CU-Boulder, biotech firm team up on python project in search for human cardiac therapeutics

August 25, 2008

The University of Colorado at Boulder is teaming up with a Boulder biotechnology company to use pythons, which dramatically increase their heart size for a short time after swallowing prey, as models for new therapeutics to treat cardiac diseases.

Hiberna Corp., a Boulder-based company developing drugs based on natural models of extreme metabolic regulation, has signed an exclusive agreement with the university's Technology Transfer Office on the effort. Hiberna licensed technology developed by CU-Boulder Professor Leslie Leinwand based on the natural ability of pythons to increase their heart size by up to 60 percent and speed their metabolism by 40-fold after feeding episodes.

Leinwand said the ability of pythons and other constricting snakes to enlarge and then decrease their heart muscle mass in just days may help researchers target new drugs for treating cardiac growth in response to disease, which causes human heart muscle to thicken and decreases the size of heart chambers and heart function. Leinwand is a professor in CU-Boulder's molecular, cellular and developmental biology department and director of the University of Colorado Cardiovascular Institute.

Increases in cardiac size are clinically important because heart enlargement in humans resulting from exercise is beneficial, but heart enlargement from high blood pressure is unhealthy, said Leinwand, who studies genetic heart defects. Understanding which genes are involved in regulating the python's rapid heart muscle changes may have implications for treating cardiac hypertrophy, or thickening of the heart muscle, she said.

"This may be a unique path toward potential drug development," Leinwand said of the Burmese python effort. "If we are able to understand the genetic cues involved in rapid python heart muscle increases and decreases, that to me says there is the potential to develop therapeutics for humans."

Leinwand has studied hypertrophic cardiomyopathy, or HCM, a genetic disease marked by a thickening of heart muscle related to a weakness in individual muscle fibers that causes them to work harder to pump blood and consequently enlarge. HCM occurs in one in 500 people in the United States and is the most common cardiac cause of sudden death in young athletes. About 20 genes associated with HCM have been identified and others are being investigated, she said.

In 2006 Leinwand was named a Howard Hughes Medical Institute Professor, one of 20 faculty nationwide to receive a four-year, $1 million undergraduate education award from the Howard Hughes Medical Institute in Chevy Chase, Md. As part of her successful proposal to enhance science education at CU-Boulder, she initiated an undergraduate laboratory research program known as the Python Project.

In the past two years, CU-Boulder undergraduates working with Leinwand have been studying the genome of the Burmese python, searching out and analyzing particular genes they suspect may be involved in the rapid heart muscle changes.

"Pythons can eat up to 100 percent of their body weight at one sitting, so they have to be able to respond metabolically in a dramatic way," said Leinwand. In addition to the eye-popping changes in heart muscle and metabolism, the python's insulin levels go up 40-fold and their triglycerides rise by more than 100-fold following substantial meals, changes that would "kill a human," she said.

Pythons also exhibit very little muscle loss when at rest, which is of interest to researchers studying diseases like AIDS and cancer and the inevitable process of aging. "We think several of the striking changes we see in python physiology may have significant potential for the pharmaceutical industry," she said.

Hiberna -- which received a $100,000 proof-of-concept investment from CU's Technology Transfer Office to help support the development of the new technology -- has started sequencing the Burmese python genome and also has raised some financial capital for the venture. In addition, Leinwand's colleagues at the University of Colorado Denver and Anschutz Medical Campus are analyzing python gene samples for Hiberna.

Hiberna was founded in 2006 by Tom Marr, who has studied Alaskan mammals that exhibit extraordinary physiological adaptations relevant to human health. One of Marr's star study subjects has been the Arctic ground squirrel, which has the ability to drop it's body temperature to below freezing and reduce its heart rate from 200 beats a minute to just two beats per minute during hibernation.

"There are some striking examples of extreme adaptations by animals in the wild, and I think it's a good idea from a biomedical standpoint to take a closer look at them," Leinwand said. The impetus for her python project came from a 1998 Nature paper by UCLA evolutionary biologist and Pulitzer-prize winning author Jared Diamond on extreme physiological regulation adaptations by pythons.
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Leinwand is a co-founding scientist of Hiberna along with Professor Sandy Martin of the UCD School of Medicine's molecular biology department.

University of Colorado at Boulder

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