GENETIC DRIVERS
Groundbreaking study throws up genes linked to diabetes
PARIS
An international team of scientists reported they had identified several of the most important genes linked to type 2 diabetes, a disease that is spreading at epidemic rates. The discovery should open the way to a test to identify people with an inherited risk of diabetes, thus enabling them to make lifestyle choices to help them sidestep the disease, they said.
The researchers, based in Britain, France, and Canada, said they had identified four areas on the genome where mutations in the genetic code, called single nucleotide polymorphisms (SNPs), exposed an individual to a higher risk. As much as 70 percent of the genetic drivers for type 2 diabetes could be attributed to these variants.
"The two major reasons people develop type 2 diabetes are obesity and a family link," said Philippe Froguel of Imperial College London, one of the authors. "Our two new findings mean that we can create a good genetic test to predict people's risk of developing this type of diabetes. If we can tell someone that their genetics [say] they are predisposed towards type 2 diabetes, they will be much more motivated to change things, such as their diet, to reduce their chances of developing the disorder."
The researchers carried out the gene trawl among samples volunteered by 700 people with type 2 diabetes, and compared this outcome with 700 "controls," or matched counterparts who did not have the disease. They then confirmed their findings by analyzing a further 5,000 individuals with type 2 diabetes and a family history of the disorder, to verify that the same genetic mutations were the culprit.
The paper, published by Nature, provides evidence to back previous suspicions that a variant of a gene called TCF7L2 confers a risk. It also points the finger at a gene called SLC30A8, a so-called zinc transporter involved in regulating the secretion of insulin. This throws up an avenue of research for a treatment: fixing the flawed transporter could boost insulin levels. And it identifies, but less conclusively, two other genes where flaws may hamper function of beta cells in the pancreas where insulin is produced.
To find the baulky genes, the researchers had to examine 392,000 single mutations. They add that further work may unveil more genetic causes.
Type 1 diabetes is linked to genetic predisposition. The far more common type 2 diabetes has long been suspected to have a genetic component, but its most immediate cause is an unhealthy diet and inactivity.
M AFP
AUTISM LINK
French researchers says SHANK3 plays a key role in the organization of neuron connections
PARIS
French researchers have discovered a new gene linked to autism, a mental disability that prevents sufferers from communicating and forming relationships normally and whose causes are unknown. The study published by Nature Genetics found that all of five autistic children studied had anomalies in the SHANK3 gene, responsible for making the connections in the brain necessary for language development.
The most distinctive symptoms of autism are problems with communication, forming relationships, and developing strong obsessional traits.
The Institut Pasteur study showed "the key role of the gene in the organization of neuron connections" in the brain, said lead researcher Thomas Bourgeron. "This gene, named SHANK3, does not explain all forms of autism," warned Bourgeron, but it might help explain the communication difficulties that provide major social obstacles to those suffering from autism.
The study sample included five people from three families, each suffering either from autism or Asperger syndrome, an autistic spectrum disorder (ASD) which shares most of the symptoms of autism with less severe communication problems. "[ASD] affects about one child in 200 and four times more boys," Bourgeron said.
In 2003, Bourgeron's team identified anomalies on SHANK3, which produces the proteins necessary to construct synapses, the junctions between the brain's neural pathways. They discovered significant "deletions" to various degrees in the gene. One participant, who was autistic but had learned to talk, was found to have a "duplicate" of the gene.
The causes of autism remain mysterious. Years of research have gone into identifying a genetic cause. Research is increasingly addressing the idea that autism may be caused by a combination of genetic and environmental factors.
M AFP
"LESS SINFUL"
Cloned mouse from unfertilized eggs eases ethical debate on stem-cell research
Kyoko Hasegawa, Agence France-Presse
TOKYO
Japanese scientists have succeeded in cloning mouse embryos from unfertilized eggs, a breakthrough that could help resolve the passionate ethical debate about stem-cell research.
Advocates say research involving embryonic stem cells-cells that can develop into various organs or nerves-can save lives by finding cures for diseases such as cancer and diabetes. But the research has provoked a furor among religious conservatives, who argue that it destroys a human life-albeit one at its earliest stage of development.
President George W. Bush has banned all federal funding for stem-cell studies in the United States, the world's biggest research hub.
One proposed alternative has been to use unfertilized human eggs, but this presents the major obstacle of trying to persuade healthy women to undergo the painful process of donating eggs.
A Japanese team said it has found a potential future solution-it performed in vitro fertilization with mice and found that egg cells that failed to be fertilized could be used to make cloned embryonic stem cells. The process could be put to use among human eggs that would have gone to waste during in vitro fertilization.
"If we can use egg cells that would have been dumped, then the problem of finding donors will be solved," said Teruhiko Wakayama, who led the study at the Japanese government-backed Riken research foundation. He added: "Before our findings, it was believed that only fresh eggs could be used. But if incompetent eggs can be cloned, then scientists could be given eggs that failed to be fertilized and would have been abandoned in fertility clinics."
The study appeared in the February 20 issue of Current Biology.
Japan, the largest spender on research after the US, has few restrictions on stem-cell research. In Washington, Democratic lawmakers have been pushing to lift restrictions on stem-cell research since they took control of Congress in January from Bush's largely antiabortion Republicans.
Cloning can not be ruled
Experts believe the use of unfertilized cloned eggs, if replicated in humans, could ease ethical concerns, although it would be unlikely to eradicate all opposition.
"Fertilized eggs in particular are regarded as the beginning of human life in certain religions, namely Catholicism, so destroying them for the sake of medicine can be controversial," said Ryuichi Ida, a professor of international law and biology at Kyoto University in western Japan.
"But if unfertilized eggs can be used without ethical problems such as physically hurting donor women, that's probably less sinful than using fertilized eggs," he said. "And yet, we cannot escape the question of whether it is morally okay to use any human egg cells, which are one stage ahead of being fertilized egg cells."
Some scientists also caution that there is still a long way to go before Wakayama's research can be turned to practical use.
"I think Dr. Wakayama's research is scientifically interesting, but there is a fundamental problem," said Motoya Katsuki, president of Japan's National Institute of Basic Biology.
"Scientists have never succeeded in creating a cloned organ that functions without problems, and most cloned animals so far-whether they are cows, rats, or mice-have been sick and died young," Katsuki said. "You can't transplant sick organs to patients. Thus we haven't even reached the level of discussing the ethical issues in such medical science."
Another concern on the ethical front is the risk, however remote, that cloned stem cells could grow into cloned human beings-one of the ultimate taboos for religious conservatives.
Wakayama insisted that his cloned embryonic stem cells did not turn into cloned mice. "A cloned embryo made of aged eggs which failed to fertilize is unlikely to have the capability of developing into a full offspring," Wakayama said.
But Norio Nakatsuji, president of the Institute for Frontier Medical Sciences at Kyoto University, warned that nothing was impossible in the long term. "Theoretically speaking, you can't say that cloned mice will never be created from a cloned stem cell," Nakatsuji said. "You can never tell, because science progresses with every new discovery."
M
ELIXIR OF YOUTH
Scientists identify gene that boosts life span, quality of life
Marlowe Hood, Agence France-Presse
PARIS
The elixir of youth may ultimately be hidden in a poorly understood gene that not only fosters longevity but enhances quality of life. In a series of experiments on earthworms, a team of scientists at the Salk Institute in San Diego, California have identified for the first time a gene, known as PHA-4, which plays a critical role in prolonging life without tapping into insulin-regulating neural pathways that also control the ageing process.
Molecular biologists hailed the study as a "breakthrough" that will change research agendas in the new but burgeoning field of longevity genetics. But they also cautioned that duplicating the results in humans is far more complicated.
Only within the last decade have scientists understood that single genes can significantly affect ageing, once thought to be an uncontrollable process of decay.
"There are two major ways to prolong life," biologist Hugo Aguilaniu, one of the study's coauthors, explained.
One is to decrease sensitivity at the cellular level to insulin. "This is already well known-genetically modified mice have been created that live twice as long as a result," he said. But there are unwelcome side effects, including stunted growth and reproductive malfunction.
The other way is dietary restriction. "If you give an animal 70 percent of its normal intake, it will live 20 to 30 percent longer," said Aguilaniu. In a human being, that adds up to an additional 15 to 20 years of life. A restricted diet, however, is not the same as near starvation, and must consist of a balanced mix of nutrients to be effective.
The link between eating less and living longer has been known for decades. "But we had no idea what the molecular actor of this process was," he said.
In the study, led by Andrew Dillin and published in Nature, C. elegans worms were fed a bacterium laced with genetic material that selectively switched off the PHA-4 gene. As suspected, the worms no longer enjoyed a longer life span when placed on a slimmed-down diet. But while this first experiment showed that the gene was critical for diet-induced longevity, it did not prove that the PHA-4 directly triggered longer life, so another test was devised.
"When we overexpressed the gene, the animals lived longer, up to 20 or 30 percent," even when they ate normally, said Aguilaniu.
Adding dietary restrictions boosted longevity even further.
The researchers conducted a separate set of experiments to be sure that PHA-4 was acting independently from any insulin signaling pathways.
"What is most interesting is that diet-restricted animals are more dynamic. We like to talk not just about life span but 'health-span expansion'-being healthier over a longer period of time," Aguilaniu said.
The millimeter-long C. elegans worm is frequently used in the laboratory because it is easy for researchers to disrupt the functions of its nearly 20,000 genes to determine what they do. Many, including PHA-4, have specific counterparts in humans.
Scientists familiar with the study described it as significant. "It answers a question we have been asking for a long time," commented Martin Holzenberger, a researcher at France's National Institute for Health and Medical Research. "It is certainly a real breakthrough in our understanding of diet restriction," he said, adding that the study showed PHA-4 to be "a key gene" that regulates others.
Holzenberger said PHA-4, which corresponds to the "foxa" family of genes in humans, probably works on enzymes to reduce harmful oxidation in the cells. But he said the link between diet restriction and longevity remains poorly understood. "The closer we get to humans the more complicated it gets," he said, pointing out that the technique that worked in worms can't be used on humans.
Aguilaniu agrees that the relevance for humans remains, for now, theoretical. "But all studies suggest that dietary restriction works the same way in worms as it does in mice or in men. As soon as we have a molecule that is specific, there are potential pharmaceutical applications."
Gary Ruvkun, a geneticist at Harvard in Massachusetts, also thinks the study could open up new avenues of research on ageing in humans. "There are homologs across all these organisms and one expects them to work in similar ways," he said. He predicted that other researchers would start to look more carefully at the role of PHA-4, which was previously linked only to growth of the pharynx in the C. elegans. Indeed, Ruvkun said he had overlooked the gene in his own research because he assumed that deactivating it in experiments would simply kill the worm.
But Dillin and his colleagues discovered that once the worm reaches adulthood, the gene changes function, regulating ageing instead of growth.
M
REVERSAL OF COURSE
Stem-cell therapy for type 1 diabetes makes insulin injections unnecessary
CHICAGO
An experimental stem-cell therapy designed to reverse the course of type 1 diabetes allowed patients to go treatment-free for months and in one case, three years, according to a study reported in the Journal of the American Medical Association.
Thirteen of the 15 patients who took part in testing the therapy were able to quit the insulin injections that most diabetics depend on, and remained insulin-free, the researchers said.
One of the first patients to undergo the procedure has gone three years without using any supplemental synthetic insulin to regulate their blood-sugar levels.
"This is the first therapy for type 1 diabetes to result in drug-free treatment," said Dr. Richard Burt, chief of immunotherapy at Northwestern University's Feinberg School of Medicine in Chicago and one of the senior authors of the research.
While investigators continue to monitor the patients' progress, the preliminary results raise the tantalizing possibility that type 1 diabetes may not be a life sentence, according to a prominent US diabetes researcher.
"This study by Voltarelli et al. is the first of what likely will be many attempts at cellular therapy to interdict the type-1-diabetes-mellitus (DM) disease process," said Dr. Jay Skyler of the University of Miami. "Research in this field is likely to explode in the next few years and should include randomized controlled trials as well as mechanistic studies. As these further studies confirm and build on the results of Voltarelli et al., the time may indeed be coming for starting to reverse and prevent type 1 DM."
His comments appeared in an editorial accompanying the paper. Julio Voltarelli is the Brazilian researcher from the University of Sao Paolo in Ribeirao Preto, Brazil, who oversaw the trial.
Type 1 diabetes accounts for only five to 10 percent of all cases of the disease, but can result in serious complications including blindness, kidney failure, heart disease, and stroke. The condition arises when the body's immune system attacks and destroys the insulin-producing beta cells of the pancreas, causing a shortage in the hormone required to regulate blood sugar. By the time most patients receive a clinical diagnosis, 60 to 80 percent of their beta cells have been wiped out.
The researchers in this trial hoped that if they intervened early enough they could reprogram the body's immune system, allowing the small reservoir of beta cells left to regenerate. To that end, they enrolled diabetics who had been diagnosed within the previous six weeks.
The researchers set out by harvesting stem cells from the volunteers. The patients then underwent chemotherapy to wipe out their own immune systems, and were subsequently given transfusions of their own stem cells to rebuild their immune systems.
Fourteen of the 15 (93 percent) were insulin-free for some period of time following the treatment. Eleven of those dispensed with supplemental insulin following treatment and have not had recourse to synthetic insulin since then. Periods of remission range from 36 months for the patient who had the therapy first to six months for more recent graduates of the trial.
Two other patients needed some supplemental insulin for 12 and 20 months after the procedure, but eventually both were able to wean themselves from the synthetic form of the hormone supplied in daily shots. One patient went 12 months without shots, but relapsed a year after treatment after suffering a viral infection, and resumed daily insulin injections. Another volunteer was eliminated from the study because of complications.
Further studies will be required to evaluate the safety and efficacy of this therapy, but the early signs are encouraging, in terms of the benefits and the low risk of side effects, which included one case of pneumonia and two cases of hormone dysfunction, the authors said.
M AFP
|
