Here’s the next installment…I
would say one of the best, inspiration-wise. Most of my readers know at least the
rudiments of cell biology, but here’s a look into their workings that should
offer some genuine surprises. I believe this section paints a picture of
Cellworld unlike any you’ve read about in books, emphasizing some things that
are typically downplayed or not even mentioned. Truly amazing stuff….
V. The Cell is Beyond Beyond Belief
Cells are the atoms of life, and life is what cells do.
Franklin M.
Harold, In Search of Cell History
We have learned to appreciate the complexity and perfection of
the cellular mechanisms, miniaturized to the utmost at the molecular level,
which reveal within the cell an unparalleled knowledge of the laws of physics
and chemistry…. If we examine the accomplishments of man in his most advanced
endeavours, in theory and in practice, we find that the cell has done all this
long before him, with greater resourcefulness and much greater efficiency.
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 its 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 provide a bracing sensation of
unalloyed amazement:
People commonly lack awareness of the difference in size
between prokaryotes and individual eukaryotic cells.[2]
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 60 trillion—that’s 60,000,000,000,000—cells,
there are significantly more prokaryotic microbes colonizing it (number-wise, primarily in the gut) than there are
tissue cells. Over ten times more,
ladies and gentlemen.
Also unappreciated 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—facts not much less amazing or improbable than life’s beginning in
terms of the difficulty of explaining how such a radical shift in forms
occurred. And made even more mysterious by the question of why it took so long
and, unlike so many biological innovations, 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 here—are often referred to as “miniaturized factories.”
This analogy doesn’t 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,
quite literally, the factories.) But the whole thing is contained within a
discrete province invisible to the human eye, with more separate components
than a Boeing 747. Paradoxically, this tiny metropolis is immense: there’s 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 aren’t
equipped to form mental images of what actually goes on in a cell’s liquid
interior. It’s 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, it 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, a fatty substance, are hydrophobic.
In water, phospholipids will spontaneously assemble themselves into a
two-layered sheet—a lipid bilayer—with
the hydrophilic phosphate heads outermost and the water-repelling 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 critical for all eukaryotic life
forms, are functionally ideal in many regards. Small molecules, like oxygen and
carbon dioxide, 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 various ways to allow different
classes of chemical substances free passage. Aquaporins, for instance,
are simpler affairs known as channels
that 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. The receptors and gatekeepers imbedded in the surface of a single
cell number in the tens or hundreds of thousands, held in place by the same
forces that align the phospholipids. And, like phospholipids, the various gates
and channels and receptors migrate freely within the confines of the membrane.
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.[3]
It consists of a jungle-like scaffolding of compression-resistant microfilaments and tension-bearing intermediate filaments (that 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 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;
particles within the nucleus spin at
rates far in excess of that figure. All the contents within a cell are
continually tumbling; globular proteins
rotate at perhaps a million revolutions per second.[4]
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,[5]
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. Computer-assisted 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: pleated sheets, and alpha helices. All are
remarkably elaborate and bewildering to ponder.[6]
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…hormones
like glucagon, which has only 29 amino
acids, to huge proteins like titin,
which has over 34,000….” 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 speed up, or catalyze, chemical reactions. Certain extremely important
reactions, if not induced by enzymes, wouldn’t move forward at all; others
would literally require thousands of years. In some cases they proceed billions of times faster than if left
without assistance.[7]
With cells, everything has to happen 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 own surface that
is chemically attracted to a complementary area on the enzyme’s (called an active site), causing them to
momentarily bond. Their connection is often compared to a lock-and-key type
arrangement, indicative of high specificity. This fleeting association, which
causes the protein to change shape while remaining intact, simultaneously
lowers the substrate’s activation energy,[8]
allowing the reaction to proceed much, much faster than it would otherwise. The
substrate is merely altered or splits into new substances; the reaction’s end
result (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: one of the record holders in terms of speed is
carbonic anhydrase: a single
molecule can assemble up to one million
molecules of carbonic acid per second. (The slowest enzymes require a couple of
seconds to catalyze just one reaction.) The more typical rates are still amazingly
fast. Understanding how catalysts work, combined with the knowledge that each
substrate collides with virtually every enzyme
inside the cell in little more than a second goes a long way toward giving a
sense of how business proceeds in Cellworld.
Individual proteins are fashioned into complex assemblages,
actual machines, that are built by other proteins. Whether hastily
fabricated at a moment’s notice or off duty, these versatile nano-machines undergo constant
maintenance (as do lone protein molecules). Fabricated for specific duties,
they’re 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 only minutes. Worn-out or damaged
individuals, and those being “retired,” are reduced to their modular components
for efficient 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, carbohydrates and lipids). They make hormones and antibodies. They are 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 are made of a protein building block
called tubulin.
Intriguingly, some 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.[9]
Proteins are directly involved with other aspects of a cell’s
transport system: as types of receptors embedded in both inner and outer
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 are hauled by molecular motors,
small proteins that move by actually walking
along microtubules with their relatively massive 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.) The list of proteins’ absolutely
indispensable roles is a long one.
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.[10]
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 continuous 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. (To give
a sense of their abundance: about 13 million are found on the rough ER within a
single human liver cell.) 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.[11]
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, carries 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.[12]
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. Indeed, they supply most of
the energy needs of most non-photosynthetic cells. They have two membranes: a
smooth outer one and a much-convoluted inner membrane, studded by protein
machinery. Mitochondria are former bacteria that had learned how to handle
toxic, highly reactive oxygen in a world that had been without it (until
photosynthesis arrived). They invaded—or were engulfed by—a primitive
single-celled eukaryote, forming a lasting partnership. (Mitochondria were
perhaps the first endosymbionts—organisms
that live inside other life forms, in a mutually beneficial rather than
parasitic relationship.[13])
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. There are perhaps 10 million
billion—a 1 followed by 16 zeros—in an adult human, making up around 10% of
their weight. (A later section will deal with the amazing manner in which they
carry our their primary duty. Suffice it to say that they have many roles, also
being intimately involved with sex, fertility, and cellular 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’s a world of chaotic activity, taking place inside the 60
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 disassembled piece by piece and, sooner or later,
turned back into other living things. Atoms from long-dead people, plants, and
extinct creatures without number reside inside each of us—all of them
originally forged inside several generations of stars and now 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’s 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 well-educated—have taken
reductionist thinking to its extreme and reached the conclusion that,
ultimately, life is nothing more than
a vast collection of molecules randomly careening about. And, by extension,
that living things are nothing more than machines.
No…it 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 hope to someday have a clearer understanding of life beyond how the parts work, it is
imperative that some innovative model augment or extend the old—one that
encompasses the true nature of nature.
©2016 by Tim Forsell draft
25
Feb 2016
[1]
From his Nobel Prize lecture, Stockholm, 12 Dec
1974. Albert Claude (1899–1983) was a Belgian medical doctor and cell biologist
who discovered the process of cell
fractionation, which involved grinding up cells and using a centrifuge to
isolate their contents. This led to his discovery of the ribosome and several major organelles.
[2]
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.
[3]
Bacteria and their kin have a simpler, rigid cell wall.
[4]
“Globular,” a somewhat outdated categorization,
perform many of the vital roles associated with proteins. They are often
water-soluble (forming colloids) as
opposed to the wholly structural fibrous
proteins.
[5]
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.)
[6]
“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.”
[7]
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.
[8]
This is the minimum amount of energy needed to
activate atoms or molecules so that they can undergo a chemical reaction.
[9] Experiments and theoretical calculations cast doubts
on this idea but it remains an open question.
[10]
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.
[11]
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.”
[12] 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 (MIT
Press)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 for its many minor factual errors, many of
which were due to a widely ranging subject matter and use of outdated
information to support his stance. Nonetheless, it is a fascinating and
entertaining book that presents many valid and thought-provoking arguments.
[13]
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.
