M

EDFORD, Mass. — Imagine the earliest possible snapshot of yourself, and it would look something like this: a single cell in the primordial soup of the fallopian tube, preparing to assemble itself into tissues and organs and systems, which will in turn give rise to breath and heartbeat and memory. Somewhere in there is a microscopic blueprint for the structures that allow you to be you.

If you ask how that cell is able to assemble itself among others to make the right shape — heart on the left, liver on the right, two hands with five fingers each — most people would say that’s all in the genes.

To Michael Levin, those people aren’t quite right. It’s true that genes code for proteins, and proteins are the building blocks of life. But if you want to fix a problem in the body’s structure — a birth defect, say — knowing which genes are involved will only get you so far.

“It’s like if you have a car that was missing the front axle, and I gave you a bunch of iron atoms and a bunch of titanium atoms — there you go!” he said. “I mean, it’s a good start, and it’s necessary, but it’s certainly not sufficient to know  how to put this thing together.”

In his lab at Tufts University, Levin has been trying to figure out the other steps of the equation. He’s convinced that bioelectricity — the electrical circuits that ebb and flow among cells and tissues — plays a central role.

Levin is a basic scientist: Part of his interest is simply to understand the mysterious origins of the shapes that define all sorts of creatures. But it’s also the most important medical question he can imagine.

Understand how cells and tissues cooperate to make fingers and eyes and organs that sit in their rightful places — and figure out how to intervene when something goes awry —and you’re on your way to solving birth defects, degenerative disease, and cancer, Levin says. He even imagines harnessing bioelectric circuits so that you could regrow a limb after a traumatic injury.

Most biologists would be loath to make such bold claims about their research questions, just as they’d be loath to talk about the genome as a “bag of parts.” Then again, Levin is not most biologists. He has spent the past two decades fiddling with the knobs of bioelectricity, helping to revive interest in an old and often marginalized idea.

His tinkering with these circuits has created some Frankensteins: frog embryos with organs growing in the wrong places, tadpoles that can detect light through eyes on their tails, flatworms with “cat-like” heads. In doing so, he’s shown that cellular voltage patterns can influence everything from tumor growth to brain development to the regeneration of appendages.

These interventions are still far from the clinic, but as a first step, Levin and his collaborators are now applying some of those tissue regeneration techniques to lab-grown human cells.

His tinkering with bioelectric currents has created some Frankensteins: flatworms with “cat-like” heads and tadpoles that can detect light through eyes on their tails.

Yet bioelectricity research is still far from mainstream — and some wonder if it’s the biological linchpin Levin claims it is. Even some of his collaborators, who have enormous respect for his work, don’t necessarily speak about the effect of these voltage changes in such stark terms.

Levin, though, has had bioelectricity on the brain since he was an adolescent, and he wants to spread the word. Now is perhaps a better time than any.

In March 2016, he was announced as the leader of a Paul G. Allen Discovery Center — an honor that comes with $10 million in foundation funding over four years, and the possibility of another $10 million for the next four years after that. Now he’s running constant experiments, forming collaborations with researchers all over the map, and even sending labs what he calls “gift baskets” — a package of protocols and dyes and vials that function as bioelectricity starter kits.

As Tom Skalak, executive director of the Paul G. Allen Frontiers Group, put it, “Scientists in every walk of life, from very established molecular biologists and physiologists to computational biologists, all had the same reaction to his work: He’s either going to win the Nobel Prize or prove the bioelectric code wrong.”

Surgery on an embryo the size of a poppy seed

It’s easy to imagine research on our inner electric currents as a Hollywood mad

Mike Levin
Mike Levin Courtesy Tufts University

scientist scene, with indoor bolts of lightning and bursts of smoke. But if you arrived at Levin’s lab late on a Wednesday afternoon in December, the

rewriting of the bioelectric code looked a lot more like someone doing surgery on a poppy seed.

The seed in question actually belonged to an African clawed frog, because these toothless amphibians turn out to be especially useful for research on embryos. Their eggs are enormous, by lab animal standards — at 1 millimeter in diameter, the frog-to-be is 2,300 times the size of a mouse at the same stage — and the shells are transparent, allowing scientists to watch development as if through a fishbowl.

After being exposed to an egg-inducing hormone, the mother frogs had been “hugged” — a procedure in which human hands mimic the amorous embrace of a slimy-skinned male — and then their eggs fertilized.

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Now, Vaibhav Pai, a researcher in Levin’s lab, used an eyedropper to suck up the viable embryos, which floated. He left behind the duds, which lay pancake-flat.

The delicate work was just about to begin. With tweezers in his left hand, he nudged the embryos into place. He used his right hand to maneuver a needle, which he had melted and stretched to an almost impossible thinness. Once it was just inside the membrane, his foot pressed down on a pedal, and with a hiss, a tiny drop of liquid shot into a cell.

Hands sheathed in purple gloves, eyes pressed onto the microscope, Pai didn’t exactly look like he was doing the work of a software engineer. But that’s how Levin describes much of what goes on in his lab.

We’re used to comparing our brains to computers. It’s familiar territory to think of neurons shooting electrical signals to each other, establishing patterns that allow us to learn and remember — and we know that the paths of those tiny zaps of voltage can change when we’re, say, practicing a new language. The connections can shift without anyone going in and tinkering with the cells themselves, just as you can rewrite the code on a computer without opening it up and fiddling with the wires.

“Scientists in every walk of life … all had the same reaction to his work: He’s either going to win the Nobel Prize or prove the bioelectric code wrong.”

Tom Skalak, Paul G. Allen Frontiers Group

Levin extends that metaphor to all of our cells. Their electrical charges might not shift in a split second the way neurons’ charges do, but they’re still involved in cellular communication. And to Levin, they are the software — the rewritable code — that helps turn those collections of proteins into living, pulsing bodies of tissue.

By tweaking that code, he hopes to restore form and function both in the nervous system and elsewhere. As he put it, “If you want to control what the computer (or robot) does, yes, you could mess with the wiring directly, but why would you, if you knew how to program it … and control the flow of information?”

That was what Pai was trying to do on that day in December. The bioelectric signals of cells are controlled by doorways known as ion channels, which sit in the cell membranes. He’d already found that by manipulating ion channels — and so rewriting bioelectric software — he could convert one kind of tadpole tissue into another.

“Amazingly enough, they developed fully formed, functional eyes inside the gut!” he said.

Now, Pai wanted to see if he could use his skills with living software to correct birth defects in the brain.

A scared kid with asthma finds a calling

Mike Levin story
Brightfield image of a tadpole Vaibhav P. P/Tufts University

Levin had always assumed he’d be programming computers, not living creatures.

The assumption began, in some sense, with his asthma. He grew up in Moscow, and as a kid, he didn’t have access to medications that would ease an attack. When he started gasping, all Levin could do was try to calm down — not easy for anyone, let alone a little kid who can’t breathe.

So his father would take the back off of their ancient television set, hoping his son would be distracted by the cathode ray tube and the mess of wires. It worked. It also made him dream of piecing together machines.

“This is what hit me. Somebody knew how to put all this stuff in there in exactly the right way to make the cartoons come out the other end, and … I said, ‘Well, I want to be that guy,’” he recalled.

The leap from TV innards to computer code seemed natural. He’d moved with his family from Moscow to the suburbs north of Boston, and by the time he was 13 or 14, he was writing computer code to help a local metalworker with production.

He ended up writing all kinds of software: design software and software that could parse English commands, software for computer games and software that could help back up data.

But as Levin got deeper and deeper into programming, he found that machines were nowhere near as good at adapting to new situations as creatures. “If you look at living things, you see it right away: Under every rock is a bunch of little robots that do amazing things,” he said. “So it was pretty obvious that I had to study biology, because by looking at the way living things carried out computation, then we could understand the nature of what it means to control a complex system.”

“If you look at living things, you see it right away: Under every rock is a bunch of little robots that do amazing things.”

Michael Levin, biologist

He’d already been studying computer science at Tufts as an undergrad, and he added on a bio major. He fell in love with embryos by watching the development of sea urchins, thinking they were the most beautiful computers he’d ever seen. But he figured it was mostly for fun: He didn’t really know any biologists, and wanting to be one seemed a bit like wanting to go to the moon — a remote possibility, maybe, but not particularly feasible.

“I kind of went through college and grad school both thinking that this was just sort of a pipe dream, and was going to pursue it as much as I could, and eventually I was going to get kicked out or washed out or something and then just go be a programmer,” he said.

It never happened. Even after being told, in front of a roomful of fellow grad students, that he didn’t have enough background to do a Ph.D. in biology — “I turned purple by the end of that,” he said — Levin went on to learn the techniques of genetics and molecular biology in a prominent Harvard geneticist’s lab.

But he never forgot the moment, as a high school sophomore visiting the 1986 World’s Fair in Vancouver, when he stumbled across a second-hand copy of “The Body Electric,” in which an orthopedic surgeon described the history of the field as well as his own research on regeneration. Levin loved the book — but the most important part for him was the bibliography, which allowed him to track down previous research on bioelectricity.

The idea was an old one. In the late eighteenth century, Luigi Galvani famously reported that a spark could stimulate the “animal electricity” inside legs of a dead frog, making them twitch.

There had been plenty of advances since then — including, in the 1970s, the development of the vibrating probe, an 11-milimeter-long instrument that looked like ballpoint pen, designed to pick up the electrical currents near cells — but the research remained far from the limelight, and the tools were still relatively crude.

Part of the challenge was that cells and tissues needed to be alive in order to study their electrical circuits, and many of the standard methods in molecular biology involved killing a cell and dissecting it. Even the vibrating probe, revolutionary as it was, was not ideal for making the kind of map that would show voltages changing over time across many cells.

That didn’t deter Levin, and during his postdoc years at Harvard Medical School in the late ’90s, he started to dig into bioelectricity.

A quest to cure brain defects (in tadpoles)

Fast forward some 20 years, and countless published papers, and Levin has emerged as a pioneer in the field. But even in the praise he receives for his work — and he receives a lot of praise for his work — you can hear that the idea of bioelectricity as bodily software is not necessarily textbook material just yet.

Nadia Rosenthal, scientific director of the Jackson Laboratory, opened her talk at a recent conference at Tufts by saying she admires Levin as an “iconoclast.”

Thea Tlsty, a professor in the University of California, San Francisco’s Department of Pathology, remembered hearing him speak for the first time: “His presentation knocked me off my chair. It was brilliant. It was so ahead of its time: The research was stunning and eye-opening and extremely novel.”

“His presentation knocked me off my chair. It was brilliant. It was so ahead of its time.”

Thea Tlsty, University of California, San Francisco

Some scholars credit Levin with developing his own field by studying bioelectricity using the most up-do-date tools of genetics and molecular biology.

Yet, as Jessica Whited, a researcher at Brigham and Women’s Hospital and a collaborator of Levin’s, pointed out, the relationship between bioelectricity and proteins is a complicated one. After all, the ion channels that allow these voltages to change are themselves proteins encoded in the genome.

“Things become part of the mainstream when they’ve been clearly established as important,” said Cliff Tabin, a development biologist at Harvard who was Levin’s Ph.D. adviser. “Mike’s work is very innovative and very creative and could potentially be important, but it hasn’t been established yet.”

But he added that Levin is taking all the right steps to define the precise role of bioelectricity, and to figure out how we could potentially manipulate it.

It’s painstaking work. Pai’s embryos were a case in point. After he’d injected some with a chemical that induces brain deformation, he squirted in a liquid that would change the activity of ion channels, in the hope of restoring normal bioelectric signals.

In other words, he wanted to see if rewriting the software of brain development would override the birth defects he’d caused.

He’d done this on previous batches of embryos, and the results were promising so far, but it would be a while before he would have enough data to know for sure.

“Mike’s work is very innovative and very creative and could potentially be important, but it hasn’t been established yet.”

Cliff Tabin, Harvard University

When he was done with the needle, Pai carried the Petri dish over to the sink and tipped out the viscous liquid that helps keep the embryos intact during injections. “They have a ton of yolk, so they are heavy,” he explained. He rinsed them with frog water — the lab equivalent of what you might find in your local pond — and then placed them back in the fridge.

For now, he would have to wait.

But soon, when they had grown a bit, he would put these creatures under the microscope to watch how they had been affected by his manipulations, using a fluorescent dye that flashed as the electrical circuits changed. He would anesthetize the tadpoles and look at the white lines of their brains, speckled with dark, star-like pigmentation spots, looking for differences between those that had gotten the bioelectric fix and those that had not.

Eventually, he’d train the tadpoles to swim away from certain kinds of light, again comparing those two groups. He hoped that by tweaking the bioelectric signals — by reinstating the cellular software that permitted their brains to grow — he’d have repaired the brain defect he’d introduced into some of these tadpoles. If all went well, no one would be able to tell that the tadpoles had ever had birth defects at all.

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  • I’ll be interested to see the nexus between this and the Chi pathways managed in traditional Chinese medicine. Godspeed!

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