It’s What Side Inside That Counts
People look pretty symmetrical on the outside: two eyes, two ears, two of each limb and bodies that would yield very similar shapes if sliced down the middle.
But symmetry is only skin deep. Inside, asymmetry reigns: Hearts lie on the left, spleens and stomachs even more so. Livers keep company with gallbladders and appendixes on the right, along with a larger, three-lobed lung.
It’s easy to rationalize why such asymmetry evolved: There’s only so much room in the middle and a whole mess of offal to fit in the cavity of the body.
“It’s largely a packing problem,” says Joseph Yost, a developmental geneticist at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
Asymmetry, he says, also allowed the evolution of more efficient organs: a complicated, four-chambered heart instead of the simple tube our ancient ancestral species deemed adequate; 26 feet of neatly coiling gut instead of a short, straight piece stretching straight down our middles.
But if the “why” of asymmetry is easy to comprehend, the “how” is a much tougher problem. What guides these sundry organs to develop on the correct body side?
It’s a puzzle that ranks right up there with the biggest ones in developmental biology: things like how an embryo “knows” its front from its back; its top from its bottom, its hand from its foot. How, in a nutshell, something so complex as a baby can emerge from a fertilized egg.
“It’s really a miracle. Think about getting from one single cell to your child,” says Cliff Tabin, a developmental geneticist at Harvard Medical School. “Left-right asymmetry is just a really cool aspect of that much cooler problem.”
By studying flies, fish, frogs, chicks and mice, scientists such as Yost and Tabin are starting to understand what’s going on and are ferreting out genes that guide this key step in development.
And by studying the innards of some people, scientists are learning a bellyful about how this left-right decision can go awry.
Some people, 1 in about 10,000, have bodies that are mirror images of the norm: spleen on the right, liver on the left. They fare very well unless their oddity leads to a surgical slip-up or a misdiagnosis of a condition like appendicitis because a pain shows up on the wrong side.
But some people’s innards are far more jumbled, with every organ seeming to decide for itself which side is “left” or “right” in a chaotic free-for-all. The result: two spleens or no spleens. Malformed hearts. Veins and arteries snaking through the body in odd places or linking with the heart where they shouldn’t.
That is why body asymmetry is more than just a great scientific puzzle, says Dr. Brett Casey, a pediatric pathologist at Baylor College of Medicine in Houston. Understanding it better might help avert tragedy. Casey, for one, started studying asymmetry 10 years ago after he participated in an autopsy for a baby born with a terrible heart defect: The body appeared to have developed with two right sides.
The hope, he says, is that if doctors knew more they would know how to better treat individual cases and counsel families. They could screen risky pregnancies more carefully. They could detect milder but potentially problematic defects earlier in children’s lives.
It’s even possible that someone, one day, might discover a nutrient mothers could take during pregnancy to cut down on the risk of asymmetry defects, much as enriching grains with folic acid helped slash rates of the birth defect spina bifida.
Finding the genes involved in asymmetry--understanding the process--is the challenge. And that means exploring some of the earliest days in the development of a human being.
The first obvious sign that an embryo knows left from right occurs early in the fourth week, when the developing heart, at that point a tiny, vertical tube, loops suddenly to the right as the first step in forming a four-chambered heart.
But by then the decision has been made, for how else would the heart know which way to loop? In fact, left-ness and right-ness are “decided” by the embryo roughly 10 to 15 days after conception.
“A pregnant woman has no idea she’s even pregnant at the time that this is happening,” says Dr. Martina Brueckner, pediatric cardiologist at Yale University in New Haven, Conn.
Elegant experiments by some Japanese researchers suggest how the process starts.
The key is a cluster of several hundred cells in the trough of the cup-shaped mammalian embryo. Each cell is studded with a tiny hair that whirls around, swooshing the fluid above it.
But because of the way they are built, those hairs do not swoosh the fluid randomly. When a team led by Nobutaka Hirokawa of the University of Tokyo placed tiny beads in the fluid of mouse embryos, they saw that the current created by the swooshing hairs sent the beads drifting leftward.
Hirokawa’s group also found that mice that were genetically incapable of making those embryo hairs have bodies seriously confused about left and right, with all kinds of heart defects. Brueckner’s group has made similar findings.
Those discoveries are among the evidence making scientists suspect that the hairs are crucial for setting up the left-right axis.
Perhaps, proposes Hirokawa, embryos make a key signaling chemical, the identity of which is as yet unknown.
As the chemical drifts in the fluid, those beating hairs send it to the left. The chemical binds to the leftward cells. It tells them they are lefties.
That model has attracted much support but isn’t accepted by all, Tabin says: “It’s very likely to be right in my view, but there are some things that just don’t fit.”
It is also not clear if creatures such as chickens, fish and frogs use these whipping hairs to set up left and right the way mice and probably humans do.
Later on, though, there is clearly a lot of similarity in the left-right process, with widely varying creatures using similar genes called “lefty,” “nodal” and “pitx2,” which are all activated on the left side of the embryo.
Meanwhile, other genes, such as one in a fish named “one-eyed pinhead,” are activated in a line right down the middle of the embryo, a kind of Berlin Wall of tissue that helps left and right sides stay on their correct developmental paths.
The road to asymmetry is long, involving dozens of genes signaling back and forth, turning each other on or off in response to the messages they get.
Researchers are piecing together this complicated path. They are also starting to hunt down genes in human families where left-right oddities are inherited, such as a gene in one family studied by Casey that causes affected males to have jumbled up organs and affected females to have mirror-image insides.
It’s possible, in fact, that the number of defects caused by mutations in asymmetry genes has gone underreported, says Dr. Susan Morelli, a University of Utah postdoctoral researcher. She and co-workers are studying some families where just one child has a congenital heart defect. The defects had been considered just random bad luck, but Morrelli has found that in many cases others in the family have very slight left-right abnormalities too.
But even after scientists understand how left becomes left and right becomes right, that simply ushers in a brand-new puzzle, Tabin says: how the embryo acts on that left-right information.
“Forget left and right,” says Tabin.
“What does it mean that ‘the cells on the left side express pitx2’? How does one go from that to the bending of the heart? What makes it bend? We don’t have the first clue for the most part.”
