Sunday, November 12, 2017

The Demeaning of Life...Chapter 2: Miracle Molecule

I’m re-posting chapters of my work-in-progress, The Demeaning of Life. Last winter, I did major re-writes and rearranged the order of a number of chapters. This one, about DNA, has not been significantly altered but I’m posting it again for the sake of continuity. Plus, it’s one of the most compelling accounts in the whole book. Read this, and the world will never look quite the same….


That morning, Watson and Crick knew, although still in mind only, the entire structure: it had emerged from the shadow of billions of years, absolute and simple, and was seen and understood for the first time. Twenty angstrom units in diameter, seventy billionths of an inch. Two chains twining coaxially…one up the other down, a complete turn of the screw in 34 angstroms. The bases flat in their pairs in the middle… a tenth of a revolution separating a pair from the one above or below…one groove up the outside narrow, the other wide. A melody for the eye of the intellect, with not a note wasted.
            
Horace Judson, The Eighth Day of Creation

Few things could better express this tendency of jadedness toward the natural world than how people regard DNA…and the entire subject of genetic inheritance.
Most people are at least vaguely aware of what DNA is; any high school student who has taken Biology 1A knows the gist of its story. College students learn a somewhat deeper account, still very much abbreviated. As for the entirety of the famed double helix’s astoundingly elaborate narrative: among geneticists and molecular biologists (even including educators in those fields), probably only a few are intimate with their area of interest down to its finest minutiae. Meanwhile, a multitude of able researchers resolutely work toward a goal of piecing together the final details and filling in a few gaps.
 Less than fifty years passed between the discovery of DNA and completion of the Human Genome Project—largest collaborative biological study in history. This colossal undertaking, bearing so much promise, fell short of generating the world-wide enthusiasm resulting from DNA’s discovery, despite plenty of media hoopla. Yes, times have changed, but it leaves me cold whenever I encounter this strange, distinctly blasé attitude (conveyed in speech or print) when the subject of “the miracle molecule” comes up. And what this has to say about our conception of life, our collective lack of imagination. No doubt this is partly the result of a shared cultural ennui together with DNA’s profound—even alien—nature. Some people profess to believe it is “just a chemical,”[1] just another molecule, albeit a very large one with some singular characteristics. Although DNA actually is just a chemical, nothing else is even remotely in its class. And not just in the realm of chemistry: nothing at all. DNA is absolutely beyond compare.
A quick review is in order. Prepare to be astonished.
Deoxyribonucleic acid, perhaps nature’s greatest innovation, is truly ancient. While almost universally assumed to have arisen from simpler precursors, DNA has likely changed hardly at all since life’s earliest days, so impeccably is it suited for its all-important role. Earth’s surface has been repeatedly transfigured, continents have come and gone, while this strange substance has persevered. Nothing on Earth has remained unaltered for anywhere near as long. Every individual molecule is uniquely different but identical forms of DNA reside inside every cell of all known organisms, with few exceptions.[2] Each strand has ties with the original in one unbroken hereditary chain. Though seldom acknowledged, DNA’s antiquity and continuity are statements of    tremendous import that color life’s entire story. 
The molecule is shaped like a continually twisting ladder composed of two  complementary strands. Both strands are uninterrupted chains of modular subunits known as nucleotides, each of which consists of a linked phosphate (PO) and ribose (a sugar, CHO) attached to another component called a base. Every nucleotide’s phosphate–ribose components form unvarying, identical subunits joined end-to-end to fashion the molecule’s two backbones (the ladder’s upright members). The base components, however, come in four varieties. Small, fairly simple molecules, they line each nucleotide chain in a variable sequence. The bases lie between the backbones, one from each side joined in the center by hydrogen bonds,[3] forming base pairs. In the ladder analogy, these pairings represent the rungs and their shapes and arrangement impart DNA’s twining configuration. Of critical importance: of the four bases (their chemical names by custom abbreviated T, A, C, and G), T can bind only with A, C only with G.
These bases, each with unique identities, comprise a four-letter genetic “alphabet” from which the genetic code is derived. (Genes are sequences of these “letters”[4] that are transcribed into coded instructions used to assemble ornately structured proteins—an exceptionally important class of molecules which, among their many roles, act as machines that perform a multitude of vital tasks.[5]) The two strands are complementary; during mitosis (the process of cellular division) they are physically separated and each half is used as a template to make a replica of the other.
Thus, once reconstructed, there are two copies (both identical to the original) and each daughter cell receives one. This is how genetic information is passed on; each cell bears all the information needed to construct an entire organism but most of that information is either never used or is “switched off” when not needed. In eukaryotes—life forms whose cells possess a membrane-bound nucleus where all genetic material resides—DNA is bundled into a number of discrete, paired packages called chromosomes. But in the unicellular prokaryotes (organisms such as bacteria) just one or two circular chromosomes float freely through each individual’s watery interior.
 Human cells each have 23 pairs of chromosomes (one set from both parents) for a  total of 46; the different pairs vary considerably in size depending on the quantities of DNA they contain. Also: different types of organisms have different numbers of chromosomes—a figure that can vary a great deal even in similar groups, with no obvious pattern. (For instance, the number in a single genus of ant, Myrmecia, ranges between two and 84 depending on the species.)
Consider these curious facts: In humans, if all the DNA contained in just one cell’s 46 chromosomes (by some estimates comprising around 200 billion atoms[6]) were stretched out and laid end-to-end to form a single strand, though only ten atoms wide it would be almost six feet long. In our bodies, each cell’s set of chromosomes contains an estimated 3 billion DNA nucleotide “letters”—all this compactly stored in its nucleus. Our bodies contain around 30 trillion cells, a figure that amounts to roughly 450 times Earth’s current human population.[7] Thus: if all one’s personal DNA were drawn out and laid end-to-end it would wrap around the equator [Drum roll, please!] well over one…million…times. Ladies and gentlemen! Pause for a moment and try to consider what these weird and wonderful things might signify. Keep in mind: all that DNA fits inside your body. It is inside you right now.
Normally, chromosomes are loose in the nucleus in the form of slender threads made up of the actual DNA molecules wrapped around spool-like structures called histones. These bundles are coiled tightly into chromatin fibers which, for the most part, float freely but are attached at many points to the nuclear membrane’s inner surface.  However, prior to replication they have to be isolated and further compacted. No simple matter, this is accomplished with the aid of an army of protein helper molecules. (Amazingly, there are some 4000 specific types of these assistants.) The cobweb-like array is detached from the nuclear membrane and the chromosomes twisted into tight coils. These twist into tight coils that coil yet again, resulting in a dense clump of genetic material. After replication and division, the process is reversed and the new chromosomes are unwound. But, before the chromosomes briefly take on their so-called “condensed” form (the plump “X” shape people are most familiar with) they have to be replicated.
The duplication process is staggering in its complexity and exacting coordination. Prior to mitosis the chromatin fibers are unwound, making them accessible to swarms of replicating enzymes. (Enzymes are special protein molecules that assist with reactions; more about them shortly.) There are numerous replication sites on each chromosome and the DNA is duplicated in short stretches that are detached and later rejoined. Replisomes, complexes of various protein machines involved with the duplication of the two strands after separation, work in paired teams. Around 100 pairs seize specific places on their chromosome and begin working in opposite directions, churning out new strands at the rate of 50 nucleotides per second. Each of the chromosomes are duplicated simultaneously; with thousands of replisomes operating throughout the nucleus, all the cell’s DNA can be replicated in about an hour.
A family of more than 30 types of enzymes is involved: helicases separate the two strands; DNA polymerases gather free-ranging nucleotides and place them in position. Topoisomerases “relax” the tightly coiled DNA and one type, gyrase, keeps the twisting strands from becoming hopelessly tangled by temporarily breaking them and allowing the kinks to unwind before rejoining them. While the two halves are divided they are highly reactive; to prevent them from being chemically attacked or re-attaching prematurely, single-strand binding proteins are called up to temporarily cap the exposed nucleotides. Ring-shaped clamp proteins form a sliding clamp around the DNA near the point where the two strands are separated to help the polymerase maintain firm contact with the section being replicated.
This is a mere sample of the players involved. As remarkable as it might seem, the entire, fantastically intricate extravaganza is understood in precise detail. And those details, in both number and kind, are almost beyond belief. (This limited description be-lies the true state of affairs.) What is not known, though, is how the whole performance is coordinated so seamlessly, how the strict sequences are timed and reaction rates controlled. And just how seldom things go wrong (especially compared to any human endeavor). A single mistake—just one—can be fatal for any cell. Or, if the error turns up in an egg or sperm cell, fatal to the organism’s offspring. That one slip-up could result in a defective gene, which might lead to the imprecise formation of a single type of protein, which in turn could result in something like type 1 diabetes or sickle cell anemia.
So: accuracy in the entire process is crucial. Suites of repair enzymes proofread the duplicated strands and mend damaged or incorrect sections. Robert Wesson writes:
“One set…monitors that the right amino acid is put in place; another set checks that the newly forming DNA corresponds to its template and cuts out and replaces defective sections; a third confirms the finished product,” in the case of E. coli making less than one error per billion letters. And just for a reminder that these efficient workers are complex machines and not little toy-molecules: one of the repair enzymes, composed of some thousands of atoms, is named phosphatidylinositol 3-kinase-related kinase.
Among its many astonishing properties are DNA’s surprising durability and chemical stability. Still, it is constantly being damaged due to various kinds of physical impairment, from oxidation by free radicals (highly reactive molecules and ions) or, in skin cells, exposure to ultraviolet light or X-rays. But thanks to teams of fix-it enzymes, the DNA of each individual cell can undergo repair from 10,000 to one million times per day, most of it successfully. Close to 170 specific varieties of enzymes are involved with different aspects of DNA repair (including the much different problems associated with sigle-strand repair as opposed to mending a double-strand break). The entire process is now recognized as being absolutely essential for the survival of all organisms. According to recent estimates, without these proofreading and repair systems, roughly 1% of bases would fail to be copied correctly—a quick and certain route to extinction.
Not bad…no, not too bad for something that is “just a chemical.” Bearing in mind that DNA is “only” a molecule, consider once more its bewildering sophistication: a lifeless aggregation of atoms that orders the construction of virtual armies of assistants; these helpers then unwind it, take it apart, and faithfully reattach these fragments after making sure they have been copied accurately. This, a consequence of the DNA having supplied another suite of elaborate protein machines with blueprints for the   assembly of all those helpers (together with furnishing instructions for the fabrication of the machines that built the machines.)
In addition, DNA fixes its own damaged parts and mistakes made while being rep…li…ca…ted. For some reason, incomprehensible to me, most people do not seem to think that self-assisted self-replication is too tall of an order for a mindless molecule.
And as for DNA’s role in the process of genetic inheritance: that equally remarkable saga will be delved into later. Suffice it to say, for now, that the tale shares the same qualities of neat efficiency and dazzling intricacy. Another extensive team of molecular players in backing roles help bring forth all its enormous potential.
Never overlook the fact that DNA is not only entirely passive but utterly useless without the help of its legion of confederates, each of them being equally essential. The miracle molecule is plainly not alive in any accepted usage of the word. But how can we continue to ignore the obvious? That in some sense DNA (along with the entire system-cum-process involving a host of assistants) is animated by the same quality—whatever it might be—that separates living from nonliving? At what point do these far-fetched molecular associations and interactions earn new biological status? Or, from a non-scientific point of view, at least a different sort of emotional response?
Viewing these matters through the lens of Natural Design provides a standpoint from which such wonders meld perfectly with the greater picture of what life is capable of. The double helix could be considered the ultimate expression of nature’s creativity. It did not simply “happen”—it was a necessity invented by nature to fill an indispensable role. The late Bill Gates wrote, “DNA is like a computer program but far, far more advanced than any software ever created.” As a chemical solution to the problems of reproduction and inheritence, it has functioned flawlessly for going on four billion years. True to its paradoxical nature, DNA’s unwavering stability makes life possible while an innate fluidity makes it possible for living things to evolve. And life’s built-in knack for changing through time in beneficial ways is central to its success.      

   ©Tim Forsell   draft                       27 Feb 2017                                                       



[1] Wade, N. (1995) “Method & Madness; Double Helixes, Chickens and Eggs,” New York Times Magazine.  “An ark’s worth of species flower and fade at each tick of the geological clock. Only DNA endures. This thoroughly depressing view values only survival, which the DNA is not in a position to appreciate anyway, being just a chemical.” (Wade, it should be noted, is explicitly writing with reference to Richard Dawkins’ “selfish gene” theory.)
[2] One instance is vertebrate organisms’ red blood cells, which have relinquished their DNA (and the cell’s entire nucleus) in the interest of smallness—the better to navigate through minute capillaries and carry more oxygen.
[3] Unlike covalent bonds, wherein atoms “share” electrons, hydrogen bonds are much weaker. They form between separate molecules when a weakly positive hydrogen in one molecule is attracted to a slightly negative atom in the other. Hydrogen bonds are of great importance in nature (accounting for the fluid properties of water, for instance). The hydrogen bonds between the nucleotides, it should be noted, are a most opportune balance between the strength needed to maintain the molecule’s durability and what is necessary for the two strands to be easily separated.
[4] To be clear: these “letters” form the basis of a language analogy and are unrelated to the bases’ single-letter abbreviations.
[5] Proteins are a class of organic (carbon bearing) molecules. There are around a million known varieties. Unlike inorganic polymers—chains of repeated elements or monomers—proteins are made up of highly specified sequences of modular building blocks called amino acids. Chains of amino acids are joined together to form polypeptides, which are then further processed to create the proteins. These act singly or in combination, making up the cell’s working parts.
[6] Note throughout this work that most of these impressive “facts” are, in actuality, akin to estimates or “educated guesses.” As is customary, they were conveyed without any qualification as to their range of accuracy. Some could easily be off by orders of magnitude.
[7] Estimates of extremely large numbers (some of them apparently little more than wild guesses) may be off by several orders of magnitude. Whatever the figure: it is obviously somewhat arbitrary, particularly when dependent on a number of factors.

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