The Intricate Design of Living Things

   So last time, I wrote about my experiences designing and implementing a fully functioning computer from the simplest circuits. It was a very enjoyable project and I learned a lot from it. But as complex as human designed systems are, they pale into insignificance when compared with the circuitry and engineering of living things. One thing that really excites me is that now that we humans have experience designing engines, digital circuitry and software over the last 100 years, we are discovering those same principles and methods have already been in use in creation for billions of years- but on a scale and with a power that is truly mind blowing. So that’s what I want to write about. The amazing design of living things.

   A great example is the bacteria E. Coli. While we tend to have negative view of this organism due to its role in contaminating food, it is actually an amazingly designed little creature. Here’s a picture of it. Notice the little “tails” coming off them? They rotating. If we zoom in on where that tail connects to bacteria, we can actually see it's resemblance to a motor. 

Picture and actual image of flagellar motor

   Just look at that. It’s an actual “outboard” motor and spins at up to 17,000 rpms counter-clockwise. It runs on a hydrogen ion imbalance engine. Outside the bacteria there a lot of hydrogen ions, while inside there are few (creating what is called a gradient). Like water flowing in river to turn a water-wheel, the hydrogen ions flow into the engine and in the process turn it. It’s a little more complicated than that, as the flow of protons don’t actually push the engines physically in the same way water pushes the wheel, but that’s the principle of the thing. (We'll look at how it actually works in a bit.)

   In the front of the E. Coli bacteria are a number of “sensors”, or receptors, that detect things like food (attractants) and dangerous chemicals (repellents). The motors spin the tails, moving the bacteria along like a ship. The sensors constantly sample the environment around it. If it detects food (or rather the concentration of food increases) straight ahead, it continues towards it. But if the amount of food doesn't increase or goes down, or contains a harmful substance, all the engines reverse direction and each tail turns chaotically, causing the bacteria to spin and point in a random new direction. This is called tumbling. Then the engines reverse direction again and the tails sync up into a single tail again, propelling the bacteria straight forward in that new direction sampling the new environment and starting the process anew. The fact that it can tell if it is moving toward or away from food means it is exhibiting a kind of memory, since it needs to compare the food concentration from a moment ago to that of now.

   Utterly mind blowing! How is this little single celled organism doing all that? How do its engines spin? What are they made of? How does it have a memory? How does it sense its environment and then control its motors? We humans create things that do those things but we use metal and plastics, circuitry and digital components to move and process and act on information. So again we have to ask the question, how does a single cell move? What are the processing components involved in it, especially since it lacks any kind of computing apparatus such as brain or nervous system that is found in more complex multicellular organisms? What does a single cell have?

Simple switches combined into logic
gates.

   If we look at human created circuitry, we find that at its basest level a switch. While I won’t repeat what I wrote about before in any detail, I will just say that a switch basically completes a circuit. When you flip a light switch on a wall, you are completing a circuit so that electricity flows into the bulb and it lights up. If we arrange those switches in specific ways we can create a circuit that displays simple logical behavior. We call that simple circuit a gate. One type of gate, for example, will only “light up” when both switches are closed. Because the 1^st and the 2^nd switch have to be closed for the light to come on, it is called an AND gate. These gates get combined into small functional components, which themselves are then combined into larger components, and so in. (To get a feel for this, see my previous post.) Ultimately, we are able to create a CPU, a computer’s brain that can perform a series of predefined actions on data and control the specific outputs. So what then is the equivalent of a “switch” in living systems that allows it to process (another word for 'compute') information?

 

Switching off the electromagnet
creates mechanical motion

 The same question can be asked about things like the bacterial flagella motor. Human made motors are made from various metals and wires, plastics and ceramics, all arranged in a way to generate mechanical motion. With an electrical motor, rapidly switching on and off an electromagnet in the rotor constantly repels or attracts elements in the casing, causing it to spin. The higher the voltage and strength of the magnets, the more powerful the magnetic field is and the fast the motor spins. Thus electrical energy is converted to mechanical movement. So then what is the source of mechanical movement for the flagella motor?

Chain of Amino Acids- Each segment has
a unique "stickiness"

   The primary answer to both questions is protein. The protein is the main component in living machines and circuitry and is what gives them their abilities. A protein is a chain of molecules called amino acids. These acids (there are only 20 of them used in living things) are like letters of an alphabet. Just as you combine (or chain) letters together in infinite (but meaningful) combinations called words and sentences, amino acids are chained together like a long train. Each amino acid has its own magnetic “stickiness” of varying strength. Imagine you have a segmented rope with some sort of sticky material on each segment. And imagine that some segment’s “stickiness” may be weak- just tacky to the touch. Others may be stronger, like duct-tape. And still others are in between. Now also imagine that certain segments stick tightly only to other certain segments. And that they may only stick weakly or not at all to still others. 

Chain of amino acids folding into
a protein

   You could now take this rope fold it into itself so that different segments bind to other segments. When you let the rope go, it keeps the newly folded shape. This is what happens with a chain of amino acids. After the chain of amino acids is completed, it is then folded together into a very specific shape that then holds. This folded chain of amino acids is what we call a protein. As you might guess, there are a nearly infinite number of ways to fold a protein. But for a protein to be stable and do its job properly, there are only a few shapes that it can take that will be stable and work.

   These components can then be fitted together into larger components, just as you would take bolts and nuts and metal plates and rockers and so on to make an engine. In fact, if you look back at the motor of E. Coli, all of the “mechanical” components that make it up are primarily proteins that have been folded into specific shapes and then bound to each other. So how do these individual proteins connect to each other? How does mechanical movement occur?

Protein with an available active binding
site. In (c) a molecule has bonded,
causing the protein to subtly change
shape.

   Let’s go back to our original newly folded protein made up of a chain of amino acids. There are all kinds of nooks and crannies in this protein. These spots (called active sites) are specifically shaped so that not just any molecule or protein can fit inside it. Only specific kinds of can fit, like a key in a lock. The fit is not just based on the shape but the “stickiness” of the segments in those active sites. When one comes along that fits, it physically and magnetically binds into that site. Now this new addition subtly changes the electromagnetic strengths of the various segments of the protein. In response, the protein may change its shape. Both proteins and molecules can cause these kinds of shape changes. A protein that causes a change in another protein (causing to do something like change its shape, begin or stop an action, and so on) is called an enzyme.

   It is this binding and shape changing that creates both the mechanical movement as well as computational processing of nano-machines and cells. The flagellar motor is made up of numerous components embedded into the cell wall. Part of the motor is stationary in the wall and is called the stator. Then there is the rotating rod running through the stator. Surrounding the rod are these repeating component pairs called MotA and MotB. Keep in mind that all these components are either proteins or groups of proteins formed into a unit. Exactly how movement is generated is not fully understood, but here's one a good theory (beginning at 1:16).

   When a hydrogen ion flows into the MotB channel, it binds to these acids near the bottom (depicted in blue). When that happens, MotB’s chemical structure changes, thus changing its binding strengths. The MotA structure (which is bound to MotB) now changes shape and place, producing a movement down on one side and up on the other. This is the first power stroke and it moves the underlying rotor incrementally. The hydrogen ion is now released from MotB and its structure changes again, causing MotA to return to its original position, producing the second power stroke and moving the rotor again slightly. With all the MotA and MotB pairs binding with hydrogen ions, changing shape and then moving, the underlying rotor spins, turning at between 6000 and 17000 rpms. The bottom part of the motor, referred to as Fli, controls the direction of spin. When the spin is counter clockwise it causes all the tails to sync up and move the bacteria in one direction. When clockwise all the tails spin randomly in all directions and the bacteria spins around facing random directions.

Assembling "batteries"- the rotation
moves the assembler units repeatedly.

   That same principle of using an ion imbalance (or gradient) is used many times in other turning structures. For example, inside the cell are many mitochondria. They are the power generators of the cell, producing the equivalent of battery packs to run much of the cellular machinery. Inside the mitochondria are numerous machines called ATP synthase. At their core, they are spinning structures that physically assemble the ATP “batteries” which are then shipped out to all over the cell. The spinning motion that drives the assembly is generated by an ion imbalance just like the bacterial flagella motor. You can see it working here, with the components of the ATP “battery” entering and then the completed assembly (showing that it is now “charged”) exiting:

Following the trail to higher concentrations
of food. Repeated tumbling and running-
the result of sampling the environment
and controlling the motors- gets it closer
and closer.

   So we now understand the amazing design of the motor and how physical movement is achieved. But how does the bacteria detect food or harmful substances in its environment? How does it compare that to where it has just been, exhibiting memory? And how does that information cause it to decide to keep going in the same direction or to choose a different one?

   Once again, the power comes from the protein’s ability to subtly change shapes when binding with other molecules or proteins. In the very front of the bacteria, embedded in its cell wall, are a number of protein receptors, These structures extend from just inside the cell wall to outside the wall. The part of the protein that is outside contains “locks” or active sites that will bind to certain types of substances. One type contains a lock that will fit a certain food. Another contains a lock that fits a harmful substance. There are a whole array of these different sensors in the front of the cell, all sampling the environment. When one comes into contact with something that fits that lock, food for example, then it binds with it. That binding causes a cascade of shape changes that propagate through the sensor unit so that the end that is inside the cell has also changed shape.

   Now the really ingenious thing is this. The sensors could just "wire up" directly with the motors. But that would bypass any information "processing" that would need to be done before a course of action was decided upon. So instead, an indirect connection is made, one that allows for just that thing. This design gives the bacteria the ability to process all of the sensory inputs (for all the various types of repellents and attractants) together before it “decided” whether to keep going or change direction. The amount of data it is able to process thus becomes truly staggering and is a complete representation of its environment. The “decisions” it makes then become the best possible ones for that area. That design also gave the bacteria something else: the ability to decide, not based on the concentration of attractants or repellents, but rather on whether that concentration was changing. It would consider the rate of change of attractants or repellents, not simple numerical concentrations (in calculus terms, this is a physical way of finding the derivative of a function at any given moment.) Thus it would always be seeking to move away from repellents and towards food. Why is that subtle difference so critical? If it was just acting on the concentration of attractants like food and it measured the presence of a small amount of food, it might just stay there. But because it was instead checking whether the concentration was changing, it would always move towards the richest concentration of food. And vice-versa with repellents. It is a strategy optimized for survival.

Simplified diagram illustrating
a single receptor, methyl
group binding, and control
of CheY.

   All of this is done using 3 stages of processing. 1) Chemo-reception: The binding of the attractant or repellent in the sensor protein(s). As I mentioned, this caused a subtle shape change that proceeded through the sensor’s body to the section that was inside the cell. 2) Signalling: At that end of the sensor is one unit that controls the changing states of a particular enzyme, CheY. The enzyme constantly automatically switches between one shape and another. One of those shapes (called the "active" one), binds to the Fli protein mechanism of the motors. If you remember, that Fli mechanism is what controlled the direction of the spinning flagella. When there is more active CheY binding in the motors, there is a higher chance that the motors will change direction from counter clockwise to clockwise, which will cause the bacteria to tumble, ultimately changing direction. The end unit on this sensor switches active CheY back to inactive. Then the CheY switches back on its own. And repeat.  3) Adaptation: When the sensor's switching is able to keep up with the concentration of CheY, the CheY stays inactive. Because it is constantly being switched to inactive, it doesn’t have an opportunity to build up in the motor. But if the sensor slows down its switching, then it can’t keep up. Active CheY builds up and begins to affect the motor and the chance of it changing direction gets higher.

   So then, what affects the rate of the sensor’s control of active CheY? Another subunit of the sensor is constantly binding and unbinding a molecule group called a methyl. Basically, it contains 8 spots for methyl groups to bind to. The strength and rate of that bonding can change. If it goes up, more methyl is bonded. If it goes down, less methyl is bonded. Here we arrive at the key point. What the sensor is exposed to affects that methyl bonding. When the sensor is exposed to an attractant, there are more methyl groups bonded and held on to. When it is exposed to a repellent, it releases methyl groups and binds any new ones more slowly. Thus, there are less methyl groups bonded onto the sensor. The end result is that the concentration of methyl groups reflects what the state of the environment was. It is a rudimentary memory of past conditions.

   So we have two sources of informational input to the sensor (and keep in mind that there hundreds of them on the surface of the cell and that they bind to many types of attractants and repellents.) 1) The actual state of the environment right now, based on whether it is bonded to an attractant or repellent at this moment. 2) The "memory" of the environment a moment ago- the methyl group concentration that indicated the state of the environment sampled previously. The sensor unit then responds to the combination of chemical changes from both inputs and its shape changes subtly. The resulting effect of the shape change is that it compares what it “sees” now to what it just “saw”. If the concentration of attractants has gone up, then the subunit that is controlling the switching off of active CheY keeps up, leaving it relatively inactive. And since CheY is inactive, it is not binding in the motors, decreasing increasing the likelihood of a directional change. Instead, the motor keeps on spinning steadily in a counter clockwise direction. Conversely, when the concentration of repellents has gone up, the switch control subunit slows down and active CheY builds up. The likelihood of a direction change increases. So there are hundreds of sensors all working independently, processing their data and contributing their results to the control of the motors. The net result is that the bacteria is able to go where it has the best chance to survive, eat, and reproduce.

Chemical pathways schematic of  cell
processes (link)

   What a truly brilliant designed system! And yet at its core information processing and computation, movement, and a myriad of other functions are all made possible by the same process. Proteins- chains of amino acids- changing shape as they interact with other proteins and molecules. The proteins don't "know" what they are doing. They are just following the physical laws governing electro-chemical interactions. Their behavior is regular and mathematically describable. But those 'simpler' behaviors of the initial folding, binding to molecules, and the resulting subtle shape change of a single protein have been connected to that of other proteins, creating 'simple' components, which are then assembled into larger ones, ultimately making possible a dynamic, responsive and adaptive complex system. The best analogy is the way simple switches don't do anything truly special. And yet combining them into functional units- and then combining those units into still larger ones- gives us a computer.

Transportation of proteins (in the
sack) along a "road" to a destination.

But that's where the analogy ends. The information that details how each protein is made (the sequence of amino acids that make up each protein) is encoded in DNA, whose duplication and transcription is itself an amazing thing. Little machines zip along throughout the process, aiding in the assembling and folding of the protein. Those are then transported to "construction" sites along "highways" and are in turn used to create whatever is required. And as parts and machinery break down, the cell creates new ones from raw materials, growing new machinery. The cell doesn't know what it is doing, any more than a computer knows that it is adding. It is only operating according to physical laws laid down by God and the algorithms for design he has embedded in the DNA. But the amalgamation of all of this complexity and design is life- a hard to define state that ultimately manifests itself through metabolism, response to stimuli, and reproduction. Truly a miracle.

Just look at these examples:

Translating DNA protein instructions (in RNA form) into actual protein.

Packaging and shipping proteins to locations in and outside the cell.

Assembly and dis-assembly of the "roadways" to various parts of the cell. Also displayed are motor proteins transporting sacks of proteins. We also see cyto-skeletal filaments- the equivalent of bones in a larger creature. These filaments give shape and stability to a cell and keep organelles (cell "organs") in place. The foundation "stone" of this skeletal frame is the centrisome, which contains 2 structures perpendicular to each other. This gives it great strength and stability so it can support the entire cyto-skeletal structure.

There are also some really great movies here:
http://www.youtube.com/user/ndsuvirtualcell

http://www.molecularmovies.com/showcase/

    This is just the tip of the iceberg. Just as the combination of sensors and their information processing capabilities gives E. Coli the ability to survive, eat and reproduce, so too the combination of single cells into colonies allows for the creation of still more complex, intelligent and adaptable creatures- up to and including us. The fact that our brains (the hardware) and our minds (the software OS) are the result of billions of single cells organized in the way they are (and all laid out in the DNA at conception) is nothing short of miraculous.