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IT IS the most basic unit of life. Its very name signifies self-contained
simplicity. But, according to Don Ingber, a cell biologist from Harvard Medical
School, the cell has an image problem. 鈥淭he dogma has always been that a cell is
like a balloon full of molasses,鈥� he says. This simplistic view, Ingber
believes, does no justice to reality and leaves every cell of your body as an
unexplained mystery.

Why, for example, when you squeeze a cell and then let go, does it spring
back to its original shape? Why do lone cells take on different shapes on
different kinds of surfaces? And why do flat cells divide and round cells die?
Until recently, nobody could explain simple observations such as these. You
could look at the mechanics, and you could do the maths, but in the final
analysis, the sums just didn鈥檛 add up.

In the 1980s, a few dissident voices argued that the conventional model of
the cell as a fluid-filled sac was flawed. Ingber, at the time a graduate
biologist from Yale University, began talking about a special type of
architecture called tensegrity, which, he suggested, might explain many of the
apparent mysteries of the cell. Most people ignored him. 鈥淔ifteen years ago it
was really heretical,鈥� he says.

Though his views remain controversial, today Ingber is just as likely to be
on the receiving end of effusive praise as scathing criticism. 鈥淗is
contributions to cell and tissue biology are seminal,鈥� says Peter Davies, a
bioengineer from the University of Pennsylvania. For Ingber and his colleagues
have accumulated an impressive body of evidence to support their new
architectural vision鈥攁 vision which not only answers some long standing
mysteries of cell behaviour, but also reinforces the idea of a universal pattern
in nature. 鈥淭ensegrity applies at all size scales in the hierarchy of life,鈥�
says Ingber.

Back in the 1970s, when architects were busy pushing skyscrapers to their
limits, Ingber began to explore the more intimate architecture of eukaryotic
cells鈥攃ells found in plants and animals. There was certainly a lot to
explore. Open any biology textbook somewhere near page one and you will find a
complicated picture of a cell. Looking like a pock-marked face, the cell
membrane is the cell鈥檚 outer skin. Embedded in its surface are large protein
receptors which relay information between the inside and the outside of the
cell. Bang in the middle is the cell鈥檚 control centre鈥攖he
nucleus鈥攃ontaining the chromosome-bound genes. And between the nucleus and
the cell membrane is the viscous jelly of the cytoplasm, studded with
organelles鈥攖he cell鈥檚 own miniaturised versions of the body鈥檚 organs.

Depending on how much room the artist had left on the page, you may also see
the cell鈥檚 internal skeleton or cytoskeleton鈥攎ade up of a fine meshwork of
protein filaments. The cytoskeleton is the New World of intracellular
exploration. Twenty years ago it was being talked about as a source of
mechanical support for the cell, but that was about as far as anyone was
prepared to go. Nobody was really sure how the protein filaments connected
up with one another, or indeed with other parts of the cell.

Like generations of biologists before him, Ingber was indoctrinated with the
conventional view of the cell which says that cell shape and stability are
determined by the pressure of the cytoplasmic jelly. 鈥淧eople used to think this
because they used cell `poking鈥� to measure cell mechanics,鈥� says Ingber. 鈥淭his
is like poking my abdomen with a baseball bat to define the underlying structure
that is responsible for shape stability. I could be a skin-covered jelly and
respond similarly but I am not. The same goes for cells.鈥�

Radical architect

Although Ingber had a solid training in biology and cell mechanics, he also
looked outside science for inspiration, specifically to art and architecture.
Intrigued by the tensegrity structures of the radical architect and engineer R.
Buckminster Fuller and the sculptor Kenneth Snelson, he began to see possible
parallels between the mechanical properties of these designs and the cells he
was studying.

Tensegrity鈥攕hort for tensional integrity鈥攊s a construction
principle in which tensional stresses are distributed continuously throughout
all parts of the structure. In conventional buildings, most structural
components such as the internal and external walls are under compression through
the action of gravity. But tensegrity structures maintain a more even balance
between the opposing forces of tension and compression. Fuller used this pushing
and pulling of compression and tension in the design of his famous geodesic
domes. Rigid struts, forming an extensive latticework of triangles, pentagons or
hexagons make up the dome surface. Each strut in the lattice can bear both
tension and compression. Snelson鈥檚 amazing sculptures
are slightly different in that the forces of tension and
compression are borne by distinct structural elements. Rigid compression struts
are held apart, seemingly defying gravity, by tensed wires.

Ingber wondered whether the cytoskeleton of the cell could be wired together
in a similar way. The protein filaments that make up the cytoskeleton come in
three different thicknesses, like three different gauges of wire. But could they
work together like the struts and wires of Snelson鈥檚 sculptures? There was only
one quick way to find out. Using wooden dowels and elastic, Ingber built a
simple model of the cytoskeleton and put tensegrity to the test.

He wanted to see if his model could explain why lone cells change shape on
different sorts of surfaces. On a hard surface, like the glass floor of a
culture dish, the cell and its nucleus flatten and spread out like a fried egg.
In contrast, on flexible surfaces like rubber, cells become spherical and the
surface beneath them creases up.

Ingber鈥檚 basic model consisted of three perpendicular pairs of wooden dowels,
held apart by elastic cord attached to their ends. Cutting just one cord would
cause the whole structure to collapse. A smaller but otherwise identical
tensegrity model representing the cell nucleus was suspended inside the structure by elastic cord
(see Diagram). These cords mimicked hypothetical
connections between the nucleus and the rest of the cytoskeleton.

To simulate a solid surface, Ingber stretched out a sheet, pinning it down
onto a wooden board. Using a needle and thread, he then sewed the tips of the
outer wooden dowels to the sheet, so that the model resembled a pile of sticks
and string. These attachment points represented the cellular anchors known as
integrins that are embedded in the cell membrane and secure the cell to a
surface.

As the cytoskeleton flattened, the model nucleus followed
suit鈥攃oncertina fashion鈥攋ust as it would in living cells. And to
simulate a cell on a flexible surface, Ingber simply unpinned the sheet from its
wooden base. The model instantly sprang back to its more spherical shape,
leaving the attached sheet wrinkled and creased.

In this simple but elegant experiment, Ingber showed that a tensegrity model
could mimic the behaviour of real cells. He also demonstrated that the surface
the cell was sitting on was as important to the structure of a cell as the
architecture of its cytoskeleton. But his peers were underwhelmed. 鈥淚nitially,
people said to me: `It鈥檚 too simple. You鈥檒l not be able to say anything about
anything鈥�,鈥� says Ingber. While he was convinced that tensegrity lay at the heart
of cell shape and behaviour, he still had to persuade a sceptical scientific
community. And he wasn鈥檛 going to do that with sticks and strings.

Alternative lines of inquiry began to produce more direct evidence in favour
of tensegrity. During the 1980s, the cytoskeleton was, quite literally, being
illuminated in vivid greens and reds. Fancy fluorescent labelling techniques
were producing the clearest images yet of the microscopic meshwork of protein
filaments, shining out from the black interior of the cell. Occasionally,
spectacular images hinted at geodesic designs inside the cells.

Fluorescence microscopy also made it possible to monitor changes to protein
filaments in real time while cells were poked and prodded. By manipulating the
cellular anchors at the cell surface with miniature probes, Ingber and other
scientists revealed the extensive network of connections linking the cell
surface with the underlying cytoskeleton. As more biologists got hooked on the
delights of twisting and tweaking cells, tensegrity seemed more and more
plausible.

Today, Ingber presents a fairly detailed picture of the cell鈥檚 tensegrity
design. The thinnest class of protein filaments鈥攖he
microfilaments鈥攕eems to provide most of the tension. These thin,
contractile threads, which form a vast meshwork inside the cell, are constantly
pulling the cell surface in towards the nucleus at the centre. This inward force
is balanced by the hollow microtubules鈥攖he thickest of the protein
filaments鈥攚hich act as the compression struts. The final class鈥� the
intermediate filaments鈥攃onnects the small and large filaments together.
They also acts as guy wires for the nucleus, keeping it centrally located inside
the cell. Though immeasurably more complex, the architecture of the cytoskeleton
is, conceptually at least, similar to your average tent: there are rigid poles,
tensed sheets and guy ropes holding everything in place.

Of course cells, like tents, are normally found attached to a surface. In the
lab, cells stick to glass or plastic, but inside animals where they form tissues
like skin and muscle, they are pegged down to a protein matrix which resembles a
tangle of fine chicken wire extending between the cells. For many cell types,
Ingber believes that structural elements in this 鈥渆xtracellular鈥� matrix may bear
the compressive forces in much the same way that plant stems can balance the
tensional pull of a spider鈥檚 web.

Short, sharp tug

These force-carrying networks seem to offer direct and highly specific links
between the outside world and the very heart of the cell. Recently, for example,
Ingber and his colleagues from Children鈥檚 Hospital in Boston showed that
mechanical signals at the cell surface can be transmitted almost instantaneously
to the chromosomes inside the nucleus. Short, sharp tugs on integrins at the
cell surface produced rapid changes in the position and orientation of the
chromosomes, almost as if they were hooked on the end of a fishing line. Pulling
on other types of membrane-bound receptors that are not physically linked to the
underlying cytoskeleton produced no corresponding movement in the
chromosomes.

There were more surprises in store. Using a needle just 0.5 micrometres in
diameter, Ingber and his team pierced the nucleus and harpooned an individual
chromosome. As they pulled out their catch, one chromosome after another
emerged, like a magician鈥檚 handkerchief being drawn from a sleeve. All the
chromosomes were connected by a fine molecular thread, so that pulling on one
chromosome brought all the others out with it. Although Ingber and his
colleagues are not the first to observe these chromosomal connections, they are
the first to show that the chromosomes connect to the surrounding cytoskeleton,
and to establish the molecular identity of the threads. 鈥淲e confirmed that it is
DNA,鈥� says Ingber. He believes these DNA threads may help to position the
chromosomes as cells divide.

Not only are the chromosomes mechanically linked to the outside of the cell,
all the chromosomes are themselves hooked up to one another. Everything, it
seems, is connected. You can demonstrate this web of connectivity on yourself.
Grab some skin and give it a good tug. As you increase the external force, you
should (all being well) feel an increasing resistance. This apparently simple
phenomenon is called linear stiffening, and is another aspect of cell behaviour
that pre-tensegrity, left biologists stumped.

Now think tensegrity. As you begin pulling, a vast network of molecular
struts, wires and guy ropes line up in the direction you are tugging. Even the
chromosomes inside your distended skin cells are joining in, bundling up
together like sheaves of corn. Pull harder and resistance increases as more and
more elements in the scaffold are aligned. Let go and your skin springs back as
the internal tension in the molecular scaffold returns the elements to their
original positions.

If forces at the cell surface can be transmitted right into the depths of the
cell, including the nucleus, Ingber believes that tensegrity could provide more
than just shape and structure. Perhaps it could also be regulating the cell鈥檚
biochemistry?

The cytoskeleton could act like a system of mechanical levers, transmitting
information between the inside and outside of the cell at rates much faster than
chemical diffusion would allow. Many of the enzymes involved in cell growth and
protein synthesis are known to be physically linked to the cytoskeleton. If a
mechanical force can change the shape or orientation of these enzymes, it could
alter the rate at which biochemical reactions take place inside the cell. By
reaching inside the nucleus, these forces may even affect which proteins are
made by activating different genetic switches in the nucleus.

Could the cell鈥檚 internal struts and wires act as mechanical levers, turning
genes on or off? Nobody knows. But Ingber is convinced that genes and molecules
alone will never be enough to explain such perennial mysteries as how a
fertilised egg develops into a fully grown adult. 鈥淎s we get closer and closer
to sequencing the genome, we鈥檙e no nearer to understanding the big questions,鈥�
he says.

Evidence to support Ingber鈥檚 ideas is beginning to emerge. Mina Bissel, a
biologist at California鈥檚 Lawrence Berkeley National Laboratory has shown that
mechanical stresses can trigger dormant cancer cells to divide and proliferate
into tumours. And recently, Ingber and his colleagues found that by changing the
shape of an individual endothelial cell, they could activate different genetic
programs. A flat cell divided, a spherical cell died and cells of intermediate
shapes stayed put. In other words, the shape of the cell seems to tell the cell
what to do. Cells are likely to become spherical when they are cramped for room
in overcrowded tissues. In these circumstances, something called programmed cell
death will prevent tumours forming. At the opposite end of the scale, when cells
are thin on the ground they lie flat. At the site of a wound, for example, or at
the extremities of a growing embryo, cells must divide to fill in the gaps.
Perhaps architecture is a missing piece in the conceptual jigsaw after all.

Tensegrity structures combine economy of materials with remarkable strength,
and it seems unlikely that this could have escaped the beady eye of evolution.
In fact, tensegrity crops up throughout nature: take spherical groups of carbon
atoms known as buckyballs, for instance. They lack physical struts or wires, but
the carbon-carbon bonds are exactly analogous to the rigid struts of Fuller鈥檚
geodesic domes. Ingber believes that tensegrity may account for structural
stability in a whole range of things. 鈥淚鈥檝e even been to meetings where people
have been talking about geodesic quarks,鈥� he says.

At the other end of the size scale, our bodies are perfect examples of
tensegrity in action. We live in a constant balance, with the tensional forces
in our muscles, tendons and ligaments keeping our bones under compression. Every
time we get out of bed in the morning we become Snelson鈥檚 sculptures made real,
in all our gravity-defying glory.

Critical size

Although most scientists seem to accept tensegrity at the extreme ends of the
scale, the cell, which is somewhere in the middle, remains a sticking point.
Mike Sheetz, a cell biologist at Duke University in North Carolina, admires
Ingber鈥檚 creative approach, but believes the experiments can be interpreted in
several ways. 鈥淭he debate is not over yet,鈥� he says.

Recently, for example, Steve Heidemann, a cell biologist from Michigan State
University, and a one-time proponent of tensegrity, published a paper pouring
cold water on the idea. He and his colleague Robert Buxbaum reckoned that if the
cytoskeleton was a tensegrity structure, cutting one or two of the tension
filaments should cause the cell to collapse, just as Ingber had shown with his
prototype tensegrity model. So Heidemann and Buxbaum tested the idea by cutting,
poking, prodding and slapping cells called fibroblasts with glass needles.
鈥淩ather than behaving like a tensegrity structure, the fibroblasts behaved like
a bowl of jelly,鈥� says Heidemann. 鈥淎 direct assesment of mechanical behaviour
suggests a quite old-fashioned view of cellular structure.鈥�

Ingber is unimpressed. 鈥淭his simplistic idea that tensegrity can鈥檛 be right
because if you cut one string the whole thing would fall apart is just absurd.
This is a straw man that many critics have posed, probably because they know it
is easy to show that this does not happen in cells. All agree that the human
body is a tensegrity structure. Yet if I cut my finger tendon, the shape
stability of my legs, torso, arms and neck are not affected.鈥�

Evan Evans, a bioengineer from Boston University seems to share Heidemann鈥檚
scepticism. 鈥淢y impression is that biologists like Ingber鈥檚 conceptualisation of
cell material structure,鈥� he says, 鈥渂ut most physics and engineering types, like
me, find the implications of the details of Ingber鈥檚 language seriously
诲别蹿颈肠颈别苍迟.鈥�

Tradition can be a very difficult thing to budge. But Ingber and his
supporters remainin resolute. 鈥淚 predict that the value of his work will be most
appreciated in future generations of scientists,鈥� says Davies, 鈥渢he lot of the
creative pioneer.鈥�