Some Considerations Regarding Biochemical Genetics in Man

5OME CONSIDERATIONS REGARDING BIOCHEMICAL GENETICS IN MAN HERMAN M. KALCKAR, M.D., Ph.D.* I. Apology I was once lucky enough to attend a social gathering of the National Convention ofProfessors andTeachers ofEnglish. I overheard the remark that it was regrettable that a promising young humanist, Dr. X, was unsuitable for a positionat a university since his field was eighteenth-century English poetry and the chair called for a specialist in seventeenth-century English poetry. Compartmentalization is probably not so bad in the natural sciences. Yet I would greatly hesitate to pose problems outside my working field in the laboratory, and especially those exposed in the present essay, were it not for the invitation to write in this newjournal Perspectives about "inborn metabolic errors in man." Moreover, I take the liberty of broadening this topic considerably by dealing with borderline subjects between the fields ofenzymology and genetics. . II. Biophysics and Genetics in General The impact of physics, lately especially of crystallography, on biology and the application of physical chemistry and biochemistry to genetics have fused all disciplines ofnatural sciences together. This makes the scientific thinking oftoday more demanding, yet also more inspiring. As a biologist who has studied mainly metabolic enzymes, I want nevertheless to discuss some topics which happen at the present time to occupy my mind. What have welearnedandwhat can welearn,about genes and the mode ofaction ofgenes from human genetics? The trend ofour time is certainly to study the genetics of simple micro-organisms—especially the viruses, * The author is chiefofthe Section on Metabolic Enzymes, National Institute of Arthritis and Metabolic Diseases, U.S. Public Health Service, Bethesda, Maryland. since their relative simplicity, their short generation time, and the application ofmethods ofselection make it possible to obtain an enormous number ofresultswithina reasonable spanoftime. Thereader is referred to the brilliant discussions by Benzer (i), Hartman (2), and Lederberg (3) summing up basic problems concerning the subdivision of genes and the integration of these subunits into functional units. Offhand, we cannot expect, from a study ofthe genetics ofhigher animals, to make contributions to this area, although we should never disregard the possibility of unexpected novel approaches. III. Effect ofHeterozygotism on the Properties ofGene Products The study ofhuman genetics and especially ofinheritance of human diseases has, however, been able to contribute fundamental knowledge toward our understanding ofthe action ofgenes. The most important example is the successful introduction ofthe notion of "molecular diseases," which was first based on studies by Pauling, Itano, Singer, and Wells (4) ofa human hereditary disease. Not only has the introduction ofthe name "molecular disease" been a great stimulus, but the study on which it was based represents one ofthe most elegant and refined pieces ofwork in the area of genetics in general, especially with regard to our understanding of the dependence or independence of heterozygous alleles. Sickle-cell hemoglobin might never have been discovered ifit had not been for the fact that the altered globin in the form ofa sickle-cell ferrous hemoglobin has a lowered solubility. This, in connection with the fact that the red blood cells have a very high concentration of hemoglobin (normal or sickled cells), brings about the crystallization ofthe sickle-cellhemoglobin at oxygen pressures present in normal venous blood. The crystallization gives rise to morphological manifestations, like tactoid formation and sickle-cell deformation followed by destruction ofthe cells. The increased rate ofdestruction ofred blood cells results in a manifestation of disease. It is worth emphasizing that the function of the hemoprotein is unaffected ; i.e., the oxygen dissociation curve is the same as that ofnormal hemoglobin. Individuals with "sickle-cell trait"1 are heterozygous with respect to the gene for sickling, whereas those with sickle-cell anemia are homoI . Defined here as a condition in heterozygotes similar to, but less severe than, the homozygous state. Herman M. Kalckar · Biochemical Genetics Perspectives in Biology and Medicine · Autumn igsj zygous with respect to this gene (5). Although its function is unaltered, sickle-cell hemoglobin moves faster in an electric field than normal adult hemoglobin because of a few extra charges sufficiently large to make a detectable difference. In this way it was possible to show clearly that the erythrocyte in a heterozygous individual...