Gene doping (re: repoxygen)
Bryan Bishop
http://en.wikipedia.org/wiki/Repoxygen
"""
Repoxygen is the tradename for a type of gene therapy that induces
controlled release of erythropoietin (EPO) in response to low oxygen
concentration. It is has been developed by Oxford Biomedica to treat
anaemia. It has been developed in mice, is still in preclinical
development and has not been extensively tested in humans.
It is constructed as a viral gene delivery vector carrying the human
EPO gene under the control of a so-called "hypoxia control element"
(“HRE”). The HRE is claimed to sense low oxygen concentrations and to
switch a gene on in response. Repoxygen is designed to be delivered by
injection into muscle and therefore to induce syntheses of EPO in the
muscle tissue. Normally, EPO is synthesized in the liver and kidneys.
It leads to increased production of red blood cells.
Use of recombinate EPO DNA in mice has shown protective effects for
epithelial cells and is being investigated as a prophylatic treatment
for lung tissue injury.
Excess EPO, the signalling hormone for more red blood cell production
(increased erythrocytes), can lead to erythrocytosis -- a condition of
too many red blood cells. Erythrocytosis makes the blood thicker and
more viscous, making pooling and clotting more likely, and represents
an increased stress on the heart (due to the thicker blood).
Erythrocytosis is potentially fatal, especially in endurance athletes
who are frequently dehydrated during long events.
[edit] Doping
Athletes could consider using Repoxygen as a means of increasing their
number of red blood cells. Due to its alleged self-regulating
properties it may be impossible to detect Repoxygen currently.
Repoxygen is prohibited both in and out of competition under the World
Anti-Doping Code 2006 Prohibited List.
The German track and field coach Thomas Springstein and Rashid Ramzi
are currently suspected to have used Repoxygen.[citation needed]
Repoxygen's delivery vector has triggered immune response in several
cases and resulted in at least one confirmed death directly related to
the body's immune response to the viral protein delivery vehicle.
The self-regulating properties of EPO are highly touted in cases of
deficit, however such a property actually makes it less effective to
supplement natural EPO levels in athletes, so there may be fewer gains
but this can in theory keep EPO levels under the acceptable range in
testing. Gains from traditional EPO doping are detectable in blood
samples for a few weeks after injection, eventually dissipating;
Repoxygen's prolonged effect (permanent DNA insertion) would not let
an athlete "test clean" without gene down-regulation (not currently
possible by drug injection, though DNMT studies are making man-made
control of genes just over the horizon). A doping athlete using
Repoxygen is either cheating and will test out of range for EPO, or
they're "trying" to cheat and don't get any benefit beyond natural
variance and acceptable EPO testing levels.
DNA sequencing for EPO genes is likely beyond any current sport
organizations, however the EPO gene used in Repoxygen and other gene
therapies is typically a truncated version with decreased potency
compared to natural genes in humans. This custom-EPO gene would stand
out in a sequencing of DNA, though locating the inserted gene may be
difficult without manufacturer assistance regarding tissue-target of
the vector and likely DNA insertion point of the gene. This essential
testing information has been suggested for any gene therapy legally
developed in the future, though it is currently not required in many
countries.
Sports without doping tests or regulation hold the most allure for
this product. EPO is up-regulated in anoxic environments such as
high-altitude climbing; Repoxygen and other gene therapies may find
"legal doping" applications in such sports. High-altitude mountain
climbing (i.e. attempting to summit Death Zone mountain peaks without
supplemental oxygen), or extreme deep diving (requiring ones to hold
their breath for several minutes while diving 100+ feet) are but two
examples.
The time dependant nature of EPO (once the blood goes apoxic, the gene
is activated and EPO hormone is produced and secreted from the kidneys
and liver, which through a cascade signalling system stimulates the
production of erythrocytes), this therapy has little benefit for
sprinters or events where VO2 Max levels are not being achieved
regularly.
[edit] External links
* Oxford Biomedica Article
* German coach Tomas Springstein sacked by his club
* Science news - Gene Doping
[edit] Additional Reading
* Yoshimi M, Maeyama T, Yamada M, Hamada N, Fukumoto J, Kawaguchi
T, Kuwano K, & Nakanishi Y. (2008). Recombinant human erythropoietin
reduces epithelial cell apoptosis and attenuates bleomycin-induced
pneumonitis in mice. Respirology 13(5). 639-645.
* Percy MJ. (2008). Familial erythrocytosis arising from a
gain-of-function mutation in the HIF2A gene of the oxygen sensing
pathway. Ulster Medical Journal 77(2). 86-88.
"""
I haven't read those two papers listed at the bottom yet.
Bryan Bishop
> Heck yeah?
And in general-
Gene doping - a review of performance enhancing drugs
http://designfiles.org/papers/Gene%20doping%20-%20a%20review%20of%20performance-enhancing%20genetics.pdf
And a diagram:
http://designfiles.org/papers/gene_doping_for_sports_enhancement.png
including: ACE, ACTN3, endorphins, EPO, HGH, HIF, IGF-1, myostatin,
PPAR-delta, VEGF
I was working on a myostatin gene doping project for a while, but
wasn't aware that others have already bothered with other genes. Cool.
Phil
> Heck yeah?
Heck no. My expectation is that the increased heart strain and risk
of clotting would outweigh the benefits.
Bryan Bishop
> On Feb 25, 7:01 pm, Bryan Bishop wrote:
>> Heck yeah?
>
> Heck no. My expectation is that the increased heart strain and risk
> of clotting would outweigh the benefits.
What gene are you talking about in particular?
Cathal Garvey
Not to mention viral vectors being (very generally speaking) a cancer hazard. Unless this early-to-market treatment took the time to eradicate traces of genome-integrating behaviour.
As oncolytic treatments, I'd accept that hazard as I'd already have cancer. For the novelty of holding my breath for longer, not so much.
-- You received this message because you are subscribed to the Google Groups "DIYbio" group. To po...
Daniel C.
> For the novelty of holding my breath for longer, not so much.
If you know you need an extra 2% performance gain to beat a world
record in a sport that you're passionate about, the risk/reward may
not seem so bad. Especially if you're a young athlete with more balls
than brains and the extremely common inability to see past the end of
the season. What's really too bad is that there are coaches out there
who are willing to allow their athletes to take these risks.
-Dan
Phil
> On Fri, Feb 26, 2010 at 1:30 PM, Phil wrote:
> > On Feb 25, 7:01 pm, Bryan Bishop wrote:
> >> Heck yeah?
>
> > Heck no. My expectation is that the increased heart strain and risk
> > of clotting would outweigh the benefits.
>
> What gene are you talking about in particular?
This was referring to EPO. There's already a commercial product,
Repoxygen,
that increases expression of the EPO gene, that works in humans.
It increases sports performance, but thickens the blood.
Given that heart problems and stroke are so common,
this is one self-mod I'd be very leery of.