On the Scent: The Discovery of PKU

Lofenalac, a protein formula for phenylketonuria sufferers, became the first medical food in the United States.

Lofenalac, a protein formula for phenylketonuria sufferers, became the first medical food in the United States. (Mead Johnson & Company)

Help came in the person of L. I. Woolf, a chemist at the Hospital for Sick Children, Great Ormond Street, in London. In the aftermath of World War II, Woolf had spent time working on a milk protein called casein, breaking it down into its amino acids for use as a “predigested food” to treat starving people in Europe. Now at the Hospital for Sick Children he encountered PKU for the first time. In addition to his postwar nutritional experience Woolf knew of a method published in 1943 by German chemists for removing phenylalanine from hydrolyzed casein. He realized that this method, passing the amino acid mixture through acid-washed activated charcoal, could produce a phenylalanine-free formula for PKU. Woolf had had no luck in persuading his hospital’s physicians to test this protein replacement on patients with PKU, but Bickel and Gerrard wanted to try it.

The researchers fed Woolf’s formula to Sheila, along with vegetables, fruit, and gluten-free bread and flour. She ate this low-phenylalanine diet for four weeks, during which time the researchers observed that her musty smell disappeared, the levels of phenylalanine in her plasma and urine fell to normal, and she stopped excreting phenylpyruvic acid. But, like Penrose’s PKU patient two decades before, Sheila’s body began to break down its own proteins, creating phenylalanine in the process. Bickel and Gerrard realized that they needed to find the right balance of the amino acid: one that allowed bodily growth but did not allow excess accumulation in the blood. They began to include a daily intake of milk to provide the small amount of phenylalanine needed. After several months on this diet Sheila crawled, stood, and climbed on chairs. Bickel reported that her “eyes became brighter, her hair grew darker, and she no longer banged her head or cried continuously.”

One Disease, Many Lessons

Sheila wasn’t cured, but from these modest beginnings researchers would learn that if administered from birth, this dietary prescription would prevent mental disability. Using work on PKU as a model, support for research in the prevention and treatment of mental disability flourished. Screening programs were gradually established to identify at birth children with PKU, and it became the first of many genetic conditions for which infant screening would eventually become mandatory in the United States.

In the world of science PKU research contributed to biochemical concepts like the existence of metabolic “pathways” and spurred further research on the relationship between genes and proteins. Genetic diseases also took on new meaning; they were no longer seen as inalterable. A new branch of medicine, medical genetics, would concern itself with diagnosis, prevention, and treatment of inherited disorders like PKU.

The protein formula for PKU became the first dietary therapy for a metabolic disease—and the first medical food—becoming a model for the treatment of many other metabolic disorders. Subsequent generations of pediatricians and nutritionists would work on ways to make the highly restrictive diet more tolerable for long-term use and the unpalatable protein formula more acceptable. But crucial early advances in disease discovery and dietary therapy came from chemists, without whose scientific sleuthing and creativity many more children would have grown up needlessly suffering from this preventable form of mental disability.

Donna Messner, formerly a Gordon Cain Fellow at CHF, is a research director at the Center for Medical Technology Policy in Baltimore.