Pythons are famous for swallowing enormous meals whole—including morsels bigger than their own body mass. In order to digest these infrequent feasts, the snake’s heart works overtime by increasing its oxygen use, pumping more blood and swelling in size. This rapid response requires a heart that is soft and flexible, the opposite of the stiff and fibrous heart that is characteristic of many human cardiac diseases.
By scrutinizing the cardiac muscle of recently fed pythons, researchers have revealed how the reptiles reshape their hearts in greater detail than ever before—with the hope that understanding the secrets of snakes can help us develop new cardiovascular medicines. The results appeared in Proceedings of the National Academy of Sciences on Aug. 19.
“It’s interesting that they address the function of the cardiomyocytes, the cells of the heart,” Tobias Wang, Ph.D., a physiologist at Aarhus University in Denmark who was not involved with the study, told Fierce Biotech in an interview. “It’s an important study because it contributes, with the use of very sophisticated techniques, an insight that we did not have before at the level of cardiomyocyte function.”
Study author Leslie Leinwand, Ph.D., has long studied pythons with the goal of translating her findings to human medicine. The biologist has a long track record in biotech as well; she co-founded Myogen, which sold to Gilead for $2.5 billion in 2006, and her more recent company MyoKardia was bought by BMS for a whopping $13.1 billion in 2020.
Leinwand’s group at the University of Colorado at Boulder had previously found that the python’s heart enlargement resembles something similar seen in elite athletes, rather than a heart dealing with high blood pressure or some other disease.
Following this earlier work, the researcher decided to investigate some of the properties of the heart that were more mechanical in nature, Leinwand told Fierce Biotech in an interview, “We had noticed, more or less anecdotally, that the python heart seemed much softer compared to a mammalian heart.”
To solve the squishy heart mystery, Leinwand and colleagues compared the hearts of ball pythons that had fasted for 28 days with those that had just eaten a large rat 24 hours earlier. They dissected out individual myofibrils, the proteins inside muscle cells that cause contraction and relaxation, and tested their strength and flexibility.
“Within 24 hours [after eating], the heart went much softer” compared to fasted snakes, Leinwand said. “At the same time, the heart is actually able to generate more force.”
Myofibrils become less stiff but also stronger after eating, which leads to the overall impression of a squishier heart.
In order to understand how the heart changes so rapidly after eating, the researchers honed their analysis to the level of gene expression. Genes exist on bundles of DNA called chromatin, which is then packaged into chromosomes; by loosening or tightening these chromatin bundles, cells can flexibly increase or decrease the expression of certain genes. Using a micro-imaging technique, the researchers saw that recently fed pythons had looser chromatin than fasted ones, indicating that they were undergoing changes to gene expression.
What’s more, one group of relevant gene-regulating proteins was implicated: sirtuins.
“There’s a lot of interest in sirtuins,” Leinwand said. The molecules are “master regulators” for controlling chromatin tightness, according to Leinwand. They’ve also been implicated in the body’s positive response to calorie restrictions. But the molecule that is telling sirtuins to act in engorged pythons remains a mystery.
“What are the signals that lead to those epigenetic changes that they describe, and to those changes in gene expression?” Wang said. “It might be an inspiration to look at the possibility of altering that signaling in human disease.”
Figuring out the molecular pathways snakes use to remodel their hearts could help develop medicines to treat cardiovascular diseases in humans, like by making stiff hearts softer and able to better pump blood.
Leinwand next wants to similarly examine the just-fed hearts of other python species, like the gigantic Burmese python (the second-heaviest snake after the anaconda). She also wants to dig more into the role sirtuins play, but admits that staying focused is difficult when working with an understudied animal like snakes—other organs besides the heart show dramatic changes after eating too.
“The temptation is, oh, let’s work on the liver. Let’s work on the pancreas. Let’s work on brains,” Leinwand said. “We’ve got to focus and not get distracted, because it is so easy when there’s so much new biology.”