Gravitas for Geeks

Welcome to the Gravitas Publications Molecular Machines Blog. Several of these blogs will be written by Dr. David Keller (including this one). We plan to do quite an extensive series on molecular machines—including the biology and the physics of molecular machines—but for this first installment we will just show a few cool examples (of many, many possibilities). Later we’ll go into details.

A Movie is Worth a Million Words
This topic is impossible to understand without lots of good graphics, both movies and still images. Fortunately, lots of both have been made. Unfortunately, most of them do not belong to us, so we will just link to them. Some readers have a tendency to skip over such links, but we hope you will look at them all as they come up. Much of the excitement of this topic will be lost without them.

Inside a Cell: Organization and Flexibility Combined
All living things are built from cells, and cells are built from molecular machines. The inside of a cell has been likened to a factory or a city: it is densely packed and highly organized, with centers of command and control, centers of production, and systems of distribution and transport. Here is a pretty good picture of what a cell interior looks like.

Notice that it’s absolutely packed with stuff. Most of the stuff is proteins and nucleic acids, and most of these are molecular machines of various types.

“Bacterial Cell”

At first sight it looks pretty random, like a sack full of oddly-shaped rocks. The appearance of randomness is partly an important design feature: the fact that there are few rigid structures makes cells robust and flexible. They can change shape, crawl, squeeze through cracks, and even endure punctures and still survive (rather like the silvery liquid “robot” in Terminator II!)

But the appearance of randomness is also partly illusory: a cell is actually very highly organized into elaborate networks and pathways of cooperating, interdependent machines. We will occasionally talk about this higher level of organization in this series, but our main topic will be the individual machines themselves.

Overall, the construction of a cell combines two seemingly incompatible but very desirable engineering design properties: high functional organization (like a computer or complex electronic device), together with extreme versatility and adaptability. Imagine a computer that can crawl through a keyhole!

Here is a very visually appealing movie (with cool music too!) that shows some of what goes on inside a large, complex (eukaryotic) cell.

“Inner Life of a Cell”

I will not try to explain all of what is going on (it would be difficult and take us too far afield) but here are a few things to take note of:

1. There are many proteins on the cell surface. Some of these are adhesion molecules, like “molecular Velcro”, that allow the white blood cells (leukocytes, shown as blue knobby rolling balls in the first scene) to stick to the wall of the blood vessel instead of being swept along in the flow like the red blood cells (erythrocytes).

Some are “receptors”, i.e., proteins that transmit a message to the interior of the cell. For example, early in the movie an orange-and-green claw-like molecule (a type of signal molecule) sticks to a blue-gray cradle (the receptor). Simple as it seems, an event like that can be a switch that sets off vast changes throughout the cell, e.g, for the cell to stop rolling and start crawling, as happens at the end of the movie (see example here).

“Example”

Still other molecules are pores and channels of various kinds. Basically they are holes or valves that control what passes in and out of the cell, or between the compartments inside the cell. At one point in the movie some long “wires” with protein blobs on their ends are shown snaking through pores. The “wires” are messenger RNA (or mRNA)—temporary copies of genes—passing from the cell nucleus where they are made, into the outer part of the cell (cytoplasm) where they provide the code for making new protein machines. (The process of making new proteins is shown next. Notice how the green ribosome “reads” the mRNA as it makes a new protein.)

2. The prevalence of fibers, struts, filaments etc. Cells are crisscrossed by a system of cables and rods called the cytoskeleton. The cytoskeleton gives the cell its complex and ever-changing shape. The movie shows actin filaments (pale purple thin filaments) in three-dimensional arrays and also in more random networks deeper in the cell. Actin filaments are also shown being assembled from a cloud of individual proteins, being severed by another protein, and disassembling back into single proteins.

Microtubules—stiff hollow tubes (gray-green in the movie)—are also shown assembling (zipping up along a seam) and disassembling (peeling apart). Huge meshes of microtubules and actin filaments together give the cell its shape and, by constantly disassembling and reassembling, allow the cell to flatten, crawl, extend fingers of itself, etc (here is an example).

“Example”

Microtubules are also the “ropes” that pull the chromosomes apart when a cell divides. (A centrosome—two hollow cylinders at right angles surrounded by filaments that haul in the chromosomes—is shown too). Finally, microtubules and actin filaments are both used as highways or railroad tracks for carrying cargoes from point to point inside cells. The movie shows a vesicle (light blue balloon) being hauled along a microtubule by a walking molecular motor called “kinesin”.

3. Some common protein machines. The kinesin motor and the ribosome mentioned above are two of the more important and common molecular machines. Many bacterial cells are stuffed with ribosomes, each one continually making new proteins. We will learn more about these and other machines next time.

Finally a word of warning. All movies like this tend to oversimplify, if only because showing the true complexity would be so confusing nobody could follow it. For example, the movie shows everything moving and floating in nice clear water, but in reality it’s all immersed in a thick soup of other proteins and machines. If the movie showed everything you couldn’t really see anything!

Second, on several occasions—especially when the actin filaments and microtubules are assembling—the movie shows things that are simply impossible by the laws of physics. Again, the idea is to show what happens, but not necessarily how it really happens. Clouds of proteins rushing together to form an actin filament or a microtubule is no more realistic inside a cell than anywhere else. (In fact, those scenes might have been made by letting the filament disassemble and then running the movie backwards.) Similarly, the nice straight wires of mRNA that emerge from the nucleus would really be wadded, constantly wiggling tangles in real life. The nicely choreographed events that follow—the wires forming nice circles, the ribosomes jumping into place, etc—are random, stochastic processes in reality. The same sequence of events really happens, but not in the nice neat way it is shown.

None of this takes away from the movie. For the movie’s purpose it would have been foolish to try to show too much reality. But it is good to be able to recognize what is real and what is artificial. That will also be true for movies of individual machines shown later.

Types of Cells: Prokaryotes and Eukaryotes
Finally, for future reference, a bit about the (rather large and fundamental) difference between bacterial cells and all others. As every biology textbook will tell you, cells come in two basic types.

1) Prokaryotes or bacterial cells: these are small cells, roughly 1 um (or 1 millionth of a meter) in diameter. They almost always have a rigid cell wall but have no nucleus or other internal compartments: the inside of the cell is just one big open compartment. They have only a minimal cytoskeleton, much less complex than what was shown in the movie. They usually have a few thousand genes, each of which codes for one type of protein, i.e., for one type of molecular machine.

2) Eukaryotes: these are the cells from which all plants and animals are built. They are larger (roughly 10 to 100 um), and have many complex internal compartments including a nucleus that contains the chromosomes, genes, and DNA of the cell. Animal cells are covered only by a flexible greasy membrane (basically just a thin fragile skin), but plant cells have a rigid cell wall. Simple eukaryotes have less than ten thousand genes (e.g. about 6000 for free-living yeast cells) and the most complex eukaryotes (like the cells of large animals) have a few tens of thousands (e.g., about 25,000 for mammals).

Prokaryotes are usually considered to be simpler than eukaryotes, and in many ways they are. But both prokaryotes and eukaryotes have highly structured and organized systems of machines and control circuits, and neither can be considered “simple” in any absolute sense.

To get us started I am going to recommend that you all watch a little video produced by BioVisions at Harvard University called “The Inner Life of the Cell.” They do a great job showing a variety of molecular machines inside cells doing their jobs.

Enjoy!

Rebecca