Week Ending FRIDAY April 24, 2009---------------------------News Archive
Pelvic Floor Disorders May Have Genetic Link
University of Utah researchers have identified a region of the human genome that may contribute to the development of pelvic floor disorders such as pelvic organ prolapse and stress urinary incontinence, according to a study published this week in the American Journal of Human Genetics
Kristina Allen-Brady, Ph.D., and colleagues at the University of Utah School of Medicine departments of biomedical informatics and obstetrics and gynecology analyzed the DNA of 70 women from 32 families with at least two cases of pelvic floor disorders (PFD) and found significant evidence for a gene that predisposes to PFD on chromosome 9.
"PFDs are a major public health concern for women of all ages," says Allen-Brady, research assistant professor of genetic epidemiology in biomedical informatics and lead author of the study. "Previous research has found that women with urinary incontinence are more likely to have family members with incontinence, but the genetic factors that predispose to PFD are not well understood."
An estimated one-third of all U.S. women are affected by some type of PFD, such as pelvic organ prolapse (POP) or urinary incontinence, during her lifetime. The pelvic floor refers to the network of muscles, ligaments, and connective tissues that keeps all of a woman's pelvic organs in place. PFDs occur when these muscles and tissues weaken or are injured. One in nine women will undergo surgery for PFD, and one-third of these women will require repeated surgeries.
Risk factors such as childbirth, increased age, smoking, and obesity may contribute to PFD, but they do not fully explain the development of these disorders. To better understand the genetics of PFD, Allen-Brady and her colleagues identified 32 families which included at least two closely-related female relatives affected by POP. In POP, the uterus, bladder, or other pelvic organ drops down and protrudes abnormally because supporting tissues are weakened.
The researchers studied DNA from a total of 70 women who received treatment, usually surgery, for moderate-to-severe POP. Genetic analysis of this DNA showed significant evidence that genes located in a region of the genome called chromosome 9q21 may be inherited together in related women who have POP
"This is the largest collection of families with POP that has been reported to date," says Allen-Brady. "Although it is premature to suggest that all PFDs have a common genetic predisposition, our study shows significant evidence that the chromosome 9q21 region may be linked to the development of PFD in families where multiple women are affected."
The researchers are in the process of collecting and analyzing DNA from other families that seem to be at high risk for PFDs in order to strengthen their conclusions. Although PFDs are likely a disease caused by both genetic and environmental factors, further evidence that the chromosome 9q21 region is linked to PFD can direct efforts at narrowing down and identifying a gene that is responsible for disease development.
Confirmation of genetic susceptibility could provide insight into the underlying disease process of PFD and potential ways to prevent this common condition.
Allen-Brady's co-authors on this study were Lisa A. Cannon-Albright, Ph.D., senior author and professor of biomedical informatics; Peggy A. Norton, M.D., professor of obstetrics and gynecology and chief of urognyecology; and James M. Farnham, biostatistician, and Craig Teerlink, doctoral student, both of the Department of Biomedical Informatics.
The project was funded by the Eunice Kennedy Shriver National Institute for Child Health and Human Development.
The DNA Proteome
The big challenge in biomedicine is to discover how the pieces responsible for interpreting the humane genome works
The human genome complete sequencing project in 2003 revealed the enormous instruction manual necessary to define a human being. However, there are still many unanswered questions. There are few indications on where the functional elements are found in this manual. To explain how we develop, scientists will have to decode the entire network of biological complexes that regulate development.
One of the biggest challenges is to analyse the key proteins involved in the development of a human being, namely the proteins that bind to DNA. "If the genome provides the recipe to define a human being, the DNA proteins are the "chefs" that cook it", describes Herbert Auer, manager of the Functional Genomics Facility at the Institute for Research in Biomedicine (IRB Barcelona) and co-organizer, together with Erich Grotewold, at the Ohio State University, of the Barcelona Biomed Conference, "The DNA proteome". Invited by IRB Barcelona and the BBVA Foundation, twenty-one authorities in the field of genomics present their recent work on 20, 21 and 22 April at the "Institut d’Estudis Catalans", in Barcelona.
Thomas Gingeras, from Cold Spring Harbor, and Michael Snyder, from Yale University, both at US, explain today in press conference that "we are at an exciting time in Biology. As Herbert Auer suggests we are defining the instructions encoded in the genome. For instance, we can now relate that many mutations found outside the genes are in regulatory regions for genes. This was accomplished by identifying where the regulatory networks are located".
Gingeras and Snyder are both leading scientists involved in the ENCODE project the consortium of the encyclopaedia of DNA elements -, the largest international study being performed today on discovering the functional elements of the human genome. In 2007, ENCODE provided the first surprising data on the elements that form our genome and on its regulation, breaking some of the classical ideas about what genes are like and how they are regulated. In addition, this project has provided a new perspective of "non-coding DNA", that is increasingly being seen as biological important but whose precise functions are still unknown.
Over the last decade, researchers have revealed a very large list of DNA proteins in humans, which amounts to approximately two thousand (there are still many to be discovered). These proteins include transcription factors, chromatin histones responsible for packaging DNA in the nucleus of the cell -, and DNA repair and protective proteins; two thousand components with key functions in the genome, being responsible for preserving, reading and executing instructions from the manual.
Michael Snyder explains that one of the greatest challenges is elucidating the combination of transcription factors that regulate sets of genes, or the so called regulator code. Thousands of transcription factors work together in distinct combinations to regulate thousands of genes. "This combination is only beginning to be elucidated. For example, distinct combinations of three proteins were found to regulate cholesterol metabolism whereas other combination regulate other cellular processes".
The main challenge for researchers is to reveal how these proteins cooperate to perform functions in healthy cells and compare this with what happens in disease and cancer tissues. "Most diseases arise as a result of the incorrect functioning of DNA proteins. For example, cancer is always an error or an accumulation of errors in DNA caused by the improper work of proteins that should protect, repair or read it". According to Thomas Gingeras, determining the interactions and functions of DNA proteins will allow us to understand how many diseases develop, particularly cancer".
To study the parallel activity of so many proteins through the genome, scientists require advanced modelling tools. These tools are associated with systems biology, which involves the "most fascinating" technology available in pioneering laboratories: Next Generation Sequencing, which was developed only three years ago. "Using this technology, we can get detailed maps of the protein complexes that act throughout the entire genome and we can detect those elements that are required in a precise moment for the gene to be expressed", explains Auer, expert in genomic technology at IRB Barcelona.
The power of Next Generation Sequencing is reflected in the following: a single laboratory could obtain in two weeks the same results as the human genome project, "when this project needed ten years of work and the collaboration of hundreds of labs worldwide", emphasizes Auer, who applies this technology at IRB Barcelona.
The Barcelona BioMed Conferences are a series of "think-tank" scientific meetings organized by IRB Barcelona and the BBVA Foundation that bring together leading experts on some of the hottest topics in international biomedical research.
Stem Cell Therapy for Lou Gehrig's Disease
A team of Utahns is collaborating on a stem cell therapy to fight amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease
With $5 million dollars in funding from the National Institutes of Health (NIH), Linda Kelley, Ph.D., director of the University of Utah's Cell Therapy Facility, James Campanelli, Ph.D., of University of Utah spin-out Q Therapeutics, Inc., and Utah native Nicholas Maragakis, M.D., of The Johns Hopkins University School of Medicine, have teamed up to bring the cell-based therapy to the point of human clinical trials to treat this deadly disease. The four-year NIH grant will enable critical manufacturing and testing requirements necessary to gain U.S. Food and Drug Administration approval for human clinical trials.
Kelley, principal investigator on the grant and professor of internal medicine at the University of Utah School of Medicine, said the project is a collaboration in the truest sense. "While the University will be home to the grant, the stem-cell technology that Q Therapeutics brings to the table and the clinical expertise of Dr. Maragakis are essential to the project. We are pleased to help bring this groundbreaking therapy toward human use," Kelley said. "Our collaboration is a terrific example of how public-private partnerships can make innovative therapeutic products a reality."
According to Jack Brittain, University vice president for technology venture development, "The translational research that this funding supports-beyond basic research, but not yet in clinical trials-has been traditionally very difficult to fund. This award validates the approach being taken here at the University of Utah toward emerging technologies, such as regenerative medicine. This kind of collaboration between the University and its commercial spin-out companies is something we strive for and enthusiastically support."
ALS is a progressive neurodegenerative disease that kills certain nerve cells in the brain and spinal cord. As these cells degenerate, they lose the ability to send impulses that control muscle movement for speech, breathing, limb movement, and other functions, with death from respiratory failure typically occurring from two to five years after diagnosis. ALS affects roughly 30,000 people in this country. The cell-based ALS therapeutic originates from research at the University of Utah by Mahendra Rao, M.D., Ph.D., a co-founder of Salt Lake City-based Q Therapeutics, Inc.
"Q Therapeutics is delighted to be working with the University of Utah Cell Therapy Facility and Dr. Maragakis on this groundbreaking project," said Campanelli, senior director of research and development for Q Therapeutics. "The Cell Therapy Facility is one-of-a-kind in the Intermountain West. We are fortunate to be able to work so closely with Dr. Kelley and her team. The close proximity of our two groups has allowed us to readily address manufacturing and processing issues that would have been a challenge to overcome had we needed to go outside Utah."
In bringing together cell therapy and neurology, the collaboration focuses on two of seven life science industry sectors identified by the State of Utah for long-term development. "Given the current economic climate, this type of grassroots effort is critical to both near-term job preservation and long-term development of Utah's life sciences industry," said Jason Perry, executive director of the Governor's Office of Economic Development. "This project is perfectly aligned with the state's targeted economic cluster for the Life Sciences and is a model for public and private collaboration."
Maragakis, a Salt Lake City native and graduate of the University of Utah School of Medicine, added, "This is an important milestone in the development of therapeutics to treat those who suffer with ALS. Given the lack of good treatment alternatives for this fatal disease, this project could lead to a first-in-class therapy that significantly alters the course of disease for many ALS patients." Maragakis and his team of researchers at Johns Hopkins recently published results of their work in ALS in Nature Neuroscience, showing that a specific type of brain stem cell therapy can be effective in an animal model of ALS.
Major Breakthrough in Generating Safer, Therapeutic Stem Cells from Adult Cells
Scientists completely avoid problems of genetic manipulation by instead using chemical programming
The new technique solves one of the most challenging safety hurdles associated with personalized stem cell-based medicine because for the first time it enables scientists to make stem cells in the laboratory from adult cells without genetically altering them. This discovery has the potential to spark the development of many new types of therapies for humans, for diseases that range from Type 1 diabetes to Parkinson's disease.
The study was published in an advance, online issue of the journal Cell Stem Cell on April 23, 2009.
"We are very excited about this breakthrough in generating embryonic-like cells from fibroblasts [cells that gives rise to connective tissue] without using any genetic material," says Scripps Research Associate Professor Sheng Ding, who led the research. "Scientists have been dreaming about this for years."
Normally, cells develop from stem cells into a myriad of increasingly more specialized cell types during early development and throughout a lifetime. In humans and other mammals, these developmental events are irreversible. This means that when tissues are damaged or cells are lost, there is usually no source from which to replenish them. Having a source of the most primitive stem cells available would be useful in many medical situations because these cells are "pluripotent," having the ability to become any of the body's cell typespotentially providing doctors with the ability to repair damaged tissues throughout the body.
However bright this promise, the use of stem cells in medicine has faced many hurdles. One strategy has been to work towards a therapy where doctors could take a patient's own adult cells and "reprogram" them into stem cells. This not only avoids potential ethical problems associated with the use of human embryonic stem cells, it also addresses concerns about compatibility and immune rejection that plague therapies such as organ transplantation.
A few years ago, a team of researchers in Japan made a breakthrough in this general approach by converting mouse skin cells into mouse stem cells. The Japanese team accomplished this remarkable transformation by inserting a set of four genes into these skin cells. While the study was a powerful proof-of-principle, the therapeutic potential of genetically reprogrammed cells is limited because of safety issues. One obvious problem is that the four required genes and their associated foreign DNA sequences permanently reside in the cells when transplanted. Moreover, the specific genes in question are problematic because, in living tissue, they are linked to the development of cancerous tumors.
Many scientists have been trying to find safer ways to generate stem cells from adult cells -- developing methods that require fewer genes, or techniques that can put genes in and then take them out. However, to date all of these have still harbored significant safety concerns due to the nature of the genetic manipulations. Ding and his team previously reported the discovery of drug-like small molecules to replace some of those genes, but have also hoped to go even further and find ways to reprogram adult cells into stem cells without using any genes or genetic manipulations at all.
The team of scientists accomplished this extraordinarily challenging feat by engineering and using recombinant proteins, that is proteins made from the recombination of fragments of DNA from different organisms. Many different recombinant proteins have been therapeutically and routinely used to treat human diseases. Instead of inserting the four genes into the cells they wanted to reprogram, the scientists added the purified engineered proteins and experimented with the chemically defined conditions without any genetic materials involved until they found the exact mix that allowed them to gradually reprogram the cells.
The scientists found that those reprogrammed embryonic-like cells (dubbed "protein-induced pluripotent stem cells" or "piPS cells") from fibroblasts behave indistinguishably from classic embryonic stem cells in their molecular and functional features, including differentiation into various cell types, such as beating cardiac muscle cells, neurons, and pancreatic cells.
Study Challenges Notions of How Genes are Controlled in Mammals
Scientists at the Omics Science Center (OSC) of the RIKEN Yokohama Institute in Japan along with researchers from McGill University and other institutions worldwide are challenging current notions of how genes are controlled in mammals
Three years of intensive research by members of the international FANTOM consortium will culminate with the publication of several milestone scientific papers in Nature Genetics and other journals on April 20.
FANTOM4, the fourth stage of the Functional Annotation of the Mammalian cDNA collaboration, is led by Dr. Yoshihide Hayashizaki of OSC. Dr. Josée Dostie, a biochemist at McGill’s Faculty of Medicine joined the FANTOM4 collaboration in 2007 and is its only Canadian member.
For several years, FANTOM researchers have provided the scientific community with extensive data on the genome of mammals, including detailed information on molecular function, biology and individual cell components. Now, the FANTOM4 stage of the collaboration has culminated in a breakthrough that will alter the way scientists understand transcription, the process of cellular copying and reproduction.
“This study really challenges the way we understand cellular differentiation,” explained Dr. Dostie, who participated in the primary FANTOM4 research and also authored a satellite paper for publication in the journal Genome Biology. “The dogma right now is that there are so-called ‘master regulators,’ a series of protein switches that sit in specific places on the genome and induce genes. This is supposed to lead to a cascade that leads to cellular differentiation.
“The FANTOM4 studies show that this thesis is incorrect and there are no master regulators at all,” she continued. “It’s not like turning everything on like a switch. Instead, it looks like the expression of some genes needs to be decreased while others are increased in a more subtle, but coordinated way.”
FANTOM4 is the first report of a large-scale gene network based on an experimental data-set and is likely to generate considerable excitement in the scientific community. The information is important for life science and medical researchers trying to uncover the processes by which cells undergo conversion or become cancerous. It is also related to controlling the growth and differentiation of stem cells and ensuring their safety for use in regenerative medicine.
“We are proud that we have created groundbreaking research in understanding more about how genes regulate cells at the molecular level and we want to acknowledge all consortium members for their great contribution to the research effort,” said Dr. Harukazu Suzuki, scientific co-ordinator of the FANTOM4 consortium.
THURSDAY April 23, 2009---------------------------News Archive
NIH Stem Cell Guidelines Dismay Leading Stanford Researcher
The director of stem cell research at the Stanford University School of Medicine says he is troubled by draft guidelines issued today by the National Institutes of Health that would prohibit federal funding for research on stem cell lines created through a technique sometimes referred to as “therapeutic cloning” or somatic cell nuclear transfer
Irving Weissman, MD, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, said the SCNT technique is one way to create disease-specific human embryonic stem cell lines on which to conduct research and test therapies. He also took issue with the assertion that the NIH consulted existing guidelines from the National Academy of Sciences and the International Society for Stem Cell Researchboth of which sanction the use of SCNT-derived cell linesin coming up with its draft recommendations.
“Instead of facts, the NIH placed its own version of ethics in place of the president’s clear proclamation,” said Weissman, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research. “As head of the National Academy of Sciences' panel that unanimously endorsed research using SCNT, and as a drafter of the guidelines for the International Society for Stem Cell Research, I know that this suggested ban on federal funding of SCNT-derived human embryonic stem cell lines is against our policies and against President Obama’s March 9 comments. The NIH has not served its president well.”
On March 9, President Barack Obama signed an executive order removing previous restrictions on the use of federal funds for research on any human embryonic stem cell line derived after Aug. 9, 2001. He used the ceremony to remark that it is important to ensure “that scientific data is never distorted or concealed to serve a political agendaand that we make scientific decisions based on facts, not ideology.”
In announcing the draft guidelines, acting NIH director Raynard Kington, MD, PhD, justified the restriction in part by saying that there is a lack of scientific consensus as to the necessity of funding lines derived by SCNT and that, although the technique has been used to create many embryonic stem cell lines in animals, such human embryonic stem cell lines have not yet been documented.
“We believe there is strong, broad public and scientific support for the use of federal funds for research on cell lines from embryos derived through in vitro fertilization for reproductive purposes that would not otherwise be used,” said Kington, noting that similar legislation had twice passed both the House and Senate only to be vetoed by former President George W. Bush. “We do not see similar broad support for using federal funding for research on cell lines from other sources.”
The somatic cell nuclear transfer technique involves removing the nucleus from an egg cell and replacing it with a nucleus from a different cell in order to create an embryonic stem cell line genetically identical to the donor nucleus. In the case of a donor who suffers from a condition like Parkinson’s disease, the SCNT process would yield an embryonic stem cell line that could be used to test specific therapies for that patient.
If the draft guidelines are adopted, they would underscore the continued need for the California Institute for Regenerative Medicine, which has funded grants to several scientists working to create specific human embryonic stem cell lines for research purposes. The institute was established in 2005 by Proposition 71 to counteract the effect of President Bush’s limits on federal funding of such research.
“Methods like SCNT were specifically sanctioned by Prop. 71,” said Geoff Lomax, PhD, the senior officer to the state institute’s Standards Working Group, which was instituted to develop ethical guidelines for the use of embryos in CIRM-funded research. “These potential restrictions on the range of research materials available for federal funding ensure that CIRM will continue to play a unique role in the world of stem cell research.”
“For certain types of research, CIRM could remain very important,” concurred Renee Reijo-Pera, PhD, director of Stanford’s Center for Human Embryonic Stem Cell Research and Education. Reijo-Pera said she had expected the NIH guidelines to be somewhat conservative, particularly where SCNT is concerned.
“I am happy that these are draft guidelines,” said Weissman, who noted that the NIH did not solicit input from either the National Academy of Sciences or the International Society for Stem Cell Research during the consensus process. “I’d like to remind the NIH of the principles enunciated by the president on March 9. Research in this area is moving very fast, and it’s not possible to say whether advances will come from work on adult-derived iPS cells or from embryonic stem cells created by nuclear transfer. Policy needs to be developed as the field develops, rather than precluding something based on ideology.”
The proposed NIH guidelines will be available for public comment for 30 days, and the final guidelines will be released by the agency on or before July 7. They can be viewed at http://stemcells.nih.gov/policy/2009draft. Comments can be mailed, or submitted electronically after the guidelines are published in the Federal Register by April 24.
The Primary Reason for Weight Gain
The first study to document the relative effects of calories from liquids compared with those of calories from solid food on weight loss in adults
Liwei Chen, MD, PhD, Assistant Professor of Epidemiology at the LSU Health Sciences Center New Orleans School of Public Health, is the lead author of a research paper showing that weight gain and obesity are more linked to an increase in liquid calories, particularly sugar-sweetened beverages, than calories from solid food. To our knowledge, this is the first study to document the relative effects of calories from liquids compared with those of calories from solid food on weight loss in adults over an extended period. The study is published in the May 1, 2009 issue of the American Journal of Clinical Nutrition.
The study reports four principal findings: First, a reduction in liquid calorie intake was significantly associated with weight loss at both 6 months and 18 months. Second, the weight-loss effect of a reduction in liquid calorie intake was stronger than that of a reduction in solid calorie intake. Third, a reduction in sugar-sweetened beverage intake was significantly associated with weight loss at both 6 and 18 months. Fourth, no other beverage type was associated with weight change.
It has been projected that 75% of US adults will be overweight or obese by 2015.
"Today, Americans consume 150-300 more calories a day than they did 30 years ago," notes Dr. Chen, "and caloric beverages account for approximately 50% of this increase."
The researchers followed 810 men and women, 25-79 years old, whose 24 hour dietary intake recall was measured by telephone interviews conducted when they entered the study and at 6 and 18 months. Beverages were divided into 7 categories based upon calorie content and nutritional composition.
1. Sugar-sweetened beverages (regular soft drinks, fruit drinks, fruit punch, or any other high-calorie beverage sweetened with sugar)
2. diet drinks (diet soda and other diet drinks sweetened with artificial sweeteners)
3. milk (whole milk, 2% reduced-fat milk, 1% low-fat milk, and skim milk)
4. 100% juice (100% fruit and vegetable juice)
5. coffee and tea with sugar (sweetened with sugar)
6. coffee and tea without sugar (unsweetened or sweetened with artificial sweeteners)
7. alcoholic beverages (beer, wine, spirits, and other alcoholic drinks).
Each participant's daily nutrient, energy, and beverage intakes were calculated by taking the average of 2 recalls per time point. Liquid calorie intake was calculated as the sum of calories from the 7 beverage categories. Solid calorie intake was calculated by subtracting liquid calories from total calories.
The researchers offer a couple of possible explanations for their findings. The absence of chewing when consuming liquids may result in decreased pancreatic responses. Beverages also clear the stomach sooner than solid food and may induce weaker satiety signals in the gastrointestinal tract. "Our study supports policy recommendations and public health efforts to reduce the intake of liquid calories, particularly from sugar-sweetened beverages," concludes Dr. Chen.
Bringing Life to Man-Made Tissues
Using Cotton Candy to Create Routes for Blood-flow
A lollipop at the end of a doctor's visit may ease the sobs of a crying child, but now, researchers hope to use other sugary structures with the hope of healing patients. A team of physicians and scientists from NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City and Cornell University in Ithaca, New York, may have developed a way to create engineered tissue that is better accepted by the body. Currently, engineered tissues are used to take the place of damaged tissue due to injury, burns or from surgical procedures. However, they are limited in size and often die from a lack of blood supply that provides life-giving nutrients.
"For decades, the lack of a suitable blood supply has been the major limitation of tissue engineering," explains Dr. Jason Spector, a plastic surgeon at NewYork-Presbyterian/Weill Cornell and assistant professor at Weill Cornell Medical College. "Without a network of blood vessels, only small, thin swaths of engineered tissue have longevity in the body."
Using crystalline sugar, scientists created a network of tiny tubes to act as tunnels, capable of shuttling nutrition-rich blood between the body's natural tissue and an artificial graft. To create the sugar fibers, researchers at The Cornell NanoScale Science & Technology Facility in Ithaca used a common cotton candy machine. Results from the project have been published in the most recent online issue of the journal Soft Matter.
A polymer is then poured over this matrix. Once hardened, the implant is soaked in warm water, dissolving the sugars, and leaving behind a web of three-dimensional hollow micro-channels. The study is in very early stages and is not yet approved for clinical use. However, promising early findings show that this novel method successfully infuses the implant with life-giving blood. The goal is to allow for the development of larger and more complex implants, fed by a person's own circulatory system.
Collaborators on the project include Drs. Leon M. Bellan and Harold G. Craighead, from the School of Applied and Engineering Physics at Cornell University.
Genetics Mediate Alcohol Vulnerability in Pregnancy
Drinking alcohol during pregnancy can lead to teratogenesis, the development of embryonic defects. The estimated incidence of Fetal Alcohol Spectrum Disorders (FASD), referring to a wide array of alcohol-exposure effects, is approximately one percent of live births in the US. Yet not all women who drink during pregnancy give birth to children with observable deficits. A mouse study has found that genetics may help to explain alcohol-related susceptibility and resistance
Results will be published in the July issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"Alcohol-related deficits include pre and/or postnatal growth retardation, craniofacial anomalies, central nervous system dysfunction, hand or finger malformations, a number of different skeletal malformations, and anomalies in a number of different organ systems, including the brain, eyes, and kidney," said Chris Downing, a research associate at the University of Colorado and corresponding author for the study.
"Some women who drink during pregnancy don't give birth to children with any of these observable deficits, but later on their children develop a number of behavioral deficits including hyperactivity, attention deficits, learning problems, and deficits in impulse control," Downing added. "It is thought that these behavioral deficits are due to brain damage as result of in utero ethanol exposure, but correlating specific behavioral deficits with damage to specific brain areas is a work in progress. In addition, some women who drink during pregnancy have 'normal' children with no obvious deficits."
Downing said that many factors have been shown to play a role in the development of FASD, including the amount, timing and pattern of maternal alcohol consumption, maternal age and parity, maternal ethnicity and socioeconomic status, cultural factors, maternal smoking and other drug abuse, and maternal diet/nutrition. In addition, he said, studies with humans and mice have shown that both maternal and fetal genotypes in conjunction with the environment play a role in susceptibility and resistance to the detrimental effects of in utero alcohol exposure.
"Using mice, we can control for all of these confounding variables," he said. "Within an inbred strain, all mice are virtually genetically identical, greater than 99.9 percent. When one looks at more than one inbred strain of mice, and all mice are housed and treated the same, differences between strains are taken as evidence of a genetic effect."
Downing and his colleagues looked at alcohol teratogenesis in five inbred strains of mice: Inbred Short-Sleep (ISS), C57BL/6J (B6), C3H/Ibg (C3H), A/Ibg (A), and 129S6/SvEvTac (129). Pregnant mice were given either 5.8 g/kg alcohol or maltose-dextrin on day nine (roughly equivalent to days 28-31 of human gestation) of pregnancy. They were subsequently sacrificed on day 18, and their fetuses examined for gross morphological malformations.
The B6 mice that were exposed to alcohol in utero had fetal weight deficits, as well as digit, kidney, brain ventricle and vertebral malformation. In contrast, 129 mice showed no teratogenesis, while the remaining three strains showed varying degrees of teratogenesis.
"In other words, said Downing, "certain strains were sensitive to some effects of prenatal alcohol and resistant to others. The fact that inbred strains differed showed that genetics plays a role."
Downing added that these findings can be extrapolated to humans. "Since genetic effects on prenatal alcohol phenotypes in mice have been demonstrated, and the mouse and human genomes are remarkably similar, it suggests genetics plays a role in humans as well," he said. "Human researchers need to begin to systematically investigate genetic factors mediating susceptibility and resistance to the effects of prenatal alcohol exposure."
Plant-based Flavonoids May Cut Ovarian Cancer Risk
Women who eat greater amounts of plant-based foods and drinks with the naturally occurring flavonoid, apigenin, may have a decreased risk for ovarian cancer, study findings suggest
Apigenin, found in celery, parsley, red wine, tomato sauce, and other plant-based foods may be "particularly beneficial," said Dr. Margaret A. Gates, of Brigham and Women's Hospital and Harvard Medical School, in Boston, Massachusetts.
Flavanoids are compounds with antioxidant properties that protect cells against damage by oxygen molecules. In a study that compared flavonoid intake among women with and without ovarian cancer, women reporting the highest apigenin intake had a "borderline significant decrease" in ovarian cancer risk over women reporting the lowest apigenin intake, Gates and her associates report in the International Journal of Cancer.
"These results are promising," Gates told Reuters Health, "but more research is needed to confirm this association."
The researchers assessed the foods commonly eaten over a one-week period by 1,141 women with ovarian cancer and 1,183 women without.
The women, 51 years old on average, had similar characteristics except those with ovarian cancer reported more known risk factors for the disease and had slightly greater body mass and daily calorie intake. By contrast, the disease-free "controls" had a slightly healthier overall diet.
From the food data, Gate's group calculated the women's intake of 5 common flavonoids -- myricetin, kaempferol, quercetin, luteolin, and apigenin -- frequently obtained by drinking tea or red wine, or eating apples, romaine or leaf lettuce, kale, blueberries, oranges, celery, or tomato sauce.
The investigators found no association between total flavonoid intake and ovarian cancer risk in analyses that allowed for factors potentially associated with ovarian cancer risk such as age, oral contraceptive use, childbirth, breastfeeding, history of tubal ligation, and physical activity.
Only apigenin intake, as noted, was associated with a suggestive decrease in ovarian cancer risk.
These findings, in concert with results of other studies suggesting an inverse association between intake of certain flavonoids and risk of ovarian cancer, highlight the need for further research, Gates and her colleagues suggest.
SOURCE: International Journal of Cancer, April 2009.
WEDNESDAY April 22, 2009---------------------------News Archive
Uncovering the ‘Rules’ That Govern Life Itself
Thierry Emonet was trained as an astrophysicist, but this winter he found himself teaching a Yale class full of biology, computer science, engineering and math students who want to learn how to predict the behavior of living organisms.
The life sciences are undergoing a change as profound as that experienced by astronomy and physics after Galileo and Kepler described how the earth orbits the sun, Emonet told his students in the opening lecture for his "Systems Modeling in Biology" class.
Just as 400 years ago stargazers armed with telescopes described planetary motion in unprecedented detail, today's life scientists are collecting staggering amounts of data, said Emonet, assistant professor of molecular, cellular and developmental biology and physics.
And just as Newton used that data to write the mathematical principles that explained and predicted planetary motion, today's students might soon find the rules which govern life itself, he told his class.
"It may be possible to discover rules governing life processes, just as Newton did with planetary motion,'' he said.
But if this revolution in biology is to take place, he added, experts from a host of academic disciplines will be needed to fully explain the extraordinary complexity of biological processes.
The enormous potential of the field has inspired Yale to offer an increasing number of classes - such as Emonet's systems modeling course that throw together students from a host of different backgrounds.
"Efforts to understand the operations of biological systems will depend upon defining our concepts about these systems as mathematical relationships," says Tom Pollard, Sterling Professor and chair of the Department of Molecular, Cellular & Developmental Biology, and professor of cell biology and of molecular biophysics and biochemistry. "Then we can test these concepts with computers to learn if they explain observations and predict the outcome of future experiments.''
One of the course's teaching assistants, graduate student Michael Sneddon, is an expert in computer science who has had an abiding interest in biology. As an undergraduate at the University of California San Diego, he became an expert at writing code that helped link biological activity and various types of genes. However, Sneddon realized, as many biologists have in the past decade, that the old textbook "cartoon" models of molecular biology, represented by linear one-dimensional arrows showing activation or suppression of proteins, falls woefully short of describing the overwhelmingly complex reality of cellular behavior. A cell's behavior depends not just on which specific genes are active, Sneddon knew, but on the relationship of the proteins they produce in time and space, the biochemical environment in which they exist, and the complex interactions between them.
Engineers have given scientists the tools to collect massive amounts of data, while mathematicians and computer scientists have devised calculations necessary to make the data accessible, notes Sneddon.
"I went from thinking about genes as static lists that have loose correlations to other genes, to thinking about proteins connected together in large networks with dynamic interactions that change and respond in time," he says.
He became interested in the work being done by Emonet, who helped build a mathematical model to account for many of these variables in order to understand how a cell harnesses these diverse forces and moves about in response to chemicals, a process called chemotaxis.
Sneddon says he was enthralled with the idea that such a computer modeling of cellular behavior would allow scientists in a single day to run hundreds or even thousands of virtual experiments, which in turn would lead to even theories to test. He joined Emonet's lab and signed on as his teaching assistant. And in doing so, he notes, he has discovered a new biology problem to work on.
He is teaming up with Jamie Schwendinger and Andrew Lawton, two graduate students in Emonet's class who are interested in the precise timing of the development of somites - i.e., precursors of vertebrae and muscles. Even in a relatively simple organism like the Zebrafish, the intricate molecular dance of interacting proteins is so complex it is difficult to assess the entirety of the process with traditional tools of biology, the students explain, as the "clock mechanism" governing formation of these somites is as intricate as a Swiss watch and much less accessible. The three graduate students will be working to create a computer model to help unravel that complex process.
Schwendinger, who has a background in biochemistry, took Emonet's class because she believes modeling might provide some quantifiable rules that govern the development segments which, growing sequentially, form a spine.
"It has tremendous predictive power. Modeling will help us ask the right questions," she says.
Lawton believes that to pursue a career in biology, "this is something I need to know."
The breadth of knowledge required on this new frontier is reflected in guest lecturers for the class. Lecturing this spring were Yale scientists Steven Zucker, applied math; Simon Mochrie, physics; Xiao-Jing Wang, neurobiology; and Steven Kleinstein, immunology - as well as James Faeder, a computational biologist from the University of Pittsburgh and creator of BioNetGen, a math-based modern language to describe biological processes.
Running experiments on computer screens is exciting, notes Emonet, and has the potential to speed up the pace of research by orders of magnitude. Yet tools of traditional biologists will not disappear, he asserts, as the findings will still need to be tested experimentally against living organisms.
"Scientists like Emonet are on the leading edge of a new era in biology," says Pollard, "where mathematics and computer science will help biologists test with unprecedented rigor their ideas regarding the molecular basis of life."
How Cells Change Gears
Bioinformatics researchers from UC San Diego just moved closer to unlocking the mystery of how human cells switch from “proliferation mode” to “specialization mode.”
This computational biology work from the Jacobs School of Engineering’s bioengineering department could lead to new ideas for curbing unwanted cell proliferationincluding some cancers. This research, published in Nature Genetics, could also improve our understanding of how organs and other complex tissues develop.
The UC San Diego bioengineers are part of a Japan-based global research consortium, the Genome Network Project, which generated one of the first close-to-comprehensive looks at a human cell’s entire network of proteins called “transcription factors.” Each human cell contains approximately 2,000 transcription factors, which are proteins that bind to specific locations on the cell’s DNA. Once bound to DNA, transcription factors work to either encourage or prevent “transcription”the process by which messenger RNA is generated from DNA. These messenger RNA strands then travel to cellular factories called ribosomes which churn out proteins based on the specifications of the mRNA.
“Transcription is one of the most important events in the cell…it determines cell morphology and cell function,” said Timothy Ravasi, a UC San Diego research scientist from the bioengineering department and author on the new Nature Genetics paper.
Researchers have long understood that most transcription factors in human cells do not work alone, but studying the entire network of transcription factors within a cell has been difficult until now. In the new study, the researchers used a series of computational and integrative biology approaches in order to look at how the activity of the network of transcription factors in a myeloid leukemia cell line changes over time.
“Leukemia” refers to a variety of pathologies involving uncontrolled proliferation of white blood cells. Understanding the role of the transcriptional network during differentiation in leukemia cells could offer a glimpse into the cause of leukemia, or offer possible approaches for treating leukemia, according to Ravasi.
During the laboratory phase of the project, researchers introduced a compound that stopped cell proliferation in the myeloid leukemia cell line. Next, they collected as much information as possible regarding the activity of the transcription factor network during the processes of differentiation and maturation into immune cells known as monocytes and macrophages. Computational work performed at UC San Diego after all the laboratory data had been collected allowed the researchers to identify specific subnetworks of transcription factors that were activated at particular time points.
The UCSD researchers were challenged to integrate different but related data sets in order to tease out real signals from noise. This is known as “integrative biology.”
“We take lots of measurements of the same thing…we integrate them together,” which leads to higher confidence in experimental results, Ravasi explained. Measuring both messenger RNA and protein levels, is one example. Detection of both signals provides two independent data points indicating the presence of the same protein.
“Getting to be the first to analyze and make sense of this large and fascinating data set was a huge opportunity,” said Ravasi. The UC San Diego bioinformatics team working on this project included Ravasi and two post-doctoral researchers from Trey Ideker’s bioengineering laboratory, Ariel Schwartz, now at Synthetic Genomics, and Kai Tan, now an assistant professor of internal medicine and biomedical engineering at the University of Iowa.
By monitoring the activity of the transcriptional network one hour after the onset of differentiation, the researchers identified a gene that appears to play an important role in cell differentiation in white blood cells. “It’s a long shot, but if you found a compound that inhibits this gene, you could make the cells begin to differentiate towards a normal monoblast line rather than continue unchecked cell proliferation,” said Ravasi.
Based on the new research, it appears that the network of transcription factors from the human myeloid leukemia cell line is redundant and resilient, explained Ravasi.
The researchers turned-off or “knocked down” 52 transcription factors, one at a time, in order to study their individual role within the network. Most of the single knock-downs did not result in changes to cell differentiation or cell shape.
“The transcriptional network for this cell type appears quite redundant which likely makes the network resilient to mutations or environmental agents that could interfere with transcription factor function,” said Ravasi. “My guess is that we will find similar redundancy in the transcription networks of other cell lines, and in the transcription networks that regulate other aspects of cell function, but we can’t say that from these data.”
Exercise Protects Blood-Brain Barrier
Regular exercise can prevent the disruption of the blood brain barrier that normally occurs with a dose of methamphetamine comparable to that used by heavy meth users.
A University of Kentucky study is the first to look at the protective effects of exercise on the vascular effects of methamphetamine, effects that have been found clinically to contribute to serious, lasting, and sometimes fatal cardiovascular and neurological problems. Results of the study, conducted in young male mice, were reported April 22 at the Experimental Biology 2009 meeting in New Orleans. The presentation was part of the scientific program of The American Physiological Society.
Principal investigator Dr. Michal Toborek says the level of the protective effects of exercise on the integrity of the blood brain barrier after the human equivalent of one gram of methamphetamine was surprising even to the research team.
The results provide new understanding of the mechanisms through which the brain reacts to methamphetamine, particularly those related to oxidative stress. Results also suggest why exercise might help delay the onset of neurodegenerative diseases such as Alzheimer's and Parkinson's in which leakiness of the blood brain barrier is a characteristic.
The researchers placed 25 young male mice aged three months, equivalent to the 20s in humans -- in cages where they had access to exercise wheels. For five weeks, the animals took advantage of the wheels to run continually. Another 25 young mice were housed in similar cages but without access to wheels.
At the end of this "endurance exercise training" period, all mice were injected with 10 mg. of methamphetamine over a 24-hour period. All the mice displayed some of the same effects of meth as seen in humans: they appeared agitated and increased their physical activity, and their body temperature rose. But in terms of what was happening in the capillaries of the brain, there was a marked difference between the mice who had been exercising extensively for the previous five weeks and those who had been sedentary.
In the sedentary group of mice, the small capillaries in the brain experienced increased oxidative stress, causing the blood brain barrier to become more permeable. Toxins and inflammatory cells previously prevented from crossing the blood brain barrier then had access to the brain. The exercise group showed no such changes.
Changes in the blood brain barrier, especially the role of oxidative reactions, have been little studied in the past, says Dr. Toborek; the University of Kentucky study is the first to observe that meth administration produced an upregulation of NADPH oxidase, a major enzyme that causes oxidative stress.
This is a significant finding, says Dr. Toborek, because it delineates a mechanism for how meth causes oxidative stress. It also was significant that the exercise mice were markedly protected from such upregulation and consequently from the oxidative stress that weakened the capillaries in the brains of the non-exercise mice.
Exercise by no means protects against all the harmful effects of meth use, says Dr. Toborek, and the team now plans to study the effects and mechanisms involved in chronic meth abuse. However, he says, this study adds to the growing amount of data showing the positive and protective health effects of consistent exercise.
Human Stem Cells Promote Healing of Diabetic Ulcers
Treatment of chronic wounds is a continuing clinical problem and socio-economic burden with diabetic foot ulcers alone costing the National Health Service NHS £300 million a year
Scientists in Bristol have found that human foetal stem cells can effectively be used to treat back leg ischaemic ulcers in a model of type 1 diabetes.
The researchers also found the culture in which the stem cells had been grown mimicked the wound-healing ability of the cells, suggesting that they could be used as a "factory" of wound-healing substances. Alternatively, the active ingredients in the culture, once identified, could be used instead; this would avoid the ethical concerns of using human foetal stem cells.
In humans, diabetic patients with ischaemic foot ulcers have the worst outcome of all chronic skin wounds, with higher amputation and mortality rates than patients carrying non-ischaemic ulcers. Topical gels containing single growth factors have recently been used with some success in non-ischaemic ulcers, but have been unsuccessful in ischaemic ulcers, which are also resistant to other conventional treatment. Ischaemia results when the blood supply to a tissue is greatly reduced or stopped - this can occur in diabetes since it can also cause impaired blood flow in patients.
The healing activity of stem cells is recognised for their ability to separate into the various component cells of injured tissues, as well as to discharge growth factors that may encourage the formation of new blood vessels in the patient.
Paolo Madeddu, Professor of Experimental Cardiovascluar Medicine and colleagues at the Bristol Heart Institute, previously used stem cells in models of back leg ischaemia, showing that foetal stem cells could be more therapeutically effective than adult stem cells.
Foetal stem cells possess a better ability to multiply and to graft onto host tissue, and to separate into other cell types to replace those in the damaged tissue. The group led by Bristol University's Professor Madeddu have found that foetal stem cells accelerate the closure of ischaemic diabetic ulcers, while stem cells from blood of adult donors are ineffective.
Professor Madeddu, commenting on the research, said: "This is the first study to demonstrate the healing capacity of local therapy with CD133+ stem cells in a model of diabetic ischaemic foot ulcer. The foetus-derived cells would be difficult to obtain for therapeutic applications. However, the finding that conditioned culture is also effective in stimulating wound healing may have important implications for the cure of the ischaemic complications of diabetes.
"Foetal CD133+ cells might be used in the future as a "factory" of therapeutic substances. Alternatively, synthetic replica of the conditioned medium could be produced to obviate ethical concerns surrounding the direct use of foetal stem cells."
Karen Addington, Chief Executive of Juvenile Diabetes Research Foundation (JDRF), added: "Chronic wounds and diabetic foot ulcers are serious long-term complications of type 1 diabetes. Because of the difficulties involved in managing type 1 diabetes, people living with the condition are at an increased risk of requiring a non-traumatic limb amputation. Although more work needs to be done before we can begin to think about potential new treatments, this research represents a useful way to help identify new strategies for dealing with type 1 diabetes."
The researchers discovered that a particular type of stem cell - CD133+ cells (derived from human foetal aorta) promoted blood vessel formation in order to salvage the diabetic limb. Three days following the graft consisting of collagen plus CD133+ cells, hardly any CD133+ cells were detected in the ischaemic diabetic ulcer - indicating that transplanted cells had done their task in the very first days after transplantation possibly by boosting the generation of new vessels through an indirect mechanism.
They found that the CD133+ cells released large amount of growth factors and cytokines endowed of pro-angiogenic and pro-survival potential. To confirm the importance of these released factors, Professor Madeddu and colleagues have grown the CD133+ cells in vitro, and then used the "conditioned" culture to reproduce the effects on wound healing and angiogenesis. These additional experiments confirmed that wound healing and angiogenesis are equally benefited either by giving stem cells or the stem cells' released product.
In the attempt to explain which component of the healing cocktail were really important, they withdrew likely candidates one by one by blocking antibodies. Interestingly, they found that the vascular endothelial growth factor A (VEFG-A) and some interleukins were the crucial factors accounting for the healing effect of transplanted stem cells.
Importantly, VEGF-A was recognized to be the responsible for reactivation of foetal genes, belonging to the Wingless gene family, in the wounded tissue. Withdrawal of wingless gene products also prohibited the beneficial action of conditioned medium on the wound closure and reparative angiogenesis.
This discovery provides a new perspective in the use of foetal stem cells. It is known that wounds heal so well in foetuses that no scar can be visible at birth. It is therefore possible that, when foetal stem cells are transplanted onto diabetic ulcers, they reactivate a foetal program in the recipient to allow those adult ulcers to repair as efficiently as foetal wounds do.
UCSF, Stanford Reveal Neural Networks Targeted in Brain Diseases
Scientists are reporting the strongest evidence to date that neurodegenerative diseases target and progress along distinct neural networks that normally support healthy brain function
The discovery could lead to earlier diagnoses, novel treatment-monitoring strategies, and, possibly, recognition of a common disease process among all forms of neurodegeneration.
The study, reported in the April 16 issue of the journal “Neuron,” was conducted by scientists at the University of California, San Francisco and the Stanford University School of Medicine, who characterized their finding as “an important new framework for understanding neurodegenerative disease.”
The finding inspired the image for the cover of the issue of the journal.
Researchers have known that neurodegenerative diseases are associated with misfolded proteins that aggregate within specific populations of neurons in the brain. Alzheimer’s disease, for instance, results from misfolding events involving beta-amyloid and tau proteins, which result in neuritic plaque and neurofibrillary tangle formation in medial temporal memory structures. In all neurodegenerative diseases, synapses between nerve cells falter, and damage spreads to new regions, accompanied by worsening clinical deficits.
In most cases, however, scientists have not known what determines the specific brain regions affected by a disease. The current neuroimaging study, which examined patients with five forms of early age-of-onset dementiaAlzheimer’s disease, behavioral variant frontotemporal dementia, semantic dementia, progressive nonfluent aphasia, and corticobasal syndrome as well as two groups of healthy controls, showed that each disease targets a different neural network.
“The study suggests that these diseases don’t spread across the brain like a wave but instead travel along established neural network pathways,” says the lead author of the study, William W. Seeley, MD, assistant professor of neurology at the UCSF Memory and Aging Center.
Earlier work performed by Michael Greicius, MD, senior author and assistant professor of neurology and neurological sciences at Stanford, provided Seeley with the inspiration for the present study, which extended Greicius’ work on Alzheimer’s disease to a host of additional dementias. The findings suggest that network degeneration represents a class-wide neurodegenerative disease phenomenon.
“Something about a network’s architecture or biology is either bringing the disease to networked regions or propagating disease between network nodes,” says Seeley.
At this point, the scientists have shown that the diseases cause atrophy in networked regions. “We still need to determine how the diseases impact connectivity, and we don’t yet know how, at the molecular level, disease spreads between networked areas,” says Seeley.
Greicius further commented, “These results suggest that brain imaging measures of network strength should be sensitive enough to detect these diseases at an early stage and, as importantly, specific enough to reliably distinguish one disease from the others.”
If all forms of neurodegenerative disease are propagated along synaptic connections, says Seeley, “the framework would have major mechanistic significance, predicting that the spatial patterning of disease relates to some structural, metabolic or physiological aspect of neural network biology.”
“We hope our finding will stimulate basic researchers to try to understand the molecular mechanisms for network-based neurodegeneration,” he says.
Meanwhile, Seeley, Greicius, and their colleagues plan to test neural network-based diagnostic and disease-monitoring studies in younger people with genetic predispositions to Alzheimer’s disease and frontotemporal dementia. The goal is to try to track incipient changes in neural network connectivity and, ultimately, to track how well new experimental drugs can repair or maintain connectivity once an individual begins to show signs of dysfunction.
“Our hope is to develop tools that can detect these diseases even before symptoms emerge, so that disease-modifying therapies can get started before it is too late,” Seeley concludes.
The study was funded by the National Institute of Aging, the National Institute of Neurological Diseases and the Larry L. Hillblom Foundation.
TUESDAY April 21, 2009---------------------------News Archive
First Compound to Stimulate Release of Neurotransmitter Acetylcholine in Schizophrenia and Alzheimer's
Effective drugs without side effects
For almost 20 years, pharmacological companies have known that certain compounds that activate two specific CNS receptors, causing them to release the neurotransmitter acetylcholine, are effective in treating the cognitive and motor problems related to both schizophrenia and Alzheimer's disease (AD).
But because the compounds are "dirty" scientific lingo for a lack of selectivity they activate not only the essential M1 and M 4 muscarinic receptors but also the other three members of the family, designated M2, M3 and M5, resulting in unacceptable gastrointestinal and other side effects.
That may soon change, thanks to the discovery of a truly selective agonist that targets only the M1 receptor, known to be central to cognition and thus implicated in diseases like AD and schizophrenia.
On April 20, speaking at the Experimental Biology 2009 meeting in New Orleans, Vanderbilt graduate student Evan Lebois in the laboratories of Dr. David Weaver and Dr. Craig Lindsley describes the complex, labor-intensive screening and discovery process that allowed Vanderbilt scientists to pinpoint what big pharma's computers and robots could not, and the process now underway to move the compound toward becoming an effective drug to treat AD and schizophrenia. The presentation is part of the scientific program of the American Society for Pharmacology and Experimental Therapeutics.
In stage one, the search for the appropriate molecule, Dr. David Weaver, director of the Vanderbilt Chemical Biology's High-Throughput Screening facility and co-director of the Molecular Library Screening Center, painstakingly ran high-throughput screens of every compound in the molecular library to see which ones activated the M1 receptor. Most such studies are done on computers with robots and automatic scoring mechanisms. By looking with his own eyes at the waveform reactions of every compound in the library, including those already rejected by the robotic systems, Dr. Weaver identified the molecule the scientists dubbed VU019467.
It was now time for stage two, and therefore the turn of Dr. Craig Lindsley, head of Medicinal Chemistry and Director of the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development. His task was to create an effective probe compound.
"There is no point optimizing a molecule's potency in vitro if it turns out not to work in vivo," says Lindsley. His probe works in both. The team now is trying the compound in mouse and rat models of Alzheimer's and schizophrenia to determine what dose range restores the appropriate level of signaling through the targeted receptor. In addition, this compound provides a tool of unprecedented selectivity that will allow the researchers to tease apart the basic role of the M1 and M4 receptors in CNS function and disease states to degree that has never before been possible.
The team hopes that within a year they will have a compound ready to license to a pharmacological company that can continue with preclinical development and then onward to human trials.
Fat Droplet Delivers Tumor Suppressor Gene
Overcoming resistance to treatment
Dr. Esther Chang describes the most recent developments in human trials of the first systemic, non-viral, tumor-targeted, nanoparticle method designed to restore normal gene function to tumor cells while completely bypassing normal tissue April 21 at an American Association of Anatomists (AAA) scientific session at Experimental Biology 2009 in New Orleans.
Dr. Chang, a molecular oncologist, and her colleagues at Georgetown University Medical Center's Lombardi Cancer Center, have developed a nanoparticle about one thousandth smaller than a printed period -- that can travel through the blood stream. "Decorated" with a tumor-targeting antibody, the nanoparticle is able to locate primary and hidden metastatic tumor cells and deliver its payload: a fully functioning copy of the P53 tumor suppressor gene.
Normal cells have two copies of the functioning P53 gene. The protein produced by the P53 gene is activated to either coordinate the repair process in cells or induce cell suicide. Loss of normal p53 function results in malignant cell growth and has been linked to resistance to radiotherapy and chemotherapy in a number of cancers.
In earlier work using animal models, Dr. Chang's group delivered functional p53 genes to tumor cells and tumor metastases in 16 different types of cancer, including prostate, pancreatic, melanoma, breast cancer and head and neck cancer. The presence of the replacement genes dramatically improved the efficacy of conventional cancer therapy. That suggests that use of the P53 delivery system eventually would allow physicians to use a lower dose of therapies, achieving the same or enhanced therapeutic results but sharply diminishing the side effects so troublesome in many treatments.
Dr. Chang's nanoparticle delivery system is designed to reduce side effects in another way as well. When the job of reinstating a normal P53 suppressor gene is done, the nanoparticle essentially a little fat droplet wrapped around the gene simply melts away, unlike non-biodegradable delivery systems.
Clinical trials are now underway at the Mary Crowley Medical Research Center, affiliated with Baylor University at Dallas, under the direction of clinical trial principal investigator Dr. John Nemunaitis. The trial already has enrolled six patients with various cancers and anticipates a total of 14. Early results are promising, says Dr. Chang. In addition to evaluating the safety issues for which phase 1 trials are designed, investigators are seeing anti-tumor efficacy. Dr. Chang says she is hopeful that the gene therapy will become a first line treatment that will significantly reduce the probability of recurrent tumors.
Pregnancy Hormone hCG Protects Against Breast Cancer Even in Short-Term Treatments
In an animal model of breast cancer, Fox Chase Cancer Center researcher shows how smaller doses of hCG could offer some of the same benefits of longer doses
One of the most effective ways to prevent breast cancer is through a full-term pregnancy at an early age. Studies out of Fox Chase Cancer Center have linked this protective effect to the presence of human chorionic gonadotropin (hCG), a hormone produced by the placenta to maintain the early stages of pregnancy. Their findings in an animal model of breast cancer showed that rats exposed to hCG over a 21 day period (the length of rat pregnancy), are far less likely to develop breast cancer when exposed to a known carcinogen.
Today, at the 100th Annual Meeting of the American Association for Cancer Research. Johana Vanegas, M.D., a research associate at Fox Chase, presents findings suggesting that even a much shorter exposure to hCG can prevent breast cancer in rats.
Venegas is a member of the laboratory of Jose Russo, M.D. and Irma Russo, M.D., who were the first scientists to propose hCG as an anti-cancer agent. Their studies have shown that hCG offers lasting, protective changes within breast tissue. Clinical trials of hCG in women, based on their work, are currently under way at three locations, nationally, including Fox Chase Cancer Center, and in one European country. The hCG hormone is an FDA-approved agent frequently used for fertility treatments.
"The ability to replicate the naturally protective effects of pregnancy against breast cancer will hold a significant public health value," says Vanegas. "In order to translate our finding into humans, a clinical trial with hCG as a preventive agent against breast cancer, is already ongoing in pre-menopausal women with no previous pregnancy."
Vanegas and her colleagues studied virgin female rats, which had been divided into four groups: a control group, which did not receive hCG, and three groups that received hCG for five, ten or fifteen consecutive days. Following the treatment, each rat received a single dose of a breast cancer-inducing agent.
According to Vanegas, 90.9 percent of the rats in the control group developed breast tumors, compared to 71.4 percent, 57.1 percent, and 15.4 percent in the five, ten and fifteen day-treated animals, respectively. In addition, the average tumor size was also smaller in all the animals that received any of the three hCG treatments.
"The animals that received hCG, but still developed breast cancer did so much later than the control group, which further demonstrates the protective effects of hCG," Vanegas says. "While we don't foresee side effects among humans in using hCG, it is helpful to know that even smaller doses confer benefits on breast tissue."
Neandertals Babies Didn't Do the Twist
Giving birth is more difficult - and dangerous - for modern humans than for any other primate
Not only do human mothers have to push out babies with unusually big heads, but infants also have to rotate to fit their heads through the narrow birth canal. Now, a new virtual reconstruction of the pelvis of a Neandertal woman suggests that Neandertal mothers also had a tough time giving birth to their big-headed infants - but the babies, at least, didn't have to rotate to get out.
Once upon a time, a major shift took place in the evolution of childbirth. Fossil female pelvises of a 1.2-million-year-old Homo erectus, a 3.1-million-year-old australopithecine, and a 500,000-year-old archaic modern human all contain oval birth canals that are widest transversely--from side to side--when viewed from the top. But modern women's birth canals, though also oval, change shape halfway down the birth canal so that they are widest from front to back at the bottom, near the pelvic outlet. This means that the baby has to rotate its head to fit as it moves through the birth canal. If a baby fails to rotate, another part of its body, such as its shoulders, hands, or feet, may obstruct the birth canal, which is painful and dangerous for the mother and infant.
Like many other researchers, paleoanthropologist Timothy Weaver of the University of California, Davis, thought the shift to this more complicated rotational birth predated the split between modern humans and Neandertals. That's because Neandertals, which lived until 30,000 years ago in Europe, also had big heads and, presumably, used the same evolutionary strategy to deliver their big-brained babies. But it has been difficult to test this idea. The only known female pelvis of a Neandertal, discovered in 1929 near Tabun, Israel, is fragmentary. Two earlier reconstructions of this partial pelvis suggested that Neandertals also had rotational birth, but the fossil is missing its sacrum and, hence, the birth canal.
Now, new tools have given Weaver a way to work around that problem. Collaborating with Jean-Jacques Hublin at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, Weaver got permission to make computed tomography-scans of the pelvis, which is kept at the British Museum in London. The two researchers were able to refit the pieces of the pubis, ischium, and ilium together in a three-dimensional, virtual reconstruction. They also used landmarks on the pelvic fragments to compare the pelvis to those of modern humans--and to predict the size and shape of the missing pieces, such as the sacrum and dimensions of the pelvic outlet.
The reconstruction suggests that the pelvis of the Tabun Neandertal was widest from side to side all the way down the birth canal, more like that of Homo erectus or australopithecines than modern humans. And that means that although Neandertal mothers still had difficult births because of their babies' large heads, their babies did not rotate in the womb, the team reports online today in the Proceedings of the National Academy of Sciences.
So why would our ancestors evolve such a complicated birth in the first place? Other research shows that they had to balance pressures to adapt to the hot climate in equatorial Africa--and tall, slender-hipped humans thermoregulate in the heat better than short, stocky humans (whose physiology retains heat better in the frigid latitudes). By evolving a birth canal that is wide front to back, our ancestors were able to accommodate both narrower pelvises and the delivery of big-brained babies, suggests Weaver.
But it will take more than a virtual pelvis to convince other researchers. "I don't know if I believe the reconstruction," says paleoanthropologist Karen Rosenberg of the University of Delaware, Newark. She and others have questions about the accuracy of the reconstruction of the missing parts of the pelvis, which are critical for proving there was no rotation. "Given the poor preservation of the Tabun pelvis, ... this is a bold claim," says anthropologist Marcia Ponce de León of the University of Zurich in Switzerland. She does agree, however, with one conclusion: "Birth was equally difficult in Neandertals as in modern humans," with or without a twist.
Cholesterol Appears to Promote Tamoxifen Resistance in Some Breast Cancer Cells
Breast cancer cells in the laboratory that don't respond to tamoxifen may be producing high amounts of cholesterol in order to provide a kind of shield against the drug, say researchers at Georgetown University Medical Center (GUMC)
They say their study, presented at the Annual Meeting of the American Association for Cancer Research (AACR), suggests that currently available statin drugs that reduce cholesterol might be useful in patients with tamoxifen-resistant breast cancer. Alternatively, investigators say, new agents could potentially be designed that specifically inhibit the molecules they found to be responsible for this excess production of cholesterol.
"We have shown that if you inhibit the activity of either of two molecules that we identified in these resistant breast cancer cells, cholesterol production is reduced," says the study's lead investigator, Rebecca Riggins, PhD, a research assistant professor of oncology at GUMC's Lombardi Comprehensive Cancer Center in Washington.
"We are now looking at whether these cells become re-sensitized once more to tamoxifen when cholesterol production is blocked, and our bet is that they do," she says.
The researchers are trying to understand why some women with estrogen receptor-positive (ER+) invasive lobular breast cancer do not benefit as much from hormonal therapy such as tamoxifen when compared to women with other forms of ER+ breast cancer. Each year in the U.S., approximately 127,000 women develop ER+ breast cancer, and an increasing percentage of these are specifically diagnosed with invasive lobular breast cancer.
They have concluded that cholesterol production inside these cancer cells is one culprit.
Cholesterol causes a number of important actions within a cell, Riggins says, and there are two potential explanations as to why high levels of cholesterol might be related to tamoxifen resistance, Riggins says.
"One is that cholesterol is an essential part of the plasma membrane that surrounds all eukaryotic cells. A high level of cholesterol can make this membrane more rigid, impairing the ability of drugs to enter cells and thus altering how sensitive a cancer cell is to this type of drug treatment," she says.
"A second possibility is that our tamoxifen-resistant breast cancer cells have increased amounts of cholesterol specifically in the mitochondria. Mitochondria supply a cell with energy, but they also are responsible for determining how a cell responds to a death signal," Riggins says. "High levels of mitochondrial cholesterol can delay or block cell death. This is important because many cancer drugs, including tamoxifen, have been shown to induce breast cancer cell death through the mitochondria."
This study continues a string of discoveries the researchers have made regarding tamoxifen resistance. They had earlier found that invasive lobular breast cancer has many more so-called "gamma" estrogen-related receptors than the typical "alpha" estrogen receptors that tamoxifen was designed to inhibit.
In this study, they looked at HMGCS2, an enzyme in the mitochondria known to be regulated by gamma estrogen-related receptors and AP1, a transcription factor that binds on to the receptor and activates it. HMGCS2 generates chemicals that are necessary for the production of cholesterol. They found that breast cancer cells that are resistant to tamoxifen exhibits very high levels of the gamma estrogen-related receptors, AP1, and HMGCS2, and contains significantly greater amounts of cholesterol, than do breast cancer cells that are sensitive to tamoxifen.
The investigators then found that by inhibiting AP1 with an experimental drug, the production of cholesterol was reduced, as was the expression of HMGCS2.
Much remains unclear about the connection between cholesterol and tamoxifen resistant breast cancer cells, Riggins says. Studies that have looked at the connection between statin use and breast cancer risk have had inconsistent results, and while women taking tamoxifen do have lower levels of cholesterol in their blood, that does not take into account the amount of cholesterol that may be in the cancer cells themselves.
"This study gives us a new direction to go in, and a potential treatment strategy to investigate," she says.
Scientists Discover that Algae 'Dance'
Unique footage shows 'waltzing' and 'minueting'
Scientists at the Cambridge University have discovered that freshwater algae can form stable groupings in which they dance around each other, miraculously held together only by the fluid flows they create. Their research was published today in the journal Physical Review Letters.
The researchers studied the multicellular organism Volvox, which consists of approximately 1,000 cells arranged on the surface of a spherical matrix about half a millimetre in diameter. Each of the surface cells has two hair-like appendages known as flagella, whose beating propels the colony through the fluid and simultaneously makes them spin about an axis.
The researchers found that colonies swimming near a surface can form two types of "bound states"; the "waltz", in which the two colonies orbit around each other like a planet circling the sun, and the "minuet", in which the colonies oscillate back and forth as if held by an elastic band between them.
The researchers have developed a mathematical analysis that shows these dancing patterns arise from the manner in which nearby surfaces modify the fluid flow near the colonies and induce an attraction between them. The observations constitute the first direct visualisations of the flows, which have been predicted to produce such an attraction. They have been implicated previously in the accumulation of swimming microorganisms such as bacteria and sperm cells near surfaces.
These findings also have implications for clustering of colonies at the air-water interface, where these recirculating flows can enhance the probability of fertilization during the sexual phase of their life cycle.
Professor Raymond E. Goldstein, the Schlumberger Professor of Complex Physical Systems in the Department of Applied Mathematics and Theoretical Physics (DAMTP) and lead author of the study, said: "These striking and unexpected results remind us not only of the grace and beauty of life, but also that remarkable phenomena can emerge from very simple ingredients."
Funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the work is part of a larger effort to improve our knowledge of evolutionary transitions from single-cell organisms to multicellular ones. This greater understanding of the nature of self-propulsion and collective behaviour of these organisms promises to elucidate key evolutionary steps toward greater biological complexity.
Moreover, the flagella of Volvox are nearly identical to the cilia in the human body, whose coordinated action is central to many processes in embryonic development, reproduction, and the respiratory system. For this reason, the study of flagellar organisation has potentially broad implications for human health and disease.
Study Identifies Genes that Protect Against Aging
Scientists at the University of Liverpool have developed a new method to help researchers identify genes that can help protect the body during the ageing process
The team developed a method of analysing genes in multiple ageing tissue types in both animals and humans. The analysis, which included more than five million gene measurements, highlighted the mechanisms used by the body to protect against cellular changes with age that can result in conditions such as muscle degeneration and cognitive ageing.
The new method could help further understanding into anti-ageing interventions by identifying genes that indicate biological changes as a result of ageing. Research has suggested that some genes respond to age-related conditions by increasing key protein levels, allowing the body to manage the ageing process more effectively.
Dr Joao Pedro Magalhaes, from the University's School of Biological Sciences, explains: "We developed a new algorithm to analyse microarray data of genes from different species, and combined data from multiple studies to obtain a picture of how genes respond to ageing in a whole organism. This method is similar to the way scientists study the molecular characteristics of cancer, but it is the first time it has been used to research ageing.
"Studies so far have looked at the ageing process in particular tissues, but have not been able to build a coherent view of ageing in whole organisms. Results have suggested that genes can adapt to ageing and help protect the body, or even slow down the ageing process. By combining large amounts of data from various tissue types across different species, however, we were able to identify many more examples of adaptive gene behaviour in animals and humans. This demonstrates that the body has natural mechanisms to respond to age-related conditions.
"We found that some genes previously unconnected with ageing become more abundant with age to help protect the body. We can use these genes as a biomarker or 'signature' of ageing so that scientists can help develop products and treatments that help manage the ageing process effectively."
MONDAY April 20, 2009---------------------------News Archive
UCSF Team Closer to Creating Safe Embryonic-Like Stem Cells
A team of UCSF researchers has for the first time used tiny molecules called microRNAs to help turn adult mouse cells back to their embryonic state
These reprogrammed cells are pluripotent, meaning that, like embryonic stem cells, they have the capacity to become any cell type in the body.
The findings suggest that scientists will soon be able to replace retroviruses and even genes currently used in laboratory experiments to induce pluripotency in adult cells. This would make potential stem cell-based therapies safer by eliminating the risks posed to humans by these DNA-based methods, including alteration of the genome and risk of cancer.
“Using small molecules such as microRNAs to manipulate cells will play a major role in the future of stem cell biology,” says senior author Robert Blelloch, MD, PhD, of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research at UCSF.
Scientists are interested in reprogramming because it would offer a way to create cells that provide a genetic match for individual patients. A patient’s skin cells could be reverted to pluripotent cells in the culture dish and then prompted to differentiate into adult cells, such as those of the heart, lung and brain. These cells could then be transplanted into patients, without the fear of rejection.
The study, reported in the April 12, 2009 advanced online edition of the journal “Nature Biotechnology” and scheduled for the May 8, 2009 print issue, used a combination of microRNAs and retrovirus-introduced genes to transform fibroblast cellsfound throughout the body of mice and humansinto pluripotent cells.
The current finding comes on the heels of a study published by the group in the December 2008 print edition of “Nature Genetics” that showed that microRNAs, which can be synthesized in the lab, encouraged embryonic stem cells to self-replicate, a finding that has implications for replicating stem cells in the culture dish and exploring stem cells’ role in cancers.
Previous methods for creating embryonic stem cell-like cells have relied on the introduction of DNA that encodes four transcription factors, proteins that play a role in the production of genes. The limitation of this method is that three of the four genes that code for these transcription factors oct4, klf4 and c-myc are oncogenes, meaning they promote the uncontrolled cell growth characteristic of cancer.
In the current study, led by Robert Judson, a graduate student in the Blelloch lab, the scientists induced pluripotency using a combination of infection and transfection. The infection involved introducing three viruses, each containing a transcription factor known to induce pluripotency. The transcription factor for c-myc was not included. The transfection involved a simple process in which the tiny microRNA molecules were mixed with a lipid, allowing them to pass through the cell membrane. By labeling the fibroblast cells, they showed that the treated cells could be incorporated into a mouse embryo and become every cell type in the adult animalincluding germline cells that would produce the next generation of mice.
“These are transient, non-coding molecules that do not incorporate into the genome, but promote self-replication and have the potential to induce pluripotency,” Blelloch says. “They do their thingturn a somatic cell into an embryonic stem cell-like oneand then they’re gone.”
“MicroRNAs give us a new tool to manipulate the fate of cells,” Blelloch says.
MicroRNAs are snippets of single-stranded RNA that prevent a gene’s code from being translated from messenger RNA into protein. They were debuted in 1993, when scientists reported the discovery of a microRNA in the microscopic roundworm C. elegans. Since then, the field has “exploded,” says Blelloch, with hundreds of microRNAs discovered in the last eight years across a broad range of species, from plants to animals.
Produced in the nucleus and released into the cytoplasm, microRNAs home in on messenger RNAs that share part of their genetic sequence. When they find them, they latch on, preventing the messenger RNA from being processed by the protein-making machines known as ribosomes. As such, microRNAs are able to ratchet down a cell’s production of a given protein.
Currently, Blelloch and his colleagues are working to replace all four transcription factors with microRNAs and conducting experiments that will reveal the mechanism by which these small molecules are able to induce pluripotency. The team will also be looking to determine which microRNAs might be able to turn adult cells directly into particular adult cell types, by-passing the embryonic stem cell-like stage altogether.
“The goal now is to ensure the safety of induced pluripotent stem cells and to differentiate them into cells that can be used to repair damaged tissue and treat disease,” he says.
The study was supported by grants from the National Institutes of Health, California Institute for Regenerative Medicine, Pew Charitable Trust and National Science Foundation.
Co-authors of the study are Joshua Babiarz and Monica Venere of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
Specific Forms of Blindness May be Cured With Stem Cells
BRITISH scientists have developed the world’s first stem cell therapy to cure the most common cause of blindness. Surgeons predict it will become a routine, one-hour procedure that will be generally available in six or seven years’ time
The treatment involves replacing a layer of degenerated cells with new ones created from embryonic stem cells. It was pioneered by scientists and surgeons from the Institute of Ophthalmology at University College London and Moorfields eye hospital.
This week Pfizer, the world’s largest pharmaceutical research company, will announce its financial backing to bring the therapy to patients.
The treatment will tackle age-related macular degeneration (AMD), the most common cause of blindness. It affects more than 500,000 Britons and the number is forecast to increase significantly as people live longer. The disease involves the loss of eye cells.
Under the new treatment, embryonic stem cells are transformed into replicas of the missing cells. They are then placed on an artificial membrane which is inserted in the back of the retina.
Tom Bremridge, chief executive of the Macular Disease Society, said: “This is a huge step forward for patients. We are extremely pleased that the big guns have become involved, because, once this treatment is validated, it will be made available to a huge volume of patients.”
Embryonic stem cells have the ability to develop into all types of body tissue. Their use is controversial, however, because it involves the destruction of human embryos.
Laboratory trials completed by the British team have demonstrated that stem cells can prevent blindness in rats with a similar disease to AMD. They have also successfully tested elements of the technology in pigs.
The team is led by Professor Pete Coffey, director of the London Project to Cure Blindness, working alongside Lyndon da Cruz, a surgeon at Moorfields.
Coffey said the treatment would take “less than an hour, so it really could be considered as an outpatient procedure. We are trying to get it out as a common therapy”.
He welcomed Pfizer’s agreement to manufacture the membranes, saying: “This is a major development because of the size of the partner. We need a big pharmaceutical company to scale it up.
“We have nearly 14m people within Europe with AMD. This will ensure that the therapy gets through to clinical trials in a safe and effective manner.”
Professor Peng Khaw, director of the Biomedical Research Centre at Moorfields and the UCL Institute of Ophthalmology, added: “This shows that stem cell therapy is coming of age. It offers great hope for many sufferers around the world who cannot be treated with conventional treatment.” He added: “All my patients say to me is, ‘When will this stem cell treatment be ready? I want it now’.”
Pfizer’s role would be crucial in bringing production of the membranes to an industrial level.
The team is applying for regulatory approval for trials from the Medicines and Healthcare products Regulatory Agency, the Human Tissue Authority and the gene therapy advisory committee.
The clinical trial, due within two years, is expected to be the second in the world to use embryonic stem cells on humans. The first, on patients with spinal cord injuries, will start this year in America.
Smurf Genes Help Cells Find the Path Ahead
Two critical genes that serve as beacons and give cells a much needed sense of direction in the chaotic days of early development have been identified by researchers at the University of Toronto
The new findings, from the laboratory of Jeffrey L. Wrana, a Howard Hughes Medical Institute international research scholar, were published April 17, 2009, in the journal Cell, and help explain how a cell determines its sense of space. A better understanding of this phenomenon, called planar cell polarity, may also help scientists learn how improper cellular orientation can lead to spina bifida, polycystic kidney disease, and metastatic cancer. Each of these illnesses involves cells that don’t have a proper sense of direction, so they cannot tell which way they are going.
In a developing embryo, cells need to be in the right position at the right time. To get to their proper destination, cells must understand the difference between top and bottom, forward and backward. If this orientation is off just a little, development can be disrupted or derailed. In spina bifida, for example, cells can fail to recognize front from back, leading to improper formation of the spine.
In the past decade, Wrana has helped identify the importance of two Smurf genes (Smurf stands for Smad ubiquitination regulatory factor) in helping cells move and distinguish top from bottom. Cells rely on cues from their neighbors to sense this kind of orientation, and Wrana has been trying to understand how the Smurf genes facilitate the process. Until now, he didn’t know Smurf proteins had anything to with orienting cells in the backward/forward direction, as well.
“Our results were unexpected, but also exciting because they suggest the Smurf genes are coordinating different types of cell polarity,” says Wrana, who also works at Mount Sinai Hospital in Toronto.
As part of his study, Wrana and his team genetically engineered mouse embryos so they did not have functional copies of both Smurf genes, but the embryos failed to develop properly and died before birth. When Wrana examined the embryos, he observed that they had an atypical shapethey were short and wide instead of long and thin. In addition, he saw that the neural tubethe precursor to the spinal cordhad failed to close into its proper tubular shape. This type of developmental anomaly is similar to what happens in human babies who are born with spina bifida. The findings surprised Wrana because he did not expect that the changes in top/bottom polarity would be vital in this aspect of embryo development.
Instead, these characteristics suggested that the Smurf genes were related to an important network of genes called the Wnt signaling pathway. When this pathway goes awry in early developmentwhich can happen for a variety of reasonsa number of defects can arise, including those Wrana saw in his Smurf-deficient mice. Researchers had known that Wnt signaling helps establish planar cell polarity, so Wrana investigated whether Smurfs were involved, too.
His first stop was the inner ear of the embryonic mouse. The inner ear contains hair cells, which vibrate in response to sound. To do their job, hair cells must line up neatly in a hexagonal pattern, like paving stones on a cobblestone streeta pattern made possible by planar cell polarity. But in the Smurf-deficient mice, the hair cells looked like they were laid by a drunken mason. “In the normal embryos, the hair cells were all pointing the same way in a beautiful array,” Wrana says. “But in the mutants they were disorganized and rotated and pointing the wrong way.”
This disruption suggested the Smurf genes were critical for planar cell polarity. To strengthen his case, Wrana used advanced proteomics techniques to map the interactions of proteins in a cell. Those analyses showed that the proteins made by the Smurf genes interacted with two proteins, called Prickle and Disheveled, that are also linked to planar cell polarity.
In healthy cells that know front from back, Prickle accumulates on one side of the cell, and Disheveled on the other side. This lopsidedness appears critical for planar cell polarity. Wrana found that the Smurf genes actually create this lopsidedness by destroying Prickle on one side of the cell. We believe that through this destruction of Prickle, cells establish an asymmetrical distribution of proteins, and that’s how the cells become polarized properly,” Wrana says.
Wrana is now investigating what role Smurf genes play in other tissues, such as the trachea and kidneys, where planar cell polarity is known to be important. He also wants to study their role in diseases. For example, “there are lots of hints that planar cell polarity is important in cancer,” he says. Other researchers have found that cancer cells often have an excess of the proteins made by the Smurf genes. “We think the elevated expression of Smurfs interferes with the polarity of the cells,” he says. “Within the tumor, the cells become disorganized and display aberrant behaviors, which may help them escape and metastasize.”
Guidelines for Broader Stem Cell Research Unveiled
The Obama administration released a draft of guidelines for federal funding of human embryonic stem cell research Friday
Under the new guidelines, federal funding would be allowed only for research using human embryonic stem cells from embryos created solely for reproductive purposes by in vitro fertilization. The embryos would have to no longer be needed for reproduction, and the donors would have to consent to their use for research.
Funding for research using adult stem cells and induced pluripotent stem cells will continue. Funding will not be allowed for stem cells obtained from other sources, including somatic cell nuclear transfer, also known as cloning; in vitro fertilization embryos created specifically for research purposes; and parthenogenesis, the development of an unfertilized egg.
In March, the administration asked the National Institutes of Health to draft guidelines that would address both scientific and ethical concerns.
"We considered the range of ethical issues and we believe this policy will allow substantial research that is ethically responsible and scientifically worthy," said Dr. Raynard Kington, the institutes' acting director. "We believe this is our best judgment now about a reasonable policy at this time."
Kington called this "an important day for science," saying there are reports that up to 700 stem cell lines might be available. And while it's impossible to estimate how many meet the guideline standards, he said, "We believe many of the lines that exist now that were not eligible under previous policy would be eligible under this policy."
In August 2001, George W. Bush became the first president to allow federal money to be used to fund embryonic stem cell research, limiting it to about 60 existing stem cell lines created from embryos already frozen in fertility clinics. As of October, according to the National Institutes of Health, there were 88 lines that qualified for federal funding, but only 21 actually available to researchers.
Embryonic stem cells are taken from the lining of 4- to 5-day-old embryos. Removal of the stem cells destroys the embryo -- one of the main reasons the research is so controversial and its opponents so passionate.
Researchers have long believed these stem cells hold the keys to important discoveries and treatments for conditions such as Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injuries, heart disease and diabetes.
The American Society for Reproductive Medicine and other groups say the new policy is long overdue.
"Federally funded scientists will soon be able to put forward research proposals to help us unlock the full potential of human embryonic stem cells," it said in a written statement. "That work may eventually yield treatments for some of our most stubborn ailments; it may lead to a new set of research tools, but whatever direction the research points to, we are now closer to answers."
But opponents of the research say it is not sound science and destroys human life.
"The NIH draft guidelines demanded by the president will do nothing to advance stem cell research that is showing near-term benefit for suffering patients," said Tony Perkins, president of Family Research Council.
"Instead of funding more embryo destructive research, the government should fund research using adult stem cells that are on the cutting edge of treating patients for diabetes, spinal cord injury, heart disease and various cancers. Unfortunately, this draft guidance only diverts limited federal resources to unethical stem cell research that has not successfully treated a single person for any disease."
Federal research dollars have long been available for adult stem cell research, but, unlike embryonic stem cells, which have the potential to turn into any organ or tissue cell in the body, they are much harder to turn into completely different cells.
The new regulations will be posted on the Federal Register next week for a 30-day public comment period. Final guidelines are expected on or before July 7.
"Our goal," said Kington, "is to advance science and promote health. And we believe these guidelines will be used to improve the human condition."
Exercise-Exposed Fetuses Have Improved Breathing Movements In Utero, A Marker For Healthy Development
Exercise has many benefits for adults, teens, and youngsters. It is less clear what benefit, if any, exercise may have during fetal growth during gestation. Now that scientists have determined that, generally speaking, maternal exercise poses no significant risk to a fetus, studies are underway to examine the mother/fetus/exercise/health connection
One important study is now complete. Entitled The Effects of Maternal Exercise on Fetal Breathing Movements, it was conducted by Stephanie Million and Linda E. May, Kansas City University of Medicine and Biosciences (KCUMB), Kansas City, MO; and Kathleen M. Gustafson, University of Kansas Medical Center (KUMC), Kansas City, KS. The researchers will discuss their findings at the 122nd Annual Meeting of the American Physiological Society (APS; www.the-aps.org/press), which is part of the Experimental Biology 2009 scientific conference. The meeting will be held April 18-22, 2009 in New Orleans.
Study and Background
The primary aim of the pilot project was to test the theory that maternal exercise imparts a cardiovascular benefit to the fetus. The secondary aim was to determine if exercise-exposed fetuses have increased breathing movements compared to non-exercise exposed fetuses. Fetal breathing movements are a marker of fetal well-being and reflect functional development of the respiratory system and central nervous system control.
The researchers used a non-invasive, dedicated fetal biomagnetometer to measure maternal and fetal magnetocardiograms (MCG) along with fetal movements (breathing, body movements, hiccups and non-nutritive suck). Unlike an ultrasound, which takes static measurements of anatomy, MCG records the physiology of the developing fetus.
The investigators looked at the results from pregnant women between 20 and 35 years of age. The mothers were classified as exercisers if they performed moderate intensity aerobic exercise at least 30 minutes three times per week (moderate to vigorous walking, stationary bicycling and running). Mothers in the control category did not partake of a regular exercise routine. The MCG was measured between 24-36 weeks gestational age.
Between 36-38 weeks gestational age, breathing movements were identified using specific criterion. Measures of fetal heart rate and autonomic control were analyzed during episodes of fetal breathing and non-breathing movements. Although there was no difference in the number of breathing episodes, differences were noted between the groups.
The researchers found:
Fetal HR was significantly lower in the exercise group during both breathing and non-breathing movement periods.
Fetal short-term and overall heart rate variability were higher in the exercise group during breathing movements.
Three independent measures of vagal control were higher in the exercise-exposed fetuses during breathing movements.
During periods of fetal non-breathing, there were no significant differences in measures of vagal control between groups. There were no group or breathing period differences in sympathetic heart rate control.
According to Drs. May and Gustafson, “These findings suggest a potential benefit of maternal exercise on fetal development because of the link between fetal breathing movements and the developing autonomic nervous system.” Their next step is to use exercise as a potential intervention to improve short and long term outcomes in children born to women at risk for gestational diabetes.
Teaming Up Against Cox-2 Tumor-Promoting Protein
An inflammatory protein implicated in a variety of cancers is the target of the first joint symposium between the nation's two premier cancer research organizations
The presidents of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) organized the session focused on the COX-2 enzyme and cancer treatment Monday afternoon at the AACR's 100th Annual Meeting 2009 in Denver. A similar symposium on new molecular targets will be conducted at ASCO's annual meeting in May 29- June 2 in Orlando.
COX-2 is best known as a target for preventing dangerous polyps that lead to colorectal cancer, but it is also advancing as a target for treatment of many solid tumors.
"Our symposium is timely because we are starting to see data from Phase II and Phase III clinical trials about COX-2 inhibition following post-surgical chemotherapy in colon cancer patients," said Raymond DuBois, M.D., Ph.D., president of AACR and provost and executive vice president at The University of Texas M. D. Anderson Cancer Center.
"There's been a great deal of preclinical and translational research addressing COX-2 overexpression in tumors and its role in cancer growth and survival. In prevention, inhibiting this enzyme reduces the number of high-risk precancerous polyps by 66 percent," DuBois said. "The time is ripe to combine basic science and clinical expertise to advance the therapeutic potential of this approach."
Joint efforts are critical to the development of new approaches against cancer, said ASCO President Richard L. Schilsky, M.D., professor of medicine at the University of Chicago Medical Center.
"The development of targeted therapies for cancer prevention and treatment requires the close collaboration and combined resources of basic scientists and clinical investigators," Schilsky said.
"The success of targeted therapy for cancer depends first and foremost on a comprehensive understanding of the biology of the drug target coupled with a robust assay to assess target inhibition and a drug that hits the target. With these ingredients in place, clinical trials can be designed to assess the impact of treatment in the population most likely to benefit.