Spark of Life
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Such machinations are more than just idle curiosity—by disturbing the natural process, the scientists can begin to understand how it works, and ultimately how it can be controlled. "Somebody said it's like figuring out a magic trick. The magician does a sleight of hand, and you say, ‘My God, he has a pigeon in his hand,' but you learn pretty much nothing. The minute the guy makes a mistake and you catch a glimpse of the pigeon up his sleeve, now you are starting to see how the trick is done." In this case, the pigeon up the sleeve is the six-legged frog or the two-tailed worm. "If you know how to build a structure, then you know how to fix it when something goes wrong from birth defects," Levin says. "If you know how to make a six-legged frog, that means you may know how to make a leg grow in adulthood."
Although Levin's group is the first to integrate bioelectrical techniques with molecular biology, they are by no means the first to explore the effects of electrical charges on animals. As far back as 1786, the Italian scientist Luigi Galvani discovered that animals reacted to a charge when he noticed that the muscles of a dissected frog twitched whenever he touched a nerve with his electrostatically charged scalpel. (Among those inspired by his work was a young novelist named Mary Shelley, who used it as the basis for reanimating a human corpse in her book Frankenstein.) Other Victorian scientists were able to expand on his work to show that bioelectrical charges had other effects on living systems, such as speeding the healing of bone fractures. After the turn of the twentieth century, the biologist Thomas Hunt Morgan confirmed that animals had inherent electric charges when he measured electrical polarity in earthworms. In the 1920s, a Danish scientist, Sven Ingvar, showed that when chick embryos were placed in an electric field, they grew toward the charge.
By 1950, though, research into bioelectricity fell by the wayside when the field of biology as a whole took two divergent paths. The cutting edge focused on biochemistry, leading to modern molecular biology and genetics; the other, less "sexy" offshoot focused on physiology, continuing to explore bioelectricity only in the case of the electrical signals transmitted by neurons in the nervous system.
In the 1970s and 1980s, some scientists, including the physiologist Lionel Jaffe, worked to put developmental biology and bioelectricity back together. Jaffe and his student Richard Borgens, for example, showed that limb regeneration in frogs and newts could be spurred by applying electric currents. But they hit a wall when they couldn't explain how the electricity actually caused limbs to regenerate. "We had a relatively limited toolkit, and this is where Michael Levin comes in," says Ken Robinson, a professor emeritus at Purdue University who was active in the field in the 1980s. "He put together the tools of modern genetics and molecular biology with the physiology." The two collaborated on many experiments after Levin finished his postdoctoral work and began his own lab at the Harvard-affiliated Forsyth Institute.
Malcolm Maden, a regeneration biologist at the University of Florida who specializes in using chemical cues to explore regeneration in salamanders, says Levin "has reignited the field again—with explanations, which is always better." He theorizes that bioelectrical cues precede the kind of chemical stimuli he himself has studied.
Of course, adding limbs to a frog is a far cry from regrowing limbs in humans. But Levin's experiments provide a case that, theoretically at least, it could be done. If a tadpole can be made to grow a tail past the point of development where it's ordinarily possible, then people could be made to regrow their fingertips beyond childhood.
Levin and other Tufts researchers—such as David Kaplan, the chair of biomedical engineering—have begun tackling bioelectricity in humans. In research published last November, Levin's lab, in collaboration with Kaplan and his doctoral student Sarah Sundelacruz, showed that adult human stem cells—those basic seeds of all body tissues—undergo changes in electric charge before they differentiate. By inserting ion transporters into stem cells, the researchers were able to control when the cells changed into bone or fat.
Levin believes such control could be extended to mature human cells. With the right genetic key, cells could be returned to a plastic state in which they would develop skin, blood, or bone just as surely as a tadpole regrows a tail or a deer sprouts new antlers.
It's an enticing proposition, this idea that humans could regrow legs, eyes, or fingers damaged in an accident. Levin talks about the possible future applications of these bioelectrical techniques as excitedly as a four-year-old child discovering the inside of a television set. "Once we know what the signals are, you can provide the right signals at the right time to cause the tissue to grow," he says. "Our job here is to figure out what those signals are." Such knowledge would of course transform medicine. "What we currently do as a society," Levin says, "is invent increasingly complicated and expensive ways to patch up a sinking ship as the patient ages." How much more sensible to replace your worn-out systems with brand-new healthy ones.
By changing electrical flows in the flatworm known as planaria, Levin's group has grown specimens with tails on both ends, heads on both ends, or even four heads (shown above).
And just as Levin's work could give medicine the power to make organs grow, it might also provide the power to stop organs from growing when tissues turn cancerous. "You can view cancer as a sort of disease of geometry," says Levin. "A tumor is a collection of cells that has failed to obey the patterning instructions from the rest of the body and is growing out of control." His lab has already created cancer-like cells in Xenopus frogs by disrupting the flow of potassium ions in embryonic stem cells. "Obviously, you want to go in the opposite direction," Levin says, "but if you can figure out the switches, you can learn how to control them."
But as promising as all these discoveries are, Levin admits that bioelectrical impulses are only part of the regeneration puzzle, which most scientists agree will require electrical and chemical cues to work properly. So far, Levin's work suggests that the electrical signals often occur first, that they are important "control knobs" that initiate the process. The bigger question, so far unanswered, is how they interact with the later molecular cues that tell the developing body part exactly how to form—with, say, skin on the outside, bone on the inside, and blood and guts in the middle.
Cliff Tabin of Harvard Medical School, for all his apparent pride in his former Ph.D. student (he calls Levin's work "very significant" and contends that developmental biology "is very different for Mike being in it"), reserves judgment about the importance of bioelectric signals. "I wouldn't discount that they play some role," Tabin says. "The question for Mike is, Are these things where the key decisions are being made? Or important, but not the lynchpins in the process? The only way to find out is to make some experiments."
No matter what those experiments find, the research itself satisfies Levin's hunger to understand how complex systems work. "Even if we were to find out this has nothing to do with humans whatsoever, that makes not a whit of difference to me," he says, not entirely convincingly. "This is something we are going to want to know about, how living tissues process information. And if humans don't do it, that's fine. It is fascinating for other reasons." Still, if these techniques do eventually enable humans to grow back an arm or cure a cancer, it wouldn't be the first time Levin did something that everyone told him couldn't be done.
MICHAEL BLANDING is an award-winning magazine writer whose work has appeared in The Nation, The New Republic, Boston Magazine, and The Boston Globe Magazine. This is his second cover story for Tufts Magazine.
Top photo by John Soares. Additional photos by Alonso Nichols, University Photography
This story originally appeared in the Spring 2009 edition of Tufts Magazine. It ran online on July 20, 2009.