WADA gene doping Symposium4-5 Dec, 2005, Karolinska Institutet
Welcome
improve people's health. misuse of medical tes
Richard Pound
banbury conference
wada
OM contributions shared by NOCs - but..
gene doping research $3m
gene doping panel in WADA, help with detection
new results - WADC, mar 2003 -
ME: who are stakeholders of gene doping?
Olympic charter amended stating that only countries signed to WADC can participate in Olympics
UNESCO convention Oct 19 2005 120 supporting states, observed by all 191 states
gov actions - now wider gov support
gov can do sth sports cannot sports cannot address trafficking, seizing, regulation of med professionals
trying to widen network of stakeholders recently, an athlete committee athlete outreach committee
gene doping inevitable
athletes believe they are immune to risk and their entourage seem not to care
New Trends in Anti-Doping Arne Ljungqvist
need to be ahead of the game first time in history
purpose - describe recent developments
some key years 1960 olympic games in rome - danish cyclist died in 100km road race. ioc took action, as first televised Olympics. athlete dying in front of ioc 1961 ioc mc 1964-72 testing for stimulants 1972 munich first serious case, us athlete ephedrine, controversial, still claims medal 1974 testing for AAS - tentative for 76 games in montreal 1983 IOC labs 1988 seoul -arne gave press conference in rel to johnson's positive. huge press. death of sport question. response was that this should be stopped. led to unified global effort. iron curtain drop changed this. 1999 ioc code, wada - changed med code into antidoping code 2004 wada code 2005 unesco convention
arne was olympian in1952 and nothing then,
doping code explanation
doping is definedas...
violation new 4. inadequate whereabouts information 8. administration, assisting, encouraging
prohibited list - wada publish each year
criteria - enhance, health risk, spirit of sport
(two of three)
doping need not be cheating to be banned
could say that any substance could be on list, and this is a legal prob
need common sense
substances w similar structures likewise banned, but legal difficulty to try
prohib method enhancement of oxygene trtansfer
distrib of substances 2004 - 36% anabolic 0.1% oxygen transfer enhancement
TUE
anti-doping strategy - info, educatioo, doping control,research
wada allocates 25-30% of budget to research vasst improvement since 2000
ioc never took this responsibility
strategy of doping controls - in comp - unanncounced out of comp - random - targeting (intelligence)
ME: what is current status of intelligence on gene doping?
need to improve intell
ME: how?
recent negative envts
- salt lake city experience, tendency to make use of most recent advancements. 3 cross country skiers on aranesp - The Sweeney Experience' 2002: first reported that athletes had been contacting him to see how they could benefit; - The BALCO affair 2003; shows illegal production jsut for doping - The Athens experience 2004; first olympics at whch people banned for non-analytic positive; greek athletes; were using artif device for urine - Further designer drugs 2005; don catlin found further egs
The maked Machine false urine
REcent positive evens
SLC2002 -showed that we are close to athletes; these were subsrtances that had been on market for some months - Athens - pursued cheats successfully - WADA Code - UNESCO convention - Research fund - Proactive initiatives
whycontinue fight? - in ethics session. must be unbiased ME: this is too far. to pose all or nth is mistaken.
funl facts must be mentioned 1. no support for such an idea in t sports communioty - there was a debate. but it no longer exists. everyone agrees 2. wada andunesco convention, political estab has reinforced support 3. athletes themselves dont want it. athletes commisions are strongest
ME: when asking athletes about their feelings, hat do you think they are rejecting?
President of K: what are legal conseqs for med professionals?
AL: any person assisting may be banned. will not receive accreditation to be Olympic doctors. but we have limited legal action in civ law. at World Championships some years ago, some finnish professionals weree encouraging, investigation into law. found that action could not be taken. no legal ground .this changed the law.
The Irrefutable Success of Gene Transfer for Therapy of Human Disease) Concepts and techniques of gene therapy - applicationsv to doping in spoprt Ted Friedmann
give overview of underlying baasis of justif for potential of gene doping
rationale is direct outgrowth of gene therapy itself a controversial and difficult field
now a real area of cliincal research basis to think that direct attack can be and has been therapeutic
gene based doping - realstic poss imminent threat to sport - same pressure that sustain drug doping will lead to gene doping - based on advances in gene therapy
Evol and current state of gene therapy -controversial history - tools and concepts still immature - clinical reality, effective treatment, poss cure -- serious risks, tolerable in context of therapy -- still subject to oversight and regulation
gene therapy for human genetic disease science, 1972, mar 3, 172, n 4205 friedman and robin
Proposal for human gene theerapy - needed - technically diffi -use disabled viruses as gene transfer vectors - many ethical and policy problems - reqs local and nationaal oversight - likely to be used for non-therapeuticapplics (enhnacmenet)
dark side broader than gene doping - enhancement of human traits in a eugenic sense.
LeRoy Walters, Kennedy Institute, Georgetown - somatic cell - germ cell
two major technical advances
recombinant DNA -cohen and boyer, 1973 - first efficient transfer tools (engineered viruses), 1981-1982; retrovirus vectors - Temin, Weinberg, Scolnick
retrovirus 1981-2 random integratioon, insertional mutagenesis adenovirus adeno-associate virus liposomes naked dna
ref: j biological chemistry; 1984, 25 12, 7842-9 - restored gene function and reversed phenotype
optimisms - beginnings of human clinical studies - 1989-90 - high expectations - exaggerated promises
gene transfer trials by year crash in 2000
ME: why? at the time of HGP completion
photo of jesse gellsinger
gene directly injected into liver
3 or 4 days later after injection, died react to vector not gene
Uni of Pennsylvania OTC study - a patient death -1999 - adenovirus vector to transfer ornithine transcarbamylase gene (OTTC) directly to liver - patient (JG) developed explosive
visible depression in Society of Gene Therapy
yet, heard of a diff technique
Paris study, Fischer, Great Ormond St LondonX- SCID
photo of Bubble Boy syndrome child - protect from inections
X-linked SCID,sevcombined immunodef dise - mutations in..
ex vivo study
introduiced to bone marrow cells
REF: NEJM article ,Fischer, Alain, lead Hacein-Bey-Abina, S -sustained correction of X-linked severe combined immuno
complete recovery - complete immunecorection 14 patients - some >6 yrs
but at high cost - 3 cases of T-cell leukemia -direct result of treatment - responsive to chemotherapy but reqd eventual one marrow transplantation - one death 2004
other two aree still alive and no evidence of residual disease. but diff to ustd
three cases of leukemia during effective treatment of x-scid deficiency
LMO2 oncogene has been disrupted - this is why we have leukemia
Why is this result imp? - proof - can be therapeutic - all previous studies ,potential or marginal benefits ,theoretical risks - no risk/benefit -X-SCID -quantifiable beenfits - gene transferrresearch becomes gene therapy - opens new era for med
legitmately therapy not just gene transfer
current successful therapies - X-SCID - q14 patients ,3 leuk, 1 death - ADA-SCID - 4 patients - prolonged - chronic grnaulomatous disease -2 patients
addl imminent and probable successes - cancer vaccines - introdcue genes (GM-CSF, CD40) to cancer cells to enhnace immune response (melanoma, CML, others) - restore tumour suppressor fn (p.53) - some photoreceptor degeneration andblindness -restored sight in blind dogs by gene transfer into retina - coronary artery disease
intra-tumoral...
CNS prophylaxis, new chemo agents
additional info into genome, which maintains mutant gene
now, te to fix defect - to change to wildtype gene from mutant
emerging tes - siRNA for gene modulation -especially for dominant diseasee - vector targeting -gene deliv - targetd gene modifi -zinc finger delivery of transcription factors ,transgenes
so, darker side -therapy is poss, what about enhnacement?
socially and ethically 'acceptable' enhnacement -we already do pharma, so why not gene - reelvant genes are becoming identified - tf, applic of gene tools to non-disease traits seem inevitable -
extension to sport - one of most imminent - unlikely to conform to standards of human clinical research -safety, informed voluntary consent
ME: why is informed vol consent unlikely?
sport or bioengineering? is it still sport?
ME: yes ,good photo, the q might be whether he would have been ahigh jumper if he had info about his genes
germ cell -therapy or enhance?
eugenics - old eugenics of late19th and early 20th C - new eugenics based on genetics - new potential for restrictive ,discrimintory
conclusions - all human gene transfer -immature ,exptl clinical research, not standard of care -but if i had a child with X-SCID, i would opt for genetic approach - proven concept ,truly therapeutic - many dangers, known and unknown,reqs oversight
risks tolerable in light of disease ,but for healthypeople?
conclusion -sport may lead the way - opp to define social atts and responses
in US, not entertaining proposals for enhancement
discussion
how is read out monitored ?/ dosage? how follow efficacy of therapy? if so, might be poss to detect.
ME: what lev of cooperation is expected from biotech industry?
change position but
Goldspink Kathy Howe, killing off cells. factor 9 expt study shelved becuse of immune response to vector
holy grail is sequence correction
goldspink:
tom: surprised by one thing, which was your optimism. I sat on FDA committe which looked at gene transfer when French study began. what is your assessment of the science. is it likely that LMO2 will not be repeated.
Ted: it hasnt in
Olivier: you refereed to over 700 studies, by RAC. do we have idea of success rate? are we aware of some genes, neverr been poss to transfer. some genes more capable of expression than others. how long to go from animal model to human.
Ted: not all of 700 studies led to clinical. need to learn much more about how to turn genes on and off.
Olivier: side effects?
Ted: dont see them until you see effect.
Olivier: procedure itself not harmful?
Ted: in Gelsinger it did. will not see ath going wrong until see sth happening
Q: state for muscular.
Q: leukemia. single gene as key factor .also v shiort period - 3-4 years. usually cancer 10yrs. sth peculiar of case , it is activation of agene. are ways to avoid activation.
Ted: but not activitation, but disruption
Q: 3rd case special since dif
Odile: transgene role is enormous. cannot claim thatt there are no te that could counteract potential activations.
Chair: what is view on detection of gene transfer? willl this stop? or need legislation on other level?
Ted: no, wont be enough ,but will be strong deterrent.
Coffee
Effects on organ systems/tissues
Heart - bigger, greater stroke vol - inc maximal cardiac output
Blood vessel (heart and trained skel musc) - more capillaries - improved dilatory capacity
Blood - ic total amount of red blood cells - evevn larger expansion of plsma vol, reduced blood count in a blood sample
Adipose tissue - reduced amount
Connective tissue/bone cartilage - inc amount/strengthened
efects on organs systs
endocrine system - insulin sensitivity - catecholamine and gH response to ex
skin
imune systt
lungs
nervous system/brain - inc capillaries more utilised
what factors influe performance
bouchard, C. et al 2005 - gene map - summarise what has happened in last year - prediction of health or fitness - no agreement yet on ‘key genes’ using popn genetics - difficult to validate – separate population studies reqd
how study human muscle ‘phenotype’? - skeletal muscle. - How dna, to mRNA to protein - Strength and endurance mapped to samples
Considerations - species - type/duration/intensity of intervention o aerobic, resistance, inactivityy - acute or repeated - sampling site and time(s) - amount needed - mRNA and/or protein - localisation - housekeeping genes/normalization procedures o complicates, regulation - method – broad or narrow?
ReF: fluck et al 2005,
REF: Mahoney FASEBJ 2005 - after acute ex, more genes activated in sets - limited by number of biopsies you can take. Scientists would ilke one every hour - but used 3h and 48hr
Generating a human endurance ‘transcriptome’ - 24 sedentar subjects - 240 musc biopsies - 24hr post ex - measured phenotypic by important
500 genes ‘activated’ by ex in humans - COL3A1, FABP4, IGF-1, TGFBR2
what prdicts for improved cycle performance following 6 weeks training?
What genes regulate - better oxy deliv
Timmons et al FASEB K, 2005
Gene ontology analysis
PGC-1 inc by training in following hours
Ameln et al FASEBJ 2005 - HIF-1 drives expresion of epo. - And VEGF - At protein levvel, was regulated by acute ex, bound more to Dna, drives target genes,
Does epo play role in muscle? - perhaps, protective or androgenic - thus, epo might have systemic and local eeffects beneficial for performance
receptors of VEGF go up – inc to manipulate receptor side
5wks of training, VEGF goes up
to develop gene therapy fully, must understand cocktail of things that are going on
in gene therapy, CV side things are going on, but must know more to grow complex structues such as vessels
Targets of interest at geen level - transcription factors, angiogenic, mit biogenesis, hypertrophyt
cell doping - naked cells - encapsulated – put into tissue, then remove. – safe for cheater, since no trace. Can be done with epo and inserted anywhere. - sooner than one might expect. As many cell trials. And move towards gene modified cells. - Yesterday, venture capitalist in san diego, using fibroblaysts, for parkinsons
Questions and Answers
Question: focused on up regulation, but what was freq v down reg
A: usually more up regulated, but perhaps a quarter, 3-4times more up than down
Question: how do trained, elite athletes differ?
A: some surprising, some expected. Not easy to predict.
Question: can distinguish
A: no of subjects needed to study polymorphisms v high, often differe considerably. W n24, impossible
Question: important?
A: extremely. But every thousand base is … bypassed polymorphy by looking at integrated response
Question: study in male, not female? Same for female? Each react differently to training
A: what would you expect?
REsponse:
Response: total of 16mins, can dramatically inc endurance performance, no gender related differences. Might depend on ex mode.
Olivier: concern of cell therpay, problem earlier than gene doping. Today, company proposing use of tendon cells to strengthen repair of horses. So is coming at commercial level soon. One key element in detection is time window we have. You have observed some transformation at mRNA level. What is order of magnitude of change? Concern that signature will be lost.
A: presume that gene copying intensively is more stable and chronic than when you train. I would guess there is an elevation of gene doping product.
Olivier: what level should we detect?
A: problem is legal. Ban people that have strange pattern? Cell therapy been around for long while. Blood transfusion for over 100yrs. Bone marrow transplant since 70s, skin transplant, etc. cell therpay not new, but gene modified cells is novel and cells that are hidden.
Olivier: cells that grown and reinjected
A: yes, like cell
Andren Sandberg is rapporteur
Lunch
Session 2
Chair: Odile Cohen-Hagenauer
Vectors and Delivery Methods C. I Edvard Smith, Karolinska
Gene therapy - gene could be 10,000 base pairs - virus contains maybe 3,000 base pairs - human genome, thousand books with thousand pages
today, cannot fix gene, but put in an extra one
concept oif a gene
if cell goes through many divisions and gene is in episome, will be lost. So if need to put in cells that divide many times must go for integration. Only way to ascertaint hat will be in cell.
Problem with going from outside of cell to nucleus
Local and systemic gene therapy
Gene transfer techniques - non-biol methods (plamids, oligonueclotides) o liposomes and polycations (lipofections) o electroporation o in situ naked dna injection o gene gun (biolistics) - biol methods o transduction (virus-mediated transfer, most efficient)
drawbacks to viruses
DNA complexes – plasmids or oligonucleotides - insert size no limit (can use long stretch of DNA, makes possible sequences, marker of normal) - episomal – normally this; outside chromosome - short-term expression - broad host range - unstable in vivo
is possible to remove all foreign elements. Ie design genes that do not carry any foreign elements, so harder to trace
Virus as a vector for therapeutic genes, eg hiv
How use a virus?
Concept: the packaging cell line
IMAGE
Empty particles – allow introduction
Packing cell line 2nd generation
There are a number of viruses that can be used - ecah has benefits and drawbacks
Concept: RNAi – how does it work?
IMAGE
Recent phenomenon, a decade, first observed in plants. If introduce double stranded rna has different features
In mammalian cells, if, instead of long dsRNA sequence, use short siRNA molecule, can have same effect. Si = short interferring
Regulates gene expression
Can achieve stable expression – deliver shRNA
Vectors contain unique sequences that can be trace Provided you know where and how to look Apart from t vectors there are their products
Questions and Answers
A: when expresss siRNA, is v short.
Question: if do cell culture, get up to 10,000 fold interference.
Question: will day come when can do entirely in vitro?
A: yes, should be. But viruses also have problems. They rely on cellular machinary, so good but also limitations – must use normal process of making proteins. If do invitro can avoid regulatory problems.
Vectors and delivery methods – vector and transgene vector detection H. Haisma
www.rug.nl/farmacie/tgm
in non-viral vectors, mostly have much chemical stuff added to them to allow entry to cell
adenovirus
shedding data, gene therapy stdies
shedding
excreta – semen, stool, saliva, urine, blood germ line – sperm, ovum
environmnent – next of kin
if people treated with gene therapy, can find vectors in almost any of tissues
do not find anything in germ line - ie no transfer to next generation
Gene doping detection
IMAGE OF TABLE
Dna – muscle – no shedding - months For adenovirus, shed in serum, saliva and urine, but only last days AAV – muscle – serum saliva urine – weeks Retrovirus – iv blood – semen (probably through prostate) – weeks
Vector: - protein – no, requires biopsy - dna, rna – yes, blood, urine - chemicals – no, requires biopsy - antibody response – yes, blood
clearance of free dna IMAGE OF GRAPHS
Even if inject into muscle and leaks into circulation, no way of finding. - goes to liver and is broken down – perhaps find 10% of it in blood, after 30mins
dna detection?
Baterial is immunogenic
CpG dna: - unmethylated CpG motifs are abundant in bacterial DNA - the frequency of t CpG motif is supporess and highly methylated in mammalian DNA
detection?
Transgene - protein o human original, yes, elevated blood, urine o new modified, yes if in blood, urine o human modified, yes if in blood urine - effect – yes, if in blood, urine
use effect as most promising
specific detection?
IMAGE
Isoelectric patterns of epo
REF: Lasne F et al Mol Ther 2004, 10:409-10 - can see difference in number of glucose; same gene, same protein looks different from muscle or kidney - possible fror detection
detection?
Specific – every potential drug needsa specific sampling and analysis method – also detect other doping General – profiling allows t determination of (major) changes in gene expresion pattens by: gene array or proteomics
Genetic interventions IMAGE
Serum Protein Pattern diagnostics IMAGE
DETECT MAJOR CHANGE
Proteomics IMAGE
Establshes normalised picture of sports people on proteomic level, then look for major changes
Detection by proteomics
May be indication of gene doping – ME: WHAT else might it be
Post translation modifs
Mann and Jensen, Nature Biotech, 21, 255 (2005)
Gene expression profiles
IMAGE
Alreay used for cancer patients - sample from tumour, isolate its rna, then matched on a chip, comparative analysis from arrays - in sport, chip would convey change, 25,000 patterns on chip
Gene Array
IMAGE OF CHIP
Discussion - gene doping vectors will be undetectable - proteomics and gene expression profiling are powerful generally applicable methods and will be part of diagnosis and therapy in t future - requires fresh tissue, urine or blood sample of good (RNA or protein) quality - logistic (handlig, storage) - global change in sampling handling is needed
Questions and Answers
A: once gene is active, no way of shutting it down.
Chair: Problem, because need 100% proof to commit someone
A review of current gene transfger models relevant to athletic performance
Haematological system and red cells in particular O. Cohen-Hagenauer
Launched European Society of Gene Therapy
Mainly deal with EPO
What matters, detection of EPO or that carry more level of EPO than rules permit? - v costful
do you want to detect exogenous and transgeneand rEPO, or have world athlete not go beyond a certain threshold
Epo gene transfer - can easily be monitored in vivo (hematocrit) – as hematocrit will just increase - not supposed to induce an immune reaction - therapeutic indications: epo sensitive anemias, eg chronic renal failure
epo gene transfer 1. state of t art of vector systems 2. regulatable expression – pharmacological control 3. adverse effects – alluded to by haisma 4. detection of abuse and gene doping
state of art of vector stys
state of art of vector systs 1. dna electroctransfer of plasmid dna in rate muscle- just need needle, introduce gene in muscle, then electric field and dna will stay in. 2. polymer encapsulation of xenogrenic or allogenicc fibroblasts or myoblsasts engineered to secrete epo 3. sub-cutaneous implantation of microdermis biopump 4. IM injection of epo-recombinnt AAV
IMAGES
AAV-mediated epo gene transfer 1. long term expression (over 6 yrs) 2. fatal polycythemia (excessive levels) 3. regulatory system reqd – pharmacological control by an orally administered drug 4. adverse event: auto-immune anemia 5. detection of abuse and gene-doping
regulatable expressoin (3)
companies now investing into this sector
Questions and Answers
Coffee
Gene doping and the regulation of skeletal muscle hypertrophy Lee Sweeney
Skeletal muscle
Gene delivery into muscle - primary targets are post-mitotic (non-dividing) nuclei of mature muscle fibers - gene delivery vectors o naked (plasmid) o virus • aav serotypes 6 and 8 are most efficient • capsule modified lentiviruses o non-viral dna conjugates o adult stem cells • muscle and bone marrow derived
adeno-assoviated virus mediateed gene transfer - readily infects skel musc - accommodates <4.7kb synthetic gene - delayed onset of expression (Biut self compleent and high titrs decreates) - no viral gene expressio - no immune response in mice /capsid immune response in larger animals - no integration (?) into post-mitotic nuclei – better for FDA safety - long duration of xpression (likel years to decades) – but depends on usage, since only hitting postmitotic. Eg. Normal sedentary mouse loses no expression, but if hypertrophy, then lose in matter of months o in monkeys that are not exercising, expression remains
efficiency of aav gene transfer - 50-95% of fibers show expression of reporter gene (LacZ) delivered by AAV1 - transduction of -200% of all muscle in mouse possible w high levels - looks possible for dogs now.
So, enhancement?....
potential appliocs for sskel musc - primary musc diseases, duchenne beckeer, muscl dyst - loss of muscle function during aging - secration of therpaeutic proteins into t blood (factor 9 for haemophilia)
loss of muscle function during aging (sarcopenia) - progressive loss of muscle mass and force beginning in fourth decade of life - slowed, but not prevented by exerccise - negatively impats health and quality of life - occurs in all mammals - may be due to progressive failure of skel musc to repair damage (decline in regenerative capacity) o prob with ageing when satellite cell fusion doesn’t occur as well
Muscle Growth and regeneration. - Various growth factors, HGF (hamatocrit) - IGF-1 one of key factors – imp property (most inhibit maturation of muscle cells, so if over express, would inhibit muscile) but igf-1 drives proliferation, then XXXX
IGF-1 - drieves protein synth - reduces protein degred - stimulates sat cell different
GH-IGF-1 axis - local synthesis decreases with ageing
Will inc IGFF-1 expression im muscl promote growth and refgernation pathways?
IGF-1 expression targetd to muscle - utilize aav to achieve efficient skel musc delivery - utilize musc specific promoter (MLC1/3) to limit expression to skel - igf-1 over exzpresiosn should promote growh - injected legs did not have age related loss - also stopped loss of power
hyp - igf1 overexpres should promote musc growth ad repair leading to t following outcomes
IGF-1
Conclusions – - igf1 ocer express prevents age-relationship atrophy and loss of skel musc function - skel musc regen i\
20% or more depending
prevented fibrosis due to severe injury
would it lead to enhanceemnt for athletes? If combined w trainig?
IMAGES
Igf-1 effect local- - avoids harmful side effects, since blood levels of igf-1 not eleveanted - decteion difi or impossible without biopsy, unless surrogate markers. - But difficult to seee surrogate
Could systematic delivery of any ageny provide a similar effect to that achieved w local prodn of igf-1?
- a TF-beta family membner, myostain antagonise igf-1 action, limiting skeltal musc growht. With igf-1 trying to create a balance. So knock down myostat to create effect on igf-1 - possible cardiac toxicity - relatively speciic to skeletal musc - decreases fat - loss or inhjib or myostat inc musc mass - wyeth is in phase 2 clin trials w anti-myosttin antibodies for multiple types of muscle dystrophy – scarey note: all have dlated cardiomyopathy – could exacerbate cardiac condition, but speculative at this stage. Beginning to see effects. In obse patient, marked decrease in fat
Muscle growth and regen - would inhibit prolif of sat cells, igf inrceases
myostatin inhib could allow systemic delivery - antimyostat antibody injections into t blood of mice result in muscle hypertrophy - viral delivery to liver or peripheral skel musc could generate screaion of anti-myostatin inhib in blood o could look in blood for trace - should result in inc growth and repair - not clear if harmful side effects. Not clear would prov all benefits of igf-1 especially during senesence
gene doping could be detected by screening
myostatin KO Mouse - wild type v myostatin null - in any athlete, would not want total knock out
belgian bull
young child - parents, mother is competitive athlete
conclusion - gene transfer could be used for skel musc
nuber of properties could be changed - strength, but repair, better muscle mass, strength and speed, maintainence of mass and strangth during disue, inc endurance
is genetic enhancement going to be a reality? - inevitable - banned on safety and fairness o but safety sufficient - if used in widespread for preventing aging, then harder to ban in athletic population. Especially when earlier better for intervention. - Genetic profiling of athletes ‘ raise issues of genetic ‘fairness’ - If someone has genetically decreawed myostatin, then is also unfair
Where are we now? - can do this today o naked dna o direct injection o vasula injection o regulated gene expression
acknowledgement - elizaeth barton, linda morris, rosenthal, farrar
Questions and Answers
Question: these are small animals. But how many injections for thigh muscle of human?
A: we are moving away from injection, rather vascular delivery. But problem is immune response in vector
Geoff Goldspink
Animal gene transfer model Interested in musc regulation
Looking at XXX, derived from IGF-1
IMAGES
Biol actions of gh/igf1
Mgf seems to cause sat cells to inc in no –then goes away
Igf1 also involved, but later in process
Damage
Real outcome is muscle force
With knockout myostatin not strong – lacking in functionality
35% inc in mujscle strength within 3 weeks
already company on internet creating mgf – Phoenix pharmaceuticals
ME: how did you find this?
Splicing can be induced by siRNA
Prediction
IMAGE
Put
Detection - rapid screen mas spec
confirmatory tests - antibody methods and o - cell signalling using differeential gene expression
Questions and Answers
Tom: difference of view about what happens to myostatin knockout. Does it give strenght or not?
A: JHU argue that 17% increase in Arnold Schwarzenegger mice. Not a good balance in extra weight.
Lee: agree, if knockout altogether then not much strength .
Odile: but mujst increase other body parts
Lee: bones do compensate, do get larger. But not looked at tendons. But would assume they would hypertrophy as well
Geoff: myostatin KO; if keep putting into req state, can activtate w mgf, but if keep knocking out myostatin, energy pool diminishes over time. Athletes might use on short term, .
Lee: child born with KO liely to have problems, but mother doesn’t.
Question: shown that athletes using steroids get inc in sat cells, so can detect by muscle biopsy.
Geoff: butler brown in paris when taking biopsy from steroid using athletes, telelle length – life of sat cells – diminished – whereaas we might live to 180 efore run out of sat cells, athletes and exessive exercise might run out
Mitochondrian power plants: target for performance enhancing gene therapy Doug Wallace
Mit genome - 1500 chromosomes, 37mtdna genes - all key energy genes
african
expressed through oocyte
males do not contribute
life = structure + energy
Schriner s et al 2006, science, 308, 5730, 11… - increased lifespan by 20%, assoc w marked decrease in mtDNA
mtDNA, since maternally inherited, can only change over long period of time - difference between everyone in room influences level
women started in africa about 200,000 years ago move to asian then to northern and then to americas
highly correlated w geographic origin – specifically latitude – because of temperature
mtDNA have specific point mutations that change coupling from ATP to decreasing work efficiency, hbut increaseing heat efficiency
changing of coupling efficiency
excess calories burned as heat
A nieme and k majamaa, 2005 Euro j hum gen 13 965-969 - mt dna genotypes correlates w finnish elite endurance versus sprinter athletes - functional difference between type one or two nucleotides
can radically change performance
possible that might be strand invasion of nucleiotide - if switch from tightly to loosely coupled, would introduce muation, change 1 polymorphic base, inrcease performance 5-10%
Questions and Answers
Question: what is importance of mt ….?
A:
PPAR and the creation of the Marathon Mouse Ronald M. Evans, Salk Institute
What are they? - peroxisome proliferator-activator receptors, comprise set of three related nuclear hormone receptors, that control broad aspects of lipid metabolism - expresed in different tissues and are naturally activated
Fat storage and burning - determined by relative levels of ppars,
revving up metabolism - synthetic ligand GW1516
created marathon mouse (ppar)
transgenic mouse - now expresses ppar-delta
muscling in on endurance - will also treat wildtype (ie. Normal) littermates w orally active PPARd specific rdug
red muscle increased transgenic mice - pink – glycolytpic fast twitch type ii - - suggest switch to type 1 myosin rich fibres (slow twitch) - from carbo burning to fat burning
A – better B – worse C – same
?
treadmill challenge
improved exercise performance in transgenic mice - 80% more time and distance capacity what about ppard null mice? - Total running time only 20min, compared to wildtype of over 1hr and transgenic of more than 2hrs
Under study – does GW1516 enhance performance in mice?
Future – magic pill?
Clinical - muscle wasting - weight loss mec related to inc oxidative meabolism
opp for abuse - inquiries from athletes, coaches, a horse trainer
conclusions - ppar-delta directed metabolic changes produces a mouse w a long distance running phenotype - possible to alter single component of compplex system –ie muscle fiber en burning ) to enttrain t rest of physiologic network - genetically produced ‘delta’ muscle fibers confer high performance even in absence of exercise (training) - exercise physiology can be predictively manipulated - ppar-delter receptor
lead by Yongxu Wang – now running own lab at U Mass.
Gene Doping - possible orthopedic applications Chris Evans, Harvard Medical School, Boston, MA, USA
Inflammation/arthiritis – phase I
And repair of: Bone Cartilage Ligament and tendon
Arthiritis is chronic, requiring long term gene expression, the other 3 are not – repair, then stop
Gene tansfer to the synovial fluid of joint
ex vivo and in vivo
Some success with ex-vivo
ex-vivo preclinical - safe feasible in rabbits, rats, dogs, mice horses - levels of expresion sufficient to inhiit animal models of RA
use retrovirus
phase 1 study in knuckle joint w rhumatoid arthiritis
put into joints that were due for removal
PAHSE I RA STUDY conclusion (N=2) - gene transfer to human joints is safe and feaible - intra-articular gene expresion occurs - patients accept procedure well - reported relief, but not fully documented - phase II studies merited , BUT which vector
not progressed due to lack of funding. Big pharma wont touch it, small biotech don’t have enough money, millions just to treat small number f patients, but made progress by going around with it.
REF: Evans et al PNAS 102 8698-8706,2005
Targetted genetics company in seattle study.
Also in dusseldorf on modifications to determine clinical response. First year patients respnonded dramatically.
Horses Colorado state uni collab Experimental study in horse wrist joint, experimental model. Remove cartilage and inntroduce chip, measure effects of XX.
Induced disease at day 0, introduced vector after 2 weeks, disease under way, therapeutc not prophlyactivc, at end of experiment untreated joint shows erosion of articular cartilage
Absent from horse who recent therapy
Now bone
Direct injection of adenovirus – BMP-2
V responsive to gene transfer
Do this by making hole in animal’s bone and intro virus (BMP-2)
Rate undergo surgery, where femur exposed and external XX attached 5mm defect in femur would not heal if now use adenovirus and inject 40micro ltirs
after 8 weeks,good healing
Wolf’s law – how bone responds to load
After pins removed normal mineral content returns
Effectively repairing bone that would otherwise not occur
Concluding that we can do this
Cartilage
No intrinsic ability to heal
If partial injury to articular cartilage will not repair
If goes through to bone bone marrow defect
Trying to take adv of fact
Use with rabbit
ligament and tendon - healing initiated by forming of blood clot - gene transfer to healing ligament
see if enhance healing
gel-mediated gene transfer - ad GFP placed into migration model gel - 1 week - after 3 seeks more cells transduced
Presnet status
Indication – status – relevance to doping Inflam/arthiritus – phase1 clinical – high Bone – advanced preclin - ? Cartilage – preclin - ? Tendon/ligament – experimental – high tendon-muscle
If uses it when injured, then goes back to track, is horse doping?
Overlap between legit medical use – do have arthiritis – but overlaps with doping, since reason for arthiritis is due to over-traiing, so we increae their ability to train
Questions and Answers
Arne: Different between doping and treatment is already in use as TUE. Sports peple should be able to benefit. Problem is when it may go beyond.
Monday
Chair: Friedmann Standard in medical doping involves looking for assays
Don’t worry about looking for epo if you are interested in finding it
Look for local effects Systemic Homeostatic
Need un-biased global assays Changes in gene expression patterns in distal non-target tissues
WADA Perspectives on Gene Doping in Sport Olivier Rabin
Anti-doping analyses started in 60s based on detection of drugs in urine (stimulants and anabolic steroids) Progressive incorporation of - immunassays: hcG (1987); LH (1997); hGh (2004) - electrophoresis/focusing: EPO (2000); HBOCs (2004) – human blood oxygen carriers - flow cytometry: blood transfusions in 2004 trend evolving from pure chemical analysis to incorporate more biochemistry and biology
evolution of rules - from imperative need to detect and characterize t doping substance(s) in athlete’s biol specimen - to - possibiilty to use markers of abuse of substances to report doping - as long as scientifically validated (concept and method)
markers approach already in final development phase for hGh detection: - IGF-1 (liver) - P-III-P (bone) Abnormal markers variation are used to qualify doping Hwr, almost 10 yrs of research and more than $4m
Fundamental concept
Abuse: substance – extra gene - non physiological modification (imbalance) – change in homeostasis - detection: where to look? o Genomic o Transcriptomic o Proteomic o Meabonomic
What to look for? - signatures of changes unique to doping classes of substances
cannot say one substance equals one specific signature, but can make claims about relationships
limits in - interpretation of gene modifications - protein and peptide knowledge - interpretation of metabolic changes
some gene regulations not fully understood
where to look? - accessible cells or biol fluids w minimal invasiveness (urine? Blood cell lines, buccal cells; ) - imaging (changes, markers, radiolabeled tracers)
challenges faced - identification of right target: where, what how, interpret? - Accessibility to measurable modifications (invasiveness, time window, ethical methods) - Eliminate other explanations than doping (gender, age, diseases, enviro, ethnicity) - Development of specific tools for anti-doping - Extremely sophisticated constructs w fine modulation already in animal models - Approaches may well work for gene doping or some substances, but what about cell therapy, in partic autoloous cell transplants – eg. Tendon strengthening in horses – extremely difficult to monitor. Looking for same cells in same organ. Already in application - Costs. o Money we can invest has limits. o Also limit of cost we can ask for analysis. - Layman accessible! – particularly lawyers.
Hope - epo study in monkey showed genetically transferred epo still detectable o not endog - microarrays and SAGE appear to reveal target genes or mRNA. Proteins are promising. Metabonomics will grow. - Combination of discriminant factors o Projects ongoing on physiological markers that can be followed by biochem o Have longitudinal XXX of athletes and detect unusual variations o Doubt in future that can test every athlete for gene doping. Must start
Pragmatism - science is likely to deeliver the antidote. When and how? - Resources can be v demanding on anti-doping and beyond capability. Need to partner. - Anti-doping market is limited. - Partner with academic or private org - Hope for some large scope methods, not too narrow in application - Even if gene doping applied, limited chance of success, delay in significance impact in sport, though success will come…
DHEA is an anabolic steroid like testosterone and THG: Global gene expression analysis F Labrie
Use of microarrays applied to DHEA (hormone mutant)
Thg includes a genomic signature typical of a potent anabolic steroid J of Endocrinology 2005, 184, 427-33 Labrie, …. Claude Labrie
What is DHEA? - precursor of all androgens - from adrenal or food supplement (will argue against food supp) - dhydroepiandrosterone (DHEA) - leads to DHT dihydrotestosterone
The anabolic steroid control Act of 2004 has amended the US controlled substant act to include androstenedione, but it excluded DHEA.
‘ther term anabolic steroid means any drug or hormonal substance chem or pharm relationship to testost (other than estrogenes, progestins, cortico…’
JAMA 280, 1565-1566, 1998 - qual control of DHEA dietary supplement products
HFL Jane Roberts
Difficulties, always new pharma drugs
Current methods cannot detect gene therapy
But if devevlop, perhaps could apply to other things, proteins/peptides, etc
Gene therapy to gene doping - non-therapeutic use of genes, genet elements, and/or cells that have capacity to enhance - muscular, anaemia, pain relief
alternative testing strategy - surrogate marker approach (biomarker)
cell tissue, organ, organism - complete ensable of biomolecules - reflects influecnes of t enviro introduce exogenous substance
biomarkers - transcripts - proteins - metabolites
transcriptomics vs proteomics
transcrcipts (mRNA) - cellular material o white blood cells o urine epithelial cells - differential gene expression - complementary to proteomics
proteins - serum/plasma - secreted proteins - includes PTM - simpler assay - sample stability?
Surrogate marker approach
Screening approaches
1. pattern recog (uncharac markers) a. transcriptomics i. microarrays ii. PCA, PC-DA b. Proteomics i. Gels, mass spectra ii. ANNs (WADA Grant) – artif neural networks
2. biomarkers assays (charac markers) a. transcriptomics, proteomics b. characterise proteins c. development panel assays (multiplexing)
1. pattern recog
sample prep is key- proteins in serum
Questions and Answers
Question: 4% cvould make world performance difference. Can array technology detect sorts of changes to give improvements of performance. Also legal issues – if athlete tested with array, about 36% of affeymetrix, not confident.
A: at proof of principle stage. Relies on probability
Proteomics J Yates, The Scripps Research Institute
Used for biol discovery
Ideas have been to apply technology to understand how proteins come together
Achieve total protein charcaterisation
Driven by mass spec
Single protein vs shotgun proteomics
Quantification
Global method: Would not stand up in court of law
Questions and Answers
Question: mentioned 20-30% SD, how about if shipped around world?
A: 20-30 is within sample.
Question: what preventive measures to keep stable.
Question; had possible to look at disease or treatment?
A: if biomarker, than one that shows dramatic. PSA doesn’t show much variation across sick and normal.
Question: Haima – not easy to detect in mass spec because some proetins don’t fly very well
A: at peptide level are problems
Proteomics as a tool to tdetect gene doping: intro to protein profiling C C King, San Diego, UoCalif, dept of pediatrics
How can embryonic SCs be used for …
Proteome complete set of proteins in a defined cell type, their relative quantitiates…
Outline - 2D electrophoresis: analysis and pitfalls - establishing positional databases of proteins for analywsis - frcaction - applics for wada
2D gel electrophoresis - few do this, since pattern recog alone does not give much diagnostic information - but does offer possible to analyse specific proteins
coffee
Research Report on studies Geoff Goldspink
Exercise - knee extensor weightlifting exercise - 3 sessions per week
using muscle biopsy
with elderley people
if give growth hormone and then exercise, leads to substantial inc in MGF - related to inc in cross-sectional area of muscle fibres - these old people are hormone deficient (drop by 2/3 from teenage to 70+)
relationship between MGF and muscle
studied young people next - n16 - give growth hormone, then 4 week washout, then placebo - take biopsies before and at wk2 and wk8 with blood samples - untrained indviduals
repeated with trained athletes - blood levs went up considerably
been taking muscle cells in culture and putting serum on them
use muscle cells in culture
IGF-1 gene transfer
3 Different types of IGF-1 in muscle tissue
actually 6 types (2 classes of 3)
with placebo, inc in class 2 with Gh wen down
with MGF of Class 2,
can now purchase human muscle cells
with GH, get inc in Class II with MGF, mainly class 2
Class II MGF trascripts in cells treated w Human Serum Samples - clear distinction
Present project with NHFL Newmarket and Nott Trent Uni - human and murine serium samples for o biosensor o other markers o proteomics – mass spec/neural network
Study 2 Trained Subjects Experimental protocol - n15 - from uni exercise science dept - in training - randomised o GH + training o or Placebo + training,
concern that they might be disqualified from sport
Currently collab
1. mice receiveing hgh delivered using a mini osmotic pump
mass spec can distinguish
detection - rapid screening using mass spec - confirmatroy w o antibody o cell signalling using differential gene expression
present and future challenges in detecting enhacneing substances - synthetic/recombinant analogues - generic sbstances - new methods of admin - gene doping
providing we have good methods, it’s almost immaterial whether gene doping or not
Transcriptional and proteomic effects of IGF-1 Ted Friedmann
Does igf-1 casue sig molecular changes useful for detecion? - changes? Basis for detection?
Model systems – in vitro and in vivo - initial studies in in-bred mice – avoid problem of indivd variability, polymorphisms - cultured murine and human muscle cells o C2C12 o Primary human muscle cell - In vivo, IGF-treated mice o Muscle, blood, urine, saliva, other organs
Exptl design – short term
I. transcriptional response to IGF-1 - microarray, affymetrix
candidate of genes that can be used to detct
approach to screening for IGF-1 - identify genes most markedly regulated by IGF-1
Application of microarray technology for the detection of changes in gene expression after doping w recombinant human growth hormone Rene Stempfer…. Christa Nohammer
Goal: development of target dna microarray to identify specific change sin blood cell gene expression related to t admin of hgh
Present project - feasibility study o in vitro – different blood cells o in vitro - peripheral blood mononuclear cells
microarray procedure
Application of cellular chemistry and proetomic approaches to t detection of gene doping Jane roberts
Objectives - identify and validate protein expression patterns (fingerprints) o GH IGF-1 protein gene construct o Mouse model o Applic to humans y2-3
Yr1 - show that genetic manipulation results in change in genetic fingerprint - can detect w pattern recog
Doping analysis relevant for potential application to gene doping detection James Segura, Biomedical Research Park, PRBB, Barcelona
Oxymoron - a thetorical figure in which an epigrammatic effect is created by t conjunction of incongrous or contradictory terms - eg. Not-for-profit drugs; research and physician
detection of doping substacnes - problem w substances identical to t endogenous ones (endogenous-like substances) is it possible to detect non-natural traits in natural substances?
Gene doping makes this problem harder
Peptide hormones
Indirect markers - physiological effects - popn studies: probability
direct markers - subtle chemical difference between t admin drug and t natural hhormne produced by t b - difficult to find direct markers
indirect dtection of GH
liver metabolism - igf-1, igfbp-2 and 3, als
bone metab - osteocalcine, p-III-p ; picp; ictp
gene expression of gh isoforms
need further verificaiton that change derives from gene therapy and not something else - use non invasive imaging that shows expression in an unexpected tissue o IMAGENE
A long way to go before detection
Potential for non-invasive imaging in anti-doping efforts Kurt Zinn
Outline - background - imaging - potential - points for consideratoin
potential imaging targets - direct o transferred genee o products from gene - indirect o change in metab due to chronic exposure to transferred gene products o changes in anatomy due to chronic exposure to transferredgene products o inflamm arising from gene transfer or expresed gene product o reporters of pathway activation
imaging modalities - radioactive-based - gamma-ray imaging - posittron empission tomography - xray computer tomography - magnetic resonance imagine - light-based imaging - ultrasonography
imaging that maybe immediately applicable to gene doping
Roussel et al, Fig1, J app physio, 94, 1145-1152, 2003
Richardson et al Biochem Soc Trans, 30, 2002 232-237
Potential methods - direct o imaging gene transfer agent o imaging protein gene product o eg
meausrement of firefly gene for light if mouse produces light, then gene is being expressed
Imaging tc-99m-ad-luciferase
Particle goes to liver
Shows light ommision from liver of mouse
Questions and Answers
Lunch
Session 4
Tom murray
Screening a worry
Matt
T culture of sport Natural talent and effort Natural variation of talent is intrinsic to sport – if your body doesn’t fit, then do something else
New types of sport have developed that appreciate natural talents – where certain body types suit
Equal opportunities - not part of culture of sport
cannot complain that
does not imply that sport activity is result of genetic lottery - there is no genetic lottery, but evolution of natural talent combined with effort
fair chance – if different heights where height is relevant, then is unfair – so we divide in groups - age differences, sex
limits of accessibility on fair innings argument
need sufficient number of competitors to make it worthwhile
natural variation –s mostly self-regulation
people w extreme gene mutations not become elite athletes
limits of genetic screening
gene doping for improvement talent and level of effort - opening for fair innings – set up games where GM athletes complete, but should we?
The phenotype routlette - natural phenotype is t result of a delicate balance in order to master o genetic program o epigenetic instabilities o biological chance o environmental challenges
for safety reasons - major reason against - keepin athletes healthy is difficult enough at such extremes of performance. With gene doping more complicated - delivery, expression and safety - protect athletes from their own winner instincts - protect next generation from manipulating their health - health expenss for sports moveement will likely sky rocket
if we assume safety? - natural mutations have many advantages appreciated and accepted - some can be screened for - hwe, where draw line, w gene doping, one has to screeen for many genetic variants in order to meet t same requirement
snowballing inflation -
rules of fair play - sport activities presume a pre-competition agreement about rules - winning is essnetial but so is also fair play
fairness as equal opp not part of sport
as fair share of innings – part of sport with rough measures
as fair play – intrinsic
protecting privacy - can we protect, with testing - it can, if understand what privacy is all about - often willing to give up privacy in certain conditions o enjoying sport activities is one of those conditions
gene testing – includeed in rules of fair play - accepted part of different practices - research, medical treatment, sport activities - need to regulate. How reliable? Who has access? How handle safely
yes to gene technology - no to gene doping is consistent w a yes to medical treamtnet
aging of muscles problem – fear that cannot set limits - distinc between gene transfer in care of patient, always balancing – benefits v risk - patients are closely mointored to correct for unforeseen - v different thing to do this on healthy people, where not monitoring closely
these questions not new, many drugs that used on old people that we would not use on younger
eg. Morphine good for people at end state, does not mean that give to anyone in pain
ethics and t challenge of t potential use of genetic technology in sport. Angela Schneider
Summary of effort, talent and fair play - sport is rule governed - action against rule is cheating - should thre be a rule against – yes - hwr, important practical and ethical problems
Winning the genetic lottery - is it fair to compensate for those who have lost t genetic lottery from a sport perspective but still wish to compete in elite sport by enhazncing - Hannson ‘why not allow gene doping’
Need to answer some important concepts
Contested distinctions - natural and unnatural (artif) - point of sport is to measure difference o we have allow naturally differences to affect outcomes o hwe, we wil not allow t potentially fairere gnetic equalization that would occur through enhancement. Do we have good grounds?
Ethical foundation - preventing avoidable harm - paternalism - performance enhancement - vision of sport and how gene doping fits within this context - sport for humans not humans fro sport - contested
do not design humans for sport
ME: but we do
Sport exhibits values - leadership must choose which values - eg. Equity of access; implications of genet therapy for those who currently live with disease or disability; specific sport oriented issues
Laser eye surgery - language is intructive – if describe as removing normal variation, status as enhancement clear. But if removing abnormalities, more like correction
LASIK - used in some sports. Should it be? - Enhances
Comparison w rules against doping - one point of rules is to limit risk - risk of laser eye, 5-10%, possible risk - how much risk is too much? - Not clear why sport should accept any degre of risk for beyond performance – ie enhancement - Most relevant value is definition of health
Consistency and credibility of rules In anti-doping have analogous substances
Principle at stake
Distinction between enhancement and repair - restorative and addtive distinction (fost)
repair is unprobc
incidental improvement - Tommy John elbow injjury – generalyl accepted
Surgery in absense of defect is enhancement
But Tiger Woods – laser eye
Laser correction public use now
Not like cheating in way that steroid use is
Practice doesn’t cause sufficient harm But this sets bar high
Things that are acceptable elsewhere, not aceptable elsewhere
What do with grey zones? - arbitrary, but
with strict liability
privacy issues and access to genetic information - genetic information especially private - indicative of identities in special way - puzzle – genetic make up not indicative
social question - maintaining privacy of personal genetic information vs potential role of sport community becoming wedge used to derive greater geneal
wituhout moral support, sport will not be able to preserve humanizing influecnce s if sport recognises and re
genetic modification and improving humans - enhancement
sport conflronst problems
if sport faces problems
who decides?
Sport is leading by saying we will regulate
Ethics, enhancement and sport Tom Murray
Meaning of soprt as a human activity: why the world loves the olympic games
Excellence in sport as expression of - natural talents - virtuous perfection of those talents
Aristotle – eudamonia - full good natual ilfe
there are unvirtuous ways of getting these
objections to doping control in sport - claim of incoherency - line drawing problem - resistance Is futile - appeal to individual liberty - romantic/promethean view
ME: but this ignores game theory. It’s not about the rules. It’s about the intended test.
incoherency claim - no cnpcetual ethical or practical distinction among different means of enhancement sport performance o the marathoner’s shoes
response - hypothetical
Line Drawing problem - all possible lines are arbitary - aribtrariness is fatal flaw
conflates two meaning of arbitrary - as unprincipled, indefensible - as reasonable response when o drawing SOME line is defensible o placing line IN THIS PLACE likewise
athletic virtues – fast.
Why 5 players Why not 50 players, look like rugby - ME: not really. Dimensions of playing field,
But this would not have any of the characteristics of bball
Why draw in this place? - why not 6 in team? Or 4? No 1 on 1
would not have a game of bball
ME: tom is not distinguishing different kinds of rules – he is talking about constitute rules, not regulative rules
Resistance is Futile - not a first-order ethical claim - primarily two empirical predictions o control will be impossible o bad conseques ensue - control is never perfect - depends upon o public consensus o effetive enforcement
ME: he is now switching to regulative rules
ME: breaking some rules is not bad in intelf
there are silly rules – prohibition in us
So must have a public consensus in support of rules
In sport, if ban certain things but do not enfocre
Argument from Individual Liberty
Presumption in favour of liberty Paternalism difficult to defend w adult athletes Hasting Center project - coercive impact of drugs in sport: the unlevel field
doping control done well provides level playing field
argument from liberty fails to
romantic/promethean view - humans as self-creators - understand cultural and philosophical context and implications - valorizes unfettered will and self-manipulation - relation to human flourishing? - Case of anorexia o ‘anorexia is t cultivation of a specific image as an image – it is purely artficial rceation and that is why it is so admired. Will alone produces it and maintains against considerable odds’ noelle casky, 2003, 129
Triump of Performance Principle - max performance by any means at any cost - power lifting: drug free and? - Unavoidable conseq of refusing to set limits o Greatly increased risk rules governing a practice not equal indefensible parternalism - Threat to spirit of sport
No longer throw people to lions
ME: so the level of risk in sports is just right?
Ethics of enhancement in context - non-trembling neurosurgeon - point of practice: spirit of sport - not t means per se, rather their relationship to t goals of t practice, values and human flourishing
imagine drug with no side effect
imagine drug diminishes hand tremour and neurosurgeons see benefit
let’s also assume that mperson you love most in world needs operation
2 surgeons, one says biomedical enhancement always ethically wrong, never use tremour reducing, and second says, I use it all the time
you would choose one w best results
first surgeon missed practice of surgery
point of sport is natural excellence
point of surgery is to make well
different kinds of human activity calls for different kinds of rules - partic to circum of relevance
not bad to prevent muscle wasting , but still suspect as use in sport
because of goals and values of practice
challenge of genetic enhancement in sport
what do we value in sport? - natural talents - virtuous perfection of talents
what do we disvlaue - distortion of relationship between natural talent, virtue
what makes a talent natural?
Complex phenotypes - genome as ecosyst o genes interact complexly w each other genes, w external environment - genetic difference in general not rigidly determinative for human behaviour o see behavioural genetics report at hastings center website
child who has been engineered prenatally, natural?
ME: ecosyst argument – just a complexity argument?
Differences in natural talents? - as vicious inequalities to be redressed? 1. Vonnegut’s ‘handicapper general’ • Disable smart - As expression of human of human variaton to be celebrated? - Olympic movement opts for t latter? 1. Alternative romantic/promtehan, triumph of performance principle
ME
Final session
Jacque Rogge
Test to check for drugs for neurosurgeon
Need clear rules for world of sport
Fairness – but is life fair?
Sport is arbitrary in some ways
Can this be accepted?
Is it fair that kenyan athlete born at 2000m of altitutde has special diet, runs 10km twice a day? Fair to compare with swedish athlete
Laser eye surgery, but would any physician accept to do that? Any ethical physician would refuse operation without pathology
Look at high-jumpers
Achilles tendon most fragile for fosbury
If in 10-15yrs, cell therapy to heal tendon and grow by 10% more and allow better training, forbid? – yes it should, but I need advice.
Paternalism - we cannot have been told to decide for - gov put strong warnings on sale of tobacco. But athletes do not know what is dangerous for their health.
Basis of beliefs
850million people practcising sport, 750million recreational
every recreational is competing with self
only 150million in sports contest
we believe that this pyramid provides great educational tool, for body and mind
sport taches social sskills- achieve more in a team, than alone
respct sport, respect society
sport integrates
sport brings health
sport shapes identity
we know life and soc is unfair, but social value of hierarchy – doping destroys ranking system
we believe that protect health, even if paternalism
believe in one example – that fight against doping is important for keeping explemar of sport
different between nature and nurture - virtuous perfection is essence of sport - everyone wants to reach limits – leaves sense of accomplishment - important anser against existential fear that everyone has – who am i?
recruitment - social aspect - champion is admired - not everyone born with talents, but way athlete behaves and lead life is important to protect. Genetic doping would destroy
doping rules are imperect
compensation theory - compensate up to normal level, but then are cheating, but allowing less effort athlete to be compensated, then penalising the champion
my plea is please give us clear rules – must be crystal clear
enhancement not be allowed
where draw line must be done with ethicists and scientists
Stockholm Declaration Arne Ljungqvist
Composed of olivier, ted, and arne
Today, several human genetic diseaes can be succesffuly reated by gene transfer Gene transfer is still a very immature and it is still an exptl field of human medicine
Challenge?
Change serveal to ‘a few’
Extensive and rigorous regulatory mechanisms need to ensure safety of research subjects and patients
Gene transfer procedures must - follow code and principles of human exptn and clinical research - be performed strictly in accord w local and national rules and regulations for gene transfer in clinical research
Comment: these are more general reseacrh
Tom: human beings?
Lee: clinical trials
Tom: clinical research aimed at dealing with human disease, but some of this will not be about disease. ‘Follow codes and principals governing research to human subjects’
Matt: follows nuremberg, etc
Tom: these are minimal conditions, we can elaborate
Lack of compliane w standards an rules of gene trasnfer procedures must be considered as medical malpractice and/or professional mis-conduct
Development appropriate sanction mechanism for illegal application of gene transfer in sport
Gary: who will develop?
Comment: since no legal, ma
Maybe unethical or illicit
Illegal implies court of law
Unethical and/or illegal
Promote public discussion issues on THE PROSPECT OF gene based enhancement and develop education progrms
Be developed
Comment: this implies it exists
Olivier: can argue this in animal models
Odiele: reservations, since education can be spreading
scientficic progress made through resarch projects supported by WADA and others suggest that new detecion and screening methods are likely to emerge in t near future, which will help to keep sport untainted by gene based doping methods
Cell doping? It is covered if we move entirely towards gene.
Delete ‘near’?
Lee: must emphasise need for research
Support research programs instituted by WADA and other anti-doping organizations
Comment: ‘should be supported’ at end remove support
academic and private research organizations to dedicate resources to further progress in gene doping research should be encouraged
Larry: deter, not just detect – progress to ‘deter’ gene doping
Gary: government?
Academic, government and private research
Genetic and denomic charcaterisation of athletes to determine genetic traits is contrary to the principles of sport
Rogge: contradiction with screening
Odiele: when speak of genetic trait, must speak of interited trait
Dave: might be reasons to screen for genetic traits in medicine
Tom: say something about unwise nature, but not sure contrary to principles of sport. Not because against principle of sport, but because of potential harm
Lee: must specify athletic traits, not genetic
Ted: not determination of trait, but use of it to exclude. Ie. To determine eligibility
Peter Fricker: this research has been done. Issue here is about discrimination. Need to look at genes and risk of illness.
Tom: use of genetic information about putative athletic ability to discriminate against athlete, should be strongly discouraged.
Add to ‘select’ or discriminate
Peter: must allow ethical reseearch must proceed to validate role of genetic information
Enhance awareness of potentiall illicit use of gene transfer techniques in sport
Promote knowledge on medical and physical dangers associated with gene doping
Odiele: woiuld we like to put forward idea that there are dangers?
Olivier: dangers alone?
Odiele: why not ‘misuse of gene transfer’
Olivier: risks or dangers?
How about potential risks?
Olivier Rabin
ME: why not inter-governmental rules and regulations? As well as local and national