Garrod's foresight; our hindsight.

Archibald Edward Garrod introduced a paradigm, new for its day, in medicine: Biochemistry is dynamic and different from the static nature of organic chemistry. It led him to think about metabolic pathways and to recognize that variation in Mendelian heredity could explain an 'inborn error of metabolism'. At the time, Garrod had no idea about the nature of a gene. Genes are now well understood, genomes are being described for one organism after another (including H. sapiens) and it is understood that genomes 'speak biochemistry (not phenotype)'. Accordingly, in the era of genomics, biochemistry and physiology become the bases of functional genomics and it is possible to appreciate why 'nothing in biology makes sense without evolution' (and nothing in medicine will make sense without biology). Mendelian, biochemical and molecular genetics together have revealed what lies behind the four canonical inborn errors described by Garrod (albinism, alkaptonuria, cystinuria and pentosuria). Both older and newer ideas in genetics, new tools for applying them, and renewed respect for the clinician-scientist will enhance our understanding of the human biological variation that accounts for variant states of health and overt disease; an 'unsimple' phenotype (phenylketonuria) is used to illustrate in some detail. What can be known and what ought to be done with knowledge about human genetics to benefit individuals, families and communities (society) is both opportunity and challenge.