change the drug testing landscape. Many challenges remain though, first and foremost how to interpret the results these new systems produce, as despite being human cells, they have not matured in the same way that cells do in the body, particularly for specific tissues such as those in the heart. In our IdentiPhy project, we have worked together with experimentalists to create advanced computational tools, utiltizing decades of research into biophysics and computer science, to give clear and validated insight into drug testing of compounds for their potentially dangerous side effects, as well as their potential benefits. We have focused on the potential for drugs to dangerously destabilize the heart beat, an unfortunately common side effect of many drug candidates, including some of those that have been rushed to clinical deployment in the past years of the pandemic. Our tools are intended to give improved understanding of cardiovascular risk, enabling the development of safer drugs in less time and at lower cost. The IdentiPhy Project has worked over the past 2 years to streamline data processing with our colleagues at UC Berkeley, collect key validation data sets, and improve methodology for automatic detection of cardiac drug side effects from stem cell systems, including working with UC Berkeley at the height of the pandemic to help investigate cardiac effects of COVID-19 treatments. Meanwhile, we are pursuing commercial development and the role our technology has in both in safety testing and drug development. We have developed a joint commercial venture with our colleagues at UC Berkeley, called Organos, and have deployed the technology in pilot projects with a large pharmaceutical partner. Furthermore, as a side-effect of the Identiphy project, we have studied the problem of translating results from animal studies to the effects on humans, and devised an algorithm for this based on insights in mathematical models, to increase the value we add to the industrial landscape.

We have developed a commercial implementation of systems for the mechanistic understanding and extrapolated prediction of cardiac effects of pharmaceutical compounds. This system could improve the drug development pipelines with earlier, cheaper, and more accurate assessments of potential cardiac effects. In addition, we have found that this system is not only useful for the detection of side effects of compounds, but could be used to actually discover new compounds and methods of cardiac therapy, an immense need in modern health care systems. Both better methods for cardiac toxicity assessment and new routes for cardiac drug discovery could lead to improved patient health through the faster, less expensive development of safe and effective drugs.