Michael Levin, Taisaku Nogi
Michael Levin has discovered when and how embryos determine which direction is left and right. Taisaku Nogi (background) worked with him. Staff photo by Stephanie Mitchell

One of the biggest mysteries of biology is how humans and other animals get their shapes. For example, why do most people have their heart on the left side? A few humans have it on the right side, and they apparently suffer no ill effects. In fact, some people have all their visceral organs reversed. Their bodies are mirror images of what’s considered normal, yet they live long, healthy lives.

Or take handedness. Some 90 percent of people are right-handed, but healthy left-handers live as long and are as creative as right-handers. Lefties have no special sinister diseases, but how do they get to be left-handed?

A team of scientists at Harvard School of Dental Medicine and The Forsyth Institute in Boston believes it has found the answer. And it’s electrifying.

“All living things generate all sorts of electric fields inside themselves,” explains Michael Levin, an assistant professor at the Dental School and a researcher at The Forsyth Institute. “That’s part of life. We have discovered a whole new role for these fields, not expected or explored before. We’ve found that they control the geometric arrangement, the shape, of visceral organs such as the heart, stomach, liver, spleen, and probably the brain.”

The researchers have also identified the genes that hold the blueprints of this organ geometry. And they have found that the process occurs much earlier in development than previously suspected. Levin expects that this knowledge will provide a new understanding of birth defects that involve flipped organs, and that the electric aspect of this asymmetry will impact the treatment of cancer, regrowth of missing arms and legs, and regeneration of other types of tissues.

Levin and his colleagues did their unique experiments with frog and chicken embryos, but they believe that humans develop in a similar way. “I would bet my last dollar that electric voltages determine our body’s architecture, including right-left asymmetry, and they do this at a much earlier time than previously believed,” he comments.

Off to a quick start

Finding genes involved in changes on one side of the body but not the other has been a hot research area since the mid-’90s. As a graduate student at Harvard Medical School (HMS), Levin worked on asymmetry genes in the laboratory of Professor of Genetics Clifford Tabin, then he pushed the frontier further in the company of HMS cell biologist Mark Mercola. “When we proposed that asymmetry genes get their sidedness through the generation of extremely small electric currents, everyone thought it was a crazy idea,” Levin recalls.

Now that he has his own lab at The Forsyth Institute, an independent research organization, he is part of the search to find out what goes on upstream of the genes. “This research,” Levin explains, “is directed toward finding how asymmetry gets started in the first place, the earliest time during development when an embryo figures out which direction is left and right.”

Levin, Mercola, and their colleagues discovered a gene that carries instructions for making a so-called ion pump. Ions are electrically charged atoms that the pump pushes in and out of a cell, generating a small electric current in the process. At first, genetic instructions for making the pumps are placed all over a frog or chick egg cell. After the egg is fertilized, an as-yet-unknown process either moves the instructions to one side of the egg, or destroys those on the other side of the egg.

Until the Forsyth-Harvard experiments, most biologists believed that, in frogs, the asymmetry occurs hours after fertilization, when the embryo consists of hundreds or thousands of cells. Levin’s team found it happens much sooner, at one and a half hours, when the developing embryo consists of only four cells.

In humans, the same process is believed to take days. Levin thinks that further research will turn back the clock significantly. “I firmly believe,” he says, “that we will find the beginning of asymmetry to occur much earlier than now thought in all mammals from mice to humans.”

Real flipping problems

With the help of Kenneth Robinson and Thorlief Thorlin of Purdue University, and Taisaku Nogi, another Forsyth investigator, Levin and Mercola set out to prove to the world that ion pumps are the source of asymmetry. They introduced a second pump on the side where it would not normally be found. In this situation, the same activity took place on both sides of a cell, rather than on one side only. “We got the predicted result: The embryos’ organs were completely randomized,” Levin recalls. As many frogs had hearts on the right side as on the left side.

The same thing happened when they got rid of all ion activity by disabling the one-sided natural pump with drugs. When human organs become randomized like this, every kind of combination can result. In some cases, only the heart is reversed. More rarely, all the organs flip, creating a mirror image of the usual arrangement. All the plumbing of inner tubes and blood then connect properly, and no special medical problems occur.

Doctors may not even notice the switch. Levin describes a situation where such a person had X-rays taken of a broken rib. “When the heart appeared on the wrong side,” Levin says, “the doctors thought they had simply flipped the X-ray film. They were not aware that it was the organs that had flipped.”

If all the organs go to the same side, however, the person has a real flipping problem. Not enough room exists in the body cavity, and the tubes and vessels don’t connect properly.

Then there is the intermediate case where asymmetry disappears and both sides are identical. The heart lies in the center of the chest. Instead of one spleen on the left, the person has two spleens or none at all. Normally, the left and right lungs differ, but these symmetric individuals boast two left or two right lungs.

Such misplaced organs cause more than 35,000 birth defects every year in the United States alone.

The experiments raised a new concern in Levin’s mind. He eliminated ion-pump activity in chicks and frogs with the same drugs that humans take to ease acid reflux. The condition stems from inappropriate pumping of acid ions in the esophagus and stomach. “This makes me wonder whether such drugs, if taken by pregnant women in sufficient quantity, might cause asymmetry defects in their children,” Levin says. “I have no data on humans to support such an idea, but it may be worth looking into.”

Medical possibilities

Besides providing a better understanding of birth defects, electric field experiments may lead to new treatments for cancers. “Tumors have different electric characteristics than normal cells,” Levin points out. “That might cause them to lose touch with their appropriate function in tissues and do things like multiply without control. If we could find a way to restore the normal electric cues, these abnormal cells may behave more naturally.” If that turns out to be the case, electric treatments may someday be added to surgery, radiation, and chemotherapy.

Body electricity is also involved in the regeneration of tissues. Salamanders, the poster animals for this process, can regrow legs and tails bitten off by enemies, as well as replace parts of their hearts and eyes. So-called higher animals cannot do this on their own. However, researchers have applied electric fields to spark regeneration of limbs in frogs and even mice. In other cases, young children have naturally regrown the tips of their fingers, above the top joint, following accidental amputation

The discovery by Levin and his colleagues that electric fields provide a kind of scaffolding for the growth of hearts, stomachs, and other organs will undoubtedly stimulate more research in this area. “Electric signals are not the sole fuel for growth and regeneration of body parts,” Levin reminds us. “Chemicals such as growth factors also play a major role. But now that we have a better idea how organs are shaped in the first place, we are closer to replacing a lost hand or growing a new set of kidneys.”