She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (21 page)

Some scientists have argued that CRISPR is
a genuine case of Lamarckian heredity. Of course, virus-fighting bacteria are a far cry from the leaf-plucking giraffes of Lamarck's imagination, and so the question can descend into a squabble over semantics. What's indisputably clear, however, is with CRISPR scientists have found yet another channel of heredity beyond Mendel's Law.

About 1.8 billion years ago, a new form of life evolved on Earth. Its cells were much larger than those of bacteria and archaea. Its DNA was tucked with exquisite care inside a pouch called the nucleus. It generated abundant amounts of fuel in special pods called mitochondria. Among the many forms this new kind of life would take would be our own.

These microbial monsters were eukaryotes. Their descendants would give rise to protozoans, the predators of the microbial world that hunt through soil and sea for single-celled prey. Eukaryotes evolved into all multicellular life on Earth as well, including fungi, plants, and animals like us. Along with their nucleus and large size, eukaryotes share many other traits that bacteria and archaea lack. But one of those traits matters most to heredity: Eukaryotes pass down their genes to their offspring in a unique way, one that allowed Mendel's Law to emerge.

While bacteria and archaea have a single chromosome, eukaryotes carry pairs of them. Different species have different numbers of pairs. We humans have 23 pairs, but pea plants have only 7. Yeast have 16. Some butterflies have 134.

When our somatic cells divide, they copy all their chromosomes, creating an extra pair for each one. They tear down the nucleus, pull half the chromosomes to each side, and split themselves down the middle. Each new cell now has its own 23 pairs. This kind of division—called mitosis—is fundamentally similar to what bacteria do: turn one cell into two identical cells.

Our bodies use mitosis to grow and rejuvenate themselves. But in order to make germ cells, we have to make sperm or eggs that have only one set of chromosomes rather than a pair. The simplest way to make sperm and eggs would be to simply pull apart the pairs of chromosomes in a somatic cell and allot one set to each germ cell. But our bodies do not do that. Instead, they indulge in a process called
meiosis, which is laughably baroque.

In men, meiosis takes place within a labyrinth of tubes coiled within the testicles. The tube walls are lined with sperm precursor cells, each carrying two copies of each chromosome—one from the man's mother, the other from his father. When these cells divide, they copy all their DNA, so that now they have four copies of each chromosome. Rather than drawing apart from each other, however, the chromosomes stay together. A maternal and paternal copy of each chromosome line up alongside each other. Proteins descend on them and slice the chromosomes, making cuts at precisely the same spots.

As the cell repairs these self-inflicted wounds, a remarkable exchange can take place. A piece of DNA from one chromosome may get moved to the same position in the other, its own place taken by its counterpart. This molecular surgery cannot be rushed. All told, a cell may need three weeks to finish meiosis. Once it's done, its chromosomes pull away from each other. The cell then divides twice, to make four new sperm cells. Each of the four cells inherits a single copy of all twenty-three chromosomes. But each sperm cell contains a different assembly of DNA.

One source of this difference comes from how the pairs of chromosomes get separated. A sperm might contain the version of chromosome 1 that a man inherited from his father, chromosome 2 from his mother, and so on. Another sperm might have a different combination. At the same time, some chromosomes in a sperm are hybrids. Thanks to meiosis, a sperm cell's copy of chromosome 1 might be a combination of DNA from both his mother and father.

The basic biology of
meiosis is the same inside a woman's body, but the timing is very different. The first steps take place while she's still an embryo in her mother's womb. A group of cells inside a female embryo take on a new identity as egg precursors, moving together to where the ovaries will later develop. When the embryo is seven months old, the precursor cells
begin meiosis, doubling their chromosomes, pairing some of them together, and exchanging some pieces of DNA. But the chromosomes then freeze in place midway through meiosis. They stay that way for years, until girls reach adolescence and start to ovulate.

During each ovulatory cycle, a single egg precursor turns on its meiosis and completes the cycle. As with sperm, a woman's meiosis produces four new cells, each with only twenty-three chromosomes. But only one of those cells matures into an egg. The other three cells wither down to vestiges, known as
polar bodies.

Scientists can now see how meiosis drove the patterns that Mendel observed in his garden.
When Mendel crossed tall and short pea plants, for example, he grew hybrids that were all tall. But when he crossed them, a quarter of the next generation turned out short again. Now scientists know the genes responsible for those differences. Known as LE, it makes a protein that triggers peas to grow. His short pea plants carried two copies of a mutant form of the LE gene. The LE proteins in these plants didn't work properly, stopping their growth. The hybrids had one working copy of LE, which was enough to grow normally.

When a hybrid pea plant matured, some of its cells went through meiosis before producing pollen and ovules. The cells duplicated their chromosomes, shuffled some genes from one chromosome to its partner, and then pulled them apart into four sets. It was a matter of chance whether a pollen grain ended up with the chromosome carrying the normal version of the LE gene or the mutant form. As a result, half the germ cells produced by each pea plant had each copy of the gene.

The biologist Laurence Hurst once wrote that meiosis takes place “in a manner reminiscent of drunkards returning from
an evening's revelry: one step backwards, two steps forward.” Yet this strange stumbling is also responsible for heredity's most elegant patterns.

Scientists first spotted chromosomes in the mid-1800s, but meiosis didn't come to light until decades later. In the early 1900s, a Belgian priest named
Frans Alfons Janssens stained fertilized salamander eggs so
that he could observe their chromosomes through a microscope. The stains captured them at different stages of meiosis, like frames from a movie. It looked to Janssens as if the chromosomes were intimately interacting with each other and then pulling apart.

In the brief report he published on his discovery in 1909, Janssens didn't try to draw any profound lessons about heredity. But he had a hunch it would turn out to be important. “
Are we being presumptuous?” Janssens asked. “Time will tell.”

It didn't take much time at all. While Janssens was peering at salamander cells in Belgium, Thomas Hunt Morgan was breeding white-eyed flies in New York. Morgan and his colleagues first discovered that the hereditary factor for red or white eyes was located on a chromosome. (Today, we'd say that the gene for eye color is a stretch of DNA on the chromosome.) Morgan's team also found another factor, which produced short wings on flies, on the same chromosome.

Because that chromosome happened to be the X, Morgan and his colleagues could study these factors by breeding flies. They took advantage of the fact that males have one X chromosome and one Y, while females have two X's. Morgan and his students used breeding to produce female flies with both white eyes and short wings. One of their X chromosomes carried the factor for white eyes in flies, while the other carried the one for short wings. Then the scientists bred these females with red-eyed males.

The sons of these female flies inherited only one X chromosome, all getting it from their mother. It was thus no surprise to the scientists that some of the sons had red eyes, while others had short wings. But Morgan and his students also found something extraordinary: A few sons ended up with white eyes
and
short wings. A few other sons developed red eyes and long wings. The X chromosomes of their mothers were trading hereditary factors, creating new combinations of traits.

In later studies, Morgan's team showed they could also take two factors sitting on the same chromosome and split them apart. They reared flies in which the same X chromosome carried the factors for short wings and a yellow body. Sons that inherited that particular chromosome from their mother developed both traits. When Morgan's team bred those flies, however, a
fraction of sons ended up with yellow bodies but normal-size wings. Others had normal bodies with short wings.

Morgan didn't quite know how to make sense of these results at first. By good fortune, he happened to stumble across Janssen's report. He realized that Janssen had unwittingly found the physical solution to his own experiments. Morgan and his colleagues quickly wrote up a new hypothesis that combined both sets of results. Each chromosome, they argued, carried a set of factors arrayed in a line like beads on a string. When female flies developed their eggs, their X chromosomes crossed over each other and traded segments.

The joining and splitting of traits happened only rarely, but Morgan and his students noticed that they occurred with striking regularity. A particular trait might get split from a second one in 1 percent of offspring. But it might get split from a third trait 2 percent of the time. Morgan's student Alfred Sturtevant realized that the reason for this puzzling pattern had to do with where genes sat on their chromosomes.

When chromosomes get broken into segments during meiosis, the genes that are close to each other tend to stay on the same segments. Distant genes are more likely to get separated. If someone starts ripping dictionaries apart at random places and handing you the pieces, you can bet that the chunk that contains
meiosis
will be more likely to contain
mitosis
than
chromosome.
Sturtevant's insight led the way to genetic maps, which marked how far apart genes were from each other. Heredity now gained a geography.

Time and again, the principles of heredity that Morgan's group discovered in flies proved true in other species. Meiosis was no exception. We humans, along with other animals, also turned out to be the products of meiosis. The slimy kelp beating in the tides carry out meiosis, too, as do groves of bamboo clattering in the wind, and stinkhorns heaving out of the ground. While scientists have put forward a number of explanations for
why meiosis evolved, one has gained a lot of evidence in recent years: Meiosis lets evolution do its job better.

Consider what meiosis does inside of one of Morgan's
Drosophila
flies. Like other flies, it has a collection of traits—let's say those traits include short wings, a strong immune response, and the ability to make lots of eggs. And let's say the genes for those three traits—one bad and two good—all sit on the same chromosome. Without meiosis, that fly would only be able to pass down its three alleles in one bundle, since the three genes all sit on the same chromosome. What's more, if any new harmful mutations arose on that chromosome in later generations, it would also get passed down along with the other alleles. Over the generations, the fly's descendants would sink under a burden of bad mutations.

Give the fly meiosis, and everything changes. Its descendants are no longer doomed to inherit a particular combination of alleles on each chromosome. Meiois shuffles the alleles into new combinations. Some of the fly's descendants may inherit the alleles for frail wings and a weak immune system. But meiosis also allows other descendants to end up with powerful wings and a strong immune system. These stronger flies can reproduce, and their offspring will sustain the population into future generations. The population of flies ends up with combinations of superior genetic variants, while many harmful mutations disappear into oblivion.

Michael Desai, a biologist at Harvard, tested this idea by staging a competition among yeast. He chose these single-celled fungi for their flexibility when it comes to reproducing. Yeast can either clone themselves or have sex. To clone itself, a yeast cell grows a bud that bulges from its cell wall. It copies its chromosomes and stuffs the new copies into the bud, which can then break off to become a cell of its own.

Sometimes, yeast have sex instead. The strain Desai studied exists in two so-called mating types, known as
a
and α. Each type releases a chemical that lures yeast of the other type. The
a
and α cells approach each other and fuse into one. The merged cell, which now contains a double set of chromosomes, can then multiply into new cells. But if it runs out of food, it responds by carrying out meiosis between its
a
and α chromosomes.

The yeast cell partners its chromosomes together and shuffles DNA. It then separates its chromosomes into two sets, each of which get stored
inside a spore. Those tough-coated spores can drift away, taking their mixed-up genes to a better place where they may be able to grow again.

In his experiment, Desai allowed some of his yeast to have sex every ninety generations. The rest of the yeast could only clone themselves. Desai let the clones and the sexual yeast compete in test tubes for food. Sometimes new mutations arose that made a yeast cell do better than the rest of the population, allowing it to produce more offspring. For a thousand generations, Desai and his colleagues kept track of how each group of yeast fared in the evolutionary race.

The differences between yeast that could have sex and those that couldn't were clear. Sometimes a beneficial mutation would arise in the cloning yeast, letting them reproduce faster than the clones that lacked it. But along with that good mutation, the clones passed down bad mutations. The yeast that Desai allowed to have sex could separate good mutations from bad ones, thanks to meiosis. And when more good mutations emerged, meiosis was able to bring them together in new combinations, to produce even better yeast. At the end of the experiment, the yeast that could have sex had evolved to grow much faster than the clones.