"Apparently biology cannot do without metaphor. Without stories of cellular function we have only analyses of the assays by which the facts of the case are determined. Borrr-ing. But for this very reason the metaphor must be measured vigorously against the quantifiable facts, and we must insist that an understanding of the mechanical processes always be available to unpack it. A happy metaphor is never eo ipso a happy explanation." Charles Stein
"The viruses, instead of being single-minded agents of disease and death, now begin to look more like mobile genes...We live in a dancing matrix of viruses; they dart, rather like bees, from organism to organism, from plant to insect to mammal to me and back again, and into the sea, tugging along pieces of this genome, strings of genes from that, transplanting grafts of DNA, passing around heredity as though at a great party." Lewis Thomas
Thirty years ago Lewis Thomas published a book of brief essays called "Lives of a Cell, Notes of a Biology Watcher" (from which the quote above is taken) that I think influenced a generation of would be biological scientists almost as much as "Microbes Hunters" influenced their teachers. And considering the current state of virology, this is not a cheerful thought for the future of cell biology.
Recently a group at Harvard decided to take the Lewis narrative into the 21st C. with a video depiction of the life of the cell, and of course it quickly made its way to uTube where Dean Esmay discovered it. His insticts on watching this admittedly "beautiful " piece where akin to those expressed in the Stein quotation above, and so he asked Gerald Pollack of the Univ. of Washington (Seattle) to look at it and perhaps send him a few words that he could publish on his weblog.
Below is what Prof. Pollack sent in response to this request. The video itself, and additional materials, are available at Dean's World here. [Otis]
The video depicts a multitude of cellular processes, all artfully choreographed as a series of molecular dances. The dances are charming, and surely worth viewing. One feels a sense of purpose, and even a kind of intimacy with the players.
But the play misleads. The detail of action implies that the activities keeping the cell abuzz are understood to a gnat’s eyebrow, affirming the air of confidence coming from cell-biology books — the sense that the essential mechanisms of the cell are well understood and completely in hand, and that all that remains is to fill in a few missing links.
But that is not at all the case. Even many of the fundamentals remain questionable.
Over the past half-century the predominant view of how cells function has been based on a framework that may be familiar even to those with only a low-level biology course. It goes like this: Surrounded by a membrane, the cell cytoplasm contains organelles and molecules such as the nucleus, mitochondria, RNA, proteins, ions, etc., all bathed in a sea of water. Traffic in and out of this water compartment is controlled by pumps and channels lodged in the cell membrane — each one specific for a particular type of molecule. The membrane, then, is the site of much of the critical action.
What you may not know is that this foundational framework is merely a hypothesis, and not a fact. Its essence is challenged by an increasing number of researchers, led initially by Gilbert Ling, Ludwig Edelmann, Miklos Kellermayer, Carlton Hazlewood and others, and the challenge is rapidly gaining support worldwide. Even Nobelist Albert Szent-Gyorgyi questioned central aspects of this hypothesis. Some have argued that membrane pumps are impossible – that they violate basic principles of chemistry and physics. Others have questioned whether membrane integrity itself is essential for cell function. Why? Because it turns out that even when the membrane is torn asunder, the cell continues to function.
Indeed, you might stop and contemplate that for a moment: even when the membrane is torn apart, the cell often continues to function. Many examples of this can be found. For example, when a muscle is sliced like a sausage, the region near the slice is injured as you might expect, but the regions distal to the cut survive quite well despite the absence of an enclosing membrane. The same has been shown true of nerves. And, when single cells grown in a culture dish are sliced in half with the fine tip of a tapered glass probe, half the cell dies after a day or so, while the other half continues to live, and even divides to produce progeny. All of this without a continuous membrane.
Another point that has been argued is that the inside of the cell is not merely a collection of molecules floating in water; rather, the cytoplasm is more like a gel — something akin to the inside of a raw egg.
This last point is particularly far-reaching. Even though the cell’s gel-like character is broadly acknowledged, it has also been broadly ignored. Virtually every cellular mechanism understood by contemporary biologists today rests on the assumption that the cytoplasm is an aqueous solution and not a gel. Under this presumption, constituent molecules float in a sea of water. They are entirely free to diffuse from place to place — from highly concentrated zones to less concentrated zones. It’s much like throwing a pinch of salt into the chicken soup: the salt diffuses to regions of lower concentration and the soup becomes uniformly salty. Likewise, in the cell, diffusion of various molecules from high to low concentration is implicitly figured to be a central protagonist governing numerous cellular mechanisms.
But, if the cell is a gel rather than a collection of molecular machines sitting in water and enclosed by a taut membrane, such a scenario cannot be. Molecules may diffuse easily through water, but they cannot diffuse very easily through a gel. Placing a suspension of molecules on one side of a blob of Jell-O, and waiting for the molecules to appear on the other side will require undue patience. Diffusion therefore is not likely to be a central player in cell dynamics — which instead require fast, responsive action.
Thus, biologists following orthodox approaches cannot hope to develop mechanisms that are valid, for the basic foundational presumption is wrong: molecules cannot diffuse easily. But if they cannot diffuse easily, then something else must be driving them, and that is the challenge. This situation harks of Galileo. The pre-Galilean notion of an earth-centered solar system was in good confluence with the belief system of the day, but it led to horrendously complicated planetary orbits with cycles upon epicycles — which of course turned out to be erroneous. Once the real foundation was established, the orbits became a lot simpler — and perhaps even correct.
And so it is with the cell. Building upon an invalid foundation has brought biological mechanisms to a level of complexity rivaling pre-Copernican epicycles. The beautiful video with which we started this discussion. That complexity can be appreciated by perusing the relevant chapters in any standard cell-biology book. The mechanisms they describe are extremely complicated — probably too complicated. Properly set, the video’s delicately choreographed molecular dances would turn into clumsy orchestrations of the cell’s many themes, each one out of tune with the others. The real-world result if this were all true would be a cacophony of noise.
By contrast, gel foundation yields a more satisfying framework, on which one can build for the future. It yields mechanisms that are not only in harmony with each other, but also in accord with a wealth of evidence — at least as much as the textbook views. I know I cannot hope to convince you of this in this short overview, but you might consider a few features:
- The gel foundation explains why the cell survives breaches in its membrane; Jell-O sliced in half remains Jell-O;
- It implies that a single generic mechanism (a gel phase transition) explains varied cellular actions;
- It shows how this simple generic mechanism can account for essential cellular functions (motion, division, secretion, etc.) — and can even explain the rapid movement of molecules through the thick gel-like cytoplasm.
For a more in-depth look, I believe you will find that the best information is conveyed simply and straightforwardly in my book (Cells, Gels, & the Engines of Life: A New, Unifying Approach to Cell Function), which has become something of a best seller and is being used as a classroom text in an increasing number of universities. Although it is technical, it is designed for the non-expert. You may read it and judge for yourself.
In closing: as charming as the video may be, it deceives. It depicts processes that seem simple, elegant, even graceful; but when the essence of each process is modified to fit the experimental evidence, and all processes are then melded together into what ought to be a functional cell, they add up to a confusing jumble. The cell is anything but a confusing jumble. The cell must function as a well-orchestrated ensemble — something akin to the delicately interwoven themes of a Bach fugue.
For any of you who may be interested, I encourage you to have a look at the gel/cell foundation (www.cellsandgels.com) and compare its functionality with the vaunted complexity of “authoritative” textbook mechanisms.
Gerald Pollack is Professor of Bioengineering at the University of
Washington. His home page is available here: Gerald
Pollack - Dean