Biomarkers are not just ANY indicator

1. Biomarkers: distinct indicators that help define the physiology or state of a living system

2. Biomarkers are not just ANY indicator Olivia uses this map to indicate her world travels

3. Biomarkers are not just ANY indicator Matt uses his hands to indicate the size of his endless imagination

4. When hypoxia sets in, a yawn indicates the homeostatic mechanism to increase oxygen uptake AKA the Boopathy Biomarker Biomarkers represent the complexity of life

5. Biomarkers include Any indicator of a biological phenomenon: Microbiological biomarkers to indicate cloning ampicillin resistance; blue-white screen Expression markers for cell lineage/biosynthesis gfp protein tagging Induced biomarkers as evidence of abnormality Genetic biomarkers of disease in humans

7. Cell Lineage Biomarkers 2002 Nobel Laureate: Sydney Brenner

8. Caenorhabditis elegans, Apoptosis model. Using dyes we can track all 1030 cells. 131 cells always die.

9. Behavioral biomarkers

10. Morphological biomarkers Larger tympanum = male frog

11. anatomica biomarkers normal female ovaries abnormal male testes

12. The Central Dogma of Cell Biology Induced proteins can be used as useful biomarkers of normal processes as well as disrupted processes

13. Rachel Carson published Silent Spring 1962 raising concerns on DDT Heptachlor Dieldrin Advocating integrated pest management, she referred to work by Henry Long who reported that heptachlor used to treat fire ants had INCREASED cane borer damage.

14. Only a small modification b/w estrogen and testosterone

15. Conventional Intracellular receptor MOA

16. Several environmental pollutants have been defined as estrogenic: Endocrine disruptors

17. Estrogen imparts a 3 layered effect Transcription of Primary genes Transcription of Secondary genes A stabilization of cytoplasmic mRNA Final Result: A gradual and long lasting cell response such as synthesis of vitellogenin by liver

18. The Endocrine Disruptor Hypothesis Compounds from a variety of sources, once thought to be safe, are having a non-lethal but devastating impact on normal biological signaling • Human Medicine • 2. Vertebrate Metamorphosis • 3. Invertebrate Sex determination • 4. Vetebrate Sex determination

19. 1950 – 1970s DES prescribed to prevent miscarriages DES mothers with 30% higher breast cancer 1980’s DES daughters with 9x ectopic preg, 2x miscarriage, 5x premature delivery, 2x pre-cancerous dysplasia, 3-5x cervical cancer , vaginal cancer ages 14-22.

20. John McLachlan DES studies, NIEHS, Tulane biomarkers: transferrin, uterine cancer

21. Methoprene inhibits mosqui pupation but bd products disrupt vertebrate ret acid signalling

22. Tyrone Hayes: Atrazine effects biormarker: frog gonadal abnormalities

23. Lou Guillette and Lake Apopka: 1992 feminization of gators

24. 2002 Lou says DDE is still in water; gator sexes still confused Biomarker: steroid levels

25. Chain of Causation: • Chemical spill in 1992 contained DDT, DDE and more • Juvenile alligator population has decreased • females have elevated levels of estradiol • males have depressed levels of testo • Females have altered aromatase activity • Males have poorly organized testes • Males have reduced penis size • Testes have elevated estradiol production • Females have poyovular follicles • Many contaminants bind to alligator est receptors

26. biomarkers in certain species have become useful as indicators of environmental health

27. Biomarkers for estrogen induction can be applied to test for normal reproductive health As well as Environmental Stress such as Endocrine Disruption By far the most famous endocrine disruption biomarker is the yolk protein precursor, vitellogenin made by the liver under estrogen induction, transported by the blood and stored in the oocyte

29. VITELLOGENINS AND CHORIOGENINS

31. The Victories and Dangers of Genetic Biomarkers

32. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. AUTHORS: The Huntington's Disease Collaborative Research Group aka MCDONALD,M., AMBROSE,C.M., DUYAO,M.P., MYERS,R.H., LIN,C.S., SRINIDHI,J., BARNES,G., TAYLOR,S.A., JAMES,M., GROOT,N., MCFARLANE,H., JENKINS,B., ANDERSON,M.A., WEXLER,N.S., GUSELLA,J.F., BATES,G.P., BAXENDALE,S., HUMMERICH,H., KIRBY,S., NORTH,M., YOUNGMAN,S., MOTT,R., ZEHETNER,G., SEDLACEK,Z., POUSTKA,A., FRISCHAUF,A.-M., LEHRACH,H., BUCKLER,A.J., CHURCH,D., DOUCETTE-STAMM,L., O'DONOVAN,M.C., RIBA-RAMIREZ,L., SHAH,M., STANTON,V.P., STROBEL,S.A., DRATHS,K.M., WALES,J.L., DERVAN,P., HOUSMAN,D.E., ALTHERR,M., SHIANG,R., THOMPSON,L., FIELDER,T., WASMUTH,J.J., TAGLE,D., VALDES,J., ELMER,L., ALLARD,M., CASTILLA,L., SWAROOP,M., BLANCHARD,K., COLLINS,F.S., SNELL,R., HOLLOWAY,T., GILLESPIE,K., DATSON,N., SHAW,S. and HARPER,P.S. … I count 58 authors in all

33. Poly-glutamine stretch of huntingtin coded for by CAG repeats • matleklmka feslksfqqq qqqqqqqqqq qqqqqqqqqq pppppppppp pqlpqpppqa • qpllpqpqpp ppppppppgp avaeeplhrp kkelsatkkd rvnhcltice nivaqsvrns • pefqkllgia melfllcsdd aesdvrmvad eclnkvikal mdsnlprlql elykeikkng • aprslraalw rfaelahlvr pqkcrpylvn llpcltrtsk rpeesvqetl aaavpkimas • fgnfandnei kvllkafian lksssptirr taagsavsic qhsrrtqyfy swllnvllgl POLYGLUTAMINE EXPANSION LEADS TO ELEVATED SUSCEPTIBILITY TO APOPAIN CLEAVAGE AND LIKELY RESULTS IN ACCELERATED NEURONAL APOPTOSIS

34. Huntington’s Disease Repeats Human ortholog of ced 3 is caspase 3 Huntingtin is cleaved by caspase 3, and this change is associated with neuronal death

35. Genetic Biomarkers Allow the elimination of imperfect embryos Plus… Potential for both Germline or Somatic Gene Therapy

36. Woody Guthrie 1930’s

37. Woody and Arlo, 1950’s

38. Arlo still performing in 2006

39. Woody, Krisna, Abe Guthrie Guthrie Family at Tipitina's Dec 9th

40. Biomarkers 2008 A semester-long biomarker study design of biomarker experimental induction assay and publication A survey of biomarker techniques from our department and the literature

41. Biomarkers: distinct indicators that help define the physiology or state of a living system