The Hidden Unity of Hearts

April 2000



Every second or so of every minute of every hour of every day, something remarkable happens inside your body. The valves of your heart open, blood surges into its chambers, the heart contracts, and then blood comes blasting out, either to load up with oxygen in the lungs or to flow into the rest of your body. Every beat of your heart is the result of a precise choreography of electrical impulses and swirling fluids, a choreography without which you’d be dead in minutes.

Over the past several years, scientists have gone a long way toward figuring out how this complex and vital organ evolved. By comparing the hearts of living animals and unlocking the genes that build them, they have found that while there may be no physiological truth to the expression “my heart is in my throat,” that may be exactly where hearts began. They’ve also discovered that the change from simple tube to complex, chambered organ may have happened in an evolutionary flash.

The first foreshadowings of the heart reach back to at least 800 million years ago, when the first known multicellular fossils formed. A single cell can draw in oxygen and nutrients through its membrane, but once cells start huddling together, some will be cut off from the outside world. Cells can pass nutrients to one another across their membranes, but it’s a slow process that works only over tiny distances. An animal of any size needs a plumbing system.

The ancestral heart of all creatures—from the tiny fruit fly to the enormous blue whale—may have gotten its start in the throat of a worm.

You can find a simple (though elegant) version of plumbing in sponges, which are among the most primitive animals on the planet. The sponge is shot through with tunnels that branch into smaller and smaller tunnels. Lining the tunnels are cells with little hairs that wave back and forth, pumping water through the organism at a tremendous rate; as the water flows past, the cells extract oxygen from it and filter out particles of food. These tunnels enable a sponge to bring seawater directly to all its cells, making it, in a sense, a multicellular animal trying to live a unicellular life.

But evolution later produced more complex animals, with cells that could no longer fend for themselves. The bodies of these more complex organisms have cells of many different types, each dedicated to its own specialized work. A photoreceptor cell in a squid’s eye, for example, helps the squid see but doesn’t feed itself. These animals need a circulatory system to replenish their cells, and they need something to keep that system pumping. You can find hearts, or heartlike structures, beating in the bodies of many complex animals, including mollusks, arthropods, and chordates (among which are vertebrates such as ourselves.) Yet few of these hearts, other than those of vertebrates, resemble our own.

A fly’s heart, for instance, is a muscular tube that simply squeezes the insect version of blood (called hemolymph) into the body cavity, rather than being connected to a closed system of veins and arteries. The fly’s heartbeat is somewhat like the peristalsis in your digestive tract: a simple ripple of contraction. Unlike flies (and more like us), the earthworm has a closed vascular system, but instead of a heart, it has eleven contracting vessels, each of which pumps much as a heart does. The octopus (a mollusk) has two powerful, chambered hearts, each pumping blood through a set of gills.

For decades, biologists assumed that all these hearts, which look so different from one another, had evolved independently. But in recent years, research on how genes orchestrate the development of hearts within embryos has revealed a hidden unity. In the laboratory, scientists alter or remove particular genes in animals and then look at the consequences in the developing embryo. The deformities that result from these experiments help the researchers figure out a particular gene’s usual role in development.

Much of this work has been done on mice, which have the advantage of being closely related to humans but which have some drawbacks as well; for one thing, their embryos grow inside a uterus and are difficult to observe. Other experiments have involved organisms that are less closely related to us yet easier to study, such as vinegar worms and fruit flies. A major breakthrough came in 1993, when Rolf Bodmer at the University of Michigan discovered the gene that controls the development of the fruit fly heart; a fly that lacks this gene never forms a heart at all. The gene was named tinman, after the Tin Woodman in the Wizard of Oz, who joins up with Dorothy and sets off for the Emerald City to ask the Wizard for a heart.

Tinman belongs to a special class of genes. Many genes carry instructions for making a single protein that has a specific job-to build fingernails or make hemoglobin, for example. But some genes make proteins that control other genes. Some act like master switches, triggering many different genes to work together to build a structure. Tinman is one such “master gene” for the fruit fly. Within a few years of its discovery, scientists found master genes for building hearts—named, far less poetically, Nkx genes—in mice as well.

Scientists have discovered that the transformation from simple tube to complex vertebrate heart may have happened in an evolutionary flash.

What surprised scientists was just how similar the mouse’s Nkx genes and the fruit fly’s tinman are. When they compared the genes’ sequence of base pairs (the bonds between the strands of DNA’s double helix, which carry genetic information), many parts were practically identical. What’s more, the genes that control Nkx genes, and the genes that Nkx genes control in turn, are also similar to the genes that play the same roles in flies. The only logical conclusion was that tinman and Nkx genes have a common origin in the common ancestor of insects and mammals, which scientists think was probably a flatwormlike animal that lived 700 million years ago or so. This creature most likely had a heart much simpler than any of its descendants has today—perhaps nothing more than a crude muscular tube capable of contracting regularly.

Genes also provide a hint as to where that first protoheart might have come from: the throat. The tinman and Nkx genes bear a striking resemblance to a gene that helps build the throat muscles in nematode worms. So here’s a possible scenario for how the first heart evolved. Every now and then during cell division and reproduction, one gene (or, rarely, a group of genes) is accidentally duplicated. Perhaps this happened to the genes that induced throat formation in a lineage of primitive animals. At first, the second set of throat genes may have kept on doing their original job of helping to build the throat. Then, thanks to a mutation, the genes started switching on in cells in a different part of the animal’s body. Instead of making a muscular tube that pumped food, these genes began to make a muscular tube that pumped blood.

It’s a long way from a simple tube to the chambers and valves of the vertebrate heart. A look at the history of vertebrates suggests the stage at which hearts became complex. Vertebrates probably descend from an ancestor similar to ascidians (chordates also known as sea squirts). In their larval form, ascidians have some anatomical features much like our own. They have, for example, a precursor to the backbone, a gristly rod in their backs known as a notochord. As adults, however, they root themselves to the seafloor to filter out food from the water, develop a throat with gill slits, and lose their notochord. An ascidian’s heart is little more than a glorified stretch of blood vessel.

The oldest true vertebrate fossils date back 530 million years. Less than 100 million years later, the first fish evolved, and because the hearts of all fish alive today have chambered hearts and tightly synchronized contractions, biologists assume that their common ancestor—the first fish—did, too. As it does in living fish, the blood would have flowed past the gills to pick up oxygen and then continued on to the rest of the body. A new kind of cell layer, called the endocardium, would have lined the heart, thickening it and making it more powerful. Eventually the heart itself grew larger.

“The question is, how do you transform a simple tube into a vertebrate heart in relatively little evolutionary time?” asks Mark Fishman, a geneticist at Massachusetts General Hospital. “That’s a remarkably ornate change.”

To answer that question, Fishman and other researchers turned to genes—specifically to the genes of the zebrafish (Danio rerio), a species common in home aquariums but relatively new as a “model animal.” Because it’s a fish—not an insect, such as the fruit fly—the zebrafish has a multichambered heart. And unlike a tiny mouse embryo hidden inside its mother’s uterus, a zebrafish larva matures on its own. Even better for those who want to study hearts, its body is transparent.

Keeping hard-working hearts supplied with oxygen may have been the initial pressure behind the evolution of lungs 400 million years ago.

When Fishman started studying the embryonic zebrafish heart, however, he wasn’t sure “if the heart would be decipherable, because the genes might be used more than once in development.” In other words, a gene involved in the formation of the heart might have had another job earlier in an embryo’s development, when the embryo was just a ball of cells. If Fishman created a mutation that made such a gene inactive, the embryo would never become anything more than that ball, and he’d never discover the gene’s normal role in building the heart.

“Fortunately, that turned out to be a false worry,” says Fishman. His team and others have found more than a hundred genes involved in heart development. After tinman-like genes have finished creating a simple tube, these other genes switch on, transforming the tube into the complex organ we’re familiar with. And some of the genes took Fishman by surprise. By knocking out a single one of them, his group could create a heart that was missing its ventricle but was otherwise normal; knocking out a different one produced a heart that was missing valves but nothing else. These genes seemed to be in charge of little modules of genes that worked together to build specific parts of the heart. Fishman ended up finding about a dozen heart-module genes. “It was more than we could have hoped for,” says the geneticist. “It meant we could dissect organ development, because we had individual elements that could be removed.”

Fishman also realized that the way these heart-module genes work in living fish might hold a clue to the evolution of vertebrate hearts. It’s possible that the complex, chambered heart didn’t change gradually, with many genes evolving minor mutations that changed their functions. Instead, each of the heart modules may have existed in earlier vertebrates, where they performed other, still unknown jobs. Merely by tinkering with the master gene that controlled a module, evolution could have quickly invented a new structure for the heart. To picture the difference between these two kinds of evolution, imagine building a concrete bridge. If you build it by adding sand grains one at a time, it will take a lot longer than if you assemble it from large prefabricated blocks.

With powerful chambers, valves, and all the other parts of the vertebrate heart in place, the blood of an early fish could be pumped at higher pressures and therefore travel farther from the heart. And this souped-up circulatory system meant that fish could grow large enough to hunt down smaller prey. Thanks to a genetic revolution, Fishman suggests, vertebrates changed from lowly filter feeders into the ocean’s top predators.

There’s a built-in problem with the fish heart, though. It pumps blood through the gills, where the blood loads up with fresh oxygen before traveling through the rest of the body, nourishing muscles and organs as it goes. By the time it returns to the heart, it has used up a lot of the oxygen. The heart is like a waiter who is forced to eat only the scraps left at the end of a meal.

This design can cause trouble when a fish tries to swim fast: the harder it swims, the more oxygen is devoured by its swimming muscles, leaving even less to nourish the heart. But there are a couple of ways to get around this constraint. One is to divert blood back from the gills to the heart while it is still rich in oxygen. That’s what some fish have done, evolving coronary arteries that move blood through the heart tissues. Tony Farrell, a physiologist at Simon Fraser University in British Columbia, has found that the flow of blood through the coronary arteries of a trout triples during exercise, enabling the fish’s heart to keep pumping hard.

Another way to become a stronger swimmer may be to evolve lungs. Today lungs are found not only in land vertebrates but also in a few obscure fish lineages, such as gar, bichir, and lungfish. Many other species of fish have swim bladders, which they use to control their buoyancy. For a long time, paleontologists thought that lungs had evolved from swim bladders, helping fish survive in stagnant waters, where oxygen often ran low. But the fish themselves tell a different story. About 420 million years ago, evolution split jawed fish into two great branches: cartilaginous (such as sharks and rays) and bony (everything else, from lungfish and trout to sea horses). Sharks have neither swim bladders nor lungs, suggesting that both these useful organs must have evolved in bony fish after the split. Which came first? The most primitive branches of bony fish all have lungs, while swim bladders are found only in the teleost branch. The simplest explanation of the evidence is that the common ancestor of today’s bony fish had lungs and that lungs turned into swim bladders in the lineage that led to teleosts.

The oldest fossils of bony fish all come from marine waters, where fish presumably didn’t have to worry too much about running low on oxygen. So why did fish evolve lungs, when they had gills that seemed perfectly well adapted for getting oxygen from water? Colleen Farmer, a physiologist at the University of Utah, thinks that the evolution of lungs made fish better swimmers. In air-breathing fish, some of the blood that flows through the gills gets diverted to the heart, and when these fish swim hard, they tend to breathe more air. Farmer suggests that they’re trying to keep their hearts supplied with enough oxygen. And that, she proposes, may have been the initial pressure driving the evolution of the first lungs some 400 million years ago. “These lunged fish,” says Farmer, “were active predators cruising around the open ocean.”

The question then becomes why (and when) so many fishes lost their lungs. Farmer speculates that the change started when rising to the surface to breathe became risky. About 220 million years ago, the sky began to fill with predators-scaly-winged pterosaurs and, eventually, birds-that snatched up the fish they saw while flying over the water. Perhaps fish species that lost their lungs flourished, while those with lungs became rare.

Fortunately for humans, one lineage of lunged fish hauled ashore about 360 million years ago, eventually giving rise to land-dwelling amphibians, reptiles, and mammals. In the millions of years that followed, these vertebrates have retooled their hearts in multiple ways. Hummingbirds evolved rapid-fire hearts that can beat twenty-two times per second; frogs and squirrels evolved the ability to slow down their hearts during hibernation. Whales returned to the sea and evolved huge hearts—in the case of the blue whale, a heart capable of pumping sixty gallons per minute. And crocodiles, when underwater, can redirect the flow of blood to bypass their lungs entirely. What makes these transformations all the more amazing is that the basic genetic recipe for the vertebrate heart hasn’t changed much at all. When it comes to the heart, we all swim with the fishes.

“I’ve always been fascinated by how evolution produced complicated things like the heart and the brain,” says freelance journalist Carl Zimmer, “and now scientists are coming up with good evidence for how it happened.” Zimmer put his interest in evolution to good use in his last book, At the Water’s Edge (Touchstone, 1999), which describes recent research on two of the most significant transitions in the history of life: from fish to four-legged land vertebrate and then, back to the water, from land mammal to whale. This September, Simon & Schuster will publish Zimmer’s next book, Parasite Rex, a close look at tapeworms, flukes, and other long-underestimated parasitic organisms that just may turn out to be “the dominant force in the evolution of life.” Zimmer also writes a monthly column on biomechanics for Natural History.

See also “The Virtual Heart”

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