The PKU Paradox: A Short History of a Genetic Disease

Chapter 3. Testing and Treating Newborns, 1950–1962

CHAPTER THREE Testing and Treating Newborns, 1950–1962 F F F By the 1950s, scientific medicine offered hope that the medical conditions causing mental retardation could be prevented or cured. The transformation of PKU from an obscure metabolic cause of MR to a new paradigm for the treatment of a genetic condition to prevent MR, however, required a series of conceptual , laboratory, clinical, and practical steps. Scientists and clinicians needed to agree that high levels of phenylalanine were the problem; they needed to create an affordable infant formula that controlled the intake of phenylalanine but did not exclude other essential nutrients; they needed to demonstrate that such a diet, if started early enough, would change the clinical course of PKU; and finally, they needed to devise a simple and inexpensive screening test to identify the very few infants among thousands of births who might benefit from a special diet. Although Robert Guthrie is most often associated with the success of early treatment of PKU, accomplishing each of these steps required contributions from researchers across the globe. INITIAL RESISTANCE In the 1930s, several experiments that treated children with PKU by manipulating diet had come to naught. In Britain, Lionel Pen35 rose’s strategy of excluding protein foods from the diet resulted in severe malnutrition, and an alternative strategy of creating a synthetic mixture of pure amino acids was deemed prohibitively expensive. In the United States, George Jervis and Richard Block had proposed removing excess phenylalanine from natural protein through a charcoal-filtering process, but the work was not funded and the idea soon faded from view. It would be a decade before such experiments reappeared, and the idea of treating PKU with a special diet was greeted with skepticism from an unexpected quarter: Lionel Penrose. By the late 1940s, Penrose seemed to have lost hope in a nutritional therapy for PKU. He was surely discouraged by the failure of his own and others’ efforts to produce a workable diet. But he had apparently also lost confidence in the notion that the metabolic and cognitive defects in phenylketonuria were causally related—and hence in the strategy of reducing dietary phenylalanine to mitigate symptoms of the disease. Such a claim is likely to come as a surprise to anyone familiar with the literature on Penrose and PKU, and especially his celebrated 1946 inaugural address at University College London, After all, the most oft-cited sentence in his inaugural address is, surely, “There may be methods of alleviating the condition, even though it is inborn, in a manner analogous to the way in which a child with club-foot may be helped to walk, or a child with congenital cataract enabled to see.”1 Given Penrose’s own experiments with low-phenylalanine (low-phe) diets, the common assumption that he had nutritional therapy in mind when penning that passage is understandable. But that assumption overlooks the fact that the address includes no allusions to diet. The (failed) administration of massive doses of thiamine is the only specific treatment mentioned, and this is immediately followed by a warning that “consideration of the associated abnormalities, such as small size of the head, might tend to make us cautious about expecting anything like a cure.”2 Similarly, the first edition of The Biology of Mental Defect, published in 1949, discusses PKU in de36 The PKU Paradox Testing and Treating Newborns, 1950–1962 37 tail but includes no mention of Penrose’s own experiments with or prospects for dietary therapy.3 In his writings of the late 1940s and early 1950s, Penrose consistently expressed uncertainty about the causal connection between the biochemical and mental abnormalities in PKU.4 Moreover, members of both major British groups that were working in the postwar period to develop a dietary intervention recall that Penrose was actively skeptical of such efforts. Thus, biochemist Louis I. Woolf writes that “Penrose, the leading British expert on PKU and the genetics of mental retardation, held that a single gene caused both the mental retardation and the abnormal chemistry as two independent effects.”5 John Gerrard, a member of the first group to successfully prepare and administer a low-phe formula, similarly recalls that “at a meeting in Oxford, at which Penrose was present, the great man scoffed at the suggestion that modifying the diet could have any influence on the child’s behavior—he was so sure that the...