Dr John Hoskins obituary
14 May 1940 – 8 May 2021
For many years John was an independent consultant on aspects of fibre toxicity originating from his later years of employment at the Medical Research Council (MRC).
However, in the first period of his career after obtaining a PhD in the Australian National University in Canberra, John was a member of the MRC Unit of Metabolic Studies in Psychiatry in the University of Sheffield and then the Toxicology Unit in Carshalton and Leicester.
In these years he studied aspects of amino acid metabolism including the possibility of treating phenylketonuria (PKU), a classic genetic disorder. PKU is caused by a deficiency in phenylalanine hydroxylase (PAH), resulting in neurotoxic levels of excess phenylalanine due to its lack of conversion to tyrosine.
At the time a plant enzyme phenyl ammonia lyase (PAL) was known to convert phenylalanine to cinnamic acid. So it was hoped that if a similar enzyme was administered orally to patients it would survive digestive proteolysis long enough to reduce the levels of the amino acid from food protein in the gut and therefore in subsequent plasma levels.
To explore the potential in patients, John and his colleagues in the then Public Health Laboratory Services and an adjacent NHS children’s hospital, encapsulated yeast PAL in semipermeable gelatin for oral administration. Firstly, to test its safety and impact in normal individuals, volunteers in the MRC Toxicology Unit (of which I was one) consumed VERY large steak dinners (chips were optional) followed by PAL capsules.
Blood samples and questionnaires showed no apparent adverse effects. Following on from this, multiple administration of PAL to a PKU patient showed a significant decrease in plasma phenylalanine subsequently demonstrating it as the basis for a potential therapy regimen [1].
Over the next three decades several academic and company research groups, particularly in Canada and the USA, methodically tackled the many practical problems remaining after the initial proof of concept that PAL could be an enzyme substitution therapy for PKU. Adequate supply of PAL enzymes was resolved by recombinant techniques and mouse models of PKU were developed for careful experimental in vivo studies.
Sustained intraperitoneal use caused immune responses and it was still difficult to prevent significant digestive loss if given orally. Eventually, crystal structures of PAH and PAL enzymes enabled structure-based engineering and mutants to attach polyethylene glycol molecules to stabilize and protect modified PAL enzymes while maximising activity and minimising immunogenicity following parenteral administration.
After clinical trials the final product was authorised by the FDA in 2018, not only lowering plasma phenylalanine levels after subcutaneous injection but long term improving clinical assessments of neurological performance [2]. So far, an orally active form is not available for patients.
In a 2018 review paper, major collaborators described in detail this story and acknowledged the role John had played and emphasized the importance of academic-industry collaborations [3]. In these times of generation of huge amounts of research data it’s nice to know not all old work is reported as new!
Dr John Hoskins actively promoted a wider public understanding of the benefits and risks associated with use of chemicals for over 20 years, in a voluntary capacity on behalf of the Royal Society of Chemistry.
John’s ability to communicate and explain highly complex chemical issues, helped to inform decision-makers, the media and the wider public about the important contribution of chemical sciences to human wellbeing, improving environmental health, innovation and sustainable economic growth.
He also provided expert advice to UK and EU Government bodies responsible for developing chemicals policy and environment, health and safety legislation. John was a specialist adviser to House of Commons Select Committee on the Environment.
He was a long-standing committee member of the RSC Toxicology Group, fulfilling various roles within the committee, and was an active member of the group since its inception in 1987.
[1] Hoskins JA, Jack G, Wade HE, Peiris RJ, Wright EC, Starr DJ, Stern J (1980) Enzymatic control of phenylalanine intake in phenylketonuria. Lancet 1(now vol 395), 392-394
[2} https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pku-rare-and-serious-genetic-disease
[3] Levy HL, Sarkissian CN, Scriver CR (2018) Phenylalanine ammonia lyase (PAL): From discovery to enzyme substitution therapy for phenylketonuria. Mol Genet Metab 124, 223-229
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