Abstract
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.
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REFERENCES
Adams MD,Celniker SE,Holt RA, et al (2000) The genome sequence of Drosophila melanogaster. Science 287: 2185–2195.
Anikster Y,Nyhan WL,Gahl WA (1998) NTBC and alkaptonuria. Am J Hum Genet 63: 921–926.
Applegarth DA,Toone JR,Lowry RB (2000) Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics 105(10): 1–6.
Beadle GW (1964) Genes and chemical reactions in Neurospora. Nobel Lectures; Physiology and Medicine 1942–1962. Amsterdam: 587–599.
Bearn AG (1993) Archibald Garrod and the Individuality of Man. Oxford: Clarendon Press.
Brown MS,Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47.
Calonge MJ,Gasparini P,Chillaron, J, et al (1994) Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nature Genetics 6: 420–425.
Carlson M (2000) The awesome power of yeast biochemical genetics. TIG 16: 49–51.
Carr G (2000) Survey: the human genome: The Economist (July 1) 1–16.
Carter R (1988) The Tao andMotherGoose:Myth and Meaning inNursery Rhymes. Wheaton, IL: The Theosophical Publishing House.
Cavalli-Sforza, Menozzi P,Piazza A (1994) The History and Geography of Human Genes. Princeton. Princeton University Press.
Chervitz SAAL,Sherlock G,Ball CA, et al (1998) Comparison of the complete protein sets of worm and yeast: orthology and divergence. Science 282: 2022–2028.
Childs B (1999) Genetic Medicine. A Logic of Disease, Baltimore, MD: The Johns Hopkins University Press.
Corbellini G (1994) Individuality and disease in Garrod's theory of medicine. Nuncius Annali Di Storia Della Scienza (Firenze) Anno IX, fasc. 2809–2817.
Crow JF (2000) Sewall Wright and physiological genetics. In Crow JF,Dove WF, eds. Perspective in Genetics. Madison, WI: University of Wisconsin Press, 3–4.
Dawkins R (1995) River out of Eden. A Darwinian View of Life. London: Oxford.
Denny P,Justice MJ (2000) Mouse as the measure of man? TIG 16: 283–287.
Dent CE (1947) Detection of amino acids in urine and other £uids. Lancet ii: 637–639.
Dent CE,Rose GA (1951) Amino acid metabolism in cystinuria. Q J Med 79: 205–220.
Dipple KM,McCabe ERB (2000) Phenotypes of patients with śimple’ Mendelian disorders are complex traits: thresholds, modi¢ers, and systems dynamics. Am J Hum Genet 66: 1729–1735.
Dobzhansky Th (1973) ';Nothing in biology makes sense except in the light of evolution'. Am Biol Teach 35: 125–129.
Erlandsen H,Stevens RC (1999) The structural basis of phenylketonuria. Mol Genet Metab 68: 103–125.
Erlandsen H,Stevens RC (2001) A structural hypothesis for BH4 responsiveness in patients with mild forms of phenylketonuria. J Inhert Metab Dis 24: 213–230.
Fan J-Q,Ishii S,Asano N,Suzuki Y (1999) Accelerated transport and maturation of lysosomal a-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nature Medicine 5: 112–115.
Feliubadalo L,Font M,Purroy J, et al (1999) Non-type 1 cystinuria caused by mutations in SLC7A9, encoding a subunit (bo, AT) of rBAT. Nature Genetics 23: 52–57.
Fisher RA (1928) The possible modi¢cation of wild type to recurrent mutations. Am Nat 62: 115–126.
Folling I (1994) The discovery of phenylketonuria. Acta Paediatr Suppl 407: 4–10.
Garrod AE (1902) The incidence of alkaptonuria. A study in chemical individuality. Lancet ii: 1616–1620.
Garrod AE (1909) Inborn Errors of Metabolism. Oxford: Oxford University Press.
Garrod AE (1927) The Huxley Lecture on diathesis. Lancet ii: 1113–1118.
Garrod AE (1931) The Inborn Factors in Disease: An Essay. Oxford: Clarendon Press.
Go¡eau A,Barrell BG,Bussey H, et al (1996) Life with 6000 genes. Science 274: 546–567.
Gregersen N,Bross P,Jorgensen MM,Corydon TJ,Andresen BS (2000) Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders. J Inher Metab Dis 23: 441–447.
Gregersen N,Bross P,Andreson BS et al (2001) The role of chaperone-assisted folding and quality control in inborn errors of metabolism. Protein folding J Inherit Metab Dis 24: 189–212.
Harris H,Mittwoch U,Robson EB,Warren FL (1955) Phenotypes and genotypes in cystinuria. Ann Hum Genet 20: 57–91.
Hartl DL (2000). Evolving theories of enzyme evolution. In: Crow JF,Dove WF, eds. Perspectives on Genetics. Madison, WI: University of Wisconsin Press, 97–102.
Hiatt HH (2001) Pentosuria. In Scriver CR,Beaudet AL,Sly WS,Valle D, assoc. eds; Childs B,Kinzler K,Vogelstein B (eds). The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw Hill, 1589–1600.
Jimenez-Sanchez G,Childs B,Valle D (2001) The effect of Mendelian disease on human health. In Scriver CR,Beaudet AL,Sly WS,Valle D, assoc. eds; Childs B,Kinzler K,Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw Hill, 167–174.
Jonsen AR,Durfy SJ,Burke W,Motulsky AG (1996) The advent of the ‘unpatients'. Nature Medicine 2: 622–624.
Kacser H,Burns JA (1981) The molecular basis of dominance. Genetics 97: 639–666.
Kaufman S (1989) An evaluation of the possible neurotoxicity of metabolites of phenylalanine. J Pediatr 114: 895–900.
Keightley PD (2000) A metabolic basis for dominance and recessivity. In Crow JF,Dove WF, eds. Perspectives on Genetics. Madison, WI: University of Wisconsin Press, 520–524.
Kennedy D (2000) Science and secrecy. Science 289: 724.
Kidd JR,Pakstis AJ,Zhao H, et al (2000) Haplotypes and linkage equilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of population. Am J Hum Genet 66: 1882–1899.
King RA,Hearing VJ,Creel DJ,Oetting WS (2001) Albinism. In Scriver CR,Beaudet AL,Sly WS,Valle D assoc. eds; Childs B,Kinzler K,Vogelstein B, eds. The Metabolic and Mol-ecular Bases of Inherited Disease, 8th edn. New York: McGraw Hill, 5587–5627.
Kornberg TB,Krasnow MA (2000) The Drosophila genome sequence: implications for biology and medicine. Science 287: 2218–2220.
La Du B (1998) Invited editorial: Are we ready to try to cure alkaptonuria? Am J Hum Genet 62: 765–767.
La Du BN (2001) Alkaptonuria. In Scriver CR,Beaudet AL,Sly WS,Valle D, assoc. eds; Childs B,Kinzler K,Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw Hill, 2109–2124.
La Du BN,Zannoni VG,Laster L,Seegmiller JE (1958) The nature of the defect in tryosine metabolism in alcaptonuria. J Biol Chem 230: 251–260.
Lander ES,Weinberg RA (2000) Genomics: journey to the center of biology. Science 287: 1777–1782.
Levy H (1998) Newborn screening by tandem mass spectrometry: a new era. Clin Chem 44: 2401–2402.
Mayr E (1982) TheGrowth of Biological Thought. Cambridge,MA: Harvard University Press.
Moats RA,Scadeng M,Nelson MD Jr (2000) MR Imaging and spectroscopy in PKU. Ment Retard Dev Disabil Res Rev 5: 132–135.
Moller HE,Weglage J,Wiedermann D,Ullrich K (1999) Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria. J Cereb Blood Flow Metab 18: 1184–1191.
Morello J-P,Salahpour A,Lapierrière A, et al (2000) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105: 887–895.
Morrison P,Morrison P, and the office of Charles and Ray Eames (1982) Powers of Ten. About the Relative Size of Things in the Universe. New York. W. H. Freeman.
Olby R (1974) The Path to the Double Helix. Seattle, WA: University of Washington Press.
Palacin M,Goodyer P,Nunes V,Gasparini P (2001) Cystinuria. In Scriver CR,Beaudet AL,Sly WS,Valle D, assoc. eds; Childs B,Kinzler K,Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease 8th edn. New York: McGraw Hill, 4909–4932.
Pardridge WM (1998) Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 23: 635–644.
Pascal B (1909) Penseës. 5 edn. iii: 206. Brunschvicg L. ed.
Penrose LS (1998) Phenylketonuria. A problem in eugenics. (Inaugural lecture delivered at University College on21 January 1946 and reprinted with permission from The Lancet June 29 1946, pp. 949–953). Ann Hum Genet 62: 193–202.
Plasterk RHA (1999) Hershey heaven and Caenorhabditis elegans. Nature Genetics 21: 63–64.
Ridley M (1991) Survey of science: the edge of ignorance. The Economists 1–22.
Rodriguez JM,Timm DE,Titus GP, et al (2000) Structural and functional analysis of mutations in alkaptonuria. Hum Mol Genet 15: 2341–2350.
Sarkissian CN,Scriver CR,Mamer OA (2000) Measurement of phenyllactate, phenylacetate, and phenylpyruvate by negative ion chemical ionization-gas chromatography/mass spectrometry in brain of mouse genetic models of phenylketonuria and non-phenylketonuria hyperphenylalaninemia. Anal Biochem 290: 242–249.
Scazzocchio C (1997) Alkaptonuria: from humans to moulds and back. Trends Genet 13: 125–127.
Schmidt SR,Gehrig A,Koehler MR,Schmid M,Muller CR,Kress W (1997) Cloning of the homogentisate 1,2-dioxygenase gene, the key enzyme of alkaptonuria in mouse. Mamm Genome 8: 168–171.
Scriver CR (1969) Inborn errors of amino acid metabolism. Br Med Bull 25: 35–41.
Scriver CR (1976) Genetics: voyage of discovery for everyman. (Presidential Address to the Society of Pediatric Research, 1976). Pediatr Res 10: 865–872.
Scriver CR (1989) The salience of Garrod';s’ molecular groupings’ and ‘inborn errors in disease'. J Inherit Metab Dis 12: 9–24.
Scriver CR (1995) American Pediatric Society Presidential Address1995: Disease, war and biology: languages for medicineöand pediatrics. Pediatr Res 38: 819–829.
Scriver CR (1996) Alkaptonuria: such a long journey. Nature Genetics 14: 5–6.
Scriver CR (1998) An ongoing debate over phenylalanine hydroxylase deficiency in phenylketonuria. J Clin Invest 101: 2613–2614.
Scriver CR,Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase de¢ciency: In Scriver CR,Beaudet AL,Sly WS,Valle D, assoc. eds; Childs B,Kinzler K,Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw Hill, 1667–1724.
Scriver CR,Tenenhouse HS (1992) Mendelian phenotypes as ‘probes’ of renal transport sys-tems for amino acids and phosphate. In Windhager EE, ed. Handbook of Physiology Section 8öRenal Physiology. Oxford: Oxford University Press, 1977–2016.
Scriver CR,Treacy EP (1999) Is there treatment for ‘genetic’ disease? Mol Genet Metab 68: 93–102.
Scriver CR,Waters PJ (1999) Monogenic traits are not simple. Lessons from phenylketonuria. Trends Genet 15: 267–272.
Scriver CR,Byck S,Prevost L,Hoang L, and the PAHMutation Analysis Consortium (1996) The phenylalanine hydroxylase locus: a marker for the history of phenylketonuria and human genetic diversity. Variation in the Human Genome. Ciba Foundation Symposium. Chichester: Wiley, 73–96.
Semenza GL (1994) Transcriptional regulation of gene expression: mechanisms and pathophysiology. Hum Mutation 3: 180–199.
Sober E (1984) The Nature of Selection. Evolutionary Theory in Philosophical Focus. Cambridge, MA: MIT Press.
Stearns SC (1992) The Evolution of Life Histories. New York: Oxford.
The C Elegans Sequencing Consortium (1998) The Sequence of the nematode C. elegans: a platform for investigating biology. Science 282: 2012–2018.
The International Consortium of Cystinuria (Feliubadalo L, et al) (1999) Non-type I cystinuria caused by mutations in SLC7A9 coding for a subunit (b0;AT) of rBAT. Nature Genetics 23: 52–57.
Waters PJ,Parniak MA,Akerman BR,Scriver CR (2000) Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for molecular and potential modulation of phenotype. Mol Genet Metab 69: 101–110.
Watson JD,Crick FHC (1953) Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 171: 737–738.
Weiss KM (1996) Is there a paradigm shift in genetics? Lessons from the study of human diseases. Mol Phylogenet Evol 5: 259–265.
Welch WJ,Howard M (2000) Antagonists to the rescue. J Clin Invest 105: 853–854.
Wright S (1934) Molecular and evolutionary theories of dominance. Am Nat 68: 24–53.
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Scriver, C.R. Garrod's foresight; our hindsight. J Inherit Metab Dis 24, 093–116 (2001). https://doi.org/10.1023/A:1010351630856
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DOI: https://doi.org/10.1023/A:1010351630856