She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (64 page)

BOOK: She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity
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Once this custom was in place, natural selection could favor people with mutations to LCT. In times of famine, they might be able to fall back on milk as a source of protein and carbohydrates, while others starved to death. Their descendants inherited their LCT mutations, and as lactose persistence became more common, it fostered the spread of the culture of
consuming milk. In other words, genetic heredity and cultural heredity started off blocking each other, but in later generations they ended up pushing in the same direction.

Bonduriansky and Day see another advantage to a broader view of heredity. Putting on blinders and looking only at genes leaves scientists at risk of missing important new discoveries about biology.

In the nineteenth century, for example, physicians believed that parents who drank too much alcohol could pass down feeblemindedness and other disorders to their children. The physicians were fuzzy on the details of how this happened, falling back on the Bible's promise that God “punishes the children for the sin of the parents to the third and fourth generation.”

To the early Mendelians, this talk was nothing but old-fashioned Lamarckism. It was impossible for a parent's alcoholism to extend its harm to a future generation. Instead of a cause, it was merely an effect. A faulty gene altered the brain, they assumed, causing hereditary feeblemindedness. The condition not only caused people to score poorly on intelligence tests; it also left them unable to resist dangerous pleasures such as drink.

“We may say that
every feeble-minded person is a potential drunkard,” Henry Goddard declared in 1914.

When Goddard assembled Emma Wolverton's pedigree to prove that feeblemindedness was hereditary, he eagerly noted every report of alcoholism in the family. He believed that they strengthened his case even more. In
The Kallikak Family
, Goddard popularized this explanation of alcoholism. But even as the Kallikaks appalled the world, other scientists were carrying out experiments that pointed in a different direction altogether.

At Cornell Medical School in New York, Charles Stockard and George Papanicolaou wafted alcohol fumes into the noses of guinea pigs shortly before they mated. The alcohol caused a host of troubles in their offspring. Some baby guinea pigs were deformed, and others had low birth weight; they tended to die in infancy, and the survivors had low fertility. Stockard and Papanicolaou even found the same troubles carried over for four generations of guinea pigs. They concluded that the alcohol had violated Weismann's barrier and affected the germ cells. “All future generations arising
from this modified germ plasm will likewise be affected,” Stockard and Papanicolaou concluded.

Goddard and other Mendelian-minded scientists weren't swayed by the new research. In 1920, Prohibition went into effect and brought medical research on alcohol to a standstill. By the time Prohibition was lifted in 1933, genetics had matured so far that scientists generally refused to take a fresh look at Stockard and Papanicolaou's work. “While alcohol does not make bad stock, many alcoholics come from bad stock,” Howard Haggard and Elvin Jellinek explained in their 1942 book
Alcohol Explored.
“The fact is that
no acceptable evidence has ever been offered to show that acute alcoholic intoxication has any effect whatsoever on the human germ, or has any influence in altering heredity.”

It wasn't until the 1970s that doctors realized just how wrong Haggard and Jellinek had been. David Smith and Kenneth Jones, both pediatricians at the University of Washington, noticed a cluster of four children who all shared the same symptoms: They had small heads, short statures, and slow intellectual development. They had something else in common, too: Their mothers were all alcoholics. Smith and Jones discovered that other pediatricians were seeing similar symptoms in children. Together they put forward a new condition, known as fetal alcohol syndrome. Heavy drinking during pregnancy, doctors now recognize, can cause a spectrum of symptoms, from brain damage to hyperactivity to poor judgment. In the United States, the Centers for Disease Control and Prevention estimates, up to one in twenty schoolchildren has fetal alcohol syndrome or related disorders.

To understand the biology of the syndrome, scientists in recent years have studied what happens when pregnant rats consume alcohol. Those studies suggest that fetal alcohol syndrome is an epigenetic disease. The ethanol in the drinks alters the methyl groups and other molecules around the DNA in a fetus. As a result, some genes go quiet, while some become more active. It's also possible—although the evidence is thinner—that
fathers who drink before conception can contribute to fetal alcohol syndrome, too. It's possible that ethanol can also change epigenetic patterns in their sperm, and that this change can carry over into an offspring. Even more
tantalizing are experiments finding that male rats can pass down the same epigenetic alterations through two more generations.

The molecular details of fetal alcohol syndrome remain fairly mysterious. Yet the discovery of the syndrome itself did not have to wait as long as it did. We can only speculate how much earlier it might have been recognized if scientists were open to the possibility. If Henry Goddard could have learned about it when he trained as a psychologist in the early 1900s, history might have taken a different path. In 1995, a doctor named
Robert Karp at the Children's Medical Center of Brooklyn looked over some of the materials Goddard collected to write
The Kallikak Family.
He examined the pictures of children whose parents had been alcoholics. Looking at some of them, Karp was struck by the faces: by their razor-thin upper lip, for example, and by the lack of a philtrum—the vertical groove below the nose. These are
telltale signs of fetal alcohol syndrome. Goddard's records—such as the short stature of some of Emma Wolverton's relatives—only strengthened Karp's suspicions. But Goddard himself did not recognize the symptoms. Perhaps it was impossble for him to do so, thanks to his rigid view of heredity. Today, we are still making up for that lost time.

PART V
The Sun
Chariot
CHAPTER 17
Yet Did He Greatly Dare

P
HAETHON PAID
a visit one day to his father, Phoebus, the sun god. He went to demand Greek mythology's equivalent of a paternity test.

Rumors were swirling that Phoebus was not his father, and Phaethon wanted them put to rest. “
Give me proof that all may know I am thy son indeed,” he said.

Stepping down from his throne, Phoebus embraced Phaethon. He swore to do anything to prove his fatherhood. Phaethon asked him for the one thing that Phoebus wished he could deny: to ride the chariot of the sun across the sky.

Phoebus begged Phaethon to ask for something else—anything else. The horses were too strong for Phaethon to master, the course too hard. But Phaethon, supremely confident in his own skill and strength, refused to change his mind. Phoebus realized he was trapped by his own promise and led his son to his gold-wheeled chariot.

When Phaethon climbed aboard, the horses suddenly carried the chariot high above the Earth. Phaethon went blind with fear. Simply being the son of a god did not mean that Phaethon inherited his father's mastery. The horses galloped off course, dragging the sun down toward the Earth and far away again. Where they came too close to the land, it was scorched to desert. Where they rose too high, they left frozen wastelands behind.

Phaethon's wild ride did more than permanently alter the landscape. It
also left its mark on humanity. When the lurching chariot passed over Africa, the sun dropped so close to the ground that it scorched the people living there. Their blood rose to their skin, turning it black. Their children would inherit their dark skin, as would all future generations.

Before long, the Earth cried out to Zeus for help, and he responded by hurling a bolt of lightning at the chariot. The sun god's son tumbled to Earth, blazing down like a shooting star. Nymphs buried his smoldering body and put a stone over his tomb. “Here Phaethon lies, his father's charioteer,” it read. “Great was his fall, yet did he greatly dare.”

The story of Phaethon, which survives today mostly through Ovid's telling in
Metamorphoses
, is many different stories bundled together. Among those stories is a tale about heredity. Phaethon's wild ride was an explanation for an inherited difference between people. Ancient philosophers and poets offered many such explanations for why children resembled their parents and why some diseases were inherited. Yet there's also a telling absence in their writings. As far as we know, Aristotle and other ancient scholars never offered instructions for how to alter heredity—how to extirpate inherited diseases or how to improve the animals and plants their lives depended on. Perhaps those ancient scholars thought humans could no more alter heredity than they could alter the course of the sun. And perhaps they thought that anyone who dared seize such power would be overwhelmed and die.

But there's yet another story hidden in Phaethon's tale. It's odd, when you think of it, that a god like Phoebus would have to use horses to pull his heavenly chariot. Certainly they must have been remarkable horses that could gallop across the sky, but they were horses nonetheless, complete with hooves, tails, and manes—the same animals that pulled the chariots of earthly Greeks in races and battles.

And yet the ancient Greeks and their fellow humans transformed their horses in a godlike way: They altered the DNA of the animals, steering them from the genes of their wild ancestors and
toward new domesticated sequences. They reared the horses, raising foals to replace their parents in the traces. Each new generation of horses inherited traits from their parents
that made them well adapted to this work: powerful hearts, strong bones in their legs, and a willingness to take commands from two-legged apes.

This particular combination of traits seems to have first come together about 5,500 years ago, when nomads in central Asia began to domesticate wild horses. They unknowingly picked out certain variants of certain genes for breeding. Domesticated horses then spread across much of Asia, Europe, and northern Africa in the millennia that followed. The horses of ancient Greece were thus the product of five thousand years of modification, and in later years, people continued transforming them into new breeds. Big workhorses like Clydesdales hauled heavy loads, while Thoroughbreds galloped swifly around racetracks. Every breed of horse inherited a particular combination of variants that altered everything about them—their size, their shape, and even their gait.

The Greeks and other ancient peoples had more control over heredity than Phaethon had had over his father's chariot, in other words. But they had little idea of what they were doing. They could not directly rewrite genes of horses to precisely meet their needs, creating permanent changes that would be passed down to future generations. They could only choose which horses to breed. The desirable genetic variants they blindly selected sat on stretches of DNA with harmful ones, too. Modern horses pay the price for this blind selection, inheriting genetic variants that make them worse at healing wounds than their ancestors, raise their risk of seizures, and create other vulnerabilities.

In the 1800s, a growing number of scientists tried to master heredity's chariot. They ran experiments to find its rules. And yet even in the early 1900s, controlling heredity still seemed like magic—in both the wondrous and dangerous senses of the word. It was no accident that Luther Burbank earned the nickname “
the Wizard of Santa Rosa.”

When the plant scientist George Shull spent time with Burbank, he realized that the wizard had no magic beyond a good eye for interesting flowers and fruits. And it was Shull, not Burbank, who would become the true pioneer of modern plant breeding. Back at Cold Spring Harbor, Shull ran
an experiment on some Indian corn he had rescued from the lab's horse
feed. He planted the kernels and then carefully pollinated each plant with its own pollen. In time, he created purebred lines of corn.

The two copies of every gene in each purebred plant were identical. Shull would pick out one line with a quality he liked, such as extra rows of kernels, and then breed it to another desirable line. Their hybrid offspring inherited a copy of each gene from each parent. Remarkably, the hybrid corn would show many of the traits that Shull selected in the inbred lines, while also growing bigger, healthier ears than their parents.

Shull painstakingly improved his inbred lines and found that when he crossed them, they produced even better hybrids. Scientists still argue about why his method worked. It may be that he could eliminate harmful recessive mutations without losing the traits he desired. It may also be that corn and other plants do better when they can use two versions of certain proteins rather than just one. What was immediately clear when Shull began publishing his experiments was that his method would allow farmers to get more food from their crops—what Burbank had originally claimed was his own life's mission.

By the 1920s, many plant scientists were following Shull's example, and before long farmers across the Midwest were filling their fields with hybrid corn. Not only did it produce more bushels per acre, but it also withstood the Dust Bowl droughts better than earlier strains. By the end of the twentieth century, plant breeders using Shull's methods had quintupled their yields. Yet enough genetic variation still remained in the corn plants to ensure that they could breed even better hybrid corn for many years to come.

—

Understanding Mendel's Law made Shull's hybrid corn possible. And yet Shull still worked for the most part in ignorance. He had no idea which genes he was selecting or how they made his corn better. He simply mixed the existing variations together. It was his combinations that were new.

Over the next century, scientists would gradually gain more control over heredity. Some dragged X-ray machines into cornfields and fired beams at the tassels. The radiation triggered new mutations that altered the
descendants of the corn. Plant mutagenesis, as this method came to be known, threw out new varieties of
pears, peppermint, sunflowers, rice, cotton, and wheat. Bombarding barley gave rise to new kinds of beer and whiskey. Scientists also hurled X-rays at mold,
creating strains that could make superior penicillin.

Even these successes still depended on a lot of blind luck, though. Heredity remained a slot machine, and plant mutagenesis just gave scientists an extra bucket of coins to play it. More pulls of the arm raised their odds enough that, at some point, the reels would turn up three bars.
It wasn't until the 1960s that microbiologists would discover molecular tools that gave them a more precise control over heredity.

Many species of bacteria make proteins called restriction enzymes that recognize a short sequence of DNA and cut the molecule wherever that sequence appears. These microbes use their restriction enzymes to defend themselves against attack—specifically, by destroying the DNA of invading viruses. Tinkering with these proteins, scientists found that they could also use them to cut other pieces of DNA, even genes inside human cells. Loading such a gene onto a plasmid—a ringlet of DNA—these researchers could then move the gene into a microbe.

By the end of the 1970s, researchers created strains of bacteria that carried the gene for human insulin. With the bacteria growing in fermentation tanks, scientists could now manufacture the insulin like living factories. Other researchers went on to use similar methods to do everything from giving crops resistance to viruses to giving mice humanlike hereditary diseases.

Behind these successes, however, were long stretches of effort and failure. It could take years for scientists to discover a gene worth moving from one species to another, and then years more to load it onto a vehicle that could carry it across the species boundary. And learning how to make that transfer to one species didn't help researchers with another. The tools that made it possible to import genes from jellyfish into rats were useless for moving daffodil genes into rice.

And even if scientists succeed in getting genes into a species, they might still fail. The scientists had little control over where a gene would get inserted
in an organism's DNA. It might end up in a spot where it could operate smoothly, or it might drop into the middle of other genes, disrupting them and killing its new host. None of these challenges spelled doom for genetic engineering, but they did keep it expensive and limited to labs of scientists with hard-fought wisdom.

It wouldn't be until 2013, over a century after Shull discovered hybrid corn, that scientists would report their discovery of a versatile, cheap way to control the heredity of just about any species. They hadn't thought it up. Just like restriction enzymes before it, it was a system of molecules that bacteria had been using for billions of years to alter their own heredity.

—

In 2006,
Jennifer Doudna was sitting in her office at the University of California, Berkeley, when she got a phone call out of the blue. A Berkeley microbiologist named Jill Banfield wanted to talk to her about something that sounded like
crisper
.

Doudna didn't understand what Banfield was talking about, or why she'd want to call her. But Banfield, who searched for new species of bacteria on mountaintops and ocean floors, seemed like a scientist worth talking to. At the time, Doudna studied the RNA molecules made by bacteria, humans, and other species. Most of her work took place in the quiet confines of a test tube. Banfield could enlighten her about the world beyond the tube.

The following week, Doudna and Banfield met at a café. Banfield introduced Doudna to CRISPR, at least as it was understood in 2006. She drew a diagram for Doudna in a notebook, showing the repeating sequences of DNA that some species of bacteria carried, with different bits of DNA wedged between them.

Banfield at the time was discovering CRISPR regions in the DNA of one species after another. And she could see that some of these bits of DNA had come from viruses. Other scientists had begun to explore the possibility that CRISPR was some sort of defense system that bacteria could use to fight viruses, a system they could pass down to their descendants. But nobody knew how it worked. One possibility was that bacteria made RNA
molecules to seek out the viruses. Since Doudna was an expert on RNA in bacteria, Banfield wondered if she'd be willing to help find out.

Doudna took Banfield up on the offer. She hired a postdoctoral researcher named Blake Wiedenheft to work exclusively on CRISPR, and then gradually the rest of her lab switched over to studying it. A few other labs were also investigating CRISPR at the time. In 2011, Doudna joined forces with a French biologist named Emmanuelle Charpentier, and together they figured out that CRISPR, like restriction enzymes, destroys viral DNA.

But there was a profound difference between these two lines of defenses. Restriction enzymes had a shape that allowed them to recognize only a single short stretch of DNA, which could appear in many places in a genome. Microbes protected their own DNA from this attack by methylating their own sequences. Viruses, unable to methylate their genes, were left vulnerable to attack.

The Cas9 enzymes produced by the CRISPR system were far more sophisticated. Bacteria produced RNA guides that could lead the enzymes to one—and only one—stretch of DNA. By storing different RNA guides in their DNA, bacteria could precisely recognize several different strains of viruses.

Like any molecular biologist, Doudna was well aware of how restriction enzymes had helped create the biotechnology industry. She wondered if CRISPR might have a similar power. If it could recognize any stretch of DNA in a virus, perhaps Doudna and her colleagues could create RNA guides that would lead the enzymes to a particular spot in the DNA of a cucumber. Or a starfish. Or a human.

To test this idea, Doudna and her colleagues tried to cut out a piece of DNA from a jellyfish gene. (The gene is a common tool for molecular biologists, because it makes a glowing protein that can light up a cell like a microscopic jack-o'-lantern.) Doudna and her colleagues picked for their target a twenty-letter stretch. After synthesizing RNA molecules that matched the target, they mixed all the molecules together in a test tube. The RNA guides and Cas9 enzymes combined, and sought out the jellyfish genes. When
Doudna and her colleagues looked at that DNA afterward, they discovered it was now cut into precisely the fragments they had hoped to create. Four more trials, using RNA guides that sought different targets in the gene, worked just as well.

BOOK: She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity
12.92Mb size Format: txt, pdf, ePub
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