This month — 8/8/08, to be precise — the curtain rose on what many experts believe could prove to be the first genetically modified Olympics.
For the unscrupulous or overdriven Olympic athlete, the banned practice of “doping” by taking hormones or other drugs to enhance athletic prowess may seem so last century. The next thing in doping is more profound and more dangerous. It’s called gene doping: permanently inserting strength- or endurance-boosting genes into DNA.
“Once you put that gene in, it’s there for the rest of that person’s life,” says Larry Bowers, a clinical chemist at the U.S. Anti-Doping Agency in Colorado Springs, Colo. “You can’t go back and fish it out.”
Scientists developed the technology behind gene doping as a promising way to treat genetic diseases such as sickle-cell anemia and the “bubble boy” immune deficiency syndrome. This experimental medical technology — called gene therapy — has begun to emerge from the pall of early failures and fatalities in clinical trials. As gene therapy begins to enjoy some preliminary successes, scientists at the World Anti-Doping Agency, which oversees drug testing for the Olympics, have started to worry that dopers might now see abuse of gene therapy in sport as a viable option, though the practice was banned by WADA in 2003.
“Gene therapy has now broken out from what seemed to be too little progress and has now shown real therapies for a couple diseases, and more coming,” says Theodore Friedmann, a gene therapy expert at the University of California, San Diego and chairman of WADA’s panel on gene doping.
While gene therapy research has begun making great strides, the science of detecting illicit use of gene therapy in sport is only now finding its legs. To confront the perceived inevitability of gene doping, Friedmann and other scientists have started in recent years to explore the problem of detecting whether an athlete has inserted a foreign gene — an extra copy that may be indistinguishable from the natural genes — into his or her DNA.
It’s proving to be a formidable challenge. Genetic makeup varies from person to person, and world-class athletes are bound to have some natural genetic endowments that other people lack. Somehow, gene-doping tests must distinguish between natural genetic variation among individuals and genes inserted artificially — and the distinction must stand up in court.
Scientists are fighting genetics with genetics, so to speak, enlisting the latest technologies for gene sequencing or for profiling the activity of proteins to find the telltale signs of gene doping. Some techniques attempt the daunting search for the foreign gene itself, like looking for a strand of hay in an enormous haystack.
But new research could also lead to an easier and more foolproof approach: detecting the characteristic ways that an inserted gene affects an athlete’s body as a whole.
Resurgence of gene therapy
In 1999, 18-year-old Jesse Gelsinger died during a gene therapy trial for a rare liver disease. Investigators later attributed his death to a violent immune reaction to the delivery virus rather than to the therapeutic gene. His death was a major setback for the field. It also may have scared away early would-be gene dopers.
In recent years, safety and efficacy of gene therapy have shown signs of progress in numerous clinical trials for conditions ranging from early-onset vision loss to erectile dysfunction. As scientists develop ways to use safer, weaker viruses for delivery, and as gene therapies wind their way through clinical trials, athletes and coaches might start to see gene doping as even more viable than they already do.
In the courtroom during the 2006 trial of Thomas Springstein, a German track coach accused of giving performance-enhancing drugs to high-school–age female runners, prosecutors read aloud an e-mail Springstein had written that would shock the sports world.
“The new Repoxygen is hard to get,” the e-mail read, according to press reports. “Please give me new instructions soon so that I can order the product before Christmas.”
Repoxygen isn’t merely another doping drug such as a hormone or the latest designer steroid — it’s an experimental virus designed to deliver a therapeutic gene and insert it into a person’s DNA.
British pharmaceutical company Oxford BioMedica developed Repoxygen in 2002 as a treatment for severe anemia. The therapy “infects” patients with a harmless virus carrying a modified gene that encodes erythropoietin, a protein that boosts red blood cell production. This protein, often called EPO, is itself a favorite among dopers seeking to increase their oxygen capacity, and hence their endurance.
Viruses have the natural ability to inject genetic material into their host’s DNA. The host’s cells can translate that gene into active proteins as if the foreign gene were the cells’ own. So by delivering the gene for EPO within a virus, Repoxygen could potentially increase the amounts of EPO protein — and the change would be permanent.
Athletes might also be tempted by perhaps the most tantalizing gene therapy experiment of all: the “mighty mouse.” In 1998, H. Lee Sweeney and his colleagues at the University of Pennsylvania School of Medicine injected mice with a virus carrying a gene that boosted production of insulin-like growth factor 1, or IGF-1, a protein that regulates muscle growth. As a result, the mice had 15 percent more muscle mass and were 14 percent stronger than untreated mice — without ever having exercised. The treatment also prevented the decline of muscle mass as the mice grew older.
Other genetic paths to increase muscle strength and volume could include the gene for human growth hormone or segments of DNA that block a protein called myostatin, which normally limits muscle growth.
Endurance might also be boosted by the gene encoding a protein called peroxisome proliferator-activated receptor delta, or PPAR-delta. Mice engineered to have extra copies of this gene hopped onto a treadmill and, without ever having trained, ran about twice as far as unaltered mice. The extra PPAR-delta improved the ability of the mice’s muscles to use fat molecules for energy, and it shifted the animals’ ratio of muscle fiber types from fast-twitch toward slow-twitch fibers — a change that would improve muscle endurance in people as well. Ronald Evans and his colleagues at the Salk Institute for Biological Studies in La Jolla, Calif., published the research in 2004.
Since then, Evans says, he has been routinely approached by curious coaches and athletes. “I’ve had athletes come to my lectures and go to the microphone and say, ‘If I took this drug, would it work with EPO and growth hormone?’ I mean, they would ask this publicly,” Evans says.
“Based on athletes I’ve talked with, I’d say that it’s a reasonable possibility that gene doping will be used in this Olympics, and I think there’s a very high probability that it will be used in the next Olympics,” he says.
Elusive signs
Around the time that Evans was announcing his “marathon mouse” results, WADA kicked off a funding program to focus scientific research on strategies for detecting gene doping.
“A key part of our project is to try to define what we call signatures of doping,” says Olivier Rabin, a biomedical engineer and director of science for WADA. “We are looking at the impact of those kinds of genetic manipulations at different levels.”
The first and most obvious approach is simply to look for the inserted gene among the roughly 6 billion “letters” of genetic code in both sets of a person’s chromosomes.
For clinical gene therapy trials, finding the inserted gene is fairly easy. Scientists know the exact sequence of the gene they inserted, and often they know where on the person’s chromosomes the gene should have ended up. Standard DNA sequencing techniques can reveal the genetic code for that region on the chromosomes, and the unique sequence of the inserted gene will be in plain view. With gene doping, the situation is much trickier.
“In sport, you don’t know where that gene will be put, what virus was used or even what particular variety of gene was used,” Friedmann says. “You don’t have the advantage of knowing where to look and for what, so the argument is to look everywhere.”
Another difficulty is that copies of the foreign gene wouldn’t be in all of a person’s cells. The gene-carrying viruses selectively target certain tissues such as muscle or liver (the liver helps to regulate muscle metabolism). Some blood cells might also take in the viruses’ genetic payloads, but it’s questionable whether a standard blood sample from an athlete would contain the gene. Instead, anti-doping officials would have to sample muscle tissue directly using punch biopsies, a procedure that is mildly painful.
“No one’s expecting that an athlete will agree to a muscle biopsy,” Friedmann says. “That’s a nonstarter.”
Still, direct detection of inserted genes could work in some cases. Evans points out that an artificially inserted gene for PPAR-delta would be much smaller than the natural gene. That’s because the natural gene is far too big to hitch a ride on the carrier virus. Fitting the gene onto a virus means only a trimmed down version of the gene can be used. This distinctive genetic pattern would only exist in a person who had undergone gene doping.
In other cases, genes would end up in tissues where they’re not normally active, making detection more straightforward. For example, the liver and kidneys normally produce the protein EPO, which makes red blood cells, but gene doping could deliver the EPO-coding gene directly to muscle tissues. The trick, then, is to find a noninvasive way to detect where EPO production is occurring inside the body.
One solution is to use medical imaging techniques such as PET scans. In research funded by WADA, Jordi Segura and his colleagues at the Municipal Institute for Medical Research in Barcelona, Spain, attached slightly radioactive “flags” to molecules made during EPO production. A standard PET scan can spot this radioactivity, revealing where EPO was being made in the bodies of mice injected with gene-doping viruses, the team reported in the October 2007 Therapeutic Drug Monitoring. The researchers showed that production of EPO in muscle tissue was a telltale sign of gene doping.
With radioactivity that is relatively mild, the labels are routinely used in medical imaging to diagnose diseases and don’t pose a significant hazard. But Friedmann notes that asking athletes to undergo such a procedure could be controversial.
Detection by proxy
Another approach is to look for signs of the viral “infection,” rather than for the gene itself. Even a weakened virus could trigger a mild, and specific, immune reaction that might show up in a blood test.
Perhaps the greatest challenge facing this method is that viruses aren’t the only way to deliver a gene into a doper’s body. “The reality is that you can just inject naked DNA directly into tissues” with a syringe, Evans says. “Direct injection could be more local and harder to detect.”
This relatively crude way to insert a gene won’t spread the gene as widely through a person’s body as viruses injected into the bloodstream would. But many cells near the site of injection could take in the gene, perhaps enough to improve athletic performance.
Microscopic, synthetic spheres of fat molecules called liposomes can also shuttle doping genes into the body.
To prevent dopers from evading detection by simply changing delivery vehicles, scientists are also exploring a third approach to developing tests: proteomics, the detailed study of all the proteins in the human body.
Regardless of the vehicle used, adding a new gene to the body’s tightly woven web of interacting genes and proteins will cause ripples of change to spread throughout that web. “There will be a body-wide response no matter what gene you use or where in the body you put it,” Friedmann says, “and those changes can be used as a signature of doping.”
Painful biopsies wouldn’t be required. Because the cascade of changes in protein activity would be widespread, anti-doping officials could test using blood, urine, hair or even sweat. Tools developed for the burgeoning fields of genomics and proteomics allow scientists to see the activity levels of thousands of genes or proteins simultaneously.
In preliminary unpublished experiments, Friedmann and his colleagues injected a type of muscle cell with the gene for IGF-1. Activity of hundreds of genes changed as a result, including a boost in the activity of genes that control production of cholesterol, steroids and fatty acids. All of these changes might be detectable with simple blood tests.
WADA is funding half a dozen or so ongoing studies on this proteome-based detection strategy, but research in this area is still at an early stage. “There’s good reason to think that’s likely to work, and a number of labs are having some nice results,” Friedmann says.
As for whether any tests for gene doping will be ready in time for the Beijing Olympics, anti-doping authorities aren’t giving away many hints that might help dopers evade detection. “We never say when our tests are going to be in place,” WADA’s Rabin says.
Even if detection methods do lag behind the games, dopers may want to think twice before assuming they’re in the clear, Friedmann notes. “With stored [blood and urine] samples, one always has the option of going back some months or years later and checking again with the newest tests.” Louis J. Sheehan, Esquire
Just in case the dangers of tampering with a person’s genetic makeup weren’t enough of a disincentive.
Thursday, May 14, 2009
Tuesday, May 5, 2009
Food 5.foo.2234 Louis J. Sheehan, Esquire
Childhood ear infections may not just put hearing at risk. Kids who get them may develop a strong affinity for fatty foods and could be predisposed to obesity, surveys now suggest. Researchers suspect that infections of the middle ear may alter the sense of taste by damaging a nerve that carries sensations from the tongue to the brain.
A childhood history of frequent, serious ear infections (defined as those requiring antibiotics) doubles the risk of becoming obese later in life, psychologist Linda Bartoshuk of the University of Florida in Gainesville reported on August 20 in Philadelphia during a meeting of the American Chemical Society. Those with ear infection histories also have a stronger preference for fatty foods, she said.
Three out of four children experience at least one episode of middle ear infection by their third birthday, and one out of three experiences at least three episodes, according to the National Institute on Deafness and Other Communication Disorders, or NIDCD.
Bartoshuk says frequent ear infections may permanently damage the chorda tympani nerve, which picks up taste sensations from the front of the tongue and then runs through the middle ear — the hollow located between the eardrum and the cochlea — to the brain.
The study originated from informal questionnaires that Bartoshuk and UF colleagues Valerie Duffy and Derek Snyder started handing out at scientific meetings in 1993. The team collected thousands of questionnaires, which aimed to measure how demographic factors relate to the sense of taste. Louis J. Sheehan, Esquire Snyder first noticed how the data suggested a correlation between ear infections and obesity .
Later, with the help of Howard Hoffman and Barry Davis of the NIDCD, the team looked at data from other, more formal surveys, including the National Health and Nutrition Examination Survey of the Centers for Disease Control and Prevention. The correlation was there, too. http://LOUIS-J-SHEEHAN.NET
Damage to the chorda tympani nerve appears to prime people for liking fatty foods, which are especially energy-rich, Bartoshuk says. Paradoxically, that’s not because the nerve damage increases taste sensation — in fact, it decreases it, she says. The link she proposes is more subtle.
In previous research, Bartoshuk and her collaborators showed how chorda tympani damage heightens the sensation of the texture of fatty foods, a sensation the brain associates with energy-density, she says. “Damage to taste makes oral touch feel more intense.” People who’ve had ear infections would then just receive more intense sensations from creamy, slippery foods.
In principle, heightened sensations might cut both ways, Bartoshuk admits. One effect could be that of increased pleasure. But another might be that it would take less fattiness to fool the brain into thinking it has secured enough energy. However, she says her surveys show that people with ear infections actually like fatty foods better, so that they may want to eat more of them.
Bartoshuk speculates that the link between chorda tympani damage and increased touch sensations may be an evolutionary accident. Tasting food tells the brain that food is coming, she notes. The brain ignores tactile sensations it might otherwise take as warnings — sensations that would, for example, trigger a reflex to cough.
The brain also ignores sensations of pain that may come from uncooperative food — for example, live prey that’s trying not to be swallowed. So the brain responds to the tongue’s taste by ignoring its touch. “It’s a beautiful system that’s built to make sure you eat,” Bartoshuk says.
Removing the taste sensations from the chorda tympani allows the touch sensation to be felt more strongly than usual. Thus fatty foods “feel” even fattier.
The chorda tympani is not the only nerve carrying taste sensations from the tongue, and people with a history of ear infection don’t usually report altered taste sensations, Bartoshuk adds.
Her colleague Hoffman also found a correlation between tonsillectomy and weight gain, Bartoshuk says, adding that tonsillectomy can damage a separate taste nerve.
Bartoshuk and her collaborators have presented parts of their results at scientific meetings in the past, but they only plan to publish them now, after the evidence has become more solid, Bartoshuk says. “We did not want to go public with this because it’s the sort of thing that frightens people.”
Julie Mennella, a biopsychologist at the Monell Chemical Senses Center in Philadelphia, says her own surveys of children aged 7 to 11 are corroborating the team’s findings. “What Linda has found in adults, we’re already seeing in children, too,” she says.
A childhood history of frequent, serious ear infections (defined as those requiring antibiotics) doubles the risk of becoming obese later in life, psychologist Linda Bartoshuk of the University of Florida in Gainesville reported on August 20 in Philadelphia during a meeting of the American Chemical Society. Those with ear infection histories also have a stronger preference for fatty foods, she said.
Three out of four children experience at least one episode of middle ear infection by their third birthday, and one out of three experiences at least three episodes, according to the National Institute on Deafness and Other Communication Disorders, or NIDCD.
Bartoshuk says frequent ear infections may permanently damage the chorda tympani nerve, which picks up taste sensations from the front of the tongue and then runs through the middle ear — the hollow located between the eardrum and the cochlea — to the brain.
The study originated from informal questionnaires that Bartoshuk and UF colleagues Valerie Duffy and Derek Snyder started handing out at scientific meetings in 1993. The team collected thousands of questionnaires, which aimed to measure how demographic factors relate to the sense of taste. Louis J. Sheehan, Esquire Snyder first noticed how the data suggested a correlation between ear infections and obesity .
Later, with the help of Howard Hoffman and Barry Davis of the NIDCD, the team looked at data from other, more formal surveys, including the National Health and Nutrition Examination Survey of the Centers for Disease Control and Prevention. The correlation was there, too. http://LOUIS-J-SHEEHAN.NET
Damage to the chorda tympani nerve appears to prime people for liking fatty foods, which are especially energy-rich, Bartoshuk says. Paradoxically, that’s not because the nerve damage increases taste sensation — in fact, it decreases it, she says. The link she proposes is more subtle.
In previous research, Bartoshuk and her collaborators showed how chorda tympani damage heightens the sensation of the texture of fatty foods, a sensation the brain associates with energy-density, she says. “Damage to taste makes oral touch feel more intense.” People who’ve had ear infections would then just receive more intense sensations from creamy, slippery foods.
In principle, heightened sensations might cut both ways, Bartoshuk admits. One effect could be that of increased pleasure. But another might be that it would take less fattiness to fool the brain into thinking it has secured enough energy. However, she says her surveys show that people with ear infections actually like fatty foods better, so that they may want to eat more of them.
Bartoshuk speculates that the link between chorda tympani damage and increased touch sensations may be an evolutionary accident. Tasting food tells the brain that food is coming, she notes. The brain ignores tactile sensations it might otherwise take as warnings — sensations that would, for example, trigger a reflex to cough.
The brain also ignores sensations of pain that may come from uncooperative food — for example, live prey that’s trying not to be swallowed. So the brain responds to the tongue’s taste by ignoring its touch. “It’s a beautiful system that’s built to make sure you eat,” Bartoshuk says.
Removing the taste sensations from the chorda tympani allows the touch sensation to be felt more strongly than usual. Thus fatty foods “feel” even fattier.
The chorda tympani is not the only nerve carrying taste sensations from the tongue, and people with a history of ear infection don’t usually report altered taste sensations, Bartoshuk adds.
Her colleague Hoffman also found a correlation between tonsillectomy and weight gain, Bartoshuk says, adding that tonsillectomy can damage a separate taste nerve.
Bartoshuk and her collaborators have presented parts of their results at scientific meetings in the past, but they only plan to publish them now, after the evidence has become more solid, Bartoshuk says. “We did not want to go public with this because it’s the sort of thing that frightens people.”
Julie Mennella, a biopsychologist at the Monell Chemical Senses Center in Philadelphia, says her own surveys of children aged 7 to 11 are corroborating the team’s findings. “What Linda has found in adults, we’re already seeing in children, too,” she says.
Saturday, May 2, 2009
melanoma 9.mel.432 Louis J. Sheehan, Esquire
When deciding who to choose for President, voters have to weigh a lot of factors: Who’s on the “right” side of pivotal issues; who’s most likely to remain calm, focused and decisive in times of strife; and even whether a candidate is likely to survive his term in office. Louis J. Sheehan, Esquire The last is something that many people have been discussing with regard to John McCain. If he wins the Presidential election in a little more than a week, he’d be the oldest incoming commander-in-chief.
Age, however, is no reliable gauge of life expectancy. Many people die in their 20s of accidents or even the occasional cancer. On the other hand, one of my grandmothers died at 88, the other at 100, and both of my grandfathers lived into their 90s. So the fact that John McCain is 72 does not indicate whether he’ll outlive Barack Obama (25 years his junior) much less the Republican candidate's 44-year-old running mate, Sarah Palin. Indeed, working in McCain’s favor are good genes: His 96-year-old mom is still around to vote for him. http://Louis-J-Sheehan.de
However, an individual’s medical history can point to special vulnerabilities. And McCain has one that his opponent does not: a history of cancer.
In the Oct. 25 Lancet, internist John Alam reviews what has been publicly released about the lesion removed from McCain eight years ago. It was melanoma, an especially malignant form of skin cancer. And at 2.2 millimeters thick, he says, McCain’s cancer fell into a “higher risk” category, based on something known as a Schuchter scale. Indeed, Alam writes, the Arizona senator’s predicted 10 year survival at the time of diagnosis was only 24 percent,” owing to his age at that point, his gender, and the fact that the cancer developed on the main part of his body — not an extremity.
Findings from another study that Alam cited would indicate that melanoma survivors who had initially developed a lesion as thick as McCain’s could expect to face a 12 percent risk of cancer recurrence in the ninth and the tenth years following surgery (as in 2009 and 2010) — a risk that would not be expected to decline for several years thereafter.
However, Alam points out, most such long-term-risk estimates derive from data compiled before melanoma patients were routinely biopsied for signs that their cancer had spread to lymph nodes. McCain’s lymph nodes were biopsied and showed no evidence of metastasis. So, Alam concludes, the Republican candidate’s prognosis “should be better than for the overall population in the Schuchter model.”
Two studies have focused on short-term prognosis of cancer recurrence for lymph-node-negative melanoma survivors (based on a median three-year follow-up of patients in each study). These investigations indicated that death rates from cancer recurrence in such patients were only half of that seen in melanoma survivors whose cancers had spread to lymph nodes.
Extrapolating these preliminary estimates to long-term survival, Alam says, would suggest that “McCain’s mortality risk due to melanoma is better but not eliminated, remaining at 6 percent per year.”
Is that a big deal? Well, McCain will probably have significantly better medical surveillance and care than the rest of us, should he reach the Oval Office. And early detection greatly increases an individual’s chances of survival. So I’m not too concerned that melanoma poses a huge risk.
Indeed, I would expect that for any President, stresses associated with the job — especially coping with crises such as running a war, countering threats of domestic terrorism, and reviving a devastated financial system — would pose a far greater risk of heart attack or stroke.
So why did Alam raise the issue of McCain’s melanoma? One can only guess. For what it’s worth, the Cambridge, Mass.-based physician acknowledges that “I have made voluntary contributions to the Democratic party and [Obama], but otherwise declare that I have no conflict of interest.”
Age, however, is no reliable gauge of life expectancy. Many people die in their 20s of accidents or even the occasional cancer. On the other hand, one of my grandmothers died at 88, the other at 100, and both of my grandfathers lived into their 90s. So the fact that John McCain is 72 does not indicate whether he’ll outlive Barack Obama (25 years his junior) much less the Republican candidate's 44-year-old running mate, Sarah Palin. Indeed, working in McCain’s favor are good genes: His 96-year-old mom is still around to vote for him. http://Louis-J-Sheehan.de
However, an individual’s medical history can point to special vulnerabilities. And McCain has one that his opponent does not: a history of cancer.
In the Oct. 25 Lancet, internist John Alam reviews what has been publicly released about the lesion removed from McCain eight years ago. It was melanoma, an especially malignant form of skin cancer. And at 2.2 millimeters thick, he says, McCain’s cancer fell into a “higher risk” category, based on something known as a Schuchter scale. Indeed, Alam writes, the Arizona senator’s predicted 10 year survival at the time of diagnosis was only 24 percent,” owing to his age at that point, his gender, and the fact that the cancer developed on the main part of his body — not an extremity.
Findings from another study that Alam cited would indicate that melanoma survivors who had initially developed a lesion as thick as McCain’s could expect to face a 12 percent risk of cancer recurrence in the ninth and the tenth years following surgery (as in 2009 and 2010) — a risk that would not be expected to decline for several years thereafter.
However, Alam points out, most such long-term-risk estimates derive from data compiled before melanoma patients were routinely biopsied for signs that their cancer had spread to lymph nodes. McCain’s lymph nodes were biopsied and showed no evidence of metastasis. So, Alam concludes, the Republican candidate’s prognosis “should be better than for the overall population in the Schuchter model.”
Two studies have focused on short-term prognosis of cancer recurrence for lymph-node-negative melanoma survivors (based on a median three-year follow-up of patients in each study). These investigations indicated that death rates from cancer recurrence in such patients were only half of that seen in melanoma survivors whose cancers had spread to lymph nodes.
Extrapolating these preliminary estimates to long-term survival, Alam says, would suggest that “McCain’s mortality risk due to melanoma is better but not eliminated, remaining at 6 percent per year.”
Is that a big deal? Well, McCain will probably have significantly better medical surveillance and care than the rest of us, should he reach the Oval Office. And early detection greatly increases an individual’s chances of survival. So I’m not too concerned that melanoma poses a huge risk.
Indeed, I would expect that for any President, stresses associated with the job — especially coping with crises such as running a war, countering threats of domestic terrorism, and reviving a devastated financial system — would pose a far greater risk of heart attack or stroke.
So why did Alam raise the issue of McCain’s melanoma? One can only guess. For what it’s worth, the Cambridge, Mass.-based physician acknowledges that “I have made voluntary contributions to the Democratic party and [Obama], but otherwise declare that I have no conflict of interest.”
Saturday, April 11, 2009
exciting 3.exc.0003 Louis J. Sheehan, Esquire
Scientists have found two immune proteins that orchestrate a defense against West Nile virus. By identifying the protein that initially senses the virus and another that enables immune forces to kill it, the findings might open new avenues for research into drugs for treating severe West Nile infections, the researchers say.
The study in mice shows that an immune protein called toll-like receptor 7 (TLR7) serves as the linchpin in fending off an assault by the virus. TLR7 sets in motion a cascade of events that rev up production of a second protein, interleukin-23, which guides immune cells on seek-and-destroy missions against cells infected with the virus. In mice missing TLR7 or interleukin-23, this chain reaction fails and the virus spreads, the researchers report in the Feb. 20 Immunity.
Most people fend off a West Nile infection without even developing noticeable symptoms, thanks apparently to TLR7 and interleukin-23.
But the findings suggest that elderly and immune-compromised people, who sometimes develop the brain inflammation encephalitis from a West Nile infection, may lack a full complement of TLR7, says study coauthor Richard Flavell, an immunologist and Howard Hughes medical investigator at Yale University School of Medicine.
It makes sense that TLR7 would play a part in defending against West Nile, he says. The TLR proteins are immune stalwarts that reside on the surface of immune cells and on cells that serve as linings in the body, such as skin and membranes. TLRs act as sentinels, recognizing bacteria, fungi and viruses, which stick to TLRs and cause a reaction that alerts the cell to the invader’s presence.
TLR7 binds to the RNA of the West Nile virus, the researchers report. TLR7 then uses an intermediary compound to send a signal into the cell that spurs production of interleukin-23. That protein enters the bloodstream and guides immune cells called macrophages to cells infected with West Nile virus. Macrophages do much of the dirty work of destroying these infected cells and stopping the virus from spreading, the researchers find.
In mice genetically engineered to lack either TLR7 or interleukin-23, the virus spreads unabated. About half of normal mice die from a West Nile infection. In this study, mice lacking TLR7 had a death rate of about 90 percent when exposed to the virus. In a separate test of mice lacking various interleukins, some survived as well as normal mice. But all mice lacking interleukin-23 died. Mice lacking the intermediary compound were also highly susceptible to the virus.
“This is a very exciting paper,” says immunologist Andrea Cooper of the Trudeau Institute in Saranac Lake, N.Y. At a minimum, she says, “it broadens our understanding of the activity of interleukin-23.” Louis J. Sheehan, Esquire
The study also opens other lines of research, Cooper says. For example, scientists might obtain blood from elderly populations, culture these samples in a lab and expose them to West Nile virus particles. “Then they could see whether the cells make interleukin-23 or not, whether macrophages respond,” she says. Louis J. Sheehan, Esquire
Such a test might clarify why some elderly people are susceptible to the virus. “We don’t know enough about the effect of aging on the innate immune system,” she says. “Perhaps [elderly people] can’t get cells to the right location quickly enough.” http://LOUIS-J-SHEEHAN.ORG
Flavell is also interested in testing blood, specifically from elderly people who have developed encephalitis or other severe disease from West Nile. If some people turn out to have low levels of TLR7, he says, “we could try to address that issue.”
The study in mice shows that an immune protein called toll-like receptor 7 (TLR7) serves as the linchpin in fending off an assault by the virus. TLR7 sets in motion a cascade of events that rev up production of a second protein, interleukin-23, which guides immune cells on seek-and-destroy missions against cells infected with the virus. In mice missing TLR7 or interleukin-23, this chain reaction fails and the virus spreads, the researchers report in the Feb. 20 Immunity.
Most people fend off a West Nile infection without even developing noticeable symptoms, thanks apparently to TLR7 and interleukin-23.
But the findings suggest that elderly and immune-compromised people, who sometimes develop the brain inflammation encephalitis from a West Nile infection, may lack a full complement of TLR7, says study coauthor Richard Flavell, an immunologist and Howard Hughes medical investigator at Yale University School of Medicine.
It makes sense that TLR7 would play a part in defending against West Nile, he says. The TLR proteins are immune stalwarts that reside on the surface of immune cells and on cells that serve as linings in the body, such as skin and membranes. TLRs act as sentinels, recognizing bacteria, fungi and viruses, which stick to TLRs and cause a reaction that alerts the cell to the invader’s presence.
TLR7 binds to the RNA of the West Nile virus, the researchers report. TLR7 then uses an intermediary compound to send a signal into the cell that spurs production of interleukin-23. That protein enters the bloodstream and guides immune cells called macrophages to cells infected with West Nile virus. Macrophages do much of the dirty work of destroying these infected cells and stopping the virus from spreading, the researchers find.
In mice genetically engineered to lack either TLR7 or interleukin-23, the virus spreads unabated. About half of normal mice die from a West Nile infection. In this study, mice lacking TLR7 had a death rate of about 90 percent when exposed to the virus. In a separate test of mice lacking various interleukins, some survived as well as normal mice. But all mice lacking interleukin-23 died. Mice lacking the intermediary compound were also highly susceptible to the virus.
“This is a very exciting paper,” says immunologist Andrea Cooper of the Trudeau Institute in Saranac Lake, N.Y. At a minimum, she says, “it broadens our understanding of the activity of interleukin-23.” Louis J. Sheehan, Esquire
The study also opens other lines of research, Cooper says. For example, scientists might obtain blood from elderly populations, culture these samples in a lab and expose them to West Nile virus particles. “Then they could see whether the cells make interleukin-23 or not, whether macrophages respond,” she says. Louis J. Sheehan, Esquire
Such a test might clarify why some elderly people are susceptible to the virus. “We don’t know enough about the effect of aging on the innate immune system,” she says. “Perhaps [elderly people] can’t get cells to the right location quickly enough.” http://LOUIS-J-SHEEHAN.ORG
Flavell is also interested in testing blood, specifically from elderly people who have developed encephalitis or other severe disease from West Nile. If some people turn out to have low levels of TLR7, he says, “we could try to address that issue.”
Saturday, January 10, 2009
major 5.maj.9 Louis J. Sheehan, Esquire
Virtually all the dominant strain of flu in the United States this season is resistant to the leading antiviral drug Tamiflu, and scientists and health officials are trying to figure out why.
The problem is not yet a public health crisis because this has been a below-average flu season so far, and because the Tamiflu-resistant strain, one of three circulating, is still susceptible to other drugs. But infectious disease specialists are worried nonetheless.
Last winter, about 11 percent of the throat swabs from patients with the most common type of flu that were sent to the Centers for Disease Control and Prevention for genetic typing showed a Tamiflu-resistant strain. This season, 99 percent do.
“It’s quite shocking,” said Dr. Kent A. Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York. “We’ve never lost an antimicrobial this fast. It blew me away.”
The single mutation that creates Tamiflu resistance appears to be spontaneous, and not a reaction to overuse of the drug. It may have occurred in Asia, and it was widespread in Europe last year. In response, the disease control agency issued new guidelines two weeks ago. They urged doctors to test suspected flu cases as quickly as possible to see if they are influenza A or influenza B, and if they are A, whether they are H1 or H3 viruses.
The only Tamiflu-resistant strain is an H1N1. Its resistance mutation could fade out, an agency scientist said, or a different flu strain could overtake H1N1 in importance, but right now it causes almost all flu cases in the country, except in a few mountain states, where H3N2 is prevalent.
Complicating the problem, antiviral drugs work only if taken within the first 48 hours of infection. A patient with severe flu could be given the wrong drug and die of pneumonia before test results come in. So the new guidelines suggest that doctors check with their state health departments to see which strains are most common locally and treat for them.
“We’re a fancy hospital, and we can’t even do the A versus B test in a timely fashion,” Dr. Sepkowitz said. “I have no idea what a doctor in an unfancy office without that lab backup can do.”
If a Tamiflu-resistant strain is suspected, the disease control agency suggests using a similar drug, Relenza. But Relenza is harder to take; it is a powder that must be inhaled and can cause lung spasms, and it is not recommended for children under 7.
Relenza, made by GlaxoSmithKline, is known generically as zanamivir. Tamiflu, made by Roche, is known generically as oseltamivir.
Alternatively, patients who have trouble inhaling Relenza can take a mixture of Tamiflu and rimantadine, an older generic drug that the agency stopped recommending two years ago because so many flu strains were resistant to it. By chance, the new Tamiflu-resistant H1N1 strain is not.
“The bottom line is that we should have more antiviral drugs,” said Dr. Arnold S. Monto, a flu expert at the University of Michigan’s School of Public Health. “And we should be looking into multidrug combinations.”
New York City had tested only two flu samples as of Jan. 6, and both were Tamiflu-resistant, said Dr. Annie Fine, an epidemiologist at the city’s health department. Flu cases in the city are only “here and there,” Dr. Fine said, and there have been no outbreaks in nursing homes. Elderly patients and those with the AIDS virus or on cancer therapy are most at risk.
But, she added, because of the resistance problem, the city is speeding its laboratory procedures so it can do both crucial tests in one day.
“And we strongly suggest that people get a flu shot,” Dr. Fine said. “There’s plenty of time and plenty of vaccine.” http://LOUIS-J-SHEEHAN-ESQUIRE.US
Exactly how the Tamiflu-resistant strain emerged is a mystery, several experts said.
Resistance appeared several years ago in Japan, which uses more Tamiflu than any other country, and experts feared it would spread.
But the Japanese strains were found only in patients already treated with Tamiflu, and they were “weak” — that is, they did not transmit to other people.
“This looks like a spontaneous development of resistance in the most unlikely places — possibly in Norway, which doesn’t use antivirals at all,” Dr. Monto said.
Dr. Henry L. Niman, a biochemist in Pittsburgh who runs recombinomics.com, a Web site that tracks the genetics of flu cases worldwide, has been warning for months that Tamiflu resistance in H1N1 was spreading.
Dr. Niman argues that it started in China, where Tamiflu use is rare, was seen last year in Norway, France and Russia, then moved to South Africa (where winter is June to September), and back to the Northern Hemisphere in November.
The mutation conferring resistance to Tamiflu, known in the shorthand of genetics as H274Y on the N gene, was actually, Dr. Niman said, “just a passenger, totally unrelated to Tamiflu usage, but hitchhiking on another change.”
The other mutation, he said, known as A193T on the H gene, made the virus better at infecting people.
Furthermore, Dr. Niman blamed mismatched flu vaccines for helping the A193T mutation spread. Flu vaccines typically protect against three flu strains, but none have contained protections against the A193T mutation.
Dr. Joseph S. Bresee, chief of flu prevention at the disease control agency, said he thought Dr. Niman was “probably right” about the resistance having innocently piggy-backed on a mutation on the H gene — which creates the spike on the outside of the virus that lets it break into human cells. But Dr. Bresee said he doubted that last year’s flu vaccine was to blame, since the H1 strain in it protected “not perfectly, but relatively well” against H1N1 infection.
Dr. Niman said he was worried about two aspects of the new resistance to Tamiflu. Preliminary data out of Norway, he said, suggested that the new strain was more likely to cause pneumonia. http://LOUIS-J-SHEEHAN-ESQUIRE.US
The flu typically kills about 36,000 Americans a year, the C.D.C. estimates, most of them the elderly or the very young, or people with problems like asthma or heart disease; pneumonia is usually the fatal complication.
And while seasonal flu is relatively mild, the Tamiflu resistance could transfer onto the H5N1 bird flu circulating in Asia and Egypt, which has killed millions of birds and about 250 people since 2003. Although H5N1 has not turned into a pandemic strain, as many experts recently feared it would, it still could — and Tamiflu resistance in that case would be a disaster. Louis J. Sheehan, Esquire
The problem is not yet a public health crisis because this has been a below-average flu season so far, and because the Tamiflu-resistant strain, one of three circulating, is still susceptible to other drugs. But infectious disease specialists are worried nonetheless.
Last winter, about 11 percent of the throat swabs from patients with the most common type of flu that were sent to the Centers for Disease Control and Prevention for genetic typing showed a Tamiflu-resistant strain. This season, 99 percent do.
“It’s quite shocking,” said Dr. Kent A. Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York. “We’ve never lost an antimicrobial this fast. It blew me away.”
The single mutation that creates Tamiflu resistance appears to be spontaneous, and not a reaction to overuse of the drug. It may have occurred in Asia, and it was widespread in Europe last year. In response, the disease control agency issued new guidelines two weeks ago. They urged doctors to test suspected flu cases as quickly as possible to see if they are influenza A or influenza B, and if they are A, whether they are H1 or H3 viruses.
The only Tamiflu-resistant strain is an H1N1. Its resistance mutation could fade out, an agency scientist said, or a different flu strain could overtake H1N1 in importance, but right now it causes almost all flu cases in the country, except in a few mountain states, where H3N2 is prevalent.
Complicating the problem, antiviral drugs work only if taken within the first 48 hours of infection. A patient with severe flu could be given the wrong drug and die of pneumonia before test results come in. So the new guidelines suggest that doctors check with their state health departments to see which strains are most common locally and treat for them.
“We’re a fancy hospital, and we can’t even do the A versus B test in a timely fashion,” Dr. Sepkowitz said. “I have no idea what a doctor in an unfancy office without that lab backup can do.”
If a Tamiflu-resistant strain is suspected, the disease control agency suggests using a similar drug, Relenza. But Relenza is harder to take; it is a powder that must be inhaled and can cause lung spasms, and it is not recommended for children under 7.
Relenza, made by GlaxoSmithKline, is known generically as zanamivir. Tamiflu, made by Roche, is known generically as oseltamivir.
Alternatively, patients who have trouble inhaling Relenza can take a mixture of Tamiflu and rimantadine, an older generic drug that the agency stopped recommending two years ago because so many flu strains were resistant to it. By chance, the new Tamiflu-resistant H1N1 strain is not.
“The bottom line is that we should have more antiviral drugs,” said Dr. Arnold S. Monto, a flu expert at the University of Michigan’s School of Public Health. “And we should be looking into multidrug combinations.”
New York City had tested only two flu samples as of Jan. 6, and both were Tamiflu-resistant, said Dr. Annie Fine, an epidemiologist at the city’s health department. Flu cases in the city are only “here and there,” Dr. Fine said, and there have been no outbreaks in nursing homes. Elderly patients and those with the AIDS virus or on cancer therapy are most at risk.
But, she added, because of the resistance problem, the city is speeding its laboratory procedures so it can do both crucial tests in one day.
“And we strongly suggest that people get a flu shot,” Dr. Fine said. “There’s plenty of time and plenty of vaccine.” http://LOUIS-J-SHEEHAN-ESQUIRE.US
Exactly how the Tamiflu-resistant strain emerged is a mystery, several experts said.
Resistance appeared several years ago in Japan, which uses more Tamiflu than any other country, and experts feared it would spread.
But the Japanese strains were found only in patients already treated with Tamiflu, and they were “weak” — that is, they did not transmit to other people.
“This looks like a spontaneous development of resistance in the most unlikely places — possibly in Norway, which doesn’t use antivirals at all,” Dr. Monto said.
Dr. Henry L. Niman, a biochemist in Pittsburgh who runs recombinomics.com, a Web site that tracks the genetics of flu cases worldwide, has been warning for months that Tamiflu resistance in H1N1 was spreading.
Dr. Niman argues that it started in China, where Tamiflu use is rare, was seen last year in Norway, France and Russia, then moved to South Africa (where winter is June to September), and back to the Northern Hemisphere in November.
The mutation conferring resistance to Tamiflu, known in the shorthand of genetics as H274Y on the N gene, was actually, Dr. Niman said, “just a passenger, totally unrelated to Tamiflu usage, but hitchhiking on another change.”
The other mutation, he said, known as A193T on the H gene, made the virus better at infecting people.
Furthermore, Dr. Niman blamed mismatched flu vaccines for helping the A193T mutation spread. Flu vaccines typically protect against three flu strains, but none have contained protections against the A193T mutation.
Dr. Joseph S. Bresee, chief of flu prevention at the disease control agency, said he thought Dr. Niman was “probably right” about the resistance having innocently piggy-backed on a mutation on the H gene — which creates the spike on the outside of the virus that lets it break into human cells. But Dr. Bresee said he doubted that last year’s flu vaccine was to blame, since the H1 strain in it protected “not perfectly, but relatively well” against H1N1 infection.
Dr. Niman said he was worried about two aspects of the new resistance to Tamiflu. Preliminary data out of Norway, he said, suggested that the new strain was more likely to cause pneumonia. http://LOUIS-J-SHEEHAN-ESQUIRE.US
The flu typically kills about 36,000 Americans a year, the C.D.C. estimates, most of them the elderly or the very young, or people with problems like asthma or heart disease; pneumonia is usually the fatal complication.
And while seasonal flu is relatively mild, the Tamiflu resistance could transfer onto the H5N1 bird flu circulating in Asia and Egypt, which has killed millions of birds and about 250 people since 2003. Although H5N1 has not turned into a pandemic strain, as many experts recently feared it would, it still could — and Tamiflu resistance in that case would be a disaster. Louis J. Sheehan, Esquire
Tuesday, January 6, 2009
maize 4.mai.002003 Louis J. Sheehan, Esquire
Inhabitants of southern Mexico began to cultivate maize, the major grain crop of prehistoric societies in the Americas, by at least 6,300 years ago, a new study finds. This is around 800 years earlier than previous estimates.http://louis3j3sheehan3esquire.wordpress.com
Radiocarbon dates for minute samples taken from two maize cobs converge on the older age, according to a report in the Feb. 13 Proceedings of the National Academy of Sciences. Archaeologists excavated both cobs in 1966 at Guilá Naquitz Cave in Mexico's southern highlands. The specimens are now housed in a Mexican museum.
Until now, the earliest evidence of maize growing in the New World came from a radiocarbon analysis of 5,500-year-old cobs from San Marcos Cave, located in southern Mexico's Tehuacán Valley.
The new findings can't resolve scientific debates over the precise location and timing of initial maize domestication, say coauthors archaeologist Dolores R. Piperno of the Smithsonian Tropical Research Institute in Balboa, Panama, and anthropologist Kent V. Flannery of the University of Michigan in Ann Arbor.
Previous genetic studies indicate, to some scientists, that a subspecies of the wild grass teosinte was the likely ancestor of maize. Maize domestication may have first occurred where this form of teosinte still grows, in the Central Balsas River Valley, which is located about 250 miles east of Guilá Naquitz.
Other investigators have suggested that prehistoric people living much closer to Guilá Naquitz concocted the earliest maize as a hybrid of teosinte and another wild grass species.
Whatever the case, maize cultivation didn't originate at Guilá Naquitz, Piperno and Flannery assert. The researchers found no fossilized grains characteristic of either teosinte or maize in the site's layers of earth ranging from about 10,000 to 7,000 years old.
Maize cobs found at both Guilá Naquitz and San Marcos contain securely attached grains and other features typical of modern maize, adds Bruce F. Benz of Texas Wesleyan University in Fort Worth. His analysis appears in the same issue of Proceedings of the National Academy of Sciences. http://louis3j3sheehan3esquire.wordpress.com
Remains at Guilá Naquitz from around 10,000 years ago have also provided the earliest evidence of squash cultivation in the Americas (SN: 5/24/97, p. 322). http://louis3j3sheehan3esquire.wordpress.com
Scientific clues to the origins of Mexico's three major crops--squash, maize, and beans--come from only five caves excavated 40 to 50 years ago, remarks archaeologist Bruce D. Smith of the Smithsonian Institution in Washington, D.C., in a comment published with the new reports. The limited evidence nevertheless suggests that the domestication of both squash and maize first occurred in southern and southwestern Mexico, Smith says. Beans were probably first domesticated around 4,000 years ago in western Mexico, in his view. Louis J. Sheehan, Esquire.
Radiocarbon dates for minute samples taken from two maize cobs converge on the older age, according to a report in the Feb. 13 Proceedings of the National Academy of Sciences. Archaeologists excavated both cobs in 1966 at Guilá Naquitz Cave in Mexico's southern highlands. The specimens are now housed in a Mexican museum.
Until now, the earliest evidence of maize growing in the New World came from a radiocarbon analysis of 5,500-year-old cobs from San Marcos Cave, located in southern Mexico's Tehuacán Valley.
The new findings can't resolve scientific debates over the precise location and timing of initial maize domestication, say coauthors archaeologist Dolores R. Piperno of the Smithsonian Tropical Research Institute in Balboa, Panama, and anthropologist Kent V. Flannery of the University of Michigan in Ann Arbor.
Previous genetic studies indicate, to some scientists, that a subspecies of the wild grass teosinte was the likely ancestor of maize. Maize domestication may have first occurred where this form of teosinte still grows, in the Central Balsas River Valley, which is located about 250 miles east of Guilá Naquitz.
Other investigators have suggested that prehistoric people living much closer to Guilá Naquitz concocted the earliest maize as a hybrid of teosinte and another wild grass species.
Whatever the case, maize cultivation didn't originate at Guilá Naquitz, Piperno and Flannery assert. The researchers found no fossilized grains characteristic of either teosinte or maize in the site's layers of earth ranging from about 10,000 to 7,000 years old.
Maize cobs found at both Guilá Naquitz and San Marcos contain securely attached grains and other features typical of modern maize, adds Bruce F. Benz of Texas Wesleyan University in Fort Worth. His analysis appears in the same issue of Proceedings of the National Academy of Sciences. http://louis3j3sheehan3esquire.wordpress.com
Remains at Guilá Naquitz from around 10,000 years ago have also provided the earliest evidence of squash cultivation in the Americas (SN: 5/24/97, p. 322). http://louis3j3sheehan3esquire.wordpress.com
Scientific clues to the origins of Mexico's three major crops--squash, maize, and beans--come from only five caves excavated 40 to 50 years ago, remarks archaeologist Bruce D. Smith of the Smithsonian Institution in Washington, D.C., in a comment published with the new reports. The limited evidence nevertheless suggests that the domestication of both squash and maize first occurred in southern and southwestern Mexico, Smith says. Beans were probably first domesticated around 4,000 years ago in western Mexico, in his view. Louis J. Sheehan, Esquire.
Thursday, December 25, 2008
hoxb8 t.hox.0999 Louis J. Sheehan, Esquire
All sorts of animals groom themselves regularly, which keeps them clean and healthy. However, mice with an alteration in one of the genes that orchestrate body development lose their grip on grooming, a new study finds.http://Louis-J-Sheehan.biz
These mice bite and lick themselves so hard and so often that they end up with bald patches and open sores, according to Joy M. Greer and Mario R. Capecchi, both geneticists at the University of Utah in Salt Lake City. Moreover, the same genetically altered rodents groom cage mates just as aggressively.
The mice have a mutated version of one of the homeobox, or Hox, genes, which scientists have implicated in embryo development. The new finding offers a potential avenue for exploring the biological roots of trichotillomania, a rare condition in which people tear out their hair, as well as some of the repetitive cleaning behaviors classed as obsessive-compulsive disorder (OCD), the researchers conclude in the Jan. 3 Neuron.
"This particular Hox gene may regulate the amount of grooming performed by an animal," Capecchi says. "So far, we see no other unusual behaviors in mice with this mutation."
The study adds to emerging evidence that Hox genes, which are largely the same in all vertebrate species, influence biology and behavior in a surprisingly wide variety of ways, he adds. It makes sense, in his view, that at least one of these evolutionarily ancient genes influences the comparably ancient grooming practices of vertebrates.
Greer and Capecchi altered one of the two copies of the Hoxb8 gene in individual mice from an inbred line. This enabled the scientists to compare these animals with others in the line, which shared the same set of genes except for the critical Hoxb8 mutation.
As adults, genetically modified mice displayed bald patches and skin lesions on their bodies. The researchers found large amounts of hair in the rodents' mouths and stomachs.
Videotaping for 24 hours showed that mice with Hoxb8 mutations spent twice as much time grooming themselves as the other mice did. Hoxb8 mice also doggedly groomed their cage mates.
Further evidence of a Hoxb8 influence on excessive grooming came when Greer and Capecchi found that mutant mice didn't have any other condition that might cause such behavior. For instance, the animals were as sensitive to pain as other mice were and had no irritating skin conditions.
Laboratory analyses of the brains of the mutant mice then revealed molecular footprints of Hoxb8 activity in areas that had already been implicated in control of animal grooming and generation of human OCD symptoms, such as compulsive hand washing.
Psychiatrist James F. Leckman of Yale University School of Medicine calls the new finding about the Hoxb8 gene "very exciting." Leckman's group is currently investigating possible effects of other Hox genes on OCD. Louis J. Sheehan, Esquire
The Hoxb8 mutation described by the Utah scientists may also shed light on body dysmorphic disorder, Leckman holds. In this OCD-related condition, people experience debilitating preoccupations with imagined physical defects.http://Louis-J-Sheehan.biz
Still, the Hoxb8-mutated mice behaved much as people with trichotillomania do, comments psychiatrist Lewis R. Baxter of the University of Alabama at Birmingham. Researchers need to explore whether prescription drugs that ease trichotillomania and OCD trim back grooming in Hoxb8 mice, Baxter says. These medications boost the activity of serotonin, a chemical messenger in the brain. Louis J. Sheehan, Esquire
Greer and Capecchi are already examining whether the mutation that they identified in mice appears in people diagnosed with trichotillomania. Louis J. Sheehan, Esquire
These mice bite and lick themselves so hard and so often that they end up with bald patches and open sores, according to Joy M. Greer and Mario R. Capecchi, both geneticists at the University of Utah in Salt Lake City. Moreover, the same genetically altered rodents groom cage mates just as aggressively.
The mice have a mutated version of one of the homeobox, or Hox, genes, which scientists have implicated in embryo development. The new finding offers a potential avenue for exploring the biological roots of trichotillomania, a rare condition in which people tear out their hair, as well as some of the repetitive cleaning behaviors classed as obsessive-compulsive disorder (OCD), the researchers conclude in the Jan. 3 Neuron.
"This particular Hox gene may regulate the amount of grooming performed by an animal," Capecchi says. "So far, we see no other unusual behaviors in mice with this mutation."
The study adds to emerging evidence that Hox genes, which are largely the same in all vertebrate species, influence biology and behavior in a surprisingly wide variety of ways, he adds. It makes sense, in his view, that at least one of these evolutionarily ancient genes influences the comparably ancient grooming practices of vertebrates.
Greer and Capecchi altered one of the two copies of the Hoxb8 gene in individual mice from an inbred line. This enabled the scientists to compare these animals with others in the line, which shared the same set of genes except for the critical Hoxb8 mutation.
As adults, genetically modified mice displayed bald patches and skin lesions on their bodies. The researchers found large amounts of hair in the rodents' mouths and stomachs.
Videotaping for 24 hours showed that mice with Hoxb8 mutations spent twice as much time grooming themselves as the other mice did. Hoxb8 mice also doggedly groomed their cage mates.
Further evidence of a Hoxb8 influence on excessive grooming came when Greer and Capecchi found that mutant mice didn't have any other condition that might cause such behavior. For instance, the animals were as sensitive to pain as other mice were and had no irritating skin conditions.
Laboratory analyses of the brains of the mutant mice then revealed molecular footprints of Hoxb8 activity in areas that had already been implicated in control of animal grooming and generation of human OCD symptoms, such as compulsive hand washing.
Psychiatrist James F. Leckman of Yale University School of Medicine calls the new finding about the Hoxb8 gene "very exciting." Leckman's group is currently investigating possible effects of other Hox genes on OCD. Louis J. Sheehan, Esquire
The Hoxb8 mutation described by the Utah scientists may also shed light on body dysmorphic disorder, Leckman holds. In this OCD-related condition, people experience debilitating preoccupations with imagined physical defects.http://Louis-J-Sheehan.biz
Still, the Hoxb8-mutated mice behaved much as people with trichotillomania do, comments psychiatrist Lewis R. Baxter of the University of Alabama at Birmingham. Researchers need to explore whether prescription drugs that ease trichotillomania and OCD trim back grooming in Hoxb8 mice, Baxter says. These medications boost the activity of serotonin, a chemical messenger in the brain. Louis J. Sheehan, Esquire
Greer and Capecchi are already examining whether the mutation that they identified in mice appears in people diagnosed with trichotillomania. Louis J. Sheehan, Esquire
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