Gene-iune Difficulties

As you have doubtless noticed by now, Daily Tennis occasionally devotes a feature to science as it relates to tennis — usually physics (because that’s what makes tennis possible) or biology (because that’s what makes tennis players possible). To improve our coverage, the author periodically goes through some of the science magazines and web sites looking for relevant material. The first one we noticed on today’s topic was on the web site Ars Technica, referring to a 2007 video game called BioShock. But we hardly had to look for the story. It happens every two years, and we do our best to update based on new developments in the field. (The new material in this article is on plasmids and artificial chromosomes. And, yes, the story is getting to be very long….)

We first noticed it at the time of the 2004 Olympics. As we said then, “You know the Olympics are approaching when sports-related stories reach the covers of both Scientific American and Discover, the leading American monthly science magazines.

“You know there is a problem when they both have the same story.”

The July 2004 cover of Scientific American was emblazoned, “Will GENE DOPING Change the Nature of Sport?” Discover in that month had a different cover story, on space elevators (also known as skyhooks or “the beanstalk”: devices for getting into earth orbit without rockets — a brilliant idea likely to dramatically change human society for the better, if they can be built). Still, the #3 item on the cover was “Gene Doping: There Go the Olympics.”

What, you may ask, is gene doping? Ordinary doping, of course, consists of taking some sort of drug to enhance performance. The effects may be permanent or temporary; the drug will eventually leach out of the system either way.

Gene doping is more permanent — it can even, if done completely enough, be passed on to one’s offspring. It consists of modifying one’s genetic makeup with the same sort of goal in mind as in ordinary doping: to improve performance. In very rough outline, a section of a person’s genes responsible for some particular trait is replaced or augmented by another section with a more desirable trait. It is expected that this will be done by means of a tailored virus.

A virus, as you may know, consists primarily of two parts: A protein shell designed to penetrate cells, and genetic material (RNA or DNA). The genetic material usually just takes over the cell and coerces it to make more viruses. But some viruses — retroviruses, such as HIV — actually place their DNA inside the DNA of the cell. It is believe that this is the source of a significant part of the so-called “junk DNA” in the human genome: It is the remnant of viral DNA which took up residence inside our DNA. It’s not doing anything — except managing to reproduce itself zillions of times, which is just what viral DNA does anyway.

A tailored virus would be one designed to find a particular segment of bad human DNA, cut it out, and replace it by a section of new and improved DNA. It has been repeatedly demonstrated that this can be done with viruses and cells in the lab. The trick is to make it work in the actual human body.

In sports, the typical use of this sort of genetic change would be to allow a player to build better muscles more easily, or recover from fatigue or injury more quickly, or perhaps to use air and nutrients more efficiently. That different genes can have these effects has repeatedly been demonstrated, both by mapping of the human genome to see what different alleles (variants of the same gene do) and by direct experiment — there is an instance of a rodent which had one leg gene-modified and the other left alone. The modified leg built more muscles more quickly — and also had them atrophy less slowly once the critters were allowed to exercise less. Entire animals have also been modified, and shown stronger muscles and better endurance than their un-fiddled-with cousins.

From the standpoint of policing a sport, the ethics seem to be obvious: Improving one’s biochemistry by genetic modification conveys an unfair advantage, just like using steroids. The instant conclusion: Ban it, right now, just like all the other drugs.

If all we were talking about were sports, this would be obvious. Unfortunately, it isn’t that simple.

For starters, once genetic modification (the ethically-neutral term for what we’re discussing) becomes common — and it is making very rapid progress — it will save lives. An obvious example is sufferers from cystic fibrosis. This condition results from a single defective gene (indeed, a single bad DNA “letter” in a single gene). Genetic manipulation can, potentially, cure a patient who otherwise is doomed to die young of damage to the lungs. Similarly, a single gene is responsible for a severe form of muscular dystrophy, and a genetic treatment would cure it. The list of such diseases is long.

Even for diseases with no such cure, a different genetic improvement could be helpful. A person whose lungs have been damaged by pollution, e.g., be helped by a gene that makes it easier for cells to absorb oxygen even if the underlying condition is not cured.

Well, OK, so we’ll allow those sorts of changes, right?

Once you start, though, things get murky fast. What about someone with sickle-cell trait? Sickle-cell anemia is another serious genetic condition, again caused by a single genetic variation. If someone inherits copies of the sickle-cell gene from both parents, he or she will develop sickle-cell anemia and is again likely to die young and will certainly be forced to live a very restricted life. But someone who inherits only one copy of the gene will have a relatively trivial syndrome, sickle-cell trait. The trait is a mild condition; most people who have it don’t even know they have it, and for ordinary activities, it doesn’t matter at all. Indeed, it’s common in some African populations because it helps protect against some forms of malaria. But for certain extremely strenuous activities, sickle-cell trait does impose some slight handicaps; it is likely that someone who has the trait will not be able to be the very best in most athletic activities. (At least, that’s the latest word that we’ve heard; the exact amount of handicap imposed by sickle-cell trait has been a hotly-debated topic for many years.) Should someone inherently be held back from being able to reach the pinnacle of athletic competition simply because of this trait? What’s more, if this person marries another sickle-cell carrier, one-fourth of their children can be expected to die young. Is it fair to leave them with the trait if it is possible to cure it?

OK, so we’ll allow modifications for that, right?

Then what about the discovery, announced in early February 2010, that a handful of genetic variants are strongly associated with stuttering? Stuttering isn’t fatal to anyone, obviously — but it often causes acute public embarrassment and has been found to interfere with the sufferers’ career prospects. Stuttering isn’t like sickle-cell trait, which has a good side in that it helps fight malaria; although the disadvantage is mild, stuttering conveys no advantage whatsoever on the sufferers. Is it right to make them suffer for no reason?

Surely it is only fair to allow modifications for that, right?

Or what about autism? It is genetically linked. A person with high-functioning autism — your present author is one — is badly socially handicapped, may have trouble holding a job, has difficulty making life decisions, is often an outcast, and is likely to suffer depression. But high-functioning autistics may have unusually high intelligence, or amazing special skills as a side effect. Among the probable autistics the author has known is the state of Minnesota’s best young fiddler and a person who can learn languages almost by instinct. Should we make those people more social — and less smart? Even the sufferers don’t have an answer on that one….

In the case of sickle-cell and stuttering you aren’t curing fatal conditions (though you may be preventing some); you are helping someone who is mostly healthy become a little healthier. Where do you draw the line on that? A few years ago, you could almost set your clocks by Lindsay Davenport’s and Justine Henin’s injuries. Hip problems ruined the careers of Gustavo Kuerten and Magnus Norman. Suppose genetic modification would allow Davenport’s damaged foot or Kuerten’s broken-down hip to fully recover (as it might do, since genes do affect things like that). Isn’t that reasonable? Don’t we want to keep top players in playing shape? The trick then becomes to stop the process with just healing rather than enhancing performance.

Except — once you do anything to level the playing field, you are on a slope, and people are greasing that slope even as you walk it. Being “fair” is more complicated than it sounds. Is it “fair” that Venus Williams can be 185 or so centimeters tall and still fast, while Martina Hingis was fifteen centimeters shorter and no faster, and Davenport was as tall as Venus but much slower? The short and slow players, in terms of tennis tools, are arguably just as “crippled” as the person with sickle-cell trait. Shouldn’t they be allowed to equalize? Saying “don’t cheat” is, in some cases, the same as saying “don’t be competitive.” (Note: We aren’t arguing for, or against, anything here; we’re just trying to observe how complex all this is. It’s safe and fair to ban steroids, because people’s bodies don’t make them artificially. For the most part, anyway. But some people do have genetic advantages over others; is it fair to deny player X the benefits of gene 52683-F when player Y already has it?)

And there is another side to this, too: Diagnosis. A National Public Radio story some years ago noted that an improbably high fraction of competitive swimmers have been diagnosed with asthma. Which, just by coincidence, means that they are allowed access to certain classes of drugs which help asthma — and also help athletic performance in other areas. In the case of the swimmers, you can at least cut them off if they don’t really have asthma. But suppose someone finds a doctor who diagnoses a problem and prescribes gene therapy? If it turns out the doctor was wrong or corrupt, you can’t easily undo genetic modification — creating a virus to undo a genetic modification is just as difficult as creating a virus to create it in the first place, and how do you know what the old gene was anyway?

Nor can we simply sit back and hope it doesn’t come up. One of those science magazine articles told the story of a doctor being begged by athletes for miracles. And they have reason to ask. There is a case of genetically-engineered mice which, almost without exercise, develop extra muscle. Human research has been slow, because early attempts produced some tragic failures. But much progress has been made in recent years; based on published data, it seems likely that the techniques have reached a stage where genetic modification could work. And that’s public data — who knows is being done privately? (Nor is such a secret project necessarily immoral. What if they’re trying to create a gene to protect soldiers against smallpox or anthrax, or just to let them serve more comfortably in a hotbox like Iraq? The benefits might come to everyone once the research is completed — but the researchers may not want bioterrorists to know what they’re up to right now. Generally speaking, science is best served by public research. But there may be special cases.)

And the U. S. National Cancer Institute has reported on work that created an entire artificial human chromosome, not just a gene. It has even been inserted into mice. Not humans, yet, but it shows how far the techniques have advanced.

The doping agencies, WADA and such, have not been idle. Genetic manipulation for “non-therapeutic” purposes (whatever that means in the context of the issues above) is banned. Problem is, if it’s happening, they have to detect it. And, unless you have before-and-after DNA samples, genetic manipulation is hard to detect.

No, wait, that’s not true. It’s not hard to detect. If done right, it’s impossible. As long as the manipulators use genes already found in the human genome, and manage to insert them in just the right place (admittedly a tall order), and manage to get them in every cell, there is no way to tell the genes aren’t natural. You’ve created a new genetic structure for the person — in effect, a whole new person. Had a person with that genetic structure been born rather than created, would someone object? Why, in terms of performance abilities, should one object if such a person is “made”?

There are only two ways to guarantee detection of a genetic fix. One is to test a lot of the person’s cells, and discover that they don’t all have the same genetic makeup. This is a smoking gun — but only works if the gene doping was done badly and did not hit every cell. (Plus there are the occasional false positives. It is very, very rare, but one person can have two genetic makeups — if two fraternal twins fuse in utero. Such a person is called a chimera; it is thought that Nicolas II of Russia was one.) The other, completely guaranteed, method is to take the athlete’s complete genetic sequence, and compare it with the sequence of the parents, and see that all the genes are present in the parents (or are simple mutations from those that the parents have). For a long time, this was very expensive (what we now call “DNA testing” is not the same as DNA sequencing; it “testing” involves only a handful of genes, “sequencing” involves all of them). Just in the years since 2010, that has changed; it would now be possible to test every Olympic athlete for a total cost probably in the low millions. Of course, that would require the money to come from somewhere, and we assume the money won’t come from cutting IOC perks. Plus it raises the interesting problem of what happens if one of the parents is dead? Or what if (and the possibility must be allowed) the putative father is not the actual father? It may not be a problem for the sport, but it could well be a problem for the athlete’s family!

Another thing we have to point out is that genetic manipulation may be dangerous — both for the person undergoing it and for society. In several ways. First, you can’t change every gene in every cell all at once; it takes time for the carrier mechanism to get to where it’s going, and it’s bound to miss a few cells. So there is a possibility, if a slight one, of rejection, or an immune system reaction of another sort. (That, in fact, is one of the tragic results which slowed genetic modification research some years back: Jesse Gelsinger, who participated in a trial of a cystic fibrosis “fix” a few years back, died as a result.) Second, the modifications have to be introduced by some means such as viruses. What if the viruses get loose? A virus capable of curing Duchenne muscular dystrophy in someone who has it might, theoretically, do something else in someone who doesn’t. And then, too, we can’t be sure of the long-term effects. Gene G and gene H may be safe as long as they don’t occur together, but dangerous if one person has both — and we may not know it, because G and H never occur together in nature. And there are even scarier scenarios: Perhaps a manipulation which causes muscles to grow faster will also cause cancers to grow faster. Not all steroids are dangerous, but some are, and the fact that the body is being encouraged to make them by itself, rather than getting them out of a bottle, doesn’t change the fact.

And most athletes start too young to really understand the risks.

We don’t see any solutions, other than the most extreme and expensive one: You could test everyone at birth, and if they turn to pro sports, compare their genes at age 18 with their genes at age one. But this is expensive, an obvious invasion of privacy — and may not even work if the manipulation is careful enough and the testing slightly imperfect. And, at the rate things are progressing, we’ll soon be seeing gene doping in utero — the babies will be born with their genes already modified. In a lot of ways, that’s easier than modifying adults anyway.

And things get even trickier if the manipulations are more subtle. What we have described above is “standard” gene doping, which involves actually changing a person’s genes. But there are two other possibilities — one which the author has not seen discussed, but which is inherent in recent work on genes, and which ties in with some work that won a Nobel prize a few years back; the other comes out of work on mitochondria and other “plasmids,” the things which supply energy to the body or allow plants to use the energy of sunlight.

Taking the plasmids first, these are sort of like cells within cells — it is thought that they originated as free-standing bacteria. They perform special functions. Mitochondria convert sugars into energy the cell can use; chloroplasts, in plants, are the parts that actually include the chlorophyll that uses solar energy.

Suppose, arbitrarily, that you could put chloroplasts in human skin cells. Suddenly, the person would be able to generate a lot more energy while playing outside. No need for that pesky digestive process! It could do wonders for energy and stamina.

To be sure, that trick would be easily detected — all you have to do is look for people with green skin. But suppose someone created an artificial plasmid to do something similar. How do we detect that? And plasmids can be shared between cells — bacteria do it all the time. Indeed, plasmids are the major alternative to viruses as a way to insert genes into the DNA.

The other trick is even more insidious.

You probably know that humans have 46 chromosomes (the structures in your cells which contain the genes). You can think of chromosomes as sort of like filing cabinets. You can, in effect, march down a chromosome saying, “Here is gene 1, here is gene 2, here is gene 3.” (It’s actually much more complicated than that, because genes are not continuous strings of DNA; bits and pieces may be scattered all over the chromosomes and infected with vast amounts of junk DNA. But we won’t get into that; if you want to know more, the author suggests Matt Ridley’s book Genome. But be prepared: while Genome is quite readable, it is serious science, not watered down by publishers who are afraid of school boards — which means that it, like all genuine biologists, assumes evolution and the other known laws of science to be true.)

Recall that those 46 chromosomes come in pairs, except for the X and Y chromosomes that distinguish males from females (and even those are paired in females). So you, and every other human alive, has two copies of chromosome 1. And of chromosome 2. And so forth. (Again, there are minor and partial exceptions, but we’ll ignore that.) And each copy of chromosome 1 has a gene 1 and a gene 2 and so forth. So you have two versions of every gene, except those on the X and Y chromosomes if you are male. In some cases you will have two identical copies of the gene — but often you’ll have two different alleles (variants).

So which one of the two gets to do its thing? This is extraordinarily complicated. Some genes are “dominant” and others “recessive”; if, for instance, you have one gene for type A blood and one for type O, you will have type A blood, because A is dominant and O recessive. Others sort of mix — e.g. a child with one dark-skinned parent and one with light skin will probably have an intermediate skin tone. (That actually involves multiple genes, but it gets the idea across.)

In a lot of cases, though, the body seems to just pick one gene. The other is ignored.

But how does it choose?

This has been a popular topic of research in recent years. It used to be thought that a new embryo had no influence from its parents except the actual genes. This turns out not to be true. In fact, maternal and paternal genes are often in conflict — and, by some mechanism that seems not to be fully understood, the parents have techniques for turning on these particular genes. This is known as “imprinting.” (Not to be confused with the sort of imprinting where a baby bird imprints on the first thing it sees as its mother, obviously.) It’s said that genes from the father control the placenta, e.g.

But now consider: In a lot of cases, there is no genetic reason why a particular gene should express itself as a result of imprinting. It was the result of the hormonal situation of the embryo — or something like that. It stands to reason that imprinting can go haywire much more easily ordinary reproduction of genes — this is probably one of the reasons left-handers are more prone to die young than right-handers. Left-handers have been exposed to a different, probably less suitable, prenatal hormone mix. Add a few more hormones, and maybe you can change which gene of a particular pair is active.

And there is no genetic test at all that can detect it. You haven’t changed the genes. You’ve merely switched one gene off and another one on.

Obviously this isn’t as powerful a technique as introducing new genes; you only get to use the genes you already have. But people have tens of thousands of genes. As a wild guess, perhaps five thousand affect athletic performance. We can guess that, in at least 500 cases, each of us has the less athletic gene active.

Suppose you could go through and activate the “high performance” gene in all 500 of those cases. Individually, it might not make much difference. Collectively, who knows?

Starting up and shutting down genes is high-order stuff. Andrew Z. Fire and Craig Mello won the 2006 Nobel Prize in medicine for their work on a phenomenon known as “RNA Interference.”

To explain this, we go back again to high school biology, you’ll recall that genes are stored in DNA — the famous “double helix,” which is in effect an information code for holding data on chemical structures. The structures themselves — enzymes — are built of proteins.

In between the DNA and the enzymes stands RNA. Think of it as the middle manager in a factory, transferring data from the bosses (the genes) to the assembly line (the enzymes). Or, maybe, as the input/output system of the computer, transferring data from the CPU and memory (the genes) to the monitor and keyboard (the enzymes). Block that transfer, and it doesn’t matter what the genes say. Without the RNA, the genes are as helpless as a computer microprocessor outside a computer. So, in theory, RNA interference allows bad genes, of any sort, to be turned off. Not just the ones that cause cancer or diabetes. Also the ones that cause, say, slightly slower recovery times after exertion.

This is probably not as far along as genetic modification by gene splicing. The field is too new, and the implications are still being worked out. It may be a decade or more before the first therapies are worked out on this basis. (That’s a wild, wild guess.) But in the long run, it’s likely to prove safer, easier, and harder to detect than actual genetic modification.

Having said all that, we know what the problem is. Do we know how to detect it?

On February 5, 2010, National Public Radio’s “Science Friday” program featured a biologist from a WADA advisory panel, who came on the program to discuss gene doping.

He reported that WADA is seeking tests for gene doping — but admitted that there are no such tests yet. He also said that the skills needed for gene doping, while not trivial, are not significantly greater than those required for ordinary genetic therapy.

Compared to activities like cycling and weightlifting, tennis seems to be a very clean sport in terms of ordinary doping. But who knows what genes lurk in the hearts (and muscles, and lungs, and nerves) of men?

KEYWORDS: Gene manipulation doping Olympics

Topics: 10sballs.com, Atp, gene doping, Tennis, Tennis News, Wta

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