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From Yanofsky’s BEYOND BIOLOGY: INSIDE THE NEURON (Chapter I) Continued

Part II

Neuron as Executive

As we see the nervous system as a whole in its executive function, a central command and control station, then we conceive of the individual neuron as a single miniature unit in this decision making process. The neuron or single nerve cell is a mini-executive, a single soldier in an army of neurons. Nerve cells have different rank, depending on how exactly they connect with other neurons, how many other cells they connect with, and their specific location. But the analogy goes only so far, since there is no one cell generalissimo in the brain, rather a complex feltwork of cells. Each cell is subject to a complex of inputs. In most cases the individual neuron makes a binary decision, that is, at a given moment it is either firing or not, similar to a series of 0's and 1's in a computer. The computer analogy is even more obvious but even more imperfect, as we shall see.

If the nervous system is a complex of individual cells each of which at any moment is in one of two states, excited or not, the brain is nothing more than a large scale information processor of complex binary digits (bits). Understanding nervous function, hence thought and feeling, comes from data about the either on or off state of each neuron, and a knowledge of how these neurons are wired together (their anatomy). The oft used highly seductive brain computer analogy has, until recently, been very compelling and has a number of attractions, not the least of which is the resemblance of a logic machine to its maker which is the brain. In this computer logic machine, the brain sees a reflection of itself. A computer may think and if it can its thought processes must be much like the men who created it and may even be used to model for human thought processes.

In the computer, you have the human brain creating a functional machine in its own image. Therefore brain scientists may learn a great deal from looking at computers and logic circuits. Many aspects of neural function can be understood from the vantage point of computer design. To mention just one of many examples, we tend to look at brain function today as a composite of function involving modules, circuit boards essentially. Consciousness, as we have seen, involves various groups of cells, each group responsible for a specific function. The ARAS awakens the brain, the cortex gives content to consciousness, the emotional or limbic centers color consciousness, the frontal lobes as motivation and will, and so forth. Take out a module, say the limbic system, and consciousness will be altered, perhaps the subject will be awake and aware, but will lack emotion, will be a Mr. Spock or Data. The more complex the brain and the specific function you are examining, the more useful the concept of modularity. A group of neurons is a circuit board or even a chip.

Computer engineers have learned a great deal from looking at the brain as well. They are constantly trying to emulate brain function and are hungry for knowledge about brain circuitry. Parallelism in brain function was not appreciated until fairly recently. Your ordinary computer has a single microprocessor. All information must flow through this single unit which functions at great speed, but still, every piece of data must flow through the microprocessor in sequence, one bit at a time. Logic is thus 100% sequential. The brain however, is capable of handling a lots pieces of information in parallel, through many pathways simultaneously. Each individual datum in the brain is processed by computational standards, fairly slowly. In order to walk we must simultaneously and in parallel process three dimensional visual data, input from vestibular balance centers, proprioceptive input from our peripheral nerves to mention just a few information sources, then compute a whole program of muscle activations and then vary all of this over time, all this just to walk. No wonder computers have not up until this point been able to turn out anything resembling a full human gait pattern. Sensory input in the brain and motor output, are “massively parallel”. Innumerable microprocessors, that is, neurons and groups of neurons, are working in the brain, in parallel. In recent years, computer scientists, realizing the advantages of this major divergence in design, have built it into computers, which now boast vast arrays of microprocessors working in parallel.

Computers are growing more and more powerful, partly owing to designs that emulate brain function, but far outstripping human capacities in many areas especially data storage and retrieval and in calculating ability. It makes you wonder whether computers will one day be able to “think” and whether output of advanced computers, say computer speech, literature, or musical composition will always be as inferior as it is today from the output of talented humans. Do we expect computers to become high-speed initiators of perception, thought, feeling, and action, be conscious in other words? Or computers may even best people in some intellectual endeavors. Is it possible to build into a computer self-awareness, anxiety about death, an idea of personal boundaries and space, emotion, all the things that define awareness of biological Carbon based beings? Time will tell. Superficially computers, mechanical objects based on Silicon, resemble Carbon based biological machines. (Of course, we have created a cognitive tool in our own image!!)

As neurons exist in two states only, there is an electrical action potential or there is no action potential, so computer function can be reduced to a series of 0's and 1's that is translated on higher and higher abstract levels until with all the things computers do, word processing, mathematical reasoning, switching and other tasks this series of 0's and 1's is invisible. Brains and computers are both machines, so the argument goes, and the basic structure of each is not relevant to the similarities in their behavioral output. Carbon and Silicon are enough alike in any event and each machine, brain and computer utilizes arrays of binary elements that at any given moment in time are in one of just two states. The precise configuration of binary elements, invisible when you are looking at a specific task or output, determines content. This brain-computer analogy is at once very seductive and false, seductive because it works and is actually a good description to a limited extent.

First, the binary analogy is not strictly true for neurons. Though at any given moment a neuron is either firing or not, and hence may mathematically be assigned a '1' or a '0' to describe its state, this is nearly always an incomplete description of the neuron's state at a given time. The '1' for the firing neuron is straightforward enough but after firing almost all neurons will be unable to fire again for a certain length of time, which is the refractory period for that cell. The nerve cell has an absolute refractory period over which time it cannot be made to fire under any circumstances, and a relative refractory period when it is merely more difficult to excite the neuron. A given person, is only able to achieve an orgasm at a certain frequency. For a time you may try to excite him and get no response at all. Over a longer period of time, it is difficult to excite him though that can be done. The neural action potential is similar to an orgasm. There are the absolute and relative refractory periods. The refractory period for neurons is different for each cell.

Further, at a given moment, a neuron is at a certain state of excitation. A mathematical description that assigns a single value to a neuron dependent on whether it is firing is not completely describing that cell. Superficially neurons resemble Silicon based machines whose states may be represented as a series of "all or none", firing or not firing, '0's' and ‘1’s’, but mathematical models may not take into account that at any given moment a neuron is more or less easy to get into its firing state, it is more or less excitable. We shall see that excitability can partly or wholly described by the current state of depolarization of the neuron. The neuron responds by adding up in some way all of its inputs, typically synapses, excitatory and inhibitory, which can run into the thousands for an individual neuron. If it has only just fired, it can't fire again. In addition, there are global factors that modify neuronal excitability including among many things, fatigue, hormone and drug effects, availability of energy, and Sleep/wake State, appetite, and satiety. For example, an animal that hasn't eaten in a long time is hungry and we may say accurately though in a simple-minded fashion, that neurons in a putative hunger center are poised for action.

Not all neurons are locked into a binary paradigm anyway. Some make a graded electrical response. Some of the light receptor cells within the retina of the eye function in this way, but also many other nerve cells particularly sensory cells. Nerve cells store data in a number of ways. Neurons that we know about are affected by electric charge in individual cells, but another possibility is to change in electrochemical relationships with neighboring cells. There is good evidence that changes within the nervous system are induced internally not only via the acquisition of new information (learning or change in software) expressed in changes in electric and chemical signals, but also in changes in structure. Nerve cells and synaptic connections between them form and break down over time. There are also permanent changes within nerve cells that occur with environmental change and in learning. For example, it is thought that learning may involve synthesis of intracellular chemicals such as RNA. Unlike the array of binary electrical elements within a computer, neurons are influenced by supporting cells especially changes in other numerous cells called glia (for "glue", the cells that help bind neurons together and perform myriad other functions).

EVEN ON A CHESSBOARD:

Nothing illustrates the differences between the human brain and computer as well as the game of chess. It should be emphasized that for most fields of endeavor the computer, even for modern machines, is so much more primitive than the brain there is no means for comparison. But chess is an artificial situation in which moves are confined to an eight by eight square board and pieces having restricted and well-defined geometric moves in only 2 dimensions, a task perfect, or so it would seem, to pit a calculating machine against a human brain. In real life we work in three dimensions and consider many divergent inputs at once, but even in the limited field of chess, profound differences can be seen between the workings of a conscious machine which is the human brain and a computer.

You don't have to know much about the game of chess to appreciate a difference but it helps. Chess is a game of strategy that involves analyzing one's position and a specific sequence of moves that needs to be accomplished to maximize future positions. It is meant to simulate a battlefield except that it is, eminently sequential. A real general needs to manage a number of changes occurring at the same time, Not so on a chessboard where each move occurs in sequence, hence chess should theoretically be a again a perfect task for a computer since moves are, by nature, sequential. The chessboard has become the standard field to pit brain power against computer power. It's great too because it shows fundamental differences in action between brain and machine.

A human plays the game by developing a strategy and pursuing it. The human chessplayer is a schemer capable of acting on a number of hunches at once. He looks at his position on the board, sees an opportunity and makes a plan to accomplish a perceived goal. In short, he strategizes. He may very well know his opponent and his weaknesses but the most important element is that a person keeps a specific goal in mind and makes plans on how to attain it. He may covet control of a specific space or region, say at the center or the board or may need to capture a certain piece. However a computer is a machine and so has no goals or plans. For a computer chess is a particular situation translated into numbers and values. To plan its next move it will have to evaluate its position and have some means of comparing the relative advantages and disadvantages or outcomes of all of the possibilities for subsequent moves. Each of the possibilities is assigned a relative value which and these numbers are compared, determining the next move, so that a souped up calculation is made to simulate human behavior. The computer is a calculating machine that compares relative values nothing more, but has to look like it is "deciding" on a move, which it isn't, what it is really doing is picking an alternative based on a numerical comparison of an outcome. The computer looks at the possibilities for a next move, comparing, depending on its size and power, what may happen one, two, three or more moves into the future. The bigger the computer the more calculations it can do in one second, the more moves into the future it can compare and it can look at an enormous number of alternatives which no human can do.. The bigger the computer, the faster its microprocessors, the more microprocessors there are, the more calculations it can do, the more moves it may compare, and the farther it can look into the future, the better human chess player it can beat. You can build a huge computation machine that will have all the advantage against a human player. Put in a load of microcircuits and perfect the software with appropriate input from the best players. The idea of using a big machine with rapid as possible calculation is called brute force and as things now stand it is the major method by which calculating computing machines compete against humans. And the machine won't make any stupid human errors either.

The interesting thing is that while computers can easily defeat human chess players of average ability, at this point they are not better than the best human players, the grand masters. In February of 1996 there was a well-publicized tournament between "Deep Blue" an IBM machine and the grand-master Garry Kasparov. Kasparov lost the first game, but he later won the tournament not through his incredible calculating ability, the machine was far faster than he was, but by strategizing, perceiving the weaknesses of his computer opponent, learning about the methods used and where they fell through. It is significant that he defeated the machine only later on and not in the first game that he had to learn about the weaknesses of play, that is that there was no conscious strategy at all for the machine only numerical comparisons, hence no design, no goal in mind and method to attain it. This concept is akin to motor planning, scheming and goal directed behavior which behaviors in neurology are attributed to the frontal lobes of the brain, one of the major factors that makes us human. You can't talk about a computer having tactics, or plans, not at least at this stage of the game, even on the limited eight by eight field of chess let alone in real life.

The final denouement is that in May1997 Kasparov was narrowly defeated by Deep Blue after each side won a single game (there were also three draws). This is a very close record. Some say that Kasparov at one point lost his nerve and conceded in one game before he was sure he’d lose. The computer had no nerve at all. In fact the major advantage the machine has, is the lack of psychological weakness and doubt that we are all subject to. The computer doesn’t make silly mistakes and isn't influenced by sickness, or mood. It will capitalize relentlessly on the mistakes of its human opponent.

Deep blue ended up winning its 6 game rematch with Kasparov, not by much, with a score of 2.5 for Kasparov, vs. 3.5 for the machine. There were three draws with Kasparov winning the first game of the set, the computer the second and sixth. The design of the IBM computer, the RS/6000 was ‘massively parallel’ meaning there was an array of microprocessors capable of analyzing bits of information simultaneously, not only sequentially as would have to occur if there were a single processor. Another thing the computer had in its favor was brute force, deploying tremendous computational power. The RS/6000 IBM machine could examine 200 million movers per second, which is a little faster than Kasparov’s brain. Moreover the machine was able to make up for its lack of strategy because built into its design were algorithms specifically made to defeat Kasparov himself, to capitalize on his weakness. Could the same machine defeat any other chess grand master?

The human vs. the computer in chess brings up the same arguments as were raised in man’s competition with bacteria and insects. Does the human brain which can learn and perform acts by volition, design and the deliberate strategy, have the advantage over a machine capable of examining millions of possibilities but without an aim or a goal? Bacteria and insects can mutate many orders of magnitude faster than man, exploring millions of possibilities, though quite stupidly, along the way. Man doesn’t muddle as much. He designs, but at the end, one wonders if the action by design is any better than the brute force exploration of all the myriad possibilities. Which method is ultimately more adaptive, strategy, design, intelligence or brute force? Will man win against arch bio-rivals bacteria and insects? Or you can even generalize and ask whether our world or the cosmos developed merely from the exploration of myriad possibilities or is everything the culmination of some design. The jury is still out.

Figure 1: Which will win out, the brute force examination of myriad possibilities, or the grand design?

In a sense the computer is a high-speed exploiter of possibilities though its process is aimless. A computer has no goal of its own, unless a human gives it a goal, no strategy. The computer's inability to function as competently as the human brain in less structured areas that is as its own expert has been a major disappointment. Artificial intelligence has been discussed for a very long time, and for a long time seemed within reach. There were high hopes within the field just a few years ago. Now the term is anathema as the fondest hopes and dreams have failed to become to fruition. Originally computers promised to replace humans in vast areas of intellectual endeavor. Developers of systems of artificial intelligence would, it was thought, create human reason machines that would replace highly skilled people in various fields. In medicine computers would replace experienced clinicians, and make unerring diagnoses. At the very least they would have access to huge banks of data and would not be subject to human error. Machines could take the drudgery out of diagnosis and make it more precise. Engineers, architects, and attorneys would become similarly obsolete.

As early as 1963 Joseph Weizenbaum at M.I.T., introduced a program called Eliza, designed to simulate questions of a psychiatrist. Eliza was not about to replace your analyst but was tongue in cheek, more of an intellectual sleight of hand. The program merely re-questioned the human subject utilizing key verbs and nouns culled from his previous response. "How are you feeling today."; "I'm feeling down."; "Can you tell me more about why you're feeling down today." This program had been able to fool human subjects who did not recognize that there was no cognition driving the programs responses, only the return of phrases in the form of questions. The quest for computerized simulation of human thought processes has turned out to be a giant disappointment, as early workers in the field made a series of promises that could not be kept. Major strategies involved what are known as rule based systems. The idea was to compile a set of rules used in reasoning within certain fields. Next you mix in a large data base to utilize these rules (computers are particularly excellent at storing and retrieving huge quanta of information) and create an algorithm or set procedure for following these rules to recreate the mind of an expert. In medicine a matching system may attach various numerical weights to symptoms and physical findings using programmed rules to determine a diagnosis. One can even alter the numerical weights assigned to these rules in order first to reproduce the competence of human experts and later to outperform them adjusting these values according to the success the program experiences when confronted with certain specific situations. Modifying the numerical value assignments of various characteristics is but one way a program can be made to “learn” or alter itself in order to be made to perform as well as or better than an expert.

However, while they have been useful as educational tools such systems have mostly failed to replace expert opinion. One famous example called "Mycin" attempted to diagnose bacterial infections on the basis of data presented. Unbeknownst to the creators of such systems, human experts don’t usually follow a given set of rules. We may teach our medical students to follow rules, and there is a certain basis of factual knowledge that is necessary if we are to perform an expert function. But there is also a stage if a human is to function on anything but the most rudimentary level, where rules become expendable and are no longer followed by practitioners. Experts function differently than beginners in that they depart from the program when called to do so. A student masters a subject by learning rules only to discover later that his older colleagues function at an even higher level by not following these rules precisely. Indeed, the more advanced practitioner may have cast away many rules that he depended on to learn the ropes at an earlier time in his career.

I often find medical students and residents baffled by a therapeutic course set by an experienced staff member. The experienced practitioner may not follow the rules in any precise manner but does better by the patient. In teaching examination of the patient we always have students go through a certain sequence which they initially follow closely so as not to "miss" any specific part. However all experienced clinicians find themselves looking at many aspects of the patients simultaneously, and if we're worth our salt, honing in on the particular problem(s) confronting us. In this way one misses very little, but an awful lot of irrelevant information is relegated to the scrap heap and may not be worth mentioning. You need to know what is and what is not important. In outlining for the novice precise rules utilized in recognizing disease, certain findings invariably mean more while other critical elements while usually noted, are not fully appreciated. In many instances an experienced person can make a diagnosis almost instantly without resorting to rules at all. A certain pattern of speech may make to diagnosis of amyotrophic lateral sclerosis almost unmistakable. Similarly an experienced mechanic knows before he opens an engine that a certain tapping sound comes from a loose valve cover. This is the facility of recognition which computers are not as competent at as humans. Computers follow rules exquisitely well, much better than medical students, but recognize faces and sound patterns not as well. Recognition is just one of the cognitive facilities that humans have and can call upon at any time, that computers first have to be designed to have. Then computers or any similar cognitive device would of course be expected to call upon that facility on an as needed basis as humans do, a tall order.

Prosopagnosia is a curious brain disorder that says a lot about how the brain works. In prosopagnosia there is an inability to recognize faces, those of acquaintances, relatives, even oneself, a simple function we take for granted. Recognition is accomplished holistically, not through analysis of individual elements in a picture. You don't recognize a friend by noting that his eyes are spaced a certain number of inches apart, that he has brown hair or a certain shaped mouth, you simply see his face and know it. Prosopagnosia can affect the ability to distinguish objects within a general class such as a farmer recognizing each individual cow, or picking out one's car in a parking lot. Such objects are not distinguished on the 'conscious' level by analyzing individual characteristics. However, a victim of prosopagnosia has to depend on a conscious search among distinguishing characteristics, such as the letters on the license plate of his car or the mailbox address of this house, or even nonvisual cues. This disorder celebrated in the book, The Man Who Mistook His Wife For A Hat and in a certain opera by the same name, illustrates certain principles of brain function. Firstly recognition is immediate and is not performed analytically, that is as a sequential feature-by- feature task. An entire object is not broken into its components. Secondly, a simple brain lesion, in this case a disconnection between the visual or occipital area of the brain and the recognition areas in the temporal lobes on both sides of the brain, frayed wiring, if you will, may interrupt this recognition process. For over a century there has been a debate among brain scientists between those who sought to localize particular cerebral functions in precise brain regions (the phrenologist's approach -Phrenologists attached great significance to the study of bumps on the head) and those who took a more holistic approach.

Paradigmatic among disorders in which localization of function is significant are the aphasias. These are disorders of language function localized to the dominant (usually the left) hemisphere. After long years of examining patients with localized brain lesions, strokes, head injuries, tumors, abscesses etc., neurologists discovered that disorders of language function occur when an area on the left side of the brain has been affected. Moreover they found out that destructive lesions in the frontal lobe cause weakness or paralysis, while a lesion in the parietal lobe causes numbness or a problem with sensation. Because we are built in such a way that nerve fibers cross to the opposite side of the body, destruction of the left side of the brain causes paralysis or numbness on the right or opposite side of the body. Aphasias, dysfunctions of language, follow this same general scheme. Destruction of the left posterior frontal lobe will cause a problem with movement on the right side of the body and also trouble with the motor aspect of making speech and with writing i.e. an expressive aphasia. A lesion of the parietal lobe and the temporal lobe which lie behind the frontal lobe, will cause a problem both with sensation on the right body, sometimes even visual loss on the right side, and also a problem receiving understanding and interpreting speech and written language. This can now be appreciated in the living patient using various brain scans and electrophysiologic techniques that weren't available when these discoveries were initially made. The recognition and classification of Aphasias provides one of the most reliable localizing techniques in clinical neurology, lending strong support to those who maintain that there are particular functions that reside in certain brain regions. Among the persons who believed in such localization was Paul Broca. Sigmund Freud was a no less distinguished spokesman for those who maintained a more holistic approach. But the argument for precise localization in the brain is not as simple as the mechanists would have us believe. After localized destruction occurs, other areas begin to assume a good part of the affected function. Part of the recovery process seen in patients is a goal directed. They try to recapture lost function by whatever means become available. Various supplementary areas not ordinarily used for specific functions, begin to take over function of damaged areas not only in the opposite hemisphere, as was once thought, but also on the same side as the neurological event. That brain areas initially uninvolved in a certain activity can take over this function in a pinch has profound meaning. Brain functions are controlled locally with certain brain areas destined to perform specific functions. On the other hand, most brain areas are pluri-potent, while in the natural state performing a fixed function, are able to assume other functions if necessary. This is partly how the brain repairs itself to preserve the organism. This is also not something generally observed in machines even Silicon-based machines. You don't find a hard disk taking over the function of the CPU or the printer doubling as a random access memory device. But the brain is different. In the repair process and in order to preserve function, we see such seemingly disparate areas of brain suddenly becoming active and assuming function. In stroke patients who are trying to perform a function impaired by their stroke, say trying to moved a paralyzed right arm, you can watch as far-flung brain regions are recruited to accomplish a task. One method is to use the PET scan, which looks at localized glucose utilization that in the intact person are not used to perform the task. Whereas in an undamaged person you may have seen the motor strip of the left frontal lobe become active, in a stroke patient whose motor strip is non-functional you see other areas become involved. The supplementary motor area on both sides of the brain and even the cerebellum pitch in with their effort. These areas are all recruited in order to accomplish a certain task which is second nature to an intact person but accomplished with greater effort when impaired. Now other areas of the brain have to become involved presumably as this damaged individual works harder to accomplish even a simple task. The brain may be the only machine that is able to jury rig itself in a pinch. It uses what is available. The impetus may be strong motivation to accomplish something. Motivation is not something you can observe in man made machines.

You can also see this when a less adept person who is not damaged performs as task that is more difficult for him. For example girls for certain math tasks, boys for language tasks. In order to perform the same function more widespread areas of the brain need to be called in any time a task is more difficult. A minor difference of opinion may be settled adeptly by your diplomats. If your leaders are just a little less competent you may have to call out the army. Such considerations have now become a basic feature of rehabilitation for example after stroke and head injury. The brain is at the same moment, localized and non-localized, holisitic. These contrary elements, localization vs. holism, in consideration of how the brain works are as basic to neurobiology as particle vs. Wave models are to physics. They are different aspects of the same phenomenon. The brain is a whole structure composed of modules or elements. Depending on how you ask a question you will see one or either side of its nature.

The brain is centered about performing a certain function. Whether it be writing, or reading or moving an arm, throwing a ball, it will work until the job is done. In order to accomplish a task we may have to recruit brain areas not ordinarily used to perform a given function. It's the same when you break a leg, the leg is casted and you try to walk. You will recruit the opposite leg, your arms on crutches but you know you have to walk and get from place to place and you do it. A machine is different. It's designed to accomplish a task and an algorithm or sequence of moves is incorporated into its design, in order to accomplish the task. If one part of the sequence fails the work will not get done. There is no goal direction, only a series of instructions.

The patient's frustration at his lack of function seems to speed his recovery. The human patient is goal directed something we don't appreciate in a Silicon based machine. Because the brain is plastic, it recovers function even after cell death. An inanimate machine designed for a deliberate purpose different than an organism that develops through the biological process of evolution, trial and error, in a real environment. The designed machine suffers from the same shortcomings as a planned economy in a communist country as opposed to a capitalist or natural unplanned economy. Economic planning does not work as well as a naturally derived economy. The latter, is primarily goal and task rather then design directed and is bound to be more plastic. We continuously discover how much we tend to underestimate human and animal plasticity. Plasticity is part of what defines the brain as a living tissue. Reading and letter recognition, which comes easily for the human brain, is very difficult to design into a machine. A program may possibly recognize a precise written figure on a specified background as long as parameters of shape and size are specified with mathematical precision. Even then there are problems in recognizing these patterns in a slightly different orientation or in different form for example, the same letter in a different person’s script or in a different slant or orientation. The computer's "perceptions" work again via analysis, a non-holistic approach. Images are mostly analyzed into tiny boxes (pixels or picture elements) hundreds or thousands of these making up a final form. The position of each box is mathematically described. The brain performs recognition functions easily because it does not work through analysis but rather performs its function more holistically. Computers bear little resemblance to human brains. Computers perform logical processes sequentially their responses being hard wired and determined. By contrast the human mind usually functions in a non-sequential manner. Thus a computer with one loose connection will probably cease to function. The brain loses components, nerve cells and other elements almost continuously yet still keeps on all the while improving learning and increasing function, primarily because it does not depend on sequential but instead mostly parallel and overlapping processes. As a living organ it is constantly working and repairing itself. a malfunctioning or sick brain most of the time doesn't lose its oneness, personality and basic method of coping. A human with prosopagnosia or aphasia is still the same human.

Comparing Brain to Computer

Computer scientists, realizing how the brain works as a parallel machine, have tried to emulate brain function with their electronic silicon based machines. They have realized the advantages of designing machines that reflect biological methods. This means using a strategy of parallel instead of sequential processing. In a computer everything must be processed by a centralized processing unit (termed the CPU) which is a microchip. All operations need to wait their turn and go through this tight bottleneck one step at a time, which is why machines emphasize the speed of this microprocessor (for example the Intel 486 or Pentium Chip.) Experts have designed parallel distributive processors (used even for the case of the eminently sequential game of chess, by the way). One of the tasks they have set out to mimic is recognition. In massively parallel machines with overlapping function the loss of a few elements does not shut down the function of the whole machine. For a serial processor the likes of which are our own home computer, the loss of any particular element, especially the central processing unit, would end everything. Newer machines employ parallel arrays of CPU’s instead of just one the CPU being Silicon based analog of the individual neuron. It is common knowledge that as we age, we lose tens of thousands of neurons daily, yet our performance in certain tasks, especially in our 20's, 30's and 40's actually improves as learning takes place and we see perhaps what even amounts to an increase in synaptic connections. Sooner or later the loss of neuron's effect, overtakes the offsetting process of learning and we see the ravages of aging on cognitive function. Only in recent years has this offsetting effect of learning on aging been fully recognized. It is one potent method to delay aging effects.

	COMPUTER (MACHINE)	BRAIN
PROCESSING	SEQUENTIAL	PARALLEL
ATTACK	ALGORITHM	STRATEGY
PRODUCTION	BUILT	DEVELOPS
ACTION	FOLLOWS ORDERS	INITIATES ACTION
BEHAVIOR	DETERMINED	FREE WILL?
MATERIAL	INORGANIC ( SILICON)	ORGANIC (CARBON)
REPAIR	OTHER	SELF (HEALING)
DESIGN	ENGINEERED	EVOLVED, GROWN

Table 1: How machines and brains differ. With efforts to make computers match human attributes, these distinctions blur.

Obviously the brain is functioning constantly as a correlator and user of input from numerous simultaneous sources. A football player is waiting for a pass from the quarterback, but he also has to keep alert for players of the opposing team who threaten to tackle him if a successful completion occurs. This information compared with an internal program consistent with plans for a play accentuated by practice. Then he has to position himself to make a run for the goal post. His vestibular system and cerebellum need to keep him upright and moving, but most importantly, he has to somehow estimate an optimal position for his body, and hands in order to successfully make a catch. Just some inputs include the timing and angle of the quarterback's release, estimated velocity, his own velocity and direction, all this computed instantaneously, and well beyond the capacity of any mechanical contrivance. In plain words the brain acts as an executive, receiving input from disparate sources and putting them together in order to accomplish certain goals. It must process all of this multimodal internal visual auditory input and then to issue orders for a play and run to the goal post.

The brain is an associative instrument, correlating and processing in parallel input from disparate sources. In regard to visual operations alone: "Considering the processing that takes place with visual input, sequential processing would not be possible. If it takes 500 milliseconds for a person to respond to a visual recognition test then there must be no more than 100 synaptic steps between the input and the output. Accordingly, a hypothesis that envisions a serial processing unit for visual recognition with 300 to 1000 steps cannot be right. This observation is usually followed by the inference that the brain, unlike a standard electronic computing device, is a massively parallel machine The point is 100 steps in a serial processing program is far too few to do anything very fancy."[1]*

Marriage of Carbon and Silicon

Computer scientists are not only using biological modeling for new parallel processors. They may incorporate carbon-based molecules in computer switching devices. Switches in the form of semiconductors are the heart of computers in semiconductors and storage devices. The state at a given moment is simply the sum of on-off states in storage devices made of semiconductors and information is stored on magnetic and optical media also as a series of 0's and 1's or otherwise put, "on" and "off" states. The Holy Grail of computer technology is to find complex switches having a few basic characteristics. 1: speed : A device needs to switch, in other words change from the "on" to the "off" state at incredible speeds in the modern computer somewhere in the range of billionths or trillionths of secondst . 2: Stability or reliability are critical in order to guarantee the states of the switch do not change unless we purposefully change them and the switches need to be durable enough to survive ordinary environmental hazards with no breakdowns. The switches must accurately record changes we make in them and preserve those changes until purposefully altered. 3: High storage density is critical. Huge numbers of such switches need to be placed in a very small volume in order to make storage devices and processors useful for desktop and notebook computers. Storage devices must be small. Hopefully a light or laser will be able to alter the state of the device, in other words, to write a series of "on" or "off" state changes into memory also to be able to read written changes on memory devices. In order to accomplish these goals, researchers seek to incorporate biological molecules into silicon computer devices. Molecules such as Rotaxanes which are unusual large molecules whose structure may be altered by beams of light, and Rhodopsins molecules that are multiply altered by beams of light used in the eye and by organisms to store energy. Silicon devices may be impregnated with biological molecules and beams of light used to "write" to these molecules, in other words to alter their state. Some of these molecules change variably, depending on the color of laser light shown on their surface and seem to be very stable, holding an alteration of their state until changed by other beams of light. These molecules may then be placed in a three dimensional structure appropriately addressed for location so that a storage device is produced.[2]

In the field of Optimization, biological strategies of genetics and evolution apply to design of computer software. You may wish to create a model strategy to improve financial return. To do so you write a formula. This formula achieves maximal financial gain under current financial conditions. You can write a formula but you have no idea how it will do in the real world, a financial "habitat". Why not take a hint from biology and use the methods of survival of the fittest. Hold onto the financially lucrative parts of the formula and jettison the weakest concepts in a real financial milieu instead of trying to fly by the seat of your pants and create a theory that may or may not benefit you in the real world. This formula, is the most fit, that is, it achieves the greatest financial return. A formula is either more or less fit than other formulas, which means that it either is a better or worse strategy for survival within a specific financial milieu. In biology we mean by fitness the ability to pass down the largest number of viable offspring carrying our own genes, the ability to pass down one's own genetic endowment. But this is a useful topic computationally as well and here is why. Let us suppose the financial environment changes, stocks no longer are a good investment because of inflation or something of the like, then that was once the most adaptive fit formula now no longer is and another formula, will give us a better financial return. Chances are the second fitter formula shares a lot of the characteristics with the first formula, that it is related to the first formula almost genetically. These optimization or fitness formulas have similar characteristics. They are quasi-biological entities within a financial world and may be interpreted genetically. As the financial environment changes these formulas for optimization of return need to adapt. In order to do so they will have to change slightly, to mutate. Or, possibly some of the inherent structure of this optimization formula will be borrowed from another formula in a form or translocation in much the same way as genetic material from one chromosome moves to another. In the financial as well as the real world there is the survival of the fittest. Many characteristics of these formulas may be borrowed, passed down and recombined in just the same way that genetic characters are. Financial models may borrow from biology and vice versa. The biological method thus turns into a new means to seek truth and to pass it down. More than this it gives us a design plan that adapts to changing habitats.

What we are experiencing is the intrusion of biological concepts into computation and computational models into biology. This is beside the point of attempts of computer scientists to achieve a level of parallel processing that is commonplace in the brain. Though the brain is a Carbon based organic structure and computers are Silicon based, change is inscribed in both devices in a similar manner, electrically through transfers of charges and alterations of chemical molecules. It is reasonable to expect that combination devices will be employed in computers incorporating carbon based biological molecules but also even more tantalizingly, silicon based devices may one day be implanted within the human brain. These devices may aid in functions that are deficient in most humans such as computational and analytical skills. If so human characteristics would be altered for good and there is the very real probability that the genetics of an individual, which is the Carbon-based living part of a person may not be the only characteristics that need to be preserved in future generations of progeny. Such science fiction movies as "Total Recall" and "Johnny Mnemonic" have already begun to incorporate such concepts as Silicon based structures placed inside the cranium.[3]

If such fanciful mergings of living organisms and machines never come to be, carbon and Silicon are bound together anyway. The computer revolution is unfolding right before our eyes and needs no amplification within these pages. The computer will magnify human cognitive capacities in much the same way as the invention of writing or the printing press. These inventions allowed us to record our thoughts and inventions to develop and communicate a collective consciousness, to build upon the past and work on complex concepts one painstaking part at a time. Extemporaneous thoughts and music are primitive by comparison to recorded words, plans and music. You might store in your own mind some sort of vague notion of the shape of an airplane. But write these plans down, find a way to experiment and manipulate these plans, and work on them part by part with the input of experts in various fields necessary and you will design a real flying machine. In music compare the primitive percussion of tribal music to the opera or the symphony.

Today a single human brain can be connected to information in any corner of the world. In his head is a certain picture an organization of his world, but inside his personal computer, is an alter-organization, a different world view which is also his. With a minimum of effort and skill, an ordinary human brain can be connected to the total knowledge of the rest of the globe[4]. The major impact is expansion of consciousness. We use an appliance outside the skull, not a piece of a biological organism inserted inside a computer, or of a Silicon instrument inside the skull, but some form of intimate contact between brain and machine with any of a variety of communication devices that may range from the traditional keyboard or mouse or touch screen or other pointing device to some kind of a virtual reality instrument. This allows a person to point with his eyes, for example, or other body parts using thousands of tiny points within a virtual reality suit called 'tactiles' (as opposed to visual pixels). The purpose of this information appliance is to extend the abilities of the brain. At each contact the person would focus his attention or consciousness on the contents in the device.

The concept of computers seen in science fiction novel is and on television is that of an advanced logical processor. Responses can be predicted as a function of hardwiring and software and computer logic is entirely deductive. By contrast, humans are more capable of inductive reasoning, able to recognize patterns. Humans can intuit and go from one topic to another fasciley considering a number of aspects of a problem simultaneously rather than being tied to a sequential method. Reasoning is frequently done through analogies or may even hang from a thin thread of similarities or symbolism as often happens in dreams, myths and stories. Pure logic is only mode of mental operations. Mechanists fail to see the entire spectrum of human mental operations.

The effects of such nonlogical parallel mental processes sometimes surprise me as in a delirious or schizophrenic patient moved by thoughts that appear to be irrelevant or contradictory. Yet these abberencies show how thought is driven by a different engine than machine logic. Human thought may also be saltatory or jumping after the method by which electrical impulses are most speedily conducted in nerves. Long nerve cell extensions, the axons, are covered by myelin a fatty electrical insulator. Electrical charges cannot cross this insulated barrier. But at certain intervals over the axon, the myelin insulation is interrupted by discontinuities, the nodes of Ranvier. At these nodes electrical charges cross and collect. Changes in electrical currents are conveyed down the long axon by a process of jumping termed saltatory conduction. This method for the spread of currents is extremely efficient and fast. It is similar to the most creative human thoughts which don't rely on a continuous logical process but instead occur through discontinuities and the buildup of disparate motivational and informational factors just as charge builds up on an axon membrane, which can make a seemingly revolutionary thought almost inevitable. This phenomenon has been noted repeatedly and goes by many different names depending on the field of endeavor. In psychology and religion much is made of thought processes that are essentially foreign to a computer, designated as "aha" experiences or revelations, and are considered to be bursts of understanding.

Figure 2: Neuron showing Nodes of Ranvier that allow electrical charge to jump thus speeding conduction.

[5]

The brain is an initiator of thought and feeling processes while a computer, at best, can bring an already initiated logical process to a successful conclusion. Even where it seems to be creating, for example, in providing the first move in a computer game, it is merely choosing from predetermined alternatives. If we know everything about computer hardware and software and we can define the stimulus, then we can always predict a response. Some neurobiologists believe the same about the brain. They look at the brain rather rigidly as a hard-wired complex of conduction pathways and circuits. Upon this is superimposed human experience, perhaps learned patterns of response analogous to computer software. Know everything there is to know about how the brain is built and functions and also its experiences and you will always be able to predict accurately, its response. There is a certain smugness about this mechanistic all-knowing approach, also a certain amount of backward reasoning, an assumption that computer circuits simulate the brain's function. It's much easier than admitting that human thought and action is not determined or at least that we have inadequate data to have an opinion about whether or not it's determined. To the biological mechanists human thought, feeling, and action would be one hundred per cent predictable, if only we knew more. Our inadequacy in prediction comes purely from a lack of knowledge. The observed randomness of behavior is only an illusion or false perception following from our ignorance.

Early in the twentieth century when physiologists had finally described the simplest of all nervous system responses, the deep tendon reflex, they naturally became infatuated with the idea, and an artificially inflated notion about the level of their own understanding. The brain and nervous systems responses, they reasoned, must function only as a complex of simple reflexes. If we knew everything about all reflexes then all of the brain's responses could be understood. As it turns out, higher nervous centers serve mostly to dampen the stretch reflex. The higher order neurons of the pyramidal tract synapse directly with spinal cord motoneurons, not only to convey commands from the brain, but reduce muscle tightness or tone. Others are connected to control of muscles changing the stretch receptors themselves (termed the gamma efferent system). This brings up a basic principle of nervous system function. Higher order neurons that control simpler lower order circuits do so mostly through modulation of the hard-wired lower order reflex response, in other word through inhibition. These physiologic understandings are expressed clinically in various neurological conditions. When the upper part of the spinal cord is interrupted, the stretch reflex in the lower part of the cord controlling the legs, is liberated from inhibition of the brain. The stretch reflex in the legs functions with impunity. The afflicted individual has a very active deep tendon reflexes and very increased muscle tone, termed spasticity. Many people think they are healthy if their reflexes are active. Actually, the opposite is true. Muscles become very tight even when moved passively by an examiner suddenly giving way in a clasp-knife manner through their excursion around a joint. The spastic will experience at best a very tight scissors gait and at worst, even at rest his legs will tighten or bounce continuously as his uninhibited stretch reflexes express themselves.

Drugs may be used to help such patients decrease muscle tone. These may inhibit motoneurons or affect gamma efferents or sometimes may impair the mechanism of muscle contraction itself. Neural circuits are deceptively simple and predictable only when studied in isolation.

Hard-wiring neural circuits are in higher animals and even man means a predictable series of electrical responses. We see this in a record of tiny electrical potentials in the auditory pathway of the brainstem. In a test called the Brainstem Auditory Evoked Response an auditory stimulus of short duration (a click) will reliably produce a series of 5 electrical bumps or waves as the nervous system responds by conveying the message from the lower brainstem to higher centers. This series of waves will always occur, each bump representing a way station or synapse that corresponds to an anatomical point in the auditory pathway (Figure 4). This is most useful as a test in medicine. If a bump is absent or delayed this is a sign of a problem in the specific area corresponding to the wave. After the impulses travel through this well-established pathway, electrical responses become much less predictable. This corresponds to the role of higher nervous centers (the cortex) where sounds registers in consciousness. This is a pivotal point that should not be lost. Another thing about nervous function at higher and higher levels is that responses are less stereotyped and predictable. The higher one gets within the nervous system, the less predictable the response. As a sensory impulse travels through the nervous system over the first few synapses the pathway is determined. However when you get to the cortex the electrical response is widely distributed and cannot be predicted at all. More primitive organisms have only this stereotypical nervous response. It is a sign of more advanced nervous function that you stop being able to predict a response one it achieves a certain level. It seems to me this is a general comment on higher and lower function in general.

Computer scientists are becoming less naive about nervous function as they discover that machines just cannot duplicate nervous function or reason even at a child's level. There has been some appreciation of the function of networks of neurons and function of such units. Each individual nerve cell is literally connected to thousands of others. A neuron's output may directly connect with hundreds of others through axonal branching and dendritic spines provide a much more complex array of inputs. The decision whether or not to fire may be influenced by many thousands of nearly simultaneous excitatory and inhibitory inputs from other neurons. In many instances a single neuron’s output may return to act as a feedback mechanism inhibiting further firing. Scientists are working on ways to monitor the output of arrays of neurons rather than single cells. Cultured single layers of neurons have been monitored using arrays of tiny electrodes. With this apparatus it is possible to "listen" to the integrated output of groups of neurons. Some information has already been obtained showing patterned firing in groups of cells in these primitive cultured networks. Though this does not reproduce by any stretch of the imagination, true brain function, it is an attempt to get at the sociology of neuronal response.

Figure 3: It is an important principle of nervous system function that as a general rule, the more advanced the nervous system response, the less predictable and stereotyped it is. The more synapses the less you can predict the response.

Figure 4: The auditory evoked response. Each electrical potential corresponds to an anatomic waystation in the auditory pathway. Each wave is a reliable stereotyped electrical reflex beneath the level of conscious awareness[6].

As we have seen the idealization of brain function in terms of sequences of on-off responses is suboptimal. There have been attempts to set up arrays of circuits which may simultaneously affect each other's output as neurons do, which is more like how neurons in the wild state interact. Higher thought sometimes involves the combined effects of numerous stimuli with which we have to make due even with incomplete information. Any child can recognize a person from his voice, facial characteristics even given such constraints as inadequate light, camouflage, etc. A manager has to decide on an optimal strategy for completion of a task, simultaneously considering different elements of that task, for example, differing abilities of various staff members. This is fundamentally different than strategy in a chess game, which occurs one move at a time each move affecting only subsequent advantage. Such arrays of circuits, each of which may simultaneously affect the output of other circuits, more precisely mimics actual brain function. As of yet such arrays function only on a primitive level, but they more faithfully reproduce brain processes that are usually nonsequential.

The nervous system is not static. We know that synapses constantly break down and form anew. Each time a nerve cell dies, thousands of synaptic connections are destroyed. Learning also reflects in anatomy as new synapses, connections, form. You lose mental capacity with age, Alzheimer disease through the misuse of drugs and degeneration you are really destroying more and more synaptic connections between neurons. Thus although you generally lose neurons with time and with them abundant synapses, you form others through learning and mental exercise. If you continue to learn as you age by doing problems, reading, and expanding your vocabulary, you will form new synapses. Adult life is a race between neuronal loss and synapse formation. It may be the total number of synapses formed that determines the net change in mental capacity. This is exactly the same as preservation and increase in muscle mass and bone density with physical exercise which can also retards aging and preserves or even increases capacities. Hence it may be that with mental exercise Alzheimer and related CNS degenerative diseases are staved off!!

After a nervous system injury even one producing large-scale damage and nerve cell death, functions that are lost mysteriously reappear. It helps to foster healing through physical and cognitive therapies. This is the macroscopic picture. The real change takes place on the level of the individual nerve cell. If the nervous system functions as an executive for other organ systems of the body, the neuron performs this function in miniature. On the grand scale sensory data must be organized, perhaps mulled over somewhat, but then acted upon. The neuron must also organize its response to complex inputs. Thus it may be viewed as a single molecular unit of nervous system function.

There are anywhere from ten billion to one trillion neurons in man. This estimate depends upon an accurate count of nerve cells (which is hard to come by) then the assumption that the density of neurons is everywhere about the same* (which it is not) and that this number can be integrated over the entire volume of the nervous system (which varies). The number of neurons in the brain is similar to the number of stars in a galaxy. Neurons and stars are energetic systems. Stars exert their affect upon their fellows gravitationally mostly over long distances and occasionally (in supernovas) with the explosive transfer of matter from one star to another. Neurons make more intimate contact with each other and also have their own entourage of glia and other supporting cells. The central nervous system, containing the great majority of neurons, is somewhat insulated from other organ systems by an advanced and highly organized blood brain barrier. Yet if there is a reason for the biological existence of man and all his physiology, it lies within the nervous system.

The human nervous system controls or influences all bodily function. Quite a lot has been made in popular media, by authors such as Bernie Siegel and Deepak Chopra of nervous influence on immunity. The thought has been that by influencing psychology (hence, indirectly brain function) a person's immune system may be made to play a greater role in diseases that depend on immunity, for example to help destroy certain malignant tumor cells. The logic here may be far-fetched, but the general idea that the brain is the major locus of organic control of all such functions is not far fetched at all. Nervous function arose in evolution alongside other organs systems performing their own specialized functions. The nervous system seems to us to be physiologically all important, but it very likely arose as an afterthought not the primary goal of biological process at all, an epiphenomenon, in other words.

Nervous tissue arose from the need in primitive animals composed of small groups of cells for these cells to somehow communicate. As soon as you have more than a few cells in an organism and specialization among them, you create the need for information transfer. The development and use of nervous tissue as an arbiter of information transfer between cells is but one of many strategies for survival. Brains and neurons have achieved prominence only in a small branch of the whole biological tree, namely among certain vertebrates and mammals particularly and among these especially in primates that have evolved only recently from the timeframe of biological evolution. Animals employ different strategies for adaptation. The vast majority adapt to their environment by changing their own biology over many generations, in other words genetically. Some few animals, mostly advanced animals, are able to accelerate their adaptation and change along with their environment by learning. In so doing, they may alter their response within a single or within few generations - a useful trick for organisms having a longer lifespan or long generation time. Mammals rely to a much larger extent on advanced nervous structures and have a knack for adapting over the lifespan of an individual animal. Even in the biological sense then, an individual assumes much more importance. By contrast, the most recently evolved invertebrates, highly successful ones from the standpoint of numbers, competition and speciation, especially insects, de-emphasize plasticity and learning. Thus we have two entirely different formulas for competition. Both obviously work. Insects' nervous system responses are reflexive, stereotyped and dependable. Though complex behaviors can certainly occur, these are hard-wired responses, genetically endowed. It is no big deal that adaptation can occur only over generations. The insect’s generation time is short, the number if individuals extremely high, the rate of adaptation and differentiation fast. Among insects the individual is de-emphasized. In fact, for many insects individuals are very nearly genetically identical, true in particular for social insects. The individual nerve cells of insects look and function very much like ours, but the system allows for little plasticity or learning. Mammals and insects are in hot competition for global hegemony. The farmer's constant struggle against insect pests illustrates this. As insecticides and other techniques are used insects speedily adapt, changing genetic features facilely over many generations. It's our brains and planning against insects phenomenal ability to adapt, that is, survive all of our attempts to reduce their numbers.

Bacteria and other microorganisms also show how living things can compete by genetic design. Biology pits this genetics against human brainpower and no one can guess which strategy will prevail. In the race for survival, the human brain doesn’t always win out. Take a look at the mess we've made with antibiotics. There must be well over one hundred of them in common use just in the United States. Bacteria have an uncanny ability to mutate into resistance. It’s getting so some strains have to be treated with two or three antibiotics at once, especially hospital-acquired infections, because these bacteria living in hospitals descend from strains that were exposed to and survived antibiotics. The most dangerous infection to get is a so-called nosocomial or hospital acquired infection because these bacteria have already seen and are resistant to commonly used antibiotics. For bacteria living in hospitals, their ecosystem contains our best and most potent bactericides and they have adapted to survive our most potent drugs. Bacteria commonly pass down enzymes that deactivate antibiotics or the bacteria themselves may be infected with rings of genetic material (plasmids) that code for these enzymes and allow for survival in an antibiotic laded ecosystem. Even taking into consideration the community outside the hospital, antibiotic exposure is rampant as patients demand to be treated for infections they don't have, minimal sinus complaints treated as sinus infections, discomforts in the urinary tract erroneously treated as urinary tract infections and so forth. Organisms that survive antibiotics especially fungi such as Candida then have the advantage as competing bacteria are killed off and we then see minor complaints such as vaginal discharges and itching being over treated with fungicides and so the problem propagates. Nursery schools are filled with toddlers all with middle ear infections all on chronic an recurrent courses of antibiotics that serve merely to foster reinfection and antibiotic resistance. Our profligate use of antibiotics mirrors overused of pesticides and defoliants so that it can be said without exaggeration, our very worst enemy is ourselves with overzealous over used of drugs and misuse of chemicals.

Sometimes the bacteria win out. We’re having a terrible time with multiple drug resistant tuberculosis even though we’ve developed six or seven antibiotics (some quite toxic) in common use. These have arisen from incomplete treatment of a relatively few cases but the multiply resistant TB Bacillus once acquired, is almost impossible to eradicate. TB is one of those organisms that lives within host cells for years and so is hard to get at with antibiotics or with our own immune surveillance mechanisms. Other diseases of this type include Herpes viruses, leprosy and most importantly Malaria which still kills well over one million people a year and infects 300 million persons. Bacteria and viruses that have an intracellular existence are often dormant and assymptomatic for years until they declare themselves with a chronic recrudescent infection or a fulminent acute clinical attack as does malaria.

The neuron responds to information converging upon it from one thousand or more other cells through up to ten thousand or even more synaptic connections. Neurons have their own functions, but have needs and properties at once similar and yet different form other cells. The most basic thing you can say about the neuron is that it is excitable. Thousands of converging inputs add up to a resultant firing or non-firing state and the ultimate decision rests with the neuron. Whether the cell will or will not fire is the question determined not only by input, also characteristics of the cell. Admittedly, as we shall see, some neurons particularly those involved in interpretations of sensations in the periphery, have a graded response, but most central nervous system neurons either respond with an action potential or they don't, giving rise to the expression, an "all or nothing", response. What is involved in this decision?

Inside the Neuron: How the Neuron Works

A neuron will fire under certain limited conditions. That is properly what distinguishes it from other cells. Like other cells, it is surrounded by a cell membrane that delimits it from its environment. This bilipid (fatty) layer separates two watery environments, the inside (protoplasm) and the outside of the cell. The membrane must discriminate between various substances it will let pass. Consequently, there are differences in concentrations of various substances inside vs. outside the cell. Sodium is roughly fifteen times more concentrated outside the cell, but a similar but larger singly positive charged ion, potassium, is nearly thirty times more concentrated inside. A chemical pump moves these ions maintaining these critical concentrations against electrical potentials and a concentration gradient. Because there is a tendency for substances to diffuse from areas of high to lower concentration, force (and hence, energy) is required to maintain any concentration gradient on the two sides of the membrane.

The sodium-potassium pump gets this energy from the nearly universal final common pathway for cell's immediately accessible energy, the molecule, adenosine triphosphate (ATP). ATP is produced out of the energy supplied by other chemical compounds, especially for the case of the brain, out of glucose. This chemical energy conversion is the job of the intracellular mitochondria. These independent organelles are fascinating because they contain their own genes unlike no other animal cell organelle. Plant chloroplasts actually have a very similar structure and do the opposite of mitochondria. In plants chloroplasts fix energy absorbed from sunlight into chemical energy storage in the form of sugars. The mitochondria's job is to extract the latent energy from compounds especially sugars.

Mitochondria and chloroplasts are membrane bound and have an advanced lamellated structure, almost as if they are organisms unto themselves. They are the only organelles that contain their own DNA and they reproduce independently. Mitochondria have almost a symbiotic relationship with the cell. A lot of mitochondrial protein is coded for in the nucleus of the cell, produced in the cell cytoplasm then imported into through the mitochondrial membrane. These proteins are attached to a special series of amino acids, in other words a short peptide, that acts as a code which tells the mito membrane that the protein is meant especially for the mitochondrion and needs to be imported. After importing these critical proteins, the mitochondrion uses other special proteins that cleave it, leaving its active portion. But certain other critical proteins are encoded by special mitochondrial DNA. There are a few interesting diseases that are inherited problems relating especially to mitochondria.

These disorders tend to affect muscle including the heart, preferentially. This stands to reason when you consider that mitos deal with energy utilization and muscle’s tissue is the most energy intensive tissue in the body. Second these disorders are passed down only through the mother. Your mitochondria are passed down through the ova alone and are not inherited through the sperm which carries only DNA from the nucleus. The mitos reside in the cytoplasm of the ova. This shows that the sperm merely is a vehicle that carries information from the nucleus of the father. On the other hand the mother's ovum does carry many genetically divergent mitochondria. In some of these disorders mitochondria are extremely plentiful. The cells especially muscle cells can be full of them. Maybe there is a feedback mechanism that tells mitos to reproduce if their job isn't getting done. Alternately, they may appear to be wildly abnormal under the microscope. As you might expect, they don't work well either. But there are found to be specific problems when we look for them, ordinarily with coding for a single protein as in other genetic diseases. Persons with these diseases may have something wrong with their heart rhythms, may have muscle weakness or fatigue or may not be able to process some energy containing foods especially fats and so become weak and fatigued on that basis. Just one typical example is a disease that affects only the transport of certain fats into the mitochondrion so energy can be derived. This involves a substance that helps to transport these fats called Carnitine. The brain usually functions abnormally as well. Mental retardation is a problem and the tiny muscles that move the eye will often be affected so that eye movements can be grossly abnormal and a person may have double vision. The diseases are often progressive and severe. Under the microscope a typical abnormality is what is called a ragged red fiber with grossly abnormal and proliferated mitochondria. (Figure). But the mother's ovum passes down some of these diseases. Others are not passed down probably because they are so devastating that a person with the disease does not typically reproduce. We think that there is an alteration in the Mitochondrial DNA early in life (a mutation) and that the disease occurs sporadically (non- genetically) on that basis.

Mitochondria and chloroplasts may be remnants of primordial bacteria or other small organisms that continue to live in a symbiotic relationship in every animal and plant cell. Many of the cell's organelles seem almost to be organisms unto themselves. Another example of a structure in the cell recently discovered is the peroxisome. These structures went unnoticed for many years, but are plentiful in kidney cells so that after a certain period they could not be ignored. They get their name from certain enzymes they were found to contain that help process peroxides and help to detoxify and protect the cell against free radicals that can harm it. Later these structures were also found to be important in the metabolism of fats especially long chain fatty acids and disorders in these structures among other things cause diseases of fatty acid metabolism the adrenoleukodystrophies. These diseases are often present in males predominantly (are x-linked) and cause adrenal gland insufficiency and affect the deep white matter of the brain where these fats reside. Peroxisomes may one day prove important in detoxifying free radicals which are implicated as the cause of neuron destruction In many chronic diseases especially brain diseases. But the point is the Peroxisomes are similar to mitos in some ways being delimited by membranes and almost separate from the cells containing their own enzymes made in the cell but targeted for these structures specifically, most probably by a mechanism that is similar to the mitochondria described above. Mitos though are so basic to biological organisms. All of them have to provide energy for the business of life and so mitos are present in every cell and even in the most primitive cells. Cells so primitive that they do not have a separate nucleus, still have mitochondria without a membrane delimited nucleus ie bacteria, proving that they must have become intrinsically important to life, very early in evolution. If they come from a certain symbiosis, it took place extremely early in geological history and is extraordinarily basic. In fact both mitochondria and Peroxisomes and chloroplasts too are thought to have evolved from an early bacterial or blue green algae invader of ancestral animals that eventually became a symbiote, its DNA encoded now in the nucleus of the host cell. Peroxisomes may have been in the cell earlier# and were useful once because oxygen was lethal to the primitive anaerobic cells that were at the beginning of evolution as oxygen is even today to anaerobic bacteria such as Clostridia. As time passed the peroxisome took on other chemical roles such as handling long chain fatty acids. Indeed peroxisomes seem to have lost some of their reason for being with the addition of the mitochondria which utilized oxygen for cellular energy production. The earth's life was initially anaerobic before plants with chloroplasts began to produce oxygen in large quantities that can Kill an ordinary cell.

Mitochondria handle energy for the cell and are electrically active in a sense carrying information for the cell much as the neuron does for the body. Much of what mitochondria do is to transport electrons so that in a sense mitochondria are in multiple electrical and or energy states depending on the energy cycle as are neurons. Since they handle energy needs they may well determine at least partially the particular state of excitation and the ease or difficulty of stimulation for the neuron. In their role as energy and electron handlers for neurons one may speculate that they serve some function in information handling since, as far as we know all, neuronal information is translated into an energy and electronic code.

Mitochondrial derangements cause a wide array of ills. Not surprisingly though all cells depend on mitochondria for energy handling, mitochondrial diseases are manifested as abnormalities in nerves and muscles the most energy intensive cells of the body. The first is a disorder of young children called Reye’s syndrome, which almost never occurs anymore. No one knows what was the actual cause of this deadly disease which would cause brain and liver failure, brain edema, and coma and severe neurologic impairment of young children who would survive the disease. The best theory is that certain benign viruses such as influenza and chickenpox particularly would affect mitochondria and that aspirin added to the virus' effect in children only who somehow had different or immature mitochondria. Treatment of these kids was a medical emergency and soon they would be fighting for their lives with low blood glucose, liver failure and coma and increased intracranial pressure. In the 1970's particularly we had a run on such cases which would take normal children and ruin them. Then it was realized that aspirin was part of the cause, The specific mechanism was never fully elucidated and the aspirin manufacturers at first balked at the prospect of losing an important market for their fever-lowering medicine. When the relationship was made between aspirin and Reye's after some fits and starts aspirin ceased to be used in children and the Reye's epidemic became no more.

The cell works very hard to maintain different concentration gradients for different ions inside and outside the cell membrane. In the neuron this produces a voltage gradient critical to the cell's excitatory function. The inside of the cell is kept some 70 microvolts negative with respect to the outside. Whatever energy the mitochondrion produces is expressed primarily in molecules of the immediate energy carrying chemical ATP. The ATP-consuming potassium sodium pump removes some three internal Sodium ions for every two Potassium ions that enter, maintaining cellular homeostasis. Nerve cells communicate and change their status by altering these electrical charges determined by membrane ion voltage gradients, so these membrane potentials are extremely critical.

This ion exchange is more than a theoretical voltage gradient maintainer. Water molecules diffuse into any cell along with Sodium. When this ion pump breaks down as it occasionally does when the cell is sick or does not get enough of a chemical energy supply for example, with the interruption of brain circulation, the cell becomes swollen with water. Multiple swollen brain cells accumulating water lay the basis for a dangerous form of brain edema. In the cranium an increase in volume within a closed space always causes an increase in pressure that disturbs brain function and ultimately leads to brain injury and death. We treat this situation by trying to stave off swelling with dehydrating agents. These chemicals create a concentration gradient between the brain and blood to allow water to be sucked out osmotically from the pulp of the brain. By using simple molecules such as Glycerol and Mannitol, carbohydrate derivatives, that build up a concentration gradient of solutes on the outside of the brain cells in the bloodstream as an emergency measure the cell's swelling are slowed until the basic pathologic process that caused the problem in the first place can be definitively treated. These chemicals eventually seep into the brain and compound difficulties in creating brain swelling, so that all we're really doing when we use them is to buy some time. In the meanwhile the swelling and increased intracranial pressure can be monitored closely in the intensive care unit. We use sensitive pressure devices that can be screwed in under the surface of the skull and other devices to look at the pressure inside the cerebral ventricles that contain spinal fluid.

What are some of the processes causing the individual brain cells to swell? These are serious conditions that disturb the neuron's ability to utilize energy and their Sodium-Potassium pumps. Some disorders directly affect mitochondria such as Reye's syndrome, discussed above. Reye's syndrome damages mitochondrial function and affects the brain primarily via severe swelling and increased intracranial pressure. Although the precise mode of damage is not completely understood, energy utilization especially of glucose and fats likely suffers and the individual cells cannot maintain concentration gradients. Much more commonly any process that cuts off the blood supply to the brain causes the same problem. Here I am referring to stroke where a blood vessel occludes and chemical energy thus ceases to be delivered to starving neurons and glia. Trauma and inflammatory swelling or inflammatory swelling alone as in encephalitis may induce pressure changes that left to their own devices will eventually block the circulation to the brain. All of these situations cause a malignant form of cell swelling called cytotoxic edema. Supporting cells such as glia also participate.

The neuron cell membrane separates the inside and outside of the cell. Lipid (fat), insoluble in watery environments outside and inside the cell, makes the backbone of the cell membrane. The two layers of lipid and this membrane have individual long molecules each with a water-soluble and a water-insoluble component. Like dissolves in like and the water molecule is polar, slightly charged as is one end of each lipid molecule. Each molecule thus lines up so that the polar portion is closest to water. In the meantime the nonpolar portion is hydrophobic or water-avoiding and this lines up with other lipid molecules. The membrane thus is made of two layers with polar portions lining up along watery environments on the outside and inside of the cell and nonpolar portions closest to each other (Figure 5) As we have seen, maintaining the separation between two watery worlds inside and outside the cell takes considerable energy. But the membrane's function is not simply separation. It has to selectively allow certain substances, both small and large molecules, to pass into and out of the fortress which is the cell in both directions and under special, well defined circumstances a considerable problem in chemical molecular design, when you come to think about it. It seems all parts of living systems, even cells and components of cells, play an active role in a larger plan. Proteins that traverse its bilipid layer help the cell membrane. Each of these proteins serves a specific function. Some are structural supports. Others are receptors and channels or tunnels to allow passage of certain molecules into and out of the cell. Thousands of these channels stud the cell membrane to allow passage of the Sodium ion alone. This ion whose major importance is its positive charge, flows across the membrane in different ways depending on the exact status of excitation of the neuron.

Figure 5: The cell membrane is a bilipid structure studded with ion channel proteins that respond to receptors

Figure 6: Typical pore protein traversing the membrane. Stimulation will alter ion conductance through the membrane.

One such receptor protein has been studied in detail resides at the neuromuscular junction. This is a synapse that is relatively easy to study because it's so accessible. The neuron secretes Acetylcholine in order to signal a muscle to contract. The muscle cell is similar to a neuron in many ways. It is electrically active. When excited it becomes depolarized the way a neuron does. While an electrically excited neuron ordinarily secretes a chemical, a muscle is made to contract when it gets excited.

The muscle membrane has certain receptor molecules for ACh. Only recently have we really been aware of the complex structure of this protein. It is composed of four peptide (amino acid chain) subunits. The ACh receptor protein structure twists and turns, as do other proteins, assuming a "tertiary" structure. Even though proteins are composed of peptides, most often multiple peptide chains, they do not stay straight. Instead the electromagnetic attraction or repulsion between portions of the chain, causes it to twist on itself. Electrical charges in the surrounding medium also affect the protein's conformational properties. For example, the ACh protein twists so much that it ends up traversing the neuronal cell membrane many times. By looking at specific amino acid sequences within the protein structure you can actually predict where the protein will cross into the cell membrane. Amino acid sequences that are polar (which have large separation between positive and negative charges) will naturally be attracted to a polar medium, namely the mediums inside and outside the cell which are relatively watery because they are like water and like dissolves like. By contrast, nonpolar protein regions will want to stay within the membrane composed of lipid tails. This is much the same thing as oil not mixing with water. Polar and nonpolar substances like to stay with their own kind. Water is polar, oil nonpolar.

So the ACh receptor molecule ends up criss-crossing the cell membrane four or more times. But it also has a large portion outside and a large part inside the cell. What happens is that Acetylcholine fits perfectly into a part of the receptor molecule outside the cell that is specifically designed to cradle Acetylcholine and nothing else. But this portion of the receptor molecule does more than cradle ACh. ACh also changes some electrical properties of the receptor protein and changes the protein's shape. As it does so the receptor which is going through the cell membrane literally opens up a pathway so that Sodium ions can begin to pour into the muscle cell. As discussed, Sodium is in much higher concentration outside the cell and only the cell membrane ordinarily keeps the Sodium from coming in. If Sodium is allowed to come in its positive charge will make the inside of the cell become relatively more positive and thus it will be electrically excited.

Lest someone who hasn't been exposed to physiology may think I'm going a little overboard describing obscure things like receptors for acetylcholine and its protein chemical receptors, they should be warned how extremely powerful these principles are. One thing we haven't gotten into is acetylcholine esterase (AChE) that break acetylcholine down after it has been released. Saran and other 'nerve gases’ block AChE irreversibly allowing ACh to accumulate a small thing you may say. But these are extremely potent chemicals when absorbed in incredibly minute quantity. Such nerve gases were released in a Tokyo subway and luckily there were few deaths. What happens to a person exposed to nerve gas was portrayed graphically and without exaggeration in a recent movie, THE ROCK. Subjects would simultaneously salivate, have incredible cramps, diarrhea, sweat, and convulse hard enough to fracture bones and die within minutes. The antidotes may lethal themselves. They have to be injected directly into the blood system immediately. Some antidotes are Atropine that blocks the effect on internal organs and Curarey to block the effect on muscle. Using these chemical weapons which were mostly perfected by the Nazis, fortunately is a problem on any battlefield. The reason is that it is hard to account for the spread of chemical with prevailing winds and other factors and despite your best efforts, you could easily end up destroying as many or more of your own forces when you use them. However they are easy to make and not that hard to deploy, so that the worry in a situation such as the Gulf War with Saddam Hussein, was that he was just crazy or desperate enough to deploy them, even all the while being fully aware that his own forces could be annihilated.

The Single Bit is Really the Individual Channel Protein, not the Neuron. The Neuron Makes a Decision Based on Complex Input

The ACh receptor is actually like a pore or opening which always is in one of two states: Either it is closed and doesn't allow Sodium to come in or, it is open and does. Furthermore it is in its open state only when Acetylcholine is bound to it and closed otherwise. The ACh molecule very neatly lays the basis for the binary state (either on or off) that is described above. The receptor protein, which is stimulated or not stimulated, porous to its ion or not porous to its ion, is in a binary state which may be described as a '0' or a '1' in the same way as can the state of the whole cell, excited or not excited. Thus the receptor is in a binary state that partly contributes to the state of the entire neuron which has thousands of such receptor molecules studding its membrane. Synapses too, each utilize many such protein receptor molecules. We have binaries determining binary states so the actual mathematical description of the state of a single neuron isn't so simple anymore. Each neuron does emphatically not provide a byte of information but is itself influenced by binary protein receptor and synaptic devices which makes the neuron an executive, an administrator, a decision maker such that this is a situation we may call "double binaries" in honor of binary stars, or the famous double bind which puts you in a position where it can be difficult to make a decision. These are binaries determining other binary states, but he basic determining binaries run in themselves, from the standpoint of the individual cell, into the thousands.

Therefore computer models that seek to describe the individual state of a neuron in an all or none way as either firing or not, mathematically as a '0' or a '1', vastly oversimplify. Really on some level we may view the individual neuron not as a simple binary element as computer persons have tended to look at it, but actually as a microprocessor in an of itself, a little living executive. In fact I am not sure the role of the individual nerve cell can be precisely translated into a computer binary model at all. The complexity of the neuron with double or triple binaries and all permutations of the status of receptor molecules is near impossible for the mind to fathom. Now, when they take the next step and use arrays of neurons to model brain function computationally it is with a little bit of hubris, the thought that even these simple arrays of neurons can possibly model processes served by groups of neurons, say ganglia or nuclei within the brain. Furthermore, on the other side of this issue, the notion that arrays of binary elements such as switches and microprocessors mirror cerebral function is also presumptuous. These electronic arrays perhaps model the membrane of a single cell, studded, as it is with binary elements, the ion channels. Even here it is debatable that an electronic analogy can ever be made. The point is the level of generality of abstraction in computer science is such that persons in the field flatter themselves into thinking their methods reproduce in some way function of sets of neurons whereas what hey are really mimicking is the working of a single membrane of the cell, if that!

The individual neurons is always in a more or less excited state, that is pretty much of a continuum. How do you measure the degree of excitation of the individual neuron? In at least two ways. The neuron is more or less "polarized" that is the negativity of the neuron differs by more or less of an amount with the outside of the cell. If it is more polarized or hyperpolarized, the inside of the cell may be 70 microvolts negative with respect to the outside, less polarized and it may be 60 microvolts different than the outside and so on. Also the neuron may be more or less excitable. It may be harder or easier, again on a continuum, roughly proportionate to the polarization of the cell, to stimulate it, in other words get it to have an action potential. In very rough terms brain excitability, sleep and wake states etc corresponds to some average excitability of a large group of neurons and depending on a task, certain regions of the brain may be more or less excitable. More excitable regions generally draw more energetic compounds such as glucose for their function which can be seen on such functional tests as the PET scan which looks at regional utilization of glucose in the brain. The EEG too, described above shows slow waves when large areas of the brain are less excitable, with neurons hyperpolarized and fast waves (high frequency) when de-polarized or more excitable.

It happens that the muscle cell has an excitable membrane just like the neuron with its own action potential. Like most neurons it is at any one point in time either excited or not. The muscle cell is also a little different because it is not responsible for integrating a lot of signals from disparate parts of the membrane and sending a message along to the next muscle cell down the line as is the neuron. in the case or muscle a single synapse will determine whether the small fiber that is directly connected to the nerve cell axon will contract or not contract.

Ultrastructural studies show the receptor molecule is shaped like a pore or hole in the cell membrane. This interesting finding links proteins to actual structural characteristics. Proteins are not mere amino acid chains but in terms of three-dimensional "microscopic" structure that reflects function. This single protein has a remarkably specific design. Its non-polar portions snake in and out and through the cell membrane; its outside portion cradles ACh, and ACh specifically which will end up changing the conformational properties of the rest of the receptor protein causing it to act as a gate for the flow of Sodium ions responding to ACh binding, laying the basis for the on or off status of the muscle cell. One receptor molecule is far from sufficient as many have to respond, each letting in some Sodium ion before the muscle is depolarized enough to cause the muscle to have an action potential. The muscle action potential signals it to contract, in a process known as excitation-contraction coupling. Significantly, certain neurons also have ACh receptors similar to those in muscles. Other chemical receptors share many characteristics with this particularly well known receptor molecule so that it serves as a model for receptor function.

Figure 7: Typical synapse. Secretion of neurotransmitter alters the ion conductance in the next neuron's membrane# .

Research on the ACh receptor was made possible by scientist's ability to extract large amounts of the stuff from organs that naturally contained loads of it. These were the electrical organs of the stinging ray, Torpedo. This animal has adapted muscle like membranes to be strung along in series rather like very low voltage batteries so that a significant charge can be generated to stun prey.

Among other things, the cell membrane is a capacitor that arrests the jump of electrically charged ions in the watery environments on both sides of the membrane. If the membrane's two molecule thickness is taken into account, which is extremely thin for any charge separation, this capacitor stores a charge of some 100 thousand volts per centimeter. This electric field changes the conformational structure of the proteins that pass through it. The channel proteins are designed to allow different fluxes of Sodium depending on changes in the surrounding electric field.

These particular proteins are made to fit a number of constraints. First of all they allow passage of a single positive ion that carries a certain electrical charge. They do, for example, exclude the larger Potassium ion, which has its own membrane channel protein. Most of the time the Sodium ion cannot penetrate its channel protein. Its permeability changes dramatically within small fractions of a second, first increasing at the right times, then decreasing again. Recall that Sodium is much more concentrated outside the cell. When the channel opens Sodium will rapidly rush in. In addition there is an electrical force attracting any positive ion to the inside of the cell because the inside is negatively charged. When a Sodium ion with its positive charge rushes in the inside of the cell is less negatively charged in relation to the outside, thus depolarized, as the cell becomes excited enough once it reaches a threshold of depolarization with enough Sodium ions to finally have an action potential. Within hundreds of thousandths of a second (milliseconds) the Sodium floodgate opens, allowing a gigantic influx of positive charge to momentarily make the inside of the cell some twenty millivolts positive compared with the outside. Then the channel will close also within a very small timeframe. The electrical milieu is responsible for making the necessary conformational changes in the structure of membrane channel protein because it contains portions with differing electrical charges. Suddenly the permeability to the Sodium ion (Sodium conductance) is severely decreased. Almost simultaneously, the Potassium conductance in its own channels increases allowing the single positive charge carried by each potassium ion to flow outside of the cell.

The concentration gradients for the various ionic species, mainly Sodium, Potassium, and Chloride determine the voltage gradients inside and outside the cell membrane when ion channels for the individual ions are in either the open or closed position. Suppose the Sodium Channel protein alone allows Sodium to free flow inside the cell, then the membrane potential, the electrical voltage gradient on the inside vs the outside of the cell membrane will move closest to the voltage gradient for Sodium alone. Given that Sodium is almost 15 time more concentrated outside the cell, the ion wants to flow into the cell and the voltage gradient for Sodium alone is closest to +70 mV. For Potassium, which is about 30 times more concentrated within as opposed to outside the cell, this membrane potential is closest to -98mV. (Figure 8). In recent years a whole host of diseases that are caused by abnormalities in these channel proteins has been described. These are genetic disorders that most commonly cause defects in brain or muscle, though Cystic fibrosis is caused by a defect in the Chloride channel and is not a muscle or brain disease.

Figure 8: The electrical potential on both sides of the cell membrane is determined by what combination of ion channels is open[7].

This is the simple model of receptor protein function. In some other cases, which include most molecular receptors, the receptor protein initiates action of a second messenger, either a simple molecule or protein itself. This second messenger will have some modulation effects on the post-synaptic neuron causing a change in the flow of ions such as Calcium inside the cell or by some other mechanism. A couple of examples of 'second messengers' are the nucleotide GDP turning to GMP (for Guanine di and Guanine mono phosphate) which in turn affects other proteins changing conductances of channel proteins or other proteins and thereby affecting the excitability of the cell. When acetylcholine from a motoneuron reaches a muscle membrane ACh receptor it excites the muscle through the influx of Sodium ions and initiates excitation-contraction coupling that ends in the muscle cell contraction. The Calcium ion is made to traverse a part of the muscle cell, the sarcoplasmic reticulum, and this ends by exciting other molecules, Actin and Myosin within the muscle to slide over each other (a process consuming energy in the form of ATP) and the muscle cell will contract. This Rube Goldberg like harebrained scheme or chain of events, or whatever you may choose to call it, lies behind all muscle contraction in the entire animal kingdom. Such cascades of events, even far more complex ones, are nearly universal in biology, by the way, underlying nearly all important biological processes from clotting to inflammation. Unlike what we experience in real life, in our macroscopic world, where complex schemes tend to fail, in biology complex cascades seem to extremely reliable for some reason, but it means that something could conceivably go wrong at any phase or stage of the cycle. However such complex schemes have the advantage of working, and working well, where you need to have an extremely reliable response occur under very narrow limited circumstances. One of the best examples is clotting. Blood needs to clot to stop a hemorrhage in the event of injury obviously and to keep out microbes where you have an open wound. But imagine what would happen if blood clotted freely as it flows in our arteries, veins an capillaries. We would die instantly. So it has to be made to clot under extremely narrow, well-defined, situations but not the vast majority of the time. Consequently we have a cascade involving at least 12 steps and conversion of different enzymes or factors at each step along the way from an inactive to an active moiety. The very same holds for muscle contraction. Right now, as you are reading this, what percentage of your muscles do you think are contracting and under how much force? You need to control them precisely, maybe not at the level of the Olympic athlete but muscle contraction and neural excitation for that matter need to occur according to narrowly defined parameters.

An interesting pastime popular in Japan is eating Fugu or raw Japanese puffer fish that contains one of the most potent toxins known to man, tetrodotoxin. Tetrodotoxin poisons the neuron's, voltage sensitive Sodium channel. This channel is most important to the neuron because a change in membrane voltage first lets a rush of Sodium ions in creating an action potential and little useful can occur if one can't generate action potentials. Skilled chefs prepare it so that only a trace of the poison remains, enough so that the thrilled gourmet will come from an inch of losing his life. He may feel a certain tingling in his tongue and mouth. In rare cases a paralysis results which does not cause an alteration of consciousness or memory for the event (perhaps not enough of the stuff actually seeps into the brain but instead mostly impairs peripheral nerve and muscle cells).[8] We have now defined disorders of channels, so called channelopathies as a class of diseases[9]. I've already alluded to cystic fibrosis, a disorder of the Chloride channel of certain cells. There are other diseases, some caused by animal toxins but more important and common, genetic abnormalities affecting one or another channel, for example the Potassium channel in muscle cells may be affected causing paralysis

Proteins are very long combinations of twenty-one amino acids molecules produced en masse in different areas of the body far from their areas of use in the brain or in other organs. Ten "essential” amino acids are not actually made by humans and have to be consumed from animals and plants. You can take the reductionist’s view of humankind that we are nothing but a complex of chemical reactions. It is a point of view that makes sense when thinking about proteins and their functions. As enzymes, proteins control the type of chemical reactions and their rate. Proteins also play a role in making up the basic building materials of cells, organs and extra-cellular substances in the body that determines structure. It is a basic tenet of biological thought that the determinants of protein structure create the entire form and function of the organism, responsible for the entire phenomenology of life. This hypothesis is worth closer scrutiny. Everyone knows that living creatures are composed of various kinds of chemicals that bear little resemblance to proteins determining living forms including fats, chains of various sugar moieties, water soluble substances and ions in specific concentrations arranged in a certain way to define the organism. Proteins can act as structural elements to compose for example the skeleton of cells (as in microtubules) but more importantly they increase the rate of certain chemical reactions. Protein enzyme systems for example catalyze the joining of two sugar molecules and help in the formation of simple sugars before they are joined, making possible the chains of sugar building blocks that ultimately will become familiar starch and cellulose. Other proteins will aid the organism under the right circumstances in digestion of these formed products. Still others aid in the formation and breakdown (anabolism and catabolism) of other proteins. They are ubiquitous helpers of biochemical function.

Proteins Make the Organism

Thus protein is the start of a chain of events entirely determining an organism's form and function. The information system that dictates the formation of protein molecules is thus all-powerful in the biological sense. Strands or multiple strands of amino acids in a precise conformation, control everything in an organism. Miraculously, proteins formed of these 21 simple amino acid building blocks have proven to be extremely diverse in their function. Th only information necessary to completely determine the form and function of an organism, spells out the structure and quantity of its various proteins. Just determine all the proteins and the whole animal or plant will come together of its own accord. Fruit fly is different from human only by virtue of a difference in their protein vocabulary. A protein can change as it functions as the ACh receptor and second messengers. Other enzymes can help add side chemicals to the amino acid backbone of a protein. A protein may be composed of hundreds of amino acids, in multiple chains, but if you exchange or leave out just one amino acid you may alter its function and even render it useless.

For example sugar derivatives (hence glycoproteins) may be added to increase protein diversity. Hence proteins which determine structure and form in a diverse biosphere are built out of simple components that are relatively few in number. It is the basic work of science to divine a set of simple unifying principles or elements that explain all diverse phenomena. For physicists the eternal dance of the heavenly spheres if one wants to describe this so whimsically, is brought about through the relatively simple workings of just four simple basic forces, Strong, Weak, Electromagnetism and Gravity tentatively welded into equations called unified field theories. Then there is the bewildering array of elementary particles comprised of quarks, leptons, gluons etc. It seems that striving for grand simplicity explanations have become more and more complex. But the striving to find just a few simple elements and processes that determine the diversity of phenomena is the grand goal of science. In chemistry interactions between some 103 elements of ordinary matter composed of just a few different types of particles, electrons, neutrons, protons on a more macroscopic scale, is the topic of study.

On the surface biologists are less overt about a quest for ultimate beauty and simplicity that would explain biological observations. Yet they seem a lot closer to their goal than chemists and physicists. Only in the last thirty or forty years has this goal begun to be realized. Permutations of just a few simple elements produce all biological diversity.

One of the great debates when you start off in school taking your first biology courses is what should be the proper subject for study, what is living. What properties imply that the subject Is a living thing? Everyone agrees that the one-celled animal or plant is a living thing. What about something more basic like a virus, that can't reproduce without commandeering the machinery of another host cell, an obligate parasite in other words, Is a virus close to a mere combination of chemicals? A virus is primitive living creature in that it competes in evolution, indeed is altered by changes in its environment. Viruses are composed of just a few types of chemicals, protein and nucleic acids. About the only useful thing a virus does is make more of its own kind. If this is true then reproduction defines life. Perhaps in addition an organism as opposed to a thing, should struggle for existence, whatever that means, strive in some way as it is subject to evolution and natural selection. But we could devise a machine that makes copies of itself. In that case would the machine be alive?

Nature has played a little trick here I think. Living organisms don't just reproduce. They almost never make exact copies of themselves but rather close but inexact reproductions. If you look on the molecular level, DNA seems to make second copies of itself with a remarkable fidelity but we know sometimes, rarely, there are errors and when there are, a single nucleotide may be deleted or replaced by another, altering the genetic code for that cell just slightly and we have a mutation. This happens rarely and even when it does there are enzymes in most cells that correct the error and make the DNA normal again. Even so, some mutations do occur and survive the corrective process. Mutations may be made to occur with greater frequency under certain conditions, for example under chemical or radiation exposure. You can expose bacteria to low levels of ultraviolet light and over many generations they will change form.

When a cell replicates it seems to make perfect copies of itself; this is how a cell line, a species is preserved and lays the basis for how organisms survive, after all the fittest organisms are the ones best abel to survive and reproduce, but the replication is inexact. Close but inexact. The slight difference, which seems to be mere detail, makes all the difference. As we learn more about genetics, we have discovered that the inexactness of replication is far more extensive than we had ever imagined.

In addition to mutations, here are a few examples of inexact replications: Viruses infect host cells, and in doing so incorporate their own genetic instructions into the genome of the host cell. As these cells reproduce, it is conceivable that in many cases, at least some of this genetic material will be included in the host cell's DNA for good, particularly if viral DNA carries with it, instruction that will help the host adapt to its new environment. Even in a complex animal, there is every reason to believe that some of this material will eventually be incorporated into the germ cell line, may end up, in other words, in ovum and sperm cells. Living in the antibiotic era, we have seen how quickly bacteria of all kinds, acquire resistance to antibiotics. I've described this tendency above in terms of a war between our minds, which continuously invent new antibiotics to add to our armamentarium, and the "mindless" but rapidly reproducing bacteria (and insects too which resist insecticides) organisms which have to advantage in evolution of a short generation time that allows them rapidly to adapt. Humans may well be losing this war. One major reason for all of this is the frequent exchange or movement of genetic material between bacteria and viruses. For example, penicillin resistance may be passed from one bacterium to another. They actually pass on genetic material which can travel from one bacterium to another even between species. The gene for penicillinase which breaks down penicillin and thus causes penicillin resistance passed with a circular piece of DNA called a plasmid. A person or animal given penicillin will be selecting for bacteria carrying the plasmid for penicillinase - those bacteria will survive in preference to their compatriots, the billions of other bacteria inhabiting the gut and elsewhere. Resistance genes for virtually all antibiotics in almost all species of pathogenic disease causing bacteria have surfaced and natural selection has helped humans to "breed" in essence, ever more resistant and virulent strains of bacteria and viruses. The genetic complement of the organism can no longer be seen as a static entity, the organism reproducing itself with ultimate fidelity. Instead we have come to appreciate the genome even in the natural non-genetic engineered state as a continuous exchange of information with occurs even between species. This information is constantly reexchanged and reshuffled. It moves and helps determine which organisms will survive[10].

In our own bodies, we have in the past, viewed each cell, as a part of a single person partly because it contains the exact same genetic information. This is generally true. But here again there is abundant reshuffling and change in material. Our immune system is capable of producing perhaps a million different antibodies that help us to fight off invaders. It does this by reshuffling, recombining short lengths of DNA a relatively modest amount of genetic material that achieves great diversity by recombining elements that end up in plasma cells, which make all of our antibodies. B lymphocyte precursors to plasma cells make antibodies that they then "display" on the surface of the cell. That way they are showing off just who they are, displaying their true colors. They circulate in the bloodstream. When a virus or other threatening entity invades, and antibody interacts with the invader, the body has a mechanism that selects the lymphocyte displaying the proper antibody and this will differentiate producing plasma cells to produce this one antibody in abundance. In essence we have natural selection of some of our own body cells whose genetic complement will prove useful to the survival of a whole organism. This is just the same natural selection observed in bacteria with antibiotic resistance, the same natural selection seen in all of biology[11].

Cells Reproduce, but Do Not Make Exact Copies – The Secret is in the Imperceptible Difference in Cells

When you get to the level of a single cell, it can divide to make two daughter cells. This is fission or mitosis. Each daughter cell will have exact copies of genes of its parent and seems to be identical in every way. But while the difference is so slight as to be imperceptible in a single generation, if you observe the cells after many doublings, you begin to detect differences. Sometimes you see a simple degradation in reproductive product as cells down the line accumulate genetic defects. This is a mechanism for senescence of a genetic line. Down the road, the cells may lose their ability to survive in the same environment or to reproduce. Perhaps a certain number of doublings is predetermined, written in, the genetic code of each and every cell lineF . Precise genetic recombinations can then be added to viral and bacterial genes, a genetic informational exchange, make exact copies of human antibodies in abundant quantity that can be used to treat diseases such as cancer and multiple sclerosis.

In the embryo an even more interesting thing happens. The fertilized egg divides and divides again. Now there are four apparently identical cells. But they are not identical. Each will give rise to a different part of the embryo as it continues to divide giving origin to different tissues, organs and body parts. You may say that as the embryo gets to the 4 or 8 or 16 cell stage, the blastula or morula stage or whatever, that each cell, though seemingly identical with its sisters, has an intrinsic potential to have certain restricted progeny. Even though it has exactly the same genes as its sisters do, and looks in every way like its sisters, it will produce a whole line of totally different cells. That is because many of its genes begin to shut off through more and more generations and no longer function, while its sister cells have a different combination of genes that are shut off. There are other mechanisms as well. At an early embryo stage, certainly when there are just 4 cells, you can kill off three of the daughter cells and what will happen? Apparently nothing. At the end of gestation, a normal whole animal will emerge. Nothing will have happened to the pregnancy. You can even take and 'devote' three of the four cells to three other new identical embryos and you will have identical quadruplets at the end of the pregnancy. So whatever determines which way a cell will ultimately go, is decided later than the four cell stage. At that point, all four cells, though undoubtedly very slightly different, are still multipotential. As more generations of cells come into being, these cells specialize more and more and soon will be unable to give rise to a whole animal on their own.

EXAMPLE	ORGANISM	MECHANISM	RESULT
MUTATION	All	random change in gene.	diversity
MITOSIS, FISSION	CELLS, BACTERIA	systematic alteration over divisions	embryology senescence tumors
TRIPLET REPEAT	HUMANS ?ANIMALS, PLANTS	lengthening of repeat	various diseases where severity varies
PROLONGED SYMBIOSIS	SINGLE CELLS	incorporation of symbiote	mitochondria chloroplasts ?other organelles, co-evolution
SEXUAL REPRODUCTION	MOST ORGANISMS	Reshuffling and mixing of genes	increases diversity increases adaptation
ANTIBODY PRODUCTION	LYMPHOCYTES	Economy in reshuffling small numbers of genes	Diverse antibody production
GENETIC EXCHANGE	BACTERIA, VIRUSES	infection, conjugation incorporation	antibiotic resistance, increased virulence
GENETIC MANIPULATION	HUMANS	genetic engineering	curing disease "perfecting" genome?

Table 2: Examples of "inexact" reproduction. Organisms reproduce imprecisely. This little appreciated fact may lay the basis for all biological adaptation and success.

The point is that living creatures reproduce, yes, and this is perhaps what defines them as being living, but they don't reproduce exactly. It is this non-fidelity of reproduction, that in fact makes living things unique!! Even viruses mutate, fail to make exact copies of themselves. And when you get to more advanced creatures they even stop trying to make exact replicas of themselves. They reproduce sexually. Suddenly their offspring share only half their genes on average. Even so, they are usually somewhat devoted to their children's survival and that of the rest of their clan, to which they are related and whose genes they share to a greater or lesser extent.

Now you might ask what for? Why does a living thing not produce exact copies and be done with it? The answer is that variation, diversity, is the raw material for adaptation. In order to be more or less fit in a certain environment, you should be different from your contemporaries in some way. This difference will yield either a higher or a lower probability of survival. Now suppose there is an animal or plant somewhere that produces only exact replicas of itself. It's an hermaphrodite and its children are just like the single parent. It is somewhat adapted to its environment through previous evolutionary design and seems to be doing fairly well, making its living and surviving. Then the environment changes. It does not have to change that much, perhaps by a hair. Perhaps this organism is an insect, and farmers have applied a new insecticide, or the winter is a little longer one year, or any change of this magnitude that under ordinary circumstances would kill off some but not all of offspring but might kill off all of offspring that are identical, in which there is no variation. Then that animal would die out and be seen no more. Even more important this particular exactly reproducing line would have to compete with a close cousin which does not reproduce exactly, one that has built in variation. These cousins would give rise to some creatures that are poorly adapted and would not be fit, while having others that are even more fit than the average and these fitter fellows would have an advantage and eventually take over. Therefore you can easily see that those organisms that have built in some mechanism for variation will survive, while others that have not, will die out. The system of survival, evolution, built into our biosphere demands variation. You could almost say that organisms strive to be different. That is why even one-celled animals sexually reproduce, exchange genetic material, why some insects and other animals reproduce sexually in inhospitable environments and assexually in halcion times. You could argue that the greatest mass of reproduction gives identical copies. Ironic that the residuum, the tiny remainder of non-exact copy-making, is what seems to define living creatures. So, what defines life, more than anything else? What is the most basic factor that makes an item a living thing? An organism needs to be subject and product of the laws of evolution, has to be adapted by virtue of built-in inexact replication.

Elemental Biology

As chemistry is thought of on a certain level as a branch of physics that defines certain molecular interactions, biology deals with a certain set of chemical interactions that relate to life. What determines all form structure and function in nature is alteration of chains of amino acids that are parts of animal and plant proteins. But an even greater simplicity underlies protein production. Amino acid chains are specified by other chains consisting of just four different nucleic acids. In 1945 the one gene-one protein concept was first enunciated by Beadle and Tatum. Much of the subsequent work in biology has been aimed at elucidating the basic processes underlying this seminal idea. The human is estimated to produce only fifty to one hundred thousand different proteins as dictated by an equal number of genes. This is not to belittle the amount of information that this represents. The genetic information contained within every cell, just a listing of the sequence of nucleotides is enough to fill 500 volumes of 1000 pages each with 1000 words. Every cell is capable of producing only certain proteins. This functional repertoire is much less than is encoded in its genome. The production of most proteins is suppressed according to the specialization of that particular cell. Cellular differentiation occurs only because every cell surrenders its ability to synthesize certain proteins at the same time producing others in great quantity. Some of the proteins alter the form or appearance of that particular cell.

Other genes get involved with specifying the appearances of the individual tissue of which the cell is a part. Still others change the form of the organ and even help specify the appearance of the whole person. A switching mechanism turns on and off, usually permanently, a cell's ability to make proteins and thus determines all the different kinds of cells and cell products residing within the organism. What happens when their is a glitch in this process? One problem is dedifferentiation. This is part of what causes some cancers when certain cells suddenly undergo malignant change. Certain cells take on more primitive characteristics and often synthesize chemical that they are not supposed to. Under the microscope it's easy to see that malignant cells change form and grow in an amorphous haphazard manner. The most malignant cells have grotesque nuclei. Nuclei carry genetic information on Chromosomes that can, at certain stages of cell division be made out under a light microscope. Chromosomes may be unduly clumped and there can be more than the usual two copies of each that is found in the normal nonmalignant cell. There may be multiple copies genes that specify certain proteins responsible for cell growth.

Other proteins whose production is suppressed by fully differentiated cells, can suddenly start to be produced in great quantity. The Syndrome of Inappropriate secretion of Antidiuretic Hormone (SIADH) happens with some small cell carcinomas of the lung. This hormone is normally secreted only by the hypothalamus, a small mass of cells hanging beneath the frontal lobes of the brain whose purpose it is to control the pituitary gland and vital basic functions such as hunger and thirst. Antidiuretic Hormone (ADH) decreases the amount of water put out in the urine by the kidneys (diuresis) and thus helps conserve water.

ADH also increases thirst. An inappropriate overload in this hormone will cause water overload. If malignant cells secrete ADH the concentration of important elements such as Sodium drops and cells swell. The brain is affected clinically before other organs. Confusion a decreased level of awareness and even seizures can result. This is but one example of cells secreting chemicals in an uncontrolled fashion that ultimately exert profound effects.

The range of protein production by a cell determines form and function. Cells are chemical factories which may produce substances altering their own function and that of other cells. Neuronal chemicals most typically influence and control other cells. Moreover, proteins must be produced at exactly the right time, as with certain chemicals and enzymes whose secretion is carefully regulated via feedback loops. What is the switching mechanism that controls protein production and its timing? Anything along the complex pathway of protein manufacture may affect the rate and timing of protein production.

Figure 9: Protein production by Ribosomes uses a Messenger RNA template.

A single organism will house the same genes within all of its cells. The DNA is the same. If you find some cells in an animal or plant in which the DNA is different, that is a different being, perhaps a commensal, parasite or symbiote. The DNA inside the neuron is the same as that in any other cell. Yet neurons obviously differ from other types of cells and from each other. The DNA is a library with instructions for the production of all the proteins an organism is capable of making. The first stage in protein production is the manufacture of RNA made on the basis of the DNA code, a process known as transcription. The RNA is an exact complementary copy of DNA formed over its length in the nucleus. It differs from DNA only in the use of one of the four constituent bases with another i.e. Thymine of DNA with Uracil for RNA. Corresponding bases that attract each other line up, the RNA following the DNA template so that at the end of the process RNA, specifically messenger RNA, (mRNA) ends up being made in the linear base (nucleotide) sequence exactly specified by the DNA code. The RNA produced will also be a great deal more portable and there will be many more copies of it. While it is produced within the nucleus it later traverses the nuclear membrane to the cytoplasm. The cell will then produce proteins going according to the instructions of this messenger RNA (mRNA) in the protein producing part of the cell the Rough Endoplasmic Reticulum. The Rough Endoplasmic Reticulum is nothing more than a complex of membranes inside the cell studded with Ribosomes which are like round balls pictured in the illustrations that walk along the mRNA chains an keep adding single amino acids to peptides. Another good way to picture ribosomes is like tape player heads, playing the tape the mRNA that goes through them in order to make the final end product, the peptide.

The most critical stage controlling protein production is in the nucleus at the step governing m-RNA production. A single strip of DNA forms a chromosome contains instructions for up to tens of thousands of individual proteins. There are about six billion nucleotide bases in each human cell's complement of 46 chromosomes. The RNA formed from a tiny part of this nucleotide sequence gives instruction for but one of the proteins in the DNA code. It is told where to begin formation on the DNA template by a certain code on the DNA called a LOCATOR (frequently the sequence TATA). Just after this nucleic acid sequence m-RNA will begin to be transcribed. Another short nucleic acid strand on DNA serves to bind the enzyme that enables transcription (transcriptase). Still another short strand controls whether the DNA sequence will be transcribed and perhaps at what rate. This is the enhancer region of the DNA. Presumably a signal, perhaps an altered enzyme, changes the enhancer region of the DNA in some way to either encourage or prevent the formation of more m-RNA at that particular site. The LOCATOR, transcriptase binding site, and ENHANCER region together constitute the CONTROL region of a particular gene on DNA. This seems to be a uniform system for all organisms including animals, plants, bacteria and viruses supporting the notion of a common ancestry for all life.

Figure 10: The ribosome focuses on one nucleotide triplet at a time in order to add the corresponding amino acid to a peptide.

The long chain of nucleotides that is RNA corresponds to the exact instructions aboard the long chain of Nucleotides that constitute DNA and a protein enzyme responsible for this process is transcriptase, which builds strips of RNA on the basis of the DNA template. This is the first step of a long line of steps in protein production. Some viruses carry their basic genetic information in the form of RNA. Why not? Strips of RNA nucleotides carry the very same data asDNA. These viruses do no make their proteins directly as we do from their own RNA. You would think that they could theoretically use their RNA as messenger RNA , go directly into a cell and make proteins but they do not. They have to depend on the protein-making machinery of the cell that they invade and become an integral part of that cell's genetic process. Therefore for RNA viruses the first step in making proteins is to make DNA from the RNA template. To this end they utilize a reverse transcriptase which makes DNA from RNA nucleotide chains. If these viruses were to invade a cell only to utilize the cell's resources to make proteins from their own viral RNA, they would merely be "guests" of the host cell. Viruses could probably function this way and reproduce successfully. Instead they use their own RNA to make DNA with reverse transcriptase. This is very profound. Now they are inserting viral RNA produced DNA into the host cell, and in so doing are not merely guests, but part of the government of the cell. Their instructions are right in the cell's nucleus and they are part of it. They have control of the host cell's reproductive capacity. The advantage to the virus is great, much to the detriment of the host. The virus no longer needs to reproduce as a whole, making whole viral bodies or its protein. Instructions for viral production, new viral DNA, will be amplified every time the host cell, replicates DNA, or divides, as the viral infection remains dormant and possibly assymptomatic. Yet at some future time through a signaling process which is as yet unknown, the viral DNA, now replicated many times, will express itself, make m-RNA according to the virus' instruction, and unleash millions of complete viruses into an unwitting host. The HIV virus responsible for AIDS acts this way, and is just one of many RNA viruses using reverse transcriptase. The virus will then take DNA made from its RNA which is now part of the host's (in this case human host's) genome and take the first step to make messenger RNA using everything available from the human cell.

Getting back to the cell's normal reproductive processes, messenger RNA goes into the cell cytoplasm traveling as it does from the nucleus and create a corresponding chain of amino acids which is a peptide, part of a protein. Of the twenty-odd amino acids, each one is given a certain code which is three nucleotides long. For example, the triplet codon GCU for Guanine, Cytosine, Uracil would specify the amino acid Serine. The architecture of the protein peptide is a chain of amino acids and the form of the RNA molecule is also a chain, of nucleotides. These triplet codes evolved at the start of evolution. Douglas Hofstadter has drawn the analogy between computer information processing and what occurs in miniature in every cell and every nucleus. The permutations of nucleic acid sequences that in the nucleus represent sequences of amino acids as they will appear in proteins are in DNA, ATG and C for Adenine, Thymine, Guanine, and Cytosine. The Purine (Adenine and Guanine), and Pyrimidine (Thymine and Cytosine nucleotides form triplets specifying single amino acids. Each long sequence of Nucleic acids thus spells out a protein amino acid sequence. Nucleic acids are bonded together in incredibly long chains and two such complementary chains are loosely connected lengthwise to form a spiral backbone. The translation from the nucleic acid language (each word is a triplet that specifies a particular amino acid) to amino acid language is referred to as "Typogenetics". Given a triplet sequence of the four different nucleic acids, there are 64 different triplet combinations, more than enough than the number of different amino acids. Some amino acids are specified by more than one code (i.e. some sequences are synonyms). Also there are instructions such a those telling the beginning or ending of a sequence. This code is universal for all animals and plants, a lucky circumstance that makes interspecies research a great deal less complex and that makes possible the mixing of genetic material between species in feats of biogenetic engineering. IT also implies, that all life has a common origin.

A Single Mistake

A single mistake in the process of specifying amino acid chains in proteins can spell disaster. There are so many examples in which alteration of a single amino acid within a single protein causes a severe disease. On first glance this whole system seems to be a rather absurd scheme. Just a single Nucleotide replacement, a simple mistake, will code for a single different amino acid in a protein and will most likely destroy the protein's function, endangering life. Similarly one nucleotide addition yields a missense reading which throws off the entire sequence. But you have two copies of most every gene so that even if you have one bad copy of an enzyme you should easily be able to get by with your one good copy. One of your copies is inherited from your father and the other from your mother of course. For recessive traits you need to inherit two bad copies of a gene, perhaps a single nucleotide replacement from each of your two parents in order to have that disease. The best example is cystic fibrosis, a disorder of the Chloride channel protein in cells. If you have one bad copy of the gene for this protein, you will be OK, two bad copies and you have this terrible disease. Still another example is that of blue eyes. You need two copies of the blue eyes gene in order to inherit the trait which is also thus recessive. Fortunately the blue eye gene yeilds simply a variation and should probably not be considered to be a genetic disease, though you might consider it as such given the proneness of blue-eyed persons to have sunburns, melanomas and other pigment related diseases.

Translation is the process by which m-RNA specifies an amino acid sequence. We have transcription, the copying of an m-RNA chain from a DNA template, and translation, the change in language from nucleotide sequences to amino acid sequences, peptides. Enzymes help turn peptide chains into full proteins. The peptide chains bond with each other to form proteins, some made of 4 or so different chains that bond together, then side chains of other substances, especially sugars and fats can be added. These compounds determine the final shape and other chemical properties of the protein, in other words its personality. The various parts of the chain or chains of amino acids will fold multiple times depending on electrostatic forces, that will determine its the final protein structure.

Introns separate protein encoding portions of nucleic acid chains, from exons. Introns aren't merely separators or spaces between pieces of DNA that actually code for proteins. Introns carry information that controls quantities of protein produced and the method of stringing peptide sequences together. The information specifying all biological divergence, the demarcations that separate individuals within a species, even information telling the function of each cell within an organism, is contained within the nucleus of each and every cell. Added to this are specific instructions for the embryonic development of the animal, the migrations and differentiation of cells that will determine the final anatomy of the adult organism. All of this information is in contained in a volume about one micron cubed. A micron is a millionth of a meter; Hair is about 100 microns thick. The information contained in such a small space is reproduced with extreme fidelity. There is no information storage facility that stores so much data in so small a space. No miracle can match this feat of scientific reality. Science fact is more remarkable than science fiction. Biological information processing thus outstrips any system of information storage thusfar conceived by man.

Ribosome As Metaphor for Consciousness

Protein production is a metaphor for consciousness, especially that part productive of complex structures. At any given moment, it is possible to focus on just a single element, just exactly as a ribosome does in picking out a single m-RNA nucleotide triplet and assigning to it a corresponding amino acid. Then that amino acid will be added to the peptide chain. It is so easy to come up with myriad analogies in human action. The mason adds but one brick at a time, the musician, performer or composer one note or chord at a certain instant. When we discuss vision we will learn that the fovea focuses on only a tiny portion of an entire visual field, and that the brain has somehow to be responsible for forming an entire image. Gradually a peptide structure is sequenced over time. Peptides become polypeptides are bound together, modified, much as melodies and harmonies begin to come together sequentially in time. We are left with the dichotomy of an entire structure, a protein, a building, a symphony, which function as a whole, yet are pieced together sequentially utilizing an extremely narrow focus. Just as a whole human organism is making myriad proteins at one time, he is perhaps seeing, hearing, tasting, focusing on various sensory parameters all at once, still at bottom, the focus has to be narrow and particular, and considered at the level of the ribosome at the level even for a fraction of an instant, at a single nucleic acid triplet. At any instant, consciousness is seen to have a narrow focus resulting in formation of structures, buildings, symphonies, scientific theories that may be more and more complex and beautiful, even as they reach higher levels of abstraction.

Template : DNA, RNA	Template: Musical idea, emotion	Template: Idea
Amino acid	note	letter
peptide	measure	word
polypeptide	melody	sentence
peptide with side chains	melody + harmony	paragraph
multiple peptide chains bound together	connection of themes	work (story, essay)
"tertiary" folded structure	symphony	book

Table 3:A linear rendering of levels of Abstraction in creating complex structures, proteins, and music literary works. Ultimately we piece something together starting from a narrow focus:

This is relevant to the stream of consciousness, what Paul Churchland calls the Joycian stream of consciousness[12] referring to the literary technique used in Finnigan's Wake. Why does time for us seem to flow one event at a time even though we function taking many stimuli in parallel. Our consciousness seems to work like a tape-player head or a Ribosome. We have a single uninterrupted series of events like m-RNA being played like a tape over a ribosomeF . If, on the subcellular level many of proteins are made at once, on a macroscopic level, many mental processes are also taking place simultaneously in parallel and the best computer model involves, as previously mentioned, arrays of microprocessors, each taking in a single instruction at one time.

The creation of worthwhile complex forms requires laying down of a structural idea, a recording process, for which the DNA or RNA molecules are also a model. You can create appealing music without resorting to writing, but the most complex and interesting forms of music are written down. That's why a symphony or opera are a lot more rewarding to listen to than a simple song or improvisation. There's something to sink you teeth into. (I realize in this I am expressing my own musical bias.) Likewise chances are stories and literary works, the Iliad and the Five Books of Moses come to mind, were passed down orally for hundreds or perhaps more than a thousand years. Even in those times there was recording in memory of the original stories. Despite many person’s best efforts to recall these stories faithfully, they were undoubtedly subject to embellishment in being passed through myriad generations and human channels. The invention of writing allowed permanent recording, but more importantly, a great building upon a basic structure into a complex literary form.

What I have just described is protein production as a natural process. Today it has become possible to make proteins by design, and for proteins to be produced inside cells that, in their wild natural state never produce them. Technicians take Eschericia coli bacteria, usually harmless inhabitants of the colon, and teach them to produce certain substances such as Insulin and interferons for medical uses. They do this by introducing genes into the bacterium. Then it will double as bacteria do many times to produce quantities of the desired protein that is then purified.

Some disease that represent enzyme deficiencies are beginning to be treated in this way. Adenoviruses, RNA viruses that infect respiratory epithelium can be enlisted to carry the gene making the cystic fibrosis Chloride channel and that may be introduced to some of the most affected cell, namely the respiratory epithelium which is the most affected tissue in this disease of childrenÀ . The rare disease ADA or Adenosine Deaminase Deficiency. Because of a loss of this one enzyme the immune system is non- functional.

Elemental Biology Gives Man New Powers of Design –The End of Randomness

Bioethical concerns arise out of the fact that this kind of genetic manipulation, which ameliorates disease is useful but certainly doesn't stop here. It is extremely powerful. Once the meaning and effect of each gene is deciphered and scientists discover reliable methods to introduce genetic instructions into cells and for those cells to be able to go on expressing this information, biology as we know it is transformed. We've been given the keys to the kingdom, in essence. It will start with the introduction of enzyme production that will ameliorate symptoms or cure disease as in ADA deficiency, cystic fibrosis, and disorders such as Gaucher's disease where certain kind of lipid molecules build up on account of the body's inability to digest and excrete them. These diseases and hosts of others, occur because of defective proteins and all we need do to help those afflicted is introduce instructions to produce normal proteins in the proper cells at the right times. Other disorders like Alzheimer disease develop because of a certain proneness or tendency to accumulate substances, in the case of Alzheimer's Beta-Amyloid in neurons. These persons may be helped by providing a pathway to decrease production or accelerate degradation of the offending chemical. This could possibly be done by genetic alteration that reverses the inborn tendency for this substance to accumulate. The next step is the elucidation of strands of genetic material that regulate protein production, introns and other exons that code for proteins that regulate cell division and protein production. This is the control and command machinery of the cell. In these DNA strands is information that bears on all kinds of uncontrolled cell production as in cancers and may even be involved in the buildup of material in atherosclerotic plaques inside arteries. Knowledge of these processes again, will merely cure diseases. Then locked inside every cell is instruction on senescence, information bearing on why certain cell lines will stop reproducing only after a finite number of divisions. Sooner or later we will learn the facts and be able to manipulate clones of cells, from neurons that stop dividing, to other cells particularly blood elements. Technology has already developed to the stage that regulator proteins have been discovered, produced in quantity, and used to control and increase red and white cell production. For example, Erythropoetin, made by the kidney is given in kidney disease and after chemotherapy and with various kinds of anemias to stimulate red blood cell production.

Is this Knowledge Good or Evil?

The processes controlling normal aging, as the body falls irrevocably into a state of disrepair are also slowly being uncovered. At this point you may shout, "Wait!!, all of these things, genetic disease and variation, the cycle of life and death have been around throughout the history of biology and are not for us to control. We already know more than is good for us. These processes are for God or nature to control. Perhaps, but there is no way to stop people from using this information. It is debatable that we should even try. Regulate this powerful knowledge here and somewhere else someone will take advantage of this information use it. But you may protest, certain "developed” societies such as in the U.S. and Europe perhaps have such a lead on this research and development that we will hopefully be able to legislate some control in these strategic regions of the world on some rational basis. But the pendulum has swung away from government and toward private entrepreneurial control. Considering the rapid growth of knowledge and new means for dissemination of information (the computer and Internet) we will not have anywhere near the time that we had in the era of atomic energy our last great dangerous technological expansion. One hope: persons who can use this information, and discover how powerful it is, how much they would have to gain financially, will begin to keep it as a secret; there would be limits on dissemination of information by design and copyright.

It doesn't stop here. Beginning with our ability to change superficial characteristics before or after birth, such as skin pigmentation and eye color, which should be a simple matter of adding certain genes into the mix, researchers will start to manipulate certain human characteristics such as muscle mass, endurance, intelligence, emotional tone and level. At some point, perhaps in the very distant future along with elimination (and thereby also creation) of certain diseases, lengthening, perhaps indefinitely the human lifespan, we ought to be able to alter individuals, to create subjects of great beauty and monstersÆ too if we desire, beasts of burden and nobles, plebeians and patricians, perhaps various breeds of patricians designed by competing entrepreneurial entities. Men may very well not have the same appearance as they do now and may not look like their brothers. And yet we will be the ancestors the progenitors of these various different races.

When I saw the movie Star Trek -Generations, I had to consider how false a view it presents of the very distant future: Humans that are just as we know them today inhabit the scenes of the movie. Perhaps this is to help us identify with human passions and needs. But as mankind becomes adept at manipulating physical entities, so we will be able to change our distant progeny. Advances in this kind of knowledge are for the most part ignored in our future projections. We want to imagine a future world inhabited by us essentially so it will be possible to identify with the main characters, the same beings we know today. Chances are that will not be the case. Various models of humanity will be designed and tried out.

Perhaps the only hope for the future if we are to recognize it in science fantasy, is that design changes will come about, but will not be found to work as well as the model that we have today, the one that has come down to us by natural selection. This is very likely to be the case in fact, for the very distant future. But for me, at least, Kirk and Picard are mutual aliens. If ultimately the general biological form of a human is not a constant, if our form can be altered at will, then we have no base. Humanity harder to define. In that case, where the most basic picture of a person can be altered and may not resemble what we in our time view as a human at all, perhaps mankind should be defined by a historical mode , that is whatever we consider to be a human has human forebears or origins, but in current form, may resemble what we think of as human, very little if at all.

What is Man? Surely Not His Current Form or Incarnation.

I'm fully aware how much I have gotten ahead of myself. Understand, I am not talking about what is theoretically possible in the future, but getting into the inevitable, that is, if we end up surviving future man-made and natural upheavals. According to this model, the very idea that man is a part of nature is passe. To the greatest approximation up until this time, man is in nature and the great majority of natural processes are certainly not under our control. And of course without the continued working of natural processes, without human life, in other words, nothing else can take place, at least as far as we know - leaving aside religious speculations about a life apart from the real biological life that we know in this world. Also all conscious thought and speculation as we know it, occurs because of intact workings of biological machinery. And without life we have nothing, at least as far as what we can see objectively in the real world. So you may say that life, biology exerts a permissive effect, it permits all conscious action and speculation. Apart from that one can now perceive an element of design and control and even alteration of biological processes that are fruits of the brain, a part of brain work, but also still something else that reflects back, even alters brain function, some undefinable will or design or mental process that may even control or change biology. Without biology, a living structure no speculation, no manipulation of nature is possible.

The Bioplatform :

One way to picture this idea is that biology provides some kind of platform, or underlayment without which no further action is possible. Without a basic supporting structure nothing else is possible. Once that platform is provided however, the possibilities are limitless. The platform is our biology. In the future we will appreciate more and more how this platform is mere launching pad of sorts. Up until now we haven't been able to do all that much, being unable to escape its confines. If a person had a disease, it would have its way with him. If his habitat did not provide enough food, he would die of starvation because his level of knowledge was limited. Slowly we are liberating ourselves from the limits of our biology. At present we are learning to reach down and change some of the substructure of this platform. In the not too distant future, it will transform into a launching pad, and we'll begin to escape from it, in very much the same way that we've taken our first steps above and outside the confines of mother earth. It happens though few of us think of it this way every time a person determines he will not just let a disease happen to him, and he takes an active role and does something about it. There is, in other words some residuum or part of us, a will, a part of conscious thought or action that is beyond biology. At a certain phase in mental processing biological considerations cease to define the individual and we have to look at something else. This proves the case that there is more to mankind than biology alone. It seems to me reducing mankind to biological considerations will usually work, given enough biological knowledge and is a good approximation in the world as we know it, much as is Newtonian mechanics in physics. But we are demolishing the biological model as a complete system. There is a will which supersedes biological processes and seeks to control them, seen most clearly in the practice of medicine but in other endeavors as well. And in recent years, technology has developed to the extent that we finally have the wherewithal to express this quest to control biological processes. Perhaps this is most apparent in new knowledge of genetics. What is important here is not how far we've come in this process, but that we are involved in biological control at all, something no other animal has been able to do.

It is not always possible to do a real experiment, to know something empirically. Physicists are used to the concept or a thought or Gedanken experiment. It should be possible to devise an experiment utilizing reason, practical knowledge without actually having to do the experiment itself. The best example is Einstein's famous twin experiment that helps prove relativity. One twin is traveling at a high speed close to the speed of light and he comes back younger than his stationary brother. It's hard to do such an experiment but one may figure out the results that have in fact been proven at the level of subnuclear particles. In biology, since we don't yet have all of the advance warning of what is to happen in our own time perceptions of our future constitute a thought experiment. Such considerations bring ideas to life about us manipulating our own basic structure and our ability to separate ourselves from our biological underpinnings, helping us to realize how dependent on our biological machinery we are, and yet that as persons we have stepped quite beyond our biological endowment. We have already widened our horizons, stepped away from our biological heritage, but much of this has been imperceptible or at least it has gone unnoticed. Certainly we've come a long way from our origins as the erect ape of the African savanna. Humans have radiated into all of the world's inhospitable climates, learnt about shelter, and agriculture and medicine. Paradoxically the exponential increase in biological knowledge, promises to teach us even more about ourselves, especially our non-biological essence.

The cell is a protein factory, proteins being used for structural repairs and to form enzymes and hormones signaling other cells to action. Neurons, like other cells, need to produce only certain chemicals and manufacture them within certain precise time frames. Luteinizing Hormone, and Follicle Stimulating hormone are made and released precisely to bring about a normal woman's menstrual cycle. One mechanism occurs at the level of transcription or RNA. These are regulatory schemes that can intervene at different stages of the protein production sequence. Other regulatory processes come into play in translation, the process by which RNA sequences are translate into actual amino acid strands, peptides, and also in the release of these proteins inside or outside the cell.

The protein thus produced is often packaged in specialized structures made of lipid membranes, part of and similar in structure to the Endoplasmic Reticulum. This Golgi Apparatus named for Emilio Golgi, a turn-of-the-century anatomist, was first discovered in neurons where this organelle is very prominent. These laminated piles of membranes separate certain substances, particularly active newly manufactured proteins, from the rest of the cell. Some proteins and chemicals, made by the cell, would be dangerous to it if unleashed within the cytoplasm, and also for various other reasons need to be made and stored then released under controlled circumstances. Digestive enzymes like Trypsin, would reek havoc within the cytoplasm digesting everything in sight unless kept from the rest of the cell. Golgi bodies are systems of membranes that form free vesicles composed of lipid material. These lipid bubbles hold chemical that may later be useful to the individual cell or package substances later exported from the cell. Neurons are specialists in packaging chemicals for export because they are used as signals both to other neurons and also to non-neuronal cells. At a certain point when these substances are released the Golgi produced membrane of the vesicle merely fuses with the cell membrane and molecules are dumped out into the environment in a process termed exocytosis.

Numerous cells specialize in chemical production for export, guns ready to fire in a sense, except as we have seen, deciding when to fire based on myriad inputs. Some cells are secreting cells or glands, those with ducts in the digestive tract for example, and ductless cells that release hormone directly into the blood, such as the pituitary gland, the controller of other ductless glands. Plasma cells make protein antibodies in prodigious quantity. They may be considered quintessential protein factories and show it with their rough, ribosome laden endoplasmic reticulum that dominates the cell structure (Figure). Each plasma cell or clone of cells produces one specific antibody for export. The antibody recognizes and attaches to only a very specific individual chemical, foreign to the animal and needs to be neutralized for later destruction.

Neurons, like plasma cells, produce a variety of vesicle-stored chemicals for later release. These substances, a few examples include Serotonin, Acetylcholine, and Norepinephrine, carry messages. They are typically produced in the cell body, then transported down the long axon to a bulbous swelling at the end of the axon, the axon bouton. At that location, the vesicles bind with the cell membrane and release a small packet of material, remarkably an almost constant number of molecules of the material, into the extra-cellular space.

As this happens at a synapse, the junction between two nerve cells the chemical messenger will either excite or inhibit the nerve cell membrane exposed to it. At the neuromuscular junction or synapse between nerve and muscle, Acetylcholine, excites the muscle into a state of contraction. Small numbers of vesicles are always being released at the axon bouton, each containing a specific quantum of neurotransmitter. Some quantity of chemical is always spilling into the synapse and it seems just as if the neuron is always poised to release its substance. But when the neuron is excited that is invaded by an electrical action potential, then there is an enormous orgasmic release of its substance after which comes a short refractory period at which time the neuron is not excitable at all. The chemical released into the synapse in the meantime affects the electrical potentials in the adjacent cell. The released neurotransmitter will make the adjacent cell membrane (the post- synaptic membrane) either slightly more or less excitable depending whether the particular chemical excites or inhibits.

Other neurons release their own chemical messengers directly into the blood, as in the hypothalamus, which is a neural structure controlling endocrine glands. The hypothalamic neurons release short sequences of amino acids, commanding the pituitary gland which hangs from the bottom of the brain. A special circulation, a portal system, carries these commands in the blood between hypothalamus and pituitary, the blood dumping regulatory hypothalamic peptides right into the pituitary, itself a controlling endocrine organ. The pituitary, in turn, controls all of the ductless endocrine glands of the body. That is how the brain exerts control over the entire endocrine system, via carefully modulated chemical production and release of chemical products, starting in the brain.

The neuron is like other cells. It has organelles that function just like those of other cells. The neuron's structure reflects specialized function. No other cells are elongated as some neurons which can be over a yard long, yet their cell bodies are microscopic. This is part of their unique form. In fact there is such a great diversity of the structure of neurons, some of which are tiny like the granule cells of the cerebellum, others long, like sensory ganglion cells. The classic model of a neuron includes an axon which is a great length of cytoplasm and easily the most distinguishing feature of a neuron. All neurons do not necessarily contain axons, as such, perhaps not even the majority of them; some have two, some many. But the standard neuron model is that of a cell body and an axon, or cell extension. That's because the major job of a neuron is to communicate, and the axon will carry a signal from the body of the cell sometimes over a very long distance, to communicate with another cell. As an example you can take the motoneuron, a cell inside the spinal cord, which when excited, will send an action potential, an electrical signal all the way down its long axon. This action potential will reach the end of the axon, the axon bouton, causing Acetylcholine to be released into the neuromuscular junction. Acetylcholine excites the muscle membrane causing the muscle cell to contract. What you are doing is sending information, command and control, over long distances, just like a message over telephone wire.

Having a distant outpost like the end of an axon is a great responsibility. Not only electrical messages but nutrients and supplies, especially the neurotransmitter such as acetylcholine, are made, in the cell body and need to reach the distant end of the axon. As in larger animals, cells maintain their shape with a cell skeleton, a cytoskeleton. The major component is the microtubule. This is a rather complex structure comprised of peptides of tubulin subunits bonded together into protofilaments which, in turn, form the entire microtubule. The microtubule architecture is highly conserved and used by motile cells in cilia and flagella, as in sperm flagella and in basic processes such as cell division. The mitotic spindle that pulls the chromosomes apart, each daughter cell taking for itself a portion of chromosomal material, is made of microtubules. Substances made by the central cell body travel, often inside vesicles, back and forth much like railroad cars over tracks, on the microtubules that at once, preserve the shape of the cell and axon, and serve to supply the distant axonal outposts of the cell. This is a process known as axoplasmic transport or axonal transport. Diseases of neurons may derange this process. It is these structures and related ones that get involved with neurofibrillary tangles seen under the microscope in Alzheimer disease and other associated proteins, such as "microtubule associated protein" MAP which is tested in cerebrospinal fluid in Alzheimer disease. In Alzheimer's disease something disturbs the use and deposition of these proteins which alters the function of the cell, causing cell death.

Figure 11:Neurons and trees look similar. Branches are like dentrites that coalesce at the trunk, analogous to the cell body and axon. The cell body may not be prominent.

TO BE CONTINUED IN PART III

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[1]Churchland PS NEUROPHILOSOPHY Toward a Unified Science of Mind/Brain M.I.T. Press Cambridge, MA 1986 p.410

t You might argue that the refractory period for a neuron, mentioned above is merely the inverse of the switching frequency of a Silicon element, but strictly speaking this isn't so. Just some of the arguments to be taken into consideration are, the relative state of excitation of the neuron, relative and absolute refractory periods and the influence of an enormous number of inputs from other nerve cells.

[2] See Rotaxanes: These organic molecules may serve as nanoswitches SCIENTIFIC AMERICAN August 1994 Volume 271 Number 2 Page 87, Also

Protein-Based Computers by Robert R. Birge SCIENTIFIC AMERICAN March 1995 Volume 272 Number 3 Pages 90-95

[3] Silicon, the basis of computer semiconductor structure and Carbon on which all biological molecules is based, belong to the same family of elements capable of forming four separate chemical bonds. Curiously old science fiction films often featured beings from outer space that had a Silicon based biology. Both elements seem somehow peculiarly suited for information storage and in my view combinations of Carbon and Silicon based information storage machines is inevitable.

[4] See Bill Gates THE ROAD AHEAD Viking Penguin, New York 1995.

Bill Gates provides one vision of the future, with every person being connected with literary, entertainment, financial and other information through information appliances.

[5]Picture taken from “Neurosciences for Kids” website. http://weber.u.washington.edu/~chudler/chmodel.html

[6] From Stockard, James J, Stockard, Janet K., Sharbrough, Frank W. Brainstem Auditory Evoked Potentials in Neurology: Methodology, Interpretation, Clinical Application IN: ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY Michael J. Aminoff (ed.) Churchill Livingstone, New York 1980 P. 371

* It is estimated that there are 300,000 neurons under each square millimeter of visual cortex and about half this number beneath the same area elsewhere in the brain (Nauta, Walle, JH Fundamental Neuroanatomy WH Freeman and Company, New York 1986

# Peroxisomes, mitochondria, and Chloroplasts are all felt to have originated as invaders, remnants of parasitic or symbiotic organisms, in a theory popularized by biologist Lynn Margulis. This must have happened very early in evolution in cells ancestral to nearly every current animal and plant cell. Mitochondria and Chloroplasts contain some of their own genetic material. As generations pass some DNA of mitochondria and chloroplasts is passed into the nucleus of the cell. Peroxisomes must have been intracellular for so long, they no longer contain any DNA of their own and their structure is specified by the cell nucleus.

How these organelles might have gotten into the primeval cell is another interesting question. One theory is that the first anaerobic (non-oxygen using) cells were ameba like and just engulfed primitive organelle containing single celled organisms. At that time, billions of years ago there were probably no multi-celled organisms yet, or at least none with differentiated cells. Primitive single celled parasites very likely abounded and was frequent invaders of other cells. These invading intra-cellular parasites, the forerunners of other intracellular invaders we know today as mycoplasma, Rickettsiae likely evolved into symbionts or commensals of the single cell organisms that evolved into today's plants and animals all of which contain the remnants of tiny parasites from billions of years ago.

y Curare is the same as a lethal poison derived from plants shot from darts by South American Indians. It paralyzes muscles by blocking the effect of ACh on muscle membranes that can block respiratory muscle to cause death. Nerve gases result in the accumulation of ACh so you want to block it, but the problem is to determine how much might be a life-saving dose and what dose would cause a complete block and thus be lethal.

# This and the preceding two figures are taken from John G. Nicholls, A. Robert Martin, Bruce G. Wallace FROM NEURON TO BRAIN Sinauer Associates, Inc. Sunderland MA 1992 P.26,30

[7] Adapted from Michael J. Ackerman and David E. Clapham "Ion Channels--Basic Science And Clinical Disease" New England Journal of Medicine 336:1577 (1997)

[8] See Dulbecco, Renato THE DESIGN OF LIFE Yale Univ. Press, 1987. p349Ackerman, Diane A NATURAL HISTORY OF THE SENSES Random House, New York 1990 , p169

[9] Guttmann, Ludwig, and Guttman, Laurie "Axonal Channelopathies: An evolving Concept in the pathogenesis of Peripheral Nerve Disorders." Neurology 1996;47:18-21

[10] See Laurie Garrett THE COMING PLAGUE: Newly Emerging Diseases in a World Out of Balance. Penguin Books, New York © 1994 especially pages 411-457

[11] See Marks Cara, Marks James D. "Phage Libraries -- A New Route to Clinically Useful Antibodies" NEJM 335(10):730-733 (9/5/96)

F New evidence points to the ends of chromosomes, the so-called telomeres, proteins that are telomerases as one factor, at least, that inscribes as specific number of possible doublings within a given cell line. Understanding of this process may allow manipulation that may make further doublings possible or conversely control certain malignant growths where defects in telomerase is expressed causing uncontrolled growth.

[12] There is a conflict as to whether this stream of consciousness which certainly seems real enough to most of us, is, in fact real, or an illusion, part of the characteristic way that events are recollected in our minds which is not at all an accurate picture compared to the way events actually occur. This is referred to as the "virtual machine" of the brain, the way the brain perceives the flux of time and reconstructs reality by Daniel Dennett see Scientific American Profile: Daniel C. Dennett 274(2) February 1996 p. 34 by Tim Beardsley and CONSCIOUSNESS EXPLAINED by Daniel C. Dennett Little, Brown and Company, Boston © 1991

F Consciousness and experience are linear just as computer processing in a microprocessor is linear. This linearity of consciousness makes our conception of time which we also tend to appreciate on a linear scale which may not be entirely accurate, by the way when we actually come to consider the effect of time on physical processes, especially those that are far different from the ordinary experience in our own macroscopic world.

À See Wilson, James, M. Adenoviruses as Gene-Delivery Vehicles in New England Journal of Medicine 334:1184-1187 May 2, 1996. This is a good start but unfortunately does not cure the condition. Infected cells are removed by the patient's immune system which then prevents reinfection by the same virus. Somehow the gene (more precisely CFTR for the cystic fibrosis transmembrane conductance regulator) has to be administered so as to have a permanent effect.

Æ This has been a theme in science fiction. One good example is The Island of Dr. Moreau by H.G. Wells in which the diabolical Dr. Moreau retreats to an island paradise in which he is all powerful creating hideous beings, part men and part beast, to whom he is a great God as creator and controller, and maker of the law. The story is a metaphor for the animal and human elements in human behavior.