Gene Doping ConferenceFlorence, Italy 2008.10.25
Maria Luisa Giovannucci Uzielli
MODERATORS: Angela Schneider and Mauro Giacca
Arne Ljungqvist 1989 following Seoul 1988
Florence was first anti-doping conference in 1988
HM&R committee - list: 11 - lab: 8 - tue: 6 - gene: 5
Gene Doping Panel - Ted - Odile Cohen-Haguenauer, France - Lee - Doug Wallace, California - Kurt Zinn, Alabama
$7m annual budget (1999)
Torino 2006 - Austrian skiers - IOC had info from WADA on the team – training site found haematological lab – found no athletes – WADA sent message to IOC – Austrias already in Italy – IOC informed Italian authorities of suspicion – engineer was known to be around athletes – if IOC had not acted, would have been blamed – IOC indicated that it would make a surprise test on team in 48hrs – Italian authorities came back in 24hrs indicating coordinated action – troops were guided to find the skiers – Austrian team panicked and jumped, some escaped, some found – Italian authority were investigating – all tests were negative – but Italians found material (illegal in italy) – would not had been discoeverd had their not been a law in place – based on this, IOC could ban number of Austrian athletes and officials – Austrian Olympic Committee fined $1m to IOC – Italian law prosecuting now
China – did have similar law in place to allow Chinese to do the case –
Gene Doping - transfer of cells or genetic elements or the use of cells, genetic elements or pharmacological elements to modulating expression of endogenous genes t having the capacity to enhance athletic performance, is prohibited
can add something to list if makes 2 out of 3, but can
for gene doping is required that is performance enhancing – exceptional case, other elements do not have this stipulation
use of medical treatment without medical indication
PPARdelta agonists PPARdelta-AMP-activated protein kinase (AMPK) Axis aonists (eg. AICAR)
Unacceptable for medical and ethical reasons
St Petersburg 2008 Particular concern about internet distribution Boundary between therapy and enhancement
ME: what is your best guess on the schedule for how close
Applications and Grants - 27% of WADA budget goes to detection research
genomics, proteomics, microarray, imaging/detection, markers, bioinformatics
The Future - WADA is certainly the lead agency – in fact the only one that I know of – in the application of modern molecular genetics and DNA technology to t devel of improved methods for detection in doping and in averting the use of gene therapy approaches to doping’’ (Ted, friedmann in WADA Play True, 2007).
In certain circumstances we are ahead of cheaters – no evidence of use in sport yet, but have prmade progress
Francois XXX – here at conference – testing Tour de France –
We are ahead of those who might try to do this
Ted Friedmann Gene Modification in Sport: Doping and Detection
First meeting of this topic outside of WADA’s organization
Certainly possible that gene therapy has been successful and has cured people, but few are willing to say this in public, since many cases have shown disease symptoms later on (SCID-II)
Progress in treatment of childhood blindness by gene therapy (Leber’s amaurosis in children) - little doubt that has been effective.
Gene therapy as an immature technology is reserved for serious disease – “for the moment”
Springsteen - repoxygen
Bhasker and Friedmann (2008) Insulin-like growth factor-1 coordinately induces the expression of fatty acid and cholesterol biosynthetic genes in murine C2C12 myoblasts BMC GENOMICS, in press
WADA informatics digital data processing platform
Policy and Ethical Problems caused by anti-doping regulation
WADA Code 2009 –
Pietro Mennea, 1980 Olympic Champion (gold medal 100m), expert of Law "Doping in Sports Between National and EC Regulations"
can you win without drugs? Yes.
I never had any major injury, no muscle tear - I was regarded as the hardest worker in the world of athletics –
So, I still believe you can win without drugs
I was introduced to Cassius Clay – and he was told that he was the fastest man in the world – Clay said ‘You’re white’ and I said ‘yes, I’m black in side, blacker than you are’ – regardless of genetics it’s possible
Even if not predestined
Comparison between Bolt and myself – win less in Europe? No. today, Afro-Americans are winning today. Jamaicans.
What have we done for anti-doping? Before WADA was in hands of sports agencies Previously handled by IOC Purpose was to control laws
Matter of public health cannot be left to sports – state must be involved.
WADA cannot succeed in battle by themselves
We have to believe in this.
2003 WADA Code in Copenhagen – convention against doping -
BALCO – THG – Marion Jones not positive, failed to be truthful in court of law
We need a criminal law – marketing now more than it was 20 years ago, in the hands of organized crime – mafia, Italian-American, Chinese, Russian – in sale of substances
Sale in gymnasia, spas, brings in money for criminal activity
Only if the state is involve through law Community Criminal Law – now 27 nations agree – uniform the control of crime Law did not pass - up to now, nobody has put forth this kind of request. Nobody asked for passing of criminal law.
Countries with laws 1999 Denmark (recently amended) 2000 Italy 2006 France 2006 Spain – effective 2007 – spain one of the last due to Operacion Puerto 2007 Austria
doping will never be defeated because BALCO for eg – there will always be people like that – problem of making money
people in sport surrounded by businesses
Federico Bussolin, 1st at Eurojunior Championship 2008 (200m Butterfly) 2nd at World Championship 2008 (200m Butterfly) "Testimonies by a Young Athlet"
1999 WADA established I was an MEP and witnessed creation of WADA, which is doing an enormous amount of work against doping.
18:15-18.30 Voula Kozompoli, silver medal at Athens 2004 Olympic Game (Women Waterpolo), Captain of Olympic Greek Waterpolo Team at Beijing Olympic Game "Testimonies by an Olympic Athlet"
Andy Miah “Genetic Enhancement via Genetic Selection: Bioethical and Biolegal Boundaries”
19:15-19:40 “This is Florence” A short video-presentation
20:30 Guided visit to the Palazzo Vecchio
Sunday 26 October 2008, Florence Convention Center, Piazza Adua 1
7.30 Registration – Poster Exhibition Open
MODERATORS: Theodore Friedmann and Philippe Moullier
8.30 - 9.00 H. Lee Sweeney “Gene doping: How could it be done and when might it happen?”
9.05 - 9:35
Hidde Haisma “Gene Doping- Fact or Fiction”
any students in biology can do this.
9.40 – 10.10 Judith Hall “Surprises and Secrets of the Human Genome- Things to keep in Mind When Looking for Gene Doping”
In the long run, gene therapy will be untraceable
Systems biology - control of gene expreion
2003 Human Genome project completed, despite 2001 publication
20,000 genes (200,000 proteins)
only 4% of human genome are genes -
protein expression is key
15% of Asians who metabolise testosterone differently
huge variation within normal functioning
10 years from now, could have your genome sequenced for $1,000
pharmacogenomics – drug response - 5% of people have no response - 5% over respond - Must be related to metabolizing pathway
Ethical requirements for human drug research
Athleticogenomics – what factors are important – what research is needed
Genes, Metabolism and systems of interest Muscle, vaculature, nerves, bain, lung, growth factors, repair mechanisms, sources of energy (mitochondrial variation) - in some places they uncouple ther mitochondrial to make heat, but an athlete would not want to do this
Systems Biology - affecting one area affects another - nothing is in isolation
possible to enhance one pathway
we are a long way from understanding secondary effects
in development of life, you use different genes – eg. embryo uses different set of genes from adolescent, etc - haemoglobin different between foetus and adult - going back to foetal pathways could be important
gene control - expressing genes
Chromatin Structure – DNA
Micro RNA – control a whole set of proteins – not traceable
Other considerations - diet, transgenerational effects
Diet - north American diet deficient in folic acid - don’t know enough about diet Agouti mice - mutation, gene involved is an imprinted gene (only maternal inheritance), if you give mum a lot of folic acid, then can benefit the offspring - folic acid metolates intruder by turning it off
Gl flora – by-products shift metabolism and ould be used to enhance performance
What gets inherited is not a deterministic genotype,but rather a genotype that encode a potential range of phenotypes (Gilbert 2000)
Drug effects or gene therapy may be passed on to the next generation
Grandmother – mother – child - the genes of ‘child’ were being developed in the mother’s womb, during gestation in the grandmother
mosaicism - arises brand new Microchimerism - find babycells in mother’s blood - can find baby cells in mother blood, but also cells from every pregnancy. - The cells stay there for a life time - Stem cells
FetoMaternal cell trafficking (Bianchi XXX)
Fetal Maternal Microchimerism - cells can play a role in repair / Future: Easy to identify people with genetic potential for sports, Need huge amount of research to examine effects / Likely to do DNA profiles / Likely to need more tisues / Ormal human variation is enormous and mosaicism and natural microchimerismare unversal / Gene therapy today has signature but in the future my be imposible to test / Unethical to use such therapies without extensive research / Undoubtedly there will be individual variation in response
ME: scenario –
Questions & Answers
In an adult, 1 in 10,000 cells is a stem-cell
One athlete claimed on ‘vanishing twin cells’
P. Mullier: As soon as we showed results, we had athletes come to the lab asking about it
Lee: real threat is from scientists who want to make money off athletes. India and China – many people who will charge, even though no benefit.
Michael Turner: vast majority of products not by elite athletes, but by people in gym – cosmetic result. Stem cell treatment widely used in horse racing in repair of tendons – we focus too much on winner of gold medal.
10.15 – 10.35 Discussion
10:40 – 11.10 Coffee break
11:15 – 11:45 Alun Williams “Human Genetic Variation and its association with physical performance phenotypes”
23 genes – 1 in 7milion chance of existence of 1 in UK - but expect many others influence
ME: the individual who has 23 of the genes is more likely to be a good endurance athlete, but is it also likely to be more capable than an individual with 10 or 1? – is there cumulative effectiveness?
Questions & Answers
Jim: low probability of having ultimate athletic genotype, probability
Q: association studies – today, concensus that only way to do it is whole gene snip analysis – has anyone started such an approach?
11:50 – 12.20 Mauro Giacca “AAV vectors as highly effective tools for IGF-1 gene doping”
12:25-12:55 Giuseppe Lippi “Gene doping, hypoxia and enhanced erythropoiesis”
gene therapy for lng-term expression of erythropoietin in rats Proc Nat Acad Sci, USA 1995, vol92, pp 8055-68
13:00- 13:20 Anna Baoutina (scheduled scientific contribution) "Evaluetion of an approach to directly detect gene doping using EPO as a model system"
13:20-13.40 Maria Minunni (scheduled scientific contribution) "Bioanalytical approach based on affinity sensing as promising tool for gene doping detection"
13:45 – 14:30 Lunch
MODERATORS: Arne Ljungqvist, H. Lee Sweeney
14:30-15:15 Posters Presentation (eight minute each, with slides)
HFL Sport Science LC/MS/MS and quantitative proteomics Pamela Brown
Protein in serum/plasma
15.15 – 15:45 Philippe Moullier “Genetic Doping with erythropoietin cDNA in primate muscle is detectable - Part I”
15:45 – 16:15 Françoise Lasne “Is EPO Genetic Doping possible b direct approach?
16.20 – 16:45 Tea break
16:50 – 18:50 Round Table: “Gene Doping: what is possible and what is not” Theodore Friedmann, Françoise Lasne, Arne Ljungqvist, Judith Hall, Alun, Williams, H. Lee Sweeney, Hidde Haisma"
19:00 - 20:00 Buffet
20:00 Guided Visit to the National Museum of Florence, "Bargello", especially open for the Symposium Participants
Monday 27 October 2008, Florence Convention Center, Piazza Adua 1
7:30 Registration – Poster Exhibition Open
MODERATORS: Judith Hall, Alun Williams 9:15 - 9:45 Angela Schneider “Gene Doping: Ethics and Privacy Rights”
athletes not deprived of rights if demed ineligible
must still respect human rights
David Suzuki – challenged research on racial profiling in public sphere
10.00-10.40 POSTER PRESENTATIONS Jim Rupert Indirect SAGE analysis – epo Blood based test Aim to see if we can distinguish between epo and altitude chamber Epo expression in absence of hypoxia response is the main interest.
Q: if athlete goes to altitude and uses epo, can you discover? A: Assumption is that if go to altitude, you don’t need epo
Valeria Mastellone Vincenzo
Relationship between ACTN3 and ACE I/D
ACTN3 gene directly involved
ACTN3 R577CX polymorphism conists of a converstion of an arginine residue to a premature stop condon at resdue 577
Frequencies of allelic frequences in ialian population compared to elite athletes
Gayagay (1998), Alvarezz (2000), Nazarov (2001), Scanavini (2002) - indicates statistical significance
10:40 – 13:30 Round Table: “Genetically Modified Athletes: Bioethics,Technology, Legal Implications” Angela Schneider, Andy Miah, Pier Francesco Mannaioni, Michail Shapiro,, Giuseppe Lippi, Judith Hall, Hidde Haisma, Domenico Giampietro Pellegrini
13:30 – 14:30 Lunch
14:30 – 14:50 Presentation of Posters (eight minutes each, with slides)
14:50 Conclusions Theodore Friedmann Arne Ljungqvist Andy Miah Giuseppe Pieraccini Giorgio Galanti Massimo Gulisano Maria Luisa Giovannucci Uzielli
15:50 Symposium closed