An Essay Inspired by Franklin M. Harold's THE WAY OF THE CELL
Not Why, But What?
Under an endless sky in the cold of night, a forlorn traveler may wonder why s/he exists. Why this life or any of the teeming multitudes which have come to inhabit this planet in an incomprehensibly boundless universe? Any answer to such query depends upon an answer to a deeper question, posed in a modern context by Erwin Schrodinger although no doubt raised perennially since the dawn of civilization. The question: What is life? Without an understanding of what it is, we cannot even hope to grasp why it is.
As a reknown physicist, Schrodinger delivered a series of lectures on the question and published them in book form (1944) with the question as its title. Ever after in the scientific community, the question has been known as Schrodinger's Riddle. While the solution to this riddle is not yet fully resolved and, once resolved, may not point to a 'higher' purpose, the very work of riddling may help us realise how deeply we are rooted in the matrix of the cosmos. Such realisation, at the least, may serve as an antidote to personal alienation. If the cosmos in its vastness is understood to have inevitably sprung forth to generate living creatures, if each such creature is known to project its own purpose (at least to persevere), and if we human creatures are seen to grow from such roots, then we might embrace the full adventure of such cosmos.
A young man in the middle of the 20th century, Franklin M. Harold read Schrodinger's book and then went on to develop a long and successful career in biology. Now approaching the completion of his journey in science, Harold has applied his expertise to the riddle and published a masterwork: THE WAY OF THE CELL: Molecules, Organisms and the Order of Life (2002, Oxford University Press).
If we wonder through Harold's text, we may begin to suspect that the cell's way is like the way of the Tao. As an artful emeritus professor of biochemistry and molecular biology, Harold sketched the biological basics of both cell and evolution without mentioning Tao, but a careful reader gets the drift. Importantly, Harold's peers respect his exposition. With skill as a writer and a deep knowledge of biochemistry, his every statement about 'the way of the cell' has a ring of honest clarity which none in Harold's profession would deny.
While Harold may not have intended any Taoist implication, this review will flow with life's current, everso subtle as it may be. We'll return to the Tao after a brief description of an important biological insight.
The Chemiosmotic Theory
Harold's text is important for the thoughts it presents, and also because it is informed by the author's association with the discovery of an important key to the mystery of life. Way back when, young Frank was on the team that figured out just how a cell gained energy from its environment and transformed it into a useful packets. He was among the first to witness the very source of an organism's vitality!
The history of bioenergetics-- the patient experimental work which tracks the detail of biological energy-- has a century-long story to tell, but the knowledge gained in the first half of the 20th century was somewhat sketchy and a bit confused until this amazing episode in science. Harold's masterwork describes the historical turning-point: "In 1961, a splendidly eccentric English scientist named Peter Mitchell proposed a radical alternative to the biochemical wisdom of the day. Mitchell's chemiosmotic hypothesis was truly a revolutionary notion in Thomas Kuhn's sense, entailing a change of paradigm-- a transformation of the conceptual framework." (p83)
The next few pages which follow in Harold's text explain the paradigm shift brilliantly and concisely. Those pages may be supplemented by another publication [1] in which Harold wrote a chapter-- "Energy Transduction by Ion Currents"-- explaining the details of chemiosmotic energy flow. His explanation in that chapter includes a personal account of his association with Mitchell; and, hints of the struggle with the powerful upholders of the prevailing paradigm during the following decade as the Mitchell group sought evidence for an empirical foundation of the hypothesis.
Suffice here to say that the evidence demonstrates the following: A cell carefully controls loose protons which are abundantly generated as a byproduct of the cell's normal myriad biochemical transactions. [2] Furthermore, the cell channels energized electrons to pump protons into a membraned reservoir from which they are released to power an engine. [3] The channeling is accomplished by an array of enzymes (i.e., active proteins) anchored in the membrane and small electron-transporting molecules, collectively known as the respiratory chain. The protons are sequestered by a membrane in much the same way as water is held behind a dam and, as the protons are gated back across the membrane, the energy of their
electrical 'fall' is harnessed by a majestic enzyme which completes the work of the respiratory chain. That enzyme is known as ATP Synthase, shown in the 1990s to function as a tiny rotary engine driven by the proton motive force. [4] It synthesizes one small molecule of ATP (adenosine triphosphate) for every four protons passing through its gate. [5]
The channeled electrons are initially excited as dedicated enzymes harness energy gained by the cell from its environment. There are several sources of energy available in our earthly environment which are utilized by organisms to excite the electrons fed into the respiratory chain. The first source is raw chemistry: lithotrophs feed off minerals and chemotrophs feed on non-mineral chemicals. The second source is sunlight: phototrophs feed from raw photons. Organisms that use these sources to empower their metabolic needs are called autotrophic and they arose early in evolutionary history.
While litho- and chemo-autotrophs add little to the food-chain for the diet of other organisms, the photoautotrophs generate abundant carbohydrates (i.e., sugar, and starches composed of sugar) from which all other organisms (heterotrophs) derive their excited electrons. Thus the heterotrophs' source of energy is derivative and, since we humans are not photosynthetic, members of our species should never forget that fact. Our heterotrophic cells feed off the work of autotrophic cells.
Primitively, simple bacteria evolved enzymes able to snatch electrons from minerals and raw chemicals and harness the excitation for metabolism. Numerous extant lithoautotrophic lineages still graze on iron and chemoautotrophic lineages nowadays feed on sulfurous and nitrous compounds. While not technically classified as chemotrophic, several other autotrophic bacterial lineages are dedicated to specific chemicals. These include the hydrogen bacteria which thrive on molecular hydrogen; methanogens which utilize molecular hydrogen and carbon dioxide, or small carbon-based molecules including formate and acetate; and methylotrophs which diet on methane. While litho- and chemo-autotrophy were primordially the only way our most ancient ancestors and their direct descendents could acquire excited electrons, this mode of empowerment is minimally effecient when compared to what arose from this foundation.
Early in evolutionary history, cyanobacteria gained the ability to harvest energy from photons sown by the sun. The cyanobacteria became very productive and eventually filled our atmosphere with their waste product, oxygen. The lineage of cyanobacteria thrives even today and some of their descendants, the chloroplasts, have for the past two billion years powered
the eukaryotic cells which they serve symbiotically. Several lineages of chloroplast-empowered eukaryotic cells, evolving into many varieties of multicellular plants less than a billion years ago, store the fruits of chloroplast energy-harvest in simple sugars (e.g., glucose and fructose) and starches (which are simply stored chains of sugar molecules). Most organisms without chloroplasts graze on those sugars. Both photosynthetic organisms and those who feed upon their labors aerobically (i.e., using oxygen) catabolize the sugars along the glycolytic and tricarboxylic pathways. Anaerobic microbes (at least those which do not graze on raw chemicals), often parasitic or otherwise dependent upon those just mentioned, employ fermentative pathways.
By every catabolic pathway, enzymes work with smaller molecules (e.g., electron carriers, the sugars and fragments of sugars) to juggle and herd the excited electrons in pairs. As the excited electron pairs are eventually passed along the respiratory chain (by some fifteen different types of molecules employed as electron carriers) toward their final resting place, a quantum of energy is siphoned off by each of three different enzyme complexes to pump protons out from the cytoplasm and across the membrane. (Evolved to specialize in the task, the highly efficient mitochondrial respiratory chain pumps ten protons per electron pair completing the circuit.) When at last the "tired" electrons reach the end of the chain, they are united with two protons (taken from the cytoplasm) atop an atom of oxygen to create a molecule of H2O. (See note 4.) Since oxygen is used as the target, the process is 'oxidative'. And since the end-product of the respiratory chain-- adenosine diphosphate (ADP) + inorganic phosphate (Pi) = adenosine triphosphate (ATP)-- requires a phosphorylation, the entire process is called oxidative phosphorylation. The energy channeled by this process is, in effect, 'stored' in the phosphoryl covalent bond of an ATP, a highly labile bond readily employed by enzymes to power their quotidian work.
As a host of dedicated investigators demonstrated in the decades prior to Mitchell, every aerobic cell lives through oxidative phosphorylation. And as Mitchell, Harold, et al. demonstrated, it is the proton motive force which drives the system. (Even anaerobes, which thrive without oxygen, use a somewhat similar pathway by employing a different atom as
terminal electron acceptor.) Moreover, ATP is the short-term energy currency within every cell and, once produced, circulates about the cell to supply energy for every cellular activity. Enzymes in need of energy simply grab an ATP, break it into ADP + Pi, and use the bit of energy released from the phosphoryl bond to do their work.
Given this central virtue of oxidative phosphorylation, the role of the membrane (osmosis), as well as every +/- ion (the balance of which sets the direction and magnitude of electrical flow) within the cell, pH (acidity), and every chemical transaction required for metabolism, is keyed to this proton motive force. Thus to describe the whole dynamic, the chemiosmotic concept was born.
Nowadays, that is obvious and common knowledge to everyone in molecular biology-- many of whom only gained such knowledge from textbooks without much effort. By rote, as it were. In the back of such minds, it's taken for granted. Yet Harold was there at the paradigm shift and was smitten by the relationship between organization and bioenergetics (i.e., form and
function). Meanwhile in the middle of the 20th century, we must note, other biologists were cracking the gene and lauding metabolism as a function of information. Watson and Crick are famous while Peter Mitchell is not. The 'information' presumed to reside in the gene is exalted while the bioenergetic dynamic is taken for granted. [6]
Prior to Mitchell, most investigators saw the cell as a "bag of enzymes". Even today, many think of a cell as a membrane which encloses a collection of enzymes-- each an expression of information embodied in a gene-- working on molecules. In a reductionist framework, such perspective too easily ignores a complex dynamic (dare we say, the vitality of a cell) which underlies the very possibility of information-- the proton motive force. [7]
Traveling the Tao
In THE WAY OF THE CELL, Harold outlines the insights gained from Mitchell's project to prepare the ground for a definition of life. (The brackets in the following quotes are mine.)
There are several, as Harold puts it, "transforming ideas that made the chemiosmotic hypothesis so controversial at first, and that now enlarge our perception of the cell as an integrated unit. First, many (perhaps all) enzymic reactions have an intrinsic direction in space. This is not apparent in solution [i.e., via in vitro experiment], but becomes manifest when proteins [i.e., enzymes] are inlaid or plugged across a membrane; metabolic reactions then become vectorial. Second, linkage between two proteins need not be chemical, nor does it necessarily require direct contact; a flow of ions or metabolites can couple two vectorial reactions, as long as they share a common substrate and are embedded with the proper orientation in the same membrane. Third, coupling is a two-way street; either one of two coupled reactions can drive the other. [For example, ATP Synthase can 'burn' ATP to spin the Synthase motor in the reverse direction and pump protons back across the membrane; it does so when a readjustment of the ion gradient or internal acidity is required.] Fourth, chemiosmotic coupling demands a topologically closed system such as a [membraned] vesicle; a proton leak [from the enclosure] would short-circuit the system. [Certain predatory bacteria create such a leak in their cellular prey to immobilize their dinner!] Finally, oxidative phosphorylation is an emergent property, and so are many other physiological activities. There is no gene for oxidative phosphorylation, though genes do encode all its elements. Only when a respiratory chain and ATP Synthase are located in a single vesicle, and in the correct orientation, does the coupled reaction emerge.
"Mitchell's hypothesis revitalized and transformed bioenergetics... But it has a much wider significance. The chemiosmotic hypothesis explicitly introduced spatial direction into biochemistry... It also taught us how nanometer-sized proteins could coalesce into micrometer-sized systems, and function coherently. Orchestration depends on membranes, on facing in the right direction and on being connected by currents. Abstractly, the chemiosmotic theory illustrates the transition from molecules to cells." (p86-7)
That last line illustrates the art of understatement. The inspired biochemist rightly leaps to this thought: the primordial establishment of a membraned chemiosmotic system enabled the autonomy of our first ancestor cell from its environmental surround. Even if a primitive 'gene' embodied coded information prior to or concurrently with the first cell's genesis, the formed embodiment of membraned vectorial energetics is the step up into cellularity.
Ever after, both coded information (i.e., the gene) and live vectorial action are requisite. The Tao is not in the text but in the traveling.
The next section of Harold's work is titled: "Reading the Microbial Mind." [8] Harold explains how a cell can employ sensors, signal transduction, and the proton motive force to enable chemotaxis-- the pursuit of nutrients in its environment. After this one example, Harold states that "we can already draw the conclusion that the purposeful chemistry of information processing takes place within the context of the cell's spatial order. The first step, and also the last, are vectorially disposed across the membrane, and signal transduction overall has a location in cellular space. [Moreover,] chemotaxis represents one channel in the cell's energy flux [and must be integrated with the other channels. Thus] chemotaxis is not just a matter of chemistry: bacterial signal transduction operates within that higher level of organization, which is superposed upon the molecular." (p93-4)
It should be noted that, while bacteria (prokaryotes) provide the simplest examples of the cellular dynamic, eukaryotes (e.g., an amoeba or paramecium) are simply more elaborate-- and eukaryotic multicellular species (e.g., fungus, plant, animal), simply moreso. The 'higher' cells employ the same principles as the 'lower' but with more finesse. For example, vertebrate neural cells employ a mode of chemotaxis to distribute themselves vectorially in growing neural tissue; and several cell types serving our immune systems are chemotactic as they circulate throughout the body in search of foreign invaders.
After several more pages of bacterial detail, Harold states: "A cell is an orderly society whose molecular citizens weave interactive patterns on many planes-- spatial, temporal, functional, historical. [A] cell is a complex system. [As for the gene, its] adulation has got out of hand. The fallacy is the tacit assumption, taken as an article of faith, that *all* the levels of biological order are spelled out in the genome. [But this point of view is myopic for two reasons.] First, it is clear that the cell (of which the genome is a part) provides the context for the expression of that genetic network, mediates its interaction with the environment and constrains its implementation in space and in time. Second, many facets of a cell's complex and adaptive behavior arise from the interplay of its molecular components without the intervention of a central directing agency, just as the economy of a city operates quite smoothly in the absence of plan or direction. These system features, which come under the rubric of self-organization, [are the subject of this narrative]." (p96-7)
Although Harold does not extend his analogy, it might be said that, if the cell may be seen as "an orderly society whose molecular citizens" are coordinating their activities, then the difference between a prokaryote (bacterium) and eukaryote (larger cell with nucleus and organelles) is akin to the difference between a village and a city. In either case, the
municipality's DNA serves as central library and hall of records-- through the collective knowledge of which the molecular citizens organize their economy.
Who's Your Momma?
In the hubbub of daily activity, it's easy to overlook a basic fact about our own bodies. Each of us is composed of hundreds of trillions of cells, a vigorous colony of cells cooperating as a well-ordered, unified self. Every cell in our body, each of the trillions, was born of a previous cell as it divided. Just prior to division, it was termed the 'mother cell' by biologists (before gender neutrality became politically requisite). When a mother cell divides, it yields two 'sister' cells which are, relative to their progenitor, 'daughter' cells. Any one of these can be traced through its cell lineage back through time, daughter through mother; and a mother cell is born from a prior mother cell and that from one prior, all the way back to the first cell in our mother's womb, a single fertilized egg cell. That cell in turn was born from a previous mother, and so on back to the beginning of our species... genus... phylum... et cetera-- into the very roots of the biological geneology. All the way back to the very first cell that ever lived on our planet.
Years ago it was hypothetical, but nowadays it's becoming a matter of fact: Every living thing-- whether animal, plant, fungus, alga, or bacterium-- can be traced back genetically some 3.8 billion years to the same single-celled ancestor. That original source has been termed the Last Universal Common Ancestor (LUCA) and we shall have more to say about it in subsequent essays. Meanwhile, we need consider something important about the cell-- any cell, since the beginning-- which is too readily overlooked by biologists who pursue a reductionist or a genecentric interpretation of life. Harold explains that cellular reproduction is not merely a matter of bequeathing a container of chemicals or a passive set of genes to the next generation. The mother cell gives to each daughter a thriving community of diverse molecules, already dynamically engaged in well-ordered commerce.
Chapter 6 in THE WAY OF THE CELL has a title which at first blush seems but a truism: "It Takes a Cell to Make a Cell." Yet as Harold explores this theme, we come to understand that the truth of the statement is not to be taken lightly. The gift of life is not passed forward simply by providing the beneficiary with a self-enclosed membrane which contains a complete set of molecules requisite for self-maintenance. Rather, "the cell serves as the *templet* (not template), a source of configurational information, for the construction of its daughters." (p100) Current science is struggling to develop a framework for the investigation of such a dynamic. Harold offers encouraging words: "What we seek to understand emerges from the sociology of molecules, not their chemistry, and carries us into a different layer of reality. Indeed, how could it be otherwise? A growing cell is not a self-assembling set of puzzle pieces, but the product of generative processes mediated by multiple molecules, physiological pathways deployed in space." (p111)
That cellular dynamic is well described in Chapters 4-6, to which the reader is recommended. i'll spend a few paragraphs here, at risk of doing a less worthy job of it, to sketch how the multiple molecules mediate.
Broadly speaking, the community of molecules in a cell is functionally organized through the dynamic of three primary molecular species: polypeptide, polynucleotide, and phospholipid. A polypeptide is a string of amino acids (AAs)joined one-to-the-next by a chemical bond called a peptide. Polypeptides are manifest as proteins, some of which serve a structural role while the others work as enzymes. Most of the work within a cell is accomplished by enzymes-- proteins which grasp, manipuluate, and otherwise catalyze the joining and disjoining of particular atoms and molecules. Most enzymes are energized by ATPs generated by the proton motive force. Enzymes often work cooperatively, in pairs and teams. Like soldiers in a cohort or workers in an atelier, they may congregate around a common task; or, an enzyme may perform a bit of work with the raw material near at hand before passing an incomplete product to a more distant location for its finishing.
While diverse proteins work all over the cell, one cohort of enzymes is specifically dedicated to work in the gene 'library,' reading the genes as written in DNA (polynucleotides) and transcribing them one-by-one onto messenger RNA (polynucleotides) which are then translated by ribosomes (composed of both polynucleotides and polypeptides) into polypeptides. As each polypeptide is produced from the ribosome, it emerges as a long ribbon (of amino acid units strung end-to-end by a peptide bond) which begins to fold into a 3D shape. After such reconformation, we call it a protein.
It is important to note that, aside from serving as a template for transcription, the genes encoded in the DNA don't do anything. A gene is but a series of nucleotides strung together (into a polynucleotide). Each nucleotide is akin to a 'letter,' like the letters composing the words on this page. Such letters only take on meaning through a live reader. And unlike the words on a page which, once read, might be said to tell the active reader what to do and how to do it, neither DNA letters nor the gene spelled by the letters offers the cell any hint of what to do with its 'information.' The letters only specify the series of building blocks (each an amino acid) required to piece together a polypeptide. That molecule, as it takes its place as a protein in the community of molecules, takes its cues from the ongoing activity and 'knows' what to do. How a protein knows is the story of evolution on the molecular level, a subject worth an essay of its own. Suffice here to say that its prototype protein, generations earlier in the cell lineage, accidentally happened to serve a function in the ongoing activity which became requisite to every subsequent cell's survival and the gene for it was carried forward in time.
The task of genetic transcription and translation is coordinated by a variety of sensory and effector proteins, often employing smaller signaling molecules, which monitor the cellular environment (internally, as well as externally) and provide feedback to the gene-transcription cohort. The feedback loops determine which genes are expressed and when. Old and worn proteins are deconstructed for recycling even as extant polypeptides augmented by those newly produced procede (as proteins) to establish, maintain, and pursue all the pathways of molecular and ionic commerce within the space of the cell. Importantly, it is a three-dimensional space with 'time' as the fourth dimension.
The temporal dimension of the cell's current community dynamic is (1) bounded by what has already transpired along multiple molecular pathways and (2) oriented towards what is required by the community to happen subsequently. That two-fold temporal (i.e., past and future) localization is integrated with spatial borders, the largest of which is defined by the cell's bilayered membrane, formed by the third species of primary molecule, the phospholipid. [9] While the membrane defines the inside/outside of the cell as a whole, further spatial organization is determined by localized groups of protein engaged in active commerce, similar to groups of workers in business establishments connected by roadways in a human community. A more subtle spaciality is provided by multiple electrochemical gradients, so many whirls and eddies of ionic tensions which shape the flow of activities. Within in this timespace, neither ions nor molecules move simply by passive diffusion. Much of the motion is vectorial. The gradients have direction. The molecules are propelled electrostatically along the gradients and/or given a velocity at their generation or last interaction with a larger molecule in motion. Often enough, ions are transported via carrier molecules; and molecules are carried by transporter proteins (in eukaryotic cells, powered by motor proteins along proteinaceous tracks). All this vectorial activity-- myriad motions of directed force in a spatiotemporal framework-- would to an outside observer appear to be purposeful.
When the resources are available, a single cell typically grows as a result of the above-described hustle-bustle until it more-or-less doubles in size, and then it divides. However, under conditions of scarcity the cell can not grow and merely slows its activity to a near standstill. Some species of cell evolved the ability to enter into stasis, a dormant state, to survive in spite of scarcity.
Other species evolved the ability to sporulate, in which the mother cell uses its last nanogram of resources to produce a spore-- a small daughter cell born dormant as the mother dies. The spore then awaits an improvement in its environmental surround before reactivating. Another striking exception to the grow-and-divide rule is manifest by many cells in multicellular organisms which do not divide. They merely grow to maturity sufficient to fulfill a function in the larger organism and die when worn or aged; they are replaced in the organism by stem cells which have retained their ability to divide from the original egg cell. That is the function of a stem cell for the larger organism, simply to grow and divide, one daughter remaining a stem cell and the other primed to turn on genes to perform a specialized function.
When a cell is growing toward the prospect of dividing, she produces nearly twice as many polypeptides as she needs for solitary existence, and deploys additional phospholipids in her membrane to stretch near double in size. When the time approaches for cell division, the mother prepares for birthing by duplicating her DNA (polynucleotide) genome. Prior to cell division, most of the molecules have been apportioned in strategic positions-- many active all the while, with the notable exception of the genome-- such that each daughter gets a fair share when the division is enacted. To enable division, some proteins separate the duplicated strands of DNA and position them to insure that each daughter gets a copy. Other proteins act to determine the locus for partitioning the cell into two parts and perform the division. The otherwise active molecules not directly involved during the division begin performing their regular duties as soon as the division is completed.
Harold uses the 6th chapter to help the reader understand that, although the genetic component of cell biology is important, the epigenetic component-- the lively activity which arises from gene expression-- is just as important, if not moreso. And as we begin to comprehend the cell as a dynamic process, Harold employs another metaphor to underscore the mystery of life. If the DNA is like the written score of a symphony and if the active molecules, particularly proteins, are like the members of an orchestra manifesting the music, "[we] are left contemplating the disquieting notion of an orchestra without a conductor." (p113)
It may be mystifying to look for the orchestra's 'conductor' within an extant cell, and the notion of self-organization (or autopoiesis, discussed in Part 3) is at best a "label for a pigeonhole that will hold the relevant forces and rules of engagement." What then is a biologist or philosopher seeking to explain the nature of life to do? "The beginning of practical wisdom in this matter is, I believe, to be found in quite traditional concepts. Every cell comes from a parent cell, which provides a templet upon which the daughter cell is modeled; and the parent cell's epigenetic landscape acts in concert with its genes to guide the process of reproduction." (p114) In other words, every cell is born through a binary fission of a mother cell to yield two identical daughters, alive! Each daughter is born up-and-running through proteins and active pathways established in the mother. The mother cell is an active spatial, temporal, and functional (i.e., historical) 'templet' for the born-active daughters. The living is passed on livingly.
This fact of life, when comprehended alongside the question-- What is life?-- points us back in time to the origin of the first live birth. We need ultimately consider how LUCA came into being and began passing forward the gift of life. But first, Harold has some other details to consider.
Evolving from the Root
Since the beginning, living cells have grown to explore fresh possibilities through a process which Charles Darwin so aptly described as descent with variation. The descent, as we have seen, is accomplished livingly by passing the dynamic forward from mother to daughter. The variation occurs as a matter of chance: the genome of mother is randomly altered by the time it reaches the daughters. Altered genes in effect mean altered proteins which alter the molecular community dynamic. Were the alterations too radical, the daughters might lack one or more of the requisite tools or abilities to maintain life's dynamic. Were the genetic alterations too paltry, the daughters might be stuck doing the same old things in the same old ways when the environment around them had changed to make the old ways futile. Since the world is often changing, those only able to function in a past world must perish. And a modicum of genetic alteration just might enable some of the variant descendants a fresh opportunity. Others although variant might find their alterations unproductive or irrelevant and perish before passing life's gift of dynamism forward.
Initially, there were two modes of genetic variation, lateral gene transfer (LGT) and mutation through coding error. Coding error was more likely than accuracy in the earliest protocells, prior to the evolution of the first fully functional cells in the era of LUCA some 3.8 billion years ago. Prior to LUCA, we suppose a myriad community of protocells eked out an existence from the depths of prebiotic chemistry. ... As the LGT theory championed by Carl Woese explains it, these protocells had the rudiments of genetic transcription and translation (albeit rife with coding error), but lacked the ability to safeguard the integrity of their genomes or seal their membranes against penetration by foreign polynucleotides. Moreover, each protocell lacked the wherewithal to sustain within itself all the functions requisite for establishing a lineage able to populate the world with its kind. For example, some had a gene coding a protein useful for function X, some for function Y or Z. Some protocells through coding error gained or lost effeciency in functions X, Y, or Z. And none had a complete set requisite for an XYZ combined function.
Cannabilizing each other in whole or part, sometimes merging membranes by happenstance then bifurcating, and otherwise interacting, these protocells swapped genes quite accidentally and promiscuously. According to theory, the frequency of such LGT slowed somewhat as those enriched by it improved their skills at self-protection. And one, at least, having within its membrane an effecient XYZ set of proteins managed to leave its mark on the world as LUCA. As the initial generations of descendants from LUCA began to thrive amidst both protocells and cousins of lesser ability, LGT became increasingly less common-- although it still occurs on rare occasion even today.
... until gradually through fortuituous mutation and LGT the community of molecules within any one protocell happened to include suitable molecular tools for relatively effecient transcription of genes and translation into proteins, as well as replication of the genome.
By the time of LUCA, the rate of coding error had slowed enough to allow a fairly consistent transmission of the genome over many generations, with that modicum of mutation requisite for variation. The need for accuracy and the concomitant possibility of fortuitous mutation is obvious in the very nature of transcription. Simply put, genes are coded in a four letter alphabet of nucleotides: A, G, C, and T. This code is read by the ribosome in groups of three letters, each threesome specifying one of twenty different types of building blocks (amino acids) which, strung together by peptidyl chemical bonds, manifests as a polypeptide. The sequence of AAs determine how the polypeptide string folds to become a functional protein. Both the shape and ability of a protein depend upon the number and types of blocks in the polypeptide string. Although the number may range from tens to thousands, the average protein typically contains several hundred amino acid building blocks. Suppose, for example, a nucleotide code of AAGCCCTTCAGGACT... If during duplication of the genome an A replaces a C or a T replaces a G here and there in the copy, the ... risk of losing a useful protein ... but if whole gene is duplicated, in next generation one copy can be true while the duplicate accumulates error, perhaps to find a new function ...
The previous section's description of the mother's dynamic, passing live to her daughters, while applicable to every cell type is most germane for the simplest of microbes-- bacteria. The bacterial dynamic is at the very root of the tree of life, from which evolved a branch of cell type with greater complexity which branched again. According to current phylogenetic research, the first cell type branching off the root bore the microbial prototype for archea and eukarya. Subsequently, a descendant along this branch evolved a nuclear membrane to house its genetic operations. We use the Greek terms for true (eu) and nucleus (karyos) to call descendants from this branch eukaryeal. The cell-type akin to it yet without a true nucleus is called archeal (from the Greek for ancient). Descendants from the archeal lineage specialized in extreme environments, thriving in hot, acidic, and/or salty environments.
Meanwhile, the last common ancestor of all extant eukarya acquired a symbiont bacterium (which would evolve within its host's descendants to become the mitochondrion) to maximize its motive force. (See note 7.) A subsequent branch of eukarya was enabled by the acquisition of a second type of a symbiont bacterium, one with photosynthetic ability (which evolved within its host's descendants to become the chloroplast).
These three great domains of life-- bacteria, archea, and eukary-- grew to inhabit every nook and cranny on our planet, phyla from each domain specializing in an amazing variety of habitats. Some species fed off others. Many formed relationships of mutual benefit with other species, within and between the domains, to network as ecological communities. For several billion years, all thrived as single cells, passing on the gift of life from mother cell to daughters directly by fission. ... several branches of the eukaryotic lineage discovered sex to swap half their genome and, recombining the two halves, gave their descendants a fresh set of possibilities. Some descendants of these eventually mutated to present a radical phenomenon. Instead of simply dividing, then going on to lead separate lives, the daughter cells stuck together.
... Shapes. Cocci and rods. Cilia. Form and function. Desmid as example. Cell-cell communication. Morphogens. ...
Harold points to the lovely desmid as an example of beguiling biological form.
Unresolved issues from the preceding discussion are pursued by Harold over chapters seven through nine to consider morphogenesis, the relationship between biological form and function, the evolution of eukaryotes, the ciliates, and the forces of natural selection.
The next few chapters artfully describe both cell and evolutionary biology in sufficient detail for the average reader to understand the accepted framework for critical assessment of the question: What is life? That question is, of course, intertwined with this: How does life evolve? Neither question is amenable to simple answers.
Not a Clock
Almost from the beginning of cell theory in the 19th century, investigators have taken a reductionist approach, working to resolve the whole into parts and to isolate the physical-chemical transactions which enable those parts. In the paradigm of an industrial age, investigations were modeled with the concept of 'mechanism' and aimed at elucidating the small-scale structural and/or molecular linkages of cause-and-effect between part A and part B. While such approach was very useful in discerning cellular detail, it was implicitly understood by the best investigators that the details were of a different kind than a clock's gears and springs. Nevertheless, the common discourse readily gravitates toward a clockish materialism.[10] On a broader scale, evolutionary theory is fettered by a perceived need to articulate the 'mechanisms' of natural selection. For example, the literature may employ the concept of a rachet to discuss the tiny steps of point mutation and environmental constraint which 'drive' a gene toward a novel function.
At the start of the 21st century, Harold perceived the need to liberate the living bird from the metaphoric cuckoo clock. He reminds us of a venerable distinction between creature and clock. Ever since the first machine was constructed by Archimedes or his kin, we've called the creature alive but the clock is not. Harold quotes... to explain what exactly makes the difference...
... cut
"If a cell is just another machine, what is the basis for the distinction that has been drawn from ancient times between objects that are alive and those that are not? After all, what we seek to understand is not what these two categories have in common, but what sets them apart! The answer came in the eighteenth century from the German philosopher Immanuel Kant, and turns on the existence of a special category of objects called organisms.
... use this
In a machine, Kant said, the parts exist for each other but not by each other; they work together to accomplish the machine's purpose, but their operation has nothing to do with building the machine. It is quite otherwise with organisms, whose parts not only work together but also produce the organism and all its parts. Each part is at once cause and effect, a means and an end. In consequence, while a machine implies a machine maker, an organism is a self-organizing entity. Unlike machines, which reflect their maker's intentions, organisms are 'natural purposes'.
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Kant's vision was eminently sensible and remains true, but even he was stymied by the next stage: How can we ever discover the cause of that purposeful organization that is the hallmark of organisms?" (p220-1)
In the 1970s, a team of biologists (F. Varela and H. Maturana) revitalized a seldom used term for that purposeful organization: autopoiesis. Since their approach was a bit mystical in its holism, mainstream biologists were reluctant to employ the term. To his credit, Harold promotes the word in his thesis to good advantage. While its short definition is simply 'autonomous self-organization', the root-word 'poiesis' is also the root of the term 'poetry.' (Although Harold does not extol the metaphoric virtue of the notion, it could be said that the autopoietic cell is busy making its own poetic statement about being alive-- as it follows the Tao.) Besides autopoiesis, Harold also employs the more widely used term 'biopoiesis' in reference to the origin of life. He devotes a chapter to "Searching for the Beginning" and nicely reviews all the leading conjectures about the origin of cells on our fair planet, including Christian DeDuve's brilliant contribution.[11] If a case can be made as Harold suggests for energetics as the cause of biopoiesis (see below), it still remains to be shown how significant a role energetics plays in subsequent evolution.
"For Darwin and his followers, and even for most of their critics, natural selection remains the primary creative force, that generation upon generation favors the survival of the better adapted; adaptation, in turn, is the expression of a genetic program, honed and stabilized by selection among the phenotypes. For strict constructionists, organisms have no intrinsic form, organization or stability. They are mere figments of history, the ultimate in tinkerers' contraptions, and plastic as putty under the pounding of selection. [In this view, natural selection] becomes a mechanism for creating a high degree of improbability, but since these creatures are not [perceived as] governed by any laws of order, they remain at bottom unintelligible. ..." (p198) {laws of order? CogAlgo!}
(Here the non-Darwinian needs be warned against supposing Harold is preparing to propose an explanation contrary to Darwin. When you understand evolutionary biology, as Harold does, you can see why and where Darwin was on target. And when you understand bioenergetics as completely as Harold, you might also see how Darwin's insights can be taken to a deeper level, far more poetic than a strict constructionist would allow.)
To continue the quote: "This is not the universe inhabited by Brian Goodwin, Stuart Kauffman and others who approach evolution from the philosophical perspective called structuralism.
"Goodwin draws historical inspiration, not from Darwin but from Immanuel Kant and the continental tradition of rational morphology, which dovetail with the new and still-evolving field of complexity studies. ... From this viewpoint, organisms are no longer artifices cobbled together by a capricious history, but the outward expressions of their own dynamics.
Organisms recover their traditional status as fundamental entities, self-organizing and self-maintaining wholes. In principle, (and sometimes even in practice) they become intelligible because they are grounded in the laws of physics.
"Genes and gene products do, of course, retain a role in the evolutionary drama. Catalysts [enzymes] and structural molecules [with a morphology on a smaller scale] determine the numerical parameters that enter into the physical specification of each system [of the many interwoven systems within a cell], and they stabilize its organization. Much of that exploration of the range of possible forms is, in fact, carried out by mutation and recombination of genes [manifest as fresh variant small-scale morphology in the mutant enzymes which tweak the systems]. But it is system dynamics, not the genetic program, that gives rise to biological forms and functions. By the same token, natural selection retains the role that has been described as 'executioner of the unfit.' But selection has been ejected from its throne as the dominant creator of biological form. Instead, the argument [of those like Goodman and Kauffman] goes, spatial order is inherent in living systems [and] selection by itself is too weak to maintain organisms atop steep and pointed fitness peaks. Evolution is possible only because selection collaborates with that spatial order intrinsic to living systems; and this order may persist ('shine through') even in the face of contrary pressure from natural selection." (p198-9)
A few pages later, Harold explains that the neo-Darwinian "modern synthesis is assuredly not incorrect. Common descent, adaptation by natural selection, the competition for survival, reproductive success, the production of variation by mutation and rearrangement of the genetic material explain many (even most) features of life. But they fail to explain why organisms exist in the first place, and they foster a splintered view of life that is at odds with the persistence and integrity of living forms." Harold goes on to underline recent trends in evolutionary thought in which "[a] 'pluralistic' Darwinism affirms the primacy of variation and selection, but allows greater play to additional forces." From this, we may "take it as a mark of progress that, a century and a half after Darwin, it is again becoming legitimate to see evolution as the historical adventure of organisms in geological time." (p200)
After further discussion of alternative approachs to the riddle of life, including the reference to Kant quoted above, Harold implies that the initial statement of the riddle was short-sighted. "All the metaphors in common use have merit, but none is altogether satisfying; and as Kant already noted, none of them makes comprehensible the existence of even a single blade of grass. It must be significant that we still have no language that makes organisms look at home in the physical universe; they are evidently much queerer than we suppose. It may be the case that our understanding of physics and chemistry lacks an essential girder that, when found, will span the gap. But it is also conceivable that there is a deeper flaw in the contemporary research program-- Schrodinger's program, if you will-- of bringing the science of life wholly under the umbrella of the physical sciences." (p222)
Harold then digs more deeply into complex systems theory to unearth a kernel of insight. "The great virtue of systems-thinking is not that it predicts the facts of life, but that it blurs the crisp line which divides the organic world from the inorganic. There is nothing mystical or unnatural about complexity, self-organization, emergence and wholes that are greater than the sum of their parts. [Such statement applies to the dynamic of galactic, stellar, and planetary systems-- the requisite precursors of biogenesis--, although Harold failed here to point this out.] One feels encouraged to wonder just how autopoietic entities might have emerged from the much larger category of complex dynamic systems, and here energetics holds the most promising clues." (p227)
An Open Question
Our wonder leads to a consideration of the 2nd law of thermodynamics, noted by Schrodinger as a signpost at the riddle's core. This 'law', stated in various ways, simply points to the universal tendency toward the dissipation of energy. For example, stellar radiation spreads outward-- never to return. Yet life swims against this tide as each organism manages to garner sufficient energy within itself to persist. While no one, including Schrodinger, understood the profound details of this organismic feat until the chemiosmotic dynamic was unveiled, the mere fact that the universe permits cellular metabolism an abeyance of the 2nd law may have a deeper implication.
"The open question is whether the role of energy is merely permissive or actively causal: is energy required only for the workings of life, or is it the driving force for the emergence of complex autopoietic systems and their subsequent evolution? Those who envisage a fundamental link beween the thermodynamic arrow of energy dissipation and the biological arrow of the greening earth make up a small minority, and stand well outside the main stream of contemporary biological science. But if their vision is true, it reveals that deep continuity between physics and biology, the ultimate wellspring of life." (p228)
The minority view is centered on the claim "that the emergence of complex systems and of life on the primoridal earth can only be understood as a result of thermodynamic drive." In a dynamic nutshell, the argument runs as follows:
A physical substrate composed of simple structures (e.g., a random mixture of small molecules) which is subject to a continuous energy input may enhance the dissipation of that energy by forming more complex structures. For example, a substrate of simple molecules bombarded by stellar photonic (or venting volcanic thermal) radiation will increase the dissipation of that energy by absorbing some of it and then releasing what was absorbed in a degraded form as heat, plus a bit more. The dissipation is enhanced and the rule of entropy is maintained. Meanwhile, the absorption momentarily propels molecular collisions, some of which cause smaller molecules to bond together in larger molecules. The increase in order (negative entropy) represented by the bond is accounted for by the intrinsic energy released (entropy) from the component molecules as they settle into the bond.
Atomic logic and the chance events of planetary formation govern the composition of an initial molecular population. Chance alone governs the range of complex molecular species which may arise thereafter and, especially, their possible cyclic interactions. Yet a molecular substrate bombarded by a continuous energy input will insure that the dice will begin to roll and continue to roll for a very lengthy period (until all possible combinations have occured to exhaust the substrate), all in accordance with the 2nd law. If several of these more complex molecules perchance begin interacting in a cyclic fashion-- e.g., A and B collide to yield C + heat; C and D collide to yield a new A + E + heat; and around again as A and B collide--, then thermodynamics will favor the cycle as long as it continues to dissipate energy. The cycle will perpetuate itself as long as D and B are available in the environment (and thereafter, if the cycle couples with several other cycles able to generate D and B, and to take a step forward, utilize E). On the other hand, molecules which are not coupled by a cycle or, if coupled, are less effecient in energy dissipation, will not be favored.
Of course, as Harold points out, the thermodynamic principle does not guarantee that such initial complexity will arise under a given set of planetary conditions but only that it may. Moreover, the evolutionary step from a simple cycle to a set of cycles cooperating within a membrane would seem to be a huge leap. In principle, several smaller steps are plausible and their possible configurations are actively pursued by current investigators. Pending those results, even now a case can be made for the primordial membrane along thermodynamic lines, as Harold points out, since the basic molecular component-- the lipid-- is not only simple but relatively easy to produce via simulation of primordial conditions and, when present in quantity within an aqueous environment, lipids are driven to self-assemble into a closed vesicle by hydrodynamics (p229, p243). The real theoretical issue concerning membranes is the means by which one happened to contain a set of cyclically interactive molecules able to establish the rudiments of life. Several competing theories address that question.
Aside from the membrane dilemma, Harold sketches the contributions of several theorists to riddling out the first steps in life. For example, "Christian de Duve has described in considerable detail how a proto-metabolic web [composed of several simple molecules interacting cyclically], akin to that of contemporary organisms, may have arisen prior to the appearance of membranes and of cells." (p241) DeDuve, among others, has itemized the tiny steps that may have been performed by modest molecules (primitive proteins) to initiate a protometabolism, i.e., to perform a series of simple oxidative and reductive chemical operations requisite for channelling energy and components into the assembly of the initially required molecules. Presumably, the glycolytic and tricarboxylic cycles would have arisen from such humble origins (and oxidative phosphorylation arose thereafter to complete the chemiosmotic dynamic). To the next generation of biochemists, such theoretical work is promising and may prove productive.
Importantly, some theorists argue that protometabolism (via protoproteins or, alternatively, RNA 'ribozymes') arose before information was stored in nucleic acids (first RNA and later, DNA) while others argue conversely. According to most accounts, proper Darwinian evolution could not begin until information storage was established (first in the RNA 'gene' and only later in DNA) as the substrate winnowed by natural selection and, of course, the proteins expressed from that information had to be functional-- either already able to perform protometabolic functions or ready to replace the initial, albeit more primitive, molecular workers. "[T]he most fundamental relationship is that which links nucleic acids, the carriers of information, to proteins that perform functions and generate the phenotype. If a single question can stand for the whole mystery, it must be the origin of this most intimate relationship." (p245)
Over the past decade, investigators have been busy winnowing the lessor theories from those more plausible but, as Harold is careful to point out, the parameters of the initial terrestrial conditions which permitted evolution to begin may forever remain unknown. Besides which, certain supposedly critical steps in the hypothesized molecular cycles have yet to be recreated in the laboratory. One of the most intriguing theories of protometabolism, presented by Gunter Wachtershauser, offers a straight-forward extension of the thermodynamic principle. Harold admits that he appreciates Wachtershauser's ideas "because they mesh so well with my own bias that life began with energy flow and hauled itself up by its own bootstraps. But his hypothesis, like the others, soon finds itself in hot water." (p249)
Even so, as theorists pursuing this line of thought suggest, once an organism arises from the thermodynamic bootstrap, "there is a tendency for energy flow (and for life) to expand into any niche, provided there is a mechanistic path; it will diversify, radiate, speciate; and it will tend to produce structures that are increasingly complex. In [this] view, evolution need not struggle relentlessly against the forces of decay but goes with the natural flow of the universe. The manifold faces of life appear as features to be expected, not as implausible marvels that must be explained. But we must be careful not to confuse the general with the particular: biological details cannot be deduced from the second law, since organisms riding the energy stream still remain creatures of history." (p230) [12]
More to the Mystery
While a philosopher might be tempted to pursue this "natural flow of the universe"-- the Tao-- exclusively through the remaining pages, Harold is committed to a more balanced consideration of the evidentiary alternatives. Thus, returning to the question-- what is life?-- "science presently offers two answers. The first asserts that living organisms are autopoietic systems: self-constructing, self-maintaining, energy transducing autocatalytic entities. The alternative answer proclaims that living organisms are systems capable of evolving by variation and natural selection: self-reproducing entities, whose forms and functions are adapted to their environment and reflect the composition and history of an ecosystem." (p232)
While the first answer emphasizes energetics, the second depends upon genetic information and its mutation which is subject to selection. Nearly twenty pages later, Harold presents the core of his two alternatives, albeit in inverse order, more poetically:
"In the beginning was the Word; so says the gospel of Saint John. Goethe's FAUST, that prototypic modern man and scientist, thought otherwise: in the beginning was the Deed. Rephrased just a little, scholars still divide into those who seek the origin of life in information and those who look to energetics. Those who believe, as I do, that living organisms are autopoietic systems capable of evolution by variation and natural selection, must keep a foot in both camps and risk being scorned by both. But the definition really sharpens the issue: the question is not only how life arose on earth, but how nature generates organized material systems to which terms such as adaptation, function and purpose can be applied." (p249-50)
The next few pages are richer, with hints of a solution. For example, Harold's belief that "the ultimate wellspring of life [is] the thermodynamic drive of energy dissipation, creating mounting levels of structural order for natural selection to winnow." (p250) Yet the origin, the grain of sand that caused the intricate layering of structure to yield the pearl of life, is beyond imagination. Harold states the problem for primordial biopoiesis:
"The hurdle is to understand, not the origin of organic molecules [which may have been plentiful in the prebiotic environment, according to some experimental evidence], but of systems that progressively come to display the characteristics of organisms: boundaries, metabolism, energy transduction, growth, heredity and evolution. This is hardly a startling or even original proposition, but its unapologetic holism makes it a minority view.
"I hold, then, that cellular organization was not a codicil to the true origin of life, but part and parcel of it. That implies compartmentation of some kind (not necessarily lipid membranes) from the beginning. Biological order is dynamic, created and sustained by a continuous stream of energy, and that also must have been true all along. Therefore a credible biopoietic theory will be one that generates mounting levels of complexity naturally, by providing the means to convert the flux of energy into organization. But energy dissipation can only carry life over the first jump; evolution is hamstrung until the emerging 'functions' within the developing system have been codified in a 'text' of some kind that can be transmitted, executed, altered, and put to the test of utility again and again. Nucleic acids or their precursors must have come on stage early, if not when the curtain rose. No satisfying scheme of this kind is presently on the books, and I have none to offer. I have only the strong hunch that there is much more to this mystery than is dreamt of in molecular philosophy." (p250-1)
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FOOTNOTES
[1] "Energy Transduction by Ion Currents" by Franklin M. Harold and Peter C. Maloney in ESCHERICHIA COLI AND SALMONELLA TYPHIMURIUM, edited by Frederick C. Neidhardt, et al., p283-302 (1996, ASM Press, Washington, D.C.)
[2] To say a molecule is an "acid" is simply to say that, if in an aqueous solution, the molecule contains one or more atoms which are prone to losing a proton. Naked protons are a manifestation of "acidity" and their abundance in solution is measured in pH. They are typically produced in biochemical transactions as atoms of hydrogen are broken asunder, each whole hydrogen atom being but an electron with negative charge orbiting a single proton with equal but opposite positive charge. The most volatile hydrogen is manifest in a hydroxyl (OH) group, simply an atom of hydrogen sharing its electron with an atom of oxygen. Hydroxyls are typically presented upon small molecules containing 9-24 atoms which are built around a backbone made of 2-6 carbon atoms bound together by shared electron pairs.
[3] Each proton has originally come from an atom of hydrogen, bound in a hydroxyl group (OH), that is sundered as electrochemical forces jostle the proton away from its electron during the normal course of a biochemical transaction. The orphaned (-) electron then remains with the more electrostatically powerful (+) molecule to which the hydroxyl group was originally bound and is, relatively speaking, in an excited state due to its lack of a proton. Meanwhile, a variety of enzymes are busy harvesting energy (from photons or the oxidation and reduction of extant molecules to create orphaned electrons as just described) by manipulating covalent chemical bonds (in which two atoms share a pair of electrons to balance their +/- accounts) from which excited electrons (in pairs) are transported (in particular molecules) to a 'bucket brigade' of enzymes (i.e., the respiratory chain). As the excited electron pairs are transfered from enzyme to enzyme along the chain, a bit of the excitation is siphoned off step-by-step to pump
loose protons across a membrane.
[4] For crisp illustrations and technical detail on this amazing cellular motor, see "ATP Synthase-- A Marvelous Rotary Engine of the Cell" by M. Yoshida, E. Muneyuki and T. Hisabori in NATURE REVIEWS: Molecular Cell Biology, 2:669-77 (Sept 2001). A related enzymatic complex is reviewed in the same periodical (3:94-103) by T. Nishi and M. Forgac, "The Vacuolar (H+)-ATPases --Nature's Most Versatile Proton Pumps" (Feb 2002).
While the vacuolar ATPase 'burns' ATP to pump protons out from the cytoplasm and across a membrane in some cells, ATP synthase gates protons falling back across the membrane into the cytoplasm. The protons are attracted to 'fall' by an excess of electronegativity (on the cytoplasmic side of the membrane) which is faithfully maintained by the chemiosmotic dynamic. In particular, an enzyme at the end of the respiratory chain insures a stream of oxygen atoms with excess electrons; at the end of a proton's fall, the proton latches onto an electron (+/-) in the vicinity of an oxygen and, viola', an atom of hydrogen is formed instantly as the +/- is bound to the oxygen. A second hydrogen, likewise formed, yields a molecule of H2O as a byproduct of the respiration.
Depending upon conditions, the 'fall' of 3-4 protons through the ATP synthase propels the shaft of its rotary mechanism 1/3 of a turn. Each 1/3 turn of the rotary engine's shaft flexes an enzymatic domain within a bulbous knob atop the shaft. The flex squeezes a molecule of inorganic phosphate (Pi) onto a molecule of adenosine diphosphate (ADP) to prompt a covalent bond in the resulting molecule, ATP. Thereafter, the ATP circulates in the cytoplasm to distribute the energy from that covalent bond to any enzyme in need of a boost. The working enzyme in need of energy simply hydrolyzes that covalent bond (a 'downhill' reaction) and couples the dynamic to drive an 'uphill' reaction. So empowered, enzymes perform all cellular work, including that responsible for vertebrate neural and muscle cell activity. In other words, we think and act via the proton-motive force.
[5] ATP is composed of five small molecules-- a nucleic base (adenine), a sugar (ribose), and three inorganic phosphates. The adenine contains 15 atoms, the ribose 19, and each phosphate has 8. The adenine is linked with a ribose to which a molecule of inorganic phosphate (Pi) is attached to form adenosine monophosphate (AMP), a nucleic acid. It is an acid by virtue of the hydrogen atoms held by the Pi. The Pi is simply an atom of phosphorous bound to four atoms of oxygen, three of which hold an atom of hydrogen. (When its ribose is deoxyed, dAMP is more commonly known as one of the four building blocks of DNA.) The bond which attaches a 2nd Pi to the AMP is highly labile, as is that of a 3rd Pi in the completed triphosphate. The lability affords a 'downhill' reaction which can be employed by an enzyme to empower an 'uphill' reaction, so the 2nd and 3rd Pi bonds are used by the cell as a temporary store of energy.
[6] Harold's work is nicely supplemented by the dynamic perspective on a cell's informational economy presented by another mature master, Werner R. Loewenstein. Also an expert in bioenergetics, Loewenstein has taken a slightly different approach to the relationship between information and energetics in THE TOUCHSTONE OF LIFE: Molecular Information, Cell Communication, and the Foundations of Life (1999, Oxford U Press). As the title suggests, Loewenstein's perspective pays more heed to the genetic side of the question of life's definition than Harold but, nevertheless, underlines the value in the flow of information from gene to protein function and back again in a loop-- a 'flow' akin to that of energy, and on a metric (units of information) interconvertible with that of energetics (units of entropy). Importantly, Loewenstein illustrates the fact that many such loops are interwoven in a veritable 'circus' of activity. Published prior to Harold's work, Loewenstein was not informed by the latter. And unfortunately, Harold makes no reference to the touchstone.
[7] The significance of the proton motive force becomes all too easily vitiated by a fact of our lives which becomes psychologically twisted by homocentrism. Every cell known as a prokaryote (for example, a bacterium) performs all of the above independently, all by its lonesome. Eukaryotes (cells with a nucleus, elaborate membranes, and organelles) employ the
respiratory chains and ATP synthases of mitochondria (and chloroplasts, if they have them) to generate most of their ATPs. A single eukaryotic cell may have from one to several hundred mitochondria, each a direct descendant of an ancestral bacterium which was drawn into symbiosis with the ancestral larger cell. The eukaryotic 'host' controls the genes of the mitochondrial organism. The mitochondrion keeps some of its ancestral genes but the eukaryote has hijacked those most vital. So why shouldn't the host act eukaryocentric and disdain the proton motive labors of the mitochondrion?
Maynard Smith calls these symbiont organisms the 'slaves' of the eukaryotic host. Indeed, since we humans are composed of eukaryotic cells, it is easy to take the mighty work of mitochondria for granted. Afterall, they're just 'organelles' and it's really more important to focus research on human genes, especially in regard to cancer and medicine. Little research was dedicated to the mitochondrion until it was discovered, in the last decade, that this symbiont plays a critical role in apoptosis (the failure of which leads to developmental defects and cancer) and, in the previous decade, that the symbionts are inherited from the mother's egg cell (in many species, especially ours) to enable a phylogenetic tracking method. Even so, most investigators are homocentric and seldom regard ATP as anything other than 'manna' given gratis by an unseen source.
Regardless of prejudice against the mitochondrion (and bacterium), the eukaryotic cell (and its human spokespersons) must admit that all of its other pathways are woven into the chemiosmotic process. Throughout the cell, every ion, electron, and proton is dynamically integrated into the whole system. That is why the chemiosmotic theory is prime.
[8] Here Harold's narrative is akin to mine on cellular cognition. For which, more later.
[9] ... Typically, these are phospholipids, each of which is a hydrocarbon (CH2O) chain (called a fatty acid) capped by a phosphate molecule. Phospholipids are amphipathic: the 'phospho' end of each chain is hydrophilic (water-loving) and the hydrocarbon end is hydrophobic (water-fearing). As these molecules are produced within the cell's watery cytoplasm, they are driven to insert themselves into the existing membrane self-organize into membranes...
... in the watery medium of the cell's cytoplasm, self-assimilate with each other to form a bilayer in which their tails are exposed to the water and their heads are buried in avoidance of water.
[10] In his second chapter, "The Quality of Life", Harold offers a brief critique of the reductionist approach with this comment: "Indeed, even a machine is not explained by mechanical principles alone, for its construction is guided by the designer's purposes which constrain the blind operation of physical laws. In the case of living organisms, it is their hierarchical organization and their origin in the interplay of random variation and natural selection that should give pause to any radical reductionist." (p13) Dare we say that the general constraint imposed upon physical 'law' by an organism is its own purpose to stay alive? That is to say, an organism uses physics and chemistry rather than vice-versa. Particular constraints are imposed by each step in a metabolic pathway, each having arisen in sequence from the very first steps imposed through biogenesis.
[11] See Christian DeDuve, BLUEPRINT FOR A CELL: The Nature and Origin of Life (1991, Neil Patterson Publishers, Carolina Biological Supply Company, Burlington, NC). This Nobel laureate provides an excellent account of the primordial possibilities for biogenesis and a great bibliography, to which Harold's bibliography is a valuable complement. The two taken together (plus Loewenstein; see note 6) offer a comprehensive survey of the important literature available to serious students of evolutionary biology at the start of the 21st century.
[12] In the years before any of the details outlined by Harold were generally understood, Hans Jonas published a collection of essays in THE PHENOMENON OF LIFE: Toward a Philosophical Biology (1966, University of Chicago Press; 1982, Phoenix paperback). Several of Harold's thoughts-- the 'intrinsic form' of an organism, 'riding the stream', and evolution as the 'historical adventure' of organisms-- have an interesting resonance with several of Hans Jonas's ideas. Using other words for the event, Jonas articulates biopoiesis as the first instance of freedom: "[I]t is in the dark stirrings of primeval organic substance that a principle of freedom shines forth for the first time within the vast necessity of the physical universe-- a principle foreign to suns, planets, and atoms." (p3) (In Harold's terms, we might say that, while everything else in the material universe is enslaved by thermodynamics to run downhill, the cell has freed itself to struggle uphill.)
Jonas presents the notion of primordial metabolism as the first step of life into freedom in his introduction, then elaborates upon it in several of the essays which follow. For lack of space, only excerpts from one rich passage by Jonas are quoted below. It is focused upon the dynamic relationship of the organism (whether a single cell at biogenesis or, thereafter, a cellular or multicellular descendant) with the materials it must incorporate metabolically from its environment.
"[The] active self-integration of life alone gives substance to the term 'individual': it alone yields the ontological concept of an individual as against a merely phenomenological one. This ontological individual, its very existence at any moment, its duration and its identity in duration is, then, essentially its own function, its own concern, its own continuous achievement. In this process of self-sustained being, the relation of the organism to its material substance is of a double nature: the materials are essential to it specifically, accidental individually; it coincides with their actual collection at the instant, but is not bound to any one collection in the succession of instants, 'riding' their change like the crest of a wave and bound only to their form of collection which endures as its own feat. Dependent on their availability as materials, it is independent of their sameness as these; its own, functional identity, passingly incorporating these, is of a different order. In a word, the organic form stands in a dialectical relation of needful freedom to matter.
"Let us consider further this new element of freedom that appears in organism, with special reference to form. Form, we have seen, is an essential and a real, that is, efficacious, characteristic of life. It is only with life that the difference of matter and form, in respect to lifeless things an abstract distinction, emerges as a concrete reality. And the ontological relationship [first codified by Aristotle] is reversed: form becomes the essence, matter the accident. In the realm of the lifeless, form is no more than a changing composite state, an accident, of enduring matter. And viewed from the fixed identity of the changing material contents, as the inventory of each moment would record them, the living form too is only a region of local and temporal transit in their own movements, its apparent unity a passing, configurative state of their multiplicity. But viewed from the dynamic identity of the living form, the reverse holds: the changing material contents are states of its enduring identity, their multiplicity marking the range of its effective unity. In fact, instead of saying that the living form is a region of transit for matter, it would be truer to say that the material contents in their succession are phases of transit for the self-continuation of the form. ...
"The basic freedom of organism was found to consist in a certain independence of form with respect to its own matter. According to a strictly material world-account such independence is either an absurdity or a deceptive appearance. Its emergence with emerging life indeed marks an ontological revolution in the history of 'matter'; and the development and enhancement of that independence, or freedom, is the principle of progress in the evolution of life, which in its course produces new revolutions-- each an additional step in the initial direction, that is, the opening of a new horizon of freedom. The first step [i.e., biogenesis] was the emancipation of form, by means of metabolism, from the immediate identity with matter. This also means emancipation from the fixed self-identity that is matter's, to give scope to a different, viz., mediate and functional, kind of identity." (pps 79-81)
"Organic identity, however, must be of a different nature altogether. In the precarious metabolic continuity of organic form, with its perpetual turnover of constituents, no inert substratum, no single 'path' and no 'bundle' of parallel paths of cotemporaneous members, is available as referent for external identity. Internal identity of the whole, transcending the collective one of the present and vanishing substratum, must span the shifting succession. Such internal identity is implicit in the adventure of form and is spontaneously assumed on its external, morphological evidence which alone is open to inspection. ...
"An identity which from moment to moment reasserts itself, achieves itself, and defies the equalizing forces of physical sameness all around, is truly pitted against the rest of things. ... The challenge of selfhood qualifies all this beyond the boundaries of the organism as foreign and somehow opposite: as 'world', in which, by which, and against which it is committed to maintain itself. Without this universal counterpart of otherness, there would be no 'self'. And in this polarity of self and world, of internal and external, complementing that of form and matter, the basic situation of freedom with all its daring and distress is potentialy complete.
"It is the task of a philosophical biology to follow the unfolding of this germinal freedom in the ascending levels of organic evolution." (pps 82-83)
FINI