"I live on Earth at present, and I don’t know what I am. I know that I am not a category. I am not a thing — a noun. I seem to be a verb, an evolutionary process – an integral function of the universe."
~ Richard Buckminster (“Bucky”) Fuller, in I Seem To Be a Verb
Sure, you’ve heard that regular stretching is good for maintaining muscle tone and flexibility – that it might even stave off ageing. But did you know that proper stretching of an individual cell is crucial for keeping it alive? In fact, if the cells get overcrowded and do not have enough room to stretch, they turn on “suicide programs” and just die. What’s more, there are some cells that will in fact live and even thrive in these congested environs… These are, of course, the universally dreaded cancer cells, which have lost all respect for normal social etiquette.
Professor Donald Ingber of Harvard Medical School and Children’s Hospital, Boston, has made it his life’s crusade to remind the biomedical research community, through rigorous documentation in system after system, that at the very minutest levels of cellular and tissue organization, we are not just bags of enzymes turned on and off by genes, but equally important, we are finely tuned and integrated micro-machines. Every cell, depending on its location and function, has a different composition of internal scaffolding, termed “cytoskeleton” (“cyto” for cell), which push, pull, anchor and stretch the cell in myriad ways, in response to extracellular as well as intracellular cues. In fact, this network, composed of a variety of cytoskeletal elements, is not unlike the tense strings of a well-tuned violin. From the development of an embryo into an adult organism with dedicated cells and tissues, to the growth of new blood vessels to nourish a nascent tumor, these micromechanical forces are constantly at play.
The concept of Tensegrity
As is so often the case with “outside the box” ideas, Dr. Ingber got his first inspiration not from a biology textbook, but rather, from the world of sculpture and architectural design, which have been his passions since he was a youth. It is while studying the work of a contemporary sculptor, Kenneth Snelson, as an undergraduate at Yale in the 1970s, that Dr. Ingber was first introduced to the concept of tensegrity (or tensional integrity). Tensegrity refers to structures whose integrity and stability are governed not by continuous compression or gravity (as in the case of our typical rectangular buildings or a stone arch), but rather, by a sustained balance between tension and compression. A tensegrity structure is mechanically stable not because of the strength of individual members, but because of how the entire structure distributes and balances mechanical stresses.
The concept of tensegrity as a building principle was first put forward by the maverick architect turned inventor and social activist, R. Buckminster Fuller. The grandson of a Unitarian minister, Buckminster Fuller was an early environmental activist. Very aware of the limited natural resources and the severe shortage of housing in poorer parts of the world, he searched for an architectural form suitable for building houses cheaply, with the minimum amount of material and maximum strength. He came up with the concept of geodesic domes. These almost spherical structures are made up of a framework of compression bearing struts, which are connected into triangles, pentagons or hexagons. Each of the struts is oriented so as to constrain the joints of the struts to a fixed position, thereby assuring stability of the whole structure. In nature, these types of structures are seen in icosahedral viruses, as well as the famous carbon 60 Buckminsterfullerenes or “bucky balls.”
There is another, somewhat more complex class of tensegrity structures – called the pre-stressed structures. It is this form that large animal biology seems to prefer. According to Dr. Ingber, pre-stressed tensegrity structures (henceforth tensegrity structures) pervade biology at all levels – from individual cells, through to tissue and organ architecture, to the architecture of our whole body. The concept of this type of tensegrity is best illustrated by Snelson’s sculptures, including the famous “needle tower” – a 60 x 20 x 20 feet steel and aluminium affair, which is a permanent exhibit at the Hirshhorn Museum and Sculpture Garden in Washington, D.C. These amazing sculptures, which often appear to float in space, are built with isolated steel bars, held together and suspended in space by high-tension cables. In these sculptures, all structural members are always in tension or compression, and it is this continuous transmission of tension and compression that holds the structures together. In the Snelson example, the rigid steel beams are compression-bearing “struts” that stretch, or tense, the tension-bearing cables. The cables, in turn, compress the beams.
Our bodies as works of art – cells, tissues and higher levels of organization as pre-stressed tensegrity networks
Our bodies have a very analogous situation, where our bones act like the struts and resist the pull of muscles, ligaments and tendons, and the shape stability (stiffness) of our bodies varies depending on the tone (pre-stress) in our muscles. Cells, again, show the same behavior on a microscopic scale. Here, the tensional forces are borne by the cytoskeletal elements – microfilaments and intermediate filaments; and these forces are balanced by the interconnected “fixed struts” – the intracellular microtubules and the extracellular matrix adhesions. Also, in a cell, individual filaments can change roles, going from tension-bearing members to compression-bearing rigid actin bundles, like the ones seen in the filopodia (points where cells make contact with the substrate and the extracellular matrix). Just like a soda straw model of a pre-stressed tensegrity structure, a cell can be flattened under external pressure, and then spring back to its almost spherical original form when the pressure is released. This is seen in many cells when they divide – they go from flattened substrate-attached forms to round “mitotic” forms and back. It is well known that one of the ways cells respond to their environment is through the so-called “stretch-sensitive” receptors and ion channels, which then initiate various intracellular signaling cascades.
Also, just like interconnected clusters of pre-stressed structures work as one continuous tensegrity network in Snelson’s sculpture (e.g., the “triple crown” in Kansas City, MO); so is the case of neighboring cells in a tissue, which exist in intimate cell-to-cell contact.
Cancer as a breakdown of the tissue tensegrity network
Cancer research, as a field, seems to be going through a kind of identity crisis. Oncologists and surgeons often assess the presence of a solid tumor by “palpation,” i.e., by feeling for a change in the firmness, or the mechanical properties of an organ. Pathologists most often base their diagnoses on changes in tissue architecture, e.g., tissue looking more disorganized, cells of a certain type being in a place where they normally shouldn’t be, a breach in an otherwise continuous structure, such as the basement membrane, etc.
However, because of the sudden explosion of information (sequencing of the human genome), technology and reagents, almost all the emphasis in cancer causation has concentrated on the rather reductionist approach of looking at individual genes and proteins as causative agents of cancer. While individual oncogenes, suppressor genes and modifier genes are certainly important, what is not very clear is how it is all interconnected and regulated.
Each of our cells, at any given time and place, has essentially only one of four fates: quiescence, division, differentiation, or death. Thus, all the estimated 20 – 25,000 genes in the genome of each of our cells carry out actions that, in concert with surrounding and far-away cells, push that cell to one of these fates.
To what extent the concept of tensegrity, and specifically, the loss of interconnected pre-stressed structural units within tissue, plays a role in cancer causation still remains to be fully investigated. And of course, it is too early to say whether any interventions may be found in the future that address this architectural problem, as an additional approach to treat certain types of solid tumors.