This section is essentially a
quick review of genetics in the context of how genes physically manipulate
information—not how that information is put to use. The point is to emphasize
my key premise: that life itself has creative capacities beyond our current
understanding…its productions aren’t simply the result of chance and time but
are somehow under the influence of some guiding principle. Beginning with the
rediscovery of Mendel’s work, the mechanisms and methods of genes were gradually
worked out, one small step after another, with major breakthroughs along the
way. The achievement of teasing out the details of genetic inheritance has been
nothing shy of extraordinary and is truly one of science’s finest efforts, with
countless researchers building on the findings of their predecessors to piece
together a fabulously intricate narrative. While this story is far from
complete the way ahead is clear: improved methods of gathering data (and,
especially, of processing the bounteous haul) and new technologies will only accelerate the discoveries made by future
geneticists. What will they find? I predict they’ll uncover new layers of
sophistication and complexity unanticipated by those who once saw their field
as operating by simple, cause-and-effect laws. And I continue to press the
notion that a confidence bred of continual success has resulted in a sort of
“blind spot.” We haven’t quite reached a place where it’s overwhelmingly evident
that nature actually engineers solutions to the myriad problems it faces. The
essence behind the workings of DNA, the cell, inheritance, evolution…it arises
from the same thing, a thing we have no name for, which thus remains hidden in
plain sight. My goal, ultimately, is to make it impossible to ignore the
obvious: that what animates the inanimate is not what we believe it to be. All
along, we’ve been standing too close to see it clearly.
VIII. Genes, and How They Work
Evolution has been a process
of discovering ways in which organisms can be put together, and it is to be
expected that the genome must be a complexly integrated entity, like the animal
that it can organize. It is not a jumble of traits but a unitary
self-regulating and self-organizing system. In order for the organism to become established and to subsist,
it must have an almost incomprehensible inherent stability.
Robert Wesson, Beyond Natural Selection
Aside from the
study of embryological development, perhaps nothing in biology better
demonstrates the truth about life being
more than “just chemistry and physics” than the byzantine workings of genetics.
After reading
this statement, any card-carrying biologist—unable to contain themselves—would
interrupt to heatedly assure readers that such was not the case: The science of genetics
is very well understood and indisputably
a function of “just” chemistry and physics! But is this actually the case? I
say…no, given that biochemistry has exposed a nano-world where cells and even
atoms demonstrate a type of intelligence that was unrealized when one could
make such a definite statement. All matters related to genetics reveal life’s innate creative intelligence
operating at beyond-belief levels of organization.
The
complexities of the subject are legendary. Mendel’s famous experiments, with
their logical and clear-cut conclusions, demonstrate the scientific method at
its finest. To this day his results
remain the “text book” illustration
of genetic inheritance, lending themselves to precise diagrams ideal for
biology classes. (Many readers will remember them…and with mixed feelings.)
While the reasoning may have been difficult to follow, those bifurcating charts
lent the subject an aura of rational coherence. However, since Mendel’s time
all matters pertaining to genetics have grown so technical that non-scientists
can only expect to understand the most basic elements.
Recall that
one of the key premises of the neo-Darwinian synthesis was the notion that
random copying errors could lead to beneficial mutations. During a brief period
at the beginning of the 20th century it was widely thought that each
gene was responsible for the creation of one protein, which was in turn
responsible for one trait. (Yes, they were simpler times.) And in those early
days of the synthesis, lay scientists—and even some specialists—formed
misguided notions about Mendelian
inheritance’s deceptive quality of clear-cut intelligibility. This lured
some into believing the solution to existing genetic questions would prove straightforward.
In retrospect, such innocent thinking is somewhat surprising; embryology was a
rapidly advancing field at the time and it was already recognized that even the
simplest of organisms’ early development was an extremely involved affair.
All this,
then, contributed to a somewhat naïve faith in the inevitable solution of
genetic riddles. At that time there certainly was good reason to feel confident
that modern scientific methods would eventually clarify every last detail of
how genes operate. But the brand new discipline of population genetics—an
abstruse discipline if there ever was one—soon dispelled any notions of the
subject being straightforward.
A bare bones
genetics primer is in order to provide some background for the uninitiated or
biologically rusty. Again, the picture presented here of how genes “work” (as
opposed to what they “do”) is terribly oversimplified, with significant gaps in
a narrative whose intricacies already make it challenging to follow. Our
conception of genes has changed considerably in recent decades; while the
classic model retains many merits and has proven its explanatory worth, keep in
mind that genes are constantly interacting, fluid entities and no longer
thought of as having well-defined configurations. A gene is not a “thing.”
Recall that
sex cells (eggs and sperm) each have one set of chromosomes. When an egg is
fertilized the two sets unite and, in all subsequent divisions, daughter cells receive
one set of doubled copies (one from each parent). The DNA in each half of the
chromosome carries the same genes and in similar sequences, but the information
they possess will be slightly different. Genes are entirely passive and never
leave the safe environs of the nucleus.
(Some, though, are positioned on sections of chromosomes attached to the
nuclear membrane’s inner surface; this makes them accessible to molecular
messengers in the cytoplasm that can receive and carry vital instructions to
other parts of the cell or beyond.) Many act as blueprints for the construction
of proteins. Some code for the assembly of protein machines. Others, the
crucial master genes, direct many such activities—most importantly, the entire
process of embryological development, or ontogeny.
[This will be the topic of a later section.]
Some genes are
dominant while others are recessive. Dominant genes tend to be
the ones physically manifested—expressed—but
recessives, even after being hidden in a population for multiple generations,
can suddenly reappear. The trait expressed may then quickly disappear again or
spread throughout a population—under certain circumstances even achieving
dominance.
Only one of
DNA’s intertwined halves carries genetic information: the template strand. (Its complement provides the instructions needed
to create a new template strand during replication.) A gene, then, is
essentially a segment of the DNA template strand consisting of a number of the
nucleotide base “letters”—A, C, T, and G—which, collectively, act as a pattern
for the fabrication of coded instructions that are then conveyed to other
locations in the cell. They are typically several thousand bases long.[1]
Part of this
string of nucleotides consists of a coding
region (where the actual directions for building proteins reside). The
remainder comprises a regulatory region—a
series of binding sites (short
stretches of nucleotides) where special molecules called master proteins will dock, thereby influencing how and when the
gene is expressed. Each coding region consists of a nucleotide sequence
(anywhere between several hundred to a few thousand) which, in essence, is a
set of blueprints—or a recipe—written in DNA “letters.” By way of transcription a copy will be made in
the form of an mRNA molecule which then, through the process of translation, is
used to construct proteins.
Genes don’t
function autonomously (as was formerly believed) but instead act only when
prompted by other molecules. Some of these gene-regulating molecules are
synthesized in the same cell; other types, such as hormones, come from cells in
other parts of the organism. Still others, also coming from elsewhere, interact
with receptors imbedded in the cell’s outer membrane that then relay a message
to the nucleus. Many genes are seldom (if ever) switched on. Competition frequently
arises amid conflicting pressures, with gene-activating molecules arriving at
the same time as gene-inhibitors; both might interact or compete in ways that
influence a cell one way or the other. It’s now widely recognized that
environmental influences or external stresses can also turn genes on and off.
Substances from an organism’s diet also affect gene regulation; these so-called
epigenetic factors, whose impacts
were long denied, have proven to be of vital importance in many evolutionary
processes and are central to much current research.
Some genes are
passed on through thousands of generations; these remain virtually identical
(though they might differ somewhat in specific base sequences) for millions of
years and are to be found in organisms only distantly related. Such genes are
said to be highly conserved. Some—like
those responsible for the production of vital catalysts—are in bacteria that
evolved at least two billion years ago as well as humans, demonstrating
evolution’s power to preserve crucial features as well as try out new innovations.
In fact, there are around 500 genes shared by all types of life forms. More-over, aside from these so-called immortal genes, all organisms—both
plants and animals—have many other genes in common. (The more closely related,
the more shared.) Lab animals whose genomes have been meticulously documented
possess many genes that are very similar to the human counterparts. To give an
idea of just how alike: we share
around 90% of our DNA with cats, about 80% with cows, 60% with fruit flies, and
even nearly 50% with bananas. About 96% of human DNA is nearly the same as that
of our closest relatives, chimpanzees.[2] (It
should be assumed that any such figures depend to a great extent on the way
data is interpreted and, regardless of how they are derived, will likely
change.)
In humans, all
cells (aside from red blood corpuscles and platelets) contain identical copies
of the entire genome though only 5–20% of the genes are active in any one cell.
Some are activated only at certain times (such as during the course of
embryonic development) or can remain unexpressed during an organism’s entire
lifetime.
As for how the
information carried by genes is actually stage-managed: Before a protein-coding
gene can be expressed it first has to be located, activated, and transcribed. Regardless of original
source (that is, whether from inside the cell or elsewhere) signal-bearing molecules
first have to enter the nucleus and locate both a targeted gene and the section
of DNA bearing regulatory portions that govern it. Called activators, these highly specific proteins are responsible for
initiating the entire process. In eukaryotic organisms there are usually
several activators; in some instances a dozen or more.[3]
Some of these moor at binding sites on a segment known as the promoter, changing shape in the fashion
of enzymes as they pile up. Other activators, chemically attracted, in turn
bind to these until the whole freeway-crash attains a specific shape. At this
point, one of the largest known biological molecules—RNA polymerase—shows up to begin transcription, but it can’t
recognize the promotor without help.
Neurobiologist Debra Niehoff tells about the
enzyme’s assistants, “a corps of mechanics and decision makers that biologists
call transcription factors,” and
what happens next:
These proteins come in two flavors.
So-called general transcription factors assemble at the promoter sequence where
transcription begins; they recruit the polymerase and orient it correctly.
Other transcription factors are activators and repressors that permit or forbid
gene expression. They bind to a distinct regulatory sequence that is not part
of the gene itself and may…be located a considerable distance upstream or downstream.[4]
Gene activators give a thumbs up to RNA polymerase, recruit and organize the
enzyme’s crew of general transcription factors, and exhort the whole
conglomerate to work harder and faster. Repressors
stifle gene expression by blocking the binding of activators, interfering with
their recruiting efforts, or smothering the DNA in more protein.[5]
When the
polymerase is ready to step in, it begins transcribing the gene by unzipping the double helix, separating both
strands, and reading the gene’s code. Building materials are
required to synthesize a complementary strand of mRNA; in this case, instead of nucleotides being delivered by
helper enzymes, they’re foraged: a multitude roam freely within the cytoplasmic
tumult and are continually zipping by; the polymerase (somehow) recognizes what
it needs and simply grabs them in sequence. Transcription is completed when the
polymerase runs into another diagnostic sequence that tells it to stop. It
releases the mRNA bearing the copied gene, which carries these instructions out
of the nucleus and into the cytoplasm where teams of ribosomes will begin
construction of the protein. After releasing the mRNA, the polymerase rejoins
the fray; assisted by more enzymes, the DNA strands zip shut and the gene is
thus switched off. It can be reactivated whenever needed…left on…or never used.
This should provide
at least a taste of the amazing process of gene activation.
Then, to
further complicate matters: the vast majority of eukaryotic DNA consists of
non-gene sequences. Only a small portion of those millions of nucleotide
“letters”—less than 2%—actually code for proteins. The coding segments, known
as exons, are located between
stretches of non-coding material called introns.[6]
Formerly known as junk DNA, introns
are often significantly longer than the coding parts, sometimes consisting of
thousands—even millions—of repeated sequences. (As it turns out, introns
actually contain crucial regulatory information in the form of switches and
most likely serve other functions not yet known.)
Eukaryotic
genes, then, are not in uninterrupted stretches but are interspersed by
introns. During transcription the non-coding material is faithfully copied onto
mRNA before subsequently being removed and discarded by editing enzymes. The leading end of the gene consists of regulatory
segments such as the promotor and neighboring enhancer regions.
This should be
more than enough to give an idea of the ultra-elaborate system in place simply
to locate and influence genes. Attempting a basic review of DNA’s actual utility (in its role as the bearer of an
organism’s genetic material) is almost counterproductive; a synopsis can’t
convey any real sense of how the immense amount of information contained in
just a single molecule can be manipulated in such a way as to result in a
living creature—and one that, in a manner of speaking, has all its fingers and toes.
And I have yet to address the even more remarkable matter of how genes actually
make fingers and toes…and assemble them in their proper places.
While it’s still conceptually helpful to speak of
genes as if they were minute objects, “doing things” in some sort of logical
fashion, in truth the word itself has perhaps outlived its utility. According
to James Shapiro, “This term has no rigorous and consistent definition. It has
been used to designate countless different features of genome organization. In
other words, the use of ‘gene’ gives the false impression of specifying a
definite entity when, in fact it can mean any number of different genomic
components.” He suggests that in the case of, say, protein manufacture, the
terms coding sequence be used to
refer to sections of DNA (proximate or not) that account for protein
construction and genetic locus to
indicate coding sequences, switches, and sections that encode for mRNA which,
collectively, code for the fabrication of proteins. (I will carry on with
portraying genes in the traditional manner but readers should be aware that
geneticists no longer think of them as being discrete packages of information.)
Years ago it
was realized that, as then conceived, the number of human genes could not
account for the genetic information required to build and maintain a human
being—regardless of whether it is the currently accepted figure of around
20,500[7]
or even one high-end estimate (circa 1969) of 2 million. Counterintuitively,
other creatures have considerably more genes than us: mice have around 23,000;
the puffer fish, about 28,000. Even far less complex organisms have a proportionately
larger number: the fruit fly, Drosophila
melanogaster, about 17,000.
It is the
ability to rearrange and recombine gene segments (affording enormous numbers of
potential combinations) that occasions the vast number of specific instructions
required to assemble any organism. During transcription, the spatially
separated exons can be shuffled and spliced back together. Individual exons
often code for functional modular units so their recombination can result in
the creation of a whole suite of related proteins. Those at higher levels
exploit this capacity—termed exon
shuffling[8]—to
a much greater extent but genomes still can’t supply nearly enough information
to account for the myriad details that result in each species’ unique form. Imagine how much information is
needed to account for all the nuanced design details on display in something
like a bird’s wing, a mammal’s heart, or the shape of a skull. (Not to mention
building an adult anything from
scratch.) However, the relatively new field of evolutionary developmental biology—known as “evo-devo”—has
revolutionized embryology and goes a long way toward explaining how fertilized
egg cells turn into things such as albatrosses and anglerfish…or, past tense,
into ichthyosaurs and placoderms.
How scientists arrived at
our present understanding of genes and embryonic development (and their
implications for evolutionary theory) following the publication of Origin of Species and up to the time of
the modern synthesis is another intriguing story. A quick look at the
intellectual climate during those decades reveals that—contrary to what many
people believe—Darwin’s revolutionary ideas were not “the only game in town.”
Far from it.
©2016 by Tim Forsell 14 May 2016
[1] The longest known, which codes for a protein found in
muscle, holds 2.4 million bases.
[2] A 2005 study
amends the oft-quoted figure of 99% originating from a 1976 paper. While
endlessly repeated, the number was derived through highly speculative means.
[3] The large number of activators reflects a cell’s need
to act in harmony with trillions of others; the abundance or scarcity of one
can influence the number of times that a proper combination can join forces to
switch on their targeted gene. “The life of a multicelled organism depends on
an extraordinarily complex interplay of thousands of different chemical signals
coming from each cell and going to some or all of the other cells that make up
the republic…that is the human body.” (Rensberger, p 93.)
[4] These are terms used to indicate the position of DNA
regions relative to the direction of the advancing transcription.
[5] For prokaryotes, the way genes and signaling proteins interact is a
considerably less involved process than it is with higher organisms. Unlike
bacteria, eukaryotes have several types of RNA polymerase. In the nucleus of a
human cell, around 40,000 of the variety that assemble mRNA are present at any
given time. Several will be transcribing a gene at the same time, adding around
60 nucleotides per second.
[6] “Exons” refers to sections that are expressed, “introns” to intervening sections. Prokaryote DNA has
no non-coding regions.
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