Inhuman Hearts: Whitman Fellow Explores Cardiovascular Disease Through Frogs and Squids
Heart disease is the leading cause of death worldwide, killing 18 million people each year. In the United States, 697,000 people died in 2021 to heart disease — that’s one in five deaths in the country. Governments and institutions spend billions of dollars researching treatments, but testing their effectiveness is difficult for a simple reason: There’s a lot we don’t know about how our heart develops.
Most heart disease treatments are tested not on humans but on stem cell cultures of human heart cells. These cultures produce immature, partially developed heart cells, similar to those in a fetal heart. The drugs being developed, though, are meant to treat adult hearts, and it is difficult to test the viability of treatments for adult hearts using immature cells.
“If you want to model disease,” said Gert Jan Veenstra, a professor of molecular developmental biology at Radboud University, “you want to do it with the real thing the patients have.”
To culture more mature heart cells, scientists need a deeper understanding of how the heart develops. Veenstra, a Whitman Fellow at the Marine Biological Laboratory (MBL) this summer, is studying heart development in two model organisms to better understand how the human heart goes from a cluster of cells to a functioning organ.
The heart of a frog
Veenstra’s team at Radboud University has been studying the mysteries of heart development for years, so they arrived with an assortment of genes to study. These genes are conserved in some species and could play a role in human heart development. The first part of Veenstra’s research involves working with Xenopus tropicalis, a species of African frog that is common in developmental biology research. MBL maintains the National Xenopus Resource (NXR), a center for Xenopus research and training directed by Senior Scientist Marko Horb. “Marko is running an excellent facility here with the NXR,” said Veenstra.
Veenstra has begun examining the roles of these candidate genes using Xenopus. “We are looking into some genes that we initially identified as potential regulators of heart muscle differentiation in human stem cell cultures,” Veenstra said. These include genes with well-known functions outside of the heart, such as those that regulate neural tissue patterning.
“It is quite surprising to find that these genes are highly expressed in developing heart muscle cells, both in humans and in developing Xenopus embryos,” Veenstra said.
Life with three hearts
Veenstra is also studying the development of another model organism, though one with a decidedly stranger heart: Doryteuthis pealeii, or the longfin inshore squid. Cephalopods are relatively well studied in some respects, said Veenstra, but “this is one particular aspect — heart development — that we know very little about.”
Like birds and mammals, cephalopods like Doryteuthis have a complex, closed-circulation heart that pumps blood twice per cycle. Unlike us, though, squid spread these pumping duties across three different hearts.
Here’s how cephalopods’ three hearts work. The larger systemic heart pumps hemolymph (the equivalent of blood in these animals) from the gills to the body. Then, the oxygen-depleted blood travels to one of two branchial hearts on either side of the body, which pump the blood into the gills to be resupplied with oxygen.
Mammalian hearts, meanwhile, use one organ to move blood, with the left side pumping oxygenated blood and the right pumping the deoxygenated blood. “It's a different solution to the same problem,” Veenstra said.
Cephalopods and mammals evolved these complex heart systems independently from each other, and it shows in the different approaches they take to circulating blood efficiently. The question that fascinates Veenstra is whether cephalopod hearts might share a developmental origin with the human heart.
“How can you make three hearts from a developmental perspective? What is conserved? And what is more derived?” Veenstra asked. “It's very cool basic science.”
Already, Veenstra and his collaborators have gathered preliminary data on where the different hearts come from: “It looks like all three hearts have a shared developmental origin, but this is something that we need to confirm,” he said.
The embryos seem to develop their branchial hearts before their systemic heart, but what this finding indicates is unclear. Intuitively, one would assume the centrally located systemic heart would be analogous to the single heart of other species. On the other hand, the single heart of fish (the simplest vertebrate heart) pumps deoxygenated blood to the gills like the branchial hearts do. “Intuitions can be wrong, in fact often are,” says Veenstra, “so we need to examine the key master regulator genes of their development, to see what the hearts have in common at that level. This, in fact, is what we are currently doing.”
Veenstra is fascinated by this radically different approach to making a heart because it reveals what could be possible in the human heart.
“When you're working with different species, people tend to focus on what is conserved [between species]. But I think the things that are different are equally informative,” he said, adding, “I think the squid can be a source of inspiration” for scientists trying to model a human heart from stem cells. He hopes that his research into squid hearts can help biologists unlock the secrets of the human heart.
Veenstra came to the MBL in large part for the resources available, including the NXR, as well as the chance to collaborate with fellow biologists Carrie Albertin of MBL and Whitman Scientist Karen Crawford of St. Mary’s College of Maryland.“They are both wonderful colleagues,” Veenstra said. “Without their help and expertise this project would not be possible. The wonderful thing about MBL is that it facilitates and encourages people to come and spend time together on projects like this.” His other reason for coming, though, was more philosophical.
“One of the risks in modern science,” he said, is that “you become too focused, too narrow-minded on a particular question and have only one way of thinking about it.” Working at MBL, he said, “widened the scope of our research, and thereby opened up new opportunities.”