Too Much of a Good Thing

CHAPTER 1

How Our Bodies Became What They Are

Timothy Ray Brown, who was originally labeled the "Berlin patient" by doctors who tried to protect his anonymity, was in his twenties when he became infected with the human immunodeficiency virus (HIV)—the virus that causes AIDS—in the 1990s. Doctors successfully treated him with the usual HIV medications of that era, and he did well until he developed acute leukemia. His leukemia was initially treated with aggressive chemotherapy, the side effects of which required that he temporarily stop the anti-HIV medicines. Without these drugs, his HIV blood levels soared, an indication of persistent infection and susceptibility to full-blown AIDS. His doctors had no choice but to reduce his chemotherapy and restart the anti-HIV drugs. The only remaining option for treating his leukemia was a bone marrow transplant, which had about a fifty-fifty chance of curing it. Fortunately, his doctors found a compatible bone marrow donor, and Brown beat the odds—the bone marrow transplant cured his leukemia, and he remains leukemia-free more than five years later.

But the story doesn't end there. His doctors also knew, from studies of unusual people who were infected with HIV but never progressed to severe infection or full-blown AIDS, that just one mutation in a single gene, if inherited from both parents, can prevent HIV from entering cells that it otherwise has no trouble infecting. Unfortunately, less than 1 percent of northern Europeans and even fewer of the rest of us have this fully protective mutation. Remarkably, Brown's doctors found a compatible bone marrow donor who also had this unusual mutation. And the successful transplantation of those bone marrow cells didn't just cure Brown's leukemia—it also made him the world's first person ever to be fully cured of advanced HIV infection.

The first case of AIDS was reported in San Francisco in 1980. What followed was a series of remarkable scientific feats: HIV was confirmed to be the cause of AIDS by 1984; tests to screen for the virus were available by 1985; the first medication to treat it was formulated by 1987; and effective multidrug therapy began to turn HIV infection into a commonly treatable chronic disease by the mid-1990s.

Scientists also looked back and documented HIV in human blood as early as 1959, including in a small number of people who had died of undiagnosed AIDS in the decades before the first reported case. Based on genetic studies of the virus itself, scientists postulate that what we now call HIV originated as a slightly different virus in monkeys in central Africa and probably was first transmitted to humans sometime in the 1920s.

But let's imagine a different scenario: What would have happened if HIV had spread from monkeys to humans before the late-twentieth century advances in virology and pharmacology? HIV infection likely would have spread gradually but persistently throughout the world, especially because infected people are highly contagious for months or years before they develop symptoms. Of course, before the era of modern transportation, the spread initially would have been slower, but we still would have expected the virus to spread wherever humans had intimate contact with one another. If everybody infected with HIV subsequently got AIDS and died, the only remaining humans would either have been those rare people who had this protective mutation or people who were somehow sufficiently isolated or far enough from central Africa to avoid exposure.

The reality, though, is that nothing—no famine, infectious disease, or environmental catastrophe—has ever wiped out the human race. To understand how we've survived, we need to understand where we came from and how we got here. We'll start by going back in time to look at our ancestors.

THE HUMAN FAMILY'S ANCESTRY.COM

My parents always told me that they named me after my maternal great-grandfather Louis Cramer. But when my wife decided to trace both our families on Ancestry.com, census records showed that his name really was Leib Chramoi. The Internet, the most transformative human invention of my lifetime, shed new light on my genealogy and emphasized how much the world has changed in just three generations.

But how about our collective genealogy over thousands of generations? How could our ancestors have survived the myriad threats that antedated HIV but that potentially could have wiped out 99 percent or more of us long before modern medications were available? And going back even further, why did we survive while most species didn't?

If we really want to understand how we got from the first anatomically modern humans—known as Homo sapiens, based on our genus (Homo) and our species (sapiens)—to my great-grandfather Leib, we'll have to understand how our genes define who we are. And in telling that story, we'll also learn how those same attributes are now a mixed blessing—sometimes still saving our lives but increasingly causing modern maladies.

The earliest archaeological evidence for Homo sapiens begins about 200,000 years ago in Africa. Some adventurous Homo sapiens apparently first moved out of Africa and into the Arabian Peninsula about 90,000 years ago before dying or retreating back to Africa during the Ice Age because of the cold climate and advancing glaciers. But another group of Homo sapiens tried again around 60,000 years ago, migrating first to Eurasia, then spreading to Australasia about 50,000 years ago and later to the Americas about 15,000 years ago.

Archaeological remains also tell us that we weren't the only Homo species ever to walk the earth. Based on the dating of fossils, paleontologists estimate that the earliest member of the Homo genus, called Homo habilis, dates back to around 2.3 million years ago. By 1.8 million years ago, Homo ergaster in Africa, then Homo erectus in Africa and Eurasia, were as tall as modern humans, although with somewhat smaller brains. Between 800,000 and 500,000 years ago, other Homo species in Africa, Europe, and China had skull sizes and presumably brains that were approximately as big as ours. Some of their descendants, including Neanderthals and Denisovans, appeared about 350,000 years ago, followed later by the first Homo sapiens about 150,000 years later.

Although paleontologists used to think that each successive Homo species replaced the prior, "less human" one and that each more modern species inherited the earth from its predecessor, the reality isn't so simple. Neanderthals and humans, for example, probably overlapped for more than 150,000 years, and we know from fossil remains that humans, such as the cave-painting Cro-Magnons in France and Spain, lived near or even with Neanderthals beginning about 50,000 years ago and continuing for perhaps 10,000 years. Genetic evidence suggests that at least some interbreeding occurred pretty quickly and that Neanderthal-derived genes now comprise about 2 percent of the DNA of modern Europeans and Asians. And since we don't all have the same Neanderthal genes, it's clear that the interbreeding wasn't a one-time phenomenon. We don't know the functions of most of these Neanderthal genes, but as we'll show in chapter 2, they seem to have helped our ancestors adapt better to their new, out-of-Africa environments.

The Denisovans probably lived in Siberia as recently as 50,000 years ago. Based on DNA recovered from a Denisovan girl's tiny pinkie finger bone, scientists conclude that Denisovans interbred with Neanderthals as well as with humans. For example, today's Tibetans, Australian aboriginals, and Melanesians have some Denisovan DNA. By comparison, Africans have substantially less Neanderthal DNA and no detectable Denisovan DNA—but about 2 percent of their DNA apparently comes from yet another unknown prehistoric Homo group that lived in Africa about 35,000 years ago.

Scientists estimate that the Neanderthals across Europe and Asia never exceeded a population of about 70,000 and more likely peaked at about 25,000. And the Denisovan population likely was no larger. As the glaciers receded and the world warmed up, humans eventually outcompeted the brawnier but slower-footed Neanderthals as well as the Denisovans to become the only surviving Homo species by around 40,000 years ago.

On the one hand, it seems easy to assume that humans survived simply because we're smarter than all other animals. But on the other hand, it's pretty remarkable. It's true that our brains are big, but dinosaurs once dominated the earth despite their proportionally tiny brains. To put things into perspective, let's look at it another way: What percentage of species that ever inhabited the earth is still in existence today? The answer: about one out of 500—just two-tenths of 1 percent.

Yes, we're here today because of the ultimate triumph of our brainpower, but our survival has always been contingent on our brawn—not so much our raw muscular strength but rather all the inherent traits that helped our ancestors survive and even flourish. Our brain's capacity for art, science, philosophy, and technology never could have been realized if our bodies hadn't been vigorous enough to survive in challenging and even hostile environments. Our ancestors had to be able to gather nuts and berries, hunt and kill wild animals that were often bigger and faster than they were, and survive the Ice Age, not to mention droughts and infectious plagues.

In the digital age, a nonathletic, antisocial nerd with poor eyesight and bad asthma can become a billionaire. But for most of human existence, we required robust physical attributes just to survive, not to mention compete for the mate who would help pass our genes on to future generations.

We survived against these daunting odds because of the attributes and resilience of the human species—what we're made of and how our bodies have evolved and adapted over the course of about 200,000 years and 10,000 generations. We're here because no prehistoric predator, climate disaster, or HIV-like infection ever wiped out our ancestors.

NATURAL SELECTION: SURVIVAL OF THE "FITTEST"

Year in and year out, men and women probably always competed for mates mostly in terms of their physical attributes—not unlike the prom king and queen or the football captain and the head cheerleader. But survival of the fittest doesn't mean the survival of the biggest, fastest, or prettiest. Although these physical traits help, they're just the beginning of the story.

We're here rather than the Neanderthals, the Denisovans, or the never-born offspring of humans who failed to procreate because our own ancestors were fitter—they had the wherewithal to meet the earth's environmental challenges and to outcompete others for food, water, and mates. Survival of the fittest explains how natural selection works: over the course of generations, people with the "fittest" genetic attributes live long enough to have the most children, who themselves survive to have more children, and so on. Simply put, if you and your descendants survive and procreate, your DNA will be perpetuated. And if you don't, your DNA, just like your family name, won't.

Our DNA resides on 23 pairs of chromosomes—one member of each pair inherited from each parent. In 22 of these pairs, each of the two paired chromosomes has similar—but not absolutely identical—DNA. The 23rd pair defines our sex—girls inherit an X chromosome from each parent, whereas boys get an X chromosome from their mothers and a corresponding (but smaller and very different) Y chromosome from their fathers.

Each of our chromosomes is composed of a varying amount of DNA, which in aggregate comprise about 6.4 billion pairs of nucleotides, with about 3.2 billion pairs coming from each parent. These 6.4 billion pairs, which are commonly called base pairs, can be thought of as the letters that make up the words (genes) that define who we are.

Our chromosomal DNA collectively contains about 21,000 genes that code for corresponding RNA, which then codes for each specific protein that is critical for our bodies to function normally. Surprisingly, these 21,000 genes comprise only about 2 percent of our chromosomal DNA. Another 75 percent or so of our DNA contains about 18,000 more—and generally larger—genes that don't tell RNA to code for proteins but instead send signals that activate, suppress, or otherwise regulate the protein-coding genes or the functions of their proteins. The remainder of our DNA, about 20 percent, doesn't code for any currently known proteins or signals and is sometimes called junk DNA, although scientists may well discover important roles for it in the future.

Since we have two sets of chromosomes, we normally might expect to have two identical versions of each of our 21,000 genes, one inherited from each parent. But although each half of a child's genes—and his or her DNA—should be an exact replica of the DNA of the parent from whom it came, even the best-programmed computer can make a rare typographical error. When DNA replicates, an imperfection—or mutation—occurs only once every 100 million or so times. As a result, each child's DNA has about 65 base pairs that differ from those of her or his parents. Over time, these mutations add up. All humans are about 99.6–99.9 percent identical to one another, but that still means we each have at least six million base pairs that can differ from other humans. These mutations define us as individuals and also show how our human species has evolved over generations.

Mutations themselves are random events. But their fate—whether they spread, persist, or disappear—in future generations is determined by whether they're good (advantageous), bad (disadvantageous), or indifferent (neutral). In natural selection, an initially random genetic mutation is perpetuated if it's sufficiently beneficial to you and your children. By comparison, disadvantageous mutations are usually eliminated quickly from the population even if the child survives. Slowly but surely—across 10,000 or so generations of humans—our genome has changed substantially because of the random appearance but selective perpetuation and spread of beneficial mutations.

Neutral mutations don't spread as widely as beneficial mutations, but they can hang around and accumulate over time. Some neutral mutations are totally unimportant and invisible—our DNA code changes, but we still make the identical protein. It's the same principle as if we were to spell a single word two different ways—such as gray and grey or disk and disc—without any alteration in meaning. Some neutral mutations change us—determining, for example, whether a person's chin is dimpled or not—but have no survival impact. But some currently neutral mutations might theoretically become advantageous or disadvantageous in the future. Imagine, for example, a mutation that could make us more or less sensitive to high-dose radioactivity, which isn't a problem now but would become critical if there were a thermonuclear war.

Every now and then, a new advantageous trait might be so absolutely critical for the ability to survive an otherwise fatal challenge—such as an epidemic of infectious disease—that it will become the new normal almost immediately, because everyone without it will die. But most beneficial genetic changes simply confer a relative competitive advantage, perhaps only in limited geographical locations or in specific situations.

Not surprisingly, the rate at which a genetic mutation spreads depends on how much relative advantage it brings. The spread will be slow at first and then speed up as it disperses more broadly within a closed population. It's like when you bet one chip to win one chip, bet two chips and win two more chips, and keep on going. Once something "goes viral," it increases rapidly because every previous carrier becomes a transmitter—whether we're talking about infectious diseases or a favorable mutation.

Imagine, for example, a mutation that carries a 25 percent survival advantage for you and your children if you get it from both parents and half that advantage if you get it from one parent. This mutation will spread to less than 5 percent of the population in about 50 generations (circa 1,000 years) but to more than 90 percent of the population in 100 generations (2,000 years) and to essentially the entire population by 150 generations (3,000 years). By comparison, if a single new mutation carries just a 1 percent advantage, it will spread more slowly—but it will still spread to nearly 100 percent of a population of a million people in about 3,000 generations, or around 60,000 years. Interestingly, these calculations don't depend much on the size of the population. For example, it will only take about 1.5 times as long for a mutation to spread throughout an entire population of 100 million people as it would take for it to spread to a population of 10,000 people. Slowly but steadily and inexorably, natural selection has defined which genes—and, as a result, which people—inhabit the earth.

NATURAL SELECTION IN ACTION

If every one of us shares a particular gene, it's hard to know what less advantageous gene it may have replaced. But we can get a good appreciation for natural selection by looking at genes that are common or even ubiquitous in some parts of the world, where they presumably have a strong advantage, and rare or even nonexistent in other parts of the world, where they have no advantage or even are deleterious. Two examples are (1) worldwide variations of skin color and their link to our need for strong bones and (2) lactose tolerance and its link to the domestication of animals.

Strong Bones

Adult humans have 206 discrete bones, somewhat fewer than our children, because some bones fuse together as we grow. In aggregate, our bones make up about 13 percent of our body weight. In order to have healthy bones, we need to have their key building block in our diets: calcium. We also need an activated form of vitamin D to help us absorb calcium in our intestines and to regulate its incorporation into our bones.