On the Scent: The Discovery of PKU

The Hospital for Sick Children, now known as the Great Ormond Street Hospital, in 1910. Chemist L. I. Woolf, working at the hospital in the early 1950s, developed a phenylalanine-free formula for children with phenylketonuria.

The Hospital for Sick Children, now known as the Great Ormond Street Hospital, in 1910. Chemist L. I. Woolf, working at the hospital in the early 1950s, developed a phenylalanine-free formula for children with phenylketonuria. (Great Ormond Street Hospital for Children NHS Trust)

Creating an appropriate meal plan, however, was not simple. As a basic building block of plant and animal proteins, phenylalanine is found in almost all foods. Only water, refined sugar, pure starch, and pure oils are completely free of it. Penrose fed his sole PKU patient—1 out of 500 institutionalized patients he screened with the ferric chloride test—nothing but fruit, sugar, olive oil, and vitamins. Initially, success beckoned when phenylpyruvic acid disappeared from the patient’s urine. Penrose rejoiced, thinking that he saw some improvement in his patient’s mental state. But Penrose’s dietary formula was nutritionally inadequate. After about two weeks phenylpyruvic acid appeared once more in the patient’s urine: lacking dietary protein, the starving patient’s body had begun to metabolize its own protein. The experiment had to be discontinued.

What was needed, Penrose decided, was a protein-replacement formula lacking phenylalanine. He posed the question to Frederick Gowland Hopkins, a Nobel-laureate biochemist at Cambridge University. Hopkins replied that it was possible to create a synthetic phenylalanine-free diet, but the cost would be approximately £1,000 per week, more than many middle-class families earned in a year. Penrose dropped the question.

“She Awaited Me Every Morning"

Ultimately, protein replacement would wait until the end of World War II. During the war years pioneers of PKU research like Følling and George Jervis worked on genetic and biochemical questions rather than therapeutic ones. They worked out the pattern of inheritance, elucidated the metabolic pathway of PKU and where it went awry, created and improved methods of chemical analysis of blood and urine for diagnosis, and looked for biochemical means to identify genetic carriers. Over this period Penrose became convinced that the metabolic anomaly, while always present, did not cause the mental defects seen in PKU patients. Dietary therapy was therefore not worth pursuing in his opinion, and he, too, turned to questions of PKU genetics and carrier detection.

Meanwhile, the two men who would publish the first successful trial of PKU dietary therapy, Horst Bickel and John Gerrard, were serving as medical officers on opposite sides of World War II—Gerrard with the British Army and Bickel with the German Navy. Bickel’s first introduction to PKU took place after the war, while working under famed pediatrician Guido Fanconi in Zurich. PKU’s rarity, and the significant distractions of war, meant that many doctors still knew nothing about the condition. Early one morning in 1949 Fanconi read a report on PKU and during morning rounds surprised Bickel by asking why their mentally deficient patients had not been screened with the ferric chloride test. Bickel had to admit he had never heard of PKU. They immediately began testing their patients for phenylpyruvic acid. After months of screening they found none with the characteristic abnormality, and the ferric chloride bottles disappeared from the shelves. But Bickel would now be watching for it.

Bickel got his opportunity to study PKU firsthand later that year as a new research fellow at the Children’s Hospital in Birmingham, England. Like Zurich, Birmingham turned out to have an excellent pediatrics center. Wanting to impress his new colleague, Gerrard, Bickel asked why they were not screening for PKU in Birmingham. Caught unaware, Gerrard promptly introduced the ferric chloride test to the pediatric ward. They got a positive result on the third child tested, a two-year-old girl named Sheila.

Sheila could not stand, walk, or talk. She showed no interest in food or in the surrounding world and spent her time groaning, crying, and banging her head. She also had the smell, described by Bickel as mouselike. As he later remembered it, Sheila’s mother “was not at all impressed when I showed her proudly my beautiful paper chromatogram with the very strong phenylalanine spot in the urine of her daughter.” The mother wanted more. “She awaited me every morning in front of the laboratory asking me impatiently when I would at last find a way to help Sheila.” The distraught mother would not accept the lack of any known treatment for PKU.