The Origin of Left and Right

By studying twisting snails, scientists have identified the earliest molecules that make us asymmetrical.

Donny Osmond: his heart is in the right place.  (Mario Anzuoni / Reuters)

On the surface, people are more or less symmetrical. Aside from small differences, our right sides mirror our left. The same isn’t true for our innards. The heart, stomach, and spleen typically sit slightly to the left, while the liver and gall bladder sit to the right. That’s the usual set-up, but it’s mirrored in one in every 10,000 people, who have a condition called situs inversus. Donny Osmond has it. So did James Bond’s adversary Dr. No, who once survived a murder attempt because his would-be assassin stabbed the left side of his chest and missed his heart.

Whether standard or inverted, there is asymmetry, which raises the obvious question: What creates it? We begin life as a single fertilised cell, which divides again and again into the trillions of the adult form. At what point in that process does left begin to differ from right?

The standard answer, as least for the embryos of back-boned animals, is that tiny beating hairs called cilia push fluid in a typically leftward direction. This current concentrates molecules on one side of the embryo, including those that steer its subsequent development, including one called Nodal. Hence: asymmetry. That’s why people with genetic disorders that disable their cilia have 50:50 odds of owning a right-sided heart.

But that can’t be the whole story because by the time the cilia start to beat, the embryo is already asymmetrical. There must be some earlier symmetry-breaking event.

To find it, Angus Davison from the University of Nottingham turned to pond snails, some of the most obviously asymmetrical animals around. Their shells spiral in either a right-handed clockwise direction or a left-handed anticlockwise one—an obvious outward difference that reflects subtler internal ones.

In 2010, Reiko Kuroda showed that these asymmetries begin in the snail’s earliest moments. Like all of us, they begin life as a single cell, which divides into two, and then into four. At this stage, all the cells are the same size and shape. But the next division is unequal, pinching off a small cell on top of a big one—picture four ping pong balls sitting on top of four tennis balls. The ping pong-sized cells then rotate to nestle between the furrows of the tennis-sized ones. If they rotate clockwise, the snails end up with a right-handed shell. When Kuroda nudged them anticlockwise, using glass rods and exceptional dexterity, she produced left-handed shells.

But what makes the smaller cells do the twist in the first place? Back in the 1920s, scientists showed that handedness is pond snails is heritable. Individuals inherit a gene from their mothers that defines the direction of their twist, and the version that causes clockwise rotations is dominant. But which gene?

Davison found it by teaming up with geneticist Mark Blaxter at the University of Edinburgh. After several years of work, they eventually homed in on a gene called Ldia2, which produces a protein called formin. To their astonishment, the team found that even when snail embryos consist of just two cells, they’re already asymmetrical—one of the cells contains more formin than the other. And by the four-cell stage, formin is largely confined to just one cell.

Formin interacts with a cell’s cytoskeleton, a mesh of long, wiry proteins that give it shape and structure. Davison and Blaxter think that formin interacts with the cytoskeleton in an asymmetric way, which puts a twist on the cell’s shape, and triggers the early rotations.

The team supported this idea by dousing snail embryos with a chemical that stops formin from interacting with the cytoskeleton. In doing so, they changed genetically right-handed snails into left-handed ones. And they found that naturally left-handed snails inherit a version of Ldia2 that’s missing a single DNA letter, and produces a stunted, broken version of formin. The cells destroy the faulty protein, so no rotations occur, and the snails grow up left-handed.

“But we don’t really know,” stresses Blaxter. They have the gene, and they know how it differs in right-handed and left-handed snails, but they still need to confirm how it works. “That’ll take another four years of careful cell biology.”

This isn’t just about snails, though. Working with Michael Levin from Tufts University, the team exposed embryonic frogs to the same formin-blocking chemicals, and found that many grew up with mirror-imaged internal organs. Snails and frogs have been separated by almost 900 million years of evolution. If the same molecule—formin—affects asymmetry in both of them, then it’s more than likely it plays a similar role in humans and other mammals, too.

The study is also relevant to a longstanding idea about asymmetry, involving a scientific Macguffin called an F-molecule. “The idea is that there’s an inherently asymmetric molecule, whose asymmetry gets amplified into the asymmetry of the organism,” explains Blaxter. “It’s an invention. It would be nice if it existed, and there has been a hunt for some years for it. If formin the F-molecule? Blaxter doesn’t think it’s that simple. “We’ve identified just one component of a very large system,” he says. “I don’t think the F-molecule is a single thing. It’s more of an F-complex.”

“It’s really interesting that symmetry is broken at the cellular level (at the two-cell stage) well before we can observe any asymmetric organization in the embryo,” says Silvia Paracchini from the University of St Andrews. She’s keen to know whether the same is true for other species, and how these early asymmetries influence later ones. For example, formin might affect the layout of organs, but does it, say, influence the asymmetry of the human brain, or whether people are right-handed or left-handed?

Chris McManus from University College London, author of the superb Right Hand, Left Hand, thinks that’s unlikely. Snails have two copies of the formin-producing genes, so they can tolerate mutations in one. In humans, such mutations are more likely to be lethal.

Nonetheless, McManus says that Davison and Blaxter’s study should reinvigorate the study of asymmetry. “It had all got rather slow after the exciting [discovery of] the nodal cilia, a decade or two ago,” he says. “There are clearly lots of details to be sorted out, but this at last seems to open up the process once more.”

“It made me think,” says Blaxter. “For years, I’ve picked up snail shells on the beach and I’ve known that they’re handed and the question never struck me: Why?