IN THE LATE 1990S, Joel Hirschhorn became a pediatric endocrinologist at Boston Children’s Hospital. As an expert on hormones, he saw a lot of children with diabetes. But he saw almost as many children who were short. “You have parents coming in with their child, and they’re worried because their child is not growing quickly—or as quickly as their friends,” Hirschhorn told me when I paid him a visit in his office.
Being very short is sometimes a sign of a serious medical problem—an inability to make growth hormone, for example. Mostly, though, Hirschhorn spent his visits with short children calming their parents. “You would end up saying there’s probably nothing wrong,” he said. “And I would say a good majority of the time, one or both of the parents themselves are short. And so you would just explain how height is inherited.”
Hirschhorn would tell the parents about their genes, and how they had given some of them to their children. “You have some versions that make you a little on the shorter side, and you passed some of those to your child, so now they’re probably going to end up a little on the shorter side,” he said.
The parents sometimes asked Hirschhorn about those genes. He would say that he could be sure there were genes involved, but he couldn’t name them. Nobody knew their identity. “And about the twentieth time,” Hirschhorn said, “I thought to myself: We could find out what those genes are.”
In addition to his work as a doctor, Hirschhorn was doing research on the side. Working at the Whitehead Institute nearby, he developed new methods for pinpointing genetic variants that caused medical conditions such as diabetes. Compared to such disorders, height seemed like an easy thing to study. Diabetes, for instance, takes years to develop, depending in part on what people eat. It’s also possible that there are different sets of genes that can make different groups of people at risk for it. Height, by contrast, is simple: It’s easy to measure, and you can measure it in anyone. Hirschhorn thought he could just compare tall and short people, look at their DNA, and find the variants that tended to raise or lower their height.
In 2004, Hirschhorn left the Whitehead and moved to the next building over, joining the Broad Institute to continue to study height. And when I visited him at the Broad in 2017, he was still studying height. He had just gotten a new office, which was almost completely bare. He had a phone and a laptop. On a whiteboard, someone had written Flour and Flower. Hirschhorn looked about as close to average height as a man could be.
During the seventeen years that Hirschhorn had been studying height, he explained, he and his colleagues had made progress. Now his conversations with parents sound a little different. “Instead of saying, ‘we don’t know what they are,’ I usually say, ‘we know what some of them are.’”
But if parents came to Hirschhorn with the DNA sequence of their child and asked him how tall their child would become, he still wouldn’t be able to tell them. “It’s not implausible that we could be there at some point—at least before I retire,” he told me.
As I have worked on this book, my daughters have gotten taller. They have entered that phase of life in which they start looking down at their relatives, one by one. There’s usually at least one back-to-back comparison at every family gathering. Our girls stand at military attention, the rest of us squinting across the crowns of their heads and patting down their hair. Throughout their growth spurts, Charlotte and Veronica have been good sports. You can tell that they are indulging us, that they don’t pay much mind to their increasing height—certainly not compared to an upcoming recital or the insufferable wait for the revival of The Gilmore Girls. I can see something of myself when they roll their eyes and smile politely at their height-obsessed elders.
I remember the years when my brother, Ben, and I were barreling upward. The lines that our parents drew on the kitchen doorframe were like the hands of a clock, tracking family time. The jump from one line to the next made clear that both Ben and I were going to outgrow our mother, then our father. As I reached six foot, and Ben six foot one, our heights became a marvel among our shorter relatives. They would tilt their heads up to take in our stature. Sensing an unaccustomed crane, they’d ask, “Where did you get that from?” They would vaguely recall a towering great-grandfather, or try to remember the story a great-aunt told about a tall cousin. They searched our genealogy for someone from whom we might have inherited our own height. They talked about height as if it were a diamond that an ancestor could have stored away in a safe-deposit box, where it could sit for a century until Ben and I brought it out into the light again.
Sometimes heredity does act with a diamond-like simplicity. Two defective copies of the PAH gene will cause PKU. But heredity’s influence is usually much harder to decipher. It’s hidden in clouds of complexity, a complexity generated both within our genes and outside of our bodies. It’s hard to imagine anything simpler than height. It’s nothing but a number, one that can be obtained with a hardware-store tape measure at that. And yet the heredity of height can be as baffling as quantum physics. Light can be at once a particle and waves. Height can be at once shaped by heredity and governed by our experience. Height was among the first puzzles that early scientists of heredity tried to take apart, and yet they haven’t finished solving it yet.
All of written history is laced with stories of giants and dwarves. The Bible describes races of giants who lived before the Flood. Og, king of Bashan, slept in an iron bed measuring nine cubits (thirteen and a half feet). In other stories from around the Near East, Og and his height also appear. According to one tale, he escaped the Great Flood by wading alongside the ark, the oceans lapping around his knees. In another, one of his bones was laid across a river to serve as a bridge.
The ancient Greeks and Romans would sometimes unearth dinosaur bones and house them in temples, believing them to belong to the skeletons of humanlike giants. They also marveled at the true giants who walked among them, exaggerating their stature with each retelling. According to Pliny the Elder, two men who stood ten feet tall settled in Rome during the reign of Augustus. Similar reports of extraordinarily tall people popped up from time to time all the way into the Renaissance. A seventeenth-century physician named Platerus claimed he once met a man in Luxembourg “nine foot high complete.”
By the 1700s, tall people had become professional attractions. In 1782, an Irishman named Charles Byrne, standing eight foot two, dazzled London society. He had been born a normal-size baby, but had quickly begun to grow far faster than other boys. The people in his village said that he grew so tall because his parents had conceived him atop a haystack. As a teenager, Byrne toured fairs around Ireland before traveling to England to make his fortune.
“This truly amazing phenomenon is indisputably the most extraordinary production of the human species ever beheld since the days of Goliath,” ran one London newspaper ad. Clad in a frock coat, knee breeches, silk stockings, and frilled cuffs, “the Irish Giant” received paying visitors twice a day, six days a week, in a handsome apartment. Byrne earned more than seven hundred pounds before dying at age twenty-two, reportedly from excessive drinking. “The whole tribe of surgeons put in a claim for the poor departed Irish Giant,” one newspaper reported, “and surrounded his house just as Greenland harpooners would an enormous whale.”
At the other end of height’s spectrum, people with dwarfism were also singled out, sometimes for reverence but more often for great cruelty. In ancient Egypt, dwarves served Pharaohs as sacred dancers, jewelers, textile makers, and priests. The chiefs of some West African tribes appointed dwarves as their attendants, perceiving a connection between them and the gods. The Romans had a brutal fascination, watching dwarf gladiators fight to the death or keeping male and female dwarves around their houses like pets. Often the dwarves simply wandered the houses of their masters, naked except for jewels around their necks. In the 1500s, an Italian noblewoman named Isabella d’Este built miniature marble-lined apartments in her enormous palace to house a colony of dwarves. They would entertain her by performing somersaults, or pretending to be priests, or pissing drunkenly on the floor.
In time, some dwarves were accorded more dignity in European society, although they were no less fetishized. At the royal courts of countries such as England and Russia, dwarves served as royal painters, nurses, and diplomats. Dwarves competed with giants for audiences in the eighteenth century. In 1719, a man named Robert Skinner, who reportedly stood just over two feet high, met an equally short woman, Judith, while they were traveling from exhibit to exhibit. They fell in love, got married, and retired from touring. Their fourteen children all grew to normal height. Somehow, the Skinners’ stature had failed to imprint itself on their family.
Twenty-three years after they met, the Skinners ran out of money and went back to London in 1742 to earn some more. This time, they displayed not only themselves but their towering children. The mismatch so astonished London society that the Skinners made a small fortune over the course of two years and were able to retire for good. They spent their retirement traveling around St. James’s Park in a custom-built carriage pulled by two dogs and driven by a twelve-year-old boy clad in purple-and-yellow livery.
The Skinners stood out, even within their own family. But there also were rumors since ancient times of entire races of miniature people. According to some stories, they lived in India—or maybe it was Africa—and rode miniature horses into battle against cranes. The forests of northern Europe were reputed to be rife with dwarves and gnomes. Off the coast of England, one of the Hebrides islands was known as the Isle of Pigmies; underneath a chapel, it was told, several miniature human bones had once been dug up.
In 1699, a British anatomist named Edward Tyson tried to dash these stories. Having performed the first dissection of a chimpanzee, Tyson declared that “the pygmies of the Ancients were a sort of Apes, and not of Humane Race.” It wasn’t until the mid-1800s that European explorers in Africa encountered groups of humans, such as the Baka and Mbuti, who typically never grow taller than five feet. It turned out there were slivers of truth embedded in the old fantasies.
In other parts of the world, European explorers sent back reports of towering peoples. Ferdinand Magellan rounded the southern tip of South America in 1520 and, in the words of his chronicler Antonio Pigafetta, spotted “a giant who was on the shore, quite naked, and who danced, leaped, and sang, and while he sang he threw sand and dust on his head.” Magellan claimed that the giant’s tribe—which came to be known as the Patagonians—stood ten feet tall. A century later, Sir Francis Drake visited the Patagonians and dismissed that measurement as a lie. The Patagonians were clearly just seven feet tall, Drake said.
With more time, the giants of the world shrank to more realistic heights. Nevertheless, the fact remained that people in some countries were taller than others. In 1826, the British ethnologist James Cowles Prichard observed that the Irish, although not especially tall on average, produced a remarkable number of giants like Charles Byrne. “We can hardly avoid the conclusion that there must be some peculiarity in Ireland which gives rise to these phenomena,” he said.
Prichard believed the peculiarity had something to do with the land of Ireland rather than its people. He subscribed to an idea that dated back at least to Hippocrates. “Such as dwell in places which are low-lying, abounding in meadows and ill ventilated, and who have a larger proportion of hot than of cold winds, and who make use of warm waters—these are not likely to be of large stature,” Hippocrates explained. Tall people, Hippocrates said, were “such as inhabit a high country, and one that is level, windy, and well-watered.”
Hippocrates was well aware that his patients, who all lived in Greece, grew to different heights. He ascribed their differences to the changing weather, which could disrupt the concentration of a man’s semen, altering his child’s development. “This process cannot be the same in summer as in winter, nor in rainy as in dry weather,” Hippocrates declared.
Ancient Greeks seem to have thought about height only in rough figures. “In about five years, in the case of human beings at any rate, the body seems to gain half the height that is gained in all the rest of life,” Aristotle wrote. Even in the Renaissance, scholars didn’t see the need for precision. In 1559, the Italian physician Pavisi declared that “the growth of infants and children is quite swift, and often in two or three years they add two or three cubits.” Three cubits would be four and a half feet. Either Pavisi didn’t pay very close attention to infants, or he lived among giants.
The Enlightenment brought a new rigor to measuring height. In 1708, Great Britain enacted the Recruiting Act, requiring that army conscripts be at least five foot five. In 1724, one Reverend Mr. Wasse wrote to the Royal Society to warn that measuring height might be harder than the army realized. Reverend Wasse fixed a nail above a chair high enough that he could just barely touch it with his fingertips. He then pushed a garden roller for half an hour. When the reverend sat down again, a half-inch gap lay between his hand and the nail. Apparently, he had shrunk during his exercise. Reverend Wasse reported to the Royal Society that he also measured the height of “a great many sedentary People and Day-Labourers.” He found that people could grow taller and shorter over the course of a day—by as much as an inch in some cases.
“I mentioned it to an Officer,” Reverend Wasse reported, “and thereby kept some Persons from being turn’d out of the Service.”
The military’s cherishing of height helped endow it with a moral value. Tallness turned into a sign of virtue and nobility. The fact that highborn boys ended up taller than lowborns seemed no coincidence. In England, the gap was staggering: At the end of the eighteenth century, the wealthy sixteen-year-old boys who went to the military school at Sandhurst were nearly nine inches taller than the poor boys of the same age entering the Marine Society.
At the same time, the natural philosophers of the Enlightenment began to track the growth of children, with a precision that previous generations hadn’t bothered with. The first data came from a French nobleman named Philippe Guéneau de Montbeillard. In 1759, he laid his newborn son on a table and measured him from head to toe. Every six months, except for a few gaps, he would make a new measurement of his son, switching from horizontal to vertical once the boy could stand. Montbeillard saw more than just a series of numbers in these records. They revealed an upward velocity, one that accelerated during growth spurts and later dwindled to zero.
When Montbeillard’s work was published, it inspired others to make similar recordings of the height of children in schools and hospitals. As they looked at the multiplying curves, they started to see broad patterns. Children tended to grow at similar velocities even if they were of different heights. A few children broke the rule: late bloomers experienced last-minute surges, while the growth of sick children slowed down drastically, leaving them short for life.
In the early 1800s, a French physician named Louis-René Villermé realized that the height of a group of people could tell him something about their well-being. Serving as a surgical assistant in the Napoleonic Wars, Villermé observed how food shortages afflicted both soldiers and civilians. Children suffered most of all, their growth permanently stunted. When Villermé left the army and began working as a physician, he could see how peacetime ravaged the poor. Traveling across France to study textile workers, child laborers, and prisoners, Villermé became convinced that social reforms were “absolutely demanded by conscience and humanity.” Thanks in part to his efforts, France passed a law in 1841 forbidding children between eight and twelve from working over eight hours a day, or doing any night work. School became mandatory till age twelve.
Villermé succeeded because he made his case with data. He determined the rate at which poor people died, which was gruesomely higher than the rate among the wealthy. He also tracked people’s heights, measuring the stunting power of poverty. Conscripts from poor regions were shorter than ones from rich regions. In Paris, Villermé documented that the people in wealthy neighborhoods where families owned their homes were taller than in poor neighborhoods where people could only rent.
“Human height,” Villermé concluded, “becomes greater and growth takes place more rapidly, other things being equal, in proportion as the country is richer, comfort more general, houses, clothes, and nourishment better, and labour, fatigue and privation during infancy and youth less.”
It was controversial to say such things in the early 1800s. Many of Villermé’s fellow doctors still followed Hippocrates, believing height was set by air and water, not economics. To advance his cause, Villermé gathered allies. One of his most important converts was a wandering astronomer named Adolphe Quetelet.
In 1823, the twenty-seven-year-old Quetelet came to Paris from Belgium to inspect the city’s telescopes. He was in charge of building Belgium’s first observatory, and he wanted to see how the French did it. While in Paris, Quetelet met with the greatest mathematicians of the age, people who were developing equations to track the heavens, who were finding hidden order in randomness. Quetelet enjoyed meeting Villermé and learning of his ideas about society, but Quetelet’s ambitions were pointed in an entirely different direction. As soon as his observatory was finished, Quetelet would make Newton-grade discoveries about the universe. He once scribbled his motto in the margin of a book: Mundum numeri regunt, “Numbers rule the world.”
But just as Quetelet was finishing his grand telescopic tour and preparing to go home, Belgium fell into a revolution. Rebels moved into his unfinished observatory, and Quetelet realized that his path to fame wasn’t going to run through astronomy after all.
He decided to follow Villermé’s example instead. Quetelet turned his attention to people, hoping to find an order in the chaos that had upended his life and his country. He began building a science he called social physics. Like Villermé, he chose to study the statistics of height. Gathering large numbers of measurements of children, he searched for equations that could predict their growth velocity. As Quetelet examined his results, he was startled to see a familiar pattern. Most children were close to average height, and tall and short children were rarer. Plotted on a graph, their heights formed a curving hill, its peak centered on the average.
Quetelet had already seen this hill—known as a bell curve—in the heavens. To calculate the speed of a planet, astronomers would watch it travel across a glass etched with two parallel lines, timing how long it took to move from one line to the other. If two astronomers observed the same planet, they often ended up with different figures for its speed. One astronomer might be slow to check his pocket watch, the other too quick. If the measurements of many astronomers were plotted on a single graph, they formed a bell curve as well.
On his trip to Paris, Quetelet had met mathematicians who had derived an astonishing proof about astronomical bell curves. Even if most astronomers were wrong in their measurements, the average of all their observations ended up being close to the true value. Quetelet came to see a special power in the peaks of bell curves. And when he saw his height measurements form a bell curve as well, he decided that the average height was humanity’s ideal. Anyone shorter or taller than average was flawed. He extended this same importance to every other trait in the human body, from weight to the shape of the face. If there was one person who combined all the qualities of “the average man,” Quetelet said in 1835, that individual would “represent all which is grand, beautiful, and excellent.”
Word of Quetelet’s research spread across Europe. The theory he applied to height—known as the law of error—could also bring order to many other kinds of statistics, be they crime records or weather patterns. Francis Galton saw the law of error as a revolutionary advance for all of science. “It reigns with serenity and in complete self-effacement amidst the wildest confusion,” he said. “The huger the mob, and the greater the apparent anarchy, the more perfect is its sway. It is the supreme law of Unreason.”
Galton set about measuring British heights. He invented a purpose-built device for the task, complete with a sliding vertical board, pulleys, and counterweights. He had it manufactured and then sent to teachers across England, along with instructions for how to use it on their students. When they sent back their measurements to Galton, he ended up with a bell curve much like Quetelet’s.
To Galton, these two curves looked like evidence that height was inherited. Only heredity, he believed, could account for the fact that he drew a bell curve of height a generation after Quetelet drew his. Galton couldn’t say how heredity was re-creating the same curve in each generation, though. He also recognized a massive paradox he didn’t yet know how to solve. “The large do not always beget the large, nor the small the small,” he noted, “and yet the observed proportions between the large and the small in each degree of size and in every quality, hardly varies from one generation to another.”
To tackle this paradox, Galton pioneered a new way of studying heredity. While Mendel was tracing isolated, all-or-nothing traits from one generation to the next, Galton set out to study a trait that graded smoothly from one extreme to the other. His work on this paradox would be the most important of his career. Long after his calls for eugenics became a source of shame, his work on height remains part of the foundation of today’s research on heredity.
For his new project, Galton needed more than just a bell curve of height. He needed a way to compare the height of one generation to its descendants. “I had to collect all my data for myself,” he later recalled, “as nothing existed, so far as I know, that would satisfy even my primary requirement.”
When Galton described his project to Darwin and others, they urged him to start simple. Rather than study human height, he should raise peas and measure their diameter. If he had to study animals, it would be better to study the wingspan of moths. Galton gave the sweet peas a go, taking over Darwin’s garden to grow enough plants for his research. The initial measurements he got were promising. But Galton grew impatient waiting for the plants to develop, and decided it would actually be faster for him to collect data on human height—“to say nothing of its being more interesting by far than one of sweet peas or moths,” he added.
Galton posted a newspaper advertisement, asking for family records and promising prize money for the best entries. He sent cards to his friends, requesting they ask brothers for their heights. In the 1880s, he gathered more data by turning his research into something of a carnival attraction, setting up a public laboratory at the 1884 International Health Exhibition in London. He had handbills printed up and passed around, describing the lab as being “for the use of those who desire to be accurately measured in many ways, either to obtain timely warning of remediable faults in development, or to learn their powers.” Over the course of a year, Galton’s staff measured 9,337 people at the exhibition. In 1888, he set up a similar lab at the Science Galleries of the South Kensington Museum and examined thousands more. Galton had their height measured, along with many other traits, from their hearing to their hand strength.
A “computer”—a woman who could carry out fast, accurate calculations by hand—worked her way through Galton’s thousands of height records, organizing them on a grid. Each column represented the combined average height of the parents (including an adjustment for the shorter height of the mothers). The rows represented the height of the children. The computer put a number in each square to show the number of families with each combination of heights.
Galton would often stare at this grid, trying to make sense of it. In some regions, the grid was blank. Some squares had only one family marked inside them. Others had dozens. Finally, staring at the grid one day as he waited for a train, it came to him. The numbers formed a football-shaped cloud. They clustered around an invisible straight line that extended from the lower left corner to the upper right. The taller parents were, the taller their children tended to be. Some parents had children who were shorter or taller than they were. Very short parents had children who grew taller than they were, and vice versa, drawing their children closer to the average.
Like Mendel, Galton had discovered a profound pattern of heredity. But he was no more clear about what it meant. Galton tried to explain his results by arguing that each child inherited less than half of each trait from each parent. They somehow inherited the remainder from even older ancestors. That extra inheritance, Galton claimed, pulled children back away from the extremes toward the ancestral average. While Galton’s “ancestral inheritance” would eventually be proven wrong, his discovery of heredity’s signature remains a tremendous accomplishment.
In the 1890s, a young colleague of Galton’s named Karl Pearson recognized the importance of his work and gave it a proper mathematical makeover. Pearson invented a formula that let him put a number on how closely children resembled their parents. He could use the same formula to compare siblings as well. To try out his equation on real children, Pearson enlisted his own squadron of teachers to measure the height of their students (along with other traits like the circumference of their heads and the span of their arms). He found that the traits were correlated. In other words, pairs of brothers would tend to have similar traits, presumably due to heredity.
Right around the time that Pearson was developing these new mathematical techniques, Mendel came back to light. A coalition of geneticists, the Mendelians, dismissed the measurements that Galton and Pearson were making. It was more important to them to study heredity the way Mendel did, by tracking recessive and dominant traits. Pearson gathered allies of his own. His coalition—known as the biometricians—accused the Mendelians of being time wasters who were obsessing over the few oddball traits that happen to fall in line with Mendel’s simple law. A trait like height was not either/or. People were not either tall or short as Mendel’s peas might be smooth or wrinkled. Pearson called for a more powerful explanation for heredity to account for this sort of smooth variation.
In 1918, a British statistician named Ronald Fisher brokered a peace between the Mendelians and the biometricians. He demonstrated that the two kinds of heredity were opposite sides of the same coin. The variation in a trait could be influenced by one gene, or a few, or many. The difference between a wrinkled pea and a smooth one that Mendel studied would turn out to be controlled by variants of a single gene. But a trait like height, with a smooth distribution from short to tall, was likely the result of variations in many genes. People could inherit a vast number of different possible combinations of variants, and for most people, the combined effects of all those variants would leave them close to average. Fewer people ended up very tall or short. The result would be Quetelet’s bell curve.
Fisher also found an elegantly mathematical way to take into account the fact that genes do not have sole control over traits such as height. Along with nature, nurture might have a part to play. Fisher argued that the overall variation in a trait could be the result of both genetic variation as well as variations in the environment. Genetic variation might be strong for some traits, and environmental variation might be more important for others. The fraction caused by genetic variation—in other words, the variation that could be inherited through genes—came to be known as heritability. If genetic variation has no influence over the variation in a trait, then its heritability is zero. If the environment has no influence, then the heritability is 100 percent.
Heritability is one of the trickiest concepts in modern biology. It describes variations only across an entire population. If the heritability of a trait in a group of people is 50 percent, that doesn’t mean that in any given person, genes and environment are each responsible for half of it. And if a trait has a heritability of zero, that doesn’t mean that genes have nothing to do with it. The heritability of the number of eyes is zero, because children are virtually all born with a pair of them. When we walk down the street, we don’t pass someone with five eyes, another with eight, and another with thirty-one. If someone has only one eye, it’s probably because they lost the other one in an accident or from an infection. Yet we all inherit a genetic program that guides the development of eyes.
As tricky as heritability may be to grasp, it’s been a powerful tool for making sense of heredity. Our well-being depends on it, in fact. To a large extent, heritability feeds the world.
How much food farmers can harvest from a given acre of land depends largely on the traits of the crops they plant. A plant that winds up short may produce a low yield. Taller is better, but only up to a point. If plants have to dedicate a lot of resources to reaching a great height, they’ll have little left over to produce the seeds or fruit we want to eat. They may also run a greater risk of toppling to the ground and leaving a farmer with no harvest at all.
If the height of a crop were entirely heritable, that would mean that the differences in the plants’ height were entirely due to the differences they inherited from their ancestors. Short plants would always produce short plants, tall plants tall. If the heritability equaled zero, on the other hand, the genes of different plants would have no effect on their variation whatsoever. All the differences would arise from their environment. A field of plants growing with the same rainfall, the same rhythm of heat and cold, the same pests and blights, would all grow to roughly the same height.
To measure the heritability of a trait in a crop, scientists can raise plants under carefully controlled conditions and observe how differently they turn out. They grow genetically identical seeds in precisely controlled greenhouses. They can pot them in identical soil, spray them with identical fertilizer, and measure their growth each day of their existence, down to the millimeter. These studies show that height is strongly heritable in some species, and only moderately so in others. This knowledge has helped plant breeders transform crops through artificial selection. It led to the production of “semi-dwarf” breeds of wheat and rice that produce a better yield than taller varieties, because the wind can’t flatten them.
Scientists who study human heritability, on the other hand, don’t raise babies in laboratories. They don’t measure the mashed peas parents feed their toddlers, down to the microliter. Instead, scientists have to hunt for volunteers to study. They can only gather stray fragments of information about their subjects’ lives. Errors can thus creep into estimates of human heritability. If children grow to be as tall as their tall parents, that doesn’t necessarily mean that the genes they share are the reason. Instead, they might have spent their childhood in the same growth-favoring environment that their parents did.
When Galton first began studying the inheritance of height and other traits, he recognized how hard it would be to reach firm conclusions. But Galton had an inspired idea: Scientists could take advantage of a natural experiment in human heredity. They could study twins.
Galton had no way of understanding the genetic links that twins share, but he had an intuition that they must share a strong common inheritance. He loved to share stories about the eerie coincidences in the lives of twins. A pair of twins simultaneously came down with the same kind of eye irritation, even though one was in Paris at the time and the other in Vienna. Another set developed the same crook on the same finger of the same hand. Yet another pair decided to buy surprise gifts for each other. They each chose precisely the same set of champagne glasses.
While Galton acknowledged that the experiences of twins might also influence how they turned out, he considered heredity to be paramount. The shared heredity of twins drove their lives along the same path. Galton believed twins demonstrated that everyone’s inborn nature had an overriding influence. It guided people through life the way sticks thrown in a stream travel with the current.
“The one element that varies in different individuals, but is constant in each of them, is the natural tendency,” Galton said. “It corresponds to the current in the stream, and inevitably asserts itself.”
Other scientists soon began investigating twins more rigorously for clues to heredity. But it wasn’t until the 1920s that a German dermatologist named Hermann Werner Siemens tapped their full power. By then, scientists had come to recognize that fraternal twins and identical twins are genetically different. Fraternal twins develop from two eggs, each fertilized by a separate sperm. Identical twins arise from a single fertilized egg that splits into two embryos. Fraternal twins are thus no more genetically similar to each other than any other pair of siblings, having on average 50 percent of their variants in common. Identical twins, on the other hand, are essentially clones.
Siemens realized that these two kinds of twins were an opportunity to study heritability. Twins grow up in similar environments, from the womb onward. But the genetic closeness of identical twins would make them more similar in highly heritable traits. By comparing the similarities in both kinds of twins, Siemens could estimate the heritability of a trait.
As a dermatologist, Siemens was most interested in skin diseases. Did people develop them simply due to bad luck, he wanted to know, or because of bad genes? He counted up the moles on the skin of twins and discovered that identical twins didn’t develop identical constellations of moles. Those differences told Siemens that the environment had a hand in their development.
But while their moles might not be identical, they did correlate. An identical twin with a lot of moles tended to have a twin sibling with a lot as well. If a twin had only few moles, it was a safe bet the other didn’t have many. The moles on fraternal twins were also correlated—but only with half the strength as in identical ones. Siemens concluded that genetic variations played an important part in developing moles, although the environment mattered, too.
Siemens’s remarkable study inspired other scientists to use his method to study height. A British researcher named Percy Stocks searched for twins in London’s schools and had teachers report on how tall they were. He found that fraternal twins tended to be fairly close in height. But identical twins were closer. The difference between them made it possible for scientists to put a number on the heritability of height. As the studies grew larger, that estimate grew more precise. In 2003, a Finnish researcher named Karri Silventoinen studied the height of 30,111 pairs of twins. He estimated that height was strongly heritable: 70 to 94 percent in men, and 68 to 93 percent in women.
Even a study as sprawling as Silventoinen’s rested on a big assumption: that the environmental influences shared by a pair of fraternal twins are no different from those of identical twins. If a trait is more similar in identical twins than fraternal twins, genes can be the only explanation. Scientists can’t know that for sure, however, because twins grow up in the wilds of real life, not in a terrarium. Some critics raised the possibility that parents treat identical twins differently from fraternal ones. Since fraternal twins look different, parents might treat them more like ordinary siblings.
Scientists developed twin studies as a way to study human DNA in an age when it was impossible to examine it directly. Once it became possible to read genetic markers in people’s genomes, new ways emerged to measure heritability. Peter Visscher and his colleagues found that pairs of siblings can vary tremendously in their genetic similarity, sharing as little as 30 percent of their genetic variants in common to as much as 64 percent. If a trait is highly heritable, Visscher reasoned, then it should be more similar in siblings who have more DNA in common.
In 2007, Visscher and his colleagues examined the height of 11,214 pairs of regular siblings. They found that “twin-like” siblings—those who shared more than half of their DNA—tended to grow to more similar heights. Siblings with less genetic similarity were not so similar. The scientists used these correlations to calculate the heritability of height. They ended up with an estimate of 86 percent.
That’s an exceptionally high figure. Nicotine dependence has a heritability of 60 percent. The age at which women go into menopause is 47 percent. Left-handedness is at a mere 26 percent. In the world of heritability, height stands tall.
Even a trait as strongly heritable as height, however, can also be drastically shaped by the environment. In his own research, Louis-René Villermé watched the average height change over the course of a few years. During the Napoleonic War, the average height of young French soldiers declined—the result of wartime food shortages, he guessed. After the war’s end, the army’s average height rebounded a little—thanks, Villermé said, to “a decrease, however slight, in misery.”
Villermé’s insight went neglected for the next 150 years, until a small group of economists led by the Nobel Prize winner Robert Fogel started charting height in different countries over the course of decades. They made a compelling case that height could serve as an economic barometer, recording the well-being of societies. They were the first researchers to discover the huge gap between rich and poor boys in late eighteenth-century England, for example.
Their research also gave statistical heft to the stories that Frederick Douglass and other former slaves told about growing up in the antebellum South. Douglass recounted how the sole piece of clothing he was given at age six was a coarse linen shirt. His diet was gruel, served to slave children with as much dignity as slop to pigs.
This cruelty was based on cold economic reasoning: Since slave children were too young to earn money in the fields, their masters chose not to invest in them. When Fogel’s followers analyzed plantation records, they found that enslaved American children were much shorter than free ones. But those records also showed that slaves experienced an extraordinary growth spurt in adolescence. That rapid rise was likely the result of the extra food slave owners gave their slaves once they were old enough to turn a profit.
After some small-scale studies in the 1970s, Fogel and his fellow economists widened their spotlight, carrying out a systematic survey of height through history. They looked at military records of conscripts, prison archives, and any other historical data they could get their hands on. They moved from one country to another and pushed back deeper than before into history. When written records failed the researchers, they measured bones from ancient skeletons.
The longest record of height can be found in Europe, where it stretches back thirty thousand years to the Gravettian culture. Gravettian men stood on average six feet tall. When agriculture arrived in Europe some eight thousand years ago, people experienced a tremendous drop in stature. Men lost eight inches of height. The drop was likely the result of Europeans switching to a grain-rich diet much lower in protein. For the next seven thousand years, European stature hardly changed, wavering just an inch or two from century to century. In the eighteenth century, the average European man stood just five foot five.
But they were not locked in at that height. When English people emigrated to the American colonies, men swiftly climbed to five foot eight, becoming the tallest men in the world. By the end of the eighteenth century, American apprentices at age sixteen stood almost five inches taller than poor sixteen-year-olds in London.
In both the United States and Europe, the average height dipped in the first half of the nineteenth century. But then, starting around 1870—at the time Galton began puzzling over height—people in both Europe and the United States started getting taller. Over the next century, Americans grew about three extra inches on average, hitting a plateau in the 1990s. In Europe, the boom was even more dramatic. With each succeeding decade, Europeans added about half an inch of average height, and kept growing that way into the twenty-first century. Northern and central European countries were the first to begin this ascent, but the southern regions started catching up by the mid-1900s. Today, Latvian women have become the tallest women in the world, jumping from about five foot one to five foot seven. Dutch men rose from five foot seven in 1860 to just over six feet tall, making them the tallest men on Earth.
In 2016, an international network of researchers extended this survey to the world. Over the past century, they found, some countries outside of Europe experienced equally impressive gains. South Korean women experienced the biggest gain, growing eight inches in one hundred years. Among men, Iranians grew the most, now standing six and a half inches taller than they did in the early 1900s. Some people barely grew at all: Pakistani men gained just half an inch. And some countries in Africa, such as Niger and Rwanda, shot up in the first half of the twentieth century only to lose an inch or two after 1960.
Overall, though, the world has gotten much taller. It may be hard to believe that Guatemalan women today—standing only four foot eleven—could have been any shorter in the past. In fact, they have gained four inches since the early 1900s.
Three million years ago, our ancestors in East Africa stood only about a yard high. By 1.5 million years ago, Homo erectus grew as tall as five foot seven. Natural selection may have favored genes for greater height because they gave our ancestors long legs that could carry them for long distances across the savanna. Our ancestors kept evolving to greater heights; by 700,000 years ago, they had evolved to our modern stature.
But in some places, natural selection has worked in the opposite direction, making people shorter. African pygmies—to be more accurate, African ethnic groups such as Baka and Mbuti—evolved a new growth velocity. As children, they grow fast, but then they stop early. Some studies suggest this pattern evolved because Baka and Mbuti children faced a higher chance of dying. If children reached sexual maturity faster, they were more likely to have children of their own.
The height boom that started in the late 1800s was too swift to be a product of evolution. If natural selection had been responsible, people with genes for greater height would have had more children than shorter people. The difference would have been stark. Gert Stulp of the University of Groningen and Louise Barrett of the University of Lethbridge estimate that the height boom in the Netherlands would require that a third of short people in every generation of Dutch people have no children at all.
Nothing of the sort actually happened in the Netherlands, and that leaves only one explanation: The environment stretched people out.
How tall children grow depends intimately on their health and diet. A child’s growing body demands fuel both to stay alive and to build new tissues. A healthy diet—especially one rich in protein—can meet both demands. If the diet falls short, the body sacrifices growth for survival. Diseases can also stunt a child’s growth, because the immune system needs extra resources to fight off infections. Diarrheal diseases are especially brutal, because they also rob children of the nutrients in their food. This fate can get locked in tightly in infancy. As a result, the height of children at age three correlates well with their height in adulthood.
Before the nineteenth century, Europe’s rich and powerful families enjoyed the best food and health on offer and got close to their full potential height. The poor were left stunted. Europeans who traveled to the American colonies escaped this growth trap. They moved to a place where they could grow plenty of food for themselves, but where the population was sparse enough that they didn’t suffer all the outbreaks that struck Europe’s crowded cities.
When the Industrial Revolution came to the United States in the 1800s, these height-favoring conditions faded, and Americans grew shorter. Europeans shrank as well. People who got jobs in factories earned more money than their ancestors, but they had to crowd into cities for the work. Even though the cities were still surrounded by productive farms, the technology did not yet exist to get affordable milk and meat to their residents. As a result, the per capita consumption of meat in the United States dropped by a third in the middle and lower classes. Americans got 2 to 4 percent fewer calories, and they consumed 8 to 10 percent less protein. Making matters even worse, the Industrial Revolution took place decades before the discovery of the germ theory of disease. On the crowded streets of American and European cities, outbreaks flared up and doctors had little idea how to stop them.
By the end of the nineteenth century, things had gotten much better, and people’s height reflected the improvement. Clean water and sewer systems helped children stay healthy. Railroad networks brought high-protein food into cities at affordable prices. At the same time, the size of families shrank, making it possible for parents to provide more care to fewer children. Now the scales of the Industrial Revolution tipped in height’s favor. Americans started to grow. Europeans started out short at the beginning of the nineteenth century, and they got shorter with the Industrial Revolution. But the balance tipped in the late 1800s, and they sprang up even faster than the Americans.
Similar stories have played out in many other countries. After the Korean War, South Korea’s economy rapidly grew to be the eleventh largest in the world, and the country established a universal health care system in 1977. North Korea, meanwhile, stagnated, channeling its income into nuclear weapons and its military while its population starved. South Koreans are now over an inch taller than North Koreans.
No one knows how much taller people in developed countries can become, but in developing countries there’s plenty of room for growth. In a 2016 study, researchers at Harvard estimated that 36 percent of all two-year-olds in developing countries were stunted. Improved sanitation, medicine, and nutrition would get rid of much of that deficit and produce much taller people in the future.
But the gains the world has achieved could be easily wiped away. In the late 1900s, shifting economics left many countries in Africa struggling to feed themselves, with the result that children became stunted and their average height declined. The economy of the United States, the biggest in the world, has not protected it from a height stagnation. Height experts have argued that the country’s economic inequality is partly to blame. Medical care is so expensive that millions go without insurance and many people don’t get proper medical care. Many American women go without prenatal care during pregnancy, while expectant mothers in the Netherlands get free house calls from nurses. Making matters worse, Americans have shifted to a diet loaded in sugar and to sedentary habits. Instead of growing tall, we’re growing obese.
When Jaime Guevara-Aguirre was growing up in a small town in Ecuador, he would sometimes notice grown-ups who stood as tall as a first grader. Otherwise they were like everyone else, with a normal intelligence and life span. Guevara-Aguirre learned to call them pigmeitos.
When he grew up, Guevara-Aguirre went to medical school and became an endocrinologist in Quito, where he studied how hormones control people’s growth. He wondered about the pigmeitos back home in the province of Loja. Sometimes he would get a chance to examine one of them in his office, and he noticed that they all had certain traits missing from other people born with dwarfism. The whites of their eyes had a blue cast, for example. They had trouble extending their elbows. Their voices were high. Blood tests allowed Guevara-Aguirre to make a formal diagnosis: All the pigmeitos shared the same condition, known as Laron syndrome.
Before Guevara-Aguirre and his colleagues published their discovery in 1990, only a few people had been identified with Laron syndrome anywhere on Earth. The inherited disorder traveled down through a few families, likely caused by a rare recessive mutation. In Spain, doctors had previously recorded a few cases of Laron syndrome, leading Guevara-Aguirre to suspect that a Spanish immigrant brought the mutation to Loja. In the isolated villages of the province, the mutation managed to become unusually common, and some carriers had children together, creating a cluster of pigmeitos. Guevara-Aguirre carried out the first systematic survey of Loja for the condition, traveling back roads from village to village. By the time he was done, he had found one hundred people with Laron syndrome.
At his Quito clinic, Guevara-Aguirre began providing long-term medical care to pigmeitos while studying them closely to understand how exactly they ended up so short. They produced growth hormone, he found, but somehow it didn’t cause them to reach normal heights. In his research, Guevara-Aguirre also noticed something extraordinary: Pigmeitos almost never got cancer or diabetes. Whatever was arresting their growth was also shielding them from diseases that arise as our bodies get old.
After Guevara-Aguirre and his colleagues described the people of Loja, they set out to find the genetic basis of their condition. The scientists drew blood from thirty-eight pigmeitos in Ecuador and shipped it to Stanford University. They also sent blood from other members of the pigmieto families who were of normal height. At Stanford, a geneticist named Uta Francke and her colleagues pulled immune cells from the blood, and extracted their DNA.
Comparing the pigmeitos to their tall relatives, the scientists found one crucial genetic difference. Out of the thirty-eight pigmeitos, thirty-seven shared the same mutation on the same gene, a mutation missing from the other subjects. In 1992, the scientists reported that the mutation struck a gene called GHR. GHR encodes a protein that sits on the surface of cells, where it can grab growth hormone molecules. Each time the GHR protein snags one, it sends a signal to the interior of the cell, causing it to turn on a network of growth genes.
Charles Byrne, the “Irish Giant,” has provided some clues about how heredity can push people to the opposite extreme from the pigmeitos. This was certainly not what Byrne would have wished for. As he lay dying, Byrne grew terrified that grave-robbing anatomists—“resurrectionists,” as they were known—would dig his body out of the ground. He begged his friends to bury him at sea. After Byrne died, they put him in a massive iron coffin. The coffin was dumped into the English Channel, but later it turned out that the coffin contained only stones. Somehow—possibly by means of a bribe to an undertaker—a physician named John Hunter ended up with Byrne’s skeleton. Shortly after Byrne’s death, Hunter posed for a portrait, seated at a table covered with a bell jar and anatomical books. In the upper righthand corner of the painting dangle the foot bones of the Irish Giant.
Yet Hunter appears to have never carefully studied Byrne’s skeleton. Instead, the bones were stored in the Hunterian Museum, where they remained until the museum was bombed in World War II. Today, Byrne’s skeleton looms on display in the Royal College of Surgeons. A bust of John Hunter sits on a shelf above him, the surgeon pursuing the giant long after their deaths.
In 1909, two doctors, named Harvey Cushing and Arthur Keith, first gave Byrne’s skeleton a close look. They thought his bones might have some clues about how humans grow. In the early 1900s, endocrinologists began deciphering the language of hormones that give commands to our bodies. The pituitary gland, located at the base of the brain, releases growth hormone, which stimulates bones and other tissues to get bigger. When Cushing and Keith opened up Byrne’s skull, they found a large pit where his pituitary gland had once been. They hypothesized that Byrne developed a tumor in his gland, causing it to produce extra growth hormone, and to keep producing it long after it normally would have shut off. Decades later, other scientists took X-rays of some of Byrne’s bones and confirmed Cushing and Keith’s suspicion. When Byrne died at age twenty-two, his bones were growing at the rate you’d expect in a seventeen-year-old boy.
Byrne’s condition is now known as acromegaly. About sixty people per million suffer from it. While the hormone-producing tumor itself isn’t fatal, it can nevertheless cause an early death by spurring runaway growth throughout the body. Doctors now treat acromegaly by surgically removing the tumor, blasting it with radiation, or giving patients drugs that can counteract the extra growth hormone circulating through their blood. When geneticists studied acromegaly, it seemed to fall in a hereditary gray zone. It didn’t run in families as starkly as PKU or Huntington’s disease. But sometimes a person with acromegaly turns out to have a cousin with it, too.
In 2008, Márta Korbonits of the William Harvey Research Institute in London and her colleagues identified a mutation that was common in families with acromegaly. It affected a gene called AIP, which encodes a protein whose role scientists still don’t understand very well. About one in five people who inherit the AIP mutation develop a tumor and may go on to grow to a tremendous height. It’s likely that the mutation only triggers its dramatic effects in people who happen to inherit mutations in other genes still to be discovered.
Korbonits’s team found that different mutations of AIP could produce acromegaly. But they were surprised to find an identical AIP mutation in four families in Northern Ireland, not far from the village where Charles Byrne had been born. Their clustering suggested that they might have inherited it from a distant common ancestor.
The scientists arranged with the Hunterian Museum to drill into two of Byrne’s teeth. More than 220 years after his death, they were able to extract his DNA. Byrne turned out to have a mutation in the same spot in his AIP gene as the living Irish people Korbonits and her colleagues studied; they also found that the DNA flanking the AIP gene was identical. They estimated that this mutation arose in Ireland roughly 2,500 years ago. James Cowles Prichard may have been onto something when he speculated that there was some “peculiarity in Ireland” that produced its giants. It may have been nestled in the DNA of some of its residents, passed down through a hundred generations.
The genes behind Laron syndrome and acromegaly supplied some important clues about human height. By studying people with these conditions, scientists could observe what happens when growth hormones dry up or surge like a river full of snowmelt. But for Joel Hirschhorn, these mutations, limited to a few villages in Ireland and Ecuador, didn’t help him understand the height of his own patients. He wanted to find variants that accounted for the heritability of height among billions of people.
Hirschhorn suspected there would be many genes, but he couldn’t say how many. To find people to study, he launched collaborations with researchers who were already running studies on the genetics of other conditions, such as diabetes and heart disease. In their exams, the researchers measured height as one of many vital statistics. The data were just waiting for someone like Hirschhorn to take a closer look.
Hirschhorn gathered records on 2,327 people from 483 families, hailing from Canada, Finland, and Sweden. In each subject’s DNA, the researchers had sequenced a few hundred genetic markers scattered across their genomes, separated from each other by several million base pairs. Hirschhorn and his colleagues compared the families in each country to see if the children who inherited particular markers tended to grow taller or shorter than the others. They found four regions of the human genome that showed a strong association.
When Hirschhorn and his colleagues published their study in 2001, it was one of the first times that anyone had found a clue about common variants that influence height. But it was a very modest start. Hirschhorn had been able to identify only long stretches of DNA where a genetic variant seemed to be lurking. The variants might reside in one of hundreds of genes in those regions. It was even possible that Hirschhorn’s results were a fluke that had nothing to do with height. A number of tall people might have a version of a particular marker thanks simply to chance.
Hirschhorn was not alone in his frustration. Many other scientists were trying to trace traits—especially hereditary risks for certain diseases—to specific genes. At first they enjoyed some high-profile successes, finding links to conditions like diabetes and bipolar disorder. But very often, the links would melt away when other scientists looked at larger groups of people. Soon scientists worried that they were stuck in a dead end. “Has the genetic study of complex disorders reached its limits?” two scientists asked in a 1996 article in the journal Science.
Those two scientists, Neil Risch of Stanford University and Kathleen Merikangas of Yale, argued that the answer was no. But to uncover the variants that raise the risk of common diseases, scientists would have to build new tools. Risch and Merikangas predicted that most variants would not be powerful, as in the case of Laron syndrome and acromegaly. Instead, the variants behind many diseases would be weak and numerous.
Risch and Merikangas sketched out a new way to carry out this search. Geneticists needed to step away from their beloved pedigrees. Instead, they needed to look at the DNA of hundreds of people, with no regard to their families. They could search for variants that were unusually common in people with a disease, compared to those who did not suffer from it. Risch and Merikangas dubbed their hypothetical method a genome-wide association study.
It took until 2005 for genome-wide association studies to get their first hit. Josephine Hoh, a geneticist at Yale University, wanted to find genes involved in the leading cause of blindness, a disease called age-related macular degeneration (AMD for short) that ravages the center of the retina. Hoh knew that having a relative with AMD raised the odds that people would develop it in their own life. But studies on families with AMD had failed to reveal a gene associated with the disease.
Hoh and her colleagues gathered DNA from ninety-six people who had AMD, as well as from fifty people who didn’t. They scanned the genetic markers and noticed an unusually common one among people with AMD located on chromosome 1. Closely examining that region, they came across a variant in a gene for a protein made by immune cells, called complement factor H. They found that having two copies of the variant drastically raised a person’s odds of developing AMD.
The job of complement factor H is to stick to pathogens, triggering inflammation to fight them. Hoh’s research indicated that mutant forms of the protein stick instead to retinal cells, causing the immune system to attack the eye. Hoh’s findings were later confirmed in other studies. But with such a small group of people in her study, she might very well have missed complement factor H if its effects had been any weaker. She was right, and she was also lucky.
To use genome-wide association studies to find subtler variants, scientists recognized they would have to study thousands or even millions of people. In 2007, a consortium of laboratories working through the Wellcome Trust in England published the first such large-scale study. Examining fourteen thousand people, they identified twenty-four genes with variants that raised the risk of diseases such as diabetes and arthritis.
After his own frustrating experience studying the height of families, Hirschhorn also turned to genome-wide association studies. He and his colleagues used some of the data from the Wellcome Trust study, adding to it people who had been part of a diabetes study in Sweden. All told, nearly five thousand people became part of the study. The technology for sequencing genetic markers had improved drastically since Hirschhorn had started investigating height. Now, instead of looking at a few hundred markers, he could look at a few hundred thousand of them. The denser spread of genetic markers made it possible to zero in on smaller regions containing fewer genes.
This time, Hirschhorn got a solid hit. One variant, located in a gene called HMGA2, was significantly more common in tall people than in short ones—so common, in fact, that it couldn’t be dismissed as a fluke. Hirschhorn and his colleagues tested the association by looking at HMGA2 in more than twenty-nine thousand other people. In the bigger group, taller people once again were much more likely to carry the same variant of HMGA2.
Yet Hirschhorn couldn’t say how precisely HMGA2 influenced people’s height. A few experiments carried out over the years offered a handful of clues. In experiments with mice, some mutations to HMGA2 could turn the animals into dwarves. Others turned them into giants (by mouse standards).
The evidence about HMGA2’s function in humans was even scarcer. In 2005, geneticists at Harvard Medical School published a case report on an eight-year-old boy who had a mutation clipping his HMGA2 gene short. He seemed normal at birth, but at three months he sprouted his first tooth. By the time the boy was eight years old, he was over five foot five, the average height for a fifteen-year-old. His legs and fingers grew crookedly, and he developed lumps of fat and blood vessels under some parts of his skin.
These studies suggest that HMGA2 normally acts like a brake, slowing down our growth-spurring genes. A mutation that shuts down HMGA2 entirely may cause runaway growth. The common variant in HMGA2 that increases height may lift the genetic foot off the brake just enough to make people grow a bit taller—but not enough to lead to deformities or tumors.
The discovery of HMGA2 was like a quarter-carat sapphire: solid, glittering, and tiny. It marked the first time that scientists found a common variant strongly associated with height. Later, when other scientists studied even larger groups of people, they confirmed the link. But the HMGA2 variant accounts for a vanishingly small amount of the variation in the human population. When I got my genome sequenced, I found that I carry one copy of the height-raising form. On average, people with one copy are about an eighth of an inch taller than if they didn’t have one. That’s the equivalent of putting on a warm pair of wool socks. If I had two copies, it would be like putting on a second pair. And when scientists look at the full range of variation in height, they find that this variant in HMGA2 explains very little—only about 0.2 percent.
Hirschhorn’s 2007 study also uncovered some tantalizing clues about many other genes. They contained variants that were more common in tall people than in short ones, or vice versa. But the differences weren’t as stark as HMGA2, leaving open the possibility they were the result of chance. To rule out randomness, Hirschhorn would need to measure more people’s heights.
Hirschhorn and his colleagues created a new network of hundreds of research groups around the world. They called their consortium the Genetic Investigation of ANthropometric Traits—GIANT for short. The GIANT team examined the height of tens of thousands of people, then hundreds of thousands, and the bigger numbers allowed them to pick out more genetic variants, first dozens, then hundreds. Most of the genes they discovered had a smaller influence than HMGA2. But they also found a number of genes that had a far bigger one. If people carry two variants of a gene called STC2, for example, those alleles will lift them up about an inch and a half. These powerful genes had gone overlooked in earlier studies of height because they were too rare, found in less than 5 percent of the population. In 2017, a decade after the first genome-wide association study of height, GIANT published a study on more than 700,000 people, bringing the total number of genes influencing height to almost eight hundred.
To some observers, however, such results seemed like a colossal disappointment. The combined effect of GIANT’s eight hundred–odd genes accounted for just over 27 percent of the heritability of height. The rest remained missing.
Height was not unusual in this regard. Missing heritability dogged many studies of other traits and diseases, too, even after scientists could study thousands of people. The shortfall was all the more glaring because of all the money that had gone into making genome-wide association studies possible. “The reason for spending so much money was that the bulk of the heritability would be discovered,” the geneticist Joseph Nadeau told a journalist.
Some critics saw missing heritability as much more than an annoyance. To them, it was a symptom of a scientific disease. In 2015, two French researchers, Emmanuelle Génin and Françoise Clerget-Darpoux, argued that missing heritability revealed the futility of genome-wide association studies. Génin and Clerget-Darpoux describe the research as “Garbage-In Garbage-Out Syndrome.” The scientists running the studies were trying to use brute force to discover the deepest secrets of biology. Yet their repeated failures simply led them to redouble their efforts, and journal editors to publish more of their papers. To Génin and Clerget-Darpoux, it seemed as if geneticists had become trapped in a game they couldn’t stop playing. “Unfortunately, genetics is a clear loser,” they concluded.
Other critics say that missing heritability reveals our profound ignorance about heritability itself. Some attacked twin studies, claiming they lead to estimates of heritability that are much too high. Others argued that heritability studies miss the way some mutations make the effects of other mutations stronger. One plus one, in the world of heredity, may be far more than two. Some critics went even further, arguing that missing heritability is hiding beyond genes, in some other form of heredity scientists have yet to grasp.
When I asked Hirschhorn if missing heritability was giving him existential doubts, he shrugged the problem off. “I think a lot of it is just hidden,” he told me. “If we had all six billion people on Earth in a genetics study, we would actually get to most of the heritability.”
Part of Hirschhorn’s confidence came from his own experience over the previous twenty years. The more people he and his colleagues measured, the more heritability they could explain. Some of the genes they found were common but weak, while others were strong but rare. If he could study more people in the future, he expected to find more of both kinds.
Hirschhorn also drew confidence from the work of Peter Visscher, who has given geneticists a new way to study human heritability. Visscher came to research on humans after years of work on livestock. Animal breeders study the heritability of cows to figure out how to get them to make more milk, of pigs to put on more pork. In the 1900s, they used elaborate pedigrees to track the influence of genes on these traits. But at the end of the century, breeders got their hands on technology for reading genetic markers in their animals.
At first, they searched for candidate genes that might have a big effect on their own. Soon it became clear that a trait like milk output was controlled by many genes, each with a tiny effect. Animal breeders found that they could improve their livestock by comparing all their genetic markers in different animals. Animals that were genetically similar overall tended to have similar traits. Breeders could choose which animals to breed based on these so-called genomic predictions.
When Visscher switched from animals to humans in the early 2000s, he realized that he could use genomic predictions on people, too. Visscher and his colleagues took the method out of the barnyard and adapted it to human genetics, dubbing their method Genome-wide Complex Trait Analysis. To see how well it worked, they unleashed it on the best-studied complex trait of all, human height.
The researchers delved into the data from earlier genome-wide association studies and looked at the genetic markers from thousands of people. They came up with genetic-similarity scores between each pair of people. Heredity turned out to work a lot in humans as it does in chickens. Pairs of people with high scores tended to have similar heights. That tendency reflects the heritability of a trait. The stronger the tendency, the greater the heritability.
When Visscher and his colleagues estimated the heritability of human height from genetic similarity, they ended up with a number close to what had been estimated in earlier studies on families and twins. In 2015, when they published these results in the journal Nature Genetics, they declared the missing heritability of height to be “negligible.”
Toward the end of my visit with Hirschhorn, I noticed his eyes drifting to the clock on his desk phone. He had a conference call coming up soon with a lot of his collaborators. They were about to take another leap, from 800,000 people to perhaps two million. But before I left, Hirschhorn explained that the years of work he had put into the inheritance of height were not simply to create a catalog of genes. He wanted to use the catalog to understand the mysteries of height. If you stop and think through what it means to grow, the process is astonishing. Each part of the body has to change its shape and size to match every other part. There’s no central blueprint for the construction of an adult human. Each cell has to decide for itself, using nothing more than chemical signals and its own network of genes, RNA molecules, and proteins.
As Hirschhorn’s list of genes has grown, he and his colleagues have searched them for patterns. They turn out not to be a random assortment. “Most of the action is at the growth plate,” Hirschhorn said.
Growth plates are thin layers of cells located near the ends of limb bones. In children, some of the cells in the plates produce signals, which then trigger neighboring cartilage cells to multiply. As the cells divide, the bones get longer. Eventually the cartilage cells change, producing bone instead. They finally commit suicide, tearing themselves open to dump out chemicals that make the surrounding bone even harder.
Hirschhorn and his colleagues found that many of the genes on their list are unusually active in growth plate cells. Obviously, other parts of the body have to grow as well in order for people to become taller. But it’s possible that the growth plates lead the parade. Mutations to the genes used by growth plate cells speed up or slow down the increase in limb bones. The rest of the parade has to adjust its speed to follow the leader.
Yet Hirschhorn knew that he would have to find other stories to tell about height. HMGA2, the first gene he and his colleagues discovered influencing height, remained the strongest common variant. It’s active in embryonic cells, not in growth plates in children. And despite a lot of research by Hirschhorn and his graduate students, he still couldn’t say why it’s so important. “That one still boggles my mind,” Hirschhorn admitted.
It’s possible that Hirschhorn will have to become a Scheherazade of the genome to tell all the stories about how the genes we inherit influence our height. In 2017, Jonathan Pritchard, the scientist who invented STRUCTURE, tried to predict how many genes scientists would ultimately find linked to height. Would Hirschhorn reach a thousand genes and be able to close down his shop? Pritchard thinks the answer is a definite no.
For their study, Pritchard and his colleagues took a closer look at a genome-wide association study that Hirschhorn and his colleagues published in 2014. In that study, Hirschhorn’s team scanned 2.4 million genetic markers in a quarter of a million people. They looked for variants at each of the markers with a very strong link to height—so strong that they could confidently reject the possibility that the links were just coincidences.
That study gave Hirschhorn and his colleagues a list of about seven hundred strongly supported genes. But they also found many other ambiguous variants that didn’t quite meet their strict standards. Those variants might have a weak effect on height, or they might simply have turned up in Hirschhorn’s study by chance. Pritchard used new statistical techniques on those ambiguous variants, to see if he could separate the genetic wheat from the chaff.
He and his colleagues looked for people who carried two copies of each variant and checked their height. Then they looked at the height of people with only one copy of the variant, and that of people with no copies. In many cases, this comparison revealed a small but measurable effect. Two copies of a variant might make people shorter than average, while one copy made them a little taller, and no copies made them taller still. Pritchard and his colleagues then turned to an entirely different group of twenty thousand people to test these results. They found the same effects from the same variants.
What made this study startling was just how many of these variants Pritchard and his colleagues found. At 77 percent of the markers they studied—almost two million spots in people’s DNA, in other words—they could detect an influence on height. The markers were not clumped around a few genes on one chromosome. They were instead spread out across all the chromosomes, encompassing the entire human genome.
These variants likely altered the sequence of many genes, changing the structure of their proteins. But they probably also changed the regions of DNA that act like switches to turn the genes on and off. Each of the nearly two million variants had, on average, an exquisitely tiny effect—adding or subtracting the width of a human hair. But collectively, this vast army of weak variants accounted for much more variation in height than the strongest genes that Hirschhorn and his colleagues put together in their catalog.
Traditionally, geneticists have called height polygenic—meaning “many genes.” Pritchard thinks a new word is called for: omnigenic.
If height really is omnigenic, as Pritchard believes, we may need to rethink the way our cells work. There may be a core group of genes lurking in growth plates that take the lead in determining how tall we get. But some of those genes also have other jobs. They work with other genes in other kinds of cells. You can think of our genes as a set of networks. There’s a network of genes that work together in growth plate cells. And you can draw a line from some of those genes to other networks. Thanks to the way these networks are organized, it may take only a few steps to go from any given gene to any other gene in the human genome. With all these connections, a mutation to a single gene can have wide-ranging effects. It can alter a gene that has nothing directly to do with height, but its influence can reach across the networks to affect the ones that do. In science’s hunt for how we inherit height, scientists may have to expand their search to the entire genome.