Pharyngula

Many of you have already seen the gorgeous video below: it’s a spectacularly beautiful animation of the activity in a cell.

I like it, and it’s a useful illustration, but … there’s something fundamental that it gets completely wrong. So today I’m not going to praise it, I’m going to criticize it. It’s a substantial criticism, too, one that means I wouldn’t show this video in my classes without spending more time explaining the error than it takes to show it.

Here’s the central problem: molecules don’t behave that way. What is portrayed is wonderfully precise movement; it looks like the molecules are all directed, purposeful, and smooth. Take for instance the behavior of kinesin, that stalk-like molecule seen marching in a stately way down a tubule, with two “feet” in alternating step, towing a large vesicle. That’s not how it moves! We have experiments in which kinesin is tagged — it’s towing a fluorescent sphere — and far from a steady march, what it does is take one step forward, two steps forward, one step back, two steps forward, one back, one forward … it jitters. On average it progresses in one direction, but moment by moment it’s a shivery little dance. Similarly, the movie shows the monomers of tubulin zooming in to assemble a microtubule. No! What it should show is a wobbly cloud of monomers bouncing about, and when one bumps into an appropriate place in the polymer, then it locks down. I made this same criticism in my review of Mark Haw’s excellent book, Middle World, which does get it right. For purposes of drama and minimizing complexity and confusion, though, the animators of that video have stripped out one of the most essential properties of systems at that scale: noise, variability, and the stochastic nature of chemical interactions.

That’s particularly unfortunate, because it is the seeming purposefulness of the activity of the cell that has made that clip so popular with creationists. It fits with their naive notions of directed activity at every level of the cell, and of their denial of the central role of chance in chemistry and biology. It allows them to say ridiculous things like this:

Well, I am a biochemist and biochemistry studies molecular basis of life. And in the past 50 years, science has discovered that at the very foundation of life there are sophisticated molecular machines, which do the work in the cell. I mean, literally, there are real machines inside everybody’s cells and this is what they are called by all biologists who work in the field, molecular machines. They’re little trucks and busses that run around the cell that take supplies from one end of the cell to the other. They’re little traffic signals to regulate the flow. They’re sign posts to tell them when they get to the right destination. They’re little outboard motors that allow some cells to swim. If you look at the parts of these, they’re remarkably like the machineries that we use in our everyday world.

That’s Michael Behe, a biochemist. Biochemists should know better. There’s a reason modern biology programs are inseparable from a foundation in chemistry — that’s where our students are supposed to get a good foundation in ideas like equilibria and thermodynamics and the properties of molecules. I use that quote all the time in my lectures on creationism because it is such a perfect example of failing to understand a scientific concept. It’s also hilarious because Behe doesn’t seem to understand the meaning of the word “literally”.

I am not a biochemist, but even I understand the idea. I have had a little bit of training in neuroscience, though, so let me illustrate the real noisiness of the cell with an example that is familiar to me, the properties of ion channels.

Neuroscientists have a technique that allows them to examine the behavior of single molecules, called patch clamp, illustrated below.

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What’s done here is that you use a fine glass microelectrode with a tiny polished tip, and you press it against the cell, ideally in such a way that a single channel protein is isolated. Then the voltage of the cell is modified with another electrode, and the current through the patch is measured with the patch electrode. That is, if the channel is open, charged ions can flow through it — a current — and the electronics attached to the electrode will report back the fractions of an ampere moving across the membrane. If the channel is closed, no ions can move, no current will be generated, and 0 amps will be measured. It’s difficult in practice, but easy to describe and understand. We have a senseitive tool for measuring the state of a single pore in a membrane, whether it is open or closed or some state in-between.

Here’s what the results look like.

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Time is recorded along the horizontal axis, and current along the vertical. When the channel is closed, the current is 0; when it is open, it jumps up to a tiny, fixed value. There is a quantal nature to the current flow at this level, as a single channel allows a fixed number of ions to move through it per unit time, just as opening a faucet tap allows only a certain volume of water to flow. We can see that the transition state for an ion channel between open and closed is very brief; it flicks open and closed quickly. (By the way, the blue trace below the dark one is an idealized version, with the electrical noise removed.)

But now look at the whole trace, from beginning to end. Is the channel open or closed during the period of recording? You should answer that it’s both — sometimes open, sometimes closed. Like the kinesin molecule I described above, it’s jittery.

This is where the simple answers break down. The channel itself seems to be binary, either open or closed, but when we look over time and ask how it affects the cell, we see both states represented in our recording. The binary condition is actually translated into a kind of analog representation — we ask, “how often is it open relative to being closed?” As shown below, when we say it’s closed, we mean that most of the time it is in the closed state, but you can see that it also flicks open occasionally. When we say it’s open, we mean it is in the open state most of the time, as shown in the bottom trace, but yes, it still flicks shut now and then.

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This particular channel is voltage gated. That means that its permeability, whether it is open or closed, is regulated by the voltage across the cell membrane. When the voltage is positive, it should open; when it is negative, it should close. What we actually see is that the single channel is jiggling open and shut all the time, and that changing the voltage in a positive direction simply shifts the likelihood of it being open to a greater and greater value. We can plot the average behavior as a predictable increase in permeability even though the instantaneous behavior is either fully open or fully closed. The permeability of a channel is actually a measure of the probability that it will be open.

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From many small chance events, one can still get a predictable aggregate behavior. At a larger scale, triggering a small voltage change across a membrane causes a predictable inward pulse of sodium as many channels open. Watch a single channel, you see it is open with greater likelihood at the start of the voltage shift; record 3 at once, and they sum nicely at the beginning; record dozens or the thousands in the whole cell, and smooth curve emerges.

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This is what bugs me about the “Inner Life of a Cell” video. They’re portraying the behavior of single molecules, and the movie has them dancing a slow waltz, steadily moving through fixed patterns. It should look more like a mosh pit filled with meth addicts; real chemistry doesn’t direct single molecules, it shifts overall equilibria so that the random activity of single cells has certain probabilities of throwing them off a thermodynamic cliff into a new state. Those kinesin “feet” should have been pitter-pattering all over the place, occasionally falling into a more stable position that led them in a particular direction — what was needed was a portrayal of a hyperkinetic ratchet. Anyone who uses a microscope or looks at the activity of small numbers of molecules or studies thermodynamics and reaction equilibria (like, say, a chemist or biochemist) ought to be familiar with the stochastic properties of the world on such a small scale.

The closest example on a macro scale that I can think of is a casino. People go in and out of a casino, and they engage in many small probabilistic events. Some people win big, some lose big, and all states in between are represented…but the house always has its small, advantageous odds in its favor. They don’t shake down the crowd deterministically and demand a cut from each, instead what they have done is basically tipped the the reaction equilibrium gently to favor the transfer from one state — your pocket — to another state — their bank. From the aggregate kinetics of a great many transactions with only a tiny edge in one way, they have constructed a powerful and reliable siphon hose to draw off your money. (I suspect that’s also one, perhaps unconscious, reason why gambling establishments are fanatical about keeping out people with even a hint of a successful gambling system; it doesn’t take much of a shift in the percentages to reverse the flow in their money siphon.)

If you watch single individuals in the casino, rather than the rising total profits for the whole institution, you wouldn’t see a smooth and steady drain of money, though. Over long periods of time the trend would appear, but moment-by-moment? No. You’d see a herky-jerky random pattern of wins and losses.

And that’s what I would want to see portrayed in my ideal version of an animation of the chemistry inside a cell: not a ballet, a jostling mob on an uneven floor. Show me more noise and chaos.

By the way, I’ve always wondered if chemists might have a better resistance to the temptations of gambling than people who are less familiar with the mathematical properties of reaction equilibria. I know I find it impossible to gamble any more — visions of reaction kinetics run through my head when I see chips on a table, and I see bankruptcy and ruin at the thought of miniscule odds against me amplified by prolonged trials. Small numbers have the potential for great power, as the casino owners all happily know.

Comments

  1. #1 David Marjanovi?, OM
    February 3, 2008

    I have wondered if I believe in a Creator, should I be called a Creationist?

    Depends on if you intrude into the affairs of science. I wouldn’t call John Paul II a creationist — he believed the body had evolved and the soul was created; the existence of a soul in the first place is an untestable and probably useless hypothesis.

    Yet in every fiber of my being I sense that I have been created by something greater than myself.

    You don’t. You believe — you don’t sense. :-)

    Will I be able to prove it to anyone. It seems not.

    Relax. Science cannot prove, only disprove.

    But I also know with all the new knowledge we develop about the universe, there is yet a person out here who can tell me what started it all.

    Yep, but we’re working on it.

    Lots of great ideas, but no absolutes.

    Does it logically follow from this that the absolute “Yet in every fiber of my being I sense that I have been created by something greater than myself.” must therefore be right?

    “Only the Sith deal in absolutes.” — Obi-Wan Kenobi

  2. #2 David Marjanovi?, OM
    February 4, 2008

    Comment 36 says it.

    ——————

    Docere, that is to say Teacher.

    No, it means “to teach” (verb in the infinitive). To say “teacher”, you need magister… or doctor.