(ANIMAL SCIENCE) BOULDER, CO — For the past six years scientists at the University of Colorado, Boulder have been researching the python’s ability to double the size of their organs when digesting larger animals. The goal of the research is to potentially produce a snake oil that may help humans fight heart disease just as Gila monster saliva aided in developing Byetta, a Diabetes drug. Read on for more on the research being done and past lab breakthroughs. — Global Animal
A python devours its large prey, a Florida alligator. Photo credit: Paul Zenk/PBS Nature

The New York Times, Lawrence K. Altman

BOULDER, Colo. — Pythons are known for their enormous appetites. In a single meal they can devour animals at least as big as they are — deer, alligators pigs and house pets, for example.

Equally remarkable is what happens inside the python as it digests its prey. Within a day, its heart and other organs can double in size. The metabolic rate and production of insulin and lipids soar.

Then, like an accordion, the python’s organs return to normal size in just a few days. Metabolism slows. Then the snake can fast for months, even a year, without losing muscle mass or showing any ill effects, ready to ambush new prey.

How this process happens so rapidly is a biological mystery with important implications for human health, particularly when it comes to heart failure. Now scientists at the University of Colorado here are reporting that they have partly solved it.

In a paper in the current issue of Science , they report that a gorging python expands its heart by enlarging existing cells — a process called hypertrophy — and not by creating new ones. (It is not known whether snakes get heart disease.)

A second finding is that a specific combination of three fatty acids produces enlargement of a python’s heart, intestines, liver and kidneys. (The brain does not expand, presumably because it is confined by the skull.) Injections of the combination produce similar growth in the heart of a mouse.

Understanding such exaggerated variations, the researchers say, could help them develop novel ways to delay, prevent, treat or even reverse various hereditary and acquired human diseases.

Pharmaceutical companies have scientifically manipulated substances from other reptiles to develop marketed drugs. For example, Byetta, a diabetes drug, is derived from a hormone found in Gila monster saliva.

And the day may come when doctors literally prescribe snake oil for heart disease. “Heart failure is the goal” of the python research, said Leslie A. Leinwand, a Howard Hughes Medical Institute professor at the University of Colorado and a senior member of the research team. She added that the findings might also lead to treatments to prevent sudden death in young athletes, as well as ailments like diabetes, high blood pressure and obesity.

A gorging python produces an opaque milky plasma composed of fatty acids and other lipids in amounts so huge they would damage a human heart, Dr. Leinwand said. Trigylcerides, the main components of natural fats and oils, zoomed to 50 times the fasting rate.Dr. Leinwand had been fascinated by a journal article by Stephen M. Secor and Jared Diamond urging other scientists to explore extremes of lifestyles among wild animals. The python research in Boulder began in 2005, when Cecilia A. Riquelme, who had earned a Ph.D. in cell biology in her native Chile, sought a fellowship in Dr. Leinwand’s laboratory.

An expert in the molecular workings of the heart, Dr. Leinwand knew little such research had been done on pythons. There are structural differences — a python heart has three chambers, a human heart four. Yet she thought experiments in comparative biology might advance human heart research.

Adult pythons can grow as long as 25 feet and as thick as telephone poles, far too large for her laboratory. So she bought a supply of five-footers and asked Dr. Riquelme, “How would you feel about working with pythons?”

Dr. Riquelme was not crazy about the idea; pythons are not venomous, but she feared being bitten. Still, the challenge was too tempting to pass up, and after a harmless bite she overcame her fear, though she and her colleagues always handled the slithering snakes with healthy respect.

She started by observing how the python’s organs grew while the intact prey was in the stomach. Then the organs regressed in size over a period of about two weeks.

There was nowhere she could buy the biological materials she needed to conduct experiments involving python tissues, so she had to make her own.

An early effort was to develop chemical stains to measure cell size and the number of nuclei seen under a microscope. The observations showed that the python heart expansion was from hypertrophy, not formation of new cells.

Hypertrophy of the human heart occurs in two types. One, from ailments like high blood pressure and heart attacks, is a leading predictor of death. The second type is beneficial and occurs from exercise in well-conditioned athletes.

The Colorado scientists found that the enlargement of a python’s heart is analogous to the growth seen in the heart of a human athlete. Among their goals is to better understand how plasma components instruct individual cells to develop into the beneficial ones among athletes or bad ones in disease.

After a year, Dr. Riquelme determined that she could enlarge the heart of a starved python by injecting blood from a feasting one. She then proposed adding the blood’s straw-colored plasma to rat heart cells to determine whether it had the same effect.

Dr. Leinwand doubted that the experiment would work. But it did, and Dr. Leinwand “jumped up and down,” Dr. Riquelme said, adding that she believed her own findings only after repeating the experiment several times.

Dr. Leinwand called it “the critical finding that motivated us to translate the python biology into mammals.”

Still, a major mystery remained: What component of the python plasma caused the cells to enlarge?

Dr. Riquelme used gas chromatography and additional techniques to analyze the proteins, lipids and other components of python plasma in fed and starving pythons.

Several pieces of evidence pointed to fatty acids, which are important in the body’s energy production and metabolism. In additional experiments, Dr. Riquelme and other members of the Colorado team found that only the specific combination of three fatty acids from a sated python produced the same hypertrophy when injected into a fasting one. The three fatty acids that enlarge the python’s cells (myristic, palmitic and palmitoleic) occur in proportionately higher amounts in pythons than in humans. Injections of one fatty acid, or a combination of two, did not produce hypertrophy.

Another mystery was what protected the python heart from the toxic effects of huge amounts of the lipids. Further research determined that the protective substance was an enzyme, SOD (for superoxide dismutase), an antioxidant that defends cells exposed to oxygen.

By March 2010, Dr. Riquelme’s husband, Hugo Olguin, had joined the faculty of Catholic University in Santiago, Chile. They had two young children and wanted to return to Chile. So Dr. Riquelme left Boulder, expecting to write a scientific paper about the python research and to get an academic position in Chile. But a giant earthquake struck there just before their departure, delaying her plans for months.

Dr. Riquelme had done the pioneering experiments in Boulder and had to leave it to her colleagues in Colorado to carry out additional ones. In one, blood plasma from bloated pythons was injected into live mice. Again, surprisingly, mouse heart cells enlarged as they would in a well-conditioned athlete.

Along the way, the Colorado team asked Dr. Secor, who had moved from the University of California, Los Angeles, to the University of Alabama in Tuscaloosa, to join in the research. He is an author of the new paper in Science.

The findings leave a number of mysteries still open to research. What causes the organs to shrink to their fasting size? How would such findings apply to the death of human cells in processes called atrophy or apoptosis? And will repeated injections of the fatty acid combination safely lead to sustained increase in organ size?

Dr. Leinwand said she carried out the python research with support from federal and Colorado taxpayers and the American Heart Association. But the federal National Institutes of Health rejected her requests for direct financing, calling the relationship between reptiles and human heart disease too remote. In 2007, Dr. Leinwand became a founder of the Hiberna Corporation of Boulder to develop drugs derived from the study of exaggerated variations in animal metabolism. The company helped pay for some of the research.

More New York Times: http://www.nytimes.com/2011/11/01/health/python-digestion-study-holds-promise-for-human-heart-health.html

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