Cooperation Created Fiercer Competitors;… Collagen Caused Kindness Through Specialization Of Cells;… Collagen;… Good Proteins Come In Small Modules;… You Are A Monkey’s Aunt (Or Uncle);… After Life Comes Glue;… Extracellular Space Can Be A Busy Place;… How Your Tissues Hold Their Water;… Proteoglycan Is The Answer.
Cooperation Created Fiercer Competitors
In the beginning, all were adversaries. While solar-powered photosynthetic life competed to the death for light, space and nutrients, all others preyed upon photosynthetic life and each other. Laboriously gained solar energy was the prize ever again ripped from the still living body of its most recent owner. Nothing was sacred or secure. The battle for life could be won repeatedly but lost only once.
Those displaying particular nucleotide sequences might come and go like mirages but DNA itself would abide. At its most basic level, life’s turmoil and frenzy repre- sented unending unorganized elimination bouts between randomly revised wraith-like momentarily embodied information packets. And those combatants who survived long enough to pass along a slightly revised DNA sword and shield thereby armed their descendents for further mindless and ever more complex battles.
While this might seem an incredibly wasteful way to proceed, advances came from everywhere, everyone played, everything served. With no goal in sight, all changes had equal significance. Though the latest innovation rarely endured, that passing blur was life in its usual fast-forward setting.
However, all was not just “kill or be killed”. At times, unplanned cooperation suddenly became the only pathway toward survival. Not uncommonly this oc- curred when one bacterium or cell penetrated or engulfed another, yet neither could dominate. Under such chaotic circumstance, cooperation sometimes brought unexpected dividends. And if certain of these interlocked former combatants came 133
to control critical information or metabolic processes, the improvement in cell capability and organization often brought significant reproductive advantages to all participants. So after one or two billion years of life’s fumbling and bumbling about, some descendents of formerly free-living individual bacteria found them- selves in new roles as chloroplasts and mitochondria that came with full eucaryotic benefits. But despite their release from the burdens of solitary existence, these symbiotic subcontractors remained under intense pressure to enhance efficiency—
otherwise they and their cell mates could not prosper. Increasingly it paid to be helpful to other subcellular organelles, for the success of that home cell determined the survival of all. Yet just as in politics, long-range planning did not exist at any level, the public interest was irrelevant and even though progress was defined as any outcome of competition by any means, relentless changes continuously added ever-growing complexities to the overwhelming information burden.
Despite many constraints, innumerable simple partnerships also developed between individuals or groups of free-living bacteria or cells, with utterly selfish participants inextricably entangled in some mutually sustaining reproductively fa- vorable relationship. Larger gatherings of closely related cells also occurred. However, the organization of any multicellular cooperative still depended primarily upon adherence among soft and easily torn cell membranes. And when such a group of cells was ripped apart, any surviving cell had to fend for itself or it left no descen- dents. So the individual cell partners within most multicellular arrangements remained very similar in their abilities and needs, since few would gain reproduc- tive advantage by irreversible specialization within what might be just a temporary group. The inevitable competition between such similar cells placed severe con- straints on group size and information processing abilities in the pre-collagen era.
Collagen Caused Kindness Through Specialization Of Cells
Animal evolution never really took off until sturdy extracellular collagen frame- works became available to stabilize multicellular systems and thereby guarantee individual cells lifetime employment. As in subcellular communes, closely related member cells remained under desperate pressure to enhance the group’s efficiency in the face of ever-growing challenges by competing organisms. Although surpluses generated were immediately reinvested, each evolving design soon succumbed to newer, more fortunate or effective organizations. However, by making it possible for animal life to take this next huge step up the organizational ladder, collagen brought the first measure of kindness to intercellular relationships. Before collagen, every cell had to fight for its own reproductive opportunities. After collagen, it
took cell specialization to keep a multicellular animal in the running. And under that relentless pressure to specialize, most member cells gave up their own repro- ductive potential so that the group might survive—placing their reliance upon those pampered sex cells to move the group’s shared DNA into the next generation.
Thus your brains, brawn, beauty and metabolic skills reflect the successful repro- ductive efforts of your ever more efficient, specialized and talented multicellular ancestors as a myriad of less well-endowed creatures (our subjective judgment) fell by the genetic wayside. Of course, having such a huge number of specialist non-sex cells in charge of the production and distribution of your eggs or sperm explains why being female or male has played such a major role in your growth and devel- opment. And why you have so much trouble getting your mind off sex. It is all quite delicately balanced. If you devoted any more time and attention to sex it could become a serious reproductive disadvantage, for you might starve or other- wise neglect your daily needs or safety. On the other hand, any less time and effort devoted to reproductive concerns might leave the best opportunities to those more eager.
Certain conclusions seem inevitable. One reason children usually survive child- hood is that they have become tough through natural selection—after all, not one of your direct ancestors ever died in childhood. Furthermore, you are here only because your parents took a lot of extra time and went to a great deal of trouble to engage in frequent sexual intercourse rather than indulge in other less strenuous or repetitious activities then available to them. This despite the fact that those other activities might have left them healthier, wealthier and wiser, or at least more rested and better fed. And fortunately for our fully populated Earth with all of its nearly identical people, it has again become possible for humans to separate the enjoy- ment of sexual information transfers from the duties and pleasures of reproduction, just as their bacterial forebears did at the start. Not surprisingly, when given the opportunity and despite all religious teachings to the contrary (for many religions thrive on subverted sex drives and guilt), most humans tend to favor other cur- rently beneficial activities over maximizing their personal reproductive success.
Indeed, where decent health care and reliable contraceptives (means for the avoid- ance of pregnancy other than giving up sexual intercourse) are readily available, the birth rate automatically settles toward population sustaining levels. Thus human experience confirms what you already knew instinctively (via inherited informa- tion)—that there are two separate fundamental drives—sexual desire and the urge to reproduce. Ordinarily, the more frequent desire to enjoy heterosexual intercourse obscures the more basic urge to have children. That sexual activities are usually so
pleasurable simply emphasizes their importance in encouraging reproductively ad- vantageous behavior.
Thus it really shouldn’t matter if sexual intercourse originated as deviant bac- terial behavior caused by a perverted attack of mutant plasmid information. It only matters that such DNA exchanges proved reproductively advantageous for both the plasmid and its bearers who, once they learned how, lived sexually ever after (and apparently enjoyed it). Only when sexual intercourse becomes difficult or distasteful, or where contraception reliably prevents pregnancy, does reproduction depend primarily upon the wish to bear children. Your strong primary sex drive certainly makes evolutionary sense, for it often takes repeated sexual intercourse to bring about a successful pregnancy. But it also helps to have another even more basic urge to fall back upon if sexual interactions somehow fail to please. So effec- tive and safe contraception remains a blessing from any reasonable point of view, for it helps man and woman to bond in a warm mental/physical/sexual relation- ship according to their needs and desires, while reproduction becomes a preplanned, eagerly anticipated event rather than an unexpected, often dreaded or even intoler- able burden (see Reproduction).
Collagen
A glance from the window of an average American home suggests that Earth is owned and operated by humans—yet we are but the tiniest sample of all the wild and wonderful creatures that have roamed through sea, land and sky. This may be your big moment in life’s endless succession but collagen is what allowed the entire competitive escalation of multicellular complexity and information-processing ca- pability to begin—for only collagen could ensure that altruistic sacrifices made by closely related cells for their peers would not be in vain. Small wonder that collagen is the most common animal protein, one quarter of your dry weight.
Life struggled ceaselessly for three billion years before collagen was invented.
Undoubtedly, an endless number of other equally essential and even more immedi- ate concerns also held up evolutionary progress. But just think how far you might have evolved and what sort of place Earth might now be if this sturdy extracellular protein had entered common usage one or two billion years earlier. So why did that insoluble extracellular fibrous framework take so long to develop? Might it have been a mere conceptual impasse rather than a complex biochemical problem? That a cell cannot afford to specialize in the absence of collagen fibers, yet a cell must specialize in order to produce collagen fibers? Perhaps some of what is known about collagen can help you to contemplate that question.
While it comes in many varieties, the fundamental collagen polypeptide is a helical (spiral-shaped) molecule about 1000 amino acids in length. Three such polypeptide chains—tightly wound together and hydrogen bonded—create a triple- stranded rod-like protein molecule 3000 A° long and 15 A° wide (to keep that in scale, remember that one Angstrom =10-10 meters, so 10 billion Angstroms = 1 meter.
More importantly, individual cells often measure about 10 microns across and 10 microns = 105 A° or one hundred thousand Angstroms—which provides some sense of the difference in size between an ordinary cell and a very large extracellular molecule). Each long and rope-like procollagen triple helix is initially secreted as part of a loose fiber bundle by elongated cells known as fibroblasts. Once delivered into the extracellular space, the procollagen molecule has its protective amino acid end-tufts trimmed off by extracellular enzymes known as procollagen peptidases.
Those freshly trimmed procollagens, now referred to as tropocollagens, rapidly self- assemble into orderly layers with 400 A° gaps between adjacent tropocollagens in the same line—those 400 A° gaps are staggered between rows so that only every 5th row matches. The stiffness of the resulting collagen fibers and sheets depends primarily upon the extent of covalent cross-linkages among tropocollagens—par- ticularly between lysine and hydroxylysine—amino acids that are especially common in collagen.
So there you have the simple basic structure that possibly delayed your arrival for billions of years—a regularly repeated sequence of three amino acids (com- monly glycine-proline-hydroxyproline) in each of three long tightly twisted amino acid chains that together form a straight fiber capable of resisting great tension.
Once in the extracellular space and trimmed, those fibers rapidly self-aggregate into the sturdy cross-linked water-insoluble extracellular fibrous meshwork that holds you together while also resisting and transferring pressures and tensions due to muscle contractions, gravity and other accelerating forces.
Good Proteins Come In Small Modules
Interestingly, every collagen gene includes about 50 short exons and half of these exons are just 54 nucleotide pairs in length—which allows them to specify a helical polypeptide 18 amino acids long that makes exactly 6 full turns. This ar- rangement positions a glycine centrally within the triple helix during each complete three-amino-acid turn. And that is essential, for were a larger amino acid to take glycine’s internal position, the resulting unsightly bulge would prevent hydrogen bonding between the –C=O and H–N– of adjacent polypeptide chains, thereby allowing easy unraveling and a disastrous loss of tensile strength (just as a localized separation anywhere along its length will weaken a fully closed zipper).
Collagen is certainly an unusual protein (if one can call something that com- mon “unusual”) but other strong extracellular protein fibers such as silk and elastin are similarly based upon regularly repeated amino acid sequences. In addition to resisting tension, elastin can stretch to several times its original length and still spring back to the starting condition. That elasticity may result in part from the way covalent bonds crosslink a great many elastin molecules into a meshwork pattern with easy extensibility in all directions. Furthermore, the many hydrophobic amino acid side chains of each 700-amino-acid-long elastin molecule tend to form tight water-excluding hydrogen-bonded spirals in between those sturdy covalent crosslinks—the way such hydrogen bonds separate and reform apparently gives the entire elastin structure a spring-like response to being stretched.
Elastin is a major component of elastic tissue, along with fibrillin, a connec- tive tissue protein that is particularly abundant in elastic tissues (and also found in the periosteum of your bones and the suspensory ligaments of your eye lens). Elas- tin has minor importance in most collagenous connective tissues except where its ability to store tension can reduce work, as in certain modified leg tendons that give more bounce to horses and kangaroos, or in the neck tendon of grazing ani- mals that must frequently raise their heads to detect approaching carnivores, or in your own stretchy aorta that stores your arterial blood at elevated pressures (see Circulation). But the ongoing formation of covalent crosslinks causes elastin to gradually stiffen with advancing age.
You Are A Monkey’s Aunt (Or Uncle)
Certain modifications of the primary collagen molecule allow it to become more heavily cross-linked in locations such as your Achilles tendon where stiffness is a virtue. Other variations include carbohydrate to encourage formation of col- lagen sheets rather than tendons. But successful collagen formation always requires an adequate supply of Vitamin C (ascorbic acid), for this strong reducing agent maintains prolylhydroxylase (an essential enzyme) in its reduced ferrous (Fe++) active state. The least cross-linked (hence lowest-melting-point) collagen is found in soft- fleshed cold water fish, while heavy hydroxylation of prolines is necessary to stabilize the more chewy collagen of warm-blooded creatures. Most animals produce their own Vitamin C, but all primates (you and your ugly ape and monkey relatives) and guinea pigs as well, have lost that ability. Presumably that need for dietary Vitamin C arose by separate but similar mutations in an ancestral primate and an ancestral rodent since no other mammals have that problem—or does God perhaps require Vitamin C, just like man in His image? Although hunter/scavenger/gatherer diets
generally consist of fresh (living or recently deceased) foods containing plenty of Vitamin C, the inadequate preservation of your animal and vegetable victims for future use could lead to a diet deficient in Vitamin C. And if you subsist exclusively on such an inadequate (because long-dead) diet for several months, your continu- ously reconstructed collagen may then become inadequately hydroxylated—such poorly bonded collagen fibers will melt (separate) at ordinary warm-blooded body temperatures.
On the other hand (for reasons that remain unclear), the sturdy collagen of deep sea hydrothermal vent worms includes little hydroxyproline, yet it remains stable at far higher than boiling temperatures (maybe even up to 250°C) under pressures that exceed 260 atmospheres. Perhaps those pressures squeeze such col- lagen fibers together sufficiently to enhance their van der Waal’s interactions (just as high undersea pressures reduce cell membrane fluidity)—in which case, these worms should pull apart easily if rewarmed (nearly boiled) at the sea surface. Signs of scurvy (Vitamin C deficiency disease) include loosening of teeth, spontaneous skin bruising, poor healing of wounds, weakening of blood vessels and a great many other distressing complications of weak collagen up to and including death.
Vitamin C has additional important functions unrelated to collagen—for example, in the metabolism of certain amino acids and the construction of your adrenal steroids. Ordinary amounts of Vitamin C appear to enhance your resistance to infection—the effects of larger doses are still under investigation (e.g. as antioxi- dants to minimize intracellular accumulations of those oxidised and therefore dysfunctional proteins that are associated with aging).
After Life Comes Glue
So how did this family of sturdy, insoluble, fibrous proteins ever get a name like collagen (meaning “to produce glue” in Greek)? What possible relationship is there between glue and such strong stringy stuff? Well, not so long ago, as automo- biles rapidly replaced horses, the perplexed driver of an obviously disabled vehicle at the roadside often received merry but unwanted advice such as “Get a horse!”
from passers-by whose own transport still happened to be working. Large numbers of dead and disabled vehicles soon littered the countryside, providing a marked contrast to the quiet patiently plodding hayburners of yesteryear that only rarely were encountered in a disabled or dead condition. In good part, of course, the lack of end-stage horses lying about was explainable by their large stores of readily recy- clable organic materials. Unlike a dead car that might remain more or less intact for recycling at anyone’s convenience, dead horses rapidly became very offensive when
undergoing spontaneous decay with the aid of bacteria, worms, insects, birds and other reducing-power-attracted opportunists such as your freshly washed dog. On the other hand, if delivered under its own power in a timely fashion to a glue factory (rendering plant), that faithful worked-out old dobbin could return to ser- vice as soap, explosives, cat food, leather belts, cowboy boots and fertilizer. Any collagenous left-overs (bones, tendons, ligaments, noses and hooves) were readily boiled down to create animal glue or produce those fine flavorless packets of cook- ing gelatin. So how does boiling convert a naturally tough stringy insoluble protein into a soluble denatured protein that firmly fastens unfinished wood surfaces to- gether or tastefully stiffens a hot liquid into a jiggling solid as it cools?
You may recall that a great many hydrogen bonds (which occur when the rela- tively positive hydrogen already in covalent bondage to one O or N is irresistibly attracted toward an adjacent relatively negative O or N) stabilize each triple-stranded tropocollagen into a very strong protein string. But when such protein strings are heated to boiling, the added thermal energy causes such a flailing of individual polypeptide strands that the hydrogen bonds between them are progressively dis- rupted. As they then whip about ever more freely, these long twisted polypeptides become inextricably entangled about each other and their covalent crosslinks. Thus in contrast to linear DNA (which lacks covalent crosslinks and is most stable when complementary double-strands match perfectly), collagen becomes so entangled during complete denaturation that it can never regain its linear triple spiral form.
Of course, all of those disrupted hydrogen bonds make denatured collagen very attractive to adjacent polar water molecules, which encourages denatured collagen fibers to dissolve in hot water and then produce a stable jelly as those cooling gelatin molecules whip about less vigorously. In other words, gelatin stiffens water by forming an interlocking water-attracting tangle or lattice structure throughout the solution. That allows boiled turkey bones and other dead animal parts to be- come nicely jellied soups as they cool. And gelatin glue naturally adheres to any nearby polar (thus wettable) surface as its multitude of hydrogen bonds become available through evaporation or absorption of water molecules into the wood.
Despite that useful role as glue, gelatin lacks an organized fibrous structure, so it would not resist your tissue tension even as well as the most defective collagen produced without Vitamin C. Or as they say, ask a simple question…
Extracellular Space Can Be A Busy Place
Collagen is laid down in large parallel bundles at locations where it must transfer a great deal of tension between two bones (as a ligament) or between a