The Edge of Evolution Page 7
In a real-world experiment involving this basic principle, scientists from Catholic University in Washington, D.C., showed that resistance to one drug (called 5-fluoroorotate) at a particular concentration was found in malaria cells at a frequency of about one in a million. Resistance to a second drug (atovaquone) was about one in a hundred thousand. Sure enough, resistance to both drugs was the multiplied odds for the two cases, about one in a hundred thousand times a million, that is, one in a hundred billion.
Using a combination of drugs is a common strategy to delay the onset of resistance. In addition to the battle with malaria, for example, drug cocktails are used in the fight against AIDS and tuberculosis. Delaying the onset of resistance, though, is not the same as stopping it altogether. The researchers from Catholic University warned that, although the combination of drugs they tested would be likely to cure any given person since the likelihood the person would harbor a resistant bug would be small, “a large enough patient population will inevitably allow selection of parasites that are resistant to both compounds.”14
TWO FOR THE PRICE OF ONE
Suppose that P. falciparum needed several separate mutations just to deal with one antimalarial drug. Suppose that changing one amino acid wasn’t enough. Suppose that two different amino acids had to be changed before a beneficial effect for the parasite showed up. In that case, we would have a situation very much like a combination-drug cocktail, but with just one drug. That is, the likelihood of a particular P. falciparum cell having the several necessary changes would be much, much less than the case where it needed to change only one amino acid. That factor seems to be the secret of why chloroquine was an effective drug for decades.
How much more difficult is it for malaria to develop resistance to chloroquine than to some other drugs? We can get a good handle on the answer by reversing the logic and counting up the number of malarial cells needed in order to find one that is immune to the drug. For instance, in the case of atovaquone, a clinical study showed that about one in a trillion cells had spontaneous resistance.15 In another experiment it was shown that a single amino acid mutation, causing a change at position number 268 in a single protein, was enough to make P. falciparum resistant to the drug. So we can deduce that the odds of getting that single mutation are roughly one in a trillion. On the other hand, resistance to chloroquine has appeared fewer than ten times in the whole world in the past half century. Nicholas White of Mahidol University in Thailand points out that if you multiply the number of parasites in a person who is very ill with malaria times the number of people who get malaria per year times the number of years since the introduction of chloroquine, then you can estimate that the odds of a parasite developing resistance to chloroquine is roughly one in a hundred billion billion.16 In shorthand scientific notation, that’s one in 1020.
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BOX 3.1
Scientific Notation
Scientists often have to deal with numbers that are very large (say, the number of stars in the universe) or very small (say, the mass of a proton). To do so conveniently, scientific notation can be used. In scientific notation a ten is written and the number of zeroes in the number is written as a superscript to the right of the ten. For example, instead of 10, 100, and 1,000, the numbers ten, one hundred, and one thousand are written as 101,102, and 103, respectively. Instead of writing out a big number such as a trillion as 1,000,000,000,000, in scientific notation a trillion is written simply as 1012, which is easier on the eyes and saves space. One has to keep in mind that numbers increase very, very quickly as the superscript (called the exponent) increases. For example, compare the numbers 104and 1010. They might not seem so different at first blush. However, a minimum wage worker might earn 104(ten thousand) dollars per year; only someone like Bill Gates might earn 1010(ten billion) dollars per year. The difference of just six between the ten and the four in the exponents means that the numbers differ by a million-fold. The figure below shows a scale with numbers written in both common and scientific notation, and corresponding population numbers to put things in perspective.
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MATCHING TWO
Let’s compare the two numbers for the odds of achieving resistance to atovaquone, where just one mutation is needed, versus chloroquine, where (presumably—since if a single mutation could help, chloroquine resistance would originate much more frequently) two are needed. The odds are, respectively, one in a trillion (1012) and one in a hundred billion billion (1020). The ratio of the two numbers shows that the malarial parasite is a hundred million times (108) less likely to develop resistance to chloroquine than to atovaquone. This is reasonable since the genome size of the malarial parasite is in the neighborhood of a hundred million nucleotides. The implication is that if two amino acids in a protein have to be changed instead of just one, that decreases the likelihood of resistance by a factor of about a hundred million.
Even though the odds are tremendously stacked against it, P. falciparum was able to develop chloroquine resistance because there are an enormous number of parasitic cells (about a trillion) in an infected patient’s body, and about a billion infected people in the world in a year. So the parasite has the population numbers to get around the terrible odds. Spontaneous resistance to atovaquone can be found in roughly every third sick person.17 Spontaneous resistance to chloroquine can be found perhaps in every billionth sick person, and since there are usually close to a billion sick people on the planet every year or so, that means chloroquine resistance is usually waiting to be found in at least one person, somewhere in the world, at any given time.
FEWER PLAYERS, LONGER TIMES
Suppose that P. falciparum were not quite as prodigious as it actually is. What if, instead of a trillion malarial cells in the typical sick person, there were only a million? How long would it then take for chloroquine resistance to pop up? If all other things were equal, it would take about a million years. The reason is that if there were fewer parasites per person, and therefore fewer in the world’s population, then the parasite would have to wait a proportionately longer amount of time for the right combination of mutations to come along. The number of players in the lottery would be decreased a millionfold, so the length of time needed to get a winner would be increased a millionfold.
This straightforward example carries an obvious implication. Species in which there are fewer living organisms than malaria (again, other things being equal) will take proportionately longer to develop a cluster of mutations of the complexity of malaria’s resistance to chloroquine. Let’s dub mutation clusters of that degree of complexity—1 in 1020—“chloroquine-complexity clusters,” or CCCs. Obviously, since malaria is a microbe, its population is far more vast than any species of animal or plant we can see with the unaided eye. Virtually any nonmicroscopic species would take longer—perhaps much, much longer—to develop a CCC than the few years in which malaria managed it, or the few decades it took for that mutation to spread widely.
Consider a species that is dear to our hearts—Homo sapiens. The number of human players in the world is much fewer than 1020. For most of the past ten million years the population of the line of primates leading to humans is thought at best to have been roughly about a million or so.18 Only in the past few thousand years did that number accelerate up to today’s population of 6 billion.
What is the total number of creatures in the line leading to humans since it split from the line leading to modern chimps less than ten million years ago? If the average generation span of humanoids is rounded down, conservatively, to about ten years, then a generous estimate is that perhaps a trillion creatures have preceded us in the past ten million years.19 Although that’s a lot, it’s still much, much less than the number of malarial parasites it takes to develop chloroquine resistance. The ratio of humanoid creatures in the past ten million years to the number of parasites needed for chloroquine resistance is one to a hundred million.
If all of these huge numbers make your head spin, think of it this
way. The likelihood that Homo sapiens achieved any single mutation of the kind required for malaria to become resistant to chloroquine—not the easiest mutation, to be sure, but still only a shift of two amino acids—the likelihood that such a mutation could arise just once in the entire course of the human lineage in the past ten million years, is minuscule—of the same order as, say, the likelihood of you personally winning the Powerball lottery by buying a single ticket.
On average, for humans to achieve a mutation like this by chance, we would need to wait a hundred million times ten million years. Since that is many times the age of the universe, it’s reasonable to conclude the following: No mutation that is of the same complexity as chloroquine resistance in malaria arose by Darwinian evolution in the line leading to humans in the past ten million years.
Instead of concentrating on us humans, we can look at the odds another way. There are about five thousand species of modern mammals. If each species had an average of a million members,20 and if a new generation appeared each year, and if this went on for two hundred million years,21 the likelihood of a single CCC appearing in the whole bunch over that entire time would be only about one in a hundred.
Let that sink in for a minute. Mammals are thought to have arisen from reptiles and then diversified into a spectacular array of creatures, including bats, whales, kangaroos, and elephants. Yet that entire process would—if it occurred through Darwinian mechanisms—be expected to occur without benefit of a single mutation of the complexity of a CCC. Strict Darwinism requires a person to believe that mammalian evolution could occur without any mutation of the complexity of this one.
Here’s a possible point of confusion. We estimated the odds of a CCC—one in a hundred billion billion (1020)—by looking at the number of malarial parasites needed to develop the double mutation of a particular protein of a particular gene. Someone might object that, since there are thousands of other proteins in an organism, much other DNA, and many other kinds of mutations than just amino acid changes, aren’t the odds of finding some beneficial complex of mutations much better than the odds of finding just the specific complex of mutations we isolated?
No. Many, many other mutations in addition to the ones we discussed have popped up by chance in the vast worldwide malarial pool over the course of a few years. In fact mutations in all of the amino acid positions of all of the proteins of malaria—taken both one and two at a time—can be expected to occur by chance during the same stretch of time. And other types of mutations besides just changes in amino acids would also occur (such as insertions, deletions, inversions, gene duplications, mobile DNA transpositions, changes in regulatory regions, and others, perhaps even including whole genome duplication—some of these types of mutations are discussed in the next chapter). Although some other mutations in some other proteins are thought to contribute to chloroquine resistance,22 none are nearly as effective as that in PfCRT. That means that of all of the possible mutations in all of the different proteins of malaria, only a minuscule number have the ability to help at all against chloroquine, and only one, PfCRT, is really effective. Natural selection gets to choose from a staggering number of variations, yet at best only a handful help. So a CCC isn’t just the odds of a particular protein getting the right mutations; it’s the probability of an effective cluster of mutations arising in an entire organism.
EVEN WORSE
The development of chloroquine resistance isn’t the toughest problem that evolution faces. We know that for certain, because the malarial parasite solved that problem but hasn’t solved others, such as sickle hemoglobin. How much more difficult than a CCC would a challenge have to get before Darwinian evolution would essentially be ineffective, even for simple single-celled creatures such as malaria?
First think of it this way. What if, to win a super-Powerball lottery, instead of matching all the numbers on one ticket, some person had to match all the numbers on two tickets? The likelihood of that happening would be about the square of the odds of matching the numbers on one ticket, roughly a hundred million squared. If that were the case, then (if other things were equal) it would take millions of years for any person at all to win the lottery.
Recall that the odds against getting two necessary, independent mutations are the multiplied odds for getting each mutation individually. What if a problem arose during the course of life on earth that required a cluster of mutations that was twice as complex as a CCC? (Let’s call it a double CCC.) For example, what if instead of the several amino acid changes needed for chloroquine resistance in malaria, twice that number were needed? In that case the odds would be that for a CCC times itself. Instead of 1020 cells to solve the evolutionary problem, we would need 1040cells.
Workers at the University of Georgia have estimated that about a billion billion trillion (1030) bacterial cells are formed on the earth each and every year.23 (Bacteria are by far the most numerous type of organisms on earth.) If that number has been the same over the entire several-billion-year history of the world, then throughout the course of history there would have been slightly fewer than 1040 cells, a bit less than we’d expect to need to get a double CCC. The conclusion, then, is that the odds are slightly against even one double CCC showing up by Darwinian processes in the entire course of life on earth.
Put more pointedly, a double CCC is a reasonable first place to draw a tentative line marking the edge of evolution for all of life on earth. We would not expect such an event to happen in all of the organisms that have ever lived over the entire history of life on this planet. So if we do find features of life that would have required a double CCC or more, then we can infer that they likely did not arise by a Darwinian process.
As we’ll see, life is bursting with such features.
MAKING DISTINCTIONS
We’ve come a long way in a short space by drawing out implications from the long trench war of attrition between humanity and malaria. Perhaps, however, we’ve moved a bit too fast. Even with its limited resources, Darwinian evolution has a number of tricks up its sleeve, tricks that can easily be overlooked if you’re not careful. In order to be as confident as we can of where to draw the line marking the edge of Darwinian evolution, we need to have a thorough appreciation for what random mutation can do. In the next chapter we’ll survey the kinds of tools that are available to evolution and look at examples of where it has acted.
4
WHAT DARWINISM CAN DO
COMMON DESCENT VERSUS RANDOM MUTATION
“How stupid of me not to have thought of it!” So lamented the naturalist Thomas Huxley upon first hearing of Darwin’s theory of evolution. While his ideas may not explain all of biology, from the moment they were published in 1859 all biologists have realized that they do explain a great deal. In this chapter we’ll focus on what clearly can be explained by Darwin.
Bear in mind, throughout, that common descent is a distinct concept from the mechanism of natural selection acting on random mutation. It isn’t always easy to keep them apart. In practice, if you’re not careful, it’s easy to mistake the effects of common descent for the effects of natural selection. In fact, it’s so easy that even Darwin himself mixed them up. Writes Ernst Mayr:
That writers on Darwin have nevertheless almost invariably spoken of the combination of these various theories as “Darwin’s theory” in the singular is in part Darwin’s own doing. He not only referred to the theory of evolution by common descent as “my theory,” but he also called the theory of evolution by natural selection “my theory,” as if common descent and natural selection were a single theory…. [Darwin] ascribed many phenomena, particularly those of geographic distribution, to natural selection when they were really the consequences of common descent.1
To find the edge of evolution we need to take care to distinguish the two. Although human-malaria trench warfare shows that random mutation is severely limited in scope, the idea of common descent has a lot more going for it.
Descent is often the aspect of Darwi
n’s multifaceted theory that is most emphasized. For example, in the final sentence of The Origin of Species Darwin waxed lyrical.
There is grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved.2
Over the next few sections I’ll show some of the newest evidence from studies of DNA that convinces most scientists, including myself, that one leg of Darwin’s theory—common descent—is correct. Let’s begin by looking at something Darwin knew nothing about—the genetic basis of life, and how it can change.
VARIETY SHOW
In The Origin of Species Darwin proposed that natural selection acts on variation in the living world, rewarding the more fit and weeding out the less fit. At the time the underlying basis for variation within a species was unknown. Darwin had to simply assume that there was some mechanism, unknown to the science of his age, to generate differences.
One of the greatest triumphs of twentieth-century science was its discovery of the basis of biological inheritance. In a classic experiment in the 1940s Oswald Avery showed that DNA is the carrier of genetic information. Watson and Crick deciphered the elegant double helical shape of that molecule. Marshall Nirenberg cracked its genetic code. More recently, scientists developed methods to clone, synthesize, and sequence DNA. In June 2000 President Clinton and Great Britain’s prime minister Tony Blair jointly announced the completion of the sequencing of the human genome. The announcement marked an unparalleled milestone in human intellectual achievement. Yet it was only a way station, not a terminal, in the investigation into the foundation of life on earth. Since then the genomes of hundreds of other organisms have been sequenced, and thousands more are planned. Most of those organisms are single-celled microbes, whose genomes are much smaller (about one-thousandth the size) than those of animals like us. But the genomes of some larger plants and animals have also been sequenced, including those of the chimp, dog, zebrafish, and rice.