Fritz vs. 'Them'

I would like to begin this post by apologizing to my mother for the headshot that appears in Bryan's last post. To any readers who don't know me personally: I promise I don't usually look like that.

My current thinking on the NCAA is fairly well-captured by a column that Bryan and I ran in the Middlebury Campus newspaper last week, and what I want to get into here is essentially an expounded version of that piece. For posterity: let it be known that Bryan and I penned the column before the NCAA changed its policy on feeding athletes. Call us game-changers.

The NCAA's (from henceforth, 'them') most basic orientation to its athletes is two-fold: to make sure that we are brand ambassadors for the national organization (see Bryan's post) and to ensure that we behave in a way that reflects positively on the brand. The latter point is, in my view, a vehicle to a deeper sort of criticism of how they conduct business.

Consider three anecdotes from my weekend in Lincoln:

1. In the athlete hospitality room, there was a staff member (Tyrone) on hand to ensure that we did not take an unreasonable number of snacks.
2. The championships featured an elaborate and fairly confusing credentialing system. There were certain areas designated for spectators, for athletes, coaches, media folks, etc. There were scores of staff stationed at choke-points to ensure that no one was in violation.
3.When we wanted to go to the field house to warm-up on Friday, they assigned us a volunteer to supervise as we waited for the bus. His name was Alex. I'm not sure what exactly he was looking out for, but I was probably the only athlete who spoke with him all weekend. This show was surely just as dehumanizing for the scores of "volunteers" as it was for us.

The point here is simply that they treat their athletes like children. This point isn't in itself that damning; many 18-22 year-olds probably deserve to be treated like children, and I happen to have the privilege to be part of an athletic program that trusts its athletes to drive college-owned vehicles, host recruits and do their own homework.

It is a bit suspicious, however, that this paternalistic attitude is paired with indulgence. When you're at the championships, they pay for everything: travel, hotel, meals, snacks, gear. I got the sense that all of this expense was supposed to make us feel important, like we were being celebrated for all of the hard work that it took just to qualify for the meet. For most of my teammates, this effect was realized; it just left me feeling like I was being manipulated.

Mark Emmert doesn't stand a chance.

Here is the part where I wave my English-major flag a bit. There is a word in literary criticism for this sort of indulgence that is used to cover up a less fun reality: carnivalesque. The idea comes from Mikhail Bakhtin, who thought of the carnival as a way for those in power to keep their subjects contentedly suppressed. The carnival presents a warped version of reality in which traditional standards and power structures are temporarily put aside and subordinates get to feel like they run the show, if only for a short while. Think Mardi Gras or, in a lesser sense, Halloween.

The NCAA championship doesn't feel like real life. It feels like a slightly altered form of real life in which people are constantly showering you in attention and free stuff, asking in return only that you abide by a few rules that easily go unquestioned in the face of so much free stuff. Bakhtin's point, and mine here, is that we should try to look past such a system to see what is really going on.

What is really going on at NCAA championship events is that athletes are being combed to be NCAA spokespersons who return to their real lives after a weekend of "carnival" to show off their flashy new gear and tell stories about how amazing it all was. As long as that system is working and we all continue to "participate" (their favorite word, but not in the way that Bakhtin uses it) in the big show, no one is likely to ask questions like "What does the NCAA do for me?" and "Why does all of this exist in the first place?" (or, if you are a Division-I men's basketball player, "Where is all this money going?") When people start to do that, they realize, it will mean an end to all the fun and games.

Image courtesy of Wikipedia

Tacit approval of what we don't approve of

Last month, I qualified for and Participated in the NCAA Division III Indoor Track & Field Championships.  While the weekend in Lincoln, NE, and the frantic fortnight leading up to the event could be the subject of decently-lengthed short story perhaps of interest to a non-trivial number of people, I'd rather use this space to talk about my first personal experience with the NCAA; specifically, the manner in which the NCAA uses its student-athletes as advertisements for itself.

Briefly, some background.  I qualified for the meet running the second leg of Middlebury's 4x400m relay.  Fritz Parker, blog co-contributor, ran the first leg.  Middlebury also qualified one guy in the mile, a women's DMR, a woman in the 400m (she ran the 800m leg on the DMR), and a woman in the high jump.  We arrived in Omaha, NE, on a Thursday night and left before dawn on the following Sunday.  The Championships were on the intervening Friday and Saturday.  In terms of performance, my relay came in 12th (out of 12, but saying we were 12th in the country sounds a lot better than last), but we also entered the meet seeded 12th (again, last).

F. Parker             B. Holtzman             A. Nichols               P. Hetzler

As I mentioned, this weekend was my first direct experience with the NCAA.  Prior to my Participation, I had perceived the NCAA as two factions: the governing body of big-time college football (and basketball, but I don't follow CBB the same way I do CFB) and as the name of the national meet which I had spent four years trying to qualify for (much in the same way that, back in my day, Nike Indoor Nationals was the namesake of the national T&F meet run by the NSSF).  I never gave much thought to its governance over other sports and student-athletes.  The NCAA had never affected me before so I never considered it in that context.  The only NCAA regulation I ever cited was its ban on gambling as an excuse to get out of playing poker for money while home on school breaks.

That said, I have historically been a skeptic of the NCAA in regards to how it treated its high-profile athletes and teams.  I always thought the organization was out to get the odd athlete or program instead of protecting those athletes and programs (some examples, and it would be irresponsible not to mention that Oklahoma had to self report an NCAA violation because a few players ate too much pasta.  Thanks in large part to comments by Shabazz Napier, schools can now feed their athletes).  This historical skepticism was recently compounded by a renewed interest in the NCAA manifest largely by reading numerous news articles both criticizing and defending it.  With this in mind, I undoubtedly--perhaps subconsciously--approached my experience with disdain for the NCAA.

The NCAA Experience is one of continuous overstimulation.  Everywhere I looked, the NCAA was present.  From being constantly babysat to the countless number of blue logos emblazoned around the track, there was no escaping the watchful eye of the NCAA (nor the constant reminder that we were at UNL: popcorn isn't just popcorn, it's Husker popcorn; the time on the clock isn't simply just time, it's Husker Time, which, it's worth noting, was incorrect).  This made me uneasy.  Forgetting to wear my Participant badge made me feel like I was accumulating an NCAA infraction for each minute I was without it.

The NCAA has, in a sense, adopted the "everyone gets a trophy" attitude towards the championships.  By qualifying, I will eventually be sent an NCAA pull-over I can proudly wear around telling the world I Participated in an NCAA event, a drawstring bag, and a commemorative medallion.

(Side note--really wish I could do foot/endnotes on this blog: I am usually stoutly against the "everyone gets a trophy" attitude, but not in this case.  For example, I did not receive an All-American trophy by simply Participating, so there was some separation between the winners and the Participants.  Additionally, the commemorations are a nice reward for the accomplishment of qualifying.)

Right at the door to the track was an ad hoc gift shop selling shirts, sweatshirts, and hats with the NCAA logo and the event printed on them.  Items were flying off the shelves, appealing to the athlete's desire to be marked as a Participant when they return to their respective institutions (I'm guessing they don't have to wear a badge at school labeling them as a Participant).  I am guilty of purchasing apparel: I bought a quarter-zip sweatshirt and an Under Armour technical shirt.

Wearing my gear makes me uneasy on two fronts: first, I feel kind of obnoxious by showing such an outward display of my accomplishment.  Realistically, nobody cares that I Participated in the meet.  I also separate myself from my teammates; they don't need a reminder that we went to NCAAs--they all know we did.  Second, by wearing my gear, I passively tell the world I support the NCAA in whole when I staunchly do not.

We are Participants

The second point is what really gets me.  At most schools around the country, some segment of students (athletes?  student-athletes?  Participants?) are wearing NCAA sponsored apparel.  Here at Middlebury, I see students who have NCAA patches sewn on their backpacks, students carrying NCAA water bottles (officially sponsored by Powerade), etc.  Even when you're not at an NCAA event, the NCAA is present and ever-looming.  We Participants are propagators of its presence and the NCAA knows this.  It knows the Participants will display their free mementos and commemorations creating a walking advertisement out of every Participant.  When you add up EVERY athlete in EVERY sport in EVERY division, this number becomes quite large.  I'd wager 90% of them will show the world a piece of their memorabilia with some frequency.  This reminds everyone who sees such memorabilia a. that the NCAA exists and b. that Participating in an NCAA event is good.  To the second point, if one qualifies for NCAAs in something, one is obviously good at what they do.  The association of NCAA = good is immediate.  Unfortunately, there is not much depth to this association.  The achievement of making NCAAs is remarkable, but the associated approval of the NCAA--either by the wearer or viewer--is not questioned when it should be. 

This brings me to my concluding question: how can the accomplishment of competing in an NCAA event be separated from the NCAA (and thus tacit support of the NCAA)?  Students should not feel even the slightest amount of guilt about showing the world a memento of their accomplishment.  They should be proud of their accomplishment.  I am proud, damnit.  But I cannot, in good conscious, show my pride.  This, to me, is unfortunate and is a slight to every athlete in the country.

EPO: From Cytokine to Speed

Background

Last fall, I was enrolled in a metabolism course at Middlebury.  We were assigned a 40 minute presentation on a metabolic disease.  To the eleven other students in the class who were planning on going to medical school, this was an interesting topic and was designed with their interests in mind.  Metabolism is a fascinating field of study with many aspects, so I asked my professor if I could do my presentation on a different metabolic topic: PEDs.  After some preliminary research, I settled on presenting about EPO.  The following is what I came up with (there is some overlap with a previous post).

What is this "EPO" thing, anyway?

EPO--short for erythropoietin (derived from erythropoiesis, combining the Greek erythro meaning red and poiesis meaning generation; an erythrocyte is a red blood cell, or RBC--the cells responsible for transporting oxygen in the blood)--is a cytokine (protein signaling molecule) that induces red blood cell production by preventing red blood cell progenitors from committing apoptosis (cellular suicide or death) and allows them to proliferate and differentiate.  EPO occurs naturally in your body!  It is a 34 kilodalton glycoprotein that is about 165 amino acids long.  Roughly 40% of its weight comes from glycosylation, which is the addition of sugar groups to amino acid residues on the peptide chain (in the case of EPO, this is mostly N-linked glycosylations, mainly occuring on asparagine residues).  In addition to its primary role as an inducer of RBC production, EPO has a variety of secondary functions, including neural production during stroke (EPO can cross the blood-brain barrier) and implication in apoptotic pathways through the PI3-kinase pathway.  In the fetus, the EPO gene is expressed in the liver and after birth it is expressed in the kidney.  In addition to its well documented use as a PED, synthetic EPO is an incredibly successful drug in the clinic, used mainly to treat patients with anemia (RBC deficiency).  It has also been used in patients who have diabetes, Alzheimer's and cardiovascular disease.  There are some drawbacks, though, particularly in cancerous patients (many of whom are prescribed EPO): synthetic EPO has been shown to block tumor cell apoptosis, enhance tumor progression rates, increase the metastatic rate of cancer, and negating radiation treatment by assisting in tumor angiogenesis (for those of you keeping count, that's 4 out of the 6 Hall Marks of Cancer--original paper and follow-up; some of the more generally interesting and accessible journal articles you'll find).

How does EPO get produced in the body?

http://www.sciencedirect.com/science/article/pii/S0006295211004291

I'm going to start large and then get smaller.  EPO production is dependent on physiologic conditions: hypoxia in arterial blood running through the kidney or anemia.  Under these conditions, the EPO gene is expressed in the kidney and produces the EPO protein (this is known as the Central Dogma of Molecular Biology: DNA is transcribed into RNA, which, after processing, is translated into a protein).  EPO is then directed to cells expressing its receptor, EPOR.  Remember that EPO is a signaling molecule: that means it "swims" around the extracellular matrix and blood until it finds a receptor protein on the surface of a cell specifically tailored for it to bind to.  Compounds of EPO's size cannot move directly through the cell membrane to catalyze chemistry in the cell; instead, they bind to a receptor that can then catalyze many things inside the cell.  In this case, EPOR is a Type I transmembrane receptor protein (example).  Type I means that it is composed of alpha-helicesand transmembrane means that the protein sits directly in the plasma membrane and has parts of it exposed to the outside of the cell and into the inside of the cell.  EPOR is a member of the cytokine receptor superfamily, which is a group of cytokine receptors that have four conserved cysteine residues and a conserved Trp - Ser - X - Trp - Ser motif in the extracellular domain (conservation, in this sense, means those amino acid residues appear in roughly the same place in the amino acid sequence in many different proteins that have similar functions.  Conserved sequences are usually pretty important for function.  Wikipedia page).  EPOR is mainly expressed in red blood cell progenitors as they are nearing death either to rescue them from apoptosis or to induce their proliferation.  There has also been research showing EPOR being involved in RBC differentiation (specialization of a cell's function).

All right, we have EPO, and it's found a receptor.  What does it do now?

Previously, I briefly mentioned that EPO works via a JAK-STAT signaling mechanism.  I'm now going to go through that in more detail.  I truly believe that one does not need a background in biology or chemistry to understand what I'm about to explain.  All you need is a healthy dose of common sense, because when you think about what's going on, it does make sense.

http://www.jbc.org/content/282/28/20059.short

Signaling that occurs via cytokine receptors is promoted by enzymes in the cell known as protein tyrosine kinases (PTKs) and is thought to be terminated by enzymes known as protein tyrosine phosphatases (PTPs; I will revisit this idea in a bit).  Like I said before, EPO is directed to cells expressing EPOR.  EPOR sits in the membrane as a homodimer (a dimer is two proteins associated with one another; thus, a homodimer is two of the same protein associated with one another) in an inactive conformation.  EPO comes in and binds to the receptor dimer and causes it to change conformation, activating it.  This idea of active and inactive conformations dependent on ligand binding or ambient conditions is a huge theme in biology; it provides a simple mechanism to turn proteins/enzymes/receptors/etc. on and off.  Upon the conformation change, JAK2 (a random kinease--seriously, JAK stands for Just Another Kinase.  Kinases are enzymes which phosphorylate things), which is associate with EPOR, is activated via an autophosphorylation mechanism (phosphorylating itself).  Phosphorylation is the addition of a phosphate group (PO4(3-)) to a moiety.  Phosphorylation is the way by which just about everything in the cell is activated; when you hear about ATP (adenosine triphosphate) being the energy currency of the cell, it activates things by putting one of its phosphate groups on that thing and becomes ADP (adenosine diphosphate).  This autophosphorylation, in addition to activating that particular JAK, promotes further autophosphorylation of other JAKs and promotes further kinase activity.  This is a positive feedback loop, which means when this thing happens, it makes more of either itself or another thing happen.  Upon the autophosphorylation of JAK2, eight tyrosine residues on the cytoplasmic side of the cell (the inside) are phosphorylated (tyrosine phosphorylation happens a lot in protein signaling pathways).  The tyrosine phosphorylation leads to SH2-dependent recruitment of STAT5.  SH2 is a conserved protein domain (in larger proteins, different parts of the protein will fold up and form their own ball-like structures that act basically independently from the other domains/rest of the protein) that is roughly 100 amino acids long that selectively binds or docks to phosphorylated tyrosine residues on other proteins.  STAT5 (Signal Transducer and Activator of Transcription 5) is activated by this selective docking.  Once STAT5 has been activated, presumably via phosphorylation, it forms an antiparallel dimer with itself (proteins aren't symmetrical and have some form of directionality, so in this case, the two STATs are running in opposite directions of one another, kind of like a two-way street) and translocates to the nucleus.  The nucleus of the cell has its own membrane (well, it really has two, but that's besides the point), so the STAT dimer manages its way through those membranes into the body of the nucleus.  Once it's in the nucleus, it acts as a transcription factor for important erythro-regulation genes as well as possibly activating GATA-1, another transcription factor for erythro-regulating genes.  Transcription factors are proteins that promote the expression of a gene into a protein (running through the Central Dogma: DNA --> RNA --> protein).

References

1. Bodary, P. F.; Pate, R. R.; Wu, Q. F.; McMillan, G. S. Effects of acute exercise on plasma erythropoietin levels in trained runners. Med. Sci. Sports Exerc. 1999, 31, 543-546.

2. Chateauvieux, S.; Grigorakaki, C.; Morceau, F.; Dicato, M.; Diederich, M. Erythropoietin, erythropoiesis and beyond. Biochem. Pharmacol. 2011, 82, 1291-1303.

3. Klingmüller, U.; Lorenz, U.; Cantley, L. C.; Neel, B. G.; Lodish, H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 1995, 80, 729-738.

4. Kretz, A.; Happold, C. J.; Marticke, J. K.; Isenmann, S. Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation. Molecular and Cellular Neuroscience 2005, 29, 569-579.

5. Maiese, K.; Chong, Z. Z.; Shang, Y. C. Raves and risks for erythropoietin. Cytokine Growth Factor Rev. 2008, 19, 145-155.

6. Roels, B.; Bentley, D. J.; Coste, O.; Mercier, J.; Millet, G. P. Effects of intermittent hypoxic training on cycling performance in well-trained athletes. Eur. J. Appl. Physiol. 2007, 101, 359-368.

7. Sasaki, A.; Yasukawa, H.; Shouda, T.; Kitamura, T.; Dikic, I.; Yoshimura, A. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J. Biol. Chem. 2000, 275, 29338-29347.

8. Schindler, C.; Levy, D. E.; Decker, T. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 2007, 282, 20059-20063.

9. Smith, J. A. Exercise, training and red blood cell turnover. Sports medicine 1995, 19, 9-31.

10. Tong, W.; Zhang, J.; Lodish, H. F. Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Blood 2005, 105, 4604-4612.

11. Yao, Z.; Cui, Y.; Watford, W. T.; Bream, J. H.; Yamaoka, K.; Hissong, B. D.; Li, D.; Durum, S. K.; Jiang, Q.; Bhandoola, A.; Hennighausen, L.; O'Shea, J. J. Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 1000-1005.

A Dose in Doping Theory

Why do athletes take performance enhancing drugs?

Recovery.

Why do athletes take performance enhancing drugs?

Recovery.

Why do athletes take performance enhancing drugs?

Recovery.

Got that?  If you take nothing else out of this blog, remember that athletes use PEDs for recovery.  That should be drilled into your head.

Let me first dispel the notion that dopers are lazy and would rather shoot up than work hard.  Simply not true.  Athletes dope so they can do more.  In ESPN's 30 for 30: 9.79* documentary, Ben Johnson said that when he was on anabolic steroids, he could max in his lifts twice a day as opposed to once every 3 days when he was clean.  Ask anyone who has tried to max-out a lift: it isn't easy, and it sure as hell isn't lazy.

You might be able to see where this is going.  Drugs do not immediately lead to more strength, endurance, etc., with the end goal being better performance.  Rather, they enable the user to have a higher workout volume to achieve higher levels of strength or endurance.  The impetus is still on the athlete to work harder than ever, as his/her body is literally incapable of the work naturally.

So, here's how it works, the very crux of doping in non-skill sports (i.e., track and field, cycling, Nordic skiing, swimming...basically sports that don't involve a ball): say you have a 3 month long competition period.  That means you have a 9 month out of competition period where 7 or 8 of those months are spent actually training.  Testing is much more stringent in competition season--out of competition testing is largely lax (or sometimes doesn't happen at all; see end of article).  The probability of getting caught out of season is on the order of magnitude of a fraction of a percent (I can't immediately recall anyone who's gotten busted for an out of season test).  So, you dope up on whatever is the rage of the day, be it anabolic steroids back in the 80s, or EPO, HGH, and testosterone now.  You know how long it will be in your system.  You almost have to be stupid to get caught, seeing as anyone who can consult a calendar will know when to dose and when not to.

Let's take the case of a male distance runner.  The bulk of off-season training consists of running a ton of miles.  Run too much though and his body breaks down, he'll get fatigued and start displaying diminishing marginal returns on his training.  But, take some PEDs (in this case, the big 3 of the modern day: EPO, HGH, and testosterone) and his body can handle more.  Instead of running 90 mile weeks he can tackle 105 mile weeks like no problem.  He can do his long runs a little bit faster.  Instead of lifting twice a week he has the energy to lift three times a week.  Pile this on for six-odd months and this athlete is going to be in the best shape of his life.  By the time workouts start rolling around, he'll be able to handle higher volume and higher intensity in those as well.

Now it's time to race.  Our athlete is what I'll call "currently clean"--that is, his urine won't trigger any positive tests nor is he on any sort of in-season doping regime--I hesitate to call him clean for reasons I'm about to explain.  Nothing can take away the training that this runner has accomplished over the past year.  All those extra miles, faster miles, extra lifting sessions, higher quality workouts, longer workouts are in his legs, his muscles, and his lungs.  Because of this, he'll be able to smash his PRs in a drag race and be able to close like a freight train (this is what a freight train looks like) off of paces where he was previously hanging on for dear life.  When asked how was able to improve so much, all he has to say is that he had a quality year of training at the highest level.  And he isn't even lying. 

Pretty simple, isn't it?  Cycle on the drugs, train your tail off, cycle off, and reap the rewards.  Now, the "currently clean" term I dubbed: the runner in my example is still dirty as all sin.  His fitness level is a result of his drug use.  Without the drugs, his year of training would have been marginally successful instead of wildly successful, all other things being equal.  I would say that his fitness is dirty, even though his pee-cup is saying otherwise.  Thus, he is currently clean, but he sure is not clean.  It's hard to do much about it, except something along the lines of weekly testing out of season, which is near impossible to facilitate (find me the following in rural Kenya: a drug lab, means of sample preservation, certified testers who want to go to Kenya, etc.).

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Recovery is not only important for higher quality training (or in the TDF and others, racing), but also in dealing with injuries.  Rodney Harrison was suspended by the NFL in 2007 for using HGH, which he said he used to accelerate the healing process from various injuries and not to gain a competitive edge (of course, an accelerated healing process is a competitive edge, but that's neither here nor there).  Whenever I hear a report on ESPN that such and such player is making a miraculous recovery from an injury and is months ahead of where doctors thought he would be, I just shake my head and wonder when anyone is going to question why these recoveries are being made so quickly (I'm not making accusations, but here's an example of what I'm talking about).  It just doesn't line up.

Shifting gears a little bit, when baseball's "Steroid Era" was outed in the early 2000s, many pundits said that they didn't think pitchers were doping because they didn't need to be huge in the same way hitters did.  While the part about being huge might be true--you can be as strong as you want, but if your fastball isn't moving, you're going to get hit--the part about them not doping is absolute baloney.  We've established what doping is about (hopefully you remember), and a starting pitcher is a prime candidate for someone who needs to recover quickly.  Every five days, a starter is charged with the task of throwing basically until his arm falls off.  If his arm starts falling off in the third inning, his bullpen is in for a long night his team will be at a disadvantage for the next couple of games.  Come the dog days of August when the pennant races are heating up, a pitcher might need a little help to be at his best each start.  PED use would allow him to be effective through the late summer months and into the fall when the playoffs begin.

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In the five months preceding the 2012 London Olympics, Jamaican track and field athletes were subject to one out of competition drug test.  Not one test each.  Just one athlete was tested once in those five months by Jamaica's anti-doping agency, which is responsible for upholding WADA and IAAF codes.  I'll let the readers make their own conclusions about this, but I will say that mine is not a particularly good one.

Asafa Powell, a 2012 Jamaican Olympian, was recently whacked for doping

Why do athletes take performance enhancing drugs?

EPO: Injection to Detection

A few weeks ago a poster on a track forum I frequent started a thread titled "EPO: injection to detection in elite athletes".  This is the text of the original post:

Popular media has suggested there are 80-100 undetectable substitutes for EPO. I know EPO is a naturally occurring hormone in the body but know next to nothing beyond that. I am wondering if someone with a solid background in chemistry, physiology, bio-genesis, etc. can take the time and explain how it all works, injection to detection. For instance, I can't imagine a 3:42.7 guy takes EPO or a substitute the night before and all of a sudden magically runs 3:28.81 on race day.
Unless everyone here is a PhD in biochemistry or a laboratory scientist of the sort I am guessing others are in similar positions. They know what EPO is but not how it works and enhances performance. It would help if examples were catered to the running perspective (ex: effects on training) and wasn't overly loaded with jargon. I am also personally very interested in:

• "gene doping" vs "traditional doping"
• intricacies of testing methods
• why "substitutes" are undetectable

Article: Doping-Undetectable new blood boosters available says expert

For some reason, I decided to write a response to this poster, and I think that it would be worth posting again here.

EPO

As has been previously stated, erythropoietin, or EPO, is a signalling molecule (cell signaling) that eventually leads to the production of more red blood cells (erythrocytes). EPO binds to a receptor on the outside of the cell, causing that receptor to change shape (known as conformation; the change here is a dimerization). The newly changed receptor can then bind and activate another protein (a protein kinase), and then after several more steps, molecules (transcription factors) reach the DNA and causes more production of proteins that are necessary for red blood cell maturation (transcription factors cause increased synthesis of mRNAs that code for proteins required for erythrocyte maturation; this is an example of a JAK-STAT system). Source: Lehninger 443-4.

1. Regarding substitutes.
In chemistry, molecules can be analogues of one another. That is to say, they are structurally basically the same, but have a minor difference that may or may not affect function. An example of this would be sucrose (table sugar) vs. sucralose (Splenda).

Sucrose (sugar) vs. sucralose (Splenda)

These two molecules have the same basic backbone and differ only in three functional groups (they are circled). The hydroxyls (OH) on sucrose are changed to chlorides (Cl) on sucralose. As most of you know, sugar and Splenda taste basically the same but Splenda has no caloric value. Why? The slight structural change leads the body to not uptake sucralose and instead you just poop it out. However, it serves the same function as sucrose.

Now, what does this have to do with EPO? Proteins, as they are molecules as well, can have analogues much in the same way small molecules can. These analogues can have essentially the same structure and function, but small variations in the structure (amino acid sequence) can change their detectability. This is similar to how your body does not "detect" Splenda--you reap the benefits of sucralose, but you don't pay the caloric price of sugar because your body doesn't have the receptors. When you mention that there are 80-100 "substitutes" for EPO, they are undetectable insofar as they have subtle differences that prevent them from being picked up by the test but do not change their overall function. I don't know how synthetic EPO is tested for (other than way back when they would test for plastics found in the bags they were stored in), so I can't give any more insight into where and what these changes are.

2. How EPO affects performance.
As we have said, EPO leads to the increased production of red blood cells. I'm not sure the time between injection and RBC production, but I would guess that it's on the order of hours, and I think I've read that RBC levels normalize after about 3 days. So, one would benefit from shooting up the night before, but it isn't going to take you from 3:42 to 3:29, no way, no how. The strength of EPO, and any PED, comes from what they allow you to do in training. If you have more RBCs, you're going to able to run faster and longer in your workouts, do more miles per week, etc. If you're on the juice for 9 months and your training load is exceeding what you're body can naturally handle, when you come off it, you're going to be in ridiculous shape. You come off the juice, ramp down your training, and race. You'll pass your in-season tests because you're off the stuff, but you've already reaped the benefits of the PEDs because you were able to have higher quality and quantity of training over the previous nine months. The competition season becomes about doing maintenance work to keep that level of fitness. Your body can also probably now handle a higher level of training, but not as high as when you were on the juice. A program like this is probably what lead to Ramzi's stupid drop in time between 2003 and 2004.

It is also worth mentioning that young RBCs are more efficient oxygen carriers than are older RBCs (RBCs have a life cycle of ~120 days). It is thus beneficial to induce the production of RBCs because your body will have a higher percentage of newer and more efficient cells delivering oxygen to the muscles (source). Tyler Hamilton talks about the use of EPO between stages on the Tour in his book (which is worth reading).
See also: http://www.sportsscientists.com/2007...mance-who.html

3. Gene doping vs. traditional doping.
WADA defines gene doping as "the non-therapeutic use of cells, genes, genetic elements, or of the modulation of gene expression, having the capacity to improve athletic performance". EPO abuse is a form of gene doping; as I previously explained, EPO increases the expression of genes important in RBC production. Read more here.

I'm not exactly sure what you mean by "traditional doping", but if you provide an example of what you mean, I'll try to expand.

4. Intricacies of testing methods.
I don't know too much about how EPO is tested for--I don't think that information is out there. Here are some general testing methods:
-Biologic levels: some PEDs alter the levels of certain naturally occurring compounds in the body. So, while the drug itself isn't being tested for, the effects of the drug are. An example of this is the testosterone/epitestosterone ratio (although this is a little more direct). In normal humans, these are produced in roughly the same amounts (an Australian study found the mean T/E ratio to be 1.15:1). But, when Mary Slaney pops a T/E of greater than 6:1, you know something's up. Sometimes epitestosterone is administered as a masking agent for synthetic testosterone to keep the T/E ratio down. A second example is measuring hematocrit (% RBC in blood) for blood doping. Back in the late 90s and early 2000s, the UCI allowed hematocrit levels of up to 50. As long as you were under that number, you were good to go. If you tested higher, you got popped, as you basically had to be on something to get that level of RBCs.
-Testing for the compound itself: not sure how often this is done, but in the case of a synthetic compound that has a long half-life, a chemist could design a test to look for the presence of the molecule.
-Testing for carrying devices: as I previously mentioned, tests used to be done for the plastics in blood bags. Those aren't supposed to be in your body.

Post by AJ Acosta in the same thread:
Doping programs are incredibly sophisticated and the new rage these days is "microdosing."The idea is that by using a patch or fast acting cream, the steroids or whatever drug you are using is out of the system fast. Remember, the half life of EPO is something ridiculously short like 5 hours, so by microdsoing you significantly decrease your chances of being caught. And as other and smarter posters have laid out, the chemists will change chemical compositions of the drugs to make it even harder for hte drugs to be detected.

My response: Yes. Tyler Hamilton talks about this.

Another post by AJ:
You dont "use" up blood cells technically, although i suppose when you dig in the well a little too deep you start using your iron storage levels a bit.

My response: This sounds about right. My understanding is that stressful exercise can lead to RBC destruction due to depletion of protectants (eg antioxidants).