She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (20 page)

PKU is rare, but its story has been told many more times than far more common disorders. It has a powerful moral, but the moral depends on who tells the story.

For some, the story of PKU embodies the triumph of genetics. Mendel's early followers had been mocked by those who couldn't believe that
experiments on peas could account for why like engenders like. Mendel's work opened the way to the discovery of genes, and now scientists were finding precise effects of genes on health. Genetics not only explained how PKU arose but allowed doctors to tame it.

In the mid-1980s, a gigantic project took shape that would allow future generations of researchers to quickly find the mutations behind any hereditary disease. Rather than examine the DNA of a single gene, they wanted to sequence every bit of DNA in all forty-six human chromosomes—the entire human genome. “
The possession of a genetic map and the DNA sequence of a human being will transform medicine,” promised the Nobel Prize–winning biologist Walter Gilbert.

To show how this transformation would happen, Francis Collins, the director of the National Center for Human Genome Research at the time, offered the PKU story. Scientists found the inherited flaw and then devised a rational treatment for it. “
If you simply remove foods with phenylalanine from the child's diet, he or she will live a normal and healthy life,” Collins declared. Sequencing the entire human genome would make it possible for scientists to pinpoint mutations that caused thousands of other diseases, and potentially open the way to treatments for them as well. “
PKU is the example where the paradigm was proven,” Collins said.

To other scientists, however, PKU demonstrated the
deep flaws in such gene-centered research. From the earliest days of genetics, researchers recognized that it was a fallacy to talk about a gene being “for” a trait or a disease. Genes don't have so much power. They exist in an environment, and their effects may be very different in different surroundings. Thomas Hunt Morgan, for example, had observed how a mutation in his flies made them sprout extra legs—but only in cold temperatures.

Once researchers discovered a diet for PKU, it became an even better illustration of the malleability of genes. In 1972, the British biologist Steven Rose declared that PKU demonstrated how pointless it was to talk about something like a “high I.Q.” gene. A variant of the PAH gene could lead to low intelligence test scores if a child was left untreated. Or the same child could score in the normal range if given the right diet.

“Hence the environment has ‘triumphed' over the genetic deficiency of
the individual,” Rose said. “To talk of ‘high I.Q. genes,' or to try to disentangle the genetic programme from the environment in which it is expressed is
both disingenuous and misleading.”

No matter which moral people drew from PKU, their stories had one thing in common: Science had triumphed utterly over the disease. In 1995, the journalist Robert Wright told his own PKU story as a way to attack the idea that our intelligence is fixed by the genes we inherit. In the absence of any treatment, Wright observed, PKU mutations will reliably cause children to have devastating intellectual disabilities. “
It turns out,” he cheerfully wrote, “that if you put all infants on a diet low in the amino acid phenylalanine, the disease disappears.”

It should come as no surprise that neither Wright, Rose, nor Collins themselves had PKU, or ever had to care for a child with it. Even with the most sophisticated diets and supplements medicine can offer, PKU never disappears. Starting in the 1950s, children with PKU began to escape the devastation of brain damage, but only if they stuck relentlessly to the dreary regimen of foul-tasting concoctions. Over the years, the PKU foods became tastier, but
children growing up on a low-phenylalanine diet still had to watch their friends gorge themselves on pizza and ice cream, sometimes ending up feeling isolated from society.

When the first generation of children with PKU grew up, doctors allowed them as adults to switch to a regular diet. They soon suffered a new round of symptoms as the phenylalanine surged back into their bodies. Now people with PKU are urged to stay on the diet for their entire lives. It's often a struggle to get the right balance of nutrients each day while avoiding even the slightest trace of phenylalanine. For now, the experience of the disease is a tense negotiation between heredity and the world in which it unfolds.

I
N 1901
, W
ILLIAM
B
ATESON
sent an urgent report to the Royal Society on “the facts of heredity.” Those facts, Bateson explained, had just been thrown into sharp relief with the rediscovered, newly appreciated work of Gregor Mendel. Bateson and other scientists were confirming the patterns that Mendel had observed. Those patterns were so trustworthy and so profound, Bateson said, that they deserved
one of the loftiest titles in science: “Mendel's Law.”

A scientific law predicts some aspect of the universe, usually with a short, sweet equation. Isaac Newton discovered the laws of motion that came to bear his name. Robert Boyle is memorialized with Boyle's law, which predicts the pressure of a gas from its volume. Mendel's work likewise gave heredity a numerical clarity. Parents have a fifty-fifty chance of passing down either of their two copies of a given gene. Mendel's Law ensures a three-to-one ratio between dominant and recessive traits. It doesn't matter if the trait is a wrinkled coat on a pea or PKU in humans. The numbers stay the same.

Mendel's discovery was indeed one of the most important in the history of science. But the patterns he saw aren't really a law. Newton's laws of motion are as true in a distant galaxy as they are here on Earth. They were as true thirteen billion years ago in the universe's infancy as they are true today. Mendel's Law has far narrower boundaries. It is only relevant
to places where life exists—in other words, as far as we know, only on Earth. Even when life first emerged some four billion years ago as single-celled microbes, Mendel's Law did not yet exist. Microbes are not like pea plants or people, and, as a result, they don't have dominant or recessive characters.

Mendel's Law would have to wait for a couple billion years or so for a new lineage of life to emerge—one that would give rise to plants, fungi, and animals like us. Mendel's Law, in other words, is less like Boyle's law than it is like our spleens or our retinas: It emerged as life evolved. Earth is actually home to many different kinds of heredity, each arising through a combination of natural selection and lucky flukes.

Life likely emerged as its early, simple chemistry got complicated. Amino acids, bases, and other molecular building blocks were present on the early Earth. Short chains of these compounds may have concentrated together, perhaps trapped in oily films on the seafloor or encased in cell-like bubbles. Crowded into these cramped spaces, their chemistry may have accelerated, pushing them over the border dividing nonlife from life.

It's likely that the first life-forms were profoundly unlike life today. Today, animals, plants, and bacteria—all cellular life, in fact—encode their genetic information in DNA. But DNA would be an unlikely candidate for the first hereditary molecule, because it's both helpless and demanding.

In order for a cell to read the information stored in its DNA, it needs to deploy many proteins and RNA molecules at once. When a cell divides, it needs another army of molecules to make a second copy of its DNA. The first life on Earth must have had a simpler beginning.

One possibility is that life started out without DNA or proteins. Instead, it relied solely on RNA molecules. A primordial cell might have contained a few different types of short RNA molecules that helped each other replicate.

Experiments with RNA molecules suggest how this would have unfolded. One RNA molecule might grab bases and weld them together, using
a second RNA molecule as a template. That second molecule might do the same for a third. If the last RNA gene in the line turned around and helped the first one, the entire circle could feed back on itself. These primordial RNA molecules would have had a twofold form of heredity: They inherited the genetic information from their ancestor, and also the same twisted shape that allowed them to help build new molecules.

This first heredity would have also been sloppy. Sometimes a new RNA molecule would turn out to be slightly different from its template. This error would often be fatal, making it impossible for the RNA molecules to copy themselves any further. But in a few cases, it would actually improve the chemistry. Faster-replicating cells would have outcompeted their slower rivals.

RNA-based life, living in an ocean or a tide pool, may well have lived amidst loose amino acids. As their RNA molecules evolved into more sophisticated forms, some of them may have begun connecting amino acids into short chains, called peptides. These peptides may have been able to do jobs of their own inside of cells. And with time the peptides may have grown into large, complex proteins.

It's also possible that some RNA-based life evolved to make DNA as well. The double-stranded DNA molecules would have proven more stable than single-stranded RNA, and also less prone to damage. When the early DNA-based organisms copied their genes, they made fewer mistakes. Their newfound accuracy could have opened the way for more complexity in life, since they had a lower risk of ending up with a life-stopping mutation.

Once DNA-based life took hold, it overran the planet. By about 3.5 billion years ago, these single-celled microbes had diverged into two great evolutionary branches, known as bacteria and archaea. They're impossible to tell apart under a microscope, but they have some important differences in their biochemistry. Bacteria and archaea use different molecules to build their cell walls, for example, and use different molecules to read their genes.

But both lineages of microbes proved astonishingly versatile, adapting
to just about every bit of Earth where they could get water and energy. Microbes adapted to grow on the sea surface, catching sunlight; on the seafloor, where they ate sulfur and iron; deep in the Earth, where they harnessed the energy of radioactivity. Scientists estimate that Earth is home to about a million billion billion microbes, which
may belong to a trillion different species.

But none of them follow Mendel's Law.

A typical microbe—say, the
Escherichia coli
dwelling in your gut—has only a single chromosome: a long circle of DNA. Arrayed along that loop are several thousand genes. If
E. coli
can draw in some glucose or another sugar from your breakfast, it can grow until it's ready to replicate. It elegantly unwinds the two strands of the circle. Onto each strand, the cell builds a second one, creating two nearly identical chromosomes. The cell then cuts itself in two. It drags its two chromosomes to opposite sides and then builds a wall down its middle. Each of the new microbes is a near-perfect copy of its ancestor, inheriting a chromosome as well as about half of the molecules in the ancestor cell.

We humans can have the opportunity to get to know our parents. For microbes, that chance never comes, because their ancestors vanish—or, to put it another way, split into their daughter cells. Mendel's Law describes how hereditary factors from two parents combine to produce an organism. To a microbe, it's meaningless.

The heredity of microbes is different from ours in another important way: They can inherit genes along many different routes. They can gain genes as we do, as copies of the genes of their direct ancestors. This process is known as vertical inheritance. But they can also inherit genes from unrelated microbes, through
horizontal inheritance.

Horizontal inheritance helped scientists discover what genes were made of. In the 1920s, researchers discovered that if they killed deadly strains of bacteria and mixed them with harmless ones, the harmless strains turned deadly. What's more, when the transformed bacteria divided, their descendants inherited their deadliness. Later, a microbiologist named Oswald Avery and his colleagues isolated the different kinds of
molecules inside bacteria to figure out which was the mysterious “transforming principle.” Through many rounds of experiments, they came down in favor of DNA.

It turned out that the bacteria Avery studied were being transformed by taking up loose DNA and incorporating some of it into their own chromosome. They gained genes that they could use to make their hosts sick. But later research has revealed that horizontal inheritance can also take place by other means. Along with their main chromosomes, for example, microbes often carry ringlets of DNA, called plasmids, with genes of their own. Microbes will sometimes build tubes that they stick into other microbes, pumping in their plasmids. The plasmid may then float in its new host, or it may paste itself into the chromosome.

Horizontal inheritance may seem bizarre, but it happens all around us. It even happens inside us. An experiment carried out in 2004 by a team of Danish scientists showed how a species called
Enterococcus faecium
horizontally inherits DNA within our own bodies. Over the past few thousand years, the species has evolved into strains that colonize the human gut and skin, and others that prefer living in animals. Most strains of
E. faecium
are harmless, but some can cause potentially fatal infections in the blood and bladder.

The standard treatment for an
E. faecium
infection is a dose of antibiotics. There was a time when that treatment always got the job done. But by the early 2000s,
E. faecium
had evolved into a medical nightmare. More and more often, doctors found that the bacteria carried genes that allowed them to resist drugs. When a resistant strain takes hold in a patient, the bacteria multiply without check, passing down their resistance genes vertically to their descendants.

In 2004, half a dozen brave souls agreed to drink two cups of milk. In the first cup were a billion
Enterococcus faecium.
They belonged to a strain isolated from humans and could be easily killed by an antibiotic called vancomycin. Three hours later, the six volunteers drank a second cup containing another billion
E. faecium
that came from chickens, carrying a gene that made them resistant to vancomycin.

This milk drinking was part of an experiment at Denmark's National Center for Antimicrobials and Infection Control. Over the following month, the Danish scientists collected stool samples from the six subjects and surveyed them for the two strains of
E. faecium
. The chicken strain quickly became rare and then disappeared after a few days. The human strain, better adapted to its new home, lasted longer.

But in three of the six subjects, the scientists found that the human strain had changed. Now each generation of bacteria passed down a new gene they didn't have at the beginning of the experiment. They inherited the chicken strain's gene for vancomycin resistance.

Microbes can even inherit genes horizontally from their greatest enemies: viruses. Viruses—protein shells containing genes—have a form of heredity distinct from that of cellular life. A virus does not reproduce by copying its own genes and dividing in two. Instead, it invades a host cell. A virus that attacks bacteria—known as a bacteriophage—typically lands on the cell wall of a host and injects its DNA inside, like shooting a piece of spaghetti out of a syringe. Bacteria have several ways of recognizing this DNA and destroying it. But none of them are foolproof. If the virus's genes survive long enough, they commandeer the cell. The cell makes proteins from some of the virus's genes, which then drive the cell to make new viruses, complete with new copies of the original virus's genes.

When it comes to viruses, heredity is almost an abstraction. They have no material bond to their ancestors, since all the atoms in a new virus come from the host cell where it formed. For viruses, heredity is an invisible thread of information joining one virus to its progeny.

As viral genes get packaged into new viruses, sometimes things go awry. A gene from their microbial host may get swept up inside a viral shell. The new viruses that leave the microbe carry that host gene with their own, and they may later inject it into a new host. In some cases, the microbial gene may end up in its new host's chromosome. Viruses can thus act like accidental ferries, transporting microbial genes from one organism to another—sometimes even moving them between species.

As scientists examine microbes more closely, they have discovered still more strange forms of heredity. One particulary weird kind of microbial inheritance came to light in the early 2000s as scientists were investigating how bacteria fight against viruses.

It turns out that when many species of microbes are exposed to a new virus, they can learn how to stage a swift, precise attack against it. Vertebrate animals like ourselves have the same capacity. When we get attacked by influenza or a cold virus, our immune system can build antibodies that will wipe these strains out as soon as they try to attack us again. Bacteria can't use an immune system made up of billions of cells—each microbe is one cell that has to fend for itself. But they manage this feat all on their own, using
a system of molecules called CRISPR-Cas.

When viruses infect bacteria, they typically land on their victim and inject a string of DNA inside. Many microbes can chop off the tip of this incoming DNA and insert it into a stretch of its own DNA, called a CRISPR region. (
CRISPR
is short for
clustered regularly interspaced short palindromic repeats
.)

If microbes manage to survive this initial attack from a virus, they will be equipped to resist the next one. They prepare for a subsequent infection by building a short RNA molecule that matches the bit of viral DNA they grabbed from the first attack. A protein called a Cas enzyme folds itself around the RNA molecule, and the two together float off through the cell.

If the same strain of virus tries to inject its DNA into the microbe, the CRISPR-Cas system latches onto the incoming genes. The Cas enzyme pulls the viral DNA strands apart and chops them into pieces. Shredded into harmless debris, the virus cannot take over the microbe.

As a microbe battles virus after virus, it may store away samples from a dozen of its enemies. And when it divides, it passes down this accumulated knowledge to its descendants. When the microbe copies its chromosome, it copies its CRISPR region along with the rest of its DNA. August Weismann's
germ line barrier may prevent the experiences of animals from altering their germ cells. But for bacteria, no such barrier exists. In a sense, soma and germ are bound up in a single cell.