Genes & Medicine: How DNA is Improving Your Health U3A Mountford, June 2004

1. Genes & Medicine:How DNA is Improving Your HealthU3A Mountford, June 2004 • Dr Martin Kennedy • Department of Pathology • Christchurch School of Medicine & • Health Sciences • University of Otago

2. What this talk is not about No, I’m not the waiter. I’m the genetic engineer. How would you like your lamb?

3. What this talk is about: • Why is genetics important? • Disease genes • inherited disease • complex diseases • The human genome project • Genetically modified animals • Treating disease • finding new drugs • tailored drug treatment • gene therapy

4. Conquering disease • Recognition and naming • Observation and measurement • Understanding of aetiology/pathology • Understanding of molecular mechanisms Development of treatments & preventative strategies

5. DNA, chromosomes & genes

6. Chromosome structure

7. Why is recombinant DNA needed?

8. Recombinant DNA (GM)

9. Run for the hills - the recombinant DNA has escaped! 1980

10. 1978

11. Why try to understand genes? • To provide a window on the disease process • Diagnostic or prognostic markers • Drug targets • Prediction/prevention The vast majority of our knowledge about human genes comes via genetic modification techniques

12. Environment Genetics Genetics Genetics Environment Environment cystic fibrosis adult onset diabetes AIDS Genetics contributes to most disease

13. Environment Genetics Genetics Genetics Environment Environment cystic fibrosis depression AIDS Genetics contributes to most disease

14. Environment Genetics Genetics Genetics Environment Environment cystic fibrosis coronary artery disease AIDS Genetics contributes to most disease

15. Genetic disease • Mendelian disease • one gene • genes are causative • genetic mutations • environmental influences • eg CF, PKU, haemochromatosis

16. Genetic disease • Complex disease • polygenic • genes confer susceptibility or risk • genetic variants (polymorphisms) • environmental influences • eg Diabetes, IBD, CAD, autism, anorexia, coeliac disease, Alzheimer’s, asthma, bipolar disorder

17. Genetic disease • Congenital disorders • loss or gain of genes • usually sporadic • eg Down’s, Williams, PWS

18. Cancer • All cancer is caused by damage to genes • Damage to several or many genes is required to initiate and progress cancer • Some cancers display an inherited susceptibility

19. The human genome project

20. The Human Genome “This scaffold has been handed down to us from our ancestors, and through it we are connected to all other life on earth.” Svante Pääbo, 2001

25. Molecular characterization of Mendelian diseases

26. Understanding major disease Alzheimer’s Disease Third leading cause of death Asthma Affects 150 million people worldwide Breast cancer Accounts for 20% of female deaths Heart disease The world’s biggest killer Migraine 1.4 billion attacks worldwide each year Depression Ranked 4th in W.H.O. global burden of disease analysis

27. Isolation of “susceptibility genes” Korstanje & Paigen 2002, Nature genetics 31, 236-7

28. Major outcomes of HGP • Discovery of: • causative genes in Mendelian disorders • susceptibility genes in complex disease • Improved: • drug design • drug treatment • disease management • Understanding of human history

30. Microbial genomes

31. Completed microbial genomes • 165 Bacteria including: • Yersinia pestis • Helicobacter pylori • Haemophilus influenzae • 1790 Viruses including: • SARS • HIV • Several herpes viruses • Several papilloma viruses • Several influenza viruses • Polio

33. Transgenic organism A plant, animal or microbe that has incorporated, in its own genome, genetic material from another organism.

35. Transgenic mice • Adding genes “Conventional” transgenics (developed early 1980s) • Subtracting genes “Knockouts” (developed late 1980’s)

36. Why? Transgenic animals • Understanding gene function • Modelling diseases • “Bioreactors” for vaccines, drugs, etc

38. Nature Genetics, 2000 • Approximately 280 research papers. Of these, 80 (28%) directly focused on GM mice: • Cancer: 11 • Cardiovascular disease: 7 • Development: 15 • Neurological or behavioural: 11 • Reproduction: 7 • Obesity and diabetes: 7 • Vision or hearing: 7 • Technology development: 9 • (including two large scale international programs that generated and screened 40,000 mice, producing 747 new mutants) • Others: 6

39. DNA and the treatment of disease

40. GE and drug development • Identification of new drug targets • Production of drugs • Structure aided drug design • Pharmacogenetics

41. Pharmacogenetics • The study of genetic variation underlying differential responses to drugs

42. Adverse drug effects

43. Why pharmacogenetics? • Prediction of adverse drug reactions • 100,000 deaths annually and 2 million hospitalizations (USA alone) • More appropriate prescribing • Medicines targeted for specific genotypes • Rescue “failed” drugs • Making better use of existing drugs

44. Antidepressant treatment of depression

45. Bronchodilators treatment of asthma

46. Inflammatory Bowel Disease

47. Pharmacogenomics

50. DNA is a potentially powerful drug