by Carl Sagan
You can see that the substitution of one nucleotide for another might have only minor consequences—you could, for example, substitute one structural amino acid for another (in the “handle” of the machine tool) and in no way change what the resulting protein does. But it could also have a catastrophic effect: A single nucleotide substitution might convert the instructions for making a particular amino acid into the signal to stop the transcription; then, only a fragment of the molecular machine in question will be manufactured, and the cell might be in trouble. Organisms with such altered instructions will probably leave fewer offspring.
The subtlety and nuance of the genetic language is stunning. Sometimes there seem to be overlapping messages using the same letters in the same sequence, but with different functional import depending on how it’s read: two texts for the price of one. Nothing this clever occurs in any human language. It’s as if a long passage in English had two completely different meanings,9 something like
ROMAN CEMENT TOGETHER NOWHERE …
and
ROMANCEMENT TO GET HER NOW HERE …
but much better—on and on for pages, perfectly lucid and grammatical in both modes, and, we think, beyond the skill of any human writer. The reader is invited to try.
In “higher” organisms, many long sequences seem to be nonfunctional genetic nonsense. They lie after a “STOP” and before the next “START” and generally remain ignored, forlorn, untranscribed. Maybe some of these sequences are garbled remnants of instructions that, long ago, in our distant ancestors, were important or even keys to survival, but that today are obsolete and useless.* Being useless, these sequences evolve quickly: Mutations in them do no harm and are not selected against. Maybe a few of them are still useful, but elicited only under extraordinary circumstances. In humans some 97% of the ACGT sequence is apparently good for nothing. It’s the remaining 3% that, as far as genetics goes, makes us who we are.
Startling similarities among the functional sequences of As, Cs, Gs, and Ts are seen throughout the biological world, similarities that could not have come about unless—beneath the apparent diversity of life on Earth—there was an underlying and fundamental unity. That unity exists, it seems clear, because every living thing on Earth is descended from the same ancestor 4 billion years ago; because we are all kin.
But how could machines of such elegance, subtlety, and complexity ever arise? The key to the answer is that these molecules are able to evolve. When one strand is making a copy of the other, sometimes a mistake occurs and the wrong nucleotide—an A, say, instead of a G—will be inserted into the newly assembled sequence. Some of them are honest replication errors—good as it is, the machinery isn’t perfect. Some are induced by a cosmic ray or another kind of radiation, or by chemicals in the environment. A rise in temperature might slightly increase the rate at which molecules fall to pieces, and this could lead to mistakes. It even happens that the nucleic acid generates a substance that alters itself—perhaps thousands or millions of nucleotides away.
Uncorrected mistakes in the message are propagated down to future generations. They “breed true.” These changes in the sequence of As, Cs, Gs, and Ts, including alterations of a single nucleotide, are called mutations. They introduce a fundamental and irreducible randomness into the history and nature of life. Some mutations may neither help nor hinder, occurring, for example, in long, repetitive sequences—containing redundant information—or in what we’ve called the handles of the molecular machine tools, or in untranscribed sequences between STOP and START. Many other mutations are deleterious. If you’re crafting superb machine tools and, while you’re not looking, someone introduces a few random changes into the computer instructions for manufacture, there isn’t much chance that the resulting machines, built according to the new, garbled instructions, will work better than the earlier model. Enough random changes in a complex set of instructions will cause serious harm.
But a few of the random changes, by luck, prove advantageous. For example, the sickle-cell trait we mentioned in the last chapter is caused by the mutation of a single nucleotide in the DNA, generating a difference of a single amino acid in the hemoglobin molecules that nucleotide helps code for; this in turn changes the shape of the red blood cell and interferes with its ability to carry oxygen, but at the same time it eventually kills the plasmodium parasites those cells contain. A lone mutation, one particular T turning into an A, is all it takes.
And, of course, not just the hemoglobin in red blood cells, but every part of the body, every aspect of life, is instructed by a particular DNA sequence. Every sequence is vulnerable to mutation. Some of these mutations cause changes more far-reaching than the sickle-cell trait, some less. Most are harmful, a few are helpful, and even the helpful ones may—like the sickle-cell mutation—represent a tradeoff, a compromise.
This is a principal means by which life evolves—exploiting imperfections in copying despite the cost. It is not how we would do it. It does not seem to be how a Deity intent on special creation would do it. The mutations have no plan, no direction behind them; their randomness seems chilling; progress, if any, is agonizingly slow. The process sacrifices all those beings who are now less fit to perform their life tasks because of the new mutation—crickets who no longer hop high, birds with malformed wings, dolphins gasping for breath, great elms succumbing to blight. Why not more efficient, more compassionate mutations? Why must resistance to malaria carry a penalty in anemia? We want to urge evolution to get to where it’s going and stop the endless cruelties. But life doesn’t know where it’s going. It has no long-term plan. There’s no end in mind. There’s no mind to keep an end in mind. The process is the opposite of teleology. Life is profligate, blind, at this level unconcerned with notions of justice. It can afford to waste multitudes.
—
The evolutionary process could not have gone very far, though, if the mutation rate had been too high. In any given environment, there must be a delicate balance—simultaneously avoiding mutation rates so high that instructions for essential molecular machine tools are quickly garbled, and mutation rates so low that the organism is unable to retool when changes in the external environment require it to adapt or die.
There is a vast molecular industry that repairs or replaces damaged or mutated DNA. In a typical DNA molecule, hundreds of nucleotides are inspected every second and many nucleotide substitutions or errors corrected. The corrections are then themselves proofread, so that there is only about one error in every billion nucleotides copied. This is a standard of quality control and product reliability rarely reached in, say, publishing or automobile manufacture or microelectronics. (It is unheard of that a book this size, containing around a million letters would have no typographical errors; a 1% failure rate is common in automobile transmissions manufactured in America; advanced military weapons systems are typically down for repair some 10% of the time.) The proofreading and correction machinery devotes itself to DNA segments that are actively involved in controlling the chemistry of the cell, and mainly ignores nonfunctioning, largely untranscribed, or “nonsense” sequences.
The unrepaired mutations steadily accumulating in these normally silent regions of the DNA may lead (among other causes) to cancer and other illnesses, should the “STOP” be ignored, the sequence turned on, and the instructions carried out. Long-lived organisms such as humans devote considerable attention to repairing the silent regions; short-lived organisms such as mice do not, and often die filled with tumors.10 Longevity and DNA repair are connected.
Consider an early one-celled organism floating near the surface of the primeval sea—and thereby flooded with solar ultraviolet radiation. A small segment of its nucleotide sequence reads, let’s say,
… TACTTCAGCTAG …
When ultraviolet light strikes DNA, it often binds two adjacent T nucleotides together by a second route, preventing DNA from exercising its coding function and getting in the way of its ability to reproduce itself:
�
� TACCAGCTAG …
The molecule literally gets tied up in knots. In many organisms enzymatic repair crews are called in to correct the damage. There are three or four different kinds of crews, each specialized for repairing a different kind of damage. They snip out the offending segment and its adjacent nucleotides (CC, say) and replace it with an unimpaired sequence (CTTC). Protecting the genetic information and making sure it can reproduce itself with high fidelity is a matter of the highest priority. Otherwise, useful sequences, tried-and-true instructions, essential for the adaptation of organism to environment, may be quickly lost by random mutation. Proofreading and repair enzymes correct damage to the DNA from many causes, not just UV light. They probably evolved very early, at a time before ozone, when solar ultraviolet radiation was a major hazard to life on Earth. Early on, the rescue squads themselves must have undergone fierce competitive evolution. Today, up to a certain level of irradiation and exposure to chemical poisons, they work extremely well.
Advantageous mutations occur so rarely that sometimes—especially in a time of swift change—it may be helpful to arrange for an increased mutation rate. Mutator genes in such circumstances can themselves be selected for—that is, those varieties with active mutator genes serve up a wider menu of organisms for selection to draw upon, and serve them up faster. Mutator genes are nothing mysterious; some of them, for example, are just the genes ordinarily in charge of proofreading or repair. If they fail in their error-correcting role, the mutation rate, of course, goes up. Some mutator genes encode for the enzyme DNA polymerase, which we will meet again later; it’s in charge of duplicating DNA with high fidelity. If that gene goes bad, the mutation rate may rise quickly. Some mutator genes turn As into Gs; others, Cs into Ts, or vice versa. Some delete parts of the ACGT sequence. Others accomplish a frame shift, so the genetic code is read, three nucleotides at a time, as usual, but from a starting point offset by one nucleotide—-which can change the meaning of everything.11
This is a marvel of self-reflexive talent. Even very simple microorganisms have it. When conditions are stable, the precision of reproduction is stressed; when there’s an external crisis that needs attending to, an array of new genetic varieties is generated. It might look as if the microbes are conscious of their predicament, but they haven’t the foggiest notion of what’s going on. Those with appropriate genes preferentially survive. Active mutators in placid and stable times tend to die off. They are selected against. Reluctant mutators in quickly changing times are also selected against. Natural selection elicits, evokes, draws forth a complex set of molecular responses that may superficially look like foresight, intelligence, a master Molecular Biologist tinkering with the genes; but in fact all that is happening is mutation and reproduction, interacting with a changing external environment.
——
Since favorable mutations are served up so slowly, major evolutionary change will ordinarily require vast expanses of time. There are, as it turns out, ages available. Processes that are impossible in a hundred generations may be inevitable in a hundred million. “The mind cannot grasp the full meaning of the term of a million or a hundred million years,” Darwin wrote in 1844, “and cannot consequently add up and perceive the full effects of small successive variations accumulated during almost infinitely many generations.”12
The time scale problem was formidable when Darwin wrote. Lord Kelvin, the greatest physicist of the late Victorian age, authoritatively announced that the Sun—and therefore life on Earth—could be no more than about a hundred million (later downgraded to thirty million) years old. The fact that he provided a quantitative argument, plus his enormous prestige, intimidated many geologists and biologists, Darwin included. Is it more probable, Kelvin asked,13 that straightforward physics was in error, or that Darwin was wrong? There was in fact no error in Kelvin’s physics, but his starting assumptions were mistaken. He had assumed that the Sun shines because of meteorites and other debris falling into it. There was not the faintest hint in the physics of Kelvin’s time of thermonuclear reactions; even the existence of the atomic nucleus was unknown. As late as the first decade of the twentieth century it was believed that the Earth was only 100 million years old, instead of 4.5 billion, and that the mammals had supplanted the dinosaurs only 3 million years ago, instead of 65 million.
On the basis of these misconceptions, Darwin’s critics argued—properly—that even if evolution worked in principle, there might not be enough time for it to do its stuff in practice.* On an Earth created less than ten thousand years ago, it was absurd to imagine that species flowed one into another, that the slow accumulation of mutations could explain the varied forms of life on Earth. It made sense, not merely as an expression of faith, but as legitimate science, to conclude that each species must have been separately created by the same Maker who had only a moment before created the Universe.
The breakup of rocks by the waves, the transport of rock powder by the winds, lava flowing down the sides of a volcano—if the Earth is only a few thousand years old, such processes cannot have much reworked the face of our planet. But the most casual look at the landforms of Earth reveals a profound reworking. So if you imagined from biblical chronology that the world was formed around the year 4000 B.C., it made sense to be a catastrophist—and believe that immense cataclysms, unknown in our time, have occurred in earlier history. The Noachic flood, as we’ve mentioned, was a popular example. If, though, the Earth is 4.5 billion years old, the cumulative impact of small, nearly imperceptible changes over the course of ages could wholly alter our planet’s surface.
Once the time scale for the terrestrial drama had been extended to billions of years, much that had once seemed impossible could now be readily explained as the concatenation of apparently inconsequential events—the footfalls of mites, the settling of dust, the splatter of raindrops. If, in a year, wind and water rub a tenth of a millimeter off the top of a mountain, then the highest mountain on Earth can be flattened in ten million years. Catastrophism gave way to uniformitarianism, championed by Lyell in geology and by Darwin in biology. The accumulation of vast numbers of random mutations was now inevitable, unavoidable. Great cataclysms were discredited and special creation became, both in geology and biology, a redundant and unnecessary hypothesis.
Many advocates of uniformitarianism denied that quick and violent biological change had ever occurred. T. H. Huxley, for example, wrote, “There has been no grand catastrophe—no destroyer has swept away the forms of life of one period, and replaced them by a totally new creation: but one species has vanished and another has taken its place; creatures of one type of structure have diminished, those of another have increased, as time has passed on.”14 In the light of modern evidence, he was right in general, right for most of the history of the Earth. But he went too far; clearly it is possible to acknowledge the importance of slow, cumulative, background change without denying the possibility of occasional global cataclysms.
In recent years it has become increasingly evident that catastrophes have swept over the Earth, generating vast alterations both in land-forms and in life. Major worldwide discontinuities in the record in the rocks are readily explained by such catastrophes; and abrupt transitions in the forms of life on Earth, occurring in the same epoch, are naturally understood as mass extinctions, times of great dyings. (Of these, the late Permian is the most extreme example, and the late Cretaceous—when the dinosaurs were all snuffed out—the best-known). Previous ecologies are then supplanted wholesale by new teams of organisms. The fossil record shows that long periods of very slow evolutionary change are often interrupted by rarer, episodic intervals of quick change, the “punctuated equilibrium” of Niles Eldredge and Stephen J. Gould.15 We live on a planet in which both catastrophes and uniform change have played their roles. In the purported distinction between all-at-once and slow-and-steady, as in much else, the truth embraces seemingly antithetical extremes.
The case for special creation has not been strengthened by this
new balance. Catastrophism is an awkward business for biblical literalists: It suggests imperfections in either the design or the execution of the Divine Plan. Mass extinctions permit the survivors to evolve quickly, occupying ecological niches formerly closed to them by the competition. The painstaking selection of mutations continues, catastrophes or no catastrophes. But the wiping out of whole species, genera, families and orders of life, the randomness of mutation, the infelicities in the molecular machinery of life, and the slow evolutionary fiddling displayed in the fossil record—of trilobites, say, or crocodiles—all reveal a tentativeness, a hesitancy, an indecision that hardly seems consistent with the modus operandi of an omnipotent, omniscient, “hands-on” Creator.
——
Why are many cave fish, moles, and other animals that live in perpetual darkness blind, or nearly so? At first the question seems ill-conceived, since no adaptive reward would attend the evolution of eyes in the dark. But some of these animals do have eyes, only they’re beneath the skin and don’t work. Others have no eyes at all, although anatomically it’s clear that their ancestors did. The answer seems to be that they all evolved from sighted creatures that entered a new and promising habitat—a cave, say, lacking competitors and predators. There, over many generations, no penalty is paid for the loss of eyesight. So what if you’re blind, as long as you live in pitch darkness? Mutations for blindness, which must be occurring all the time (there being many possible malfunctions in the genetic instructions for vision—in eye, retina, optic nerve, and brain), are not selected against. A one-eyed man has no advantage in the kingdom of darkness.