Topic A COURSE IN MEDICAL GENETICS (24+ lectures) (to be offered coherently with Biochemistry) al coverage (these topics are not necessarily part of this formal course and many would advantageously be included in the sequence of other courses). Aim is exposition of basic principles with exemplification in man and his parasites when convenient. l. 2. Be he 56 6. 7. 8, 90 10. ll. 12. 136 Ae General considerations: individuality and the chemical basis of biological specificity; linear structure of proteins and nucleic acids; elementary concepts of information theory; vegetative growth and general requirements of genetic theory; Sexual reproduction and genetic recombination. .Diploidy. Chromosomes as pragmatic units of genetic analysis /observed behavior of chromosomes in mitosis ami meiosis and its genetic significance. Pedigres as research tool in human genetics. Collection and recording of family data. Principal types of inheritance and their cardinal signs. Ascer— Genetic prognosis and counseling. Empirical risk tabulations. Effects of consanguinity. Structure of human populations. Scientific problems of eugenic efforts. Rare mutants in man = specific examples. (Much of this material in particular could be deferred to pediatrics, hematology etc. though there would be some value in going over a few conrete histories at this stage). Concept of genetic blocks in metabolism (Inborn errors). Hemophilia; abnormal hemoglobins; phenylpyruvic oligophrenia; galactosemia, etc. Developmental pathways of gene action. Polygenic inheritance (general constitutional factors; disease predispositions; - mental disease) Correlation methods. Use of twins. Determination of sex. Gametic selection. Twinning. Blood groups and imminogenetic diseases. Application in forensic medicine. Erythroblastosis fetalis. Racial differences in blood group gene frequencies. Correlations of blood groups with duodenal ulcer, gastric cancer, etc. The chromosomes of man, Linkage in mane Mutagenic effects of radiations and chemicals. Chemical mechanisms. Effects on populations. Behavior of structural changes in chromosomes. Genetics of somatic cells - chimerism™m. litc&ic anomalies; somatic crossing— over and mtation. ~- transplantation compatibility and acquired tolerance. Nuclear transplantation. Tumor initiation and progression. - in vitro culture and genetics of cell clones. Genetics of bacteria. Quantitative mutation study. Preadaptive mutation: drug resistance. Recombination mechanisms: DNA =- transduction; virus-mediated trans— duction; sexuality. The immunogenetics of Salmonella. Genetics of virulence. Genetics of viruses. Mutation and recombination in influenza and vaccinia. Heterozygosis., Phenotypic mixing. Reconstitution of virus protein and nucleic acid and genetic function of isolated nucleic acids, =u Text material: none entirely satisfactory. Will probably assign Stern's "Human Genetics" when revised edition appears and use additional reference material: Neel and Schull; Sarsby; Harris; some reviews for microbial aspects. This is a tentative outline. Variation of emphasis will depend on the level of premedical training (this syllabus presupposes very little formal preparation in genetics) ani the planned coverage of these topics in other courses. I would be quite pleased to have many of the topics taken up throughout the curriculum once the students have assimilated the basic principles and vocabulary, Joshua Lederberg The following summary is a crude outline of areas of genetic research that have some relevance to medicine. HUMAN GENETICS 1. Hereditary factors in disease , Statistical methodology. Pedigree analysis. Population analysis. Trin studiss. Clinical genetics ‘Single factor ayndromes (e.g., hemophilia; retinoblastoma xeroderma pign. ) Complex determination (eeges epilepsy; diabetes) Biochemical or developmental analysis of gomtic defects (e.ge, alcaptonuria or phenylpyruvic oligophrenia; sickle ’ gell anemia) Mutation rates 2. Individuality Blood groups Transplantation specificity Sensory modalities (e.ge phenylthiourea taste) Metabolic individuality (#1) antibody response (#2) anthropometry; skin and hair; features; ‘race! 3. Cytogenetics 4. Genetic hygiene and population gens tics Eugenics (#3) . (Counselling) (#4) Environmental mdieine (*5) Detection of haterozygous carriers — EXPERIMENTAL MAMMALIAN GENETICS (SELECTED TOPICS) 1. Mutations radiation effects 6. Transplantation— histocompati- 2, Cytogenetics bility and acquired tolerance (*6) 3. Developmental analysis of gene effects 7. Susceptibility to infectious 4. Biochemical do. disease (notably 13) 5. Experimental evolution 8. Cancer Research— host variations 7 and genetics of tissue and tumor cella (#7) MICROCRGANISMS Mutation. Radiation effects. Chemical mtaggenesis. Mechanisms of killing cells. Evolutionary patterns in natural populations (esp, of pathogens) Genetic factors in pathogenicity. Genetic recombination analysis. Nature and origin of viruses. Notes: . Genetic research characteristically cuts across many other disciplines. This List already would imply sones of dependence on or collaboration with virtually any departasnt in the medical school. l. This de readily recognized in characteristic metabolic diseases, bub may be equally important in personal differences, as Koger williams has emphasized, Individuality may thus be reflected in characteristic patterns of excretion of various matabolites and has a large, certainly not an ax- clusive, genetic basis. It is algo reflected in differences in therapeutic response, 0.2.) to isoniazide, and may be a too often neglected factor in idiosyncratic responses to other druga. Explicit genetic analysis of the latter situations remains to be carried out. 2. For example, in the polio vaccination program, 4t has been noted that gome children make a poor antibody response. It is not known whether this has a genetic basis, nor whether this is general unresponsiveness or 4 specific unreactiveness to the polio virus. Fink (at Colo.) and others have given experimental evidence for genetic variability in antibody response in mice. This ficld should be om af the more important areas of development for practical medical understanding. The general question of individualized reactions to pathogens is not far distant. 3. In ay own opinion, the overzealous pushing of active eugenic controls (e.ge, the sterilization of the so called Nunfit') is largely responsible for the hiniered devalopment of medical genetics, Such negative controls are essentially futile for the reduction in incidence of rare recessive mutations in any avent, ani involve matters of publics policy that far over~ ‘peach the authority of the medical profession per se. Hany modern students (cf. Neel and shull) share the view that mich mre scientific knowledge of human genetics is needed before one can advocate any far reaching social controls of human reproduction. ‘The present role of the human geneticist 4s to inform his colleagues and through them the public, rather than advo~ cate drastic interference by society, especially when the calculated social effects are so small. Medicine may someday be faced with formulating an attitude on another desue where genetic control may be more effective, namaly the sex ratio. This has not been the subject of much work lately, but it is at least theoretically possible (in my own view almost probable) that techniques will ultimately be developed to enable the sex of offspring to be voluntarily controlled. ost of us would hope that day to be deferred indefinitely, but this illustrates the tremendous impact that human genetics is bound to have, ultimately, on medicine and on society. (Since this draft was first pre- pared, a credible report has been published on the separation of % and ¥ spermatozoa of rabbits by means of electrophoresis: Gordon, a. Jes Contrel of Sex Ratio in Rabbits by Electrophoresis of Spermatozoa, Proc. Natl. Acad. Sei. Ue Ses 43:913-918, 1957). 4. Counselling. Many schools have set up "Heradity Clinics" as part of their program in medical genatics. ‘these are valuable centers for the collection of data, and there can be no question of public interest in -~2~ these problems. I would not advocate such a service in which the genetic specialist dealt directly with the patient. The counsellor inevitably mist IV vo influence the patients’ reprocuctive decisions, matters so involved with his total personality that such consultation should ordinarily be made with his own physician. The department should be in a position to consult wit physicians, and inevitably will. 5. “Environmental medicines" is taken here to encompass tha genetic hazards from industrial and professional operations, as well as from atomic bombs. Almost all the emphasis so far has been spent on radiations (from bonbs, fluorescopy or mineral extraction), ani except that some hazard is involved, little enough is known. iithout minimizing the tremendous importance of radiation hazards from, for example, fallout, it seams to me that there is a much broader problem of which radiation is only one part. Until recently, radiations were considered the only artificial agency by which mutations could be imiuced. It is now realized that a wide variety of chemical reagents . can induce mitations. Radiations undoubtedly have freer access to the germ calls, but the mitagenicity of such compounds as hydrogen peroxide, formalde- hyde, nitrogen mstard, azaserine, and caffeine raisss ths question whether genetic effects should be considered aa ons aspect of chronic toxicity of compounds which are part of the everyday environment of modern man. 6, Experinental etudies have now firmly established the immunogenetic basis of transplentation compatibility in mecwale, Jt 4s disheartening to see how often these factors are overlooked or underemphasized in surrical trials, The finding that prenatal expesure of xice to heterologous tissue antisense provokes a tolorance to the postnatal transplantation of other heterolorous tissues 18 a new and important lead to the overcoming of thie difficulty. 4 technique for overcoming histecoupatibility barriers would open up @ vast naw territory of surgical replatenant of defective tissues and organs, It might also anever one of the gystorious questions of izmmology? why does the orgenism fall to produce antibodies to 44s own antifeng, 7. Moet of the emphasis in genetic cancer research has been in the propertics of specific lines of mice, which are indeed indispensable research tools, More reoontly, technical advances are leading to loser examination of the genetics of the tiesue cell itself, as in the ascites tumor studiss of Hauschka and