Developing drugs to halt polycystic kidney disease and hydrocephalus
For many scientists, research that confirms a hypothesis is the name of the game. It validates an informed hunch, confirms an astute observation, or evolves a budding theory.
But that's not always how trailblazing discoveries are made. Just ask Bonnie Blazer-Yost.
Shortly after arriving at IUPUI in 1993, she worked with GlaxoSmithKline to determine why rosiglitazone, a Type 2 diabetes drug, caused users to retain fluid. But her studies revealed that the drug affected a different electrolyte channel than the drug company expected.
What happened next helped transform her career.
"We had this hypothesis. We disproved the hypothesis. But I am so glad I took the next step in asking 'why was the hypothesis wrong,'" said Blazer-Yost, a professor of biology in the School of Science at Indiana University-Purdue University Indianapolis. "That led us into tissue culture studies that were followed by animal studies showing that this particular drug, a diabetes drug, might be useful in treating polycystic kidney disease."
Today, clinical trials on a similar drug known as pioglitazone, funded under a three-year, $600,000 Food and Drug Administration grant, are underway with volunteers who have the disease, also known as PKD, at the IU School of Medicine. If successful, the trials will yield a long-term therapy against a painful and debilitating genetic disorder that ultimately causes renal failure in about half of all patients.
Between one in 400 and one in 1,000 people suffer from autosomal PKD, the most commonly inherited form, according to the National Institute of Diabetes and Digestive and Kidney Diseases. While healthy adult kidneys are fist-sized and weigh less than a pound, polycystic kidneys can weigh 20 to 30 pounds and grow as big as a football before renal failure occurs. Other complications include high blood pressure, blood vessel problems in the brain and heart, and cysts that develop in the liver.
From there, only dialysis or a transplant can ward off death. Yet because Blazer-Yost continued to pursue a line of initially unsuccessful research more than two decades ago, medical science stands on the cusp of stopping the disease's progression squarely in its tracks. In turn, this would significantly prolong the quality of life for many sufferers.
"I'll tell you what I tell my graduate students," Blazer-Yost said. "I have seen way too many people hold onto their hypotheses—and way past the point where they should. We tend to not be very good at hypotheses, so don't become attached to them.
I'm consistently amazed by how many people I see in my field who can't give up their hypotheses ... Sometimes disproving a hypothesis is more interesting than proving it.
"I'm consistently amazed by how many people I see in my field who can't give up their hypotheses. You have to be able to do that. Let it go. Move on to the next one. Sometimes disproving a hypothesis is more interesting than proving it."
The ongoing clinical trials are but one battle that Blazer-Yost is waging against PKD. She is also studying lysophosphatidic acid, or LPA, a natural chemical concentrated within the fluid of cysts that form on the kidneys, and has patents in progress for a treatment.
"When the cysts become very large, they leak fluid or burst. This fluid bathes the outside of the remaining cysts, and LPA stimulates additional cyst growth," she said. "My colleagues and I have identified the most pertinent LPA receptor on the cysts, which makes it a specific and promising drug target to control growth in the disease's later stages."
Blazer-Yost also has patents in progress for a potential treatment of hydrocephalus, an overaccumulation of fluid in the brain. The condition affects up to two of every 1,000 newborns and about 375,000 older Americans, according to the National Institute of Neurological Disorders and Stroke. Those studies were funded by a $75,000 IU Collaborative Research grant, which led to a $50,000 grant from the Hydrocephalus Association.
As with Blazer-Yost's research into PKD, her work on hydrocephalus took a familiar turn. Once again, a hypothesis didn't quite pan out. But Blazer-Yost's teaching and experience have taken root with the next generation of researchers.
"We used another drug for PKD with the idea it would alleviate cyst growth in our animal model that also had hydrocephalus," she said. "As it turned out, the PKD drug did not help the cystic kidney disease, and it seemed to have the opposite effect of our original drug, which seemed to have a positive effect on the hydrocephalus. It was an astute graduate student who first noted the effects in the animal, and members of the laboratory have been studying it ever since."