Your love for chocolates may have something to do with your genes!

It turns out that whether you like dark chocolate or milk chocolate may have a little bit to do with your genetics.

We know that our bitter and sweet taste perceptions are highly associated with different genetic variants.
A lot of work has focused specifically on bitter taste perception associated with a variant in the TAS2R38 gene. Some people have it and some don’t.
About a quarter of 23andMe customers don’t have the bitter taste variant — making them more likely to have a taste for hoppy beer, broccoli or dark chocolate. A variant in theTAS2R38 gene enables some to perceive the bitterness of the chemical propylthiouracil, or PROP. Some so-called supertasters not only perceive bitterness but also can discern more saltiness, sweetness and spice, suggesting that there are other genes involved in food our food preference.
So of course the TAS2R38 variant doesn’t explain everything. While surveys of in the United States show that more than half of Americans prefer milk chocolate to dark, among 23andMe customers dark chocolate wins out. Almost half of 23andMe customers prefer dark chocolate, while about 39 percent say they like milk chocolate. That may have to do with genetics, but it is more likely related to a mix of other non-genetic factors.
And there are plenty of genetic factors that researchers are still exploring. For instance, a genome wide association study done last year found 17 genes related to liking certain foods — including among other things dark chocolate, blue cheese and liver — that belong to the groups of genes that apparently have nothing to do with taste or smell perception.

All this just goes to show that, like love, our food preferences are complicated.

you can read the original article here:
http://blog.23andme.com/health-traits/chocolate-its-complicated/

Why hopeful Dads should quick smoking now

A new research report appearing online in the FASEB Journal, scientists show for the first time in humans that men who smoke before conception can damage the genetic information of their offspring. These inherited changes in DNA could possibly render an offspring in the womb susceptible to later disease such as cancer.

This provides evidence showing why men should be urged to stop smoking before trying to conceive in the same way women have been urged to quit. Interestingly, a fertile sperm cell takes about three months to fully develop; therefore men would ultimately need to quit smoking long before conception to avoid causing genetic problems.

"That smoking of fathers at the time around conception can lead to genetic changes in their children indicates that the deleterious effects of smoking can be transmitted through the father to the offspring," said Diana Anderson, Ph.D., a researcher involved in the work from the School of Life Sciences at the University of Bradford, in the United Kingdom. "These transmitted genetic changes may raise the risk of developing cancer in childhood, particularly leukemia and other genetic diseases. We hope that this knowledge will urge men to cease smoking before trying to conceive."

To make this discovery, Anderson and colleagues used DNA biomarkers to measure genetic changes in the paternal blood and semen around conception, as well as maternal and umbilical cord blood at delivery in families from two different European regions in central England and a Greek island. Information regarding the lifestyle, environmental and occupational exposures of these families was taken from validated questionnaires. The combined analysis of exposures and DNA biomarkers was used to evaluate the role of exposures before conception and during pregnancy in the causation of genetic changes in the offspring. These results have strong implications for the prevention of disease.

"This report shows that smoking is a germ cell mutagen. If dad uses cigarettes, his kids will be affected even before they are born," said Gerald Weissmann, M.D., Editor-in-Chief of theFASEB Journal. "As Father's Day approaches, family members may want to give dads and prospective dads the help they need to quit smoking for good."

Federation of American Societies for Experimental Biology. "Another reason why dads and hopeful dads should quit smoking now." ScienceDaily, 23 Jun. 2012. Web. 25 Jun. 2012.

Genes Predict Mesothelioma Treatment Response

Mesothelioma is a fast-growing cancer triggered by exposure to asbestos.  It is often treated with multiple modalities, including chemotherapy.  As more is understood about the impact of genetics on medication response, chemotherapy for cancers like mesothelioma is moving away from a ‘one-size-fits-all’ approach to a more tailored approach based on individual cellular characteristics. 

University of Chicago researchers have released the results of genetic studies they hope will shed some light on why some mesothelioma patients respond well to pemetrexed (Alimta) while others do not.

This is a copyrighted article hence cannot publish the entire thing here. But for more information on this you can visit the site at http://www.survivingmesothelioma.com/

 

Existing Technique Can Detect Fetal Genetic Abnormalities in Maternal Blood

Non-invasive procedure could make prenatal testing easier, but it comes with ethical problems.

Until last week, scrutinizing a fetus's DNA for indications of genetic abnormalities meant tapping into the mother's womb with a needle. Now there's a test that can do it using a small sample of the mother's blood. MaterniT21, a Down's syndrome test that Sequenom of San Diego, California, launched in major centres across the United States on 17 October, is the first of several such tests expected on the market in the next year. It signals the arrival of a long-anticipated era of non-invasive prenatal genetic screening, with its attendant benefits and ethical complications.

With the technology in place to sequence the fetal DNA carried in a pregnant woman's bloodstream, geneticists predict the list of conditions that can be detected by non-invasive means will grow rapidly. Another company, Gene Security Network of Redwood City, California, says its forthcoming test will also check for other genetic abnormalities, and Sequenom is studying the feasibility of expanding its test.

"There's every reason to think that in the future you'll be able to extract an enormous amount of information from that sequencing data," says Peter Benn, director of the Diagnostic Human Genetics Laboratories at the University of Connecticut Health Center in Farmington.

Sequenom's test sequences 36-base-pair fragments of DNA to identify sections from chromosome 21. Normally, the chromosome contributes 1.35% of the total maternal and fetal DNA in the mother's blood. An overabundance of this material indicates the genetic abnormality that marks Down's syndrome.

Sequenom is marketing its test as an add-on to current screening methods, which estimate the chance that a woman is carrying a fetus with Down's syndrome from ultrasound results and protein markers in the blood. Such non-genetic screening can detect 90–95% of Down's syndrome cases, but falsely indicates that up to 5% of women are carrying a baby affected by the condition. Sequenom's test could be taken after a positive screening result to help a woman decide whether to undergo amniocentesis, a test that extracts amniotic fluid with a needle and carries a small risk of miscarriage. A study published this month, and paid for by Sequenom, found that the company's test has a false positive rate of 0.2% (G. E. Palomaki et al. Genet. Med. http://dx.doi.org/10.1097/GIM.0b013e3182368a0e; 2011).

It could spare some women from having amniocentesis after a false-positive screening result. But Benn says that the test will also pose difficulties. For instance, because it would take 8–10 days to get the results of Sequenom's test, if a woman did still opt for amniocentesis, and the result confirms that the baby has Down's syndrome, there would be little time left to decide whether to terminate the pregnancy. And some women who test positive on MaterniT21 will probably choose to terminate pregnancies immediately rather than have amniocentesis.

"Inserting this new test in the way that Sequenom is proposing is very difficult, from the patient perspective, and difficult for physicians and counsellors to manage," Benn says.

Ethicists also caution that using such easy screening methods ever earlier in pregnancy might worsen the gender imbalance seen in countries such as China and India. And if it becomes routine to check for many different kinds of genetic abnormalities, ethicists predict that more couples may face the quandary of whether to carry an 'unhealthy' fetus to term.

"The idea that couples have choices about whether to continue their pregnancies may become strained because parents may be seen as irresponsible for allowing 'defective' pregnancies to go to term," says Mildred Cho, an ethicist at Stanford University in Palo Alto, California. Other ethicists worry that fears of eugenics will be raised if testing can be done for less-serious conditions.

Sequenom is solely focused on developing tests for conditions that are already part of prenatal screening programmes, says Mathias Ehrich, the company's senior director for research and development diagnostics. "We do not want to invent new applications. Our focus is on making existing clinical applications safer," he says. "I don't think that we are in a position to say that we should determine what hair colour the baby has."

Gene therapy offers hope for Parkinson's disease

An experimental gene-therapy treatment for Parkinson's disease has eased the movement problems of a small number of patients and raised no major safety concerns. The study, reported in The Lancet Neurology¹, is the first double-blind clinical trial to show a benefit of gene therapy to patients with the neurodegenerative condition.

Parkinson's disease is characterized by tremors, slowness and cognitive problems, and is caused by the death of neurons in brain circuits that makes dopamine. The effects cascade through interconnected brain regions involved in movement, with some areas becoming overactive.

Many patients are treated with the drug levadopa (L-DOPA), a chemical precursor of dopamine, and regain control of their movements. Over time, however, patients become less sensitive to L-DOPA and burdened by its side effects, which include psychological and physical problems.

Long-term fix

Gene therapy could offer a longer-lasting solution, says Andrew Feigin, a neurologist at the Feinstein Institute for Medical Research in Manhasset, New York, who led the trial along with Michael Kaplitt, at Weill Cornell Medical College in New York and Matthew During, at Ohio State University in Columbus. This involved 45 patients aged between 30 and 75 years old, and was funded by Neurologix of Fort Lee, New Jersey, which holds the patent for the therapy.

Half of the patients received an infusion of a virus engineered to deliver a gene called glutamic acid decarboxylase (GAD) into a brain centre that is overactive in Parkinson's disease — the subthalamic nucleus. GAD encodes a neurotransmitter called GABA, which quiets neurons in this area. Another treatment for Parkinson's, deep brain stimulation (DBS), uses electricity to silence neurons in the same region.

The remaining patients underwent brain surgery, but did not receive the gene therapy.

Six months after these surgeries, Feigin's team measured improvements in both sets of patients using a standardized assessment of Parkinson's disease that looks at factors such as gait, posture, and hand and finger movements. Patients who had received the gene therapy exhibited a 23.1% improvement on this scale, compared with a 12.7% boost for patients who had undergone the placebo surgery. However, patients given the gene therapy did not, as a whole, see any more quality-of-life benefits than the other group.

Feigin's team excluded six patients who may not have received the gene therapy because of problems in its delivery. He says that this is justifiable in a small trial intended to test whether or not a treatment works. "If you included people who didn't get the therapy it could easily wash out the benefit you might see," he says.

In safe hands

One patient who received the gene therapy required treatment for a bowel obstruction 4 months after surgery, but Feigin says this was not related to the therapy.

"I'm very excited to see that it's safe," says Stéphane Palfi, a neurosurgeon at Henri Mondor Hospital in Creteil, France who was not involved in the trial.

However, he notes that DBS typically offers much more benefit to patients with Parkinson's disease. And, he adds, unlike gene therapy, DBS can be tuned up or down depending on a patient's current condition.

Despite this, Palfi remains enthusiastic that gene therapy could provide another tool with which to manage Parkinson's disease. He is involved in an early-stage safety trial for delivering genes involved in making dopamine to the brains of patients with Parkinson's disease. Palfi says that, so far, nine people have received the treatment.

Other scientists are testing gene therapies that prevent neuron from dying in patients with Parkinson's disease.

Marc Panoff, chief financial officer at Neurologix, says that the company will seek permission from the US Food and Drug Administration later this year to conduct a larger clinical trial.

Source: http://www.nature.com/news/2011/110317/full/news.2011.167.html

Gene therapy offers hope for Parkinson's disease

An experimental gene-therapy treatment for Parkinson's disease has eased the movement problems of a small number of patients and raised no major safety concerns. The study, reported in The Lancet Neurology¹, is the first double-blind clinical trial to show a benefit of gene therapy to patients with the neurodegenerative condition.

Parkinson's disease is characterized by tremors, slowness and cognitive problems, and is caused by the death of neurons in brain circuits that makes dopamine. The effects cascade through interconnected brain regions involved in movement, with some areas becoming overactive.

Many patients are treated with the drug levadopa (L-DOPA), a chemical precursor of dopamine, and regain control of their movements. Over time, however, patients become less sensitive to L-DOPA and burdened by its side effects, which include psychological and physical problems.

Long-term fix

Gene therapy could offer a longer-lasting solution, says Andrew Feigin, a neurologist at the Feinstein Institute for Medical Research in Manhasset, New York, who led the trial along with Michael Kaplitt, at Weill Cornell Medical College in New York and Matthew During, at Ohio State University in Columbus. This involved 45 patients aged between 30 and 75 years old, and was funded by Neurologix of Fort Lee, New Jersey, which holds the patent for the therapy.

Half of the patients received an infusion of a virus engineered to deliver a gene called glutamic acid decarboxylase (GAD) into a brain centre that is overactive in Parkinson's disease — the subthalamic nucleus. GAD encodes a neurotransmitter called GABA, which quiets neurons in this area. Another treatment for Parkinson's, deep brain stimulation (DBS), uses electricity to silence neurons in the same region.

The remaining patients underwent brain surgery, but did not receive the gene therapy.

Six months after these surgeries, Feigin's team measured improvements in both sets of patients using a standardized assessment of Parkinson's disease that looks at factors such as gait, posture, and hand and finger movements. Patients who had received the gene therapy exhibited a 23.1% improvement on this scale, compared with a 12.7% boost for patients who had undergone the placebo surgery. However, patients given the gene therapy did not, as a whole, see any more quality-of-life benefits than the other group.

Feigin's team excluded six patients who may not have received the gene therapy because of problems in its delivery. He says that this is justifiable in a small trial intended to test whether or not a treatment works. "If you included people who didn't get the therapy it could easily wash out the benefit you might see," he says.

In safe hands

One patient who received the gene therapy required treatment for a bowel obstruction 4 months after surgery, but Feigin says this was not related to the therapy.

"I'm very excited to see that it's safe," says Stéphane Palfi, a neurosurgeon at Henri Mondor Hospital in Creteil, France who was not involved in the trial.

However, he notes that DBS typically offers much more benefit to patients with Parkinson's disease. And, he adds, unlike gene therapy, DBS can be tuned up or down depending on a patient's current condition.

Despite this, Palfi remains enthusiastic that gene therapy could provide another tool with which to manage Parkinson's disease. He is involved in an early-stage safety trial for delivering genes involved in making dopamine to the brains of patients with Parkinson's disease. Palfi says that, so far, nine people have received the treatment.

Other scientists are testing gene therapies that prevent neuron from dying in patients with Parkinson's disease.

Marc Panoff, chief financial officer at Neurologix, says that the company will seek permission from the US Food and Drug Administration later this year to conduct a larger clinical trial.

Source: http://www.nature.com/news/2011/110317/full/news.2011.167.html

Old Genes Can Learn New Tricks, Horned Beetles Show

A popular view among evolutionary biologists that fundamental genes do not acquire new functions has been challenged by a new study in the Proceedings of the National Academy of Sciences.

Indiana University Bloomington biologist Armin Moczek and research associate Debra Rose report that two ancient genes were "co-opted" to help build a new trait in beetles -- the fancy antlers that give horned beetles their name. The genes, Distal-less and homothorax, touch most aspects of insect larval development, and have therefore been considered off-limits to the evolution of new traits. In the two horned beetle species Moczek and Rose studied, the genetic sequences of Distal-less and homothorax were hardly different, suggesting the two genes have retained their unique identities because of selective pressures not to change. What changed was not the genes themselves, but when and where they are turned on.

"Evolutionary biologists have a good idea of what it takes to change the shape of a wing, the length of a leg, or the anatomy of an eye," Moczek said. "What we have struggled with, though, is how these traits originate in the first place. How do you evolve that first wing, limb or photoreceptor from a flightless, limbless and blind ancestor?"

To investigate these questions, Moczek and Rose examined three development genes that are so old, all insects have them: Distal-less, homothorax and a third, dachshund. The genes were first characterized in fruit flies, and are categorized as "upstream" regulatory genes because they influence a wide variety of genetic processes in insect cells, such as the development of legs, antennae and wings. Moczek said that in horned beetles, each of the three genes is likely to have hundreds to thousands of downstream targets.

A tenuous consensus among evolutionary biologists was that such genes -- upon which so many different and important processes depend -- could not be easily modified, because any modification would affect countless aspects of the insect's development, any one of which could be bad for the individual insect, reducing its fitness relative to its peers.

Moczek and Rose's PNAS paper confirms one aspect of this idea. All three genes were sequenced and found to be highly conserved, or unchanged, not only among the individuals of each beetle species they examined, but also between the two species, Onthophagus taurus (Italy) and Onthophagus binodis (South Africa), whose lineages diverged about 24 million years ago. But that isn't the whole story.

To understand the effects of the three genes on horned beetle development, Moczek and Rose employed a new and promising technique, RNA interference, which disables the action of specific genes without compromising other genetic processes. Humans are only mimicking nature here; RNA interference is also a natural method of gene regulation in eukaryotes.

Moczek and Rose divided beetle larvae of both species into three treatment groups: no injection, buffer injection with nonsense RNA and buffer injection with RNA interference transcripts designed to disrupt one of three crucial developmental genes.

Moczek and Rose learned that two of the three genes, Distal-less and homothorax, are used by both O. taurus and O. binodis in the development of beetle horns. While Distal-less was found to affect both the development of thorax horns (which form just behind the head) and head horns, homothorax was only found to influence thorax horn development. The gene dachshund appears to have no effect whatsoever on horn development in either species.

"The evolution of novel features does not require the evolution of novel genes," Moczek said. "A lot of innovation can grow from within the organism's genetic toolbox."

More importantly, Moczek and Rose learned all developmental genes are candidates for such recruitment, not just the genes whose development functions are considered non-essential or limited in their effects.

Moczek also says the PNAS paper may compel evolutionary biologists to revisit pleiotropy, the foundational concept of one gene influencing many traits.

"It may be that our understanding of pleiotropy is too simplistic," Moczek said. "Now that we know fundamental development genes can acquire new and diverse functions with relative ease, pleiotropy may not be nearly as constraining as we have thought."

New Cellular Targets For HIV Drug Development

Focusing HIV drug development on immune cells called macrophages instead of traditionally targeted T cells could bring us closer to eradicating the disease, according to new research from University of Florida and five other institutions.

In the largest study of its kind, researchers found that in diseased cells — such as cancer cells — that are also infected with HIV, almost all the virus was packed into macrophages, whose job is to "eat" invading disease agents.

What's more, up to half of those macrophages were hybrids, formed when pieces of genetic material from several parent HIV viruses combined to form new strains.

Such "recombination" is responsible for formation of mutants that easily elude immune system surveillance and escape from anti-HIV drugs.

"Macrophages are these little factories producing new hybrid particles of the virus, making the virus probably even more aggressive over time," said study co-author Marco Salemi, Ph.D., an assistant professor in the department of pathology, immunology and laboratory medicine at the UF College of Medicine. "If we want to eradicate HIV we need to find a way to actually target the virus specifically infecting the macrophages."

At least 1.1 million people in the United States and 33 million in the world are living with HIV/AIDS, according to the Kaiser Family Foundation.

The researchers set out to see if HIV populations that infect abnormal tissues are different from those that infect normal ones, and whether particular strains are associated with certain types of illness.

They tackled the question using frozen post-autopsy tissue samples, pathology results and advanced computational techniques. They analyzed 780 HIV sequences from 53 normal and abnormal tissues from seven patients who had died between 1995 and 2003 from various AIDS-related conditions, including HIV-associated dementia, non-Hodgkin's lymphoma and generalized infections throughout the body. Four patients had been treated with highly active antiretroviral therapy, called HAART, at or near the time of death.

The researchers compared brain and lymphoma tissues, which had heavy concentrations of macrophages, with lymphoid tissues — such as from the spleen and lymph nodes— that had a mix of HIV-infected macrophages and T cells.

The analyses revealed great diversity in the HIV strains present, with different tissues having hybrid viruses made up of slightly different sets of genes. A high frequency of such recombinant viruses was also found in tissues generally associated with disease processes, such as the meninges, spleen and lymph nodes.

The researchers concluded that HIV-infected macrophages might be implicated in tumor-producing mechanisms.

The higher frequency of recombinant virus in diseased tissues likely is because macrophages multiply as a result of an inflammatory response, the researchers said.

"The study points to macrophages as a site of recombination in active disease," said neurobiologist Kenneth C. Williams, Ph.D., a Boston College associate professor and AIDS expert who was not involved in the study. "So people can say this is one spot where these viruses come from."

T cells — the so-called conductors of the immune system orchestra, whose decline is the hallmark of HIV disease — are an obvious target for HIV drug development because they die soon after infection, and are readily sampled from the blood and cultured. But although current drugs are effective at blocking infection of new cells and lowering viral loads to barely detectable levels, they never reduce the viral level in an infected person to zero.

"Where is it coming from?" said Michael S. McGrath, the University of California, San Francisco, professor who led the research team. "We believe it's coming from these macrophages."

Macrophages, like T cells, can be infected multiple times by HIV. But unlike T cells, when they get infected, they don't die within days, but live for several months, all the while being re-infected with multiple viruses of different genetic makeup. That situation is ripe for the emergence of hybrids.

"Most people who look at viral sequences assume that evolution of the virus is linear. In the real world that doesn't happen — large parts of the virus are swapped in and out. This group has shown that in this model," Williams said. "It sort of overturns the old way of trying to match virus sequence with pathology."

McGrath's group is now developing macrophage-targeting drugs that, through a grant from the National Institute of Mental Health, should be in human clinical trials in a few years.

"This is one of the last frontiers — killing off what we believe is a so far untouched reservoir," he said.

The work was published recently in the journal PLoS One.

Gene-laden Bubbles Grow New Blood Vessels

Progress in human gene therapy -- the insertion of therapeutic DNA into tissues and cells in the human body -- has been slower than expected since the first clinical trials in 1990. One of the biggest challenges for this technology is finding ways to safely and effectively deliver genes only to the specific parts of the body that they are meant to treat.

Cardiologist Jonathan Lindner of Oregon Health and Science University will discuss his latest experiments in gene therapy, which use microscopic bubbles chemically modified to stick to the cells that line blood vessels.

This technique, ultrasound-mediated gene delivery (UMGD), exploits the properties of contrast agents, microparticles that are normally injected into the body to improve the quality of ultrasound images. In UMGD, the tiny particles are microbubbles composed of pockets of gas encapsulated by thin membranes that are coated with DNA before injection. A targeted pulse of ultrasound energy "rings" the bubbles like a bell, popping them in a specific location and releasing the DNA into the surrounding tissue.

To improve the specificity of this targeting, Lindner grafts long arm-like molecules to the outside of the bubbles. These arms, which do not interfere with the DNA attached to surface, are designed to recognize and bind to molecules on the outside of specific cells in the body, allowing the bubbles to attach to a tissue before being popped. In theory, this should improve both the specificity and efficiency of the gene therapy.

Lindner created an arm designed to attach to endothelial cells lining blood vessels. He will present data evaluating the behavior of these "targeted" bubbles in living tissue. The ability to stick these gene-laden microbubbles to the lining of blood vessels increased the amount of gene transfection. This strategy may be particularly important for delivering therapeutic DNA to the walls of blood vessels. For example, Dr. Lindner and collaborators have successfully stimulated the growth of new blood vessels using UMGD with microbubbles carrying a gene for vascular endothelial growth factor. This therapeutic use could be important for treating ischemia in patients who have had a heart attack, peripheral artery disease, or stroke.

The team is also investigating using the bubbles to transport small doses of drugs. "If you're trying to deliver a nasty drug to part of the body, this may be a way to improve safety," says Lindner.

The talk "Targeted microbubble technology and ultrasound-mediated gene delivery" by Jonathan Lindner will be presented at the 157th  Acoustical Society of America Meeting to be held May 18-22 in Portland, Ore.

Fish Oil Protects Against Diseases Like Parkinson's

Dr. Nicolas Bazan, Director of the Neuroscience Center of Excellence, Boyd Professor, and Ernest C. and Yvette C. Villere Chair of Retinal Degenerative Diseases Research at LSU Health Sciences Center New Orleans, will present new research findings showing that an omega three fatty acid in the diet protects brain cells by preventing the misfolding of a protein resulting from a gene mutation in neurodegenerative diseases like Parkinson's and Huntington's.

He will present these findings for the first time on April 19, 2009 at the Ernest N. Morial Convention Center, Nouvelle C Room, at the American Society for Nutrition, Experimental Biology 2009 Annual Meeting.

With funding from the National Eye Institute of the National Institutes of Health, Dr. Bazan and his colleagues developed a cell model with a mutation of the Ataxin-1 gene. The defective Ataxin-1 gene induces the misfolding of the protein produced by the gene. These misshapened proteins cannot be properly processed by the cell machinery, resulting in tangled clumps of toxic protein that eventually kill the cell. Spinocerebellar Ataxia, a disabling disorder that affects speech, eye movement, and hand coordination at early ages of life, is one disorder resulting from the Ataxin-1 misfolding defect. The research team led by Dr. Bazan found that the omega three fatty acid, docosahexaenoic acid (DHA), protects cells from this defect.

Dr. Bazan's laboratory discovered earlier that neuroprotectin D1 (NPD1), a naturally-occurring molecule in the human brain that is derived from DHA also promotes brain cell survival. In this system NPD1 is capable of rescue the dying cells with the pathological type of Ataxin-1, keeping their integrity intact.

"These experiments provide proof of principle that neuroprotectin D1 can be applied therapeutically to combat various neurodegenerative diseases," says Dr. Bazan. "Furthermore, this study provides the basis of new therapeutic approaches to manipulate retinal pigment epithelial cells to be used as a source of NPD1 to treat patients with disorders characterized by this mutation like Parkinson's, Retinitis Pigmentosa and some forms of Alzheimer's Disease."

Earliest Evidence Of Domesticated Maize Discovered: Dates Back 8,700 Years

This is so fascinating. According to Ranere, recent studies have confirmed that maize derived from teosinte, a large wild grass that has five species growing in Mexico, Guatemala and Nicaragua. The teosinte species that is closest to maize is Balsas teosinte, which is native to Mexico's Central Balsas River Valley.

"We went to the area where the closest relative to maize grows, looked for the earliest maize and found it," said Ranere. "That wasn't surprising since molecular biologists had determined that Balsas teosinte was the ancestral species to maize. So it made sense that this was where we would find the earliest domestication of maize."

The study began with Piperno, a Temple University anthropology alumna, finding evidence in the form of pollen and charcoal in lake sediments that forests were being cut down and burned in the Central Balsas River Valley to create agricultural plots by 7000 years ago. She also found maize and squash phytoliths -- rigid microscopic bodies found in many plants -- in lakeside sediments.

Ranere, an archaeologist, joined in the study to find rock shelters or caves where people lived in that region thousands of years ago. His team carried out excavations in four of the 15 caves and rock shelters visited in the region, but only one of them yielded evidence for the early domestication of maize and squash.

Ranere excavated the site and recovered numerous grinding tools. Radiocarbon dating showed that the tools dated back at least 8700 years. Although grinding tools were found beneath the 8700 year level, the researchers were not able to obtain a radiocarbon date for the earliest deposits. Previously, the earliest evidence for the cultivation of maize came from Ranere and Piperno's earlier research in Panama where maize starch and phytoliths dated back 7600 years.

Ranere said that maize starch, which is different from teosinte starch, was found in crevices of many of the tools that were unearthed.

"We found maize starch in almost every tool that we analyzed, all the way down to the bottom of our site excavations," Ranere said. "We also found phytoliths that comes from maize or corn cobs, and since teosinte doesn't have cobs, we knew we had something that had changed from its wild form."

Ranere said that their findings also supported the premise that maize was domesticated in a lowland seasonal forest context, as opposed to being domesticated in the arid highlands as many researchers had once believed.

"For a long time, I though it strange that researchers argued about the location and age of maize domestication yet never looked in the Central Balsas River Valley, the homeland for the wild ancestor," said Ranere. "Dolores was the first one to do it.'

In addition to Ranere and Piperno, other researchers in the study included Irene Holst of the Smithsonian Tropical Research Institute, Ruth Dickau of Temple, and Jose Iriarte of the University of Exeter. The study was funded by the National Science Foundation, National Geographic Society, Wenner-Gren Foundation, Smithsonian National Museum of Natural History, Smithsonian Tropical Research Institute and the Temple University College of Liberal Arts.

Glucose-To-Glycerol Conversion In Long-lived Yeast Provides Anti-aging Effects

Cell biologists have found a more filling substitute for caloric restriction in extending the life span of simple organisms. In a study published May 8 in the open-access journal PLoS Genetics, researchers from the University of Southern California Andrus Gerontology Center show that yeast cells maintained on a glycerol diet live twice as long as normal -- as long as yeast cells on a severe caloric-restriction diet. They are also more resistant to cell damage.

Many studies have shown that caloric restriction can extend the life span of a variety of laboratory animals. Caloric restriction is also known to cause major improvements in a number of markers for cardiovascular diseases in humans. This study is the first to propose that "dietary substitution" can replace "dietary restriction" in a living species.

"If you add glycerol, or restrict caloric intake, you obtain the same effect," said senior author Valter Longo. "It's as good as calorie restriction, yet cells can take it up and utilize it to generate energy or for the synthesis of cellular components."

Longo and colleagues Min Wei and Paola Fabrizio introduced a glycerol diet after discovering that genetically engineered long-lived yeast cells that survive up to 5-fold longer than normal have increased levels of the genes that produce glycerol. In fact, they convert virtually all the glucose and ethanol into glycerol. Notably, these cells have a reduced activity in the TOR1/SCH9 pathway, which is also believed to extend life span in organisms ranging from worms to mice.

When the researchers blocked the genes that produce glycerol, the cells lost most of their life span advantage. However, Longo and colleagues believe that the "glucose to glycerol" switch represents only a component of the protective systems required for the extended survival. The current study indicates that glycerol biosynthesis is an important process in the metabolic switch that allows this simple organism to activate its protective systems and live longer.

"This is a fundamental observation in a very simple system," Longo said, "that at least introduces the possibility that you don't have to be calorie-restricted to achieve some of the remarkable protective effects of the hypocaloric diet observed in many organisms, including humans. It may be sufficient to substitute the carbon source and possibly other macronutrients with nutrients that do not promote the "pro-aging" changes induced by sugars."

Funding for the study came from the American Federation for Aging Research and the National Institute on Aging (NIH).

Groundbreaking Study Reveals Intermediary Steps Of Genetic Encoding For The First Time

The scientists report that they were able to crystallize a very large complex of a macromolecular "machine" in the human cell and determine its structure or what it actually looks like, thereby zeroing in on the process of genetic encoding. Importantly, 15 to 20 percent of all human genetic disorders, including muscular dystrophy, are caused by defects in this genetic encoding process known as RNA splicing.

Using x-ray crystallography, the scientists for the first time were able to create a three-dimensional structure of an integral complex of the human spliceosome, which consists of specialized RNA and protein subunits. The spliceosome's job is to modify the message relayed from our genetic material—DNA—by clipping, or splicing, genetic bits in such a manner that they are acceptable for translation into protein. Importantly, the spliceosome also rearranges the genetic bits of the message in such a way that it can generate multiple and varied proteins which can and do have dramatic effects on human development, said lead author and Brandeis biochemist Daniel Pomeranz Krummel.

"The process of RNA splicing is vital to human cell development and survival," said Pomeranz Krummel. "In this process, the regions of our DNA encoding for protein are removed from non-encoding regions and brought together—quite often in alternative arrangements. Defects in this process can have disasterous repercussions in the form of genetic disorders," said Pomeranz Krummel, adding that neuronal development can be particularly affected when things go awry. Indeed, defects in this process have recently been implicated in various human neurological disorders, including epilepsy.

Specifically, this macromolecular machine clips, or splices, gene sequences transcribed as part of a precursor to the mRNA, removing them before the final mRNA product is translated into protein. The spliceosome must clip these sequences, known as introns, at the right place in the precursor mRNA.

"In human cells one gene can be made into a variety of proteins, so if the process just goes slightly wrong, the genetic alteration can lead to incredible disaster; yet on the other hand, this incredible complexity has led to our amazing evolutionary progress," said Pomeranz Krummel. "The human genome is not terribly different from the earthworm's with regards to its size, but the process of RNA splicing that occurs in our cells is different. The fundamental difference between us and the earthworm is that our cells have evolved to utilize this process of RNA splicing to generate a whole other dimension to the transmission of genetic information."

Pomeranz Krummel's lab will next focus on understanding how this complex interacts with other macromolecular machines in the human cell. The study was funded by the Medical Research Council (U.K.) and the Human Frontier Science Program.

Did you know?? Omega-3 Kills Cancer Cells

Docosahexanoic acid (DHA), an omega-3 fatty acid found in fish oils, has been shown to reduce the size of tumours and enhance the positive effects of the chemotherapy drug cisplatin, while limiting its harmful side effects. The rat experiments provide some support for the plethora of health benefits often ascribed to omega-3 acids.

DHA is an omega-3 fatty acid that is commonly found in cold-water fish oil, and some vegetable oils. It is a major component of brain gray matter and of the retina in most mammalian species and is considered essential for normal neurological and cellular developments. According to the authors, "While DHA has been tentatively linked with protection against cardiovascular, neurological and neoplastic diseases, there exists a paucity of research information, in particular regarding its interactions with existing chemotherapy drugs". The researchers found that, at the molecular level, DHA acts by reducing leukocytosis (white blood cell accumulation), systemic inflammation, and oxidative stress – all processes that have been linked with tumour growth.

El-Mowafy and his colleagues have called for greater deployment of omega-3 in the fight against cancer. They write, "Our results suggest a new, fruitful drug regimen in the management of solid tumors based on combining cisplatin, and possibly other chemotherapeutics, with DHA".

Human Genes Required For Hepatitis C Viral Replication Identified

Massachusetts General Hospital (MGH) researchers are investigating a new way to block reproduction of the hepatitis C virus (HCV) – targeting not the virus itself but the human genes the virus exploits in its life cycle. In the March 19 Cell Host & Microbe, they report finding nearly 100 genes that support the replication of HCV and show that blocking several of them can suppress viral replication in cultured cells.

"We identified a large number of genes that have not been previously known to be involved in hepatitis C replication," says Raymond Chung, MD, director of Hepatology in the MGH Gastrointestinal Unit, the study's senior author.

Lead author Andrew Tai, MD, PhD, also of the MGH Gastrointestinal Unit, adds, "We may be a few years away from developing therapies based on these findings, but this study is a proof of principle that targeting host factors is a viable therapeutic strategy."

Usually spread by blood-to-blood contact, HCV infection becomes chronic in 70 to 80 percent of patients, and long-term infection can lead to liver failure or liver cancer. Today HCV-related liver disease is the most common diagnosis underlying the need for liver transplantation. HCV infection is usually treated with a six- to eleven-month regimen combining peginterferon and the antiviral drug ribavirin, but treatment is not successful in many patients and has serious side effects some cannot tolerate. Other therapies targeting viral enzymes are being developed, but there is concern that HCV's ability to mutate rapidly would lead to the emergence of resistant strains, so strategies directed against factors in the infected host rather than the virus may offer a complementary approach.

These strategies are being explored in a number of diseases – including influenza, West Nile virus and HIV – and previous studies have scanned a limited number of human genes for host cofactors of HCV infection. For the current study the researchers examined whether blocking each of the approximately 21,000 predicted messenger RNA transcripts in the human genome with small interfering RNAs (siRNAs) had any effect on HCV replication. Chung notes that this approach does not rely on any prior assumptions about gene function and can thereby identify genes not previously suspected of involvement.

The siRNA scan found 96 genes that appear to have a role in viral replication, and the research team studied several of them in greater detail. One gene codes for an enzyme called PI4KA, which is believed to be involved in the formation of membrane structures within the cell that may be the site of HCV replication. Another group of genes contribute to formation of the COPI coat that covers several types of cellular vesicles and is known to have a role in the replication of poliovirus. The researchers also focused on the gene for hepcidin, a liver protein that regulates iron absorption, since iron levels in the blood and liver rise in chronic HCV infection. They found that blocking each of these genes also blocked HCV replication, as did drugs that inhibit PI4KA and COPI, although the tested agents might not be suitable for therapeutic use.

"Now we need to work to uncover the molecular mechanisms by which these genes support HCV replication to get a better idea of which would be advantageous therapeutic targets," explains Chung, an associate professor of Medicine at Harvard Medical School.

Additional co-authors of the Cell Host & Microbe paper are Yair Benita, PhD, Sun-Suk Kim, MD, and Ramnik Xavier, MB,ChB, MGH Gastrointestinal Unit; and Naoya Sakamoto, MD, PhD,Tokyo Medical and Dental University. The study was supported by grants from the National Institutes of Health, the Massachusetts Biomedical Research Corporation, the American Gastrointestinal Association and the American Liver Foundation.

Mutated Gene In Zebrafish Sheds Light On Blindness In Humans

Described in a paper published in the Proceedings of the National Academy of Sciences (PNAS), the landmark study of retinal development in zebrafish larvae and the genetic switch it has identified should shed new light on the molecular mechanisms underlying that development and, consequently, provide needed insight on inherited retinal diseases in humans.

From FSU's Department of Biological Science and Program in Neuroscience, doctoral candidate Karen Alvarez-Delfin (first author of the PNAS paper), postdoctoral fellow Ann Morris (second author), and Associate Professor James M. Fadool are the first scientists to identify the crucial function of a previously known gene called "tbx2b." The researchers have named the newfound allele (a different form of a gene) "lor" -- for "lots-of-rods" -- because the mutation results in too many rods and fewer ultraviolet cones than in the normal eye.

"Our goal is to generate animal models of inherited diseases of the eye and retina to understand the progression of disease and find more effective treatments for blindness," said Fadool, faculty advisor to Alvarez-Delfin and principal investigator for Morris's ongoing research. "We are excited about the mutation that Karen has identified because it is one of the few mutations in this clinically critical pathway that is responsible for cells developing into one photoreceptor subtype rather than another."

"What is striking in this case is that the photoreceptor cell changes we observed in the retinas of zebrafish are opposite to the changes identified in Enhanced S-cone syndrome (ESCS), an inherited human retinal dystrophy in which the rods express genes usually only found in cones, eventually leading to blindness," Alvarez-Delfin said. "Equally surprising is that this study and others from our lab show that while alterations in photoreceptor development in the human and mouse eyes lead to retinal degeneration and blindness, they don't in zebrafish. Therefore, the work from our Florida State lab and with our collaborators at the University of Pennsylvania, Vanderbilt University and the University of Louisville should provide a model for better understanding the differences in outcomes between mammals and fish, and why the human mutation leads to degenerative disease."

Morris calls the zebrafish an ideal genetic model for studies of development and disease. The common aquarium species are vertebrates, like humans. Their retinal organization and cell types are similar to those in humans. Zebrafish mature rapidly, and lay many eggs. The embryos are transparent, and they develop externally, unlike mammals, which develop in utero.

"This lets us study developmental processes such as the formation of tissues and organs in living animals," she said.

"From a developmental biology perspective, our research will help us unravel the competing signals necessary for generating the different photoreceptor cell types in their appropriate numbers and arrangement," Morris said. "The highly specialized nature of rods and cones may make them particularly vulnerable to inherited diseases and environmental damage in humans. Understanding the genetic processes of photoreceptor development could lead to clinical treatments for the millions of people affected by photoreceptor cell dystrophies such as retinitis pigmentosa and macular degeneration."

The mosaic arrangement of photoreceptors in fish was first described more than 100 years ago, but the J. Fadool laboratory at Florida State was the first to successfully take advantage of the pattern to identify mutations affecting photoreceptor development and degeneration.

"Imagine a tile mosaic," Fadool said. "That is the kind of geometric pattern formed by the rod and cone photoreceptors in the zebrafish retina. This mosaic is similar to the pattern of a checkerboard but with four colors rather than two alternating in a square pattern. The red-, green-, blue-, and ultraviolet-sensitive cones are always arranged in a precise repeating pattern. Human retinas have a photoreceptor mosaic, too, but here the term is used loosely, because while the arrangement of the different photoreceptors is nonrandom, they don't form the geometric pattern observed in zebrafish.

"So how do we ask a fish if it has photoreceptor defects?" he asked.

Fadool explained that because the mosaic pattern of zebrafish photoreceptors is so precise, mutations causing subtle alterations are easier to uncover than in retinas with a "messier" arrangement.

"Just as we can easily recognize a checkerboard mistakenly manufactured with some of the squares changed from black to red or with all-black squares, by using fluorescent labeling and fluorescence microscopes we can see similar changes in the pattern of the zebrafish photoreceptor mosaic," he said. "Karen showed that within the mosaic of the lots-of-rod fish, the position on the checkerboard normally occupied by a UV cone is replaced with a rod. The identity of the mutated gene is then discovered using a combination of classical genetics and genomic resources."

Funding for the Fadool laboratory's zebrafish research comes in large part from a five-year grant totaling more than $1.7 million from the National Institutes of Health.

Gene Therapy Demonstrates Benefit In Patients With Rheumatoid Arthritis

Researchers have reported the first clinical evidence that gene therapy reduces symptoms in patients with rheumatoid arthritis, an important milestone for this promising treatment which has endured a sometimes turbulent past.

Described in the February issue of the journal Human Gene Therapy the findings stem from a study of two patients with severe rheumatoid arthritis conducted in Germany and led by an investigator at Beth Israel Deaconess Medical Center (BIDMC).

Originally conceived as a means of treating genetic diseases, such as cystic fibrosis and hemophilia, gene therapy involves implanting a normal gene to compensate for a defective gene in the patient. The first clinical trial to test gene therapy was launched in 1990 for the treatment of a rare, genetic immunodeficiency disease.

"This study helps extend gene therapy research to nongenetic, nonlethal diseases," explains principal investigator Christopher Evans, PhD, Director of the Center for Advanced Orthopaedic Studies at BIDMC. "Rheumatoid arthritis [RA] is an extremely painful condition affecting multiple joints throughout the body. Arthritis is a good target for this treatment because the joint is a closed space into which we can inject genes," adds Evans, who is also the Maurice Muller Professor of Orthopaedic Surgery at Harvard Medical School.

A classic autoimmune disease, RA develops when, for unknown reasons, the body's immune system turns against itself, causing joints to become swollen and inflamed. If the disease is inadequately controlled, the tissues of the joint are eventually destroyed. Although anti-inflammatory agents and biologics can help to mitigate symptoms, there is no cure for the condition, estimated to affect more than 2 million individuals in the U.S. alone.

Evans has spent many years studying the molecules responsible for the breakdown of cartilage in patients with arthritis, identifying interleukin-1 as a good target. But, he adds, once he had this answer, another question was not far behind: How could he effectively reach the joints to block the actions of this protein?

Gene therapy provided the answer.

By implanting a gene in the affected joint, he was able to stimulate production of a human interleukin-1 receptor antagonist protein, which serves to block actions of the interleukin-1 protein.

"The idea is that by remaining in place, the new gene can continuously block the action of the interleukin-1 within the joints," says Evans. "In essence, the gene becomes its own little factory, continuously working to alleviate pain and swelling."

In 2005, in a study published in the Proceedings of the National Academy of Sciences (PNAS), Evans and colleagues demonstrated that the IL-1Ra gene could be safely transferred to human joints in patients with RA. In this new paper, the authors aimed to prove that the therapy was not only safe, but that it was of therapeutic benefit.

Two study subjects were recruited. (The number reduced from six study subjects following severe adverse events in an unrelated gene therapy trial taking place elsewhere, according to Evans.) Both subjects were postmenopausal females under the age of 75 with a diagnosis of advanced rheumatoid arthritis. After tissue was removed from the subjects' knuckle joints, a harmless retrovirus was inserted into the tissue cells, in order to serve as a "vector" to transport the gene into the patients' joints. After being placed in culture to grow and replicate, the cells were injected back into the afflicted joints.

After four weeks, patients reported reduced pain and swelling, according to Evans. "In one of the two subjects, these effects were dramatic, and the gene-treated joints remained pain-free even though other joints experience flares." Subsequent laboratory tests showed that tissues removed from the subject's joint tissue synthesized lower amounts of disease-related proteins, confirming that the reduction in pain and swelling resulted from the actions of the implanted gene.

"Existing treatments for rheumatoid arthritis are costly and need to be administered regularly," says Evans, adding that in addition to risk of side effects, not all patients respond well. "This paper provides us with the first real evidence that painful symptoms can indeed be lessened through gene therapy."

Ongoing work will focus on the use of gene therapy for the treatment of osteoarthritis, as well as rheumatoid arthritis.

This study was funded, in part, by grants from the National Institutes of Health and Orthogen, a German biotechnology company.

Study coauthors include Peter Wehling, Julio Reinecke, Axel Baltzer, Marcus Granrath, Klaus Schulitz, Carl Schultz, and Rudiger Krauspe of the University of Dusseldorf School of Medicine, Germany; Theresa Whiteside, Elaine Elder and Paul Robbins of the University of Pittsburgh School of Medicine; and Steven Ghivizzani of the University of Florida College of Medicine.

Is There A Relationship Between Sleep-wake Rhythm And Diabetes?

An international research team with German participation including Helmholtz Zentrum München, among other institutions, has succeeded in identifying a new gene variant which is associated with elevated fasting glucose levels and a high risk for type 2 diabetes. The gene mediates insulin secretion indirectly via the release of melatonin, which implicates a previously unknown relationship between the sleep-wake rhythm and the fasting glucose level. The finding could open up new possibilities of treatment which go far beyond the primarily symptomatic therapy approaches to diabetes that have been practised until now.

Diabetes mellitus and diabetes-associated late complications are among the most frequent chronic diseases and causes of death worldwide. In Germany there are approximately six million people with type 2 diabetes who are aware that they have the disease. In addition, there is a relatively high estimated number of undiagnosed diabetics. Besides lifestyle factors such as overweight and lack of exercise, genetic factors play an important role in the pathogenesis of this disease.

The international MAGIC Consortium (MAGIC = Meta-Analyses of Glucose and Insulin-related traits Consortium) combined the data from 13 case-control studies with over 18,000 diabetic and 64,000 non-diabetic study participants and was able to identify a variant of the MTNR1B gene which is associated with both elevated fasting glucose levels as well an elevated risk for type 2 diabetes. The goal of the MAGIC Consortium is to identify gene variants which regulate the fasting glucose levels in healthy individuals.

Germany is represented within the framework of the KORA studies by scientists of the Helmholtz Zentrum München (Assistant Professor Thomas Illig; Director of the KORA studies: Professor H.-Erich Wichmann) and the German Diabetes Center in Düsseldorf (Dr. Wolfgang Rathmann, Dr. Christian Herder; Direktor: Professor Michael Roden).

The MTNR1B gene is expressed in insulin-producing islet cells, among other cells, and encodes one of the two known melatonin receptors. It is assumed that this receptor inhibits the release of insulin via the neural hormone melatonin. The melatonin level in the body is high at night and declines in daylight, whereas the insulin level is higher during the day than in the night. Taken together, these new data implicate an association between the sleep-wake rhythm, the so-called circadian rhythm, and fasting glucose levels, which was not known previously.

Until now an efficient strategy for prevention and for therapies to treat the cause of the disease has been missing in diabetes research. The Helmholtz Zentrum München is working intensively on new approaches in the study and treatment of diabetes. Further studies will show which role melatonin plays in the regulation of insulin secretion, fasting glucose levels and the development of diabetes and whether this finding will lead to new treatment options.

Target That Could Ease Spinal Muscular Atrophy Symptoms Discovered

There is no cure for spinal muscular atrophy (SMA), a genetic disorder that causes the weakening of muscles and is the leading genetic cause of infant death, but University of Missouri researchers have discovered a new therapeutic target that improves deteriorating skeletal muscle tissue caused by SMA. The new therapy enhanced muscle strength, improved gross motor skills and increased the lifespan in a SMA model.

“This therapy does not directly target the disease-causing gene; instead it targets the pathways that affect muscle maintenance and growth,” said Chris Lorson, investigator in the Christopher S. Bond Life Sciences Center and associate professor of veterinary pathobiology in the MU College of Veterinary Medicine. “We administered a particular protein, follistatin, to SMA mouse models to determine if enhanced muscle mass impacts the symptoms of SMA. After treatment, the mice had increased muscle mass, gross motor function improvement and an increase in average life span of 30 percent.”

 With the therapy, MU researchers inhibited myostatin, a protein that limits muscle tissue growth. Myostatin activity can be reduced significantly by enabling several proteins that bind to myostatin, including follistatin. When myostatin is inhibited, muscle mass and strength increase.

SMA is caused by the loss of survival motor neuron-1(SMN1). Humans have a nearly identical copy gene called SMN2. Because of a single molecular difference, SMN2 alone cannot compensate for the loss of SMN1.

“While most work in the SMA field has logically focused on targeting the SMN2 gene, the results of this study suggest that skeletal muscle is a viable therapeutic target that may reduce the severity of some SMA symptoms,” said Lorson, who also is the scientific director for FightSMA, a private spinal muscular atrophy research foundation in Richmond, Va. “Because follistatin does not alter the expression level of SMN protein, the most effective treatment would combine strategies that directly address the genetic defect in SMA as well as SMN-independent strategies that enhance skeletal muscle.”

In Jan 2009, Lorson was awarded a $370,000 grant from the Muscular Dystrophy Association to continue his research on the role of muscle in SMA.

Gene Abnormality Found To Predict Childhood Leukemia Relapse

Scientists have identified mutations in a gene that predict a high likelihood of relapse in children with acute lymphoblastic leukemia (ALL). Although the researchers caution that further research is needed to determine how changes in the gene, called IKZF1 or IKAROS, lead to leukemia relapse, the findings are likely to provide the basis for future diagnostic tests to assess the risk of treatment failure. By using a molecular test to identify this genetic marker in ALL patients, physicians should be better able to assign patients to appropriate therapies.

The findings of the Children's Oncology Group (COG) study, led by scientists from St. Jude Children's Research Hospital, Memphis, Tenn., the University of New Mexico Cancer Research and Treatment Center, Albuquerque, N.M., and the National Cancer Institute (NCI), part of the National Institutes of Health, appear online Jan.7, 2009, in the New England Journal of Medicine, and in print on Jan. 29, 2009.

ALL, a cancer of the white blood cells, is the most common childhood cancer, in that it affects about one in 29,000 children annually. Using currently available therapies, cure rates for ALL are now upwards of 80 percent. However, those therapies carry with them substantial side effects, and even with treatment, only 30 percent of children who experience a relapse of ALL will survive five years. Determining the risk of relapse faced by an individual patient would help physicians tailor treatment intensity appropriately, but until now there has been no good marker for predicting outcome.

"Great progress has been made in recent years in improving the cure rate of childhood ALL," said Stephen Hunger, M.D., chairman of the COG ALL committee and the lead COG investigator on this study. "The findings of this study help us further subdivide those patients who are unlikely to be cured, and identify patients in whom different therapies should be tested."

In the study, researchers analyzed genetic data on leukemia cells obtained at diagnosis from 221 children with high-risk leukemia (i.e. a high chance of relapse) who had been treated in an existing COG study. They conducted their analysis using microarrays and DNA sequencing – technologies which allow researchers to quickly and efficiently identify and analyze multiple genes simultaneously in the same cell. Using these technologies to identify genetic abnormalities in leukemia cells, the investigators examined the DNA of the leukemia cells at the time of diagnosis and then determined if any of the identified genetic changes predicted relapse. To confirm that specific genetic changes were associated with relapse, the scientists also examined a second group of 258 children with ALL who were treated at St. Jude.

"We looked across the genome in an unbiased fashion in an attempt to pull out any genes that were significantly associated with outcome," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology and the paper's first author. "From these findings, we identified a group of genetic abnormalities that together predicted poor outcome."

The most significant association was with the deletions or changes in the IKAROS gene. Mutations of IKAROS were shown to identify a subgroup of patients who were treated in the COG study that had a very poor prognosis. The prognostic significance of these genetic alterations was validated in the independent St. Jude patient group, a finding of particular importance since different types of therapies were used in these two groups of patients.

Previous research has shown that the IKAROS gene serves as the blueprint for the production of the IKAROS protein, which regulates the activity of many other genes. The IKAROS protein plays an essential role in the development of lymphocytes, the white blood cells that, when changed, give rise to pediatric ALL. The way in which IKAROS abnormalities contribute to the development of relapse remains to be determined.

The study also examined gene expression in the leukemia cells using microarray chips, and found that leukemia cells from patients with IKAROS alterations expressed primitive, stem cell-like genes, suggesting that the cells are less mature and possibly more resistant to the effects of drugs used to treat ALL. "These findings show how detailed analysis of leukemic cells using complementary techniques can enhance our understanding of the genetic basis of leukemia," said co-author Cheryl Willman, director and CEO, University of New Mexico Cancer Research and Treatment Center.

The researchers also tested whether the presence of IKAROS alterations was associated with levels of minimal residual disease, another measure of treatment response in ALL.

"Measurement of levels of minimal residual disease is widely used to monitor treatment responsiveness and also to alter patients' therapy if they have a very poor response to treatment," said James Downing, M.D., St. Jude scientific director and the paper's senior author. "An important analysis we conducted was to see whether identifying the association of IKAROS alterations with poor outcome added anything to just measuring levels of minimal residual disease. And, indeed, it did."

The researchers' analysis indicated that identifying IKAROS alterations may be clinically useful and will complement existing diagnostic tests and measurement of minimal residual disease levels.

While a clinical test for alterations of IKAROS could prove valuable for predicting poor outcomes in children with ALL, complexities remain. There are different types of deletions in the gene, some that involve the entire IKAROS gene and others that involve only parts of the gene. Because the genetic alterations in IKAROS in ALL are not uniform or limited to a single mutation or deletion, it may be necessary to develop a panel of different tests to detect IKAROS lesions and identify which patients are at highest risk for relapse.

This research was done as part of the NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to utilize the study of genomics to identify therapeutic targets in order to develop more effective treatments for childhood cancers. The first two cancers being studied in the program are ALL and neuroblastoma, a cancer that arises in immature nerve cells and affects mostly infants and children. Combined, these two cancers account for 3,000 new cases each year, and in both cancers, there are some children who have a very favorable prognosis and others who are at high risk for treatment failure. By determining the genetic factors that distinguish these groups, the hope is that researchers can use this information to improve patient outcomes and develop better treatments, particularly for those in the high-risk group.

"In the long term, our goal is to develop effective therapeutic interventions, directed toward vulnerabilities that leukemia cells acquire as a result of the genomic abnormalities identified through the TARGET initiative," said Malcolm Smith, M.D., Ph.D., of NCI's Cancer Therapy Evaluation Program.