Using Mathematics to Look at Disease as a Whole-Body Problem

Hypertension and heart disease arise from many contributing and interacting factors: genetics, food, and exercise, as well as problems with heart, liver, or kidney function. Although patients can find experts in each separate area, science and medicine often struggle to integrate the complex role that each organ plays in the initiation and progression of disease and how those roles change over the course of the disease, especially in multifaceted diseases like hypertension.

Now, a multi-disciplinary team of researchers at Jefferson has created a new computational tool that demonstrated how disease process that led to hypertension actually initiated in the brain, in one model of the disease. The research was published in the open access journal PLOS Computational Biology.

The tool can integrate data from multiple organ systems at different time points to help understand where a complex disease like hypertension originates, and how multiple organs contribute over the course of the disease development and progression. In the future, it could be used to study other complex disease processes in order to understand the best time to intervene.

“To truly understand disease, we need to take a broader view,” says Jefferson computational biologist Rajanikanth Vadigepalli, PhD. “Only when we integrate experimental data, modeling of dynamic systems, and an ability to crunch large datasets, can we begin to glean truly transformational insights about complex diseases.”  

By applying their mathematical tool, the researchers were able to identify the very start of the disease, and track which organ drove all of the other organs in a whole-body-influence network toward dysregulating blood pressure and eventually leading to heart disease. Strikingly, the organ that began the cascade in this model was the brain.

After gene expression began to change in the brain, other organ systems followed, leading to inflammation, kidney dysfunction and finally heart disease.

“Our data aligns with real-world, clinical observations,” says Dr. Vadigepalli. “There are some types of hypertension in humans that have a strong neurological component, where the nervous system really drives the development and progression of hypertension.” While the brain is known to play a major role in some types of hypertension, this is the first detailed evidence of a cascade of cross-organ influences that ultimately lead to a rewiring of the whole body physiology in disease.  

The researchers are developing their mathematical approach into an open-access tool that can be used to create new hypothesis about complex diseases more broadly. More work needs to be done before the tool can be applied to human data, but “that is a critical challenge to overcome, as it takes a fundamentally different approach to clinical and translational studies,” says Dr. Vadigepalli. That said, we think this tool could eventually be useful in identifying novel early biomarkers and treatments for chronic or complex diseases.”

You can find a more detailed version of this article here.