She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (37 page)

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.