She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (18 page)

Over the next few years, an American researcher named George Jervis confirmed Penrose's hypothesis and worked out the chemistry of the disease.
Normally, an enzyme known as phenylalanine hydroxylase breaks down the body's extra phenylalanine. In people with PKU, the enzyme doesn't work. The body's phenylalanine reaches toxic levels and spreads throughout the body, wreaking havoc.

As the biology of PKU became clearer, Penrose realized that it might not be inevitable, even if it was hereditary. Penrose reasoned that a diet low in phenylalanine might prevent people with PKU from becoming poisoned.

But because phenylalanine is so abundant in food, Penrose found it difficult to draw up a diet for his patients. He restricted the diet of one patient to only fruit, sugar, and olive oil, supplemented with vitamin pills. It lowered his patient's phenylalanine levels for a couple of weeks, but they bounced back up. Seeking help, Penrose contacted Frederick Gowland Hopkins, a Cambridge biochemist who had won the Nobel Prize in 1929 for the discovery of vitamins. When Penrose told Hopkins about PKU, Hopkins declared that a diet for the disorder would cost a thousand pounds a week.

Penrose abandoned a search for a diet, but he continued to study people with PKU. Whenever he visited a new institution, he would sniff the air for a musty odor. If he discovered patients who he suspected of having PKU, he would examine them for other telltale features of the condition, such as fair hair and blue eyes. Then he would order a simple urine test.

In 1939, while on a trip through the United States, Penrose paid a visit to the Vineland Training School. There he met the nineteen-year-old Carol Buck. “
I was informed that this patient was the daughter of a distinguished writer but that, in spite of obtaining all the best opinions in the United States, no cause for the defect had been found,” Penrose later wrote.

Penrose met Carol at the cottage her mother, Pearl, had built for her. “Everything was beautifully appointed,” he recalled. But when Penrose sniffed the air, he detected the familiar mustiness. He noticed Carol's blue eyes and fair hair. He checked her reflexes. “I felt quite certain of the diagnosis and told my hosts what I thought,” Penrose said.

Penrose was dismayed that his hosts didn't know what he was talking about. It had been five years since Følling had published the first account of PKU. Even at an advanced institution like Vineland, however, no one recognized it as a possible cause of retardation. “‘Impossible,' they said. ‘How
can you come here and in a few minutes find something which all our best clinicians have missed?'” Penrose wrote.

The next morning, Penrose tested Carol's urine. He saw “the wonderful green color.” But no one at the school ever told Carol's mother about Penrose's diagnosis.

Penrose, a lifelong pacifist, sat out World War II in Canada. In 1945, he got an invitation back home, to become the next Galton Professor of Eugenics at University College London and director of the Galton Laboratory. The irony of the titles was not lost on him.

Francis Galton, the scientist who had coined the term
eugenics
, had left some of his family fortune to pay for a professor to run a eugenics research lab, gathering data about heredity in the hopes of improving the human race. After Galton's death in 1911, the lab buzzed with research for three decades, until it fell to German bombs. Penrose agreed to rebuild it, but it would not be the same when he was done. He sought to wipe eugenics away. He even changed the name of his position to Galton Professor of Human Genetics—but only after a legal battle that lasted until 1963.

As the new Galton Professor, Penrose was required to give an inaugural lecture. He used the opportunity to let the world know that things had changed, and he used PKU as a case study. The title of his talk was “
Phenylketonuria: A Problem in Eugenics.”

As Penrose drafted his lecture in 1945, the memories of the Holocaust were still horrifically fresh. It had been less than a year since Auschwitz, Dachau, and Bergen-Belsen had been liberated. The Nazis had justified the horrors of their “race hygiene” by pointing to the work of eugenicists. In the postwar years, Penrose now worried that eugenics might survive their defeat. Leading eugenicists in England and other countries were still pushing their agenda. In the United States, sterilization laws justified on the basis of eugenics remained on the books, and people were being regularly robbed of the chance to have children.

In his lecture, Penrose directed his wrath at lingering eugenicists, showing how their calls to manage human reproduction for the betterment of
the species were absurd—“pernicious ideas based upon emotional bias,” as he put it. And Penrose used PKU as a case study for why the eugenics agenda should be thrown out.

By 1946, scientists had studied some five hundred people with PKU, and their family histories clearly demonstrated that the disease was hereditary. In other words, children had to inherit the same version of a gene from both parents. Scientists still didn't know what genes were, but to a eugenicist, Penrose speculated, that wouldn't matter. To get rid of PKU, all that would be required would be to stop people from passing the gene down to future generations.

“This view, however, is incorrect,” Penrose said. “We cannot take the same attitude here that we might with regard to some noxious pest and simply ask to have the offending genes exterminated.”

PKU was a recessive condition, meaning that a child had to inherit two faulty copies of the same gene to develop the diseases. As far as Penrose and other scientists could tell, people with a single copy of the defective gene were healthy—so healthy, in fact, that it was impossible to identify carriers until they had children with PKU. Based on the number of cases he had found, Penrose estimated that 1 percent of people in Great Britain were carriers. (Later research would indicate that the true figure is probably twice that.)

“To eliminate the gene from the racial stock would involve sterilizing 1% of the normal population, if carriers could be identified,” Penrose declared. “Only a lunatic would advocate such a procedure to prevent the occurrence of a handful of harmless imbeciles.”

When Penrose treated people with PKU, their relatives would anxiously ask him how likely it was that they might be carriers. Should they not have children? Penrose worked through the odds. The chances of a sibling of someone with PKU being a carrier is two in three. Penrose estimated that the chances of a prospective mate also being a carrier was one in a hundred. And the chance of a child of two carriers inheriting PKU was one in four. Multiplying all those probabilities together led Penrose to conclude that the chance of a relative of someone with PKU having a child with PKU was only one in six hundred.

“In my opinion,” Penrose said, “this risk is no adequate ground for discouraging the union.”

In a sly aside, Penrose also noted that PKU undermined the Nazi myth of an Aryan race that was superior to races of Jews or blacks. In the United States, Jervis had not found any Jews or blacks with PKU. Instead, many of the people with the disease were Germans and Dutch. “A sterilisation programme to control phenylketonuria confined to the so-called Aryans would hardly have appealed to the recently overthrown government of Germany,” Penrose said.

To finish up his lecture, Penrose predicted that the story of PKU would turn out to be similar for many other diseases. “Many rare recessive disabilities have been identified in man, and doubtless many more lie awaiting detection,” he said. “Not improbably, about two people out of every three are carriers of at least one serious recessive defect.”

Humanity, in other words, was not some genetically uniform stock that could be purged of a few defectives. Penrose saw our species as rich with genetic diversity, and forever falling short of genetic perfection. To eliminate imperfection would demand eliminating humanity itself.

After his attack on eugenics, Penrose went on to build the first large medical genetics program, designed to identify new hereditary disorders. The geneticists under Penrose's leadership in the early 1950s examined patients, ran blood tests, and drew pedigrees. They traced the inheritance of genes, despite still not knowing what genes are. But if they had taken a stroll down Bloomsbury Street to King's College London, they could have watched a woman take X-ray pictures that would soon start to unravel that mystery.

By the 1920s, Thomas Hunt Morgan and his colleagues had persuaded their fellow scientists that genes were physical things, located in chromosomes. Chromosomes were chemical mixtures, including proteins as well as a mysterious molecule called deoxyribonucleic acid, or DNA for short. By the early 1950s, researchers had performed some elegant experiments
with bacteria and viruses that made it clear that DNA, not proteins, was the stuff of genes. When viruses infected bacteria, for example, they only injected DNA; none of their proteins made it into the cells.

In 1950, a thirty-year-old scientist named
Rosalind Franklin arrived at King's College London to study the shape of DNA. She and a graduate student named Raymond Gosling created crystals of DNA, which they bombarded with X-rays. The beams bounced off the crystals and struck photographic film, creating telltale lines, spots, and curves. Other scientists had tried to take pictures of DNA, but no one had created pictures as good as Franklin had. Looking at the pictures, she suspected that DNA was a spiral-shaped molecule—a helix. But Franklin was relentlessly methodical, refusing to indulge in flights of fancy before the hard work of collecting data was done. She kept taking pictures.

Two other scientists, Francis Crick and James Watson, did not want to wait. Up in Cambridge, they were toying with metal rods and clamps, searching for plausible arrangements of DNA. Based on hasty notes Watson had written during a talk by Franklin, he and Crick put together a new model. Franklin and her colleagues from King's paid a visit to Cambridge to inspect it, and she bluntly told Crick and Watson they had gotten the chemistry all wrong.

Franklin went on working on her X-ray photographs and growing increasingly unhappy with King's. The assistant lab chief, Maurice Wilkins, was under the impression that Franklin was hired to work directly for him. She would have none of it, bruising Wilkins's ego and leaving him to grumble to Crick about “our dark lady.” Eventually a truce was struck, with Wilkins and Franklin working separately on DNA. But Wilkins was still Franklin's boss, which meant that he got copies of her photographs. In January 1953, he showed one particularly telling image to Watson. Now Watson could immediately see in those images how DNA was shaped. He and Crick also got hold of a summary of Franklin's unpublished research she wrote up for the Medical Research Council, which guided them further to their solution. Neither bothered to consult Franklin about using her hard-earned pictures. The Cambridge and King's teams then negotiated a plan to
publish a set of papers in
Nature
on April 25, 1953. Crick and Watson unveiled their model in a paper that grabbed most of the attention. Franklin and Gosling published their X-ray data in another paper, which seemed to readers to be a “me-too” effort.

Franklin died of cancer five years later, while Crick, Watson, and Wilkins went on to share the Nobel prize in 1962. In his 1968 book,
The Double Helix
, Watson would cruelly caricature Franklin as a belligerent, badly dressed woman who couldn't appreciate what was in her pictures. That bitter fallout is a shame, because these scientists had together discovered something of exceptional beauty. They had found a molecular structure that could make heredity possible.

DNA, they discovered, is a pair of strands twisted into a double helix. Between the strands, a series of compounds called bases bonded to each other. Over the next thirty years, scientists worked out how this structure allowed DNA to carry genes. Each gene is a stretch of DNA, made up of thousands of bases. Each base can take one of four different forms: adenine, cytosine, guanine, and thymine—A, C, G, T for short. A cell carries out a series of chemical reactions to translate a gene's sequence of bases into a protein. A cell first makes a copy of the gene, creating a single-stranded series of bases called ribonucleic acid, or RNA. That RNA molecule is taken up by a molecular factory called a ribosome, which reads the sequence of RNA and builds a corresponding protein.

The discovery of DNA seemed to reduce heredity to a reliably simple recipe. It came down to turning one DNA molecule into a pair. A cell's molecular machinery pulled apart the two strands of a DNA molecule and then assembled a new strand to accompany each of them. Each base could bond only to one other: A to T, C to G. The cell could thus build two perfect copies of the original DNA—like engendering like, but on an atomic scale.

Sometimes cells make mistakes, however. These errors leave one of the new DNA molecules altered. A single base may change from A to C. A stretch of a hundred bases may be accidentally copied out twice. A thousand bases may be cut out altogether. These are the mutations that scientists like Hugo de Vries and Thomas Hunt Morgan spent years trying to figure
out. Mutations can produce new versions of genes—alleles, as they came to be known. Sometimes alleles work the same as before. But, in cases such as PKU, they fail to work at all.

Later generations of scientists would use this discovery to determine the molecular details of PKU. The enzyme Jervis had discovered, phenylalanine hydroxylase, is encoded by a gene called PAH. In our livers, cells translate the PAH gene into the enzyme, which can then break down phenylalanine. In carriers, such as Pearl and Lossing Buck, one copy of the PAH gene carries a mutation that prevents cells from making the enzyme.

Pearl and Lossing had no idea that anything was wrong in their DNA, because their other copy of the PAH gene lacked the mutation. They could make enough phenylalanine hydroxylase for their metabolism to run properly. But when a child like Carol inherited a faulty copy of the PAH gene from both her parents, she could not make any working enzymes and suffered the consequences.