 FIXIN' A BROKEN HEART
Growing living-tissue heart valves from a patient's own stem cells may be a reality in three to five years
Human sperm made from bone-marrow cells
PARIS
Scientists have succeeded in turning human stem cells into immature sperm cells that researchers said could lead to treatments for male infertility, but experts in cell biology cautioned that the results must be evaluated with caution and may not lead to the hoped-for developments.
The results of the experiment conducted in Germany were published in Reproduction: Gamete Biology.
Lead scientist Karim Nayernia, who last year succeeded in using sperm cells created from mouse embryonic stem cells to fertilize mice eggs resulting in seven live births, and his colleagues took bone marrow from human volunteers and isolated a type of stem cell that normally grows into other body tissue, especially muscle. They then cultured the cells in a laboratory in such a way that they became male reproductive cells, bearing genetic markers specific to partly developed sperm.
In most men, these "proto-sperm"-known as spermatagonial cells-develop into mature, functioning sperm, but in the experiment the growth stopped at the most preliminary stage.
"We're very excited about this discovery, particularly as our earlier work in mice suggests that we could develop this work even further," said Nayernia. "Our next goal is to see if we can get the spermatagonial stem cells to progress in mature sperm in the laboratory."
But other experts suggest that it is too soon to conclude that therapies could evolve directly out of these experiments. "The observations are interesting but one must be cautious about drawing conclusions based purely on the expression of a few molecular markers, without supporting functional data," said Peter Andrews, a biomedical scientist and codirector of the Center for Stem Cell Biology at the University of Sheffield in England. In general, manipulating stems cells, he warned, can cause lasting genetic changes with unpredictable results.
Mice yield clues on OCD
PARIS
Scientists have stumbled on a mouse gene that, when disabled, provokes behavior similar to obsessive-compulsive disorder (OCD). When the gene is reactivated, or when the mice are given drugs used to treat the syndrome in humans, the compulsive actions diminish, said a study, published in Nature.
The discovery suggests new strategies for treating the disorder, which affects nearly two percent of the world's population, more than 100 million people. Famous sufferers include 18th-century English writer Samuel Johnson, American magnate Howard Hughes, and-by his own admission-celebrity footballer David Beckham, who said he obsessively stacked up cans of soft drinks.
A team of researchers led by Duke University molecular geneticist Guoping Feng discovered the link between the gene, known as SAPAP3, and compulsive behavior by accident while conducting basic research on the striatum, a portion of the brain that controls the planning and execution of movement. In normal brains, the SAPAP3 protein facilitates the transfer of nerve signals across synapses from one nerve cell to another, helping them communicate via the glutamate-messenger system.
Glutamic acid is thought to be crucial to cognitive functions like learning and memory.
"When we looked closely at the brain cells of these mutant mice"-which had been genetically modified to suppress the gene-"we found that there were defects in the synapses," Feng said. As a result, the mice engaged in compulsive grooming until their faces were raw, and also exhibited anxiety-like behavior, hiding in corners and hesitating to take risks. But when the gene was switched back on, "the synaptic defects were repaired and their OCD-like behaviors subsided," Feng said.
The researchers also found that a class of drugs known as selective-serotonin-reuptake inhibitors, also used to alleviate the symptoms of OCD, worked almost as well, establishing an even stronger link to humans. Like SAPAP3, serotonin is a chemical involved in nerve communication in the brain.
While Feng's mutant mouse could prove to be a useful model for studying OCD in humans and the development of new drugs, many problems remain, noted Harvard neurobiologist Steven Hyman in a commentary, also published in Nature.
"It is highly unlikely that such animal models will ever recapitulate human psychiatric disorders in their entirety," he wrote, pointing out that the main cause of anxiety in OCD patients is unwanted intrusive thoughts. "Sufferers are anxious because they cannot be sure the door is locked, the gas has been turned off, or that they are free of deadly microbes," a fear that leads to the emblematic symptom of continuous hand washing. It requires a stretch of the imagination, he suggests, to think that mice experience comparable feelings.
Moreover, like other major psychiatric disorders, OCD probably stems from a mix of chemical imbalances along with developmental and environmental factors, reducing the role that a single gene might play.
How can you mend a broken heart?
PARIS
Surgeons will soon be able to literally mend a broken heart using live tissue grown from a patient's very own stem cells. The whole procedure-harvesting cells from bone marrow, growing tissue, and surgically implanting the heart muscle or valve-could take as little as six weeks and could become routine within three to five years, researchers reported in a special issue of the Philosophical Transactions of The Royal Society B in Britain.
One reason heart attacks are so debilitating, even when they are not fatal, is the human heart-a massive muscle surrounding four valves controlling the body's blood flow-does not regenerate. Damaged tissue stays damaged.
Most problems occur with age, when the old ticker simply begins to wear out. "But the highest medical need for tissue-engineered heart valves is in the treatment of congenital heart malformation," which affects nearly one percent of all newborns, said Simon Hoeurstrup, lead author of one of the studies.
Artificial heart valves currently available must be periodically replaced as children grow, leading to great suffering and higher death rates than in adults. Bioengineered heart muscle that could be grafted onto a patient's living tissue without fear of rejection by the immune system has long been a holy grail of cardiovascular medicine.
Artificial replacements "do the job and save people's lives," said celebrated heart surgeon Magdi Yacoub, who coordinated the 20-odd studies. "But they cannot match the elegant, sophisticated functions of living tissues."
While durable, mechanical hardware increases the risk of bacterial infection in the heart's inner lining, as well as abnormalities in blood flow. Recipients must also take medication to prevent blood clots, boosting the chances of internal bleeding and embolisms.
Cardiovascular disease, the number one killer worldwide, claimed some 17.5 million lives in 2005, according to the World Health Organization. Many of these deaths might have been avoided by timely surgery to implant replacement valves and heart muscle.
There are currently two broad techniques for making bioprosthetic heart valves, and both have serious drawbacks.
Animal grafts, especially from pigs, are readily available, but differ in structure and tend to wear out. Human valves from donors work much better, but are in chronically short supply and can easily provoke immune reactions.
In the tissue-engineering approach favored by Yacoub and Hoerstrup, the patient's own stem cells-taken from bone marrow-are isolated and expanded in the laboratory using standard cell-culture techniques. They are then "seeded" onto a special matrix in the shape of a heart valve that is positioned in a device called a "bioreactor" that tricks the cells into growing in the right shape. Once mature, the living-tissue heart valves can be implanted in the patient. The whole process unfolds in a matter of weeks.
This procedure has already been extensively tested in sheep, but several years of follow-up are required before it can be deemed effective and safe, said Hoerstrup. Another hurdle, he said, is that the capacity of some patients to yield suitable stem cells may be compromised by diseases such as diabetes.
Gene that causes exfoliation glaucoma identified
CHICAGO
Scandinavian researchers have identified the gene that causes the visual disorder called exfoliation glaucoma, a leading cause of blindness in the elderly. The findings suggest that mutations in the LOXL1 gene are the exclusive cause of the difficult-to-treat syndrome.
"This discovery is remarkable and important because genetics has led us directly to what appears to be the sole cause of a devastating common disease," said Kari Stefansson, chief executive of Decode Genetics Inc., an Iceland-based company that specializes in DNA analysis. "The risk conferred by these variants is such that it accounts for virtually all cases of exfoliation glaucoma, meaning that if we can neutralize the impact of these variants we might eliminate the disease," said Stefansson, who also worked on the study.
Glaucoma is an umbrella term for a group of diseases characterized by damage to the optic nerve and which results in progressive loss of vision that can lead to blindness. There are no symptoms, and the loss of vision is often imperceptible in the early stages of the illness.
Exfoliation glaucoma is a subtype that afflicts between 10 and 20 percent of people 60 and above, and one that does not respond well to drugs. It is caused by unusual deposits that line the aqueous-bathed surfaces of the eye's anterior.
In searching for the genetic fingerprints of the disorder, the researchers analyzed the DNA of 16,000 glaucoma patients and healthy controls from Sweden and Iceland. They quickly honed in on two genetic mutations or variations located on the LOXL1 gene on chromosome 15. They found that one variant was associated with a 26-fold increase in risk, while the other conferred an eightfold greater risk for the condition vis-à-vis people who didn't carry either mutation. Individuals with both variants were 700 times more likely to have the sight-threatening disorder than individuals who had neither variation.
The investigators believe that LOXL1 codes for a protein that is involved in forming elastin polymer fibers that accumulate in the eye, causing exfoliation glaucoma. They are hopeful that the gene will provide a promising target for future therapies to treat the condition.
It could take years to develop those therapies, but in the meantime the gene could be used to screen for people at risk for the disease, which would allow them to consider surgical treatment before they have suffered any loss of sight, Stefansson said.
He said that Decode Genetics plans to market a blood test to screen for the genetic mutations by the end of 2007. Scientists at Decode Genetics, the National University Hospital in Reykjavik, and Uppsala University in Sweden worked on the study which appears in Science.
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