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Here is a post from friend-of-the-blog Igor Kulic. He describes the road that led to our paper on intracellular transport last year. If you don’t have a subscription, you can get the pdf from Igor’s site or free from PubMed Central. You can see from his fun, conspiratorial style why it’s such a pleasure to work with him. It also doesn’t hurt to have a talented theorist around to sharpen your intuitions!
-Andre
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We all know how intracellular transport works from textbooks—at least roughly. Molecular motors, kinsein and dynein pull their cargos (organelles and molecules) along microtubules from point A to B within the cell.
During this motor-hauling-a-cargo transport process, microtubules are assumed to be comparably immobile, at least far less mobile than the molecular motors along them. However newer data seems to sharply contradict this simplistic picture. And maybe we even have to overhaul it entirely. The road/vehicle distinction in the case of microtubules and their motors seems to be an artificial and inaccurate approximation. In fact the whole microtubule cytoskeleton seems constantly in a strange turmoil—a random very fast back and forth motion mixing and pumping everything through the cell interior.
Here is how it came about.
The story began some years ago when we analyzed the movies from the Gelfand and Selvin labs of fluorescently labeled organelles moving along microtubules in drosophila S2 cells. This is a nice well controlled actin-free model cell where microtubules are strongly polarized with their “plus” ends pointing radially outwards in small bundles (processes) from the cell nucleus to the periphery. After first visual inspections of some of the movies from these cells one thing hit the eye: The organelles were moving in a weird manner: erratic, back and forth like a drunken sailor along a line (the microtubule bundles). This happened seemingly without any plan, or bias towards any microtubule end.
As it soon turned out such a motion was actually well documented in the literature and the term “bidirectional transport” was coined for it. While nobody really knew what it was, people commonly speculated that it could be a peculiar form of competition—an epic struggle between the molecular motors kinesin and dynein sticking to the same cargo, fighting for the direction of motion. Even if we took this explanation for truth, it is hard to anticipate why the motion is so symmetric with kinesin and dynein being such two very unequal rivals having different biochemistry, running speeds, and forces. If you go into the details of this popular “coordinated kinesin-dynein tug-of-war” model you quickly notice that the explanation becomes increasingly elusive (with a similar incomprehensible voo-doo flavor of e.g. string theory).
The question we asked was, could this motion be the signature of something completely different? We had some initial idea, but were hesitant to push the heresy without hard evidence. So we went on the journey to better document the strange phenomenon. When we looked then more carefully at fluorescently labeled cargos we realized that some of them seemed to move in unison.
The strongly correlated motion of distant objects (several microns apart) allowed only one logical conclusion: somehow the “immobile” background—the frame of reference—must be in motion. However when looking at the whole cell and the microscope cover-slide we were sure that the motion was not due to a global displacement of the cell or any such artifact. Furthermore, the motion was only along the apparent microtubule direction.
Eventually we had collected enough data to conclude: The roads—the microtubules themselves—were moving in a very rapid random-oscillatory fashion with large speeds (up to 10s of microns / sec) and amplitudes (several microns). Despite its randomness, this microtubule motion is biochemically active (ATP consuming) and kinesin motor dependent—as we showed by knocking down kinesin.
We could in fact visualize this motion directly by staining the microtubules in chic mCherry-red. [see movie in less chic grayscale -AB] So microtubule motion was the reason for cargo correlations…
Interestingly however, sometimes coherently moving cargo pairs lost their correlation and distance between them ceased to be constant. We concluded that cargos did bind and unbind from such shaking microtubules and engage something that we called “hitchhiking” mode of transport. This motion resembles a randomly moving conveyer belt (microtubules) on which cargo is loaded and unloaded also in a random fashion. This eventually leads to a long range distribution of cargo throughout the whole system. [As Igor showed previously [arXiv] -AB]
So is all the transport in the cell “shook up” in this manner? We analyzed the statistical properties of cargo positions in time and found some characteristic power-law signatures of the microtubule shaking process. Using this method we came to the preliminary answer: Not all, but a substantial portion (>50-70%) of cargos in drosophila S2 cells is engaging in this exotic non-textbook form of transport.
How universal is the hitchhiking in other cells? There are some first hints that it could be very common in many cell types. The present answer is: we don’t know yet for sure… In any case we learned one simple lesson: Often you see things by … just watching.
More (and bigger) surprises are waiting to be revealed by cellular paparazzi yet to come. Never mind the umbrellas initially flying at your head, trust your eyes, rely on intuition.
It’s your turn now.
Dear friends,
I’ve just moved to Harvard and got settled in my new office. The first impressions : I am surrounded by a bunch of inspired nerds with eyes shining (through thick nerdy glasses) and I enjoy the atmosphere of being among my kind…
It looks like its gonna be a big party time for me here in the next year. I will mostly work with Great Guru L. Maha (devan). He is a real artist among the scientists and quite exceptionally inspired guy even for this place.
I ll also be (hyper) diffusing on the campus, catching interesting people and learning from them.
The other thing I want to figure out is: what the hack is this V.E.R.I.T.A.S thing that I see adds for all over the place? It must be something like the local A.A. or A.A.A. or Y.M.C.A ….. Anyhow, I will keep you posted on that.
Comment [3]
Despite their relatively sessile nature on macroscopic length scales plants are in fact quite motile on molecular and cellular level. They posses microtubules, actin filaments and corresponding molecular motors and use them to transport cargos through their cells pretty much in the same manner as animals do.
Interestingly plants (as animals) possess efficient motile organelles called axonemes that propel their sperm cells with a similar efficiency as in animals. Indeed plants feature all the basic components necessary to build muscles. So why did they “decide” not to follow this strategy? There is probably some deeper evolutionary mechanism behind this. My first guess: Muscle usage and maintenance requires a large energy throughput which might induce a supercritical entropy production in the environment if employed by every single species. This might render the whole ecosystem unstable.
Are plants indeed selfless evolutionary altruists dispensing with energetically expensive and aggressive muscle usage?
Of course we know of remarkable exceptions like the Venus flytrap not obeying the plant non-violence doctrine. The WMD of this rogue fellas seem to consist of an elaborate elasto-hydrodynamic system that generates a 100 msec super fast snapping of its “jaws”.
Another prominent way of moving in plant kingdom is hitchhiking. The essential philosophy behind is as simple as effective: Harness macroscopic fluctuations caused by other (motile) organisms to achieve motility without dissipating own energy. The list of hitchhiking plants is long and some of them are pretty stunning . In fact the Swiss engineer de Mestral was inspired by them to the extent that he came up with his Velcro mechanism. This was probably the first industrial bestseller driven by a truly biomimetic idea.
As kids we used to play with foxtail barleys (hordeum murinum). Although they belong to the same family of hitchhiker plants (as de Mestral’s Velcro muse Burdock) foxtail barleys are still exceptional. We used to put them between palms and by gently sliding our hands with respect to each other one could make the little green fella miraculously move uphill!
The origin of the underlying ratchet effect is interesting and is related to the geometric and elastic polarity of foxtail barleys surface structure.
I’ll post more on our foxy friend soon but here are already some appetizers (you need flash player >8 to view them):
1. Make a SEM journey on a foxtail barley hair and find out what makes it a ratchet.
2. See the barleys and other ratchet folks swirling around on a laboratory shaker. Note the strong directional component in their motion despite isotropic shaking.
To be continued…
Comment [4]
Biocurious is written by Andre Brown and Philip Johnson, since 2005. Content of the weblog is licensed under a Creative Commons Attribution-Share Alike 3.0 License.
