By William J. Cromie

Gazette Staff

Symmetry seems to rule the animal kingdom. Fish, birds, mice, whales, and humans are all symmetrical, that is, their left and right sides are mirror images of each other.

But symmetry is only skin deep. All these creatures have hearts on the left side. All of them have stomachs and spleens on the left, and their livers on the right.

How come hearts are on the left, and not in the middle, or on the right side? Harvard scientists who have pondered that question are coming up with some intriguing answers.

"We're like jigsaw puzzles on the inside," says Cliff Tabin, associate professor of genetics. "Our lungs fit around our hearts. Our intestines, stomach, liver, and spleen have asymmetrical shapes, and each has to fit snugly with the others. Studies of fish, frogs, chicks, and mice reveal similar genes that control the positions of these organs. There is evidence that the same type of control occurs in humans. We would be shocked if it didn't."

These genes begin acting even before organs form in a fetus or fertilized egg. They produce proteins that determine on which side of the body a heart, stomach, or gut will appear.

Other genes control the actual growth, so it's possible to grow a healthy heart on the right side, and a healthy liver on the left side.

"There's a rare genetic condition in humans in which all the organs are flipped, and the intestine coils counterclockwise instead of clockwise," Tabin notes. "These people are perfectly healthy. However, when organs are randomized -- some on the normal side, some not -- the embryo doesn't survive. The pieces of the jigsaw puzzle do not fit together."

Getting A Head

Tabin specializes in the development of chicks; other Harvard researchers study mice, frogs, and fish. All of them find that a gene known as "nodal" is one important source of signals that determine the orientation of organs. It first influences which end of an embryo will be the head and which the feet. If this gene is mutated in a certain way, a mouse will have no head.

Nodal later is involved in setting up the midline of an embryo, the part that will become the spine and separate left and right sides.

"The role of nodal was probably fixed early in evolution and has been passed down from fish and frogs to birds and mammals," Tabin remarks. "There's strong suspicion it works the same way in mice and humans."

Nodal also plays a major part in locating organs on the left or right side. The heart is a good example. In birds and mammals, it initially forms as a tube in the middle of an embryo. Then a signal from the protein made by the nodal gene determines which way the tube bends or loops as it develops into a chick's or human's heart.

"If this loop is to the right, the heart will form on the left, as it does in the vast majority of cases," Tabin explains. "If the tube loops to the left, the heart becomes located on the right side."

Later, nodal and other genes determine the "handedness" of the stomach and the direction of coiling of the intestine. "Every organ makes an independent decision about its left- or right-handedness," Tabin points out. The heart doesn't determine what the stomach or liver will do; the latter organs respond separately to "go left" or "go right" signals.

Of course, nodal does not act alone. At any time during development, many genes switch on and off and influence the formation of different organs, nerves, muscles, and bones simultaneously.

In the early part of development, blocks of cells lie on either side of the midline. Some of these cells will form a spine, pelvis, and ribs, others will make muscles or skin.

If these cells see a lot of the protein made by a gene called sonic hedgehog, they form bones that make up the trunk. [The gene was named by a post-doctoral affiliate in Tabin's laboratory for a computer game that features an electronic hedgehog.] If the cells see other combinations of gene products, they become muscles or part of the skin.

In fish, chicks, and mice, sonic shapes the brain and spinal cord. Mutations of this gene in mice can result in monstrous deformations that mimic abnormalities in unfortunate human infants. Sonic is also responsible for turning on nodal in birds.

Siamese Twins

Gene activity in twin chicks provides insight into some peculiar and previously unexplained phenomena in Siamese, or conjoined, twins. In half the pairs of human twins joined at the chest, the twin on the right side has its heart on the right side.

Drucilla Roberts, assistant professor of pathology, and Michael Levin, a graduate student, found an explanation for this strange occurrence while working in Tabin's lab.

The first gene signal identified to date comes from the right, and it turns on nodal on the left side. The heart tube actually bends away from nodal's signal, or to the right. The twin on the left gets the "go right" sign in a normal way. But the twin on the right sees its own "go right" sign as well as the "go right" signal from its twin.

"That leads to confusion," Tabin says. "Without clear directions, the choice is made randomly. One half of the right-side twin chicks have their hearts in the right place -- on the left -- the other half develop hearts on the right side. We think the same thing happens in humans."

Is Left Right?

Does having a heart on the left give men and women, mice and frogs any advantage? Did the heart become positioned this way because it provides some kind of survival benefit?

"From the point of view of evolution, we don't think that it's important to put any organ on one side versus the other," Tabin answers. "The important thing is that when you put an organ on one side, everything else has to fit appropriately. The evolutionary advantage is that everything fits together."

The left side might have been a random choice in the case of our oldest ancestor with a heart. Once it worked well, there was no point in changing things. Like the jigsaw puzzle, once it has been solved, there's no point trying to do it in a different way.

Today, when it is done in different ways, serious birth defects can result.

"Some children are born with problems that are due to abnormal left-right decisions," Tabin says. "One example is a heart that is symmetrical, that is, the same on both sides. In a normal heart, the left side is adapted to pumping blood through the body, the right side pumps it to the lungs. When a heart has two left sides or two right sides, its owner cannot live normally."

Instead of being born with a spleen on the left side, some infants are born with spleens on both sides, or no spleen at all. Those changes make it more difficult to clean the blood and fight infection.

"The signals we study occur before the organs actually form, so it's difficult to see how this knowledge could be used for treatment," Tabin says. "What we get from it is more insight into how certain classes of birth defects occur, plus a greater appreciation of how the wonderful and beautiful events of development are orchestrated."