She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (56 page)

Years of subsequent research revealed that mitochondria performed an essential job: They use oxygen and sugar to create a cell's fuel supply. Researchers also discovered that mitochondria were shared not only by all animals but also by plants, fungi, and protozoans—in other words, by all eukaryotes. Tracing these lineages on the tree of life revealed that mitochondria must have evolved in the common ancestor of eukaryotes, some 1.8 billion years ago.

In the early 1960s, an astonishing fact about mitochondria came to light: They contained more than just proteins. Scientists also discovered they store their own DNA—if only a little. Human mitochondria have only thirty-seven genes, compared to about twenty thousand protein-coding genes in the nucleus. Nevertheless, the discovery of mitochondrial DNA baffled scientists. Our cells have many compartments—lysosomes for breaking down food molecules, for example, and the endoplasmic reticulum for moving proteins around the cell. But of them all, only mitochondria have their own set of genes.

Lynn Margulis, a biologist at the University of Massachusetts, argued that there was only one way to make sense of the discovery: It was time to revisit the old theories of Altmann and other early cell biologists. The evidence pointed to mitochondria starting out as free-living bacteria, and still holding on to a few of their original genes.

Margulis would be proven right. Starting in the 1970s, scientists began sequencing mitochondrial DNA. When they looked for the most similar genes in other species, they found that mitochondria most resembled bacteria. They were even able to narrow the genetic resemblance down to one lineage in particular, a group of species called
alphaproteobacteria.

Before gaining their mitochondria, the evidence now suggests, our ancestors were microbes that survived by slurping some kind of molecular debris from their surroundings. About 1.8 billion years ago, a small species of bacteria—an alphaproteobacteria, to be specific—ended up permanently inside of them. Living alphaproteobacteria have given scientists inspiration
for ideas about
how this merger happened. Some researchers have argued that the alphaproteobacteria slipped into the larger cells as parasites. Their host did their best to destroy the invaders, but the alphaproteobacteria evolved defenses. In time, they stopped spreading from cell to cell. When their host divided, the alphaproteobacteria wound up in both the daughter cells.

Other scientists have proposed that the two microbes lived side by side at first. They traded essential nutrients, helping each other thrive. The closer they were to their partners, the more reliably they could exchange these gifts. Eventually, they merged entirely.

Whichever is the case, gaining mitochondria marked one of the great leaps in the evolution of life. A cell now could harvest the fuel made by its new lodgers. The more mitochondria a cell could house, the more energy it could use. This symbiosis spiraled upward, allowing eukaryote cells to become far bigger, far more complex, than any cell before. Instead of feeding on molecular debris, eukaryotes now had enough fuel to chase after bacteria and engulf them. Later, these single-celled predators began clinging together, evolving into multicellular creatures.

Ensconced in their new home, mitochondria followed the same path that endosymbionts so often do. They abandoned many of the genes they had once needed to live freely on their own. Yet mitochondria never gave up their own form of heredity. Altmann might have been wrong to think that mitochondria were independent life-forms. But he was right to think of bacteria when he saw mitochondria dividing. Within a cell, a mitochondrion will sometimes split in two, and the daughter mitochondria inherit copies of its DNA, just as their free-living ancestors did nearly two billion years ago.

When our own cells divide, their daughter cells inherit a portion of their mitochondria, which keep dividing over the course of our lifetime. Our bodies don't get overrun by mitochondria because our cells sometimes destroy them, keeping their numbers in check. Our deaths bring an end to the lineages of mitochondria in our bodies; the only ones with a chance to escape to the future are those that dwell in women's eggs. A man's
mitochondria have no future, because their sperm destroy them during fertilization.

The fact that mitochondria are inherited only down the maternal line makes their DNA a powerful genealogical tool. It allowed some scientists to reunite the family of the Tsar Nicholas. It allowed others to reunite all living humans, tracing our mitochondrial DNA to a single woman in Africa 150,000 years ago. Yet
mitochondria's distinctive patterns of heredity have also created deep confusion.

When mitochondria copy their DNA, they can make mistakes and introduce mutations. Some of those mutations can disrupt their fuel-generating assembly line, while others can cause devastating hereditary diseases. They can make eyes go blind, ears go deaf, muscles waste away. Many of these mitochondrial diseases went overlooked for decades by geneticists, because they flouted Mendel's Law. In some families, a disease will only sporadically strike relatives over the generations. In other families, the same disease will reliably occur in every child of a mutation-carrying mother.

It wasn't until the late 1980s that scientists began pinpointing the genetic basis of mitochondrial diseases. Since then, they've identified hundreds of these disorders, which together afflict one in four thousand people. Strangely, though, these people often have relatives who carry the same mutations in their mitochondria but don't suffer the same symptoms.

This confusion dissolves when you bear in mind that mitochondria are our resident bacteria, following their own rules of heredity. If a single mitochondrion mutates, the cell that carries it will continue functioning normally, because it still has hundreds of other healthy ones. When the cell divides, one of its daughter cells inherits that one mutant mitochondrion. As the mutant mitochondrion itself divides, it becomes a bigger burden on cells. When the number of mutant mitochondria rises above a certain threshold, a cell will start to fail.

Mutant mitochondria can continue to become more common from one generation to the next. A woman with low levels of mutant mitochondria may give birth to children who cross the threshold into a full-blown
mitochondrial disease. Thanks to chance, some of her children may get sick, while others remain healthy.

Studying mitochondrial diseases may eventually lead scientists to an answer to the biggest question about their heredity: Why does it follow only the maternal line? We all need mitochondria, males and females alike, to stay alive. Sperm need mitochondria to power their swim toward conception. Scientists have discovered a few species in which both parents pass down their mitochondria to their offspring.
Ink cap mushrooms are one. Geraniums are another. In mussels, sons inherit mitochondria from both parents, while daughters inherit them only from their mothers. But in the overwhelming majority of species, fathers never pass down their mitochondria.

All these clues hint that there must be some powerful advantage to limiting mitochondria to the maternal line. It's possible that this kind of heredity evolves because mixing together mitochondria from two parents can be a disaster for children. In 2012,
Douglas Wallace, an expert on mitochondrial diseases at the University of Pennsylvania, and his colleagues injected mitochondria from one healthy line of mice into the cells of a genetically distinct line. They then used those blended cells to produce mouse embryos. When the animals became adults, they suffered a host of problems, especially in their behavior. The mice became stressed-out, lost their appetite, and did badly at learning their way out of a maze.

Limiting mitochondrial heredity to one parent may help organisms move ahead in the evolutionary race. And once a species restricts mitochondria to eggs, mothers sometimes evolve ways to
inspect their eggs, eliminating ones with too many mutations. The bacteria that sometimes infected our ancestors have now become so much a part of our heredity that their quality is the standard by which new human lives can come into existence.

CHAPTER 15
Flowering Monsters

T
IM OVER HERE
has the original Linnaeus flower.”

I had come back to Cold Spring Harbor, this time for its plants. A transplanted Englishman named Robert Martienssen met me in front of his lab, and we spent the morning admiring his mats of duckweed and tall stands of experimental corn. We went to one of the laboratory greenhouses to meet the farm manager, Tim Mulligan. He brought with him a black plastic pot with a flower.

Mulligan set it down on a counter made of planks, and I leaned in to inspect it. The pot contained a single plant, sprouting a dozen or so bright yellow blossoms. The flowers looked to me like miniature herald trumpets. The petals wrapped around each other to create a long, closed tube. Each tube curled out at the end, forming a spiked, five-sided rim.

It was a lovely plant, but if I encountered it on a walk through a meadow, I might well have crushed it under my boot. To Martienssen, however, it was one of the most interesting organisms in the world. It represented an enduring mystery about heredity and the forms it can take.

The flower I was looking at has a clear-cut pedigree. It's a direct ancestor of a plant that was discovered in 1742 by a Swedish university student named
Magnus Zioberg. Zioberg was hiking on an island near Stockholm when he happened to notice a trumpet-flowered plant. It confused him, because—aside from the flowers—it looked like a familiar plant called
toadflax. The flowers of normal toadflax plants have a mirrorlike symmetry. They grow a few small yellow petals, some sprouting off to the left and others to the right, and a spike develops at the base of these flowers, pointing toward the ground. The flowers on the plant that Zioberg stumbled across had a circular symmetry instead.

Zioberg plucked the flower out of the ground, pressed it in a book, and brought it back to Uppsala University to show to his professor Olof Celsius. Celsius was thunderstruck. He immediately brought the flower to his colleague—and one of the most important naturalists in history—Carl Linnaeus.

Linnaeus was working at the time on a new system for classifying all plants and animals. It's the system we still use today. To classify plants, Linnaeus paid particular attention to the shape of their flowers. When he looked at Zioberg's discovery, he thought Celsius was having a joke at his expense. Celsius must have glued flowers from another species onto a toadflax plant to fool him. But Celsius assured Linnaeus it was genuine.

Zioberg had found a monster, Linnaeus decided. But such monstrous flowers were supposed to be sterile, and Linnaeus discovered that Zioberg's specimen was fertile, growing the structures it would need to produce viable seeds. Linnaeus became even more astonished the closer he studied the structure of the flowers. They were unlike anything that Linnaeus—or any botanist before him—had ever seen. He begged Zioberg to go back to the island and bring him back some plants that were still alive.

Zioberg did so, and returned to Uppsala with a living plant that still had intact roots and stems. It was planted in the university's botanical garden, but it languished and died. Linnaeus desperately made the most of the flower's brief existence, writing down a wealth of observations. He produced a long report on that single plant, his surprise radiating off each page.

“This is certainly no less remarkable than if a cow were to give birth to a calf with a wolf's head,” Linneaus declared. He considered the trumpet-shaped flower a species of its own. He named it
Peloria—
from the Greek for “monster.”

To make sense of this “amazing creation of nature,” as he called it,
Linnaeus speculated that it descended from ordinary toadflax. Pollen from another species had fertilized a toadflax plant, somehow triggering a sudden leap into a new form. To say such things in the 1740s—a century before Mendel's and Darwin's work—verged on heresy. Species were supposed to be fixed since creation. Heredity could not abruptly change course and make a new species.

“Your
Peloria
has upset everyone,” a bishop wrote in an angry letter to Linnaeus. “At least one should be wary of the dangerous sentence that this species had arisen after the Creation.”

In his later years, as he studied other specimens, Linnaeus became less sure of what the plants really were. He discovered that sometimes a single
Peloria
plant grew a mix of monstrous trumpet flowers and ordinary mirrorlike ones. He couldn't decide whether they were indeed a species of their own or some kind of strange variant that defied botany's rules.

Peloria
would continue to intrigue later generations of botanists. Reared in botanical gardens across Europe, the plant went on passing down trumpet flowers to later generations. Goethe, who was just as interested in flowers as he was in poetry, made sketches of
Peloria
alongside toadflax flowers. Hugo de Vries thought for a time he might discover proof for his mutation theory in
Peloria.
The monstrous flower must have arisen through a mutation to an ordinary toadflax, he believed, creating a new species in a single jump.

Peloria
refused to surrender to such an easy explanation. If a mutation really had produced the plant's trumpet flowers, it would have rewritten a piece of toadflax DNA. Later generations of
Peloria
would have inherited that mutation. Instead, the descendants of the original
Peloria
plants sometimes grew ordinary mirror flowers and sometimes monstrous trumpet ones, displaying no clear pattern that Mendel would have recognized.

In the late 1990s, a group of English scientists turned their attention to
Peloria
, using the tools of molecular biology
.
Enrico Coen of the John Innes Centre in England and his colleagues examined a gene involved in making flowers, called L-CYC. In order for ordinary toadflax plants to develop flowers, they must switch on the L-CYC gene in the tips of their stems. In
Peloria
, Coen discovered, L-CYC stays silent.

This difference is not due to a mutation that altered the gene for L-CYC in
Peloria
. Coen and his colleagues found that the gene is identical in toadflax and
Peloria
. The difference between them was not
in
their DNA but
around
it.

Coen found a different pattern of methylation around the L-CYC gene in
Peloria
and in normal toadflax. In
Peloria
, L-CYC had a heavy coating of methyl groups, preventing the flower's gene-reading molecules from reading it. Coen and her colleagues noticed that as they bred new
Peloria
plants, they sometimes produced flowers that looked more like those of regular toadflax. When the scientists inspected the L-CYC gene in these throwbacks, they found that the gene had lost some of its methylation, allowing it to become more active again.

In
Peloria
, it seems, heredity has traveled down two channels. The flower has passed down copies of its genes, which guided the development of toadflax-shaped plants. But these plants also inherited a peculiar pattern of methylation that was not encoded in their genes. At some point before Zioberg stumbled across it in 1742, a toadflax plant accidentally added on methyl groups to its L-CYC gene. By silencing the gene, this methylation caused the flower to develop into a new shape. This newly altered flower then produced seeds, which inherited the same epigenetic mark. They fell to the ground, sprouted, and produced the same monstrously lovely flowers. Over the centuries that followed, some of their descendants lost the epigenetic mark, blooming into ordinary toadflax flowers once more. But other
Peloria
plants continued to inherit the wolf's head of botany.

When I visited Martienssen, he was starting an experiment on
Peloria.
No one knew exactly how these plants kept inheriting the epigenetic marks for their monstrous flowers for so many generations. Martienssen had an idea for how to find out, but his experiment almost didn't happen. When he asked Coen where he could get a supply of
Peloria
, Coen told him the flower had vanished. As far as Coen could tell, no one in the world had any
Peloria
left.

“They lost it at Kew Gardens,” Martienssen told me. “They lost it at Oxford Botanic Gardens, where they had it for two hundred years.”

After months of searching, Coen finally discovered a cache of the historically important flowers. He found it not in a botanical garden or in a scientific laboratory. A California nursery offered to ship
Peloria
anywhere in the world. Martienssen put in a big order, and once the plants arrived in Cold Spring Harbor, he and Mulligan started building up a supply of their own.

“We're trying our best to make sure we don't lose it,” Mulligan said.

—

In the late 1800s, Charles Darwin and Francis Galton first turned heredity into a scientific question. Scientists such as Hugo de Vries and William Bateson believed that in genes they had found an answer. They found a way by which living things today could be correlated with their biological past. But in the process, they didn't just look for evidence in favor of genes as a vehicle for heredity. They also sought to refute any other alternative.

When August Weismann argued that the germ line carried heredity, walled off from somatic cells, he singled out Jean-Baptiste Lamarck as his opponent. Chopping off mouse tails was his way of refuting Lamarck's claim that acquired characters could be passed down. “
If acquired characters cannot be transmitted, the Lamarckian theory completely collapses and we must entirely abandon the principle by which alone Lamarck sought to explain the transformation of species,” Weismann said in 1889.

Weismann cleared a scientific path for geneticists to follow in the early 1900s, and they, like him, fashioned themselves as opponents of Lamarck and the so-called Lamarckians of their own day. In 1925, Thomas Hunt Morgan declared that genetic studies “furnish, in my judgment,
convincing disproof of the loose and vague arguments of the Lamarckians.” Any Lamarckian who did not abandon those loose and vague arguments in the face of all the evidence had to be confusing wishful thinking for science. “The willingness to listen to every new tale that furnishes evidence of the inheritance of acquired characters arises perhaps from a human longing to pass on to our offspring the fruits of our bodily gains and mental accumulations,” Morgan sniffed.

Lamarck has remained an icon of pre-genetic thinking ever since. It's a role
that's unfair both to him and to history. The inheritance of acquired traits had been widely accepted for thousands of years before Lamarck was born. In Europe, scholars from the Middle Ages to the Enlightenment treated it as fact. When Lamarck developed his theory of evolution from the inheritance of acquired traits, he felt no need to argue that it was true, because the matter had been settled so long ago. “
The law of nature by which new individuals receive all that has been acquired in organization during the lifetime of their parents is so true, so striking, so much attested by the facts,” he once said, “that there is no observer who has been unable to convince himself of its reality.”

Regardless of whose name should be put on the idea, it continued to fall out of favor over the course of the twentieth century. As genetics explained more and more about life—with the discovery of the structure of DNA, with the fine details of its inheritance charted in thousands of experiments—the evidence for other forms of heredity remained weak: an odd frog or a stray stalk of wheat that seemed to pass down acquired traits. But
some scientists continued to fight for conceptual room for more than one form of heredity. If we simply redefine heredity as genetics, they argued, we will never even look for those other channels.

—

Toward the end of the twentieth century,
a few cases came to light that looked an awful lot like the inheritance of acquired traits.

In 1984, a Swedish nutrition researcher named Lars Olov Bygren launched a study of people in Ö
verkalix, a remote region of Sweden where he had grown up. For centuries, Bygren's relatives had eked out a difficult existence along the banks of the Kalix River, fishing salmon, raising livestock, and growing barley and rye. Every few years, they suffered devastating crop failures, leaving them with little food to eat during the six-month-long winters. In other years, the weather would swing far in their favor, bringing bumper crops.

Bygren wondered what sort of long-term effects these drastic changes
had on the people of Överkalix. He picked ninety-four men to study. Studying church records, he charted their genealogies and discovered a correlation between their own health and the experiences of their grandfathers. Men whose paternal grandfathers lived through a feast season just before puberty died years sooner than the men whose grandfathers had endured a famine at that same point in their life. Women, Bygren found in a later study, also experienced an influence across the generations. If a woman's paternal grandmother was born during or just after a famine, she ended up with a greater risk of dying of heart disease. It had long been known that a woman's health while she was pregnant could influence a fetus, but Bygren's research suggested the effects could stretch even further, to grandchildren or beyond.

Experiments on animals produced some similar results. In the early 2000s,
Michael Skinner, a biologist at Washington State University, and his colleagues stumbled across one while they were investigating a fungus-killing chemical called vinclozolin. It's used by farmers to protect fruits and vegetables from mold, despite some evidence it can interfere with sex hormones.

Skinner and his colleagues gave vinclozolin to pregnant rats, and their offspring developed deformed sperm and other kinds of sexual abnormalities. Later, one of Skinner's postdoctoral researchers mistakenly bred these offspring and produced a new generation of rats. That error allowed Skinner to discover something he would not have expected: The grandsons of the poisoned rats also produced defective sperm, despite having no direct exposure to vinclozolin.

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