Ever since Darwin, biologists have recognized that variation is the raw material of evolution by natural selection. Darwin himself scribbled that insight in a private notebook as a young man, at a very early point during his groping search for a theory of what he had begun calling the “transmutation of species.” In November 1838, two years after arriving home from his voyage on HMSBeagle, he wrote to himself, with careless disregard for grammar and punctuation:
Three principles, will account for all
(1) Grandchildren. like. grandfathers
(2) Tendency to small change. . <<especially with physical change>>
(3) Great fertility in proportion to support of parents
He was right. Those principles did account for all. The first is heredity, which yields offspring somewhat resembling their ancestors; the second is variation, such that inherited similarity is always imperfect and offspring differ in significant ways, both from their ancestors and from their siblings; the third is “excess” reproduction, whereby natural fecundity produces more offspring than habitat or food supply can support. The inevitable result, Darwin realized, is competition among offspring and differential survival, with success based on those variations, yielding body shapes and other physical attributes—long necks among giraffes, great speed among cheetahs—progressively better adapted to meet the challenges of local environments at particular times. In a word (a word that Darwin himself didn’t use until years later): evolution.
It was a large insight for a twenty-nine-year-old Englishman whom his own father had dismissed, not many years earlier, as feckless. But another twenty-one years passed before Darwin—delayed by caution, bad health, professional and personal distractions, and his sensible determination to gather a vastness of supporting evidence and argument—went public with his wonderful and dangerous idea.
When the time did come, in 1859, Darwin gave variation due prominence in his grand opus, On the Origin of Species, devoting the first two chapters—“Variation under Domestication” and “Variation under Nature”—to it. His third chapter, “Struggle for Existence,” and fourth, “Natural Selection,” which carried the main burden of sketching his theory, would have made no sense without variation. And then he returned immediately, in chapter 5, to what he termed “laws of variation.” So it’s ironic to recall that, for as much as Darwin recognized the paramount importance of variation, he had no idea of its source. The word “variation” resounds throughout his book, but the word “mutation” scarcely appears at all.
There was good reason for that. Darwin had no viable theory of heredity. To him the phenomenon of heritability of traits—traits that become blurred and shuffled over generations—was a dark mystery. Gregor Mendel’s theory of particulate inheritance, based on the inference that heritable traits are conveyed by pairs of discrete units (like particles), with just one unit coming from each parent, and not by cumulative blending as though of fluids, would have helped Darwin. But Mendel’s crucial paper wasn’t published until seven years after The Origin, and then so obscurely that it would remain unnoticed by Darwin throughout his life, and undiscovered by other influential biologists until 1900. The medium of those discrete units, that molecule we now know as DNA, would not be identified until 1944. Its structure would not be solved until 1953. And without an understanding of how the DNA molecule is built, how it replicates itself (often imperfectly) within a cell, how it self-regulates the repair of damage to itself, how it bundles itself into packets called chromosomes, and how those packets are parceled out to progeny cells, with the randomness of a blind butcher sorting sausages—without all that, it’s not possible to understand how life’s imperfections have yielded life’s magnificent diversity.
Later biologists who were also historians of biology, such as Ernst Mayr and Stephen Jay Gould, likewise recognized that variation is crucial to evolution. Mayr devoted the third of the three major parts of his monumental but pleasantly readable chronicle The Growth of Biological Thought (1982)to variation and its inheritance. Gould’s massive The Structure of Evolutionary Theory (2002), tirelessly explanatory (in fact, tiresomely over-explanatory) at 1,433 pages, had its own agenda in many ways but placed variation, as young Darwin had, at the “syllogistic core” of natural selection. Variation is what gives natural selection leverage; it constitutes the physical differences by which the fittest are winnowed from the less fit.
And the chief source of genetic variation is mutation—that is, damage, inaccuracy, mistakes in the genome, expressed in observable and functional bodily traits. Julian Huxley, playing a riff on Shakespeare, called it “the only begetter of intrinsic change in the separate units of the hereditary constitution”—that is, in the genes. It is fundamental, dynamic, and consequential. Which is why Roxanne Khamsi, a science journalist who focuses on genetics and medicine and a contributing writer at The Atlantic, has made mutation the subject of her multifarious, crosscutting new book, Beyond Inheritance.
I call it “crosscutting” because Beyond Inheritance goes sideways from inheritance as well as beyond it,ranging widely across diseases (some of them rare) triggered by mutation, other diseases (even rarer) repaired by mutation, and the broader implications of recognizing that each of us is a “mosaic” (Khamsi’s word) of different genomes, guiding our various cells toward various imperatives, sometimes harmoniously and sometimes with the discord of a bar brawl among ten drunken gangs.
Mutations are not rare. To say they happen frequently is an understatement, though they accumulate at different rates in different kinds of living creatures, and faster in some kinds of cells than in others. Some occur at a micro scale, as single-point changes in the string of “letters” (the structural units adenine, thymine, cytosine, and guanine, represented as A, T, C, and G) that constitute the informational content of a DNA molecule. A point mutation has happened, for instance, when TCATG in the DNA template becomes TCACG in the copy. Other mutations occur at a relatively macro scale, as major rearrangements of whole stretches of genome or structural aberrations in the chromosomes. Mutations can be caused by external mutagens, such as ultraviolet light or DNA-unfriendly chemicals, and they can appear spontaneously, when the DNA of a dividing cell imperfectly copies itself to yield two offspring cells, making what amounts to a typographical mistake. They exist throughout all forms of life, from bacteria to elephants, which is what has allowed so much diversity to evolve. But let’s ignore all the mutating genes in microbes and pachyderms and tulips and giraffes, for convenience, to consider just humans and human mutations, as Khamsi does in her book.
There’s a lot of confusion afoot about how mutations affect people. They sound bad. They sound fateful. Public misunderstanding of the changes that rattle continuously through human DNA is partly traceable, Khamsi rightly notes, to the exultant announcement on June 26, 2000, when President Bill Clinton stood at a White House podium and said, “We are here to celebrate the completion of the first survey of the entire human genome.” It was the crescendo of the Human Genome Project, a collaborative international effort that took thirteen years and cost about three billion dollars, toward the goal of sequencing “the” human genome.
A cantankerous observer might well have asked: Which human genome? Whose? There isn’t just one, of course. We’re all different. “Our genomes are around 99.5 percent similar to one another’s,” Khamsi writes. That might seem like a very close match, but it means that the scope of divergence among humans—half of one percent of our otherwise shared DNA, amounting to more than 15 million single-letter differences—is substantial. So we encompass, collectively, an abundance of genetic variation. But Khamsi points out that “what goes largely overlooked is that a multitude of genomes exist within one individual.” Walt Whitman wasn’t the only person to contain multitudes.
Each human body consists of roughly 30 trillion cells, and each cell carries its own genome, its own sequence of the DNA letters, which may differ from the genomes in most or all other cells of the same body. The differences derive from that inexorable process, mutation. More specifically, the differences among the cell genomes in one person’s body arise by somatic mutation. A somatic mutation (from the Greek soma, meaning body) is a change in the DNA of a body cell, as distinct from a germline mutation, a change in the DNA of an egg cell or a sperm cell or the stem cells that produce those reproductive cells. A germline mutation—for example, the mutation causing Huntington’s disease, which produces a faulty protein that damages nerve cells in the brain—is passed along to progeny. A somatic mutation—such as a mutation in a lung cell that may push it toward cancer—is not passed along, because it doesn’t affect the germline. Somatic mutations may begin soon after an embryo starts to grow and continue throughout life, but the good news is that their cumulative burden isn’t visited on the children.
Identical twins are the extreme case. You might assume that they have identical DNA at birth. But according to one study Khamsi cites, they may differ from each other, even in the womb, by an average of five somatic mutations, acquired during their embryonic development, and then more with passing time as they grow through childhood into adults. “By some estimates, you acquire trillions of new mutations a day,” Khamsi tells us. Her book explores the potential consequences of those mutations: the health problems they cause—and, in rare cases, the health problems they fix.
Cancer is the most ubiquitous and familiar mutation-driven disease. It’s not so much a single disease as a whole category of diseases, all sharing a short list of characteristics. In a famous paper published a quarter-century ago, the biologists Douglas Hanahan and Robert A. Weinberg termed those characteristics the “hallmarks” of cancer, which included runaway cell replication, refusal of cells to die, tissue invasion, and aggressive dispersal of cancerous cells (metastasis) to other parts of the body.
How does cancer begin? As Khamsi explains, the prevailing notion among many researchers throughout most of the twentieth century was what’s called the somatic mutation theory. The basic idea is that acquiring a certain number of mutations, each one affecting a crucial gene, is enough to tip a single cell or cell lineage into malignancy. How many mutations are required? For some childhood cancers, such as retinoblastoma (a cruel cancer of the retina, mainly affecting kids under age five), it might be as few as two. For some cancers among adults, researchers have posited, the number might be four, five, or six, and those mutations need to turn off or turn on certain critical genes, such as (turning off) the tumor-suppressor gene TP53, or (turning on) the cancer-triggering gene KRAS.
But thinking has changed during the twenty-first century, and many cancer scientists no longer consider the somatic mutation theory adequate to explain cancer initiation. Six mutations to critical genes might be necessary, but not sufficient, to turn a cell cancerous. Some other factor or element—maybe inflammation of tissues, or disruption of cell-to-cell signaling, or aging itself—might be required.
With the availability of improved scientific tools and methods, such as duplex consensus sequencing (never mind what that is), researchers have found ways to sequence genomes in ever-smaller samples of cells, lately to the extreme of even just a single cell. That has revealed high numbers of mutations where they weren’t expected: in normal cells that continue functioning normally. And these are not just loads of randomly scattered changes but mutations to the critical cancer-related genes. Yet those cells haven’t turned cancerous. Khamsi mentions the work of the scientist Iñigo Martincorena, at the Wellcome Sanger Institute in the UK, who along with his colleagues has found that normal cells of human eyelids (which receive high exposure to UV radiation) and in the human esophagus (which gets challenged by all the things we swallow, such as alcohol, grilled meats, and traces of arsenic in drinking water) sometimes contain startling numbers of cancer-associated mutations. But, to repeat, often those cells aren’t cancerous. So our bodies are more tolerant of mutation, and more riddled with it, than we thought.
That’s cancer, still mysterious and multifactorial. Other diseases, some of them rare and obscure but equally punishing, are also linked to mutations. A blood disorder with the formidable name paroxysmal nocturnal hemoglobinuria (PNH) derives from a mutation in a gene called PIGA,which produces a protein that helps protect blood cells from attack by the body’s immune cells. When a mutated PIGAgene produces the wrong sort of protein, the immune system becomes suspicious and attacks the red blood cells, spilling their hemoglobin into the urinary tract, so that urine turns red, burgundy, or even black. Nobody wants black urine, but the condition can also be painful and debilitating, as a shortage of red blood cells leads to other complications, including sometimes death.Part of what’s notable in this disease is that it’s seldom an inherited condition but almost always begins with a spontaneous mutation, a sudden tweak to the PIGAgene in stem cells that produce the person’s blood—a reminder that the individual genomes in our cells are crackling with change and dire possibilities as we live our lives.
Chapter by chapter, Khamsi takes us through other diseases, with their tongue-twister names and their lamentable manifestations, that in some cases result from inherited mutations, in others from spontaneous mutations,going fatefully boing in a person’s genome and introducing a new kind of woe. The cardiac condition known as long QT syndrome, a life-threatening disruption of the heart’s electrically timed functions, is caused by mutation in a gene called SCN5A. Usually the mutation is inherited. But the case of an infant named Astrea, born in 2013 (at a hospital affiliated with Stanford) with what appeared to be signs of long QT syndrome, was more complicated. Astrea was already in extremis upon delivery and so, at just three days old, she underwent a blood draw for genetic analysis. The DNA readout showed a mutation to the SCN5Agene, suggesting (because she was so young) that she had gotten the bad gene from one of her parents. But then her parents tested negative for the mutation.
Based on that and some other ambiguous evidence, the pediatric cardiologist James Priest ordered a follow-up sequencing of just her white blood cells. The SCN5Agene in those cells was normal. Likewise for the cells afloat in her urine and the cells in her hair follicles: normal. “Priest and his colleagues began to suspect that Astrea’s body contained a mosaic of genetically different cells,” Khamsi recounts. Evidently the mutation had occurred after her parents had contributed their egg and sperm cells, each of which carried a normal SCN5A gene,but before her birth. It must have happened during Astrea’s fetal development, spontaneously, in one cell, and early enough that the mutated cell passed its genome along, through the consecutive cell divisions by which a fetus grows, to some of her body cells but not all of them.
Still, there was a gap of uncertainty. Long QT syndrome affects the heart, but did the muscle or nerve cells in Astrea’s heart carry the fateful mutation? Was her problem in fact long QT syndrome, for which she could be medicated, or possibly something else? Priest and the other doctors were unsure; they couldn’t safely sample and sequence the cells of Astrea’s heart, because a heart is sensitive and deeply buried away in the body. Then, at the age of seven months, Astrea suffered a cardiac crisis. It was so severe, and she was so lucky, that she received a heart transplant two months later. That allowed her original heart to be sampled and sequenced—confirming that the mutation was present in her heart cells and that it had almost killed her by way of long QT syndrome.
Yet sometimes, as Khamsi shows, spontaneous mutations can deliver biological benefits and even relief from a medical problem. Consider the white blood cells known as B cells, which are a central element of the adaptive immune system. The role of B cells is to produce antibodies that fight against infection by invaders, such as bacteria, fungi, or viruses, by fitting tightly onto their surface proteins, thereby marking them for destruction. The potential invaders are vastly diverse, so the B cells have to be capable of producing a vast diversity of antibodies. Research has revealed that this is accomplished by a nifty trick: when infection occurs, the B cells commence to replicate with an exceptionally high degree of inaccuracy, acquiring mutations hither and thither that allow them collectively to generate an extraordinary diversity of antibodies—among which at least some are likely to be well suited to combat the invader. If you like jargon, you’ll enjoy knowing that this overdrive mode of B cell diversification is called somatichypermutation.
The story of Fanconi anemia is simpler. (Virtually everything is simpler than the human immune system.) It’s an inherited blood disease involving failure of the bone marrow to produce blood cells, plus some physical anomalies, such as small body size or head size, and heightened risk of cancer. The cause is a mutation in one gene among a group of related genes, most frequently the gene FANCA. When that mutation spontaneously mutates back into the normal form of FANCA—as it does, not infrequently—a person may enjoy complete remission of the disease. According to Khamsi, that may happen in as many as 5 percent of Fanconi anemia cases. “We so often think of mutation in a negative light,” she writes, “but sometimes it can be a force for healing.”
Many of Khamsi’s explanations and stories circle back to Darwin and natural selection. It’s not just cancer cells that are Darwinian, competing and evolving. In the case of Fanconi anemia, one team of scientists found evidence of a “selective advantage” for the reverted-to-normal cells if those cells were part of the stem cell production line making new cells in the patient’s bone marrow. The advantage was manifested as the reverted cells producing more copies of themselves than the mutated cells did. In other words, Khamsi explains, those cells that “regained a working version of the gene were winning out against the others in a Darwinian race.”
Likewise with the PIGA gene that produces black urine and other aspects of the PNH blood disease—likewise, but not so happily. Scientists found that a mutated PIGAgene gives a selective edge to the blood-producing cells that carry it, allowing them to replicate in greater abundance than normal cells do, and therefore flood the blood with dysfunctional red cells. Darwin had good intuition—so says the PNH researcher Lucio Luzzatto, in a slightly condescending judgment, as quoted by Khamsi—but Darwin couldn’t anticipate how his theory, evolution by natural selection, would apply not just to populations of organisms but also to populations of replicating cells.
That’s true, as truisms are. Darwin couldn’t foresee everything. He didn’t have Mendel’s work on genetics at his disposal, or Thomas Hunt Morgan’s work on chromosomes, or an online subscription to the Journal of Molecular Evolution,or an Illumina sequencing machine or any other such fancy tools. He was a brilliant plodder who bred pigeons to see the range of variation, who conducted kitchen-lab experiments on how far asparagus seeds might disperse in seawater, and who wrote letters to scientists around the world and manuscripts for publication using a metal-nib pen. But no one gets rich by underestimating Mr. Darwin—by ignoring or minimizing what he got right that’s still right, what he anticipated, what he foreshadowed, what intellectual doors he opened.
It’s a felicity of Roxanne Khamsi’s book that Darwin is quite present within it, cited and alluded to repeatedly on his lifelong journey toward understanding the ramifications of inheritance, variation, and natural selection. There he is, twenty-two years old and a seasick landlubber, trying to adjust to sleeping in a hammock in the tiny poop cabin aboard the Beagle during its first days out of England. There he is, middle-aged and persisting at his work on evolution despite a mysterious lingering illness that caused headaches, heart palpitations, and chronic vomiting. There he is, nine years after On the Origin of Species was published, producing a book titled The Variation of Animals and Plants under Domestication, in which he discusses the idea that a whole organism such as an animal “consists of a multitude of elemental parts, which are to a great extent independent of each other,” a comment Khamsi takes as prefiguring the modern understanding of divergent spontaneous mutations. There he is, a venerated influence on the German medical researcher Wilhelm Roux, who went a step beyond Darwin and became obsessed with the rather wacky-seeming notion that individual parts of a human body compete against one another—not just cell against cell, but organ against organ, tongue against teeth competing for space, mammary glands against bones competing for calcium. Roux published an 1881 book titled Der Kampf der Theile im Organismus (The Struggle of the Parts of the Organism), crediting Darwin’s “struggle for existence.”
And there is Darwin again, more than a century later, inspiring the cancer researcher Robert Gatenby to develop a mathematical model of cancer as an evolutionary phenomenon, with cancerous cells competing against other cells for reproductive success. The work of Gatenby and like-minded colleagues over recent decades has raised an entirely new edifice of thinking about cancer, with important implications for treatment. You could call it “Darwinian oncology.” At its core are Darwin’s three principles, as listed in that 1838 notebook entry—heredity, variation, and excessive proliferation, which forces competition and adaptation. Cancers adapt against chemotherapy, among other challenges. Mutation, in case I haven’t said this enough already, is what supplies the variation.
Khamsi’s book is a valuable contribution toward better public understanding of that new edifice. But the work of Gatenby occupies just one of her nine chapters, with the rest variously devoted to other diseases known by ponderous names and brisk initials (dysgammaglobulinemia and CHIP as well as long QT syndrome and PNH) that are caused by mutations; other problems (such as the skin disease epidermolysis bullosa as well as the blood disease Fanconi anemia) that lucky mutations can partly or completely fix; and the wider truth that each of us is a composite, comprising myriad cells, each cell with its own genome, many of those genomes acquiring aberrations all their own and diverging, click by click of the mutational ratchet, from the DNA in the zygote from which we have grown. So forget your Platonic essentialism when it comes to human identity. We are jumbles, as Khamsi variously illustrates. That’s why I called Beyond Inheritance a crosscutting book. It cuts across disciplines and diseases, across fortunate accidents and piteous dilemmas, across time and across scale, to remind us of the wisdom of Heraclitus: the ultimate constant is change.