SUNDAY - December 9, 2007---------------------------------------------News Archive/Return to Today's News Alerts

Brain Overgrowth in 1-year-olds Linked to Autism

Brain overgrowth in the latter part of an infant’s first year may contribute to the onset of autistic characteristics, according to research presented today at the American College of Neuropsychopharmacology (ACNP) annual meeting.

Lead researcher Joseph Piven, M.D., Director of the Neurodevelopmental Disorders Research Center at the University of North Carolina, Chapel Hill and an ACNP member, says that behavioral studies of infants at high risk for autism suggest that the onset of most behavioral symptoms for the disorder, such as problems with and social interaction, occur at about age one.

“One reason these findings are important is because early post-natal onset raises the possibility that there may be a window for early treatment and prevention that could be identified by future studies,” Piven says.

Autism is characterized by severe deficits in social interaction and communication, and is associated with a restricted range of activities and interests, as well as repetitive behaviors such as lining up toys in a certain way or requiring repetitive routines.

In normal brain development, neuronal connections are eliminated through a process called “pruning” a process which refines normal brain connections and increases the efficiency of remaining connections in the brain. Piven says one possibility is that there is less pruning in children with autism, their brains become larger than normal.

Piven cautions that while the study seems to suggest a link between brain overgrowth and autism, there are many variants of autism among children, so the ways in which autistic children develop and are affected by brain growth can vary greatly.

Piven says he will continue to study brain development in autism through a study which is part of the new Autism Centers of Excellence funded by the National Institutes of Health.

This study will examine more than 500 infant siblings of autistic individuals with magnetic resonance imaging at the University of North Carolina, Children’s Hospital of Philadelphia, Washington University of St. Louis and the University of Washington in Seattle. Siblings of autistic children will be examined at 6, 12 and 24 months. Some of them are expected to develop autistic behavior during the course of the study.

Previous studies of both brain development on MRI and behavioral development have not been conducted in children this young at risk for an autism spectrum disorder. This study will provide important new information on brain changes in infancy that are associated with the development of autistic symptoms.


Presented at the meeting of the ANCP- American College of Neuropsychopharmacology

Previous studies of autism and brain development: International Journal of Developmental Neuroscience ; Developmental and Behavioral Pediatrics


Ancient Case Of Tuberculosis Found In 500,000-year-old Human

Although most scientists believe tuberculosis emerged only several thousand years ago, new research from The University of Texas at Austin reveals the most ancient evidence of the disease has been found in a 500,000-year-old human fossil from Turkey.

The discovery of the new specimen of the human species, Homo erectus, supports the theory that dark-skinned people migrated northward from low, tropical latitudes. But it also suggests, just as today, dark skin produces less vitamin D, which adversely affected the immune system of these early migrators.

Prior to this discovery in western Turkey - which helps fill a geographical gap in human evolution - the oldest evidence of tuberculosis in humans was found in mummies from Egypt and Peru that date to several thousand years ago.

Paleontologists have spent decades prospecting in Turkey for remains of Homo erectus, widely believed to be the first human species to migrate out of Africa. After moving north, the species had to adapt to increasingly seasonal climates.

This specimen of Homo erectus is identified as a young male based on aspects of the sutures on the skull, sinus formation and the size of the ridges of the brow. Equally important were the series of small lesions found etched into the bone of the cranium. The shape and location of these lesions are characteristic of the Leptomeningitis tuberculosa, a form of tuberculosis that attacks the meninges of the brain.

After reviewing the medical literature on the disease that has reemerged as a global killer, the researchers found that some groups of people demonstrate a higher than average rate of infection, including Gujarati Indians who live in London, and Senegalese conscripts who served with the French army during World War I.

The research team identified two shared characteristics in the communities: a path of migration from low, tropical latitudes to northern temperate regions and darker skin color.

People with dark skin produce less vitamin D because the skin pigment melanin blocks ultraviolet light. And, when they live in areas with lower ultraviolet radiation such as Europe, their immune systems can be compromised.

It is likely that Homo erectus had dark skin because it evolved in the tropics, John Kappelman, professor of anthropology at The University of Texas at Austin, (and part of an international team of researchers from the United States, Turkey and Germany who have published their findings in the Dec. 7 issue of the American Journal of Physical Anthropology. The Leakey Foundation and the Scientific and Technical Research Council of Turkey funded the research) explained.

After the species moved north, it had to adapt to more seasonal climates. The researchers hypothesize the young male's body produced less vitamin D and this deficiency weakened his immune system, opening the door to tuberculosis.

"Skin color represents one of biology's most elegant adaptations," Kappelman said. "The production of vitamin D in the skin serves as one of the body's first lines of defenses against a whole host of infections and diseases. Vitamin D deficiencies are implicated in hypertension, multiple sclerosis, cardiovascular disease and cancer."

Before antibiotics were invented, doctors typically treated tuberculosis by sending patients to sanatoria where they were prescribed plenty of sunshine and fresh air.

"No one knew why sunshine was integral to the treatment, but it worked," Kappelman said. "Recent research suggests the flush of ultraviolet radiation jump-started the patients' immune systems by increasing the production of vitamin D, which helped to cure the disease."

Published December 7, 2007 in the American Journal of Physical Anthropology.

Silenced Genes May No Longer be Hidden

A program that teaches itself to recognise DNA patterns in silenced genes could help us better understand many diseases.

Mammals have two copies of each gene: one from the mother and one from the father. Normally, both are expressed, but occasionally one is imprinted, or silenced, which gives the other the deciding role.

If this active gene is a mutation that would otherwise have been recessive, it can lead to disease. But, if the silenced gene is harmful in some way, imprinting can be beneficial.

Investigating this phenomenon is difficult, as often the only distinguishing feature of an imprinted gene is that it has a methyl group attached, and this doesn't show up in ordinary gene scans..

Although 1 per cent of the 20,000 genes found on chromosomes 1 to 23 are estimated to be imprinted, only 40 have actually been found. "If you went through all of our genes, you'd have to search 100 to find one imprint," says Alexander Hartemink at Duke University in Durham, North Carolina.

To speed up the search, Hartemink and his colleagues turned to an artificial intelligence technique called machine learning. A computer program is fed examples of imprinted and non-imprinted genes and teaches itself how to tell the difference between them. Machine learning has previously been used to create software that can identify DNA patterns known to be associated with increased susceptibility to cardiovascular disease or diabetes.

The researchers started by defining 7000 patterns in DNA sequences that they thought might possibly be present around imprinted genes. They then "trained" two different machine-learning programs by showing them 40 known imprinted genes. Once the programs had learned the patterns found in these genes, they were able to narrow the list of sequences down to around 800 likely candidates.

When they turned the programs loose on the entire human genome, they were able to identify 156 genes that contained some of the likely sequences. So far the group has shown that two of these are indeed imprinted. One of them, DLGAP2, appears to play a role in suppressing bladder cancer when active, while the other, KCNK9 may contribute to bipolar disorder and some forms of cancer.

"The programs identified 156 genes that were likely to have been silenced".

The next step will be to test whether the rest of the 150-odd genes identified by the software really are imprinted. Hartemink suspects around 95 per cent are, but even if that falls to 50 per cent, it is still a useful tool.

The two imprinted genes were found on the eighth chromosome, which was not previously thought to contain imprints, highlighting the software's potential to speed up discovery of imprinted genes.

Published November 30, 2007, in the journal Genome Research.

SATURDAY - December 8, 2007------------------------------------------News Archive/Return to Today's News Alerts

Procedure Detects Fetal Heart Defects With of 3-D Ultrasound

GE Healthcare, the leading manufacturer of 3D/4D ultrasound systems, has licensed a technique patented by an Eastern Virginia Medical School (EVMS) obstetrician that can automate the acquisition of ultrasound images used by physicians to diagnose fetal heart defects.

Alfred Abuhamad, M.D., chairman of obstetrics and gynecology at EVMS – recognized worldwide for his skills in using ultrasound to detect fetal heart defects – developed the automation protocol, called Sonography based Volume Computer Aided Diagnosis (SonoVCAD).

“This is going to change the way ultrasound is practiced,” said Abuhamad. “With some heart defects, infants can die without surgery soon after birth. With an earlier diagnosis months before birth, clinicians and the mother can plan delivery in tertiary care centers with surgeons prepared.”

With this software, an ultrasound clinician identifies a standard starting point, for the four-chamber view of the fetal heart. Abuhamad has created algorithms that allow the other planes to be generated from that four-chamber view. Those views allow physicians to identify the type and severity of fetal heart defects.

This proprietary SonoVCAD technology displays all of the 2D planes, which complies with the recommended standard screening exam of the fetal heart, as outlined by the American Institute of Ultrasound in Medicine (AIUM), the American College of Obstetrics and Gynecology (ACOG), the American College of Radiology (ACR) and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). This includes identification of the four-chamber, left outflow tract and right outflow tract views of the fetal heart.

With the software, an ultrasound clinician identifies a standard starting point, for the four-chamber view of the fetal heart. Abuhamad has created algorithms that allow the other planes to be generated from that four-chamber view. Those views allow physicians to identify the type and severity of fetal heart defects.

“The Voluson E8 is yet another example of ultrasound’s potential to unlock the future of advanced imaging by helping detect diseases early, when they can be more effectively treated.”


For more information, visit the American Heart Association Web site

Canadian Retailer Pulls Plastic Water Bottles Off Shelves

Vancouver-based Mountain Equipment Co-op became the first major Canadian retailer to stop selling products that contain bisphenol A over fears the chemical can leach from plastic food and water containers.

"Inconclusive science and regulatory uncertainty presently surrounds bisphenol-A (BPA)," the company said in a statement.

"For these reasons, MEC has stopped selling polycarbonate water bottles and food containers until guidance is provided by the Government of Canada on the health risks posed by BPA."

The Canadian co-operative joins U.S.-based Patagonia in dropping the products because of health concerns.

The chemical, which can mimic the effects of the hormone estrogen in cells, has been surrounded by controversy. Some North American researchers and environmentalists have shown it can cause several types of cancer as well as developmental, neural, behavioral and reproductive harm in animals.

Industry says the products are not dangerous, citing studies from government agencies such as the U.S. Food and Drug Administration that food and beverage containers manufactured from polycarbonate do not pose a health risk to humans.

"Rarely has a chemical been the subject of such intense scientific testing and scrutiny, and still, important agencies across the globe agree that there is no danger posed to humans from polycarbonate bottles," said Tom Cummins, spokesman for Nalgene and Nunc Brand Products, which manufacturers the popular Nalgene polycarbonate water bottles.

Besides hard-plastic water bottles, bisphenol A is also used in some baby bottles and the linings of some food cans, including most major brands of infant formula, according to a study co-released this week by Environmental Defence Canada and the Washington-based Environmental Working Group.

"We have study after study showing that this chemical is toxic,... and there are safe and available alternatives that are affordable," said Aaron Freeman, policy director of Environmental Defence Canada.

Canada's health department declined to comment before it releases preliminary results of a review of the chemical's effects next spring.

"We are looking at as much research as we can to make a very science-based assessment," said Joey Rathwell, a spokeswoman for Health Canada.

Norway and the European Union are also reviewing the product. Japanese manufacturers decided voluntarily to stop making products using polycarbonate plastic five to six years ago.

Published December 6, 2007 in the journal Neuron.

How Fruits and Veggetables Reduce Cancer

Just three servings a month of raw broccoli or cabbage can reduce the risk of bladder cancer by as much as 40 percent - by making you pee out toxins.

Dark-colored berries can reduce the risk of cancer too - adding more evidence to a growing body of research that shows fruits and vegetables, especially richly colored varieties, reduce the risk of cancer.

The Roswell Park Cancer Institute in Buffalo, New York, surveyed 275 people who had bladder cancer and 825 people without cancer - asking especially about cruciferous vegetables such as broccoli and cabbage - rich in compounds called isothiocyanates, which are known to lower cancer risk.

The effects were most striking in nonsmokers, the researchers told a meeting being held this week of the American Association of Cancer Research in Philadelphia.

Compared to smokers who ate fewer than three servings of raw cruciferous vegetables, nonsmokers who ate at least three servings a month were almost 73 percent less likely to be in the bladder cancer group.

Among both smokers and nonsmokers, those who ate this minimal amount of raw veggies had a 40 percent lower risk. But the team did not find the same effect for cooked vegetables.

"Cooking can reduce 60 to 90 percent of ITCs, (isothiocyanates)," Dr. Li Tang, who led the study.

A second team of researchers from Roswell Park tested broccoli sprouts in rats.

They used rats engineered to develop bladder cancer and fed some of them a freeze-dried extract of broccoli sprouts. The more they ate, the less likely they were to develop bladder cancer, said Dr. Yuesheng Zhang, who led this research.

The compounds were processed and excreted within 12 hours of feeding. "The bladder is like a storage bag, and cancers in the bladder occur almost entirely along the inner surface, the epithelium, that faces the urine, presumably because this tissue is assaulted all the time by noxious materials in the urine," Zhang said. By excreting the toxic compounds quickly, there is less time for harmful exposure.

In a third study, a team at The Ohio State University fed black raspberries to patients with Barrett's esophagus, a condition that can lead to esophageal cancer.

Black raspberries, sometimes called blackberries or blackcaps, are also rich in cancer-fighting compounds.

Ohio State's Laura Kresty and colleagues fed 1.1 ounces (32 grams) of freeze-dried black raspberries to women with Barrett's esophagus and 1.6 ounces (45 grams) to men every day for six months.

They measured urine levels of levels of two compounds - 8-isoprostane and GSTpi - that indicatea whether cancer-causing processes are going on in the body.

Kresty said 58 percent of patients had marked declines of 8-isoprostane levels, suggesting less damage, and 37 percent had higher levels of GSTpi, which can help interfere with cancer causing damage and which is usually low in patients with Barrett's.

Presented December, 2007, at the meeting of the American Association of Cancer Research.

FRIDAY - December 7, 2007----------------------------------------------News Archive/Return to Today's News Alerts

Reprogrammed Skin Cells Strut Their Stuff

Skin cells reprogrammed to act like embryonic stem cells - a breakthrough reported just 2 weeks ago - are already showing promise as therapeutic agents. In today's online edition of Science, researchers describe using induced pluripotent stem (iPS) cells to alleviate symptoms of sickle cell anemia in mice. The technique is not yet safe to try in people, but scientists say it is proof of principle that iPS cells could someday treat human disease.

Induced pluripotent stem cells excite scientists because they represent a way to obtain custom-made stem cells without the ethical hurdles of using embryos or oocytes. Researchers hope that they might be able to use the technique to replace faulty cells in the body with healthy cells with the patient's own DNA.

Tim Townes of the University of Alabama, Birmingham, and his colleagues wondered whether iPS cells might prove useful in a mouse model of sickle cell anemia. (Blood cells are much easier to replace than tissue cells.) In afflicted humans, red blood cells become curved and block blood vessels. Mice show many of the symptoms that human patients do, and so are an especially good candidate to test iPS cells' abilities, says stem cell researcher Rudolf Jaenisch of the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, both in Cambridge, who collaborated with Townes on the project.

The researchers took skin cells from the tails of sickle cell mice and inserted them with copies of four genes that induced them to have the pluripotent quality of embryonic stem cells - also adding a corrected hemoglobin gene that coaxed them into becoming blood-producing stem cells. Then they injected these cells into sickle cell mice already treated with radiation to kill their own blood stem cells. Within a few weeks, the new cells were producing mature blood cells, and the symptoms of sickle cell disease had dramatically improved.

Townes says he and Jaenisch initially collaborated on a project that used nuclear transfer to make corrected stem cells, a process called therapeutic cloning. But the experiments failed, because nuclear transfer was too inefficient to produce the needed cells. The iPS cell technique "is amazingly efficient," he says.

The paper is an important step forward, says Jose Cibelli of Michigan State University in East Lansing. The lab results for iPS cells have been impressive, "but if they do not have therapeutic value, they will be far from getting to the point of replacing the whole idea of therapeutic cloning."

The important next step for the field, Cibelli says, is to find reliable ways to differentiate the cells into a variety of useful cell types and to be sure that no undifferentiated cells remain to cause potential tumors.

Edited from article by Gretchen Vogel, ScienceNOW Daily News, Published December 6, 2007 in the journal Science.

Additional information on Sickle Cell Anemia.
Missing Protein May be key to Autism

A missing brain protein, called CASK, may be one of the culprits behind autism and other brain disorders, according Li-Huei Tsai, a researcher at MIT's Picower Institute for Learning and Memory.

CASK helps in the development of synapses, which neurons use to communicate with one another and which underlie our ability to learn and remember. Ill formed synapses could lead to mental retardation; gene mutations encoding certain synaptic proteins are also associated with autism.

Li-Huei Tsai, Picower Professor of Neuroscience at MIT, studies a kinase - kinases are enzymes that change proteins - called Cdk5. While Cdk5's best-known role is to help neurons form and migrate to their correct positions during brain development, "emerging evidence supports an important role for Cdk5 at the synapse," says Tsai.

A key scaffolding protein, CASK is one of the first proteins on the scene of a developing synapse.

Scaffolding proteins such as CASK are the site managers, supporting protein-to-protein interactions to make sure the resulting architecture is sound. Mutations in the genes responsible for Cdk5 and CASK have been found in mental retardation patients.

"We found that Cdk5 is critical for recruiting CASK to do its job for developing synapses. Without Cdk5, CASK was not in the right place at the right time, and failed to interact with essential presynaptic components. This, in turn, led to problems with calcium influx." The flow of calcium in and out of neurons affects processes central to nervous system development and plasticity - its ability to change in response to conditions.

Gene mutations and/or deletions in synaptic cell surface proteins and molecules called neurexins and neuroligins have been associated with autism. Problem with CASK recruitment in the Tsai laboratory investigations mimiced the same results as genetic mutations/deletions.

The Picower study is the first molecular explanation of how Cdk5 promotes synapse development, which also may go awry in neurodegenerative diseases such as Alzheimer's.

"There are still a lot of unknowns," said Tsai, a Howard Hughes Medical Institute investigator. "Causes for psychiatric disorders are still very unclear, but accumulating evidence strongly suggests that alterations in the synaptogenesis program can lead to these serious diseases."

Tsai's co-authors include Picower researcher Benjamin A. Samuels, and researchers associated with Harvard Medical School; Johns Hopkins University School of Medicine; McLean Hospital in Belmont, Mass.; and Academia Sinica in Taiwan.

Published December 6, 2007 in the journal Neuron.


Twitching Proteins Caught in the Act - Not Passive as Once Thought

Apparently, some enzymes fidget constantly, even as they wait to catalyze a reaction. The study, from Howard Hughes Medical Institute investigator Dorothee Kern, shows that enzymes may not be nearly as passive as scientists once thought.

Biologists have long thought that binding of substrate molecules triggered enzymes to change shape. But Kern has discovered that one key enzyme - and likely many more - snaps shut by itself. This change of shape happens even before the enzyme, called adenylate kinase, binds to its substrates.

“The general notion in enzymology has been that the substrate [on which the enzyme acts] induces the shape change,” said Kern, who is also a professor of biochemistry at Brandeis University. “We found that this is not true. The enzyme, in fact, changes conformations without the substrate. It's really a shift in the paradigm.”

In two papers published November 18, 2007, in advance online publications of the journal Nature, Kern and her team detail three years of experiments that prompted the paradigm shift.

Employing five different advanced techniques, her team painstakingly constructed a near real-time movie of adenylate kinase in action. Adenylate kinase is a key enzyme that processes adenosine triphosphate, or ATP. ATP is known as “cellular gasoline” because it acts as cells' primary energy source.

Her technique detects changes in the distances between two fluorescent dyes labeling the tips of the two large lids of the enzyme. As the lids move, the laser apparatus built by her brother measured the motion in real time. The data showed the lip snapping shut over a distance of just 10 angstroms, or 10-millionths of a centimeter, in about a millisecond. This experiment shows that once in a while, the enzyme closes all the way on its own, in the absence of any target proteins.

By comparing versions of the adenylate kinase enzyme used by two different organisms - one that lives in an environment where temperatures exceed 200 degrees Fahrenheit and one that thrives in more civilized temperatures - Kern found that thermal energy causes rapid fluctuations in the positions of individual atoms, leading to slower, transient changes in the shape of the protein. Importantly, Kern said, enzymes adopt the shapes they need to catalyze biological reactions.

“The novelty here is the combination of the methods to make a near real-time movie of what's going on in the enzyme. None of the methods individually would have solved the problem.” Together, Kern says, these techniques can help scientists reveal what she calls the "dynamic personality" of enzymes, and develop a realistic picture of their function.

Published December 6, 2007, in the journal Nature.

THURSDAY - December 6, 2007------------------------------------------News Archive/Return to Today's News Alerts

Broken Mouse Skulls 'Repaired With Stem Cells'

There are mice in Baltimore whose skulls were made whole again by bone tissue grown from human embryonic stem cells (hESCs).

Healing critical-size defects (defects that would not otherwise heal on their own) in intramembraneous bone, the flat bone type that forms the skull, is a vivid demonstration of new techniques being devised by hESCs for tissue regeneration.

Using mesenchymal precursor cells isolated from hESCs, the Hopkins team steered them into bone regeneration by using “scaffolds,” tiny, three-dimensional platforms made from biomaterials.

Physical context, it turns out, is a powerful influence on cell fate. In Jennifer Elisseeff's lab at Hopkins, Dr. Elisseeff and colleagues demonstrated that by changing the scaffold materials, they could shift mesenchymal precursor cells into becomming either of two of the body’s osteogenic pathways 1) intramembraneous, which makes skull, jaw, and clavicle bone; or 2) endochondral, which builds the “long” bones and involves initial formation of cartilage, which is then mineralizes into bone.

Mesenchymal precursor cells grown on an all-polymer, biodegradable scaffold followed the endochondral lineage. Those grown on a composite scaffold made of biodegradable polymers and a hard, gritty mineral called hydroxyapatite went to the intramembraneous side.

Biomaterial scaffolds provide a three-dimensional framework on which cells can proliferate and differentiate, secrete extracellular matrix, and form functional tissues, says graduate student Nathan Hwang. In addition, their known composition allowed the researchers to characterize the extracellular microenvironmental cues that drive the lineage specification.

The promise of pluripotent embryonic stem cells for regenerative medicine hangs on the development of such control techniques. Left to themselves, hESCs in culture differentiate wildly, forming a highly mixed population of cell types, which is of little use for cell-based therapy or for studying particular lineages.

Conventional hESC differentiation protocols rely on growth factors, co-culture, or genetic manipulation, say the researchers. The scaffolds offer a much more efficient method.

As a proof of principle, Elisseeff and colleagues seeded hESC-derived mesenchymal cells onto hydroxyapatite-composite scaffolds and used the resulting intramembraneous bone cells to successfully heal large skull defects in mice. The researchers believe this is the first study to demonstrate a potential application of hESC-derived mesenchymal cells in a musculoskeletal tissue regeneration application.

Presented December 2, 2007 at the 47th annual American Society for Cell Biology.


Stem-Cell Therapies for Brain More Complicated Than Thought

Stem cell therapies for the brain could be much more complicated than previously thought, an MIT research team’s latest findings suggest.

In a study published in Public Library of Science (PloS) Biology on Nov. 13, MIT scientists reported that adult stem cells produced in the brain are preprogrammed to make only certain kinds of connections--making it impossible for a neural stem cell originating in the brain to be transplanted to the spinal cord, for instance, to take over functions for damaged cells.

Type 1 diabetes occurs when the immune system attacks and destroys insulin-producing cells in the pancreas. For years, T cells were considered enemy number one, because they commit the actual attacks.

But more recently, scientists have eyed another potential culprit: B cells, which may be turning T cells off by presenting them with antigens - proteins that stimulate the immune system.

The drug rituximab, made by Genentech, is an antibody that depletes B cells and has been shown to combat rheumatoid arthritis, another autoimmune disease. With that in mind, an international network of researchers successfully lobbied for a clinical trial of the drug in type 1 diabetes, even though mouse studies were lacking. That trial, begun last year, has enrolled 82 people - the youngest is 8 years old - and will take another year or so to finish.

The absence of mouse studies is "a concern in our scientific community," says immunologist Li Wen of Yale University. With that in mind, she, along with Yale immunologist Mark Shlomchik and their colleagues, genetically engineered a mouse model to test the drug. Wen's animals are predisposed to diabetes and have the human version of CD20, the molecule rituximab targets, on the surface of their B cells. Wen and her colleagues were reluctant to work directly with Genentech and acquire rituximab from them (companies often impose restrictions on publication and other matters, she says), so instead they designed a rituximab-like antibody to test.

They tested the drug in mice of various ages, including 4- and 9-week-old animals that didn't have diabetes and older mice within 6 days of diagnosis. In the animals that were still healthy, about 70% of those receiving the antibody therapy were diabetic by 35 weeks of age, compared to nearly 100% of those that received a placebo. This translates to a 10- or 15-week delay in developing diabetes--the equivalent of 10 or 15 years in humans, says Wen.

In the 14 mice with established diabetes, five stopped needing insulin for more than 2 months, some for up to 5 months.

Wen and her colleagues also found that as the animals regained their B cells, those cells were better behaved than their B-cell predecessors. For example, the new B cells were less likely to produce autoantibodies that often precede type 1 diabetes, suggesting that the drug had somehow recalibrated the immune system.

Mark Pescovitz, a transplant immunologist at Indiana University, Indianapolis, and head of the rituximab clinical trial, is heartened by the results. "[I'm] even more confident that our study will succeed," he says.

Still, Pescovitz worries that the new mouse findings will cause physicians to jump the gun. "I would hope that [doctors] aren't going to run out there with their next diabetic and throw rituximab at them, but there's nothing to stop them," he says.

The drug is not without side effects such as infections and rashes, and although Pescovitz is impressed with the mouse work, he notes that many drugs that work in mice fare less well in people.

Published November 3, 2007 in the journal Public Library of Science (PloS) Biology.

Waste Energy, Fight Disease

Mice genetically engineered to burn energy less efficiently live longer and are resistant to several age-related diseases, including cancer, hardening of the arteries, and obesity.

This finding suggests that drugs based on a strategy to make cells be less efficient could one day help stave off these age-related conditions in people, the researchers say.

The mitochondria in each cell produce a molecule called ATP that provides energy for the body. The weight loss drug 2,4-dinitrophenol (DNP) blocks this process, causing mitochondria to produce heat instead of ATP and forces cells to metabolize carbohydrates and fat for energy. making ATP energy production less efficient - the energy that is normally produced from cellular respiration is wasted as heat. An excessive rise in body temperature results from the heat produced during uncoupling.

Although popular in the 1930s, DNP was discontinued in 1938 after several people died from overheating. Now research in mice shows that uncoupling proteins in the mitochondria that work like DNP, may offer an alternative weight reduction strategy. Endocrinologist Clay Semenkovich of the Washington University School of Medicine in St. Louis, Missouri, has found that uncoupling protein 1 (UCP1) may also help ward off other conditions.

UCP1 is normally found in body fat, but Semenkovich's group genetically engineered mice to express low levels in their skeletal muscles. The mice had higher rates of metabolism but appeared healthy otherwise, and their core body temperature was only 0.5ºC higher than normal. The UCP1 mice lived longer, dying at 30 months compared to the 27-month life span of normal mice. Although lymphatic cancer was the most common cause of death in the normal mice, killing 12 of 53, only four of the 51 UCP1 mice died from that disease.

Thats not all. Mice that normally develop hardening of the arteries didn't when bred to express UCP1 in their skeletal muscles. When UCP1 expression was triggered in the skeletal muscles of mice already obese, weight and blood pressure decreased, whereas weight increased in normal obese mice.

Semenkovich's team speculates that UCP1 increases metabolism, triggering molecular pathways that result in less of the chronic inflammation associated with age-related diseases. Physiologist Kevin Conley of the University of Washington Medical Center in Seattle thinks instead that the inefficient muscles may spur the genesis of more mitochondria, leading to "a rebuilding of the cell that reverses cellular damage that occurs with age and age-related diseases."

Regardless of the mechanism, Semenkovich believes the approach may be applicable to humans. "If we can figure out a way to target therapies to do this in skeletal muscles of people, it might be a way to treat age-related diseases." Biologist Patrick Schrauwen of Maastricht University in the Netherlands agrees, but adds that little is known about uncoupling proteins in humans and more investigation will be needed before attempting to manipulate them to prevent disease.

Edited from article By Steve Mitchell, ScienceNOW Daily News 4 December 2007.


WEDNESDAY - December 5, 2007------------------------------------------News Archive/Return to Today's News Alerts

Mutant Sperm May Guide Clinicians to New Diseases

Using 'reverse genetics', new methods of research can move from genome to prediction of consequences for patients.

It appears some rearrangements of the human genome occur more frequently than previously thought, and scientists from the Wellcome Trust Sanger Institute are leading a new identification system of genes involved in disease to improve the diagnosis of genomic disease.

The scientists looked at four unstable regions in the genome where rearrangements cause genetic diseases - so called 'genomic disorders' - and found that some appeared in sperm much more frequently than expected.

In November 2006, a team led by Dr Matt Hurles, showed that losses or duplication of 'chunks' of the human genome occurred frequently in apparently healthy people. These losses or gains of DNA regions are called Copy Number Variants (CNVs), and can be found all over the genome in every individual.

Some of the mechanisms thought to produce CNVs were expected to produce about one duplication for every deletion. But clinical records for genomic disorders show only a few duplications, compared with hundreds of deletions.

As there is no global measurement system to determine the rate at which human DNA is gained or lost relative to deletions, a system that would require thousands of human genomes, investigators at the Wellcome Trust Sanger Institute carried out a study on four clinically important regions using human sperm cells.

"Sperm cells give us an unbiased snapshot of CNVs. Using our new highly-sensitive assays we can detect one rearrangement in a million cells" explained Dr Matt Hurles. “The team looked for regions known to be affected by three particular birth defects including one that causes male infertility. Their study showed that duplications are about half as frequent as deletions.

"It is likely that deletions are more harmful than duplications, perhaps because a vital gene is removed, and so less likely to survive," explained Dr Hurles. "However, for some of the genomic regions we looked at, duplications can cause milder symptoms. Perhaps we can improve diagnosis with improved understanding of the possible consequences of duplications."

In Williams-Beuren Syndrome, loss of a genomic region (which can vary in size) can have very severe effects, including narrowing of arteries, facial and other skeletal deficiencies and impaired mental development. By contrast, duplications of the same regions have a milder effect, resulting most commonly in the delay of speech development. With the results of this study, the team hopes improved diagnosis might result from examining speech-delay for CNVs in this region.

"Although some of these CNVs arise much more frequently than anyone thought, they are still comfortingly rare: we see them in about 1 in 50,000 sperm cells," explained Dr Hurles. "These are unfortunate accidents of the essential shuffling of our genetic deck of cards, a process essential to human life. We need a new deal for each new person."

Detecting rearrangements where none were suspected and predicting new disease-causing variants is the ultimate goal. One of the duplications that was detected in sperm has not been observed in the clinic, and yet it can be expected to cause disease, as smaller duplications in the same region cause Potocki-Lupski syndrome.

Clinical genetics usually proceeds from observations in a patient down a long road to identifying the gene involved. The new CNV work opens a new and possibly quicker, route of using new mutations found in sperm to lead to disease-causing mutations in patients.

Published December 2, 2007 in Nature Genetics.


Antibody Therapy Shows Promise for Diabetes

An antibody therapy that's approved to treat certain cancers and arthritis has helped prevent - and even beat back - type 1 diabetes in mice.

Researchers have already launched a human trial of the therapy, rituximab. But there are concerns that diabetes patients and their doctors will start trying the drug before it's been shown to work in humans.

Type 1 diabetes occurs when the immune system attacks and destroys insulin-producing cells in the pancreas. For years, T cells were considered enemy number one, because they commit the actual attacks.

But more recently, scientists have eyed another potential culprit: B cells, which may be turning T cells off by presenting them with antigens - proteins that stimulate the immune system.

The drug rituximab, made by Genentech, is an antibody that depletes B cells and has been shown to combat rheumatoid arthritis, another autoimmune disease. With that in mind, an international network of researchers successfully lobbied for a clinical trial of the drug in type 1 diabetes, even though mouse studies were lacking. That trial, begun last year, has enrolled 82 people - the youngest is 8 years old - and will take another year or so to finish.

The absence of mouse studies is "a concern in our scientific community," says immunologist Li Wen of Yale University. With that in mind, she, along with Yale immunologist Mark Shlomchik and their colleagues, genetically engineered a mouse model to test the drug. Wen's animals are predisposed to diabetes and have the human version of CD20, the molecule rituximab targets, on the surface of their B cells. Wen and her colleagues were reluctant to work directly with Genentech and acquire rituximab from them (companies often impose restrictions on publication and other matters, she says), so instead they designed a rituximab-like antibody to test.

They tested the drug in mice of various ages, including 4- and 9-week-old animals that didn't have diabetes and older mice within 6 days of diagnosis. In the animals that were still healthy, about 70% of those receiving the antibody therapy were diabetic by 35 weeks of age, compared to nearly 100% of those that received a placebo. This translates to a 10- or 15-week delay in developing diabetes--the equivalent of 10 or 15 years in humans, says Wen.

In the 14 mice with established diabetes, five stopped needing insulin for more than 2 months, some for up to 5 months.

Wen and her colleagues also found that as the animals regained their B cells, those cells were better behaved than their B-cell predecessors. For example, the new B cells were less likely to produce autoantibodies that often precede type 1 diabetes, suggesting that the drug had somehow recalibrated the immune system.

Mark Pescovitz, a transplant immunologist at Indiana University, Indianapolis, and head of the rituximab clinical trial, is heartened by the results. "[I'm] even more confident that our study will succeed," he says.

Still, Pescovitz worries that the new mouse findings will cause physicians to jump the gun. "I would hope that [doctors] aren't going to run out there with their next diabetic and throw rituximab at them, but there's nothing to stop them," he says.

The drug is not without side effects such as infections and rashes, and although Pescovitz is impressed with the mouse work, he notes that many drugs that work in mice fare less well in people.

Published December 3, 2007 in the Journal of Clinical Investigation.

Additional commentary on B cell depletion and diabetes: B cell depletion: a novel therapy for autoimmune diabetes?
Replacing The Cells Lost In Parkinson Disease


Parkinson disease (PD) is caused by the progressive degeneration of brain cells known as dopamine (DA) cells.

Replacing these cells is considered a promising therapeutic strategy. Although DA cell - replacement therapy by transplantation of human fetal mesencephalic tissue has shown promise in clinical trials, limited tissue availability means that other sources of these cells are needed.

Now, Ernest Arenas and colleagues at the Karolinska Institue, Sweden, have identified a new source for DA cells that provided marked benefit when transplanted into mice with a PD-like disease.

In the study, DA cells were derived from ventral midbrain (VM) neural stem cells/progenitors by culturing them in the presence of a number of factors -- FGF2, sonic hedgehog, and FGF8 -- and engineering them to express Wnt5a.

This protocol generated 10-fold more DA cells than did conventional FGF2 treatment. Further analysis revealed that these cells initiated substantial cellular and functional recovery when transplanted into mice with PD-like disease.

Importantly, the mice did not develop tumors, a potential risk that has precluded the clinical development of embryonic stem cells as a source of DA cells. These data led the authors to suggest that Wnt5a-treated neural stem cells might be an efficient and safe source of DA cells for the treatment of individuals with PD.

The article Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice is published in the December 3 issue of the Journal of Clinical Investigation.

Published December 3, 2007 in the Journal of Clinical Investigation.


TUESDAY - December 4, 2007----------------------------------------------News Archive/Return to Today's News Alerts

Common Contaminant May Harm Breastfeeding Infants

Scientists at the Albert Einstein College of Medicine of Yeshiva University have shown that perchlorate - an industrial pollutant linked to thyroid ailments - is actively concentrated in breast milk.

Their findings suggest perchlorate contamination of drinking water is a greater health risk than previously thought.

For decades, millions of Americans have been exposed to perchlorate through contamination of local water supplies. The U.S. Environmental Protection Agency has identified 75 perchlorate releases in 22 states, primarily California and states in the Southwest.

Perchlorate is known to interfere with the ability of the thyroid, mammary glands and certain other tissues to absorb iodide from the bloodstream.

“Our study suggests that high levels of perchlorate may pose a particular risk to infants,” says Dr. Nancy Carrasco, senior author of the study and professor of molecular pharmacology at Einstein.

“Nursing mothers exposed to high levels of perchlorate in drinking water may not only provide less iodide to their babies, but their milk may actually pass on perchlorate, which could further deprive the infants’ thyroid glands of iodide. The thyroid requires iodide to synthesize the hormones T3 and T4 that are essential for normal development of the central nervous system. Babies who don’t make enough of these thyroid hormones may become mentally impaired.”

Iodide is relatively scarce in the diet, and tissues that need to accumulate it - the breast and thyroid in particular - are equipped with a cell-surface protein called NIS (sodium/iodide symporter) that actively pulls iodide from the bloodstream and into the cells. NIS was first identified and cloned by Dr. Carrasco’s team in 1996.

“We found that the same protein - NIS - that actively recruits iodide into cells does the same thing for perchlorate,” says Dr. Carrasco. “In fact, NIS has a higher affinity for perchlorate than it does for iodide, which certainly heightens the risk posed by this contaminant.”

Published December 3, 2007 in the advance online PNAS - Proceedings of the National Academy of Sciences.


Lead Levels Well Below U.S. Standard May Affect Brain Function in Children

A new six-year study at Cornell University suggests that the Centers for Disease Control and Prevention (CDC) standard for blood-lead levels (BLLs) in children may not be low enough.

Researchers have found that even very small amounts of lead in children's blood - amounts well below the current federal standard - are associated with reduced IQ scores.

According to the CDC, about one out of every 50 children in the United States between ages 1 and 5 has a BLL above 10 mcg/dl and about 10 percent of children have BLLs of 5 mcg/dl or greater; about 25 percent of U.S. homes with children under age 6 have a lead-based paint hazard.

"Even after taking into consideration family and environmental factors known to affect a child's cognitive performance, blood lead played a significant role in predicting nonverbal IQ scores," said Richard Canfield, a senior researcher in Cornell University's Division of Nutritional Sciences and senior author of the study published in the journal Environmental Health Perspectives.

"We found that the average IQ scores of children with BLLs of only 5 to 10 mcg/dl were about 5 points lower than the IQ scores of children with BLLs less than 5 mcg/dl. This indicates an adverse effect on children who have a BLL substantially below the CDC standard, suggesting the need for more stringent regulations," he said.

In the United States over the past several months nearly 50 specific products, including millions of toys for young children, have been recalled due to excessive lead in the paint, plastics, and metal." Our findings emphasize the very real dangers associated with low-level exposures, to which lead in toys can contribute," Canfield said.

U.S. children are exposed to lead primarily from household dust contaminated by deteriorating interior lead-based paint. In addition to toys, other potential sources include contaminated soil, imported food stored in lead-glazed pottery, and certain plastic, metallic and painted products.

This most recent finding builds on the same research team's influential 2003 study, published in the New England Journal of Medicine, that reported adverse effects of BLLs below 10 mcg/dl in a group of children followed from infancy to age 5 years.

"Our new findings are based on follow-up testing of the same children at age 6, using a more comprehensive IQ test to assess cognitive function. The results provide compelling evidence that low-level lead exposure has effects into the school-age years," said co-author Todd Jusko, a Cornell alumnus and a University of Washington Ph.D. candidate in epidemiology.

"Children living in poverty disproportionately suffer from elevated BLLs," said statistician and co-author Charles Henderson, a Cornell senior researcher in human development; he also noted that "even a small decline in an IQ score is likely to be reflected in aptitude test scores such as the SAT."

"The bottom line," according to Canfield, "is that lead is a persistent neurotoxin that causes brain damage. The fact that lead has been found in millions of toys, even toys specifically designed for children to put into their mouths, presents an unacceptable risk. Our findings suggest the need to re-evaluate the current federal standards for lead in consumer products and the current definition of an elevated BLL in children."

Published November 30, 2007 in the journal Environmental Health Perspectives.

Recent Magnet Ingestion and Lead/Lead Paint Press Releases and Recalls


Researchers Want to Harness Sperm to Power Nano-Robots

Researchers at Cornell are working to use the same energy that powers sperm to power nanoscale robots - hopefully to one day deliver chemo drugs or antibiotics to sites within the body.

Midway between the head and the long tail of a sperm are the mitochondria, organelles that generate a cell's energy. But sperm also have a second energy source in their long tail. Using a process known as glycolysis to break down glucose, they make ATP which generates energy.

Glycolysis requires 10 enzymes, each tethered to a fibrous sheath running the length of the sperm tail. Cornell researchers want to re-create this glycolytic pathway by modifying each protein to tether to nickel ions instead - and on a manufactured chip.

So far, they have attached three of the 10 enzymes required to make ATP from glucose. If they manage to attach all 10 enzymes, each enzyme will ultimately generate ATP to power a nano-device. In the body, such a device could conceivably use available blood glucose as fuel.

Potential uses include delivery systems loaded with chemo drugs or antibiotics to target specific cells. Such a system would allow doctors to provide steady doses while reducing side effects that result from treating the entire body with a drug.

"Our idea is not the final product but rather an energy-delivery system," said Alex Travis, Cornell assistant professor of reproductive biology at the College of Veterinary Medicine's Baker Institute for Animal Health and the study's senior author. "As a proof of principle that this kind of strategy could work, we've shown that the first two enzymes could be attached to the same chip and act in series," added Chinatsu Mukai, a postdoctoral associate in Travis' lab and a co-author. Travis' group is trying to get funding to complete attaching the rest of the enzymes in the glycolysis pathway.

"We have a provisional patent, so if a company shows interest, we could also work with them," said Travis.

Presented December 3, 2007 at the 47th annual meeting of the American Society for Cell Biology.


MONDAY - December 3, 2007----------------------------------------------News Archive/Return to Today's News Alerts

The study of embryology covers all aspects of human anatomy from the molecular structure of the embryo and the transference of DNA from each parent - to the mother's immune system in its failure to reject the implantation of a foriegn body, the fertilized egg. Today's articles focus on the immune system and its response to cancer cells - another immune system identity challenge. Potential diagnostic and treatment procedures may grow out of these scientific observations of cancer cells and how they behave.

Entosis - New Form of Cell Death Defined

Observed for more than 25 years, scientists examining cultures of human cancer cells have occasionally spotted cells tucked within other cells.

But this phenomenon wasn't unexplored until cell biologist Michael Overholtzer of Harvard Medical School in Boston, saw the same thing while working with a line of normal breast cells. Cultured cells usually grow on a membrane or matrix. When they become detached, however, some appear to be enveloped into other cells.

Overholtzer's team found that up to 70% of the detached cells died once engulfed by another detached cell. However, up to 9% divided while enveloped and up to 18% were eventually released unharmed. Blocking the mechanisms involved in other methods of cell death like apoptosis and phagocytosis did not stop the process, apparently entosis operates in a different way.

More experiments revealed cadherins, proteins that keep cells joined to each other, are required for entosis. Still working out the details, the scientists speculate that entosis occurs with an imbalance in adhesion leading one cell to push into the other until it is engulfed, akin to pressing your fist into a balloon.

Whatever the precise mechanism, entosis appears to be widespread. The team found evidence of the process in several cell types, including breast, ovarian, umbilical cord, and kidney cancer cells. Overholtzer says tumor suppression may be one function of entosis as a chemical that suppresses it, when applied to a line of breast cancer cells, increased colony formation (tumor growth) by 10-fold.

Entosis may also be "a way for a tumor cell to escape recognition by chemotherapeutic drugs or the immune system" by hiding out inside another cell, says Maureen Murphy, a molecular biologist at Fox Chase Cancer Center in Philadelphia, Pennsylvania. That may explain why not all cells die during entosis.

Craig Thompson, a cancer biologist at the University of Pennsylvania, is more skeptical. The fact that some cells survive entosis, he says, suggests it isn't a very effective process for suppressing tumors and raises concern that it may be a phenomenon that primarily occurs in the lab rather than in the body.


Published November 30, 2007 in the journal Cell.


UV Light May Offer "Double Whammy" For Killing Tumors

Using ultraviolet light may one day offer a "double whammy" to kill cancer cells by focusing antibody-based drugs on the tumor surface, triggering the body's own defenses to eliminate tumors.

In two studies with mice, a British team cloaked antibodies - the immune system proteins that tag germs and cancer cells for elimination - with an organic oil that blocked them from reacting until illuminated with ultraviolet light.

The researchers used engineered immune system proteins, called monoclonal antibodies, made to home in on proteins known to be overactive in tumor cells.

When the light unblocked the organic coating cloaking the antibodies, the antibodies switched on and attracted killer T-cells to attack the tumor, said Colin Self, a researcher at Newcastle University, who leads the work with Dr Stephen Thompson.

The technique can help prevent damage to healthy tissue because the antibodies lie dormant in the body until lit up.

"What happens in cancer is the body can't mount a response to cure cancer," he said. "This is a way of waking the system up. The antibodies will have their local effect but the hope in all of this is you are bringing in the whole immune system."

So far there are about 20 approved monoclonal antibody-based drugs used to fight cancer and other diseases. The technique could work with any of these to fight a whole range of cancers, so long as doctors are able to find a way to shine a light on the tumors, Self said.

"You are getting a double whammy," he said. "A stronger effect and you can direct the antibody."

While the studies show promise, the technique is years away for human use and faces a long regulatory road and tough clinical trials before any approval, said David Glover, an independent pharmaceutical consultant. "There are a lot of hurdles ahead," Glover told a news conference. "We do not want people to think there is a magic bullet right around the corner.

The next step is initial clinical trials in skin cancer patients, which Self said he hoped to begin early in 2008 provided he could find funding for the research.

Published November 30, 2007 in the journal ChemMedChem.


Picking the Rotten Fruit of Cancer Cells

Cancer cells, like ripe fruit, are much softer than healthy cells, a finding that could help doctors diagnose tumors and figure out which might be the deadliest.

Researchers used a nanotechnology device called an Atomic Force Microscope that allowed them to give a little poke to healthy cells and cancerous cells that have spread from the original site of tumors.

Cancer cells taken from people with pancreatic, breast and lung tumors were more than 70 percent softer than benign cells.

"The bottom line is now we can feel the cancer cells with this technology, in addition to looking at them and analyzing them in a molecular way," says Jianyu Rao of the Jonsson Cancer Center at the University of California at Los Angeles.

The technique may represent a new method for detecting cancer, particularly in cells from body cavity fluids for which conventional diagnostic methods miss about 30 percent of cases.

If this fluid could be swiftly and accurately tested for the presence of cancer cells, doctors could make better decisions about how aggressively a patient should be treated or if any treatment is appropriate at all, the researchers said.


Published October, 2007 in the journal Nature Nanotechnology.