[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.]
By Lawrence K. Altman
Paul Zenk/PBS Nature “Invasion of
the Giant Pythons”
A giant python swallows an
alligator in
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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, adiabetes 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.