Sunday, May 15, 2016

The Demeaning of Life...Part VIII

This section is essentially a quick review of genetics in the context of how genes physically manipulate information—not how that information is put to use. The point is to emphasize my key premise: that life itself has creative capacities beyond our current understanding…its productions aren’t simply the result of chance and time but are somehow under the influence of some guiding principle. Beginning with the rediscovery of Mendel’s work, the mechanisms and methods of genes were gradually worked out, one small step after another, with major breakthroughs along the way. The achievement of teasing out the details of genetic inheritance has been nothing shy of extraordinary and is truly one of science’s finest efforts, with countless researchers building on the findings of their predecessors to piece together a fabulously intricate narrative. While this story is far from complete the way ahead is clear: improved methods of gathering data (and, especially, of processing the bounteous haul) and new technologies will only accelerate the discoveries made by future geneticists. What will they find? I predict they’ll uncover new layers of sophistication and complexity unanticipated by those who once saw their field as operating by simple, cause-and-effect laws. And I continue to press the notion that a confidence bred of continual success has resulted in a sort of “blind spot.” We haven’t quite reached a place where it’s overwhelmingly evident that nature actually engineers solutions to the myriad problems it faces. The essence behind the workings of DNA, the cell, inheritance, evolution…it arises from the same thing, a thing we have no name for, which thus remains hidden in plain sight. My goal, ultimately, is to make it impossible to ignore the obvious: that what animates the inanimate is not what we believe it to be. All along, we’ve been standing too close to see it clearly. 


VIII.  Genes, and How They Work 


Evolution has been a process of discovering ways in which organisms can be put together, and it is to be expected that the genome must be a complexly integrated entity, like the animal that it can organize. It is not a jumble of traits but a unitary self-regulating and self-organizing system. In order for the organism to become established and to subsist, it must have an almost incomprehensible inherent stability.

                                                    Robert Wesson, Beyond Natural Selection

Aside from the study of embryological development, perhaps nothing in biology better demonstrates the truth about life being more than “just chemistry and physics” than the byzantine workings of genetics.

After reading this statement, any card-carrying biologist—unable to contain themselves—would interrupt to heatedly assure readers that such was not the case: The science of genetics is very  well understood and indisputably a function of “just” chemistry and physics! But is this actually the case? I say…no, given that biochemistry has exposed a nano-world where cells and even atoms demonstrate a type of intelligence that was unrealized when one could make such a definite statement. All matters related to genetics reveal life’s innate creative intelligence operating at beyond-belief levels of organization.

The complexities of the subject are legendary. Mendel’s famous experiments, with their logical and clear-cut conclusions, demonstrate the scientific method at its  finest. To this day his results remain the “text book” illustration of genetic inheritance, lending themselves to precise diagrams ideal for biology classes. (Many readers will remember them…and with mixed feelings.) While the reasoning may have been difficult to follow, those bifurcating charts lent the subject an aura of rational coherence. However, since Mendel’s time all matters pertaining to genetics have grown so technical that non-scientists can only expect to understand the most basic elements.

Recall that one of the key premises of the neo-Darwinian synthesis was the notion that random copying errors could lead to beneficial mutations. During a brief period at the beginning of the 20th century it was widely thought that each gene was responsible for the creation of one protein, which was in turn responsible for one trait. (Yes, they were simpler times.) And in those early days of the synthesis, lay scientists—and even some specialists—formed misguided notions about Mendelian inheritance’s deceptive quality of clear-cut intelligibility. This lured some into believing the solution to existing genetic questions would prove straightforward. In retrospect, such innocent thinking is somewhat surprising; embryology was a rapidly advancing field at the time and it was already recognized that even the simplest of organisms’ early development was an extremely involved affair.

All this, then, contributed to a somewhat naïve faith in the inevitable solution of genetic riddles. At that time there certainly was good reason to feel confident that modern scientific methods would eventually clarify every last detail of how genes operate. But the brand new discipline of population genetics—an abstruse discipline if there ever was one—soon dispelled any notions of the subject being straightforward.      

A bare bones genetics primer is in order to provide some background for the uninitiated or biologically rusty. Again, the picture presented here of how genes “work” (as opposed to what they “do”) is terribly oversimplified, with significant gaps in a narrative whose intricacies already make it challenging to follow. Our conception of genes has changed considerably in recent decades; while the classic model retains many merits and has proven its explanatory worth, keep in mind that genes are constantly interacting, fluid entities and no longer thought of as having well-defined configurations. A gene is not a “thing.”

Recall that sex cells (eggs and sperm) each have one set of chromosomes. When an egg is fertilized the two sets unite and, in all subsequent divisions, daughter cells receive one set of doubled copies (one from each parent). The DNA in each half of the chromosome carries the same genes and in similar sequences, but the information they possess will be slightly different. Genes are entirely passive and never leave the safe  environs of the nucleus. (Some, though, are positioned on sections of chromosomes attached to the nuclear membrane’s inner surface; this makes them accessible to molecular messengers in the cytoplasm that can receive and carry vital instructions to other parts of the cell or beyond.) Many act as blueprints for the construction of proteins. Some code for the assembly of protein machines. Others, the crucial master genes, direct many such activities—most importantly, the entire process of embryological development, or ontogeny. [This will be the topic of a later section.]

Some genes are dominant while others are recessive. Dominant genes tend to be the ones physically manifested—expressed—but recessives, even after being hidden in a population for multiple generations, can suddenly reappear. The trait expressed may then quickly disappear again or spread throughout a population—under certain circumstances even achieving dominance.

Only one of DNA’s intertwined halves carries genetic information: the template strand. (Its complement provides the instructions needed to create a new template strand during replication.) A gene, then, is essentially a segment of the DNA template strand consisting of a number of the nucleotide base “letters”—A, C, T, and G—which, collectively, act as a pattern for the fabrication of coded instructions that are then conveyed to other locations in the cell. They are typically several thousand bases long.[1]

Part of this string of nucleotides consists of a coding region (where the actual directions for building proteins reside). The remainder comprises a regulatory region—a series of binding sites (short stretches of nucleotides) where special molecules called master proteins will dock, thereby influencing how and when the gene is expressed. Each coding region consists of a nucleotide sequence (anywhere between several hundred to a few thousand) which, in essence, is a set of blueprints—or a recipe—written in DNA “letters.” By way of transcription a copy will be made in the form of an mRNA molecule which then, through the process of translation, is used to construct proteins.

Genes don’t function autonomously (as was formerly believed) but instead act only when prompted by other molecules. Some of these gene-regulating molecules are synthesized in the same cell; other types, such as hormones, come from cells in other parts of the organism. Still others, also coming from elsewhere, interact with receptors imbedded in the cell’s outer membrane that then relay a message to the nucleus. Many genes are seldom (if ever) switched on. Competition frequently arises amid conflicting pressures, with gene-activating molecules arriving at the same time as gene-inhibitors; both might interact or compete in ways that influence a cell one way or the other. It’s now widely recognized that environmental influences or external stresses can also turn genes on and off. Substances from an organism’s diet also affect gene regulation; these so-called epigenetic factors, whose impacts were long denied, have proven to be of vital importance in many evolutionary processes and are central to much current research.     

Some genes are passed on through thousands of generations; these remain virtually identical (though they might differ somewhat in specific base sequences) for millions of years and are to be found in organisms only distantly related. Such genes are said to be highly conserved. Some—like those responsible for the production of vital catalysts—are in bacteria that evolved at least two billion years ago as well as humans, demonstrating evolution’s power to preserve crucial features as well as try out new innovations. In fact, there are around 500 genes shared by all types of life forms. More-over, aside from these so-called immortal genes, all organisms—both plants and animals—have many other genes in common. (The more closely related, the more shared.) Lab animals whose genomes have been meticulously documented possess many genes that are very similar to the human counterparts. To give an idea of just how alike: we share around 90% of our DNA with cats, about 80% with cows, 60% with fruit flies, and even nearly 50% with bananas. About 96% of human DNA is nearly the same as that of our closest relatives, chimpanzees.[2] (It should be assumed that any such figures depend to a great extent on the way data is interpreted and, regardless of how they are derived, will likely change.)

In humans, all cells (aside from red blood corpuscles and platelets) contain identical copies of the entire genome though only 5–20% of the genes are active in any one cell. Some are activated only at certain times (such as during the course of embryonic development) or can remain unexpressed during an organism’s entire lifetime.

As for how the information carried by genes is actually stage-managed: Before a protein-coding gene can be expressed it first has to be located, activated, and transcribed. Regardless of original source (that is, whether from inside the cell or elsewhere) signal-bearing molecules first have to enter the nucleus and locate both a targeted gene and the section of DNA bearing regulatory portions that govern it. Called activators, these highly specific proteins are responsible for initiating the entire process. In eukaryotic organisms there are usually several activators; in some instances a dozen or more.[3] Some of these moor at binding sites on a segment known as the promoter, changing shape in the fashion of enzymes as they pile up. Other activators, chemically attracted, in turn bind to these until the whole freeway-crash attains a specific shape. At this point, one of the largest known biological molecules—RNA polymerase—shows up to begin transcription, but it can’t recognize the promotor without help.

 Neurobiologist Debra Niehoff tells about the enzyme’s assistants, “a corps of mechanics and decision makers that biologists call transcription factors,” and what happens next:  

These proteins come in two flavors. So-called general transcription factors assemble at the promoter sequence where transcription begins; they recruit the polymerase and orient it correctly. Other transcription factors are activators and repressors that permit or forbid gene expression. They bind to a distinct regulatory sequence that is not part of the gene itself and may…be located a considerable distance upstream or downstream.[4] Gene activators give a thumbs up to RNA polymerase, recruit and organize the enzyme’s crew of general transcription factors, and exhort the whole conglomerate to work harder and faster. Repressors stifle gene expression by blocking the binding of activators, interfering with their recruiting efforts, or smothering the DNA in more protein.[5]


When the polymerase is ready to step in, it begins transcribing the gene by unzipping the double helix, separating both strands, and reading the gene’s code. Building materials are required to synthesize a complementary strand of mRNA; in this case, instead of nucleotides being delivered by helper enzymes, they’re foraged: a multitude roam freely within the cytoplasmic tumult and are continually zipping by; the polymerase (somehow) recognizes what it needs and simply grabs them in sequence. Transcription is completed when the polymerase runs into another diagnostic sequence that tells it to stop. It releases the mRNA bearing the copied gene, which carries these instructions out of the nucleus and into the cytoplasm where teams of ribosomes will begin construction of the protein. After releasing the mRNA, the polymerase rejoins the fray; assisted by more enzymes, the DNA strands zip shut and the gene is thus switched off. It can be reactivated whenever needed…left on…or never used.

This should provide at least a taste of the amazing process of gene activation.

Then, to further complicate matters: the vast majority of eukaryotic DNA consists of non-gene sequences. Only a small portion of those millions of nucleotide “letters”—less than 2%—actually code for proteins. The coding segments, known as exons, are located between stretches of non-coding material called introns.[6] Formerly known as junk DNA, introns are often significantly longer than the coding parts, sometimes consisting of thousands—even millions—of repeated sequences. (As it turns out, introns actually contain crucial regulatory information in the form of switches and most likely serve other functions not yet known.)

Eukaryotic genes, then, are not in uninterrupted stretches but are interspersed by introns. During transcription the non-coding material is faithfully copied onto mRNA before subsequently being removed and discarded by editing enzymes. The leading end of the gene consists of regulatory segments such as the promotor and neighboring enhancer regions.

This should be more than enough to give an idea of the ultra-elaborate system in place simply to locate and influence genes. Attempting a basic review of DNA’s actual utility (in its role as the bearer of an organism’s genetic material) is almost counterproductive; a synopsis can’t convey any real sense of how the immense amount of information contained in just a single molecule can be manipulated in such a way as to result in a living creature—and one that, in a manner of speaking, has all its fingers and toes. And I have yet to address the even more remarkable matter of how genes actually make fingers and toes…and assemble them in their proper places.

 While it’s still conceptually helpful to speak of genes as if they were minute objects, “doing things” in some sort of logical fashion, in truth the word itself has perhaps outlived its utility. According to James Shapiro, “This term has no rigorous and consistent definition. It has been used to designate countless different features of genome organization. In other words, the use of ‘gene’ gives the false impression of specifying a definite entity when, in fact it can mean any number of different genomic components.” He suggests that in the case of, say, protein manufacture, the terms coding sequence be used to refer to sections of DNA (proximate or not) that account for protein construction and genetic locus to indicate coding sequences, switches, and sections that encode for mRNA which, collectively, code for the fabrication of proteins. (I will carry on with portraying genes in the traditional manner but readers should be aware that geneticists no longer think of them as being discrete packages of information.)

Years ago it was realized that, as then conceived, the number of human genes could not account for the genetic information required to build and maintain a human being—regardless of whether it is the currently accepted figure of around 20,500[7] or even one high-end estimate (circa 1969) of 2 million. Counterintuitively, other creatures have considerably more genes than us: mice have around 23,000; the puffer fish, about 28,000. Even far less complex organisms have a proportionately larger number: the fruit fly, Drosophila melanogaster, about 17,000.

It is the ability to rearrange and recombine gene segments (affording enormous numbers of potential combinations) that occasions the vast number of specific instructions required to assemble any organism. During transcription, the spatially separated exons can be shuffled and spliced back together. Individual exons often code for functional modular units so their recombination can result in the creation of a whole suite of related proteins. Those at higher levels exploit this capacity—termed exon shuffling[8]—to a much greater extent but genomes still can’t supply nearly enough information to account for the myriad details that result in each species’ unique form. Imagine how much information is needed to account for all the nuanced design details on display in something like a bird’s wing, a mammal’s heart, or the shape of a skull. (Not to mention building an adult anything from scratch.) However, the relatively new field of evolutionary developmental biology—known as “evo-devo”—has revolutionized embryology and goes a long way toward explaining how fertilized egg cells turn into things such as albatrosses and anglerfish…or, past tense, into ichthyosaurs and placoderms.                            

How scientists arrived at our present understanding of genes and embryonic development (and their implications for evolutionary theory) following the publication of Origin of Species and up to the time of the modern synthesis is another intriguing story. A quick look at the intellectual climate during those decades reveals that—contrary to what many people believe—Darwin’s revolutionary ideas were not “the only game in town.” Far from it.


     ©2016 by Tim Forsell             14 May 2016                                                                                                                                                                            




[1] The longest known, which codes for a protein found in muscle, holds 2.4 million bases.
[2] A 2005 study  amends the oft-quoted figure of 99% originating from a 1976 paper. While endlessly repeated, the number was derived through highly speculative means.
[3] The large number of activators reflects a cell’s need to act in harmony with trillions of others; the abundance or scarcity of one can influence the number of times that a proper combination can join forces to switch on their targeted gene. “The life of a multicelled organism depends on an extraordinarily complex interplay of thousands of different chemical signals coming from each cell and going to some or all of the other cells that make up the republic…that is the human body.” (Rensberger, p 93.)
[4] These are terms used to indicate the position of DNA regions relative to the direction of the advancing transcription.
[5] For prokaryotes, the way genes and signaling proteins interact is a considerably less involved process than it is with higher organisms. Unlike bacteria, eukaryotes have several types of RNA polymerase. In the nucleus of a human cell, around 40,000 of the variety that assemble mRNA are present at any given time. Several will be transcribing a gene at the same time, adding around 60 nucleotides per second. 
[6] “Exons” refers to sections that are expressed, “introns” to intervening sections. Prokaryote DNA has no non-coding  regions. 
[7] A recent study (2014) suggests that the figure may be closer to 19,000. 
[8] Exon shuffling is an important mechanism in the evolution of novel proteins.

Sunday, May 1, 2016

The Demeaning of Life...Part VII

Nature is fantastically complicated. This one feature has impressed me as much or more than the countless wonders we see around us whenever we step out the door. I’ve taken the view that this inherent complexity has crucial meaning of its own as regards living things and this has been a central message throughout this treatise. In a later section I’ll address the “meaning” of the layers-upon-layers of complexity found in every detail of the living matter and how this quality supports my thesis: Nature has some innate capacity to “design” itself and its myriad fantastic inventions are, in most cases, the ideal solutions to the difficulties and limitations it faces. Photosynthesis and DNA repair systems and all the metabolic processes are simply too convoluted to have just “evolved” in a stepwise fashion without some sort of direction. Read this and see if you can still insist that all these things are simply the result of natural selection and just “happened” through a long series of chance events. This is the story we’ve all been told. But, one more time: we don’t even know what life is, nor what it’s capable of.

VII.  Why Do Things Have to Be So Complicated?


Interviewer:  What do you mean by functional complexity?                                                                    
Schützenberger:  It is impossible to grasp the phenomenon of life without that concept, the two words each expressing a crucial idea. The laboratory biologists’ normal and unforced vernacular is almost always couched in functional terms: the function of an eye, the function of an enzyme, or a ribosome, or the fruit fly’s antennae. Functional language matches up perfectly with biological reality. Physiologists see this better than anyone else. Within their world, everything is a matter of function, the various systems that they study—circulatory, digestive, excretory, and the like—all characterized in simple [and] functional terms. At the level of molecular biology, functionality may seem to pose certain conceptual problems, perhaps because the very notion of an organ has disappeared when biological relationships are specified in biochemical terms. But appearances are misleading. Certain functions remain even in the absence of an organ or organ systems. Complexity is also a crucial concept. Even among unicellular organisms, the mechanisms involved in the separation and fusion of chromosomes during mitosis and meiosis are processes of unbelievable complexity and subtlety. Organisms present themselves to us as a complex ensemble of functional interrelationships.
                                                 Marcel-Paul Schützenberger, interview [1]
   
The simplicity and tidiness of the mechanistic worldview has proved ideal for school textbooks and an increasing number of publications written for laypeople, a genre we know as pop-science. No author consciously intends to limit their readers’ awareness of our world’s complexities (which, indeed, usually require at least some explanatory simplification for the sake of clarity). However, widely read books continually portray the workings of life in an unnecessarily simplistic fashion. Oversimplification doesn’t profit our technically fluent society—one that thrives on complexity—but may be an unavoidable consequence of the need to reach readers with broad ranges of knowledge.
In truth, everything having to do with living matter is staggeringly complicated—with no exception. Educators necessarily simplify descriptions of life-processes to bring such matters within intellectual reach; those who actively promote a conception of nature operating by “simple” rules are furthering a reductionist, mechanistic viewpoint.
Take any generalized account of, say, cell division: readers will be warned of this being a highly involved affair. Following that disclaimer, multiple layers of mentally numbing complexity aren’t merely deemphasized—usually they will not even be alluded to…or even touched upon as a sort of reminder that can prove helpful in acquiring perspective on complicated subjects. Incurious readers seldom think to ask tough questions, having been schooled to assume that the entire train of events takes place automatically and isn’t especially noteworthy to begin with. After all, It’s just chemistry!
Moreover, as fresh data and new findings compel the revision of biological models to reflect added details and nuances, there is typically a considerable time lag in imparting the latest information. (In fact, presenting up-to-date facts and ideas my readers may not have heard about is a major reason for taking on this work.) Another aspect of this struggle with getting current knowledge to the public can be traced to school textbooks; many are repeatedly revised and distributed in the form of new editions without antiquated information being checked for veracity and retired as needed; a good deal of superseded or inaccurate material is disseminated in this fashion.[2] Finally, the broad range of informational veracity found on the internet has created further impediments to attaining quality knowledge. 
Long after it should have become universally recognized that cells are far more complicated than was previously imagined, they continue to depicted in a manner that  makes light of their extraordinary intricacy. Researchers continue to unravel our thorniest problems and many biologists believe that, sooner or later, various lingering unknowns will be clarified. Meanwhile, thanks to biological complexity being undervalued in textbooks and works of pop-science (plus a tendency to flagrantly dumb-down media and internet renderings), our “scientifically engaged” public has acquiesced to a flawed and deficient view of how the living world functions.
 Here are two passages from an excellent book about the cell and current (circa 1996) biochemical research by Boyce Rensberger—at that time, science writer for The Washington Post—that are illustrative of this effectively trivialized approach:
The discovery of self-assembly explains many events in cells that once seemed utterly mysterious. It is akin to learning that the steel skeleton of a building will assemble spontaneously once a load of girders is dumped at a construction site. The genes cause a load of protein molecules to be synthesized in the cell, but the proteins, needing no further control, spontaneously assemble themselves into larger structures. The plan of the final result is implicit in the structure of the components. 
To back up this assertion, he then cited two classic examples of structural self-assembly: the case of microtubules (which spontaneously form when molecules of tubulin—a protein synthesized in all cells—join together in a uniform spiral pattern) and the self-ordering of phospholipids into the bilayer membranes common to all eukaryotic cells. Rensberger promotes a sense that such auto-assemblage is marvelous, yes, but simply the result of an opportune coincidence of chemical properties. 
Rensberger’s descriptions are a bit misleading, though, given that the two key processes are far from entirely automatic (plus, the components have to first be fabricated within the cell). In the case of microtubules, a number of specialized protein machines assist with the construction of new (and degradation of old) tubules along with their attachment to organelles or the cell wall. As for lipid bilayers: thanks to the powerful chemical attraction of lipids in an aqueous solution, they do readily assemble into sheets and vesicles…but functional cellular membranes are actually constructed piecemeal within the cell by the endoplasmic reticulum, then further processed in the golgi, and finally transported in vesicular form to fuse with the targeted membrane.
In the second excerpt, he again de-emphasizes complexity in favor of furthering an impression of straightforwardness and simplicity:
Amazingly enough, some of the regulatory DNA sequences are not situated near the gene they control. They may be hundreds or tens of thousands of bases away. And yet, if the right regulatory proteins don’t bind to them, the gene won’t be expressed. How can this be? How can the gene or the RNA polymerase “know” whether certain proteins have grabbed onto the DNA strand…? Simple. DNA is flexible. It simply forms a loop in itself, bringing the distant regulatory protein into contact with other proteins on the promoter. In the case of the beta hemoglobin gene, there are several regulators…that speed up the gene-activation rate to varying degrees and some that slow it down to varying degrees. Somehow they work it out among themselves how often the gene should be allowed to express itself.
These two examples are typical—not nearly as striking as other cases I’ve encountered—of the cavalier language and rhetoric used to explain such phenomena. Many modern books about these types of subjects are peppered with similar instances; when some involved process requiring multiple steps and coordinated assistance is described, the whole affair is frequently put across in a fashion that deftly underplays its elaborate nature. (A later section will examine this phenomenon more closely.) 
Unquestionably, individual molecular interactions are events involving straight-forward chemical and electrical attractions (or repulsions). The occasional use of superlatives like “amazing” and “wondrous” in books like Rensberger’s Life Itself merely allude to the uncanny ways in which inanimate molecules behave. The reader is routinely assured that such things happen automatically and according to just such types of rationally ordered but non-intentional activity (often with emphasis on there being no mysterious agencies involved—so strange can these happenings seem to non-scientists).
No doubt many, if not most, of the sort of complicated issues I’ve broached have been at least partially explained. However, answers to the kind of questions I’ve posed don’t seem to be included in pop science books. The information I seek is to be found in the plethora of technical literature published in scientific journals.[3]
One thing I’ve noticed, reading technical papers—a noticeable pattern: various molecular participants arrive on the scene of some reaction to play a part in some key process with no word of how they were manufactured, where they came from, or what regulatory agency was involved in their appearance. Such tangential information may have been deemed non-essential or beyond the subject matter’s scope…but its absence often strikes me as intentional (possibly unknown?). Things simply “show up.” 
And show up they do. In their frenetic comings and goings, molecules display a sort of purposefulness that only higher-level organisms are thought to enjoy. Are their coordinated actions, taken together, purely mechanical? Microbiologist James Shapiro writes about “the growing realization that cells have molecular computing networks which process information about internal operations and about the external environment to make decisions controlling growth, movement, and differentiation”:
Bacterial and yeast cells have molecules that monitor the status of the genome and activate cellular responses when damaged DNA accumulates. The surveillance molecules do this by modifying transcription factors so that appropriate repair functions are synthesized. These inducible DNA damage response systems…include so-called “checkpoint” functions that act to arrest cell division until the repair process has been completed…. One can characterize this surveillance/inducible repair/checkpoint system as a molecular computation network demonstrating biologically useful properties of self-awareness and decision-making.
This is not a conventional portrayal of mindless molecules at work. Recall that, in the second excerpt from Life Itself, Rensberger wrote of regulatory enzymes: “Somehow they work it out among themselves.” Obviously, the author didn’t intend to allege truly purposive action being displayed in using this offhand way of explaining the solution to an arcane problem, but simply wanted to carry on with his narrative. In the course of my research, though, never have I seen so much as a hint of there being anything out of the ordinary about the way protein machines bustle about in resolute teams, with individual members making crucial decisions.
Returning to my original statement regarding the nature of life: it has its own intelligence and a quality of self-directedness that is displayed by all organisms—even manifesting at the molecular level. It would be a mistake to equate this form of willful discernment with its human analogue. Nonetheless, these traits are called to mind as it becomes ever more obvious that living things function according to singular kinds of molecular organization—with involvements that go way beyond the ordinary chaotic collisions that make things proceed in cell-world. And behind all such activity there is often an element suggestive of intent.
In fact, enzymes display intelligence-mimicking behavior in the form of a functional property called allostery, made possible by an enzyme’s capacity to change shape such that an active site can no longer bind with its substrate.  
Say a particular enzyme’s job is to catalyze a reaction that produces a chemical whose concentration causes problems, maybe even a fatal toxicity, when exceeding certain limits. How does it “know” when to stop? Solution: the catalyzed reaction’s product (or, if the reaction results in more than one product, one of its elements) also serves as a control molecule. When this product’s concentration reaches a certain level, it starts binding to a second active site on the enzyme, changing the enzyme’s shape so that the substrate is no longer able to dock…and production of the chemical in question ceases. This is what’s known as a negative feedback loop, a vital feature exhibited throughout nature from the nano-scale to the planetary (where, for instance, forms of self-correcting regulation are seen at work in the carbon and hydrological cycles).
Allostery forms the basis of regulation in cells. Physicist-turned-microbiologist Peter Hoffman adds further perspective on the intricacy of these regulatory systems: 
There are more complicated schemes that involve vast networks of interacting enzymes. The product of one enzyme may act as the control molecule for another enzyme, either enhancing or inhibiting its activity. The product of this second enzyme may again control the first enzyme, forming a two-enzyme feedback loop…or the product may influence a third enzyme, which influences a fourth, and so on. Complicated schemes of feedback loops and mutual enhancement or inhibition provide the computing power that makes living cells seem intelligent.
This dual-functionality of proteins—their ability to both carry out reactions and adjust results to some necessary end—is a crucial feature in the regulation of cellular metabolism. Allosteric enzyme activity is essential to prevent the chemical chaos that would result if not delicately tuned to a cell’s strict requirements. Jacques Monod, who discovered the phenomenon in Paris in the early 1960s while working on bacterial cell metabolism, felt the significance of allostery to be so indispensable that called it “the second secret of life.” (The “first” being the genetic code itself.) Horace Judson, in The Eighth Day of Creation:
Allosteric proteins were relays, mediating interactions between compounds which themselves had no chemical affinity, and by that regulating the flux of energy and materials through the major system, while themselves requiring little energy, The gratuity [“the freedom from any chemical or structural necessity in the relation between the substrate of an enzyme and the other small molecules that prompted or inhibited its activity”] of allosteric reactions all but transcended chemistry, to give molecular evolution a practically limitless field for biological elaboration.
These are all attributes whose subtlety deserves more emphasis whenever cellular functions are under discussion. Instead, we find a marked tendency to de-emphasize the sophistication of features such as auto-regulation. By the same token, it’s not just the subtlety and phenomenally clever quality of all these things, but the way they are all entangled and their activities so precisely coordinated. This higher order of interaction is what has such weighty implications: this is where the impression of intelligence and intentionality is grounded. 
For instance, during cellular division: How do all the players involved initially gather and position themselves? How do they know exactly when to perform their assignments, avoid interfering with other teammates, and recognize when to cease and desist? How do they all get to the game on time? What “master gene” calls them to their tasks? What controls those master genes?
I can hear the skeptic’s answer: Yes, yes, yes…we know how each of these things take place: it’s all by gene-controlled chemical signals…markers, couriers, vesicular transport. Regulatory genes. Allosteric proteins. The subtlest details are being worked out at this very moment; these automatic processes are all well-understood, at least in general outline. It’s all chemistry!
About those “upper-echelon proteins”—whether self-regulating or controlled by genes…the ones that initiate and direct the actions of whole assemblages of nano-scale machines: how do they fulfill their roles? What orders them up and accounts for all the functions carried out in their vital, higher-level tasks? How are the actions of allosteric enzymes coordinated with those of genes, when neither has controlling influence over the other? And one last element that exposes yet another aspect of these profound, multifaceted interactions: time. During the many stages of mitosis, including DNA replication, all the cell’s genes are dormant. (In the case of humans, this means for some hours.) Hence, all instructions relevant to division have to be issued beforehand; all the suites of enzymes and protein machinery involved have to be synthesized, tagged for recognition, and somehow “programmed” in advance. Many individuals will need to be repaired or replaced while they wait. Once provided with their orders, though, they join the throngs careening about the cell, killing time until they hear a bell ring.
Andreas Wagner, specialist in the new field of computational biology, provides an answer (of sorts) to all these quandries and seeming bottlenecks. (This elucidation is likely about as straightforward as can be achieved using plain language.) He writes:
The answer lies in regulation…. And what regulates the regulators? Simple: more regulators…. And what about these regulators, how are they regulated? Through other regulators. All these regulators often form daisy chains, regulation cascades….[This] would seem enough complexity…but alas, regulation can get much more complicated: Regulators form not just linear chains but complex…circuits where regulators regulate each other…. Each [activates or represses] a gene [and] can twiddle the knobs of other genes—up to hundreds—outside the circuit…. Inside a cell these influences create a symphony of mutual activation and repression, where each instrument in the orchestra of genes responds to the melodic cues of others with its own notes, until the circuit reaches an equilibrium—like a polyphonic closing chord—where the expression of      circuit genes no longer changes and their mutual influences have reached a balance.[4] 
Wagner’s portrayal of symphonic regulation provides an ideal context for the asking of three Big Questions that approach the heart of what I’ve termed Natural Design: At what point do all these circles close? What is the nature of these highest levels of organization and control? Can something be identified that, ultimately, is “in charge”?
Whatever it is, whatever might be considered the “conductor,” appears to operate by way of a multilayered complexity that is beyond description or even our limited imagination. This…thing…is rooted in the underlying character of life. Immanuel Kant (whose insights are still pertinent today) thought the whole subject inaccessible to causal explanation. As he urged, we may be better served by simply taking life’s nature as a given and let biology proceed from that starting point (thus saving both philosophers and scientists valuable time that they could put to better use). There is, after all, some precedence for this stance, it being essentially the way we treat matter, time, and the elemental forces—core principles not subject to further elucidation.
Regardless: hopefully all my readers have come around to the notion that nature is inherently complicated and, as such, biological systems require consideration and study with an explicit recognition of this complexity—even though such practice will unavoidably hamper straightforward communication. This exacting way of viewing natural processes will always present conceptual challenges given that the intellectual capacity to sustain awareness of many things interacting simultaneously is a gift few are endowed with. However, such awareness—even an approximation—is essential in the effort to understand life. 
Few would disagree with these propositions. Still, I continually see an acute lack of appreciation for the subtext beneath nature’s profound intricacy…a resistance to the idea that this ineffable quality has pivotal meaning on its own. Biological complexity is rooted in one of life’s most distinct attributesthe capacity of its productions to be both self-governed and harmoniously organized. This shadowy, indefinable quality can’t specifically explain the things examined in this section but provides structural support for reassessing the so-called emergent properties—patterns, behaviors, or traits that can’t be deduced from either lower or higher levels of association. (The deliberate, organismic behavior of DNA helper molecules being a fine example.)
At present, however, many people—including leading experts in their fields—often create an impression of not being fully awake to this crucial truth: in biological systems, at all scales and each level of organization, different types of the attribute  Marcel-Paul Schützenberger termed functional complexity are in operation. At each organizational stratum, new structures or regularities appear: the property of emergence. And each stratum calls for its own manner of describing relationships between parts or processes that often aren’t even present at levels above or below. 
Once again: life is much more than the elaborate interaction of molecules.
                        
   ©2016 by Tim Forsell     draft            30 Apr 2016

 





[1] Dembski’s book is a collection of essays. The majority of contributors, like Dembski himself, are staunch creationists with obvious agendas. Others, scientists all, are not anti-evolution but at odds with various aspects of Darwinism (some of which have been addressed and even resolved since the essays were written). Schützenberger (1920–1996) was in the latter group; he was a member of the French Academy of Sciences, a medical doctor, mathematician, and according to a memoriam, “was passionately interested in the many flaws in the Darwinian theory as it is commonly presented…. [He] became one of the first distinguished scientists in the world to point out that a theory of evolution that depends on uniformly randomly occurring mutations cannot be the truth because the number of mutations needed to create the speciation that we observe, and the time that would be needed for those mutations to have happened by chance, exceed by thousands of orders of magnitude the time that has been available.” This interview was originally printed in La Recherche [The Remembrance], a French science monthly, shortly before his death.
[2] Paleontologist Simon Conway Morris referred to such information being “still routinely cited…in that zoo of good intentions, the undergraduate textbook.” A classic example is the formerly ubiquitous embryo drawings by Ernst Haeckel illustrating his long-discredited “biogenic law” with its notorious tongue-twisting axiom, “ontogeny recapitulates phylogeny,” found in generation after generation of biology texts. Only 30 years after Haeckel produced the compelling drawings (around the turn of the 20th century) his biogenic law had been refuted, yet they continued to appear in textbooks for decades. 
[3] Twenty thousand scientific papers were being published daily, according to a figure quoted in Calder. Also: as of 2010, there were about 24,000 different scientific journals in all fields. This figure, which includes all aspects of natural and social sciences, plus arts and humanities, is quoted in Larsen and von Ins.  
[4] While remaining true in spirit, this excerpt is a significant reduction of Wagner’s much lengthier account.