1. GENE THERAPY IN SPORTS Mechanisms & Bioethics

2. Gene Therapy Gene transfer in somatic cells to heal or treat disorders Strategy that can be applied to: chronic,acute or preventive treatments hereditary or acquired diseases

3. Why “somatic” Somatic cells do not contribute to the germ line Germ cells alterations will be transmitted to progeny

4. Gene transfer manner Ex vivo: cells explanted-cultured-gene transfer- transformed-reinfused In vivo local: intramuscular, intrajoint etc, localised diseases indication,limits toxicity of gene transfer & contamination of germ line In vivo systemic:intravascular,intraperitoneal- no specific trapping, germ line ?

5. Non Viral & Viral transfer vehicles Non viral: cell membrane not strong barrier but lack of transport into cell nucleous Viral: get internalised,remain protected from cytoplasmic enzymes,genetic load into nucleous

6. Non viral Naked DNA: complex formulations into liposomal particles Oligonucleotides: small gene fragments, swamp pathological factors,gene repair inducers, short persistance (good candidates in transient treatments in doping arena)

7. Viral Adenoviruses: favourite system,relatively large,can carry big gene, valnerable to attack from immune system Adeno-associated viruses(AAVs):smaller, less valnerable,transfer small-size genes Retroviruses: risk of insertional mutagenesis, can affect non dividing cells (ex: brain)

9. Gene therapies that can be abused in sports Systemic proteins:EPO,growth hormone Wound or injury healing: bone repair factors,PDGF, KGF Increase muscle mass: angiogenic factors to skeletal and heart muscle,IGF 1 Blood vessel growth:FGF-1,2,4 or 5, vascular endothelial growth factor

10. …. Pain relief: endorphins, enkefalins, analgesic peptides Neurological: hormone/growth factors, pituitary/hypothalamic cognition/memory enhancers,mood altering

11. Feared potential side effects Viral vectors can stimulate immune system (acute toxic shock) Repeated dosing leads to antibodies against virus which is stopped before gene delivery (ex. Muscle damage through exercise) Over expression (monkeys with too much EPO need bleeding)- new nucleotides insertion to switch on/off the gene(Lin et al)

12. Side effects Expressed gene product can be recognised as non self in individuals(factor VII in haemophiliac dogs) Random integration in the genome (oligonucleotides) is genotoxic- increases risk of cancer Germ cell contamination

13. Ways to detect Gene therapy Antibodies to viral proteins- viral DNA Quantitative gene chip analysis before and after Over/under expressed gene’s product New Scientist journal, “gene cheats” 2000

14. Ethics Accumulation of values and principles that address questions of what is good or bad in human affairs www.austlii.edu.au/au/other/alrc protection of human genetic information

15. Bioethics The Romantic View integrity of sport threatened by technology The Entertainment View extraordinary performance- genetic modification desirable The Techno-Centered View GM simply a sophisticated technological character –eventualy can make the game fair

16. Is “natural” mutation an unfair advantage? Eero Mantyranta two golden medals in cross-county skiing in 1964 Winter Olympics Mutation in gene that produces the receptor for EPO O2 normal- EPO receptor should shut down epo production but not in Mantyranta (mutation turned off this crucial feedback)

17. questions “Elite” genes Pre selection of athletes according to geno type Bioethics about children and even embryos DNA data of the whole population with severe even political implications