tafnut wrote:See, Pego? My cyborgs are coming! :-)
Yes, they are. They'll win La Tour de France and drop dead of a heart attack or stroke from hypercoagulopathy. One of the reasons women have lesser and later instances of vascular events is their lower hematocrit. Hematocrit at 80%? Incompatible with life.
Totally agree. But there are many other sports where there is no haematocrit threshold imposed on its athletes so an athlete could dope quite easily to 55-60% and with the right re-hydration strategies prevent any serious side-effects.
Also there are drugs that can 'turn-off' a gene to prevent over-production of red blood cells.
unclezadok wrote:Actually riders with a hematocrit level too high are not allowed to start or continue in the Tour de France. I think the level is 60. They are not sanctioned, at least initially, just disqualified on medical reasons. Of course, later a swat team breaks into their house in the middle of the night.
The UCI threshold is 50 for males and 47 for females. They can only return to competition when ther levels fall back beneath these levels.
Daisy wrote:There is an interesting review on this topic:
Drugs for Increasing Oxygen Transport and Their Potential Use in Doping: Authors: Gaudard A.; Varlet-Marie E.; Bressolle F.; Audran M. Source: Sports Medicine, Volume 33, Number 3, 2003, pp. 187-212(26)
From the abstract: The aim of this review is to present methods, and drugs, known to be (or that might be) used by athletes to increase oxygen transport in an attempt to improve endurance capacity. These methods and drugs include: (i) blood transfusion; (ii) endogenous stimulation of red blood cell production at altitude, or using hypoxic rooms, erythropoietins (EPOs), EPO gene therapy or EPO mimetics; (iii) allosteric effectors of haemoglobin; and (iv) blood substitutes such as modified haemoglobin solutions and perfluorochemicals.
Included in that review is a flow chart of all the potential options.
Rob Parisotto wrote:Has anyone heard of Repoxygen? This 'genetic' drug also works by providing extra copies of a certain gene (HIF gene) which is stimulated under hypoxic conditions to produce more EPO and therefore more blood.
But one has to ask why would an athlete use the very dangerous and untested gene therapy approach? Sure you can get the gene into the body. But what happens if it starts to express all the time? It's not so easy to deliver a gene to a cell and get a reliable titered expression.
Why wouldn't they just go with one of the undetectable synthetic EPO proteins that can be controlled to give EXACTLY the correct dose required to enhance performance to the sub lethal level?
Rob Parisotto wrote:With anti-doping authorities struggling to keep abreast with the drugs we already know about (and possibly many we don't know about as well), genetic doping methods really mean that the future is bleak unless anti-doping authorities get on top of them.
Rob this seems a little melodramatic. Sure, the drug testers are finding it hard to detect EPO but it will be possible for anyone who takes the gene therapy approach to be busted (as well as risking their health for a multitude of reason). There is a limited repertorie of ways to get such a gene into ones cells and all methods will leave a genetic signature that can easily be detect by PCR, in your book do you outline how they will avoid detection by PCR methods?
Rob Parisotto wrote:I make no apologies for informing the public about the possibilities and the dangers of genetic doping. Principal Researcher EPO 2000 Project Author BLOOD SPORTS
All well and good. Are you a writer by trade?
Daisy,
I have worked with Audran in the past and he is 'on the money' with the potential blood and/or oxygen boosting drugs. In Blood Sports I have listed these and many other drugs that are either being used or can be used in the future, including breast milk which has high levels of 'natural' EPO in it!
No drug is too dangerous for an athlete hell-bent on cheating. I mentioned previously there are drugs that can stop certain genes from over-expression and when one reached a haematocrit of say 55, they could simply pop a pill to inhibit the gene. It has been experimentaly done already.
Certain types of gene doping methods will be able to be detected with current technology. Inserting extra copies of EPO genes for instance should be easily picked up by a technology known as microarray analysis. The first research project using this detection method should be published soon. I was involved in this project at the beginning.
The problem with certain genetic doping methods is that the effect will be permanent whether it produces a good or bad effect. That's why gene doping may be such a big problem in the future.
However, when gene doping methods involved 'cutting and pasting' genes I don't know if there are any capabilities of being able to detect this type of gene doping unless every athletes 'gene map' is known (from birth). This is potentially a huge ethical and privacy issue as well.
Again I can't rabbit on for to long other than to say that I give both sides of the story in the book.
Daisy wrote:There is an interesting review on this topic:
Drugs for Increasing Oxygen Transport and Their Potential Use in Doping: Authors: Gaudard A.; Varlet-Marie E.; Bressolle F.; Audran M. Source: Sports Medicine, Volume 33, Number 3, 2003, pp. 187-212(26)
From the abstract: The aim of this review is to present methods, and drugs, known to be (or that might be) used by athletes to increase oxygen transport in an attempt to improve endurance capacity. These methods and drugs include: (i) blood transfusion; (ii) endogenous stimulation of red blood cell production at altitude, or using hypoxic rooms, erythropoietins (EPOs), EPO gene therapy or EPO mimetics; (iii) allosteric effectors of haemoglobin; and (iv) blood substitutes such as modified haemoglobin solutions and perfluorochemicals.
Included in that review is a flow chart of all the potential options.
Rob Parisotto wrote:Has anyone heard of Repoxygen? This 'genetic' drug also works by providing extra copies of a certain gene (HIF gene) which is stimulated under hypoxic conditions to produce more EPO and therefore more blood.
But one has to ask why would an athlete use the very dangerous and untested gene therapy approach? Sure you can get the gene into the body. But what happens if it starts to express all the time? It's not so easy to deliver a gene to a cell and get a reliable titered expression.
Why wouldn't they just go with one of the undetectable synthetic EPO proteins that can be controlled to give EXACTLY the correct dose required to enhance performance to the sub lethal level?
Rob Parisotto wrote:With anti-doping authorities struggling to keep abreast with the drugs we already know about (and possibly many we don't know about as well), genetic doping methods really mean that the future is bleak unless anti-doping authorities get on top of them.
Rob this seems a little melodramatic. Sure, the drug testers are finding it hard to detect EPO but it will be possible for anyone who takes the gene therapy approach to be busted (as well as risking their health for a multitude of reason). There is a limited repertorie of ways to get such a gene into ones cells and all methods will leave a genetic signature that can easily be detect by PCR, in your book do you outline how they will avoid detection by PCR methods?
Rob Parisotto wrote:I make no apologies for informing the public about the possibilities and the dangers of genetic doping. Principal Researcher EPO 2000 Project Author BLOOD SPORTS
All well and good. Are you a writer by trade?
Daisy,
I am not a writer but have dabbled with writing over the past few years resulting in the book (many press and magazine articles etc). I am a scientific researcher by trade and worked at the Australian Institue of Sport leading the EPO research project which came up with the first blood tests for EPO at the Sydney Games.
gh wrote:Note that this is the first post by that handle. And he doesn't specifically say he posted here.
Noted, he must have done a search for his name. it did come up in one of those threads with respect to scaremongering and it was me
In a previous thread I wrote:I just noticed the article on the front page. Seems to be a big splash about an Aussie scientist/scaremonger, Robin Parisotto, who claims gene therapy is just around the corner.
Call me a cynic, but I just noticed he is also on a book tour promoting his book Blood Sports. Is it possible (note sarcasm) that he has an ulterior motive for making such claims?
In the article that I quoted above (front page), it says:
"Robin Parisotto will collaborate with researchers at Vancouver's University of British Colombia on the development of a genetic blood doping test, funded by the World Anti-Doping Agency (WADA)."
So Rob, I am very interested in your perspective with respect to athletes taking EPO versus gene doping. Which is easier to detect? Which do you think is easier for the athlete to use?
My bias would make me lean towards gene doping as the easier to detect and for exogenous EPO to be more effective than gene doping. If this is true, then I wonder why athletes would wish to use gene doping (dangers and the fact it is an infant technology aside). What am i missing? You're closer to the reality, rather than my academic perspective. I admit I am sceptical, but I would be interested to hear your informed perspectives.
With respect to detecting EPO testing, as far as I am aware, the only difference between the exogenous (rHuEPO) and endogenous EPO is a missing glyco group. I am assuming that since no effective test against EPO has been developed that this is not a very antigenic site. What is the current status with regard to testing?
Do you think it will be possible to get an antibody for Elisa tests? I assume the mass spec option has been tried extensively too? What next? Until we have a reliable test for EPO i don't see any reason for the athletes to move to gene doping. Even then, why not get EPO from human culture cells?
Daisy,
All very good questions but I could hardly do justice in answering them in the forum, so I'll be brief as possible.
Currently EPO doping is by injection with the synthetic drug. I imagine that EPO administration will be by diffusion thru an implanted cartridge under the skin so the EPO is released as needed (eg. under hypoxic conditions). I think this method of EPO administration is entering the final stages of research so I would expect full clinical trials in the next year or so. Watch out Beijing!
The cartridge under the skin would obviously be an easier method and given the EPO will be 'identical' to the natural version, the current Urine EPO test would become obsolete.
But using gene maps an athletes response to any form of blood doping whether it was by synthetic EPO or insertion of cartridges under the skin, blood transfusion or gene doping etc would be detected as an over-expression (or under-expression) of genes responsible for red blood cell production. Albeit an indirect method but if the same principle was applied as for the haematocrit test, these athletes could be banned until they demonstrated 'normal' gene expression.
The advantages of gene based blood doping over regular EPO injections is that the EPO produced will be 'natural' (too much if not controlled though) and be undetectable and that a single insertion/addition of EPO genes will have an effect from anywhere betyween 3-8 months, doing away with weekly jabs. But there are other drugs under trial that will also be long-acting (up to three months with one jab - haematide and CERA). Because of the seemingly endless array of blood doping drugs the impact of genetic doping is more likey to be seen in the 'physical' changes of athletes (ie. bigger muscles, bigger limbs, bigger lungs etc) rather than in blood doping. But nothing would surprise me though.
With respect to the current EPO test, more than 70 athletes have tested positive and have been sanctioned since 2001 so its being pretty effective. Of course the test is still OK while the cheats use the current versions of EPO but may become useless soon. To counter this potential weakness I think you will find a move to make greater use of indirect blood tests such as the use of gene maps and established blood markers like the Simulation Index (so called ON and OFF- models) in the next few years.
I think that because EPO doping in the future will comprise 'extra' release of natural EPO that there is little if any chance of raising any antibodies. At the end of the day no matter what blood doping agent is used though (synthetic drugs or gene doping) the potential use of gene maps to indirectly detect blood doping will provide a strong deterrent. Its only the rules then that would need changing to apply penalties/bans/suspensions for blood doping cheats.
I hope I have been able to answer some of your questions. If you would like more comprehensive answers perhaps the forum facilitators could pass on my personal email details to you rather than clogging up the forum with voluminous science.
tafnut wrote:See, Pego? My cyborgs are coming! :-)
Yes, they are. They'll win La Tour de France and drop dead of a heart attack or stroke from hypercoagulopathy. One of the reasons women have lesser and later instances of vascular events is their lower hematocrit. Hematocrit at 80%? Incompatible with life.
Totally agree. But there are many other sports where there is no haematocrit threshold imposed on its athletes so an athlete could dope quite easily to 55-60% and with the right re-hydration strategies prevent any serious side-effects. Also there are drugs that can 'turn-off' a gene to prevent over-production of red blood cells.
Cheers. Rob.
1. 55-60 is dangerous. Rehydration would eliminate benefits of the higher hematocrit, so would be counterproductive.
2. Tell me what those drugs are, please. Why would anybody use a gene therapy and promptly turn it off?
3. I'd be scared shitless of inducing erythropoetic proliferative disorders. Do you have any information in that regard?
4. I can see gene therapy carefully employed in pathological situations. To administer it to the healthy young population to nominally improve some aspect of their performance is a Dr. Frankenstein's lab. as far as I am concerned. It may be possible (doubt it, though), but utterly immoral.
tafnut wrote:See, Pego? My cyborgs are coming! :-)
Yes, they are. They'll win La Tour de France and drop dead of a heart attack or stroke from hypercoagulopathy. One of the reasons women have lesser and later instances of vascular events is their lower hematocrit. Hematocrit at 80%? Incompatible with life.
Totally agree. But there are many other sports where there is no haematocrit threshold imposed on its athletes so an athlete could dope quite easily to 55-60% and with the right re-hydration strategies prevent any serious side-effects. Also there are drugs that can 'turn-off' a gene to prevent over-production of red blood cells.
Cheers. Rob.
1. 55-60 is dangerous. Rehydration would eliminate benefits of the higher hematocrit, so would be counterproductive.
2. Tell me what those drugs are, please. Why would anybody use a gene therapy and promptly turn it off?
3. I'd be scared shitless of inducing erythropoetic proliferative disorders. Do you have any information in that regard?
4. I can see gene therapy carefully employed in pathological situations. To administer it to the healthy young population to nominally improve some aspect of their performance is a Dr. Frankenstein's lab. as far as I am concerned. It may be possible (doubt it, though), but utterly immoral.
Pego,
During the EPO research trials we had many subjects who reached levels of 55 with no ill-effects. Even though you would 'dilute' a haematocrit of 60 back down to 50 or below (to beat threshold tests like the UCI's 50% haematocrit rule) by infusing saline you would still have a total greater blood volume with greater oxygen carrying capacity. ie. you would still get a benefit.
The list of drugs runs to almost five pages, too many to list here. We are not too far away from a blood 'pill' though!
The most common haematological abnormality (apart from death!) from the overuse of EPO is a condition known as aplastic anaemia. Basically the body produces antibodies against the foreign EPO molecules and in doing so also neutralise the natural EPO produced by the body. This results in anaemia, the condition EPO is supposed to treat in the first place There has been some evidence that EPO can exacerbate some cancers and or leukaemias. EPO use can lift blood pressure and cause the clot forming parts of the blood (platelets) to become more 'sticky' and a increased tendency to form clots, therefore causing heart attacks and strokes.
If we can clone sheep and pigs with genetic technology it is highly possible that similar technologies will spill over into humans. As a consequence it will inevitably end up affecting sport as well. Do a google on Lee Sweeney and you will see why gene doping is possible and will be used by someone determined to cheat irrespective of the side-effects.
tafnut wrote:See, Pego? My cyborgs are coming! :-)
Yes, they are. They'll win La Tour de France and drop dead of a heart attack or stroke from hypercoagulopathy. One of the reasons women have lesser and later instances of vascular events is their lower hematocrit. Hematocrit at 80%? Incompatible with life.
Totally agree. But there are many other sports where there is no haematocrit threshold imposed on its athletes so an athlete could dope quite easily to 55-60% and with the right re-hydration strategies prevent any serious side-effects. Also there are drugs that can 'turn-off' a gene to prevent over-production of red blood cells.
Cheers. Rob.
1. 55-60 is dangerous. Rehydration would eliminate benefits of the higher hematocrit, so would be counterproductive.
2. Tell me what those drugs are, please. Why would anybody use a gene therapy and promptly turn it off?
3. I'd be scared shitless of inducing erythropoetic proliferative disorders. Do you have any information in that regard?
4. I can see gene therapy carefully employed in pathological situations. To administer it to the healthy young population to nominally improve some aspect of their performance is a Dr. Frankenstein's lab. as far as I am concerned. It may be possible (doubt it, though), but utterly immoral.
pego
i agree with virtually all you've said
( although i'm not too sure about hydration off-setting haematocrit - increased haematocrit is a proxy for total increased red cell mass in the circulation ( more total rbc present ) compared to "normal" haematocrit level of ~ 45 - hydration won't affect the increased total red cell mass already present in the circulation, but will drop the haemaocrit
Rob Parisotto wrote:Currently EPO doping is by injection with the synthetic drug. I imagine that EPO administration will be by diffusion thru an implanted cartridge under the skin so the EPO is released as needed (eg. under hypoxic conditions). I think this method of EPO administration is entering the final stages of research so I would expect full clinical trials in the next year or so. Watch out Beijing!
The cartridge under the skin would obviously be an easier method and given the EPO will be 'identical' to the natural version, the current Urine EPO test would become obsolete.
But using gene maps an athletes response to any form of blood doping whether it was by synthetic EPO or insertion of cartridges under the skin, blood transfusion or gene doping etc would be detected as an over-expression (or under-expression) of genes responsible for red blood cell production. Albeit an indirect method but if the same principle was applied as for the haematocrit test, these athletes could be banned until they demonstrated 'normal' gene expression.
The advantages of gene based blood doping over regular EPO injections is that the EPO produced will be 'natural' (too much if not controlled though) and be undetectable and that a single insertion/addition of EPO genes will have an effect from anywhere betyween 3-8 months, doing away with weekly jabs. But there are other drugs under trial that will also be long-acting (up to three months with one jab - haematide and CERA). Because of the seemingly endless array of blood doping drugs the impact of genetic doping is more likey to be seen in the 'physical' changes of athletes (ie. bigger muscles, bigger limbs, bigger lungs etc) rather than in blood doping. But nothing would surprise me though.
With respect to the current EPO test, more than 70 athletes have tested positive and have been sanctioned since 2001 so its being pretty effective. Of course the test is still OK while the cheats use the current versions of EPO but may become useless soon. To counter this potential weakness I think you will find a move to make greater use of indirect blood tests such as the use of gene maps and established blood markers like the Simulation Index (so called ON and OFF- models) in the next few years.
I think that because EPO doping in the future will comprise 'extra' release of natural EPO that there is little if any chance of raising any antibodies. At the end of the day no matter what blood doping agent is used though (synthetic drugs or gene doping) the potential use of gene maps to indirectly detect blood doping will provide a strong deterrent. Its only the rules then that would need changing to apply penalties/bans/suspensions for blood doping cheats.
I hope I have been able to answer some of your questions. If you would like more comprehensive answers perhaps the forum facilitators could pass on my personal email details to you rather than clogging up the forum with voluminous science.
Cheers. Rob.
a few points to address please :
- i was unaware that they'd got drugs to "switch-off" genes : consider conditions 100 times more important medically than consideration of simple epo doping : cystic fibrosis & polycythaemia rubra vera - genetic conditions with overproduction of mucous & rbc - if they've got a drug that switches of genes, why on earth haven't they already developed it for these conditions ?
- why develop a cartridge delivery system for epo ?
why not just use an oil-based ( or similar depo method )
- why need to have cartrige delivery system to turn off epo ?
you want it working continuously producing rbc ( whether under hypoxic altitude conditions or not ) switching it on/off thru a cartridge gives sporadic output & you may not produce the required increased number of rbc
- what is this about "natural" epo ?
i read somewhere, they tried developing it a few years ago, but i believe it was unstable & coudn't be kept in storage, therefore need for the synthetic versions ( listed in table )
have they managed to develop a stable, "natural" version not dependent on the recombinant technology they use currently ?
Rob Parisotto wrote:gene doping is possible and will be used by someone determined to cheat irrespective of the side-effects
This is probably the summa summae of the whole thing. Depressing and hopefully preventable.
Pego,
Not good news and who knows where its all going to end up. If sport in general, goes the the way of professional football, baseball etc where they are at the mercy of TV sponsors hell bent on making a buck, selling it as entertainment rather than sport combining this with 'obscene' rewards for athletes then any incentive to stop doping is compromised.
Better doping equates to better perfromances which then equates to better entertainment value which translates into higher ratings.
Unfortunately the doped athlete (if caught or dies) pays the highest price for any indiscretion. the sponsors seem to avoid scrutiny but their day will come. If it doesn't we might as well pack our bags and go home and regard sport as nothing more than a reality TV program.
Rob Parisotto wrote:Currently EPO doping is by injection with the synthetic drug. I imagine that EPO administration will be by diffusion thru an implanted cartridge under the skin so the EPO is released as needed (eg. under hypoxic conditions). I think this method of EPO administration is entering the final stages of research so I would expect full clinical trials in the next year or so. Watch out Beijing!
The cartridge under the skin would obviously be an easier method and given the EPO will be 'identical' to the natural version, the current Urine EPO test would become obsolete.
But using gene maps an athletes response to any form of blood doping whether it was by synthetic EPO or insertion of cartridges under the skin, blood transfusion or gene doping etc would be detected as an over-expression (or under-expression) of genes responsible for red blood cell production. Albeit an indirect method but if the same principle was applied as for the haematocrit test, these athletes could be banned until they demonstrated 'normal' gene expression.
The advantages of gene based blood doping over regular EPO injections is that the EPO produced will be 'natural' (too much if not controlled though) and be undetectable and that a single insertion/addition of EPO genes will have an effect from anywhere betyween 3-8 months, doing away with weekly jabs. But there are other drugs under trial that will also be long-acting (up to three months with one jab - haematide and CERA). Because of the seemingly endless array of blood doping drugs the impact of genetic doping is more likey to be seen in the 'physical' changes of athletes (ie. bigger muscles, bigger limbs, bigger lungs etc) rather than in blood doping. But nothing would surprise me though.
With respect to the current EPO test, more than 70 athletes have tested positive and have been sanctioned since 2001 so its being pretty effective. Of course the test is still OK while the cheats use the current versions of EPO but may become useless soon. To counter this potential weakness I think you will find a move to make greater use of indirect blood tests such as the use of gene maps and established blood markers like the Simulation Index (so called ON and OFF- models) in the next few years.
I think that because EPO doping in the future will comprise 'extra' release of natural EPO that there is little if any chance of raising any antibodies. At the end of the day no matter what blood doping agent is used though (synthetic drugs or gene doping) the potential use of gene maps to indirectly detect blood doping will provide a strong deterrent. Its only the rules then that would need changing to apply penalties/bans/suspensions for blood doping cheats.
I hope I have been able to answer some of your questions. If you would like more comprehensive answers perhaps the forum facilitators could pass on my personal email details to you rather than clogging up the forum with voluminous science.
Cheers. Rob.
a few points to address please :
- i was unaware that they'd got drugs to "switch-off" genes : consider conditions 100 times more important medically than consideration of simple epo doping : cystic fibrosis & polycythaemia rubra vera - genetic conditions with overproduction of mucous & rbc - if they've got a drug that switches of genes, why on earth haven't they already developed it for these conditions ?
- why develop a cartridge delivery system for epo ?
why not just use an oil-based ( or similar depo method )
- why need to have cartrige delivery system to turn off epo ?
you want it working continuously producing rbc ( whether under hypoxic altitude conditions or not ) switching it on/off thru a cartridge gives sporadic output & you may not produce the required increased number of rbc
- what is this about "natural" epo ?
i read somewhere, they tried developing it a few years ago, but i believe it was unstable & coudn't be kept in storage, therefore need for the synthetic versions ( listed in table )
have they managed to develop a stable, "natural" version not dependent on the recombinant technology they use currently ?
Eldrick,
Very good questions. Its getting very late here now so I'll get back to you tomorrow. I'll need a clear head to answer them.
OK, i'm a bit late to the party here and reading all of Robs replies I have a ton of questions. Some overlapping with eldrick.
To keep this thread from being overwhelmed may be we can start with two of eldricks questions.
First: i was unaware that they'd got drugs to "switch-off" genes I too have never heard of any drug that could possibly switch off one gene ONLY. Is it possible the transgenic HIF gene is not regulated by its own promoter in the studies you are citing? It would make more sense if the HIF was controlled by an inducible promoter. Then, if you need more RBC, take the chemical that induces the HIF gene expression (i know there are promoters than can be induced by ethanol, tetracycline and estrogen). In this scenario, the transgene would be in the 'off' state, except when the chemical is added; a far safer bet. Of course the research you mention will publish the results for the 'one or two' transgenic animals that had a very low level of transgene basal expression. What of all the animals that had ectopic expression due to them being switched on by enhancers in surrounding genes (position effect) even when no inducer is present? In this situation there is no way an athlete could switch the gene off. This is the normal scenario and would probably result in death without constant medical intervention.
In my mind, the risks are so high and the technology so hard to control that 99.5% of athletes will not benefit from a gene therapy strategy. For this reason, i think that the athletes will never switch to gene therapy technology while very effective results are obtained using exogenous EPO that has the added advantage that it is hard to detect. It makes no sense to go to vastly inferior technology even if it is cutting edge.
Second: why develop a cartridge delivery system for epo ? The cassette you mention is very confusing. Reading between the lines it sounds like the cassette contains human cells that are overproducing EPO. Possibly adult stem cells from the athletes own body, that have been engeineered to overexpress EPO of HIF. Or is it a slow release mechanism for recombinant EPO?
Third From reading you various posts here it sounds as if you think the best way to catch the EPO cheats is to monitor the secondary effects of the EPO. i.e. high RBC count, or using gene expression profiles. Is this really an acceptable way to catch drug cheats? What happens if someone is a genetic freak and that is the normal expression profile? It seems that the variation in the human population, let alone in one individual (environmental and circadian effects), makes it almost impossible to set 'normal' values on anything in the body. And lets not forget that elite athletes are freakish in nature and are the very ones we'd expect to be the outliers for many gene expression levels. For example, in women, how much natural testosterone is allowed before they are banned?
OK i went on a bit more than I intended, sorry. Any references you have on these topics would help a lot and save you from having to explain the details. then we can get right to the points. My e-mail here is activated, you can find it if you go to my profile, so you could e-mail me if you prefer. Personally, i think the discussion would be great here since it will be archived for others and is VERY topical.
Daisy wrote:OK, i'm a bit late to the party here and reading all of Robs replies I have a ton of questions. Some overlapping with eldrick.
To keep this thread from being overwhelmed may be we can start with two of eldricks questions.
First: i was unaware that they'd got drugs to "switch-off" genes I too have never heard of any drug that could possibly switch off one gene ONLY. Is it possible the transgenic HIF gene is not regulated by its own promoter in the studies you are citing? It would make more sense if the HIF was controlled by an inducible promoter. Then, if you need more RBC, take the chemical that induces the HIF gene expression (i know there are promoters than can be induced by ethanol, tetracycline and estrogen). In this scenario, the transgene would be in the 'off' state, except when the chemical is added; a far safer bet. Of course the research you mention will publish the results for the 'one or two' transgenic animals that had a very low level of transgene basal expression. What of all the animals that had ectopic expression due to them being switched on by enhancers in surrounding genes (position effect) even when no inducer is present? In this situation there is no way an athlete could switch the gene off. This is the normal scenario and would probably result in death without constant medical intervention.
In my mind, the risks are so high and the technology so hard to control that 99.5% of athletes will not benefit from a gene therapy strategy. For this reason, i think that the athletes will never switch to gene therapy technology while very effective results are obtained using exogenous EPO that has the added advantage that it is hard to detect. It makes no sense to go to vastly inferior technology even if it is cutting edge.
Second: why develop a cartridge delivery system for epo ? The cassette you mention is very confusing. Reading between the lines it sounds like the cassette contains human cells that are overproducing EPO. Possibly adult stem cells from the athletes own body, that have been engeineered to overexpress EPO of HIF. Or is it a slow release mechanism for recombinant EPO?
Third From reading you various posts here it sounds as if you think the best way to catch the EPO cheats is to monitor the secondary effects of the EPO. i.e. high RBC count, or using gene expression profiles. Is this really an acceptable way to catch drug cheats? What happens if someone is a genetic freak and that is the normal expression profile? It seems that the variation in the human population, let alone in one individual (environmental and circadian effects), makes it almost impossible to set 'normal' values on anything in the body. And lets not forget that elite athletes are freakish in nature and are the very ones we'd expect to be the outliers for many gene expression levels. For example, in women, how much natural testosterone is allowed before they are banned?
OK i went on a bit more than I intended, sorry. Any references you have on these topics would help a lot and save you from having to explain the details. then we can get right to the points. My e-mail here is activated, you can find it if you go to my profile, so you could e-mail me if you prefer. Personally, i think the discussion would be great here since it will be archived for others and is VERY topical.
Daisy and Eldrick,
I had replied to all your questions and had to go out and didn't hit the submit button and unfortunately all of it had disappeared when I got back.
Here I go again.
I guess it should be kept in mind that any drugs (except recreational) are developed with sick people in mind, not healthy ones. How and what drugs the cheats choose is only a question they can answer but its certain that if any drug potentially improves performance it will be used/abused.
For blood doping cheats I concede that genetic doping is probably not the preferred method for the problems you have both identified. I would say that barring any threshold tests (like the Hct test by the UCI) the best blood doping method at the moment is autologous blood doping.
The cartridge technology involves using engineered cells programmed to release EPO at set rates and for anaemic patients especially those suffering from renal failure this means either no more transfusions and no more needle jabs.
The idea of a drug that is capable of turning off EPO genes would in most cases only be applicable when extra copies of EPO genes have been introduced into the body. (I have turned my study upside down looking for a reference for the drug that has been shown to antagonise EPO genes). The problem with something like PRV is that the out-of-control production of red blood cells is under different genetic control than EPO production. In most cases the level of EPO in PRV is usually low, so turning the EPO gene off would have little if any effect on the condition.
When I refer to 'natural' EPO this means that the synthetic version or the genetic stimulation of EPO produces the exact same chemical as is produced in the body. With the use of current hamster ovary cell lines to produce synthetic EPO to be replaced with human cell line derived EPO soon, even synthetic EPO will be identical to the natural form.
A blood pill is not that far away, maybe a decade. Already peptides which are small enough in molecular size to be absorbed thru the gut have been isolated that mimic the effects of EPO. The advances in biotechnology are accelerating at such a pace that its just a matter of time when these things materialise. Whether cheats use these technologies and /or methods is anybody's guess. It will depend on what testing methods will be out there at the time. But any doping method has to have two features for it to be used; it has to work and it has to be undetectable.
I keep coming back to the indirect blood markers and gene maps to counter all of the different drugs/methods of blood doping. The genetics research project that I alluded to in an earlier post has shown some remarkable changes and even the most intense physiological challenges don't come anywhere near the changes seen in the genes expressing for blood cell production after EPO injections and blood transfusions. (changes >10SD's). I think many will be surprised by the findings of this research. The paper should be out in the next year.
This will be the way of the future even taking into account that the normal and expected variations in any biological marker in the body usually renders such testing methods uncertain and prone to false positives and ammunition for clever lawyers. Many have already argued the case for a 'blood passport' .
This all sounds fascinating (really), but are there really 'mad scientist' types out there that will do all the R&D just to dope up some athletes, or are we talking about stealing (misdirecting?) medical supplies from people who really need them (to live!) just for some $Bucks? This sounds far beyond 'mixing up a batch' of a new type of steroid, as was the case with BALCO.
tafnut wrote:This all sounds fascinating (really), but are there really 'mad scientist' types out there that will do all the R&D just to dope up some athletes, or are we talking about stealing (misdirecting?) medical supplies from people who really need them (to live!) just for some $Bucks? This sounds far beyond 'mixing up a batch' of a new type of steroid, as was the case with BALCO.
I remain deeply skeptical about the realization of this entire concept in spite of repeated assurances of some that it is "around the corner".
tafnut wrote:This all sounds fascinating (really), but are there really 'mad scientist' types out there that will do all the R&D just to dope up some athletes
I don't know if I'd characterize these guys as "mad scientists." I think of mad scientists as guys who are figuring out ways to blow up the planet or do something only a little less drastic but certainly as evil. To me, scientists who think it's a fun challenge to help athletes run faster are no more "mad" than the athletes who cheat by using what these scientists produce. Are they "mad"? No, they're just cheats. And the scientists probably think it's just a harmless game--see if we can outwit the anti-doping cops. They don't see or care about the harm to the sport or the competition any more than the athletes do. That doesn't make them "mad." Just immoral.
tandfman wrote: That doesn't make them "mad." Just immoral.
True, but I think you're taking me too literally. A 'mad scientist' or 'evil genius' to me is anyone who uses science/intellect for immoral purposes. The EG may be neither 'evil' nor a 'genius' but he advances our field of knowledge in a way that does NOT benefit mankind. That's all I meant.
To play devil's advocate, I'd posit that many/most of them aren't immoral either. They're doing what they're doing with athletics not a whit in mind. So why are they doing it?
1. sheer scientific curiousity, looking to make a breakthrough;
2. profit motive, thinking of the bucks that would eventuate from drugs that "enhance the human condition," which is what the pharmaceutical industry is all about;
3. a legitimate desire simply to "upgrade the species"
We here may think track (sports in general) all the time, but if we think there's a whole cadre of like-minded scientists out there we're sorely over-rating our importance.
tandfman wrote:And the scientists probably think it's just a harmless game--see if we can outwit the anti-doping cops.
I am afraid, not. A scientist capable of genetic engineering is smart enough to envision medical as well as social consequences of his/her actions.
And, yes, application of science in this direction is profoundly immoral. At least in the view of this geek, that is :-).
Agree with gh - we are just not that big a deal to the super-biologists cooking this stuff up. They most certainly intend it as a boon to mankind. Which validates pego's subsequest post - if they DO consider the 'cheating possibilities' of their work, they are beneath our contempt and need to be terminated with extreme prejudice.
tafnut wrote:Agree with gh - we are just not that big a deal to the super-biologists cooking this stuff up. They most certainly intend it as a boon to mankind. Which validates pego's subsequest post - if they DO consider the 'cheating possibilities' of their work, they are beneath our contempt and need to be terminated with extreme prejudice.
My moral problem has to do more with medical consequences to the recipients of such modifiers than social implications (don't get me wrong, those are also very important, just not quite as profoundly to my way of thinking). I am afraid that next to the genetic engineering's health consequences, steroids and the growth hormone are a child's play.
gh wrote:To play devil's advocate, I'd posit that many/most of them aren't immoral either. They're doing what they're doing with athletics not a whit in mind. So why are they doing it?
1. sheer scientific curiousity, looking to make a breakthrough;
2. profit motive, thinking of the bucks that would eventuate from drugs that "enhance the human condition," which is what the pharmaceutical industry is all about;
3. a legitimate desire simply to "upgrade the species"
I read tafnut's original point to be that there are not likely to be a whole lot of mad scientists out there doing this sort of thing. My point was really that while mad scientists are few and far between, there are scientists who are simply immoral (or, for that matter, who do what they do for any or all of the reasons gh mentions) all over the place.
tandfman wrote:there are scientists who are simply immoral all over the place.
Yes, even though we place elite scientists on the pedestal of being mankind's saviors, in the final analysis, they are just 'people' who are heir to sin.
tafnut wrote:Yes, even though we place elite scientists on the pedestal of being mankind's saviors, in the final analysis, they are just 'people' who are heir to sin.
Unlike us track and field fanatics, who are merely nuts. :-)
tandfman wrote:there are scientists who are simply immoral all over the place.
Yes, even though we place elite scientists on the pedestal of being mankind's saviors, in the final analysis, they are just 'people' who are heir to sin.
Tafnut,
I think that's a good summation of why these things do happen. Scientists are just as much open to fraud and deceit as the next criminal.
Back in 1954 Dr John Ziegler the American team Physician of the US weightlifting team, on hearing that the Soviets had usd 'home grown' steriods during the 1954 World Weightlifting Champs reacted not with outrage but with envy. On returning home to the States he promptly approached the Ciba Pharmaceutical company to develop a steroid of his own. The result: Dianabol (the drug which brought down Ben Johnson).
There are many other examples of unscrupulous doctors/scientists acting unethically and immorally. Its not too big a stretch that like minded scientists and doctors won't do the same with Gene doping methods. With little regulation of gene research in most countries there is plenty of scope, opportunity, and financial rewards for rogue scientists to use their skills to the detriment ,rather than for the benefit of sport.
tandfman wrote:there are scientists who are simply immoral all over the place.
Yes, even though we place elite scientists on the pedestal of being mankind's saviors, in the final analysis, they are just 'people' who are heir to sin.
Tafnut,
I think that's a good summation of why these things do happen. Scientists are just as much open to fraud and deceit as the next criminal.
Back in 1954 Dr John Ziegler the American team Physician of the US weightlifting team, on hearing that the Soviets had usd 'home grown' steriods during the 1954 World Weightlifting Champs reacted not with outrage but with envy. On returning home to the States he promptly approached the Ciba Pharmaceutical company to develop a steroid of his own. The result: Dianabol (the drug which brought down Ben Johnson).
There are many other examples of unscrupulous doctors/scientists acting unethically and immorally. Its not too big a stretch that like minded scientists and doctors won't do the same with Gene doping methods. With little regulation of gene research in most countries there is plenty of scope, opportunity, and financial rewards for rogue scientists to use their skills to the detriment ,rather than for the benefit of sport.
Cheers. Rob.
Apologies,
The drug hat brought down Ben Johnson was Stanozolol.
and it was me 