Reverse Engineering Biology: The Dawn of Microphysiological Systems


Sri Harsha Paladugu

Reverse engineering or backward engineering is a way to understand complex systems (such as machines, software, and protocols) and repurpose them for better applications. This process became popular during the Second World War and the Cold War, wherein each nation tried to copy the other countries’ cutting-edge technology. One brilliant example is the development of the V2 rocket by the Germans, which was then reverse-engineered by the Soviets and the USA, eventually leading to the golden space era. 

One might ask, how is this relevant to biology? The answer lies in perspective. Reverse engineering takes a technology that one does not understand, breaks it down into pieces, studies them, and revamps them for better utilization. This is precisely what we have been trying to do with biology over the ages. We study intricate, but small organisms such as bacteria that we knew nothing of initially and slowly move towards complex animals, eventually advancing to humans. 

Model systems help us scale the properties and phenomena from simpler organisms to humans. But the prediction power is only as good as the model itself, which is inadequate right now. Unlike the engineering models, the scaling laws are not well understood as the complexity increases in biological systems. Nature has evolved over the centuries to develop neat tricks to get a job done more efficiently. This poses a problem because we can no longer trust other models to predict for humans.

The advent of microfabrication (borrowed from electronic chip manufacturing) has opened new avenues and paved a path to uncover otherwise inaccessible mysteries of biology. While the gold-standard biology experiments have given us some insight into the inner workings of cells, most key, basic questions remain unanswered. 

Miniaturized microphysiological chips aka organ-on-chips (OoC), try to mimic each organ by capturing its critical functional elements. OoCs come in many shapes and sizes as per application, emulating a simple cross-section of an organ. The functional elements could be the air-liquid interface for the lung alveolus model, flow stress for vascular endothelial cells or co-culture of stellate cells, Kupffer cells, and hepatocytes mimicking liver function. 

OoCs are particularly useful in the drug-discovery pipeline where companies screen for numerous drug candidates against an organ and knowing how the drug might affect other organs could be the make-or-break deal to take it forward. OoCs may also play a key role in deciphering some of the most fundamental questions in biology. Basic questions in cell-cell communication, inter-organ crosstalk, and immune surveillance could be answered with relevant systems. Existing animal models only provide end-point data but miss out on crucial real-time monitoring. But, with engineered OoCs, real-time data becomes rather easy in addition to providing many levers to modify the system, which otherwise might not be possible. 

For example, studying the role of each immune cell in wound healing is quite challenging in an animal model because of the secondary effects that may result due to the deletion of certain immune cells, accompanied, also, by ethical concerns. But, with OoCs, the study becomes easier as one can introduce a variety of immune cells, single and/or in combination, to study the effects while preserving the necessary functional aspects. The future of these systems lies in personalized medicine. 

Imagine a day, sometime in the future, when a patient is diagnosed with a disease; rather than having a doctor prescribe a generic medication, the patient-derived OoC is tested for multiple drugs to find the most effective cure without many side effects. While it might sound far-fetched, every great idea was once science fiction before it turned into reality. And the day isn’t very far away. 

(Thumbnail image by Nature Biomedical Engineering)