Our Bodies’ Amazing Electric Current – Part 5

The role electricity plays in differentiating our cells, and regeneration.

Continuing our essay series on our bodies’ electric current, this essay explores the role electricity plays in differentiating our cells through Sally Adee’s We Are Electric: Inside the 200-Year Hunt for Our Bodies’ Electric Code, and What the Future Holds.

As Adee writes:

[N]eurons rest at about 70 millivolts more negative inside than the outside … That’s what the textbooks tell you because that’s true of neurons and many other mature cells—but it’s not true of embryonic stem cells (the little guys who proliferate during the first stages of development). Stem cells’ resting voltage is much closer to zero. (That means the charge inside and outside their cell membrane is about the same, which is also the voltage of a nerve cell in its “panic at the disco” moment.) But where that zero moment is only momentary for a nerve, it is the stem cell’s permanent identity. Until, that is, it turns into something else. And that role is reflected in a cell’s electrical potential.29 You already know about the nerve cells’ potential (-70). Skin cells have the same potential. But bone cells have a higher potential, a firm and immovable -90. Fat cells are a relatively wobbly -50. What they all have in common is that they use their ion currents to keep their membrane voltage at the resting point that defines their cellular identity. A stem cell’s low potential ensures that it can become any other cell. But once it has become a bone, nerve, or skin cell, it stays there. It gets set in its ways, a bit like us.

Adee then describes experiments conducted by Dany Spencer Adams at Smith College and Michael Levin of Tufts University:

On the otherwise featureless, smooth blob of a frog embryo, the hyperpolarized (negatively charged) areas twinkled brightly against darker areas of depolarized cells, as they had before. But then, as the froglet continued to develop, the random bright patterns playing across the dark surface suddenly cohered into a picture that looked an awful lot like a couple of eyes over a mouth. And then, sometime after those shimmers had faded, real physical features began to manifest in their place. Exactly where the electric glow had presaged eyes, soon there were two actual eyeballs. Precisely in the place where the pattern had projected the ghost of a mouth, development began on the real thing. Soon all kinds of features developed exactly where she had seen their electrical premonitions. Not only could you match the voltage patch to the tissue, it perfectly predicted what kind of tissue would form, and its exact shape. It was stunningly clear: electrical signals appeared to encode the locations of anatomical features … The next question was pretty important—were these signals necessary for a normal head and face to form? Or were they just irrelevant indicator lights? To find out, Adams and Levin would need to prove that normal development was affected if you turned off the electricity. When they disrupted the ions that were responsible for the predictive patchwork quilt, that’s exactly what happened: not only did that lead to changes in gene expression, but after removing the paint-by-numbers pattern indicators, the faces that emerged from the electrical chaos were deformed … So what exactly were they disrupting? And how was it possible that these brand-new, unformed cells were able to talk to each other about their voltages, or what parts to form? How were the membrane voltages spreading from cell to cell? Well, remember gap junctions? They start to form the moment the zygote has come together—that first new cell created by fusion of egg and sperm. Right away, they establish a cellular intranet quite unrelated to the nervous system, connecting cell to cell to cell. Each new cell that cleaves off is already connected to the cells around it. Long before nerve cells develop synapses, our non-excitable embryonic cells have another, much faster, more electrical way of communicating. It was becoming clear how the whole thing worked: ion currents controlled the membrane voltage. The membrane voltage determined which tissue group a cell joined, which determined what kind of tissue it turned into. Cells changed their identities in line with cues they got from their neighbors, and the whole process was kicked off electrically … That code controls the complicated biological processes that formed you in the womb, by executing a controlled program of cell growth and death … [J]ust as … the genetic code governs heritable traits, the bioelectric code was how the body told itself about its form … [Adam and Levin’s graduate student Sherry] Aw hypothesized that “for every structure in the body there is a specific membrane voltage range” that drove the creation of that structure.35 They tested that idea in 2011, tweaking the membrane voltage on a patch of tissue on a developing frog’s gut to mimic the same hyperpolarized state Adams had seen before eyes formed on the ghost frog. It worked. An eye grew on the frog’s stomach. They did it again on the tail. Another eye grew. “You can put eyes pretty much anywhere on a frog by changing the membrane voltage,” says Adams. “It’s like an X marks the spot.”

Adee then explores the role of electrical instructions in the process of biological regeneration:

We used to think that only some animals could regenerate themselves: hydras, salamanders, crabs… nothing as interesting as a mammal. But in the twentieth century, the formal study of regeneration revealed just how widespread the phenomenon actually is in the animal kingdom. In nature, there seems to be no theoretical limit to what you can cut off and expect to get back, if you find the right animal: hydras—tiny freshwater organisms—can be cut to absolute ribbons, and the little shred will rebuild itself again into a fully functioning animal. The same is true of that freshwater flatworm we met before, called the planarian. In fact, this is how they reproduce—they tear themselves in half (you thought you had problems). If you had this capability, someone could throw a segment of your finger into the sea and a week later, it would have grown into an extra you. You can see for yourself, in fact: chop a hydra in half and the tail end will sprout a new head and the head end will sprout a new tail. Sea stars combine the abilities of hydras and planarians. In addition to being able to regenerate a new body from a severed arm, some species can regrow their entire central nervous system from scratch. They’ve been known to tear themselves in half on purpose to start a family,37 and they’ve also been known to use their own severed leg to beat off their enemies. Then there are salamanders, which can regenerate a remarkable number of their tissues and organs, including their limbs, tails, jaws, spinal cords, and hearts. A frilly red version called an axolotl can heal anything on its body without scarring, including its brain. Frogs can regenerate entire limbs and tails (and even eyes) when they are tadpoles, but they lose this ability after their metamorphosis into a frog. Same goes for humans—at least until you exit the womb. To riff off a famous phrase often attributed to Abraham Lincoln: we can regenerate all our tissues some of the time, and some of our tissues all of the time, but we can’t regenerate all our tissues all the time. Our regenerative ability follows a schedule that is strictly dependent on age and body part … A zygote is the regenerative equivalent of a planarian. Someone could slice it in two and the two cells would continue developing into identical twins.38 That ability falls off quickly, but a fetus has impressive regenerative ability even so. Most fetal injuries don’t leave scars, an insight obtained in the late 1980s when fetal surgery became routine.39 After birth, however, the superpower disappears fast, with one exception. Until between the ages of seven and eleven (for obvious reasons there hasn’t been a lot of experimental evidence to pin this down exactly), if you lose the tip of your finger, you’ll probably regenerate it in full. This phenomenon is not extensively documented in the scientific literature—and not for the pinky-decapitating reasons you might think. Ai-Sun Tseng, a professor at the University of Las Vegas who leads a lab that specializes in regeneration, recalls describing her work to a class. One of her students “totally lit up. He was like, ‘Yeah! Look at my fingers!’ He grew up in the Philippines and at some point he’d had four of his fingers chopped off above the knuckle,” she says. Because he was not yet eleven when it happened, they all grew back perfectly. But his age wasn’t the only factor. His family had been too poor to afford a doctor, so they kept the wounds wrapped and wet and clean—and eventually all four fingers regenerated perfectly, nails and all. By the time Tseng inspected them decades later, they were indistinguishable from fingers that had never been maimed. At a conference a few years later, Tseng recounted the story to a group of colleagues, one of whom was a pediatric surgeon. He pointed out that, faced with a similar situation, most parents actually refuse to take advantage of this last vestige of regenerative ability. “They’re way too scared of leaving an open wound,” he told her. “They worry it’ll get infected.” So they ask the surgeon to suture together the surrounding skin, which protects the wound with fibrous scar tissue that forecloses any hope of the finger regenerating according to its potential. “Part of the reason we know about childhood regeneration at all is because of children in developing or poorer countries without healthcare,” she recalls him telling her … Tseng had shown that all the persnickety chemical gradients, transcriptional networks, and force cues needed to orchestrate individual cells into complicated tissues could be harnessed with a comparatively simple set of electrical instructions. The genes were hardware, and they could be controlled by manipulating ion flows—the instructions from the software. Tseng and Levin soon published the seminal paper introducing their new idea: “Cracking the bioelectric code.” … Subsequent research has yielded multi-limbed frogs and other evidence of bioelectricity’s role in regeneration. Among the most startling of these, it was possible to use bioelectric interventions to make planarians that had been chopped in half grow a second head instead of a tail. And as the press loves nothing more than a mutant, all the resulting media attention translated to money. First, DARPA came calling with enough money to build the little regenerative boxes that are now on the mice in Levin’s lab. They’ve extended out to frogs, too, growing a new leg on an adult frog. The new leg wasn’t perfect, but it worked—the frog used it to swim around, and after a few months it even regrew toes … The open question now: when will it jump to humans? … In a perfect world, all these problems would have been solved by those famous stem cells. But despite the media hurrah, they have been a bit of a disappointment. The challenge has been how to stimulate them to become the cells you want them to be, and get them to go where they are needed, and keep them there in their new shape. Currently, most of the research on how to do that focuses on biochemical control. But we haven’t had much luck with anything on the wish list: identifying, growing, inducing, or safely delivering stem cells to the appropriate target. In fact, it’s rather unpredictable what will happen to stem cells once they get into your body. This is why stem cells are regulated as an experimental drug, and the problem is highlighted by some fairly grisly anecdotes. One woman who had olfactory stem cells injected to heal her spine after a car accident ended up growing the precursor to a nose in her spine. Another patient, who had stem cells injected in order to rejuvenate her face, ended up growing bones in her eyelids that were so big they clicked whenever she opened or closed her eyes (“a sharp sound, like a tiny castanet snapping shut”). After they started to interfere with her ability to open her eyes, she had an operation to remove the bones, though there is no guarantee more stem cells are not waiting in the wings with more castanets … Such examples are among the reasons stem cells for regeneration are banned on US soil, though of course they thrive in shady clinics …

This concludes this series of essays on our bodies’ electric current.  In the next series of essays, we’ll explore the other of the two main modes of communication within our bodies, namely hormones.