LECTURE 19: BIOETHICS AND THE BRAVE NEW WORLD

1. LECTURE 19: BIOETHICS AND THE BRAVE NEW WORLD

2. DNA -> RNA -> Protein X DNA Transcription X mRNA X Translation Protein Abnormal Gene Function Mutations Often Result in the Synthesis of Abnormal Proteins

3. Future-Shaping Techologies Genetic Screening - Marfan Case Gene Replacement - Bubble Babies Stem Cells Cloning - Dolly the Sheep Agriculture - Crop Modification

5. Two types of mother’s eggs + + + mf mf mf mf mf mf +/+ mf/+ + + + Two types of father’s sperm mf/mf +/+ = 1/4 offspring = Normal +/mf or mf/+ = 1/2 offspring = Normal +/mf mf/mf = 1/4 offspring = Marfan One quarter of the offspring from twoMarfan carrier parents will haveMarfan Syndrome

6. Gene = Basic Unit of Inheritance Chromosome = 1,000-5,000 Genes Genome = 30,000-50,000 Genes Gene 1 Gene 2 Gene 3 Gene 4 Gene 5 ≈ 5,000 Genes Cause Disease When Mutant Genes, Chromosomes, and Genomes

7. Mutations Carried in Mother’s Genome Mutations Carried in Father’s Genome Mass Scale IVF +

8. Normal red blood cells Sickle cell red blood cells

9. Two types of mother’s eggs + + + sc sc sc sc sc sc +/+ sc/+ + + + Two types of father’s sperm sc/sc = 1/4 offspring = Normal/ Malaria Sensitive +/+ +/sc or sc/+ = 1/2 offspring = Normal/Malaria Resistant +/sc sc/sc = 1/4 offspring = Sickle Cell One half of the offspring from twoSickle Cell carrier parents will be protected fromMalaria

10. Desirable Traits Can be Linked to Disease Genes Resistance to Malaria Low Blood Pressure Immunity to Plague Longevity Musical Ability Resistance to Flu Low Cancer Risk Reduced Risk for Alzheimer Disease

11. SCID “Bubble” Baby

12. Cloned Sheep Dolly and Kid

13. A possible picture of the most recent common ancestor of vertebrate and invertebrates Eyespot? Sensory Appendages? Head Abdomen Tail Anus/ Genitals Mouth Gills? D/V Axis A/P Axis Non-neural Ectoderm Photosensitive Protrusions or Nervous System organs appendages

14. http://homophila.sdsc.edu

15. Fly Genes similar to Human Angelman Gene

16. Alignment of Human and Fly Angelman Genes Human Protein:LRLKVRRDHIIDDALVRLEMIAMENPADLKKQL Fly Protein:LKLTVRRDQLINDALIGLEMVAMSNPKDLKKQL Match/Similar:L+L*VRRD*+I+DAL+*LEM+AM*NP*DLKKQL

17. Human Disease Genes in Flies • >2,400 of 5,000 Human disease genes identified • Many disease genes have fly counterparts • 75% disease genes related to a fly gene • 30% disease genes highly similar to a fly gene • Disease genes with counterparts in flies fall into all major categories of disorders

18. Appropriate Disease Genes to Study in Flies • Human Disease Gene Function Poorly Understood • Fly Counterpart Highly Related to Human Gene • Facility of Genetic Analysis in Fly • Identified Loci Subject to Explicit Test in Humans: “Closing-the-Loop”

19. Closing-the-Loop in Humans • Identify New Candidate Disease Genes • Alzheimer Disease (FAD) • Identify Human Modifier Loci • Primary Congenital Glaucoma (PCG) • Dissect Complex Polygenic Trait • Cardiac Defects in Down syndrome (DS) • Identify Candidate Protein Targets • Angelman Syndrome (AS) • Study host-pathogen interactions • Bacterial toxin function • Place Disease Gene in a Pathway • Dyggve-Melchoir-Clausen syndrome (DMC)

20. Placing DMC in a genetic pathway Goal: Identify genetic pathway in which DMC functions Method: 1) Mis-express human and Drosophila DMC genes in Drosophila. 2) Mutate single Drosophila dmc orthologue 3) Determine if the pathway identified in Drosophila is also affected in human DMC or SMC patients.

21. Normal DMC patient DMC: a gene in search of a function • DMC Phenotype • Short trunk dwarfism • Psychomotor retardation • Radiologically Identical to Smith-McCort Dysplasia • Encodes multispan transmembrane protein: Dymeclin • Unknown function in regulating bone growth

22. DMC: a gene in search of a function • DMC Phenotype • Short trunk dwarfism • Psychomotor retardation • Radiologically Identical to Smith-McCort Dysplasia • Encodes multispan transmembrane protein: Dymeclin • Unknown function in regulating bone growth Nakamura et al., Am J Med Genet 72:11-17, 1997 Normal Growth Plate DMC patient

23. Notch & Wg M L2 L2 BMP L3 L3 Hh L4 L4 L4 L5 L5 BMP Normal Wing BMP Pathway Mutant L2 L2 L3 L3 L4 L4 L5 L5 Hh Pathway Mutant Notch Pathway Mutant The fly wing as genetic assay system

24. En -> Hh -> Diffuses -> Dpp -> Diffuses -> dpp in A/P Organizer sal -> L2 vein brk L2 A/P sal Organizer A L3 L3 ptc, dpp P Dpp A L4 L4 P hh dpp sal En omb L5 brk L2 L2 L3 L3 pct sal L4 L4 L5 L5 Veins form at Gene Expression Boundaries

25. En -> Hh -> Diffuses -> Reduced hh function dpp in A/P Organizer A A dpp L3 ptc, dpp P P L3 L4 L4 hh dpp dpp En hh En WT Reduced hh function L2 L2 L3 L3 L4 L4 L5 L5 Hh Determines Positions of L3 and L4 Veins

26. L2 L2 L3 L3 L4 L4 L5 L5 wt ubiGAL4>dmc L2 L3 L2 L4 L5 L5 L3 L4 ptcGAL4>dmc enGAL4>dmc Ectopic dmc reduces the response to Hh

27. New CovenantJesse Bier • Nobody tells the flowers what to do, • they grow the way they please. • They don't take orders from me and you— • nor do the grasses or trees. • But that was long ago, • before the age of science. • Now that we know what we know, • we splice them to compliance. • Soon trees must do what they are told, • according to special genes. • Nothing the same as of old— • and grasses, flowers know what that means. • Next to come are you and me • after the flowers, trees and grasses. • But: Who will decide and oversee • newfounded families, permanent classes?