|
If proved, his model could explain why some cells grow and others die By lila Guterman For decades, biologists have thought of cells as life's jiggly water balloons: Push on a cell's membrane and it deforms, squishing the uniform liquid interior within it. But an independent-minded biologist is arguing for a strikingly different way to understand cells. He says that they more closely resemble the geodesic domes built by R. Buckminster Fuller. According to Donald E. Ingber, an assistant professor of pathology at Harvard Medical School and at Children's Hospital, in Boston, the cell's inner fibers push and pull on each other, influencing the cell's overall shape and how it reacts to external forces. If he's right, his architectural model could explain many mysteries of cell biology, such as why some cells reproduce and others die, or how a woman's skin cells grow when she gets pregnant. Fuller, an inventor who sought to solve design problems using as few resources as possible, popularized the geodesic dome: a light, strong structure made up of rigid rods connected in triangles. Unlike conventional brick-and-mortar buildings, which are stable because of gravity, geodesic domes maintain their shape by distributing tension equally throughout the structure. The rods in geodesic domes can each withstand both tension and compression. The artist Kenneth Snelson's rod-and-wire sculptures also use a balance of tension and compression, Dr. Ingber points out. Mr. Snelson uses the word "tensegrity" to describe this balance, which Dr. Ingber says applies to cells as well. In Mr. Snelson's graceful structures, cables are tensed between struts that bear only compression. A Snelson sculpture is a paragon of tensegrity, Dr. Ingber says, because it uses "continuous tension, pulling in all directions, but it's held stable because there's a subset of elements which can't be compressed." This balance of forces is as evident in the structure of the human body as it is in a geodesic dome, says Dr. Ingber. "We are 206 compression-resistant bones that are pulled up against the force of gravity and stabilized through a connection with a continuous series of tensile tendons, muscles, and ligaments," he says. The cell's internal scaffolding, the cytoskeleton, looks much like a Snelson sculpture, he observes. The cytoskeleton is made up of three different types of proteins linked together in a complex network. According to Dr. Ingber, the thickest protein chains, the microtubules, act like struts that bear compression. The finest proteins in the cytoskeleton, the microfilaments, seem to withstand the tensional forces, like the wires in a Snelson sculpture. Intermediate filaments, the third type of protein, hold the skeleton together, connecting the microtubules to the microfilaments. If Dr. Ingber is right, prodding the outside of a cell should affect the tension felt throughout the interlinked proteins. The protein network, he says, can account for the fact that physical pressure on the cell's exterior can cause changes deep within the cell, which are harder to explain if the cell acts like a water balloon. Such changes are key to everyday life. Pressure can govern whether a cell lives or dies by turning on a genetic program within the nucleus to dictate the cell's future. Astronauts' bones tend to degrade because the absence of gravity puts less pressure on their bones. A pregnant woman's skin grows to stretch across her belly in response to the physical pressure exerted from within. "There's no question that mechanical force regulates cell growth and gene expression," Dr. Ingber says. "The question is how." His enthusiasm for the principles of tensegrity extends beyond cell biology. In 1996, he founded a company called Molecular Geodesics, which uses Fuller's architectural principles to design new materials used in, for example, spinal-disk replacements. Dr. Ingber was first struck with the idea that the cell's architecture might be based on tensegrity when he was an undergraduate at Yale University in the mid-1970's. "I was taking a sculpture course the same week that I was learning how to [grow] cells," he recalls. He wondered why cells that grew flat in a petri dish would round out when he removed them from the dish, only to become flat again when transferred to another dish. When he saw a sticks-and-strings tensegrity model round out after having been pushed flat against a surface, he wondered if the similarity was more than coincidental. At the same time, experiments by others began to show that the cytoskeleton was filamentous. "In my mind, it was sort of self-evident that something like this must be going on," he says. He showed in the early 1980's that tensegrity could explain why a cell flattened out when attached to a rigid surface but, on a more flexible rubber surface, would contract into a ball, wrinkling the rubber. To model the cell, Dr. Ingber strung together six wooden dowels with elastic thread, forming a tensegrity structure. In the center of this "cell," he hung a smaller tensegrity structure, to model the nucleus. Then he sewed the ends of some of the dowels onto a taut, pinned-down cloth, mimicking a rigid surface. The model cell flattened down. But when Dr. Ingber released the pins to allow the cloth surface free motion, the model cell sprung back up to its original round shape, wrinkling the cloth below. Not only had Dr. Ingber's simple model simulated how cells behave on different surfaces, but the model nucleus also moved in a manner analogous to an actual cell's nucleus. When the cell was spherical,the nucleus hung from its elastic threads at the middle. But when the cell flattened out, the nucleus did as well, moving toward the bottom surface of the model cell. Models made with sticks and strings seemed like child's play, so Dr. Ingber set out to probe real cells. Measuring how a cell responded to being poked and twisted required developing delicate techniques for manipulating it. In 1993, Dr. Ingber's lab attached tiny magnetic beads to proteins in the cell's membrane. Some of those proteins attached to the cytoskeleton, and others didn't. When they twisted the beads that were not attached to the cytoskeleton, the cells "were very, very floppy," Dr. Ingber says. "But if you pulled on these [proteins] that were hooked up to the cytoskeleton, the cells would get stiffer and stiffer." The experiment, which was published in the journal Science, showed that mechanical force is transmitted through the cytoskeleton, Dr. Ingber says. A cell that resembled a water balloon would have responded uniformly regardless of where he poked it. Using a similar technique, Dr. Ingber discovered in 1997 that a quick yank on the proteins in a cell's surface that hook up to the cytoskeleton can cause changes deep within the nucleus. Within one second of pulling on the membrane, structures within the nucleus moved to line up with the direction of the tugging. Those findings suggested to Dr. Ingber that prodding the outside of a cell could control a cell's chemistry and even dictate its future. Moving the cytoskeleton by putting pressure on a cell's exterior might turn a gene on or off or speed an enzyme's reactions inside the cell, he reasoned, by distorting certain molecules or bringing distant compounds together. His lab has recently published in the journal Nature the results of experiments that suggest those ideas were right. When the researchers in Dr. Ingber's lab stuck magnetic beads on proteins in the cell membrane, they noticed that elements of the cell's protein-synthesizing machinery congregated near the bead. That region is now primed to make proteins, according to Dr. Ingber. His experiments over the years have begun to convince other scientists that his theory is not only aesthetically pleasing, but may even be correct. "The wide majority were very skeptical and extremely negative when I started 15 to 20 years ago," Dr. Ingber says. "Ten percent loved [tensegrity] from the beginning, ten percent didn't know what to do with it, and the rest hated it. That split, I would say, has flipped." George M. Whitesides, a professor of chemistry at Harvard University, praises Dr. Ingber's work as "genuinely original and interesting." Mr. Whitesides collaborated with Dr. Ingber on a series of experiments that showed that a cell's shape can control whether it lives or dies. "Don has been a leader in hypothesizing an analogy between mechanical structures that we understand — tensegrity structures — and a biological structure that we don't — the cytoskeleton," Mr. Whitesides says. Dimitrije Stamenovic, an associate professor of biomedical engineering at Boston University, was intrigued enough by Dr. Ingber's depiction of the cell that he developed a computer program to model the cytoskeleton according to the principles of tensegrity. The program mimicked well the behavior of living cells. "It has been tested in many ways and provided good predictions," he says. "In physics, people develop models and call them robust if they can explain two things, or maybe three things," Dr. Ingber says. "But [many biologists] really pooh-pooh at the tensegrity model as Buckminster Fuller's fantasy. Yet the tensegrity model predicts maybe 50 things." Among his critics is Evan Evans, a professor of biomedical engineering at Boston University and at the University of British Columbia. He says that no one has presented strong evidence for the existence of strutlike elements that can bear compression in the cell. Michael P. Sheetz, a professor and chairman of the department of cell biology at Duke University, agrees, citing experiments, published last year, in which Steven R. Heidemann, a physiologist at Michigan State University, poked at cells and found only local changes at the site of disturbance. "It disproves under those circumstances and those conditions that the struts are propagating force because of their rigidity," Mr. Sheetz says. The cell, with all its internal filaments, is behaving like a water balloon. Mr. Heidemann, who until recently was one of Dr. Ingber's staunchest supporters, told a meeting in December of the American Society for Cell Biology in Washington how he had become disillusioned with tensegrity as a model for all cells. "My complete expectation was that we were going to really put tensegrity in the winner's column, and it didn't happen," he said. However, he stressed that the architectural model may still be accurate for certain types of cells. Dr. Ingber criticizes Mr. Heidemann's experiments, saying they weren't performed in a manner that would bear on the tensegrity hypothesis. Both Dr. Ingber and Mr. Stamenovic say that they have new, as-yet-unpublished results that should shore up the tensegrity hypothesis by showing that microtubules can bear compression. "There are some controversial aspects of tensegrity in the biological world," says Peter F. Davies, director of the Institute for Medicine and Engineering at the University of Pennsylvania. "I think that's healthy." Even as he gripes that "people don't believe [that tensegrity applies to cells] because they don't want to believe it," Dr. Ingber acknowledges that key criticisms spur him on to further discoveries. "The way I respond is by devising experiments to hit the criticisms of the really smart critics. And that leads to Science and Nature papers for me, which has helped my career greatly. "In the end," he says of his critics, laughing, "I'm indebted to them." © 2000 by The Chronicle of Higher Education |