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Week Ending FRIDAY February 11, 2011---------News Archive

Fetal Spina Bifida Surgery - A Chance to Walk

Myelomeningocele is the most serious form of spina bifida, a condition in which the spinal column fails to close around the spinal cord and the cord protrudes through an opening in the spine.


Figure 1. Prenatal Repair of Myelomeningocele

Presentations each year at the Society for Maternal-Fetal Medicine's (SMFM) annual meeting, The Pregnancy Meeting ™, represent major findings in reducing high-risk pregnancies and complications.

More than two thousand physicians, some of the top obstetric and gynecologists in the world who specialize in maternal-fetal medicine, especially high risk pregnancies, gathered for their annual meeting in San Francisco to begin four days of intensive research presentations.

Catherine Y. Spong, M.D., chief, pregnancy and perinatology branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, discussed the government study that she co-authored, "Management of Myelomeningocele Study" (MOMS) at the SMFM annual meeting. An article on the study appeared today in the New England Journal of Medicine.

The $22.5 million study looked at the benefits of a surgical procedure used to repair this common defect of the spine while the baby is still in the uterus. The findings reported that the procedure greatly reduced the need to divert, or shunt, fluid away from the brain.

The surgical procedure consists of closing an opening at the back of the fetal spine, which is a departure from the traditional approach of operating on the infant after birth.

The fetal procedure increases the chances that a child will be able to walk without crutches or other devices.

"This research is a huge finding for our profession and our patients," stated Joshua Copel, M.D., professor of Obstetrics, Gynecology and Reproductive Science at Yale University. Copel is also president of SMFM and a clinical practitioner in prenatal ultrasound and prenatal therapy.

The study cautioned that there were risks involved and that, because the surgery is highly specialized, it should only be undertaken in facilities with experienced staff.

Infants who underwent the prenatal surgery were more likely to be born premature than were the infants who had the surgery performed after birth. Mothers who underwent the procedure were at risk of a thinning or tearing of the uterus at the incision. In spite of these risks though, children who underwent the prenatal surgery did much better than those who had the surgery after birth.

In fact, the MOMS study, which planned to enroll 200 expectant mothers carrying a child with myelomeningocele, was stopped after the enrollment of 183 women because of the benefits demonstrated in children who underwent the prenatal surgery.

"This study is an indicator of the medical advancements being made in preventing high-risk pregnancies and complications," Copel added.

The study was conducted in partnership with researchers at the Children's Hospital of Philadelphia (CHOP), The UCSF Benioff Children's Hospital at the University of California, San Francisco (UCSF), Vanderbilt University Medical Center in Nashville, and the George Washington University Biostatistics Center in Washington, D.C.

The Society for Maternal-Fetal Medicine (est. 1977) is a non-profit membership group for obstetricians/gynecologists who have additional formal education and training in maternal-fetal medicine. The society is devoted to reducing high-risk pregnancy complications by providing continuing education to its 2,000 members on the latest pregnancy assessment and treatment methods. It also serves as an advocate for improving public policy, and expanding research funding and opportunities for maternal-fetal medicine. The group hosts an annual scientific meeting in which new ideas and research in the area of maternal-fetal medicine are unveiled and discussed. For more information, visit www.smfm.org.

Insecticides Delay Infant Brain Development

The EPA phased out the widespread residential use of chlorpyrifos and other organophosphorus (OP) insecticides in 2000-2001 because of risks to child neurodevelopment. These compounds were largely replaced with pyrethroid insecticides. But the safety of these replacement insecticides had never been evaluated for long-term neurotoxic effects after low-level exposure.

In the first study to examine the effects of these compounds on humans and the first evaluation of their potential toxicity to the developing fetal brain, scientists found a significant association between piperonyl butoxide (PBO), measured in personal air collected in the third trimester of pregnancy, and delayed mental development of children at 36 months.

Findings from the study are online in the journal, Pediatrics.

The study was conducted with pregnant women participating in a longitudinal study of black and Dominican women living in upper Manhattan and the South Bronx, by the Columbia Center for Children's Environmental Health (CCCEH).

The insecticide permethrin was selected for evaluation because it is one of the most common insecticides used in U.S. homes. PBO, a chemical that is added to insecticides, was also selected for evaluation. Any detection of PBO in air is a marker of a pyrethroid insecticide application.

In all, 342 women were studied for permethrin exposure in personal air during pregnancy; 272 for permethrin in maternal and umbilical cord blood; and 230 were evaluated for exposure to PBO. To collect the air samples, CCCEH Mothers wore a small backpack holding a personal ambient air monitor for 48 hours during their third trimester.

The children of these mothers were evaluated for cognitive and motor development at age three. CCCEH researchers used the Bayley Scales of Infant Development. In evaluating the results, researchers controlled for gender, gestational age, ethnicity, maternal education and intelligence, quality of the home environment, and prenatal exposure to environmental tobacco smoke and chlorpyrifos.

PBO was detected in the majority of personal air samples (75%). While the results demonstrate that a significant prenatal exposure to permethrin in personal air and/or plasma (blood) was not associated with performance scores for the Bayley Mental Developmental Index or the Psychomotor Developmental Index at 36 months, children who were more highly exposed to PBO in personal air samples scored 3.9 points lower on the Mental Developmental Index than those with lower exposures.

"This drop in IQ points is similar to that observed in response to lead exposure," said Megan Horton of the Mailman School of Public Health and lead researcher. "While perhaps not impacting an individual's overall function, it is educationally meaningful and could shift the distribution of children in the society who would be in need of early intervention services".

The researchers point out that environmental and biological monitoring of pyrethroid insecticides present certain challenges.

"We know most pyrethroid insecticides are difficult to measure in the air because they are not volatile and are difficult to measure in bodily fluids because they are rapidly metabolized, and these difficulties may prevent us from seeing significant associations with neurodevelopmental outcomes," noted Dr. Horton. "Because PBO is volatile and permethrin is not volatile, we would not expect to find a strong association between the two compounds. With the exception of the increased odds of motor delay in the lowest PBO exposure group, prenatal exposure to PBO seems to have an impact on cognitive rather than motor development, which is quite worrisome because mental development scores are more predictive of school readiness."

As this is the first study of these compounds, the results should be considered preliminary but, Dr. Horton notes, they do raise a cautionary red flag about the use of these chemicals during pregnancy.

And, she adds, research at the Columbia Center for Children's Environmental Health, indicates that "integrated pest management and the non-spray application of lower toxicity pesticides are viable alternatives to the use of these spray pesticides for pest control."

"This is an important study with potentially broad public health implications," according to Dr. Robin Whyatt, Mailman School professor of clinical environmental health sciences and a co-deputy director at the CCCEH. "Further, it identifies a critical need for additional research."

The Columbia Center for Children's Environmental Health (CCCEH) carries out community-based research in northern Manhattan and the South Bronx to examine the health effects of prenatal and early postnatal exposures to common urban air pollutants, with the aim of preventing environmentally related disease in children.

The Mailman School of Public Health was founded in 1922 as one of the first three public health academies in the nation, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health, please visit www.mailman.columbia.edu


THURSDAY February 10, 2011---------News Archive

Omega 3's Build Eyes and Brains

Study reveals how Omega3s work in preventing several forms of blindness Omega-3 fatty acids - fats commonly found in fish oil - were shown several years ago to prevent retinopathy, a major form of blindness, in a mouse model of the disease.

A follow-up study, from the same research team at Children's Hospital Boston, now reveals exactly how omega-3's provide protection, and provides reassurance that widely used COX-inhibiting drugs like aspirin and NSAIDs don't negate their benefit.

The findings, published in the February 9th issue of Science Translational Medicine, also suggest that omega-3's may be beneficial in diabetes.

Retinopathy - an eye disease caused by the proliferation of tortuous, leaky blood vessels in the retina - is a leading cause of blindness, affecting 4.1 million Americans with diabetes (a number expected to double over the next 15 years) and many premature infants. Another 7 million-plus Americans have age-related macular degeneration (AMD); this too will increase as the population ages. The most common "wet" form of AMD is also caused by abnormal blood vessel growth.

The ability to prevent these "neovascular" eye diseases with omega-3 fatty acids could provide tremendous cost savings, says Children's ophthalmologist Lois Smith, MD, PhD, senior investigator on the study.

"The cost of omega-3 supplementation is about $10 a month, versus up to $4,000 a month for anti-VEGF therapy," she says, referring to drugs such as Macugen and Lucentis used in AMD and diabetic retinopathy. "Our new findings give us new information on how omega-3s work that makes them an even more promising option."

Omega-3 fatty acids, highly concentrated in the retina, are often lacking in Western diets, which tend to be higher in omega-6 fatty acids. In Smith's previous study, mice fed diets rich in omega-3 fatty acids by Smith's team had nearly 50 percent less pathologic vessel growth in the retina than mice fed omega-6-rich diets. Smith and colleagues further showed that the omega-3 diet decreased inflammatory messaging in the eye.

In the new study, they document another protective mechanism: a direct effect on blood vessel growth (angiogenesis) that selectively promotes the growth of healthy blood vessels and inhibits the growth of abnormal vessels.

In addition, Smith and colleagues isolated the specific compound from omega-3 fatty acids that has these beneficial effects in mice (a metabolite of the omega-3 fatty acid DHA, known as 4-HDHA), and the enzyme that produces it (5-lipoxygenase, or 5-LOX). They showed that COX enzymes are not involved in omega-3 breakdown, suggesting that aspirin and NSAIDs - taken by millions of Americans -- will not interfere with omega-3 benefits.

"This is important for people with diabetes, who often take aspirin to prevent heart disease, and also for elderly people with AMD who have a propensity for heart disease," says Smith. (One drug used for asthma, zileuton, does interfere with 5-LOX, however.)

Finally, the study demonstrated that 5-LOX acts by activating the PPAR-gamma receptor, the same receptor targeted by "glitazone" drugs such as Avandia, taken by patients with type 2 diabetes to increase their sensitivity to insulin. Since these drugs also increase the risk for heart disease, boosting omega-3 intake through diet or supplements might be a safer way to improve insulin sensitivity in patients with diabetes or pre-diabetes. "There needs to be a good clinical study in diabetes," Smith says.

Smith works closely with principal investigators at the National Eye Institute who are conducting an ongoing multicenter trial of omega-3 supplements in patients with AMD, known as AREDS2. The trial will continue until 2013. An earlier retrospective study, AREDS1, found higher self-reported intake of fish to be associated with a lower likelihood of AMD.

In addition, Smith is collaborating with a group in Sweden that is conducting a clinical trial of omega-3 fatty acids in premature infants, who are often deficient in omega-3. That study will measure infants' blood levels of omega-3 products and follow the infants to see if they develop retinopathy. If results are promising Smith will seek FDA approval to conduct a clinical trial in premature infants at Children's.

Meanwhile, in her lab work, Smith plans to continue seeking beneficial lipid pathways, while looking for the most harmful omega 6 metabolites. "We found the good guys, now we'll look for the bad ones," says Smith. "If we find the pathways, maybe we can selectively block the bad metabolites. We would hope to start with drugs that are already available."

Przemyslaw Sapieha and Andreas Stahl in Smith's lab were co-first authors on the study. Funders include the National Eye Institute, the Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center, Research to Prevent Blindness, the Alcon Research Institute, MacTel Foundation, the Roche Foundation for Anemia Research and the V. Kann Rasmussen Foundation.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community.

Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 392-bed comprehensive center for pediatric and adolescent health care. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's visit: Vector Blog.

Women In Labor Use 30% Less Analgesic If Self-Administered

In a study to be presented today at the Society for Maternal-Fetal Medicine's (SMFM) annual meeting, The Pregnancy Meeting ™, in San Francisco, researchers will present findings that show that when women administer their own patient-controlled epidural analgesia (PCEA) instead of getting a continuous epidural infusion (CEI) they used less analgesic, but reported similar levels of satisfaction.

Women often receive a continuous epidural infusion of analgesic during labor. This can lead to prolonged labor and an increase in assisted vaginal delivery. Several pain management studies have been done to begin looking at how much analgesia women use and what their pain experience is like when they are able to administer it themselves.

"We conducted the first double blind study, excluding inductions and including only women who were delivering for the first time, so that we could get a good sample of women with similar labor patterns," said Michael Haydon, M.D., one of the study's authors.

The study was a double-masked trial in which 270 women who had never having given birth (nulliparous) were randomized to one of three groups. In group 3 a PCEA bolus button was given to each subject and the pump acknowledged the request regardless of the woman's group assignment. The primary outcome followed was the amount of local anesthetic used. Secondary outcomes measured included obstetric outcomes and maternal satisfaction.

The study concluded that PCEA resulted in 30 percent less analgesia being used while maintaining high maternal satisfaction. There was also a trend toward reduction in instrumented vaginal deliveries in the PCEA only group.

"Though patients in each group showed equal satisfaction, we did note that there was more pain during the final delivery stage in the PCEA group," said Haydon. "The next step is to look at shortening the lock-out intervals between doses, or having the option of administering additional analgesia during the final pushing stage."

Haydon also noted that, in future, he expects the technology to move in the direction of automated analgesia delivery in response to patient need.

The Society for Maternal-Fetal Medicine (est. 1977) is a non-profit membership group for obstetricians/gynecologists who have additional formal education and training in maternal-fetal medicine. The society is devoted to reducing high-risk pregnancy complications by providing continuing education to its 2,000 members on the latest pregnancy assessment and treatment methods.

It also serves as an advocate for improving public policy, and expanding research funding and opportunities for maternal-fetal medicine. The group hosts an annual scientific meeting in which new ideas and research in the area of maternal-fetal medicine are unveiled and discussed. For more information, visit www.smfm.org.


WEDNESDAY February 9, 2011---------News Archive

Aging, Chronic Disease and Telomeres Are Linked

Those of us with many birthdays under our belts may look spry on some days and appear haggard on others, but is there any gauge for how well we really are aging within?

Elizabeth Blackburn, PhD, is not ready to predict how long you will live. But she and her University of California San Francisco - UCSF - colleagues are exploring a feature within cells that is a kind of hourglass. While the hourglass appears to mark cellular aging, she says that we may also be able to turn it upside down.

Within cells, it’s not sand, but rather DNA that is gradually slipping away. The DNA hourglass runs at different rates for different people. Sometimes it runs at different rates within the same individual at different times. And surprisingly, in some cells, in some people, this hourglass may defy time for a spell, running backward with the aid of a key enzyme.

Blackburn is optimistic that we may derive health benefits from medical tests and, perhaps, treatments based on discoveries stemming from this bit of DNA – called the telomere – and the enzyme that acts on it.

Telomeres are attached to the ends of all 46 chromosomes in all of our cells. Once telomeres become too short, cells can no longer multiply to replenish body tissues. The progressive shortening of this chromosome-capping, protective bit of DNA now appears to be associated with risk for certain chronic diseases. Studies even show that people with longer telomeres are more likely to live longer and, arguably even more significantly, to have more years of healthy life.

Already, over the past decade, Blackburn’s research group and others have found links between shorter telomeres and risks for cardiovascular disease, diabetes, some cancers, depression, pulmonary fibrosis, vascular dementia, osteoarthritis and osteoporosis.

“More and more, we are thinking about how telomeres and their maintenance are involved in issues of human health,” Blackburn said during a January 4 seminar talk at UCSF’s Mission Bay campus.

Twenty-six years ago, Blackburn, who was then at UC Berkeley, and her then graduate student Carol Greider, now at Johns Hopkins University, discovered a new enzyme that they named telomerase. When active in cells, telomerase can lengthen telomeres and prevent chromosomes from being whittled down as cells repeatedly divide to replenish their numbers.

A little bit of telomerase activity may promote the health of certain types of cells. On the other hand, while the resulting longer telomeres in normal cells of the body help reduce the chances that one will get certain cancers, telomerase becomes abnormally active in well-established tumors. This superactivated telomerase helps the already aberrant tumor cells become immortal.

For their discovery of telomerase and their studies of telomeres, Blackburn and Greider shared the 2009 Nobel Prize in Physiology or Medicine with another telomere researcher and collaborator with Blackburn, Jack Szostak of Harvard Medical School.

Today, drugs that target tumor cells by blocking their abnormally high levels of telomerase already are in clinical trials. Telomeres and telomerase also remain a focus of research aimed at deepening scientific understanding of aging, stress and chronic disease.

There is even an over-the-counter telomerase activator on the market, called TA-65, licensed by T.A. Sciences from Geron. But for now, any health benefits it might provide remain unproven.

Blackburn’s University research program has broadened, and now ranges from getting at the nuts and bolts of why the status of telomeres is important at the cellular level to measuring telomere maintenance in humans and looking for new associations with disease risk.

Blackburn and her colleagues are studying telomere length and telomerase activity in cells of the human immune system. New immune cells are generated throughout our entire lives. Because they are blood cells, they are the easiest to obtain for clinical telomere research. Blackburn’s research is strengthening evidence that the maintenance of telomere length – and a bit of telomerase activity – is associated with better health.

Seminal research by Blackburn and UCSF scientist Elissa Epel, PhD, first showed a link between chronic psychological stress and telomere maintenance capacity. In their initial study of caregiver mothers of chronically ill children and control mothers of healthy children in 2004, perceived psychological stress – and the number of years of caring for their chronically ill children – was associated with shorter telomere length and less telomerase activity in these mothers, providing the first indication that stress may have an impact on telomere maintenance.

Turning Back Telomere Time?
Can we take actions that will make our telomeres grow longer? Research reported by Blackburn and colleagues over the past few years indicates that we can.

First, telomeres are not always destined to shorten. They can even grow longer over time. For example, Blackburn and a UCSF research team led by cardiologist Mary Whooley, MD, found in a study of 608 elderly men and women with heart disease that nearly one-quarter of participants had telomeres that lengthened over five years of study.

However, being older, being male and being obese were associated with a greater likelihood that one’s telomeres would shorten.

Will telomere lengthening itself be what may make us healthier? Blackburn says that’s less clear. It is a reasonable hypothesis and there are data to support it, she says. But Blackburn wants to understand for certain the extent to which changes in telomere length are merely consequences of the internal processes driving biological aging, as opposed to these changes in telomeres more directly driving aging and the development of chronic disease. To find out, she and her colleagues are now engaged in interventional studies.

For example, in a three-month, preliminary study of 30 men ages 49 to 80 with low-risk prostate cancer, Blackburn, along with a team led by UCSF preventive medicine researcher Dean Ornish, MD, and UCSF Department of Urology Chair Peter Carroll, MD, MPH, found that comprehensive lifestyle changes – a healthy diet, stress management and exercise – increased telomerase activity.

In another Blackburn-Epel collaboration, UCSF researchers found that vigorous exercise seems to protect people under high stress from the same degree of telomere loss that they might otherwise experience.

Blackburn, Epel and UCSF mental health researcher Owen Wolkowitz, MD, were among the researchers who conducted another recent study, which found that participants who completed a three-month meditation retreat – compared with people on a waiting list –had a greater sense of purpose and control and reduced neuroticism. The magnitudes of positive changes by these measures were proportionately associated with increased telomerase activity.

Omega-3 fatty acids found in fish oil – specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – also may influence telomere length. In the same elderly, coronary artery disease patients studied by Whooley, the researchers found that a higher level of these fatty acids in one’s cells at the beginning of the study was associated with a greater likelihood that one’s telomeres would be better maintained – and even lengthen – in the next five years.

Blackburn and her colleagues are actively following up on these intriguing observational studies. Will lengthening telomeres or boosting telomerase activity in immune cells stop chronic disease? “We have to be wary about saying that,” Blackburn cautions. Associations do not demonstrate causality, although research findings to date have been encouraging, she says.

Blackburn’s research on telomere length and human disease is exploding. No longer limited to smaller studies, her lab team now is collecting telomere data on close to 100,000 people. This endeavor is part of an extensive research collaboration between Kaiser Permanente of Northern California and UCSF. During the two-year project – led by Catherine Schaefer, PhD, director of the Kaiser Permanente Research Program on Genes, Environment and Health, and by Neil Risch, PhD, director of the UCSF Institute for Human Genetics – researchers are scanning the genomes of members of Kaiser Permanente Northern California.

The wealth of genomic and telomere data obtained will be coupled with a rich and continually expanding Kaiser research resource that includes long-term medical records, augmented by already-collected survey data and information on environmental exposures that may pose health risks.

With these data, Blackburn expects to be able to identify additional associations between telomere length and disease incidence and outcome. Exploring links between depression and telomere length will be an early focus for Blackburn and colleagues. In addition, it should be possible to identify human genetic variations that affect telomere length. Already, researchers have found that at least 350 of the 6,000 genes in baker’s yeast affect telomeres, Blackburn said during her seminar talk.

Previously, it would not have been possible to measure telomere length in so many human samples in any reasonable time frame. But Blackburn’s lab team has painstakingly developed automated techniques to analyze thousands of samples per day in her University lab. The researchers expect to measure average telomere length in all samples in the study over the next few months, before the rest of the key genetic data has been completely collected.

It’s now been almost a decade since Blackburn first started collaborating on telomere research focused on human health outcomes to complement her lab studies of fundamental cell biology. But now she means to ensure that her discoveries find practical application, in part by starting a new company.

Blackburn, Epel, Blackburn lab researcher Jue Lin, PhD, and leading telomere researcher Calvin Harley, PhD – former chief scientific officer of Geron – are diving deeper into the personalized medicine field with a Bay Area startup called Telome Health, Inc. The company aims to develop and bring to market diagnostics and health monitoring based on telomere and telomerase measures. The purpose is to track health and to predict disease risk and treatment response. Other startup companies focused on telomeres also have launched in the past year.

Aging Cells, Aging Selves
While some telomere research may be ripe for commercialization, there is still a great deal to be learned from studying simple cells in simple organisms, Blackburn says. Blackburn’s own early research is a testament to the fact that some of the most important biological discoveries – and their eventual applications – are unanticipated.

Biologists have long pondered and pursued the causes of aging. Telomere research helps advance the idea that cellular aging may play a strong role in pacing the aging of the whole organism.

Long after James Watson and Francis Crick, and others in their wake, began unraveling the structure of the DNA double helix, the secrets of heredity and the mysteries of how DNA replicates as cells divide, scientists still had not identified molecular equipment that was capable of replicating DNA all the way out to the tips of chromosomes.

A little bit of DNA is lost from telomeres with each cell division. DNA in telomeres consists of the same, short sequence of nucleotide building blocks – in humans, it is TTAGGG – repeated over and over. The number of repeats can vary. The DNA in telomeres doesn’t encode vital genetic information. Instead, the telomere serves as an assembly point for a suite of proteins that help form protective end caps on the chromosome – like the aglets at the tips of your shoelaces. Some of this DNA is expendable.

But eventually, one would expect that the telomere would be used up. Important genomic DNA would then be lost. Blackburn decided to study telomeres – not in humans, but in a much simpler creature, a one-celled, pond-dwelling protozoan called Tetrahymena thermophila. The protozoan is so simple, it can be used to learn about biological chains of events so basic to life that they are found in life forms ranging from humans to the simplest one-celled organisms.

Blackburn wanted to know how single-celled Tetrahymena could keep reproducing without eventually going extinct due to a loss of genes. The answer – discovered by Blackburn and Greider – turned out to be telomerase. This strange enzyme is made up not only of protein, but also RNA. The RNA acts as a template for adding telomere DNA onto the chromosome tips, and may play other important roles as well. Blackburn’s lab team and others have shown that humans with inborn defects in this RNA component of telomerase have shorter telomeres.

Blackburn and others also use another one-celled organism as a model in which to study telomeres and telomerase – the baker’s (and brewer’s) yeast Saccharomyces cerevisiae. Yeast normally can keep dividing indefinitely, with a mother cell budding off successive generations of daughter cells, in a way that’s similar to what a human stem cell does. If loss of telomeres or telomerase within cells is directly implicated in human aging, the insight into the biological mechanisms responsible might come from yeast.

In early yeast studies, researchers found that eliminating the gene for telomerase limited the number of cell divisions to about 50. But even before telomeres become too short and cells predictably stop dividing, the dividing yeast cells begin to face other challenges.

About one in 1,000 to one in 10,000 telomerase-deprived yeast cells experience a catastrophic event – such as the fusing of normally separate chromosomes during cell division. Even cells with short telomeres can be protected from these catastrophic events with a small bit of telomerase activity, Blackburn found with her then UCSF graduate student Simon Chan, now at UC Davis.

Successful cell division, involving the replication and pulling apart of DNA and chromosomes and a divvying up of genetic and other cellular material between mother and daughter cells, is an immensely complex event in the life of a cell, orchestrated by a multitude of molecular players and directors. Evidence for the importance of telomerase in cell division is growing.

Cell division without error cannot be taken for granted. Successive generations of tumor cells within many cancers become increasingly abnormal, in part, due to faulty cell division, which can sometimes allow genetic errors to accumulate.

More subtle problems with cell division in a significant portion of noncancerous cells might contribute to compromised cellular functioning – and aging – long before any absolute limit on the cells’ ability to divide is reached.

Blackburn has found that something within yeast cells that have short telomeres often triggers delays in the movement of the cells through the stages of cell division. This discovery greatly interested many of the young scientists who attended Blackburn’s seminar.

“Yeast gives us very important insights to this day,” Blackburn said. “There is so much we still don’t understand.”

One of the biggest questions confronting the field of stem cell science is whether iPS cells - stem cells created by reprogramming adult cells - are the equal of the field’s gold standard, human embryonic stem cells (hESCs).

Now, a team of Harvard Stem Cell Institute (HSCI) researchers, in collaboration with scientists at Columbia University Medical Center, have demonstrated that many iPS cells are, in fact, the equal of hESCs in creating human motor neurons, the cells destroyed in a number of neurological diseases, including Parkinson’s.

Another HSCI group, working with the Broad Institute of Harvard and MIT, has produced a simple, quick method for testing the equivalency of iPS cell lines with human embryonic stem cells.

This group, led by Professor Alex Meissner of HSCI, Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), and the Broad, conducted a genomic analysis of 20 commonly used hES cell lines - 17 from Harvard and three from the University of Wisconsin - and created “epigenetic and transcriptional reference maps” for them.

The study, which was published by the journal Cell, then compared a dozen iPS cell lines, derived by the team of Professor Kevin Eggan at HSCI and SCRB, with the 20 hESC lines, and found that the 12 iPS cell lines showed a pattern of variation similar to that of the reference embryonic stem (ES) cells.

“The reference maps provided us the necessary understanding of the range of variation that is found between pluripotent cells,” Meissner said. “This means that when someone now creates an iPS line, they can compare it to what the map shows and see if it falls within the expected range, and, if it doesn’t, where it doesn’t.”

Doug Melton, co-director of HSCI and co-chair of SCRB, said the two “papers represent further advances in studies on ES and iPS cells, showing how careful and thorough characterization of cell lines enables one to effectively use these stem cells for studies on human development and disease.

The advance here is to use a detailed molecular characterization (transcription analysis and DNA methylation patterns) to find a signature, or scorecard, for cell lines. It is impressive to see two labs collaborate so effectively to take on such large and important projects.”

The 12 iPS cell lines used by Meissner were part of a set of 16 created by Eggan’s team and his collaborators at Columbia.

In a study published in Nature Biotechnology, the Eggan group reported that “all 16 lines were turned into motor neurons and were usable. Some needed more ‘coaxing’ than others,” Eggan said, “ but the main message is that, on average, iPS cell lines behaved as well as human embryonic stem cell lines.”

Meissner said Harvard has applied for a patent on the new cell characterization method.

“When you generate iPS cell lines, you have to put them through assays to make sure they are pluripotent,” which means they can develop into any cell type in the body. “The current test in humans generally involves generating a teratoma, a germ cell tumor, and that can take two months. This new test is a much more accurate predictor of pluripotency, and is easy to scale up to test millions of cell lines quickly,” Meissner said.

Postdoctoral fellow Christoph Bock of the Meissner lab was the first author on the Cell paper, and Gabriella L. Boulting of the Eggan lab was first author on the paper in Nature Biotechnology.


TUESDAY February 8, 2011---------News Archive

Conceptualizing Cancer Cells As Ancient 'Toolkit'

Despite decades of research and billions of dollars, cancer remains a major killer, with an uncanny ability to evade both the body’s defenses and medical intervention. Now an Arizona State University scientist believes he has an explanation.

Making physics a weapon in war on cancer

“Cancer is not a random bunch of selfish rogue cells behaving badly, but a highly-efficient pre-programmed response to stress, honed by a long period of evolution,” claims professor Paul Davies, director of the BEYOND Center for Fundamental Concepts in Science at ASU and principal investigator of a major research program funded by the National Cancer Institute designed to bring insights from physical science to the problem of cancer.

In a paper published online Feb. 7 in the UK Institute of Physics journal Physical Biology, Davies and Charles Lineweaver from the Australian National University draw on their backgrounds in astrobiology to explain why cancer cells deploy so many clever tricks in such a coherent and organized way.

Upper row shows a normal breast cell with a smooth nuclear membrane of regular shape.
Bottom row shows an aggressive breast cancer cell with a distinctively irregular nucleus and overall shape.
Left column: whole cell, cytoplasm appearing as a gray haze.
Middle column: naked nuclear membrane
Right column shows density variations in the nuclear DNA.
(Image courtesy of Vivek Nandakumar, Center for Biosignatures Discovery Automation, Biodesign Institute, Arizona State University)


They say it’s because cancer revisits tried-and-tested genetic pathways going back a billion years, to the time when loose collections of cells began cooperating in the lead-up to fully developed multicellular life. Dubbed by the authors “Metazoa 1.0,” these early assemblages fell short of the full cell and organ differentiation associated with modern multicellular organisms – like humans.

But according to Davies and Lineweaver, the genes for the early, looser assemblages – Metazoa 1.0 – are still there, forming an efficient toolkit. Normally it is kept locked, suppressed by the machinery of later genes used for more sophisticated body plans. If something springs the lock, the ancient genes systematically roll out the many traits that make cancer such a resilient form of life – and such a formidable adversary.

“Tumors are a re-emergence of our inner Metazoan 1.0, a throwback to an ancient world when multicellular life was simpler,” says Davies. “In that sense, cancer is an accident waiting to happen.”

If Davies and Lineweaver are correct, then the genomes of the simplest multicellular organisms will hide clues to the way that cancer evades control by the body and develops resistance to chemotherapy. And their approach suggests that a limited number of genetic pathways are favored by cells as they become progressively genetically unstable and malignant, implying that cancer could be manageable by a finite suite of drugs in the coming era of personalized medicine.

“Our new model should give oncologists new hope because cancer is a limited and ultimately predictable atavistic adversary,” says Lineweaver. “Cancer is not going anywhere evolutionarily; it just starts up in a new patient the way it started up in the previous one.”

The authors also believe that the study of cancer can inform astrobiology. “It’s not a one-way street,” says Davies. “Cancer can give us important clues about the nature and history of life itself.”

The Molecule That Underlies Human Deafness

New research from the University of Sheffield has revealed that a novel molecular mechanism that underlies deafness is caused by a mutation of a specific microRNA called miR-96. The discovery could provide the basis for treating progressive hearing loss and deafness.

Hair bundle morphology of immature inner hair cells (IHCs) from normal cochlea
Hair bundle morphology of immature inner hair cells (IHCs) from diminuendo mutant mouse cochlea
The research has been published this week in the Proceedings of the National Academy of Sciences journal and was based on studies of mice, which do not normally hear until about 12 days after birth. Prior to this age their immature hair cells must execute a precise genetic program that regulates the development of distinct types of sensory hair cell, namely inner and outer hair cells.

The research team, led by Dr Walter Marcotti, Royal Society University Research Fellow from the University´s Department of Biomedical Science, in collaboration with Professor Karen Steel at the Sanger Institute in Cambridge, discovered that the mutation in miR-96 prevents development of the auditory sensory hair cells.

These cells are located in the inner ear and are essential for encoding sound as electrical signals that are then sent to the brain.

The research teams found that in a strain of mice called diminuendo - which carry a single base mutation in the miR-96 gene - hair cell development is arrested around birth.

The study shows that miR-96 normally regulates hair cell development by influencing the expression of many different genes associated with a wide range of developmental processes at a specific stage.

The researchers discovered that the mutation hinders the development not only of the mechanically sensitive hair bundle on the cell apex but also the synaptic structures at the base that govern transfer of electrical information to the sensory nerves. These new findings suggest that miR-96 is a master regulator responsible for coordinating the development of the sensory cells that are vital to hearing.

Since the mutation in miR-96 is known to cause human deafness and microRNA molecules can be targeted by drugs, the work also raises new opportunities for developing treatments to treat hearing loss.

Dr Walter Marcotti said: "Progressive hearing loss affects a large proportion of the human population, including new born and young children. Despite the relevance of this problem, very little is currently known regarding the genetic basis of progressive hearing loss. Our research has provided new and exciting results that further our understanding of auditory development as well as possible molecular targets for the development of future therapies."

The work was supported by the Royal National Institute for Deaf People (RNID), The Wellcome Trust and the University of Sheffield.

The research paper is entitled miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells


MONDAY February 7, 2011---------News Archive

Native American Children Risk Leukemia Relapse

Research from St. Jude and the Children’s Oncology Group ties the genetic variation characteristic of Native American ancestry to higher odds cancer will return and highlights a strategy to ease the racial disparities in survival

The first genome-wide study to demonstrate an inherited genetic basis for racial and ethnic disparities in cancer survival linked Native American ancestry with an increased risk of relapse in young leukemia patients. The work was done by investigators at St. Jude Children's Research Hospital and the Children's Oncology Group (COG).

Along with identifying Native American ancestry as a potential new marker of poor treatment outcome, researchers reported evidence the added risk could be eliminated by administering an extra phase of chemotherapy.

The study involved 2,534 children and adolescents battling acute lymphoblastic leukemia (ALL), the most common childhood cancer. The work appears in the February 6 advance online edition of the scientific journal Nature Genetics.

The children were all treated in protocols conducted by St. Jude or COG. Although the overall cure rate for childhood ALL now tops 80 percent, and is close to 90 percent at St. Jude, racial and ethnic disparities have persisted. Based on self-declared status, African-American and Hispanic children with the disease have often fared worse than their white and Asian counterparts.

This is the first study to use genomics to define ancestry, rather than relying on self-declared racial or ethnic categories.

"To overcome racial disparity you have to understand the reasons behind it," said Jun Yang, Ph.D., St. Jude Department of Pharmaceutical Sciences assistant member and the study's first author. "While genetic ancestry may not completely explain the racial differences in relapse risk or response to treatment, this study clearly shows for the first time that it is a very important contributing factor."

This study identified a possible mechanism linking ancestry and relapse.

Hispanic patients, who have a high percentage of Native American ancestry, were more likely than other patients to carry a version of the PDE4B gene that was also strongly associated with relapse. The PDE4B variants were also linked with reduced sensitivity to glucocorticoids, medications that play a key role in ALL treatment.

"This is just one example of how ancestry could affect relapse risk," said the study's senior author Mary Relling, Pharm.D., St. Jude Pharmaceutical Sciences chair. "It is likely that many other genes are involved."

Investigators also found ALL patients with greater Native American ancestry who received additional chemotherapy as part of a COG clinical trial benefited more from the extra treatment than other children. "These are important steps on the way to personalized cancer care, whereby treatment can be tailored to provide maximal benefit to patient subgroups, and someday, individual patients," said co-author Stephen Hunger, M.D., University of Colorado professor of pediatrics and chair of COG's ALL committee.

For this study, scientists used a library of 444,044 common genetic variations known as single nucleotide polymorphisms, or SNPs, to search each patient's DNA for evidence linking ancestry and relapse. The study found that cancer was 59 percent more likely to return in patients whose genetic makeup reflected at least 10 percent Native American ancestry.

About 25 percent of patients in this study met the 10 percent threshold. The percentage was highest among the self-reported Hispanic and Native American patients, who have been reported to be at higher risk of relapse.

Native American ancestry identified patients at high risk of relapse missed by current clinical tools, including testing for minimal residual disease (MRD), which measures the cancer cells that survive the initial round of therapy. Relling said additional research is needed to confirm the findings before screening becomes part of clinical care.

This study used advances in high throughput genomic technologies to better understand why cancer treatment sometimes fails and how the failure is related to genetic ancestry.

Unlike previous research that relied on patient self-reports of race and ethnicity and focused on specific populations, this study focused on a group of patients as diverse as the U.S. and representative of the nation's entire ALL population.

The other authors on this paper are Cheng Cheng, Xueyuan Cao, Yiping Fan, Dario Campana, Wenjian Yang, Geoff Neale, Ching-Hon Pui and William E. Evans, all of St. Jude; Meenakshi Devidas, University of Florida; Nancy Cox, University of Chicago; Paul Scheet, University of Texas M.D. Anderson Cancer Center; Michael Borowitz, Johns Hopkins Medical Institute; Naomi Winick, University of Texas Southwestern Medical Center; Paul Martin, Duke University; Cheryl Willman, University of New Mexico Cancer Center; W. Paul Bowman, Cook Children's Medical Center; Bruce Camitta, Medical College of Wisconsin; Andrew Carroll, University of Alabama at Birmingham; Gregory Reaman, Children's National Medical Center; William Carroll, New York University Cancer Institute and Mignon Loh, University of California at San Francisco.

The work was supported in part by National Institutes of Health's National Cancer Institute, National Institute of General Medical Sciences and National Institute of Child Health and Human Development as well as the Jeffrey Pride Foundation, National Childhood Cancer Foundation, CureSearch and ALSAC.

Ranked the No. 1 pediatric cancer hospital by Parents magazine and the No. 1 children's cancer hospital by U.S. News & World Report, St. Jude is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. St. Jude treats more than 5,700 patients each year and is the only pediatric cancer research center where families never pay for treatment not covered by insurance.

CureSearch for Children's Cancer funds the live saving research of the Children's Oncology Group (COG), the world's largest cooperative pediatric cancer research entity. In the United States, 90 percent of children with cancer receive treatment at a COG member hospital.

Johns Hopkins Research Captures Jumping Genes

An ambitious hunt by Johns Hopkins scientists for actively "jumping genes" in humans has yielded compelling new evidence that the genome, anything but static, contains numerous pesky mobile elements that may help to explain why people have such a variety of physical traits and disease risks.

Using bioinformatics to compare the standard assembly of genetic elements - (as outlined in the reference human genome) to raw whole-genome data from 310 individuals, the Johns Hopkins team revealed 1,016 new insertions of RIPs, or retrotransposon insertion polymorphisms - thereby expanding the catalog of insertions that are present in some individuals and absent in others. Their results appeared online October 27 in Genome Research.

Retrotransposons are travelling bits of DNA that replicate by copying and pasting themselves at new locations in the genome. Having duplicated themselves and accumulated over evolutionary history, transposable elements now make up about half of the human genome. However, only a tiny subfamily of these insertions known as LINE-1 (L1) is still active in humans. Line 1 insertions are able to mobilize not only themselves but also other pieces of DNA.

"In any individual, only between 80 to 100 retrotransposons are actively copying and inserting into new sites," says Haig Kazazian, M.D., professor of human genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

"We're not only discovering where they are and who has which ones, but also finding out that they insert with a remarkable frequency: On the order of one in every 50 individuals has a brand-new insertion that wasn't in their parents."

The researchers recognized L1 retrotransposons — distinguishing them from the vast amount of fixed "fossil" transposable elements that litter the genome — because these actively jumping genes are human specific and almost exactly the same in sequence from one person to another.

"Our genome contains around half a million interspersed L1 sequences that have accumulated over evolutionary history, along with over a million more repeats, most of which were mobilized by L1 elements," explains Adam D. Ewing, Ph.D., a postdoctoral fellow in Kazazian's lab.

"Since the vast majority of these are ancestral and therefore common to all humans and even some of our primate relatives, we can ignore them and focus on L1s that contain human-specific characters in their sequences. Those are the actively mobilized elements responsible for considerable genomic diversity among human individuals."

The high frequency of these L1 insertions gives us a better idea about the extent of human diversity, according to Kazazian, whose 22-year focus on retrotransposons seeks to reveal how they alter the expression of human genes.

Just as the structural variants known as single nucleotide polymorphisms (or SNPs, pronounced "snips") serve as markers for various diseases, the hope is that RIPs — which are up to 6,000 times bigger than SNPs, and therefore may have a stronger effect on gene expression — will correlate with disease phenotypes.

"In that same way that someone had to go out and find the SNPs, this study was about finding RIPs that remain active and continue to produce new insertions," Kazazian says. "Now we have the background necessary to begin studies that may correlate these L1 insertions with everything from autism to cancer."

Support for this research came from the National Institutes of Health.

Ewing and Kazazian are the authors of the paper.















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