January 14, 2009

Grow Your Own

Michael Levin, A92, studies the mechanisms that enable living things to develop and repair themselves, which could affect treatments for everything from loss of body parts to cancer

By Helene Ragovin

In the world where Michael Levin’s vision has come to life, people who lose a limb in an accident are able to re-grow it. Birth defects can be repaired in the womb. Cancer cells are detected and rendered harmless before they become tumors. Any number of other diseases are conquered as cells are altered and adjusted.

“We are asking the question of how biological shape is determined,” says Michael Levin. “Why do organisms look the way they look?” Photo: Alonso Nichols

It sounds like a fantasy world. But it’s not, as researchers at the Center for Regenerative and Developmental Biology take their studies in innovative and largely unexplored directions. While clinical applications are years away, Levin’s lab is making significant discoveries by seeking the universal principles governing the control of biological growth and formation.

“The applications are fairly broad; they touch on almost every problem of interest to us in medicine and biology,” says Levin, A92, a professor of biology who arrived at Tufts in November. Previously, he worked at the Forsyth Institute in Boston and was an associate professor of developmental biology at the Harvard School of Dental Medicine.

“We are asking the question of how biological shape is determined,” Levin says. “Why do organisms look the way they look?” His work focuses on embryonic asymmetry, biomedical control of regeneration and information storage in cells and organs.

All animals and plants develop from single cells into complex, three-dimensional objects. If researchers can understand what drives that process and what signals the cells send to each other to enable them to assume these shapes, then we can take advantage of those signals to change or modulate the shapes, Levin says.

Thus, scientists could be able to detect and repair errors in fetal development, curing birth defects. Or when someone loses a body part, “if you know how it was shaped in the first place, you can re-create it,” Levin says. This approach ultimately extends to a solution to the problem of aging, as failing tissues and organs could be replaced through regeneration.

The applications also apply to cancer treatment. “Cancer can be looked at, in part, as a disease of geometry,” Levin says. “The tissue has escaped the normally tight morphogenetic control of the organism; you have a tumor rather than a nicely patterned structure.” Being able to take command of that “shaping process” and correct it could stop the growth of tumors. “It’s kind of a unique perspective,” Levin says.

The potential significance of this unconventional approach has not gone unnoticed in the scientific world. In 2004, the journal Nature deemed Levin’s work “a milestone in developmental biology in the last century.”

While the majority of researchers in the field right now are focusing on stem cells and biochemical factors that function in specific contexts, Levin works on natural bioelectrical signals and the systems-level properties that allow these biophysical mechanisms to create the appropriate complex structure, stop when it is complete and maintain it against injuries during life.

“All cells, not just nerve cells, use bioelectrical signals to communicate pattern information to each other,” Levin says. “We have suspected for a long time that this is important.” Levin and his colleagues have made progress in understanding how electrical signals are involved in pattern formation, “and how you can tweak those signals artificially to get them to do what you want them to do.”

In other words, it’s a “whole new set of control knobs on the cells that we can use to get them to behave,” he says.

A spectacular example of this occurred during an experiment led by Levin’s colleague, Dany Adams, in which a tadpole was able to regenerate its tail at a point in its development when it normally would not have been able to do so.

“It was a ‘eureka’ moment,” says Adams, a research associate professor of biology who came to Tufts with Levin from the Forsyth Institute. “What we seem to have found was the ‘on-off switch’—it turned on not just the process of making a tail, but the regulation of that process. It made the tail the right size. Then it stopped. It was the right shape. It wasn’t too long.”

Are They Really Your Memories?

If you had to pick an underlying theme for all his work, Levin says, it would be how biological systems store and process information.

And that comes in at least two aspects, he says. The first, as addressed in the tadpole experiment, is morphological, concerning shape and how organisms encode three-dimensional patterning during development.

The other aspect involves information learned during an organism’s lifetime—memories. “We have unique way of approaching that as well,” he says. For that work, the lab looks at flatworms, which have impressive powers of regeneration—they can actually regenerate their brain, or a portion of it—and are also capable of learning.

“We can look at what happens to the memories when the brain is regenerated,” Levin says. “We’re looking to learn at a very deep and fundamental level what it means to hold memories.”

And that question—the relationship between brain tissue and cognitive function—has many implications, not just in the philosophical sense but for basic medicine. For example, there is talk among medical researchers of finding a way to use stem cells to replace damaged brain cells in individuals with degenerative brain disease.

What will it mean to have existing brain cells replaced by “fresh” stem cells in terms of an individual’s memories or personality? “Would it still be the same individual?” Levin wonders. The fact that memory and behavior can go awry when brain tissue is damaged “doesn’t mean that’s where the memories were,” Levin says. “That’s the sort of thing our work can shed some light on.”

“What we seem to have found was the on-off switch” that can vary the length of a tadpole’s tail, says Dany Adams, on right, who works with Levin. Photo: Alonso Nichols

It All Computes

What drove Levin to take his unconventional approach to biology? “Fundamentally I’m a computer engineer,” he says. “It was the way I thought about systems, long before I knew anything about biology.” He says he was also influenced by his experience in the fields of artificial intelligence and robotics, searching for ways to create self-repairing, adaptive artificial systems.

Specifically, his interest in bioelectrical signaling was bolstered by his discovery of some of the earlier literature on the subject. “People have been poking around on this subject for about 100 years,” he says. “There’s some good work through the last 30 years looking at how important these signals are.”

But that work was done prior to the emergence of molecular biology. “When molecular biology really took off, a lot of this stuff that I thought was very important really got left behind,” he says. Levin’s goal has become to apply the techniques of molecular biology to the study of bioelectrical signaling.

Ultimately, he says, it’s important to remember that both biochemical and bioelectrical signaling play vital roles in cell regulation and growth. “All the signals are functioning in the same system. Neither one is primary or secondary to the other. In the end, we have to understand the signals and their control networks in order to get the tissues to do what we want.”

Welcome Back

The move to Tufts is a homecoming of sorts for the 39-year-old Levin, who received his bachelor’s degree from Tufts, with a double major in computer science and biology.

“I’m thrilled to be here. I had a great time at Tufts as an undergraduate,” he says, a few days after his move to Medford in November, while workmen install lab equipment and some of the 15 other researchers who arrived with him scurry about, settling in amid the sound of drills and hammers.

Tufts’ emphasis on interdisciplinary research was the draw that brought him back, he says. His own work combines biology with psychology, computer science, engineering, physics, mathematics, health sciences—even philosophy. “I already had a number of collaborations with Tufts researchers in biomedical engineering and biology—such as professors David Kaplan, Barry Trimmer and Kelly McLaughlin—and wanted to expand those efforts.

“I wanted to be in an environment where the philosophers, the cognitive scientists, the engineers and the physicists were nearby.”

Levin was born in the former Soviet Union and emigrated to the United States with his family when he was nine years old. The family settled on Boston’s North Shore; he still lives within a half-mile of where he grew up, now with his wife, Kristin, and two young sons, Sam and Arthur. When the Levin family first arrived in the U.S., neither Michael nor his parents knew any English.

“It certainly was a lot worse for my parents,” he recalls. “But it was about a year before I could say what was on my mind. And the culture shock was greater than the language issues.”

Levin began his studies in experimental biology at Tufts by working with developmental biologist Susan Ernst, who became his advisor. In Ernst’s lab, he got his start as an undergraduate research assistant, and went on to study genetics at Harvard.

“Originally, I was interested in artificial intelligence and robotics, in making devices that were able to function automatically and repair and reproduce themselves,” he says. “It became obvious fairly quickly that we’re not remotely close to that. But if you lift up any rock outside, you’ll see creatures that do that. That’s what motivated my entry into biology. I wanted to understand the mechanisms that enable living things to develop, to assemble and repair themselves, and to improve their behavior based on the lessons learned from their environment.”

Helene Ragovin can be reached at helene.ragovin@tufts.edu.

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