Can People Regenerate Body Parts? (II of V)

Scientific American Magazine - By Ken Muneoka, Manjong Han and David M. Gardiner

Many years ago studies in the laboratory of our colleague Susan V. Bryant at the University of California, Irvine, demonstrated that the cells in the blastema are equivalent to the cells in the developing limb bud of the salamander embryo.

This discovery suggested that the construction of a limb by the blastema is essentially a recapitulation of the limb formation that took place during the animal’s original development. An important implication of this insight was that the same genetic program is involved in both situations, and because humans make limbs as embryos, in principle we should already have the necessary programming to regenerate them as adults, too. It seemed, therefore, that all scientists needed to do was figure out how to induce an amputated limb to form a blastema.

One of us (Gardiner)—working with Tetsuya Endo of U.C. Irvine a few years ago—took a minimalist approach to answering the basic question of how to make a blastema. Instead of studying amputation sites on the salamander, where a blastema would naturally form, we looked at simple wounds on the side of a salamander limb, which would normally heal just by regenerating the skin. Our idea was that such wounds are similar to the site of an amputated mammalian limb that fails to generate a new limb. If we could get an entire limb to grow where a simple wound-healing response would typically occur, then we could further dissect the regeneration process.

After we made a small incision in the salamander leg, epidermal cells migrated to cover and seal the wound, as they would at an amputation site, and fibroblasts from the dermis layer of the skin also moved in to replace the missing skin. But if we carefully deviated a nerve to the wound site, we could induce those fibroblasts to form a blastema instead. Marcus Singer of Case Western Reserve University had already demonstrated more than half a century ago that innervation was required for a regeneration response, but our experiments clarified that unknown factors provided by the nerve were influencing regeneration by altering the behavior of resident fibroblasts. These induced blastemas never progressed to the later stages of regeneration to form a new limb, however. One more ingredient was needed.

The key to inducing a blastema that produced a new limb was to graft a piece of skin from the opposite side of the limb to the wound site, which allowed fibroblasts from opposite regions of the limb to participate in the healing response. The resulting accessory limb was, of course, growing out at an abnormal location, but it was anatomically normal. So the basic recipe for making a blastema seemed relatively simple: you need a wound epidermis, nerves and fibroblasts from opposite sides of the limb.

With this minimal view of limb regeneration in mind, we began to focus on understanding the roles of the individual ingredients.

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Can People Regenerate Body Parts? (I of V)

Scientific American Magazine - By Ken Muneoka, Manjong Han and David M. Gardiner

Progress on the road to regenerating major body parts, salamander-style, could transform the treatment of amputations and major wounds.

A salamander’s limbs are smaller and a bit slimier than those of most people, but otherwise they are not that different from their human counterparts. The salamander limb is encased in skin, and inside it is composed of a bony skeleton, muscles, ligaments, tendons, nerves and blood vessels. A loose arrangement of cells called fibroblasts holds all these internal tissues together and gives the limb its shape. Yet a salamander’s limb is unique in the world of vertebrates in that it can regrow from a stump after an amputation. An adult salamander can regenerate a lost arm or leg this way over and over again, regardless of how many times the part is amputated.

Frogs can rebuild a limb during tadpole stages when their limbs are first growing out, but they lose this ability in adulthood. Even mammalian embryos have some ability to replace developing limb buds, but that capacity also disappears well before birth. Indeed, this trend toward declining regenerative capacity over the course of an organism’s development is mirrored in the evolution of higher animal forms, leaving the lowly salamander as the only vertebrate still able to regrow complex body parts throughout its lifetime.

Humans have long wondered how the salamander pulls off this feat. How does the regrowing part of the limb “know” how much limb is missing and needs to be replaced? Why doesn’t the skin at the stump form a scar to seal off the wound as it would in humans? How can adult salamander tissue retain the embryonic potential to build an entire limb from scratch multiple times? Biologists are closing in on the answers to those questions. And if we can understand how the regeneration process works in nature, we hope to be able to trigger it in people to regenerate amputated limbs, for example, and transform the healing of other major wounds.

The human body’s initial responses to such a serious injury are not that different from those of a salamander, but soon afterward the human and amphibian wound-healing strategies diverge. Ours results in a scar and amounts to a failed regeneration response, but several signs indicate that humans do have the potential to rebuild complex parts. The key to making that happen will be tapping into our latent abilities so that our own wound healing becomes more salamanderlike. For this reason, our research first focused on the experts to learn how it is done.

When the tiny salamander limb is amputated, blood vessels in the remaining stump contract quickly, so bleeding is limited, and a layer of skin cells rapidly covers the surface of the amputation site. During the first few days after injury, this so-called wound epidermis transforms into a layer of signaling cells called the apical epithelial cap (AEC), which is indispensable for successful regeneration. In the meantime, fibroblasts break free from the connective tissue meshwork and migrate across the amputation surface to meet at the center of the wound. There they proliferate to form a blastema—an aggregation of stemlike cells that will serve as progenitors for the new limb.

Now, as we watch a salamander grow back an arm, we are no longer quite as mystified by how it happens. Soon humans might be able to harness this truly awesome ability ourselves, replacing damaged and diseased body parts at will, perhaps indefinitely.

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GOOGLE COULD BE SUPERSEDED

From Jonathan Richards, TIMEONLINE

The next generation of web technology is likely to be far more powerful than the current crop, Tim Berners-Lee said Google may eventually be displaced as the pre-eminent brand on the internet by a company that harnesses the power of next-generation web technology, the inventor of the World Wide Web has said.

The search giant had developed an extremely effective way of searching for pages on the internet, Tim Berners-Lee said, but that ability paled in comparison to what could be achieved on the "web of the future", which he said would allow any piece of information — such as a photo or a bank statement — to be linked to any other. Mr Berners-Lee said that in the same way, the "current craze" for social networking sites like Facebook and MySpace would eventually be superseded by networks that connected all types of things — not just people — thanks to a ground-breaking technology known as the "semantic web".

The semantic web is the term used by the computer and internet industry to describe the next phase of the web's development, and essentially involves building web-based connectivity into any piece of data — not just a web page — so that it can "communicate" with other information. Whereas the existing web is a collection of pages with links between them that Google and other search engines help the user to navigate, the "semantic web" will enable direct connectivity between much more low-level pieces of information — a written street address and a map, for instance — which in turn will give rise to new services.

"Using the semantic web, you can build applications that are much more powerful than anything on the regular web," Mr Berners-Lee said. "Imagine if two completely separate things — your bank statements and your calendar — spoke the same language and could share information with one another. You could drag one on top of the other and a whole bunch of dots would appear showing you when you spent your money. "If you still weren't sure of where you were when you made a particular transaction, you could then drag your photo album on top of the calendar, and be reminded that you used your credit card at the same time you were taking pictures of your kids at a theme park. So you wouldd know not to claim it as a tax deduction. It's about creating a seamless web of all the data in your life."

One example frequently given is of typing a street address which, if it had "semantic data" built into it, would link directly to a map showing its location, dispensing with the need to go to a site like Google `maps, type in the address, get the link and paste it into a document or e-mail. The challenge, experts say, is in finding a way to represent all data so that when it is connected to the web, links to other relevant information can be recognised and established — a bit like the process known as "tagging".

One expected application is in the pharmaceutical industry, where previously unconnected pieces of research into a drug or disease, say, could be brought together and assimilated. Mr Berners-Lee, who invented the World Wide Web in 1989 while a fellow at CERN, the European Organsation for Nuclear Research in Switzerland, would not be drawn on the type of application that the "Google of the future" would develop, but said it would likely be a type of "mega-mash-up", where information is taken from one place and made useful in another context using the web.

Existing "mash-ups", such as progams that plotted the location of every Starbucks in a city using Google maps, were a start, he said in an interview with Times Online, but they were limited because a separate application had to be built each time a new service was imagined. "In the semantic web, it's like every piece of data is given a longitude and latitute on a map, and anyone can 'mash' them together and use them for different things."

Mr Berners-Lee, who is now a director of the Web Science Research Initiative, a collaborative project between the Massachusetts Institute of Technology and the University of Southampton, sought to put into context the rapid growth of social networking sites in recent years, saying that once the semantic web was rolled out they would be thought of as one of many types of network available. "At the moment, people are very excited about all these connections being made between people — for obvious reasons, because people are important — but I think after a while people will realise that there are many other things you can connect to via the web." He also spoke about what he described as one of the key challenges of the web today — confronting the security risks associated with large databases of information that were attractive to criminals and identity fraudsters.

"There are definitely better ways of managing that threat. I think we're soon going to see a new tipping point where different types of crimes become possible and lucrative, and it's something we constantly have to be aware of. One option is to build systems which more effectively track what information you've used to perform a particular task, and make sure people aren't using their authority to do things that they shouldn't be doing."

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PRISONER'S DILEMMA EXPLAINS SPORTS DOPING (IV of IV)

When Papp came clean, professional cycling slapped him with a two-year ban... But the social consequences were far worse than that.

“The sport spit me out,” he lamented to me. “A team becomes a band of brothers,... but with a team of dopers there’s an additional bond—a shared secret—and with that there is a code of silence. If you get busted, you keep your mouth shut. The moment I confessed I was renounced by my friends because in their mind I put them at risk. One guy called and threatened to kill me if I revealed that he doped.” Papp was never a Tour-caliber cyclist, however, so perhaps the game matrix—with its implications for the rider’s own cycling career—is different at the elite level.

Not so, as I learned from another insider. “For years I had no trouble doing my job to help the team leader,” said Frankie Andreu, who was the superdomestique, or lead pacer, supporting Lance Armstrong throughout much of the 1990s. “Then, around 1996, the speeds of the races shifted dramatically upward. Something happened, and it wasn’t just training.” Andreu resisted the temptation as long as he could, but by 1999 he could no longer do his job: “It became apparent to me that enough of the peloton [the main group of riders in a cycling race] was on the juice that I had to do something.” He began injecting himself with r-EPO two to three times a week. “It’s not like Red Bull, which gives you instant energy,” he explained. “But it does allow you to dig a little deeper, to hang on to the group a little longer, to go maybe 31.5 miles per hour instead of 30 mph.”

One of the subtle benefits of r-EPO in a brutal three-week race like the Tour de France is not just boosting HCT levels but keeping them high. Jonathan Vaughters, a former teammate of Armstrong’s, crunched the numbers for me this way: “The big advantage of blood doping is the ability to keep a 44 percent HCT over three weeks.” A “clean” racer who started with a 44 percent HCT, Vaughters noted, would expect to end up at 40 percent after three weeks of racing because of natural blood dilution and the breakdown of red blood cells. “Just stabilizing [your HCT level] at 44 percent is a 10 percent advantage.”

Scientific studies on the effects of performance-enhancing drugs are few in number and are usually conducted on nonathletes or recreational ones, but they are consistent with Vaughters’s assessment. (For obvious reasons, elite athletes who dope are disinclined to disclose their data). The consensus among the sports physiologists I interviewed is that r-EPO improves performance by at least 5 to 10 percent. When it is mixed in with a brew of other drugs, another 5 to 10 percent boost can be squeezed out of the human engine. In events decided by differences of less than 1 percent, this advantage is colossal.

Italian sports physiologist Michele Ferrari, as knowledgeable on doping as he is controversial (because of his close affiliation with elite athletes who have tested positive for doping or been accused of same), explains it this way: “If the volume of [red blood cells] increases by 10 percent, performance [the rider’s net gain in output of useful kinetic energy] improves by approximately 5 percent. This means a gain of about 1.5 seconds per kilometer for a cyclist pedaling at 50 kilometers per hour in a time trial, or about eight seconds per kilometer for a cyclist climbing at 10 kph on a 10 percent ascent.” In the Tour de France, those numbers imply that a cyclist who boosts his HCT by 10 percent will cut his own time by 75 seconds in a 50-kilometer (31-mile) time trial, a race typically decided by a few seconds. On any of the numerous 10-kilometer (six-mile) climbs in the Alps and the Pyrenees, on grades as steep as 10 percent, that same blood difference would gain the rider a whopping 80 seconds per climb. If any of the top cyclists are on the juice, their erstwhile competitors cannot afford to give away such margins. That is where the game matrix kicks into defection mode.

In game theory, if no player has anything to gain by unilaterally changing strategies, the game is said to be in a Nash equilibrium. The concept was identified by mathematician John Forbes Nash, Jr., who was portrayed in the film A Beautiful Mind. To end doping in sports, the doping game must be restructured so that competing clean is in a Nash equilibrium. That is, the governing bodies of each sport must change the payoff values of the expected outcomes identified in the game matrix.

• First, when other players are playing by the rules, the payoff for doing likewise must be greater than the payoff for cheating.
• Second, and perhaps more important, even when other players are cheating, the payoff for playing fair must be greater than the payoff for cheating. Players must not feel like suckers for following the rules.

In the game of prisoner’s dilemma, lowering the temptation to confess and raising the payoff for keeping silent if the other prisoner confesses increases cooperation. Giving players the chance to communicate before they play the game is the most effective way to increase their cooperation. In sports, that means breaking the code of ­silence. Everyone must acknowledge there is a problem to be solved. Then drug testing must be done and the results communicated regularly and transparently to all until the test results are clean.

That will show each player that the payoff for playing fair is greater than the payoff for cheating, no matter what the other players do.

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PRISONER'S DILEMMA EXPLAINS SPORTS DOPING (III of IV)

In cycling, as in baseball and other sports, the contestants compete according to a set of rules.

The rules of cycling clearly prohibit the use of performance-enhancing drugs. But because the drugs are so effective and many of them are so difficult (if not impossible) to detect, and because the payoffs for success are so great, the incentive to use banned substances is powerful. Once a few elite riders “defect” from the rules (cheat) by doping to gain an advantage, their rule-abiding competitors must defect as well, leading to a cascade of defection through the ranks. Because of the penalties for breaking the rules, however, a code of silence prevents any open communication about how to reverse the trend and return to abiding by the rules. It was not ever thus.

Many riders took stimulants and painkillers from the 1940s through the 1980s. But doping regulations were virtually nonexistent until Tom Simpson, a British rider, died while using amphetamines on the climb up Mont Ventoux in the 1967 Tour de France. Even after Simpson’s death, doping controls in the 1970s and 1980s were spotty at best. With no clear sense of what counted as following the rules, few perceived doping as cheating. In the 1990s, though, something happened to alter the game matrix. That “something” was genetically engineered recombinant erythropoietin: r-EPO.

Ordinary EPO is a hormone that occurs naturally in the body. The kidneys release it into the bloodstream, which carries it to receptors in the bone marrow. When EPO molecules bind to those receptors, the marrow pumps out more red blood cells. Chronic kidney disease and chemotherapy can cause anemia, and so the development of the EPO substitute r-EPO in the late 1980s proved to be a boon to chronically anemic patients—and to chronically competitive athletes. Taking r-EPO is just as effective as getting a blood transfusion, but instead of hassling with bags of blood and long needles that must be poked into a vein, the athlete can store tiny ampoules of r-EPO on ice in a thermos bottle or hotel minifridge, then simply inject the hormone under the skin.

The effect of r-EPO that matters most to the competitor is directly measurable: the hematocrit (HCT) level, or the percentage by volume of red blood cells in the blood. More red blood cells translate to more oxygen carried to the muscles. For men, the normal HCT percentage range is in the mid-40s. Trained endurance athletes can naturally sustain their HCT in the high 40s or low 50s. EPO can push those levels into the high 50s and even the 60s. The winner of the 1996 Tour de France, Bjarne Riis, was nicknamed Mr. 60 Percent; last year he confessed that he owed his extraordinary HCT level to r-EPO.

The drug appears to have made its way into professional cycling in the early 1990s. Greg LeMond thinks it was 1991. Having won the Tour de France in 1986, 1989 and 1990, LeMond set his sights on breaking what would then have been a record of five Tour de France victories, and in the spring of 1991 he was poised to take his fourth.

“I was the fittest I had ever been, my split times in spring training rides were the fastest of my career, and I had assembled a great team around me,” LeMond told me.

“But something was different in the 1991 Tour. There were riders from previous years who couldn’t stay on my wheel who were now dropping me on even modest climbs.”

LeMond finished seventh in that Tour, vowing to himself that he could win clean the next year. It was not to be.

In 1992, he continued, “our [team’s] performance was abysmal, and I couldn’t even finish the race.”

Nondoping cyclists were burning out trying to keep up with their doping competitors. LeMond recounted a story told to him by one of his teammates at the time, Philippe Casado. Casado learned from a rider named Laurent Jalabert, who was racing for the Spanish cycling team ONCE, that Jalabert’s personal doping program was entirely organized by the ONCE team. That program, LeMond said, included r-EPO, which LeMond refused to take, thereby consigning himself to another DNF (“did not finish”) in 1994, his final race. Some who did go along with the pressure to dope paid an even higher price. Casado, for instance, left LeMond’s team to join one that had a doping program—and died suddenly in 1995 at age 30.

Whether his death resulted directly from doping is not known, but when HCT reaches around 60 percent and higher, the blood becomes so thick that clots readily form. The danger is particularly high when the heart rate slows during sleep—and the resting heart rates of endurance athletes are renowned for measuring in the low 30s (in beats per minute). Two champion Dutch riders died of heart attacks after experimenting with r-EPO. Some riders reportedly began sleeping with a heart-rate monitor hooked to an alarm that would sound when their pulse dropped too low. Just as in evolution there is an arms race between predators and prey, in sports there is an arms race between drug takers and drug testers.

In my opinion, the testers are five years away from catching the takers—and always will be. Those who stand to benefit most from cheating will always be more creative than those enforcing the rules, unless the latter have equivalent incentives. In 1997, because there was no test for r-EPO (that would not come until 2001), the Union Cycliste International (UCI), the sport’s governing body, set an HCT limit for men of 50 percent. Shortly afterward, riders figured out that they could go higher than 50, then thin their blood at test time with a technique already allowed and routinely practiced: injections of saline water for rehydration.

Presto change-o.Willy Voet, the soigneur, or all-around caretaker, for the Festina cycling team in the 1990s, explained how he beat the testers in his tell-all book, Breaking the Chain:

Just in case the UCI doctors arrived in the morning to check the riders’ hematocrit levels, I got everything ready to get them through the tests.... I went up to the cyclists’ rooms with sodium drips.... The whole transfusion would take twenty minutes, the saline diluting the blood and so reducing the hematocrit level by three units—just enough. This contraption took no more than two minutes to set up, which meant we could put it into action while the UCI doctors waited for the riders to come down from their rooms.

How did the new rules of the doping game change the players’ strategies? I put the question directly to Joe Papp, a 32-year-old professional cyclist currently banned after testing positive for synthetic testosterone. Recalling the day he was handed the “secret black bag,” Papp explained how a moral choice becomes an economic decision:

“When you join a team with an organized doping program in place, you are simply given the drugs and a choice: take them to keep up or don’t take them and there is a good chance you will not have a career in cycling.”

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PRISONER'S DILEMMA EXPLAINS SPORTS DOPING (II of IV)

Scientific American Magazine - By Michael Shermer

Game theory helps to explain the pervasive abuse of drugs in cycling, baseball and other sports.

Game theory is the study of how players in a game choose strategies that will maximize their return in anticipation of the strategies chosen by the other players. The “games” for which the theory was invented are not just gambling games such as poker or sporting contests in which tactical decisions play a major role; they also include deadly serious affairs in which people make economic choices, military decisions and even national diplomatic strategies. What all those “games” have in common is that each player’s “moves” are analyzed according to the range of options open to the other players.

The game of prisoner’s dilemma is the classic example: You and your partner are arrested for a crime, and you are held incommunicado in separate prison cells. Of course, neither of you wants to confess or rat on the other, but the D.A. gives each of you the following options:

1. If you confess but the other prisoner does not, you go free and he gets three years in jail.
2. If the other prisoner confesses and you do not, you get three years and he goes free.
3. If you both confess, you each get two years. 4. If you both remain silent, you each get a year.

Consider the choices from the first prisoner’s point of view. The only thing the first prisoner cannot control about the outcome is the second prisoner’s choice. Suppose the second prisoner remains silent. Then the first prisoner earns the “temptation” payoff (zero years in jail) by confessing but gets a year in jail (the “high” payoff) by remaining silent. The better outcome in this case for the first prisoner is to confess. But suppose, instead, that the second prisoner confesses. Then, once again, the first prisoner is better off confessing (the “low” payoff, or two years in jail) than remaining silent (the “sucker” payoff, or three years in jail).

Because the circumstances from the second prisoner’s point of view are entirely symmetrical to the ones described for the first, each prisoner is better off confessing no matter what the other prisoner decides to do. Those preferences are not only theoretical. When test subjects play the game just once or for a fixed number of rounds without being allowed to communicate, defection by confessing is the common strategy. But when testers play the game for an unknown number of rounds, the most common strategy is tit-for-tat: each begins cooperating by remaining silent, then mimics whatever the other player does.

Even more mutual cooperation can emerge in many-person prisoner’s dilemma, provided the players are allowed to play long enough to establish mutual trust. But the research shows that once defection by confessing builds momentum, it cascades... throughout the game.

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PRISONER'S DILEMMA EXPLAINS SPORTS DOPING (I of IV)

Scientific American Magazine - By Michael Shermer

Game theory helps to explain the pervasive abuse of drugs in cycling, baseball and other sports.

For a competitive cyclist, there is nothing more physically crushing and psychologically demoralizing than getting dropped by your competitors on a climb. With searing lungs and burning legs, your body hunches over the handlebars as you struggle to stay with the leader. You know all too well that once you come off the back of the pack the drive to push harder is gone—and with it any hope for victory.

Cyclists on the 1984 U.S. Olympic cycling team had told me how they had injected themselves with extra blood before races, either their own—drawn earlier in the season—or that of someone else with the same blood type. “Blood doping,” as the practice is called, was not banned at the time, and on a sliding moral scale it seemed only marginally distinguishable from training at high altitude. Either way, you increase the number of oxygen-carrying red blood cells in your body.

Imagine that my team had made performance-enhancing drugs part of its “medical program” and that I knew I could be cut if I was not competitive. Finally, assume I believed that most of my competitors were doping and that the ones who were tested almost never got caught. That scenario, in substance, is what many competitive cyclists say they have been facing since the early 1990s. And although the details differ for other sports such as baseball, the overall doping circumstances are not dissimilar. Many players are convinced that “everyone else” takes drugs and so have come to believe that they cannot remain competitive if they do not participate.

On the governance side, the failure of Major League Baseball to make the rules clear, much less to enforce them with extensive drug testing throughout the season, coupled with its historical tendency to look the other way, has created an environment conducive to doping. Naturally, most of us do not want to believe that any of these stellar athletes are guilty of doping. But the convergence of evidence leads me to conclude that in cycling, as well as in baseball, football, and track and field, most of the top competitors of the past two decades have been using performance-enhancing drugs.

The time has come to ask not if but why. The reasons are threefold: first, better drugs, drug cocktails and drug-training regimens; second, an arms race consistently won by drug takers over drug testers; and third, a shift in many professional sports that has tipped the balance of incentives in favor of cheating and away from playing by the rules.

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