Award-winning research team explores novel ways to identify drug candidates safe for the liver

In his laboratory in The University of New Mexico School of Medicine, pathologist Rama Gullapalli, MD, PhD, is shedding new light on the impact of environmental pollutants on the human liver.

In fact, some of his ideas and work just helped win an $80,000 award from the National Institutes of Health (NIH) Common Fund’s Complement-ARIE research competition. The program challenges researchers to devise better and more-effective methods of testing drugs and treatments for humans.

Gullapalli’s team, “LIVER-Combine,” includes several universities and companies from around the world. Their project proposes new, faster ways of detecting and preventing liver toxicity during drug development, he said. LIVER-Combine was one of 20 teams who won an award for the competition’s Phase 1, out of more than 160 teams who entered.

“It was a very educational as well as enlightening experience to work collaboratively with a bunch of people across the world,” Gullapalli said.

His research in the UNM School of Medicine was an important component of the winning project.

“My lab works on the problem of environmental pollutants in the context of liver diseases, and we study various types of environmental pollutants such as heavy metals and, increasingly, nano– and microplastics to understand how these things affect human liver health,” he said.

The liver is a critical organ that keeps the body running by processing food, rendering pollutants harmless, helping manufacture blood-clot proteins and much more, Gullapalli explained.

“The liver has over 500 different functions that we are aware of,” he said. “It’s a super complex organ.”

And it’s crucial to the development of new drugs.

“Over 90% of drug-development failures occur due to chemicals that are toxic to the liver and so trying to understand which sort of compounds lead to liver toxicity, and fail as a result, becomes a very important issue to understand,” Gullapalli said.

In his lab, he demonstrated a key part of his research that is going into LIVER-Combine’s NIH project. On his customized optical microscope, Gullapalli revealed something shocking in a tissue sample from a human liver: it was riddled with small, glowing multicolored particles, spread out sporadically among the many liver cells. He said his team still does not fully understand what these particles are, but it’s evident the liver was trying to seal them off from surrounding cells.

“We think these might be plastics triggering a reaction, leading them to be sequestered in various tissues of the human body,” Gullapalli said. “And if they are, what sort of diseases are they leading to? These are the kinds of questions we are trying to ask right now.”

The key to Gullapalli’s method is light.

“We use and leverage the properties of light to make these particles visible, which otherwise one wouldn’t be able to detect,” he explained. “Which is probably one of the reasons why it was not observed in detail before.”

Gullapalli said he is not only a physician-scientist, but also an engineer and inventor.

“Optics is an incredibly powerful scientific paradigm,” he said. “Trying to apply it to environmental toxicology and pollution research is something that is new and novel.”

With LIVER-Combine, Gullapalli hopes to apply this same lighting technique, and another optical-imaging technique called fluorescence lifetime imaging microscopy, to detect sooner when a drug candidate has a toxic effect on the liver.

The work is especially relevant to the state of New Mexico, which Gullapalli described as “‘Disease Central’ for various chronic diseases occurring in the liver.”

“We have some of the highest rates of chronic liver disease in this country, in this state, and not by a little,” he said. “So, we are at 36.4 per 100,000 people with chronic liver disease. The next closest is Mississippi at 31 or 32 per 100,000.”

While scientists don’t yet know why this is, Gullapalli hypothesizes that heavy metals and chemicals in the New Mexico environment are partly to blame. Alcohol is a factor, too, but it doesn’t explain everything, he said. And there is more to the mystery:

“Interestingly, and sadly, chronic liver disease is high among Native Americans and Hispanics who live in this state, for unknown reasons,” he said. “We don’t know what exactly that is.”

Gullapalli and his team will now move on to Phase 2 of Complement-ARIE, where they will gather data about their proposed new methods and try to make their project reproducible by other scientists.

If the competition overall is successful and these new technologies reach the market, it could mean faster drug-development paradigms with a wider variety of non-toxic drug candidates identified, Gullapalli said.

“So, the potential and the hopes for this technology are pretty high, but we still need to do the basic groundwork to make sure that it all works, and that’s what this competition is trying to do,” he said.