Cells are the atoms of life, and life is what cells do.
Franklin M. Harold, In Search of Cell History
Consider another illustrative example of unconsciously life-belittling thought. (Such things are so prevalent in our culture that they go unnoticed, in the same manner that people unwittingly adopt advertising slogans as figures of speech.)
How many times have you come across a commonly used expression: “primitive life form”? Most of us, without pause, instantly conjure vague mental images of a worm-like organism…something with very few “moving parts,” something considerably less complicated than modern-day descendants. In the same way, single-celled creatures are persistently viewed as being simple compared to higher forms. These are grave misconceptions; each and every living form is an unbelievably elaborate entity. The simplest known self-sustaining organisms carry out around 550 distinct biochemical processes. Single-celled varieties are merely small, not simple.
Another quick review to impart a bracing sensation of unalloyed amazement:
People commonly lack awareness of the difference in size between prokaryotes and individual eukaryotic cells. A run-of-the-mill bacterium like E. coli (2 µm) is roughly a thousandth the volume of an average-sized (20 µm) eukayotic cell. This makes it somewhat easier to begin to grasp the fact that while a human body is made up of those 30 trillion—that is 30,000,000,000,000—cells, there are significantly more prokaryotic microbes colonizing it (number-wise, primarily in the gut) than there are tissue cells.
Also underappreciated is the sudden appearance of eukaryotes in the Cambrian period (over 500 million years ago) after three billion years of unicellarity and the subsequent explosion of multicellular life forms with entirely new subcellular systems. Many scientists consider this transition on a par with life’s amazing and improbable beginnings in terms of the sheer difficulty of explaining how such a radical shift could have occurred. (Made even more mystifying by the question of why it took so long and, unlike so many other biological innovations, apparently occurred but once.) According to molecular biologist Nick Lane, “The void between bacterial and eukaryotic cells is greater than any other in biology…. [Their origin] looks far more improbable than the evolution of multicellular organisms, or flight, sight, and intelligence. It looks like genuine contingency, as unpredictable as an asteroid impact.”
Eukaryotic cells—for the sake of brevity, what will primarily be under discussion in this chapter—are often referred to as “miniaturized factories.” This analogy does not quite capture the true state of affairs; more apt would be to think of them as highly industrialized cities. (A cell’s organelles—its internal organs—are, almost literally, the factories.) But the whole entity is contained within a discrete province invisible to the human eye. Paradoxically, this tiny metropolis is immense: there is room in its interior for millions of busy molecules.
To ponder the frenzied yet perfectly coordinated activity in each and every cell is an almost futile undertaking. Humans simply are not equipped to form mental images of what actually goes on in a cell’s liquid interior. It is not the scale so much as how things behave in that close-packed setting; everything about it is utterly foreign.
Each cell has an enclosing plasma membrane. Structurally, this membrane is composed of identical molecules called phospholipids, which each have a head end made of hydrophilic (“water loving”) phosphate attached to two lipid tails. Lipids (various types of fatty substances) are hydrophobic—water repelling. In water, phospholipids spontaneously assemble themselves into a two-layered sheet—a lipid bilayer—with the hydrophilic phosphate heads outermost and the water-averse lipids sandwiched between. The phosphate heads are strongly attracted to one another, forming a resilient outer (or intracellular) membrane that instantly repairs itself if punctured or damaged. In the words of molecular biologist David Goodsell, “Each individual molecule rotates like a top, and its hydrophobic tails wag and flail. Lipids also slide rapidly past one another, always staying in the sheet, but randomly migrating sideways.”
Lipid bilayers, absolutely vital features of all eukaryotic life forms, are functionally ideal in many regards. Small molecules, like oxygen and carbon dioxide (CO₂), can readily cross the plasma membrane by simple diffusion while it remains impervious to larger ones thanks to the tightly entangled lipid tails. Large constituents—both waste products leaving the cell and essential materials entering—pass through by way of an array of molecular “gatekeepers.” These structures, some quite complex, operate in ways that allow different classes of chemical substances free passage. Aquaporins, for instance, belong to a category of simpler versions known as channels; they allow water molecules to diffuse in and out of the cell. Numerous kinds of receptors, plugged straight through the membrane, accept messages and pass them into the cell. Others, having received instructions, seize specific molecular prey in passing and drag them through the membrane into the interior. (Or, in the case of viruses, are tricked into doing so.) The receptors and gatekeepers embedded in the surface of just one cell number in the tens or hundreds of thousands, held in place by the same forces that align the phospholipids. And, like individual phospholipid molecules, the various gates and channels and receptors migrate freely within the confines of the membrane “mosaic.”
The flexible outer membrane is stiffened by an elaborate internal cytoskeleton, which is able to maintain (or alter) a cell’s characteristic shape while continually changing. It consists of a jungle-like scaffolding of compression-resistant microfilaments and tension-bearing intermediate filaments (which anchor the organelles). A third system of sturdier, hollow microtubules creates transportation and communication networks by furnishing interconnecting conduits for the orderly movement of materials and information. All three types serve multiple purposes. Microtubules and microfilaments are both continually being degraded, renewed, reattached, and re-anchored in new locations. On average, an individual microtubule lasts for only about ten seconds.
A cell’s inner matrix, or cytoplasm, is filled with a liquid—the cytosol—which is typically around 70% water and close to the same viscosity. Molecules move by normal diffusion through what they experience as a viscous, gel-like substance. Despite the densely crowded environs, they travel almost without restraint through the cytosol in a random walk caused by incessant collisions. Think of bullets ricocheting off one another in a space as crowded as a jar full of beans. Every second, each individual collides with vast numbers of others, the larger ones relentlessly pummeled by water molecules.
Electrons “orbit” atomic nuclei trillions of times per second; protons and neutrons in the nucleus spin at rates far in excess of that figure. All the contents within a cell are continually tumbling; globular-shaped proteins rotate at perhaps a million revolutions per second. It is this mad vibrational energy inherent to atoms and molecules that drives all cellular activities. Things are incessantly zipping through membranes via the aforementioned gates and channels. For example, neurons employ countless ion channels with associated pumps to manipulate the concentration of ions (charged particles, which conduct nerve impulses) and up to ten million of these crucial ions can be pumped through one in a second’s time. Everything takes place at unfathomable speed with countless things happening simultaneously in a riotous molecular tempest.
Most cellular activities are carried out by proteins. These giants of the molecular world, made up of sometimes thousands of amino acid building blocks, are tightly folded into precise shapes that lend them their specific properties. This folding, an innate property, is mostly automatic—the result of individual sections being chemically attracted to or repelled by neighboring portions. The specific form of individual molecules can now be mapped with precision. Computerized graphic representations are a terrific aid in conceptualizing protein complexity and the vast array of often random-appearing forms they take; some look like ornate cumulus clouds…others are symmetrical doughnut-shapes. Many are clearly modular and may have twisting side chains or knobby protrusions. Hidden in their forms are secondary structures such as pleated sheets and alpha helices. All are remarkably elaborate and bewildering to ponder.
David Goodsell again: “A typical bacterium builds several thousand different types of proteins, each with a different function. Our own cells build about 30,000 different kinds, ranging in size from small to very large. Whether individually, in combination, or in teams, each of those 30,000 varieties will perform at least one (sometimes several) of roughly 100,000 specific individual tasks. A cell’s physical components are largely made up of structural proteins, while the other main category, biologically active proteins, assists with all cellular processes.
The latter include those vitally important molecules, enzymes, whose job is to catalyze (hasten) chemical reactions. Certain extremely important reactions, if not induced by enzymes, would not move forward at all; others would literally require thousands of years. In some cases catalyzed reactions proceed billions of times faster than if left without assistance. In the other-world of cells, everything happens at lightning speeds; any sort of carbon-based life would simply be impossible without catalysts.
An enzyme functions by randomly colliding with a specific target molecule—its substrate. The substrate has a small region on its surface that is chemically attracted to a complementary area on the enzyme’s (called an active site), causing them to temporarily bond. Their connection is often compared to a lock-and-key type assembly, indicative of high specificity. This fleeting association, which causes the protein to change shape while remaining intact, simultaneously lowers the substrate’s activation energy, allowing the reaction to proceed much faster than it would otherwise. The substrate is either altered or split into new substances; the reaction’s end result, or product, floats off. Task complete, a catalyst automatically resumes its usual byzantine form, ready for the next customer. The ratio of catalysts to reactants is extremely small. And for an idea of their efficiency, in terms of speed: a single molecule of carbonic anhydrase can assemble up to one million molecules of carbonic acid per second. (The slowest enzymes require seconds to catalyze a single reaction.) The more typical rates are still remarkably fast. Understanding how catalysts work, combined with the knowledge that each substrate collides with virtually every enzyme inside a cell in little more than a second goes a long way toward giving a sense of how business is carried out in cell-world. The inherent order found in living matter is born of this energetic chaos.
Individual proteins are fashioned into complex assemblages—actual machines—which are built by other proteins. Whether hastily fabricated at a moment’s notice or temporarily “off duty,” these versatile nano-machines undergo constant maintenance (as do lone protein molecules). Fabricated for specific duties, they are quickly taken apart after the task is complete; in a typical cell, 20–40% of newly made proteins are dismantled within an hour. A number of kinds involved with regulation last for just minutes. Worn-out or damaged individuals, and those being “retired,” are reduced to their modular components for recycling. This essential task is carried out by a teams of machines; smaller helpers assist the giant proteosome. Goodsell writes, “Proteosomes are voracious protein shredders, but all the protein-cutting machinery is carefully hidden away inside a barrel-shaped structure.…[T]he proteosome is able to wander freely inside the cell, and only the proper proteins are fed into its hungry maw.”
Proteins construct all the chemical needs of the cell (including, for instance, lipids and carbohydrates). They manufacture hormones and antibodies. Importantly, they are also responsible for the adhesion of cells within tissues. Proteins churn out actin, the basic molecular component of self-assembling microfilaments. Also self-assembling, the hollow microtubules consist of a protein building block called tubulin.
Intriguingly, a number of reputable scientists consider it possible that the microtubule system could form part of a sort of cellular computer. No less than physicists Roger Penrose (better known for his work with black holes and relativity theory) and Francis Crick (co-discoverer of DNA) cite the coordinated behavior of cells as indication that they have some kind of information processing ability. Without offering direct evidence, they believe microtubules, which link all parts of the cell’s interior, would be ideal conduits for information transmission.
Proteins are directly involved with other aspects of a cell’s transport system: as types of receptors embedded in both outer and inner (organelle) membrane surfaces they selectively bind, in the fashion of enzymes, to targeted chemicals. The receptors release their targets after adding molecular tags so that the substance being directed elsewhere will be recognized upon arrival at its destination and permitted entry. Similarly, they also form receptors on the surface of membrane-bound cargo containers called vesicles, which are used to transport materials throughout cells. These, in turn, are hauled by molecular motors—small proteins that move by, in effect, almost literally walking along microtubules with their immense (relatively speaking) burdens in tow. Proteins form the channels, gates, and pumps that regulate the passage of diverse types of chemicals through cell membranes.
In their role of assisting with communication, both within and between cells, these incredibly diverse molecules act as identifying markers on the cell’s surface and as messengers—traveling to specific locations where they bind with some target to elicit a chemical response. (As receptors, they both accept and pass on these messages.)
Individual proteins are constructed from chains of amino acids (polypeptides) through the process of translation by one of the cell’s most remarkable machines: the ribosome. These minute factories use copied genetic information, carried from the nucleus by molecules of ribonucleic acid (RNA—specifically, a variety called messenger RNA, or mRNA). Analytical biochemist Roland Hirsch writes:
No simpler machine is known or even imagined that could carry out all of the steps in protein synthesis with such accuracy and speed. Yet no living cell can exist without the means to rapidly and continually synthesize hundreds of proteins over and over again with high fidelity to the code in its DNA. Even the formation of the ribosome itself requires a large number of synchronized steps and more than 100 proteins and 100 small RNA segments.
Ribosomes, the smallest machines known, consist of a large and small subunit that come together only when they attach themselves to a molecule of mRNA. Hundreds of thousands of free-ranging ribosome subunits roam through a cell’s interior at any given time and work in teams to fabricate proteins that stay within the cell; other proteins destined to be excreted (or implanted in membranes as receptors) are assembled by ribosomes fixed in the surface of the endoplasmic reticulum—a flattish, highly folded organelle that surrounds and is actually contiguous with the bilayer membrane enveloping the nucleus. ER (as it is generally known) comes in two varieties: smooth and rough. Both are so convoluted that together they comprise around half the membrane surface-area in a typical animal cell. Rough ER is so called because its surface, unlike the smooth form, is copiously studded with ribosomes. Smooth ER participates in a number of different metabolic processes.
Ribosomes on the rough ER’s surface extrude polypeptide chains as they are being assembled directly into its labyrinthine interior (the cisternal space) as individual free-floating amino acids are added one by one with lightning speed. Once released into the cisternal space, these partially finished proteins have other components added and a destination label affixed while molecules known as chaperones assist with what is otherwise an almost automatic folding process. Other enzymes perform a quality-check, recognizing and removing improperly formed proteins before breaking them down for recycling.
Partially formed proteins are sent to another organelle, the Golgi apparatus, where they receive further processing before being directed to their destinations. The Golgi (named for the 19th century Italian physician who discovered it) is made up of a series of flattened chambers. Unfinished proteins arrive in vesicles, which merge with the Golgi’s surface like fusing bubbles, spilling their contents inside. After each addition another vesicle, carried by some molecular motor, relays the still incomplete protein to the next chamber for further modification. The Golgi has its own quality-control system. Once complete, the finished protein is carried by one last vesicle to its final destination.
The entire process of protein formation is only one among hundreds of highly involved activities taking place in each and every type of cell. To illustrate the diversity of cell functions, Robert Wesson reports that in the human liver there are
about 500 [different] functions, including: manufacture of bile and other digestive fluids; storage, conversion, and release of carbohydrates; the storage of iron and vitamins; the regulation of fat, cholesterol, and protein metabolism; the manufacture of materials used in the coagulation of blood (some 30 substances); the removal of bacteria from the blood; and the destruction of excess hormones and many toxic substances. And almost all of these functions are performed by cells of a single type.
And then there are those cellular engines, the mitochondria, which are responsible for taking the energy of digested food and converting it into an easily transported form that can be used for most cellular functions. Mitochondria have two membranes: a smooth outer one and a much-convoluted inner membrane, studded by protein machinery. They supply virtually all of the energy needs of most non-photosynthetic cells. It is now widely accepted that mitochondria were former anaerobic prokaryotes (related to the modern-day purple sulfur bacteria) that had been engulfed but, instead of being digested, were accepted as lodgers. They eventually came to form a binding partnership with their host, trading energy production for nourishment provided in a secure environment. The bacteria-like precursor’s energy producing system provided the much larger cell with a constant and reliable power source. (Mitochondria were perhaps the first endosymbionts—organisms that live inside other life forms in a mutually beneficial, or symbiotic, relationship.)
To give an idea of their importance and ubiquity: there are hundreds of them in each cell…in some tissues with high energy demands, thousands. A typical eukaryotic cell contains about 300–400 while metabolically active varieties (found in muscle, liver, or brain tissue, for instance) contain hundreds or even some thousands of the minute organelles, occupying up to around 40% of certain cells’ volume. Up to half of a heart cell’s cytosol, for instance, is occupied by mitochondria. (Chapter 8 will focus on the amazing manner in which they carry our their primary duty. For now, suffice it to say that they have many roles, also being intimately involved with sex, fertility, and aging.)
Inside any cell, thousands of individual processes are carried out simultaneously by hundreds of thousands of molecular machines, all attending to highly specific tasks. Countless molecules rush headlong through the cell’s crowded interior, ceaselessly colliding with structural supports, conduits, other chemical substances, and interior surfaces…until by chance they come in contact with an enzyme, or dock with one of the thousands of varieties of specific receptor sites. And things happen.
It is a world of chaotic activity, taking place inside the roughly 30 trillion nano-cities that make up our bodies. Right now. While we sleep. Every day until we die…at which point that once-vibrant universe is deconstructed piece by piece and, sooner or later, turned back into other living things. Atoms that once were part of countless people, animals, and plants (including organisms long extinct) reside inside each of us. All of these atoms were originally forged inside stars—several generations of stars, in fact—and are now being ceaselessly cycled through Earth’s biosphere. Small wonder that our minds revolt when asked to confront such outlandish notions.
But out of such chaos, order is continually seen to emerge. Most of us have been persuaded to believe that the sorts of almost miraculous things described here, awe-inspiring as they might be, are nothing more than the result of chemistry and physics operating on inert matter. Personally speaking: while I have never subscribed to a belief that some supernatural agent’s unseen hand guides what happens in the universe, it is perfectly reasonable that a religiously inclined person should believe in a Creator-God. What I do find genuinely astonishing is that so many people—the highly intelligent and best-educated—take reductionist thinking to its extreme, reaching the conclusion that life is nothing particularly special, is little more than a vast hodgepodge of molecules careening about. And, by extension, that living things are simply moist machines.
No…this won’t do; the mechanistic view is a portrayal that serves only as versatile analogy. All organisms have machine-like qualities, have components that operate according to machine-like principles, but even the simplest of living forms are elaborate networks of hyper-complex organization with two overarching functions: to be…to be, and remain, alive. And to make more of their kind. They have numerous distinctive qualities that no machine will ever possess. If we aspire to an understanding of life that captures its profound depth and wholeness, its elusive essence, a fundamentally different model will be needed—one that involves some entirely new concepts.
©2017 Tim Forsell
16 Dec 2017
 For a general perspective on size: Cells and microorganisms are considered at scales ranging between the nanometer (1 nm is one billionth of a meter) and the micro-meter (1 µm is 1000 nm—one millionth of a meter). At their widest dimensions: a water molecule is about 0.2 nm; a globular protein, 2–4 nm; a small virus, around 30 nm. The smaller bacterial species are in the range of 150–250 nm with the average-sized varieties, 1–10 µm. (The abundant gut bacteria, Escherichia coli, is 1–2 µm.) A human red blood cell, our smallest form, is about 7–8 µm. Eukaryotic animal cells on average range from 10–30 µm. The largest (extant) single cell is an ostrich egg and motor neurons in a giraffe’s neck approach 3 meters in length.
 These figures have been argued for years. One scientific “urban myth,” widely quoted but neither cited nor qualified, is the claim that there is a 10:1 ratio of gut microbes to tissue cells. A review of the literature shows a range of figures spanning four orders of magnitude. While these numbers are clearly highly variable depending on size, age, and other factors, qualifiers are almost never included. The latest estimate of of an average human microbiome is around 40 trillion—a roughly 1.3:1 ratio.
 Bacteria and their kin have a simpler, rigid cell wall.
 Amino acids are small organic compounds composed mostly of carbon, hydrogen, oxygen, and nitrogen. There are about 500 known types but living things, for unknown reasons, employ only 20. (Actually, 22; two new ones have recently been discovered. One is known only from seven primitive prokaryotes.)
 “Parts…coil into helices, other segments lock into rigid rods, still others act as flexible swivels. One amino acid called cysteine binds strongly to other cysteines, forming virtual ‘spot welds’ where the chain attaches to itself. Very long amino acid chains often fold into huge wads. Parts of chains loop out, double back, cut over to the opposite side of the wad, shoot out in a great helix, then return in a straight line to the center of the wad…. In many proteins there are sequences of hydrophobic amino acids that are pushed deep inside the wad, away from the surrounding water…. Sometimes…the hardest-working part of the protein may be at the bottom of a deep pocket or cave. One enzyme, for example, is known to have a tunnel into which it pulls the substance it is to break down. Electrical charges on the outside of the tunnel attract the opposite charge on the target molecule, essentially sucking the hapless target into the tunnel. The molecule is broken apart and the pieces are ejected through another tunnel, again propelled by electrostatic charges.”
 Their functionality is often dependent on the presence of a single metal ion (such as iron, molybdenum, or copper) whose specific elemental properties lend themselves perfectly to catalytic roles.
 This is the minimum amount of energy needed to activate atoms or molecules so that they can undergo a chemical reaction.
 Experiments and theoretical calculations cast doubts on this idea but it remains an open question.
 The mRNA, like a single-stranded version of DNA, is essentially a copy—lifted from a gene—of the instructions for constructing specific proteins to the most exacting standards. It acts as a template.
 To give a sense of their abundance: about 13 million are found on the rough ER within a single human liver cell.
 Rensberger describes how chaperones “grasp the new, partially folded chain and push or pull it into one particular shape. Like a sculptor modifying an unsatisfactory clay figure, the chaperones massage the amino acid chain, nudging a helix sideways or shifting a loop from this side to that.”
 Robert Wesson (1920–1991) was a distinguished scholar and prolific author, and fellow of the Hoover Institute, a conservative think-tank. Best known for his work in political science, he was a dilettante biologist. This fascinating book, one of the earlier popular science books to openly question neo-Darwinism, is generally thought to support a creationist agenda even though the author made clear that this was not his position. It has received criticism in book reviews for its numerous minor factual errors, many of which were due to a widely ranging subject matter and use of some outdated information to support his stance. Nonetheless, it is a fascinating book that presents many compelling and thought-provoking arguments.
 A group of photosynthetic bacteria that live in anaerobic environments like hot springs, stagnant water, or lakes—places where hydrogen sulphide (H₂S) accumulates. They oxidize it, producing elemental sulfur or sulfuric acid.
 The idea was revolutionary in its time and took some getting used to—in fact, it was actively resisted for many years. Biochemist Franklin Harold writes, “The idea had been under consideration since the end of the nineteenth century, but few took it seriously until the late Lynn Margulis marshaled the evidence forty years ago. Resistance was intense. Margulis’s original 1967 paper was rejected by fifteen journals before it found a home in the Journal of Theoretical Biology, and it took another decade for the idea to enter the mainstream.” Margulis was known for doggedly promoting her unconventional ideas throughout her career and was considered something of a maverick.
 The discovery that mitochondria, chloroplasts, and possibly other organelles were former bacterial invaders (or undigested meals) turned endosymbionts was a major clue in imagining a route to the rise of eukaryotes. But many of their features, vastly different than those of prokaryotes, are enigmatic and remain unexplained.