Network Effects

From the outside, it can be hard to imagine what Raj Vadigepalli’s research is about. Yes, something about livers and neurons. Or regeneration, hypertension, and microRNA. We know he and his team study cells or tissues or organs—in vitro and in vivo—dissecting, sequencing, churning through vast quantities of data.

And yes, it is about all of the above (and below).

But as he is the first to tell you, the parts are not the point. “It’s the connections and interrelationships that make a system,” he says. “You can’t understand things on their own, because each part is implied by the others.”

Traditionally, the discipline of anatomy concerns itself with enumerating more and finer pieces and processes in search of some ultimate precision. But as vice chair of Research and a member of the Daniel Baugh Institute in the Department of Pathology, Anatomy and Cell Biology, Rajanikanth Vadigepalli, PhD, spends his time trying to understand how a body of many parts works together.

A chemical engineer by training and sensibility, he views the body not as a patchwork of parallel cause-effect relationships, but as a set of delicately entwined systems nested within systems—dynamic, nonlinear, and above all complex. (Check out “A Series of Fortunate Events” in the previous issue for more on this field.) “The minute things are connected in a feedback loop, what causes what has no meaning,” he says, “They beat your intuition about what should happen next.”

To approach their objects of study, Vadigepalli and his team use high-powered computers to design their own dynamic models of tissues and organs, comparing their mock-ups against what they observe in the lab. Because the complexity is so great, simulation is an essential tool that enables them to view many-layered processes in one view. This iterative process of trial and approximation allows them to tinker their way to understanding, as they search for those minute variables making an outsized impact on their host systems.

These “control points” are the gateways between different bodily phases—between health and disease. The most obvious example of a phase shift in nature is water: Within a certain range of temperatures, it remains liquid, but if the temperature drops too much or goes too high, then it becomes solid or gas. There is continuity within each phase, but also a sharp qualitative change across boundaries.

In much the same way, the body is a collection of systems in various phases of activity: homeostasis, decay, regeneration. By comparing and contrasting disparate organ systems and functions, Vadigepalli and his team aim to generate a more holistic perspective on how it all fits together, and what each part shares in common with the others. To this end, Vadigepalli’s primary targets are liver failure and cardiac hypertension.

His interest in the liver mirrors that of his collaborator, Jan B. Hoek, PhD, vice chair for Technology, Innovation and Infrastructure, and a professor at the Baugh Institute. Hoek has spent his career immersed in the systematic study of the organ and the diverse array of cells that allow it to filter toxins and heal itself.

“Jan said, ‘If you’re looking for something that changes a lot over time, you should look at livers—they regenerate.’ I go, ‘It regenerates?’ I had no idea because I’m an engineer who had to audit the graduate curriculum when I first got here,” recalls Vadigepalli, who laughingly recounts the conversation that launched his interest in the organ.

Taking a multiscale approach, the team analyzes the liver at the molecular, cellular, tissue, and organ levels, in order to understand how component parts flow together. This takes advantage of the fact that different processes occur in different places at different rates, offering a way of more easily teasing out cause-effect relationships from a complex of feedback loops.

What they have found is somewhat surprising. Typical views of alcoholic liver failure show an organ tolerating alcohol for a period until it ultimately decompensates catastrophically. Vadigepalli and company tell a slightly different story in which the damage is always there, accumulating over time, as cells become more sensitive to injury with each passing insult until a tipping point is reached and the larger system—the liver—can no longer regenerate.

“That inflection point is what you think of as ‘the failure,’ but it’s been there all along,” he says. “It’s not an event in that sense. It’s a progressive thing, but the nonlinearity makes it look like an event at some point.” Vadigepalli and Hoek believe that in time, they will be able to develop ways of helping diseased livers regenerate, allowing for more transplant candidates and helping recipients improve their odds.

This dovetails with research Vadigepalli does on hypertension, which dates back to work he did as a postdoc with his mentor Jim Schwaber, PhD, a systems biologist who studies neuronal processes at the Baugh Institute.

A chronic condition, essential hypertension is high blood pressure without any known cause, a more durable form of the disease that affects one in three American adults. Chronic hypertension is surprisingly resilient, resisting all sorts of interventions because, according to Vadigepalli, “half the time, the body changes to accommodate a drug, causing it to lose effect, and once that happens, it’s not the same system anymore.”

But Vadigepalli and Schwaber believe they have found some good alternatives by analyzing populations of neurons in the brain stem that are associated with cardiac activity. By sequencing the RNA profiles of these cells, they have developed a picture in which neuronal inflammation may be to blame. In animal experiments, the team was able to block a few key microRNA fragments during a sensitive period in the cells’ life cycles, curing the lab animals in the process. “The key was to find a place to press and the network effect takes over,” Vadigepalli says, amplifying the initial correction and sending the body into an altered phase—lower blood pressure, health.

These “network effects” are also part and parcel of how Vadigepalli and his colleagues at the Daniel Baugh Institute think about science, leveraging each other’s deep expertise in order to derive a result that goes beyond individual achievement. “I have never written a single principal investigator grant in 15 years,” he says. “Everything I have done has been a collaboration.”

Evoking architecture, Vadigepalli says it is the crossbeam, not the pillars, that enables a structure, the connections between parts that create stability. His research—both the topics he chooses and the way he works—is a testament to this.

“Meaning is at the convergence. It can only be found when you put everything together.”