How do bodies map out left and right?

Symmetry has often been touted as the root of beauty. But beauty, we know, is only skin-deep. Inside the human body, asymmetries abound. The liver stays to the right, the spleen to the left. The heart tilts leftward.

“Inside, you’re nearly wholly asymmetric,” says Angus Davison, an evolutionary geneticist at the University of Nottingham, UK. And that, he adds, makes sense, because the body is trying to pack all the organs into a small space.

In fact, our very molecules are often asymmetric: The complex arrangements of atoms that make up our cells usually come in mirror-image forms. As life developed on Earth, nature selected either the left- or right-handed version of each molecule to use: lefties for the building blocks of proteins, righties for the building blocks of DNA. This preference, Davison suggests, may kick off asymmetry in the early embryo. In particular, the meshwork of molecular struts that act as a cell’s internal skeleton seem to have a role in defining right and left, according to his recent work with snails.

But researchers know more about what happens at the whole-embryo level. Early in development — about Day 18 to 20 of a human pregnancy — a temporary structure called the left-right organizer forms in the embryo’s future belly. Inside it, cellular tentacles called cilia push fluid toward the left, and this sets off a chain of events that gives the embryo different left and right sides.

If something goes wrong with the process, it may or may not cause problems down the line. In about one in 10,000 people, all the internal organs are reversed: heart on the right, liver on the left, etc. Their bodies work just fine.

But in others, about one in 1,000 people, the reversal is only partial, leading to mix-ups, such as having no spleen at all. One of the biggest concerns for people born with this partial change to standard left-right organization — called heterotaxia — is heart defects, says Martina Brueckner, a pediatric cardiologist at the Yale University School of Medicine in New Haven, Connecticut. The organ might have two right atria or two left atria instead of one of each, for example. These kinds of problems threaten survival and usually require corrective surgery.

To the left, to the left

One of the earliest clues to how left-right decisions are made came from men with a condition called Kartagener’s syndrome. The condition can cause organs to be wholly reversed, as well as chronic sinusitis and lung-wall inflammations.

In addition, men with Kartagener’s syndrome often are infertile. In the 1970s, Swedish scientist Björn Afzelius and colleagues linked that infertility to problems with the tail-like flagella that sperm use to swim. This led him to suggest that similar problems with cilia, which are related structures, could underlie the organ reversal, too. It would also explain the sinus and lung problems, because those body parts use cilia to sweep away dirt and mucus clogging the airways.

“It was a leap of intuition, says David Smith, a specialist in biological fluid mechanics at the University of Birmingham in the UK, who coauthored a 2019 article about asymmetry in the Annual Review of Fluid Mechanics. And a leap in the right direction: Kartagener’s syndrome is now known as a subtype of primary ciliary dyskinesia (Greek for impaired movement). But at the time, recalls Brueckner, most scientists didn’t believe Afzelius. They didn’t think embryos even had moving cilia. It would take a couple of decades to prove his model right.

In the meantime, scientists had begun to zero in on early events in the embryo as it sets up left and right. In a 1995 paper, geneticist Cliff Tabin and colleagues at Harvard Medical School in Boston described how certain proteins segregate to one or the other side of chick embryos. One of these is an important development regulator known as Sonic Hedgehog (yes, after the Sega video game). At first, the regulator is spread all over that left-right organizer structure, but later it’s found only on the left. As it turns out, Sonic Hedgehog and some other proteins that end up asymmetrically localized activate other ones. Together, these proteins create anatomical asymmetry.

Going with the flow

But Tabin’s work didn’t explain how the initial regulators, like Sonic Hedgehog, got to the left side of the embryo. At that time, the cilia hypothesis was just one potential explanation. The breakthrough came in 1998 from Nobutaka Hirokawa, Shigenori Nonaka and colleagues at the University of Tokyo. The scientists examined mouse embryos with defective cilia. Although the embryos didn’t survive without these key structures anywhere in their bodies, the team could see that some of them were starting to arrange the heart in the wrong orientation. The researchers also captured live video, in normal mouse embryos, of cilia in the asymmetry organizer sweeping fluid toward the left. “This was really the giant step forward,” Brueckner says.

The leftward sweep occurs because these special cilia in the left-right organizer spin asymmetrically. “Like a pinwheel,” Brueckner says, “they always move in one direction.”

But how does that leftward current lead to the changes in protein location observed by Tabin? Brueckner’s team reported a clue in 2003. They found that cells on the left edge of the asymmetry organizer respond to the fluid by allowing calcium to rush into their interiors. An influx of calcium like this can set off all kinds of cellular processes, including protein production.

Every answer raises yet another question: in this case, what, precisely, these left-side cells sense in the current of fluid washing over them. Hirokawa and colleagues suggest that swept along in the leftward current are little membranous packages — like messages in a bottle bobbing along in ocean currents — containing substances like Sonic Hedgehog to promote left-ness. The alternative, suggested by Tabin and others, is that the receiving cells sense the mechanical force of the leftward current, like seagrass pushed by ocean waves.

It’s possible both ideas are right, Smith says. “Maybe what’s going on is some sort of combination of force and biochemistry.”

With a twist

While humans keep their asymmetric nature shrouded in skin, garden snails wear theirs for all to see, in the turn of their shells. Some species have shells that tend to turn clockwise, and the rare misfits that spin counterclockwise may be unhealthy and less likely to hatch. In some other species, turning counterclockwise is common and seemingly harmless. But it does affect the snail’s love life, because the genitals of counterclockwise snails are on the wrong side to mate with the clockwise critters in the rest of the dating pool.

Working with pond snails, Davison’s lab and a Japanese group recently identified a gene that controls whether a snail mother’s offspring will be clockwise or counterclockwise. The gene carries instructions for a protein called formin, known to help assemble some of the cell’s interior struts. It turns out that snails with a disabled formin gene create babies with counterclockwise shells.

Why? Actin, the molecule that makes up those struts, naturally has a twist, explains Davison, but it relaxes a bit if formin is not working.  A subtle change to actin’s twist in the mother’s egg might, he suggests, cause the early snail embryo to switch its asymmetry pattern.

That’s one way that nature’s asymmetric molecules could lead to asymmetry in whole animals. It may not be traditionally beautiful, but it works.