Looking to mechanics to explain what cells do and how they develop

Mavericks start out young, it seems. Once, after performing an advanced earth science experiment with other ninth-graders, Donald E. Ingber, M.D. ’84, Ph.D. ’84, arrived at a different result. “I wrote down 12,” he says, “even though they all wrote down 88.” The instructors informed the class that there were indeed two correct answers, but that among the few students who had discovered the less obvious solution, only one—Ingber—hadn’t scratched it out in favor of the more popular result.

“That was incredible feedback from a teacher,” Ingber says, “for people to do what they believe in and what they think is right.”

Ingber has found this message useful in the years since as he forged an often-controversial career. While most cell biologists use molecular techniques to tease out the genes at work in health and disease, Ingber, now the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Children’s Hospital in Boston, has championed the more radical notion that minute mechanical forces acting on cells—pushing and pulling, compression and tension—are crucial to their normal growth and function, and that disturbances in these forces can lead to disease.

“I’m a person who has always had a strong sense of how things work by looking at them,” Ingber says. “I’m very mechanically minded.” Ingber’s mechanical bent led to an early fascination with the work of another rugged individualist, R. Buckminster Fuller, in particular the concept of “tensegrity,” the complementary interplay of compression and tension that underlies the elegance and strength of Fuller’s geodesic domes.

While a Yale undergraduate, Ingber encountered in an art class the sculptures of Kenneth Snelson, in which pipes and wires, intricately arranged according to principles of tensegrity, create airy yet rigid forms that rise improbably into space. For Ingber, who was doing tissue culture experiments on metastasis with Alan C. Sartorelli, Ph.D., in the Department of Pharmacology at the time, Snelson’s pipes and wires called to mind the actin filaments and microtubules that make up the cytoskeleton—the internal scaffolding of the cell.

Seeing Snelson’s work had the force of a revelation, Ingber says. “I spent multiple two-week vacations in every library at Yale—the art library, the chemistry library, the physics library,” he says. “I bought every book in Atticus Bookstore related to tensile membranes or patterns in nature.”

Ingber gradually became convinced that mechanical forces, largely ignored since the rise of molecular biology, must play crucial roles in the development and behavior of cells. However, when he suggested to a postdoctoral fellow that cells might change their shape because of changes in tensegrity, he received a less than encouraging response. “He told me, ‘Don’t ever say that again!’” Ingber recalls.

But Ingber isn’t one to give up easily. As a graduate student in Yale’s M.D./Ph.D. Program, he sought out a more hospitable environment for his ideas, which he found in the laboratory of James D. Jamieson, M.D., Ph.D., professor of cell biology and director of the program. With Jamieson’s blessing, Ingber devoted a chapter of his thesis to tensegrity, and he is particularly grateful that one of his thesis advisors, the pioneering cell biologist and Nobel laureate George E. Palade, M.D., entertained his unconventional views with an open mind. “Instead of laughing, he gave me Buckminster Fuller’s book Synergetics, which he had received as a gift when he won the Nobel,” Ingber says.

When it came time for his residency, Ingber made the decision to stop his medical training to do research in the laboratory of M. Judah Folkman, M.D., at Children’s Hospital in Boston. No stranger to controversy, Folkman has fought his own long and lonely battle to prove his theory that blocking angiogenesis—the body’s recruitment of new blood vessels—is the key to treating cancer and a host of other diseases.

Shortly after Ingber joined the Folkman lab, a fungus contaminated a tissue culture experiment he was working on. Before pitching his dishes into the trash, Ingber decided to see whether the fungus had any noteworthy effects on the endothelial cells that were being used in the studies. It was a wise decision: the cells had retracted away from the fungus, and Ingber surmised that the fungus was secreting some substance that inhibited their growth. To Folkman’s delight, Ingber had happened upon a substance that led to the development of tnp-470, one of the most promising angiogenesis inhibitors ever discovered. tnp-470 showed potent antitumor activity, but it was shelved when Phase II trials revealed serious neurotoxicity. However, a young scientist now working in Folkman’s lab has recently modified the compound, and Ingber’s chance discovery may yet find its way into the clinic.

In a lab at Children’s Hospital where Ingber continues his study of tensegrity, the walls are lined with framed micrographs of such stunning beauty that they could hang in the upscale galleries of nearby Back Bay. In one, cells cultured on a surface designed to constrain various forces on the cytoskeleton have assumed a number of brilliant shapes, including multihued squares and lozenges reminiscent of Paul Klee.

Ingber believes he has finally homed in on the interface between physical forces and cell physiology. Many regulatory and signaling molecules cluster on the cell membrane around proteins called integrins, which anchor the cytoskeleton of cells to the extracellular matrix. In recent work, using miniscule magnetic beads that lock onto integrins like a molecular wrench, Ingber has shown that twisting integrins in different ways causes distinctive shape changes in the cytoskeleton, which in turn cause predictable patterns of gene expression. He also can switch cells between growth, death and differentiation by varying the degree to which cells physically distort when bound to a matrix through integrins.

To investigate these processes more deeply, Ingber has developed a femtosecond laser technique along with Harvard physicist Eric Mazur, Ph.D., that will allow him to perform highly selective nanosurgery on cells. Ingber says that the ability to obliterate some structures while retaining cells’ overall function will open completely new avenues to test his theories.

Ingber is confident that the rigor of his experimental work will eventually overcome the skepticism he has long faced, and that his ideas will slowly but surely enter the mainstream of cell biology. “A couple of big Science and Nature papers convinced a hell of a lot of people,” he says. “In science, even if it’s a wild idea, if other people start using it and find it valuable—if it works—it builds momentum.”