Does Tensegrity Make the Machine Work?

Images Courtesy of Donald E. Ingber Cell shape and function, such as directional motility, can be controlled by culturing individual cells on µm-sized extracellular matrix islands of defined geometry created using microfabrication techniques. New motile processes, stained for F-actin (green), extend preferentially from the corners when the cell is stimulated to grow by soluble mitogens. The nucleus is stained blue. A theory has only the alternatives of being wrong or right. A model has a third possibility: It may be right but irrelevant. --Manfred Eigen1 When molecular biology techniques propelled reductionism to a new height 30 years ago, scientists far and wide began isolating cellular parts. During that time, researchers described the cell as a membrane packed with protoplasm or a balloon filled with molasses, its contents moving around randomly. The idea that the cell was a highly structured, three- dimensional system was a notion that only a few initially adopted. In addition, the thought that cells could be linked to each other and an extracellular matrix was virtually unexplored. Furthermore, the suggestion that mechanical signals could be converted into chemical signals, contributing to cell physiology, was an undeveloped frontier. Since then, subcellular denizens have been inventoried and catalogued. Moreover, the recent convergence of multiple scientific disciplines, from the biological, physical, mathematical, chemical, and engineering sciences, has led biologists to revisit the cell from a holistic perspective. "For centuries, scientists have been taking nature apart and analyzing its pieces in ever-increasing detail," wrote Mark Buchanan in Nexus.2 "By now, it is hardly necessary to point out that this process of 'reduction' can take understanding only so far." CATCHING ON It's a point that Harvard professor Donald E. Ingber has promoted for years. In the early 1980s, Ingber, a trained cell biologist and medical doctor, proposed a new eukaryotic cell model.3 Presuming that cells can translate mechanical forces into physiological responses, he described the cell as a cytoskeletal-based system that provides organization and stability, based on the artist Kenneth Snelson's structural principle, later named "tensegrity" (tension plus integrity) by R. Buckminster Fuller.4 According to Ingber, "The term refers to a tensed network that stabilizes itself mechanically by incorporating other elements that resist compression."5 In the cell, says Ingber in an interview, "the microtubules act as compression-bearing struts, the microfilaments are tension-bearers, and intermediate filaments provide additional tensile connections in the structure that connect the surface to the nucleus." All told, the three work together with extracellular adhesions to keep the cell from collapsing. Ingber also wrote about structural signaling. For example, he showed that mitogen-stimulated cells can be switched between growth and apoptosis through mechanical distortion.6 Furthermore, Ingber will explore the implications of tensegrity for systems biology and biocomplexity in two upcoming articles in press.7 Viewing tensegrity on a larger scale, the human body accommodates gravity using interconnected compression-resistant bones with a continuous series of tensile muscles, tendons, and ligaments. To reach for the ceiling, a person must tense muscles from fingertips to toes. However, the body also consists of modular hierarchies: A severed Achilles tendon doesn't prevent a person from standing erect on one leg.8 The idea of tensegrity appears to be taking hold. A keyword search in the ISI Web of Science turned up 120 articles written in the past six years, compared to 34 in the prior decade. The newer articles look at tensegrity in bone, heart, and lung physiology, and protein folding. In one paper, a trained civil engineer, K.Y. Volokh, wrote about cytoskeletal architecture and mechanical behavior of living cells.9 "A specific architectural model of the cytoskeletal framework called 'tensegrity' deserved wide attention recently," he wrote. But make no mistake: Not everyone loves the idea. Kenneth Snelson, www.kennethsnelson.net EASY LANDING: Kenneth Snelson's sculpture on Baltimore's Inner Harbor embodies the tensegrity principle that Ingber has recruited into cell biology. CHEWING GUM Anybody who has reached for the sky or blown out his Achilles knows about tightened muscles or standing erect--but many scientists still question Ingber's downsizing of the body's skeletal system to the cell, tissue, or organ level. "Tensegrity is nonsense," says Micah Dembo, biomedical engineering professor at Boston University. "Most biological cells that people study in tissue culture have about as much structure as a piece of chewing gum on the sidewalk." Due to constant turnover of cellular constituents and the necessity of switching from one dynamic equilibrium to another, Dembo says that a cell is "not like a static architectural object except when dead." Steven Heidemann, physiology professor at Michigan State University, says, "Does the notion of tensegrity help people to understand the cell better? My answer is no." He notes that the cell has too many fluid behaviors for tensegrity to apply universally. Heidemann describes cell structure as "a beach ball filled with pick-up sticks." TAKING SHAPE Some agree that tensegrity is a chapter describing cellular integrity, but argue it is not the whole book. Peter F. Davies, professor and director of the interdisciplinary Institute for Medicine and Engineering at the University of Pennsylvania, espouses a more measured perspective on the tensegrity model. "Tensegrity is the most experimentally supported set of principles for the biomechanical behavior of the cytoskeleton and of cells in general," he states. However, he adds, it's unlikely that a tensegrity model alone would explain every biomechanical element that allows a cell to thrive and survive in its ever-changing environment. Despite some weaknesses, Davies says tensegrity is the dominant model currently out there, and one that he uses when designing experiments involving biomechanical transduction. Considering tissue morphology, Valerie Weaver, a Penn professor in the Department of Pathology at the Institute for Medicine and Engineering, has shown that cellular patterns in tissues are life and death issues.10 Morphology and polarity in tissue regulate not only cellular life and death, but also benign or malignant phenotype. In the abstract, she wrote: "Regardless of growth status, formation of polarized three-dimensional structures driven by basement membrane confers protection to apoptosis in both nonmalignant and malignant mammary epithelial cells. By contrast, irrespective of their malignant status, nonpolarized structures are sensitive to induction of apoptosis." Says Weaver in an interview: "We must spread the word about 3-D models of the cell." The importance of cellular structure is reflected elsewhere. One researcher, Paul Janmey, a Penn physiology professor, has localized many protein and lipid kinases, phospholipases and GTPases to the cytoskeleton after signaling.11 Also, recent work by Thomas Hope, University of Illinois, Chicago, reinforces the idea of the cytoskeleton as a highway: He has actually filmed an HIV particle using cytoplasmic dynein and the microtubule network to migrate towards the nucleus.12 In the beginning, Ingber had a tough time selling his tensegrity model. Grants were elusive, and so were audiences. "For a long time, scientists and research-ers just got up and walked out of my seminars," he recalls. "The only ones who stayed ... were technicians who said, 'I've seen what you're talking about in my tissue cultures.'" Susan Jenkins can be contacted at sjenkins@the-scientist.com. References 1. M. Eigen, The Physicist's Conception of Nature, J. Mehra, ed., Dordrecht, Netherlands: Reidel, 1973. 2. M. Buchanan, Nexus, New York: W.W. Norton & Co., 2002, p. 15. 3. D.E. Ingber et al., "Role of the basal lamina in the neoplastic disorganization of tissue architecture," Proc Nat Acad Sci, 78:3901-5, 1981. 4. T. Zung, ed., Buckminster Fuller, New York: St. Martin's Press, 2001, p. 32. 5. D. Ingber, "Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton," J Cell Sci, 104:613-27, 1993. 6. C.S. Chen et al., "Geometric control of cell life and death," Science, 276:1425-8, 1997. 7. D.E. Ingber, "Cellular tensegrity revisited I and II," J Cell Sci, in press, February/March 2003. 8. D.E. Ingber et al., "Opposing views on tensegrity as a structural framework for understanding cell mechanics," J Appl Physiol, 89:1663-78, 2000. 9. K.Y. Volokh, "Cytoskeletal architecture and mechanical behavior of living cells," Biorheology, 40:213-20, 2003. 10. V.M. Weaver et al., "ß4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium," Cancer Cell, 2:205-16, September 2002. 11. P.A. Janmey, "The cytoskeleton and cell signaling: component localization and mechanical coupling," Physiol Reviews 78:763-81, July 1998. 12. D. McDonald et al., "Visualization of the intracellular behavior of HIV in living cells," J Cell Biol, 159:441-52, Nov. 11, 2002.

Does Tensegrity Make the Machine Work?

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