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Week Ending FRIDAY February 5, 2011---------News Archive

A Way To Stop Breast Cancer's Spread To Bone?

In a discovery that may lead to a new treatment for breast cancer that has spread to the bone, a Princeton University research team has unraveled a mystery about how these tumors take root.

Cancer cells often travel throughout the body causing new tumors in individuals with advanced breast cancer - metastasis - commonly resulting in malignant bone tumors. What the Princeton research has uncovered is the exact mechanism that lets the traveling tumor cells disrupt normal bone growth. By zeroing in on the molecules involved, and particularly a protein called "Jagged1", the research team has opened the door to drug therapies that could block this process.

"Right now we don't have many treatments to offer these patients," said Yibin Kang, an associate professor of molecular biology at Princeton who led the research team. "Doctors can manage the symptoms of this bone cancer, but they can't do much more. Our findings suggest there could be a new way of treatment," one that could slow or halt these bone tumors.

Breast cancer spreads to the bone in 70 to 80 percent of patients with advanced breast cancer, and it can also spread to the brain, lung and liver. Metastatic bone cancer is also a frequent occurrence among patients with advanced prostate, lung and skin cancers. In findings that will be published online in the journal Cancer Cell on Feb. 3, the team's research shows breast tumor cells giving bone cells the wrong instructions through a process known as cell signaling - with disastrous effects for the patient.

The billions of cells in a living human body must communicate to develop, repair and effectively maintain normal physiological tissue functions. Cell signaling is part of a complex system enabling cells to communicate; but, in cancer, that system has gone awry.

Signaling molecules act through a receptor molecule on the cell surface. Once the signaling molecules connect with a receptor, a process begins which ultimately changes the behavior of the receiving cell. A chain reaction of events called a "signaling pathway" occurs. In it, a group of molecules activate each other, one molecule at a time, until a specific function results - such as renewing an organ's cells.

But in the case of metastatic breast cancer, a disruptive pathway is formed. The signaling molecule, known as a ligand, connects with a receptor molecule on certain bone cells and activates a cellular pathway that ultimately disrupts healthy bone renewal.

Kang's team identified the signaling molecule as Jagged1, and the receptor molecule as one that activates a cellular pathway known as the "Notch pathway."

This finding gives cancer researchers a specific target, Kang said - that of developing ways "to neutralize Jagged1's destructive power" and keep it from interfering with normal bone growth.

Kang's research builds on work he began six years ago looking at signaling pathways and how they promote the spread of cancer to bone. In the journal Nature Medicine in 2009, Kang showed that a pathway known as TGF beta plays a role in the growth of bone tumors.

"It turned out that tumor samples from patients with breast cancer that had spread to the bone had higher levels of Jagged1," said Nilay Sethi, who is now completing his medical degree at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.

"It's like a key finding its matching lock, and opens a floodgate of information," Kang said. "Unfortunately, in this case, the Jagged1-Notch signaling is misused by cancer cells to serve a destructive purpose."

In healthy bone, specialized bone cells called osteoclasts scour the bone surface using enzymes and acids to break down old bone, followed by bone cells called osteoblasts that deposit a new layer of bone matrix and rebuild the lost bone tissue.

Working just like excavators and paving machines, bone-scrubbing osteoclasts and bone-building osteoblasts work in sync every day renewing bone.

Tumor cells use the destructive Jagged1 molecule to make osteoclasts mature quickly from their precursor cells, known as monocytes. The massive accumulation of bone-scouring osteoclasts becomes the front line for invasion by tumor cells, speeding up the breakdown of bone tissue and clearing the way for tumor expansion into the bone.

"Meanwhile, Jagged1 instructs the osteoblasts to secrete elevated levels of Interleukin-6, a tumor growth factor, so the cancer grows even faster," Kang said. "It's a one-two punch. The link between the Jagged1/Notch and TGF-beta pathways establishes a vicious cycle, essentially driving the unstoppable expansion of tumors and the destruction of skeletal tissues" Nilay Sethi.

As a medical student, Sethi is acutely aware of the consequence of bone metastasis. "These patients suffer a lot. They have fractures, severe bone pain and debilitating nerve compression," he said. In addition, as the bone breaks down, calcium builds up in the blood, causing other life-threatening complications.

The key to stopping the process appears to be finding a way to neutralize the Jagged1 signaling molecule or its receptor Notch.

Jagged1 “signaling protein" activates molecules in the “Notch signaling pathway” (green flash) stimulating Osteoclasts (pink - specialized cells that break down bone) to release tumor growth factor TGF-beta protein (red bubbles) from the bone matrix. Notch also signals Osteoblasts (brown - specialized cells that rebuild bone tissue and the bone matrix) to secrete protein, IL-6 (orange bubbles), which promotes growth of Tumor cells (blue).
Illustration by Stephen Cheng
One way to interrupt the destructive process is to put a roadblock in the Notch pathway by halting the activity of gamma secretase - an enzyme key to activating the Notch pathway. Merck & Co. pharmaceutical has developed a gamma secretase inhibitor or GSI, and provided it to Kang's lab for testing.

The drug has already shown promise treating metastatic bone cancer, Kang said. In animal experiments, the GSI drug has blocked the disease-causing signaling between tumor cells and bone cells and reduced bone metastasis significantly, along with a dramatic reduction in bone destruction. Kang hopes this new data will result in a GSI clinical trial in the near future.

According to Kang, there are few drugs currently available to relieve symptoms associated with bone metastases, and none can completely stop breast cancer. The National Cancer Institute estimates approximately 200,000 patients are diagnosed every year with breast cancer.

Sloan-Kettering's Bromberg said Kang's recent discovery "underlies the importance of targeting the environmental milieu" in which disease develops, in this case the activity of the Notch signaling pathway and specific interactions between cancer cells and the specialized cells that break down and rebuild bone.

Kang’s work was funded by the New Jersey Commission on Cancer Research, the San Francisco-based Brewster Foundation founded by 1969 Princeton alumnus Leonard Schaeffer, U.S. Department of Defense, American Cancer Society, Merck & Co., the National Institutes of Health and the Champalimaud Foundation in Lisbon, Portugal.

THURSDAY February 4, 2011---------News Archive

Uterus, More Than Egg Quality, Impacts IVF

For women seeking pregnancy by assisted reproductive technologies, such as in-vitro fertilization (IVF), a new study shows that the health of the uterus is more relevant than egg quality for a newborn to achieve normal birth weight and full gestation.

The researchers reviewed three years of data that compared average birth weight and gestational time for single births born as a result of standard IVF, IVF with donor eggs and IVF with a surrogate.

While the ability to achieve a pregnancy is tied to egg/embryo quality, the obstetrical outcomes of birth weight and length of pregnancy are more significantly tied to the uterine environment that is affected by the reason the woman is infertile.

There were more than 300,000 IVF cycles during the time of the study producing more than 70,000 singleton pregnancies.

“This is the first time that a study demonstrated that the health of a women’s uterus is a key determinant for a fetus to obtain normal birth weight and normal length of gestation,” said Dr. Gibbons. “While obvious issues of uterine fibroids or conditions that alter the shape of the uterus are suspected to affect pregnancy rates, conditions that result in poorer ovarian function to the point of needing donor eggs are not known. Further research is needed to fully understand this complex issue.”

As assisted reproductive technologies (ART) in the U.S. mature, increasing attention is directed not just to pregnancy rates but also to the obstetrical outcomes of those resulting pregnancies – meaning the newborn’s birth weight, health and gestational age. Currently, about one percent of U.S. births are the result of ART therapies such as IVF, donor eggs, intracytoplasmic sperm injection, embryo cryopreservation, embryo donation, preimplanation genetic diagnosis, and male infertility surgery and medical therapy.

The study explored several scenarios and found that the birth weight associated with standard IVF – in which the patient carried the embryo created with her own egg – was greater than that associated with donor egg cycles, and less than that in gestational carrier cycles. This finding held true even when other factors were considered showing that the woman’s own uterus may be a determining factor.

Gibbons said the study also determined that a diagnosis of male infertility did not affect birth weight or gestational age, yet every female infertility diagnosis was associated with lower birth weight and a reduced gestational age.

Patients diagnosed with a uterine health issue, such as fibroids or other factors, had babies with the lowest birth weights and gestational ages. This led the researchers to examine the uterine environment as it relates to the type of therapy being considered.

Gibbons explains that in standard IVF, an embryo is transferred to a woman who has just undergone controlled ovarian hyperstimulation, while in donor egg IVF and gestational carrier IVF, the embryo is transferred to a “natural” or unstimulated uterus. Then, the researchers looked at IVF utilizing frozen embryo transfer in which an embryo created with a patient’s own egg is transferred to her own unstimulated uterus. They found that babies born of frozen embryo transfer cycles had markedly greater birth weights than those born as a result of standard IVF.

“That finding may help women seeking pregnancy and their physicians to consider frozen embryo transfer as a possible option if the uterine health is not a consideration,” said Gibbons. “This study shows us how so many factors are related to a successful outcome and we continue to learn where further research may be needed.”

The complete study, called “Toward understanding obstetrical outcome in advanced assisted reproduction: varying sperm, oocyte and uterine source and diagnosis,” can be found in the journal Fertility and Sterility.

The study was conducted by Dr. William Gibbons, director of The Family Fertility Program at Texas Children’s Hospital and professor of obstetrics and gynecology at Baylor College of Medicine, along with colleagues at the Society for Assisted Reproductive Technologies (SART) Marcelle Cedars, MD, and Roberta Ness, MD.

Texas Children's Hospital is committed to a community of healthy children by providing the finest pediatric patient care, education and research. Renowned worldwide, Texas Children's is ranked in the top 10 best children's hospitals by U.S. News and World Report. It operates the nation's largest primary pediatric care network, with over 40 offices throughout the greater Houston community. Get the latest Texas Children's news on Twitter: www.twitter.com/texaschildrens.

Dieting in Early Pregnancy Stunts Fetal Brains

Eating less during early pregnancy impaired fetal brain development in a nonhuman primate model, researchers from The University of Texas Health Science Center San Antonio have learned.

The researchers found decreased formation of cell-to-cell connections, cell division and amounts of growth factors in the fetuses of mothers fed a reduced diet during the first half of pregnancy.

“This is a critical time window when many of the neurons as well as the supporting cells in the brain are born,” said Peter Nathanielsz, M.D., Ph.D., director of the Center for Pregnancy and Newborn Research in the Health Science Center School of Medicine.

The study included collaborators at the Southwest Foundation for Biomedical Research (SFBR) in San Antonio and Friedrich Schiller University in Jena, Germany. The team compared two groups of baboon mothers located at SFBR’s Southwest National Primate Research Center. One group of baboons ate as much as they wanted during the first half of pregnancy while the other group was fed 30 percent less, a level of nutrition similar to what many prospective mothers in the U.S. experience.

Nutritional Environment Impacts Fetal Brains
“Our collaboration allowed us to determine that the nutritional environment impacts the fetal brain at both the cellular and molecular levels,” said SFBR’s Laura Cox, Ph.D. “That is, we found dysregulation of hundreds of genes, many of which are known to be key regulators in cell growth and development, indicating that nutrition plays a major role during fetal development by regulating the basic cellular machinery.”

Similar situation experienced by those with food insecurity
It is known that marked nutrient restriction, such as in famine conditions, adversely affects development of the fetal brain. Senior author Thomas McDonald, Ph.D., also of the Health Science Center, said the study “is the first demonstration of major effects caused by the levels of food insecurity that occur in sections of U.S. society and demonstrates the vulnerability of the fetus to moderate reduction in nutrients.”

Dr. Nathanielsz Notes That:
In teenage pregnancy, the developing fetus is deprived of nutrients by the needs of the growing mother;

In pregnancies late in reproductive life, a woman’s arteries are stiffer and the blood supply to the uterus decreases, inevitably affecting nutrient delivery to the fetus;

Diseases such as preeclampsia or high blood pressure in pregnancy can lead to decreased function of the placenta with decreased delivery of nutrients to the fetus.

“This study is a further demonstration of the importance of good maternal health and diet,” Dr. McDonald said. “It supports the view that poor diets in pregnancy can alter development of fetal organs, in this case the brain, in ways that will have lifetime effects on offspring, potentially lowering IQ and predisposing to behavioral problems.”

Long Term Effects
Developmental programming of lifetime health has been shown to play a role in later development of obesity, diabetes and heart disease. In light of this new finding, research should focus on effects of developmental programming in the context of autism, depression, schizophrenia and other brain disorders.

The study also forces researchers to review the commonly held notion that during pregnancy the mother is able to protect the fetus from dietary challenges such as poor nutrition, Dr. McDonald said.

The nonhuman primate model’s brain developmental stages are very close to those of human fetuses, the researchers noted. Most previous research in this area was conducted in rats.

Published in the Jan. 20 edition of the Proceedings of the National Academy of Sciences.

UT Medicine San Antonio is the clinical practice of the School of Medicine at The University of Texas Health Science Center San Antonio. Primary care doctors and specialists see patients in private practice at UT Medicine’s clinical home, the Medical Arts & Research Center (MARC), located in the South Texas Medical Center at 8300 Floyd Curl Drive, San Antonio 78229.Visit the Web site at www.UTMedicine.org for a complete listing of clinics and phone numbers.

WEDNESDAY February 3, 2011---------News Archive

Placenta-Derived Stem Cells Therapy For Stroke

Study suggests human amniotic cells “cross talk” with melatonin receptor MT1 to induce stem cell growth.

Researchers from the University of South Florida (USF) and co-researchers in Brescia, Italy, have discovered that placenta-derived stem cells interacting with the melatonin receptor MT1, promote recovery from stroke in laboratory mice.

Human amniotic epithelial cells, stem cells derived from human placenta left over from live births (and generally discarded) grew and differentiated when they interacted with the melatonin receptor called MT1.

This potentially therapeutic response occurred when the stem cells were transplanted into laboratory test tubes and in animal models of stroke. The same cells did not perform in a similar manner when interacting with melatonin receptor MT2.

“Along with increasing cell proliferation and survival rate, MT1 also enhanced the differentiation of placenta-derived stem cells into neuronal cells,” said the study’s lead author, Yuji Kaneko, PhD, a researcher with the USF Center of Excellence for Aging and Brain Repair. “Targeting the MT1 receptor could be beneficial as MT1 appears to enhance cell proliferation.”

According to Dr. Kaneko, placenta-derived stem cells are pluripotent – meaning they are able to differentiate into many types of cells – and current research is geared toward their ability to differentiate into neuronal cells for use in brain repair.

Dr. Kaneko and colleagues examined how stem cells “express” specific melatonin receptors. MT1 is one of two kinds of melatonin found in humans, and is the primary hormone secreted by the pineal gland. MT1 receptor is a membrane protein located in specific areas of the brain.

Although the research focused on models of stroke, the researchers conclude that human amniotic epithelial cell-melatonin treatment could also be useful in treating oxidative stress.

In addition and consistent with past studies, they found high levels of vascular (blood vessel) endothelial growth factor acts together with melatonin. The researchers believe that MT1 “solicits" vascular endothelial growth factor - which then contributes to amniotic epithelial cells and MT1 working together in a neuroprotective manner.

“This ‘cross-talk’ between melatonin and stem cells is an under explored research area,” Dr. Kaneko said.

Their results, said Dr. Kaneko, advance the concept that stem cells might be switched on with melatonin treatment, or switched off by withholding melatonin.

“This melatonin receptor technology can facilitate the regulation of stem cell growth and differentiation as well as the stimulation of the cell’s growth factor secretory capacity,” Kaneko concluded.

Dr. Cesar V. Borlongan (USF) and Dr. Ornella Parolini (Fondazione Poliambulanza Istituto Ospedaliero of Brescia, Italy) served as senior authors of this paper. Placenta cells were provided by senior co-author Dr Parolini. The cells were obtained from discarded placenta after delivery and under institutional approval and consent.

The study is published in the current issue of the Journal of Pineal Research.

USF Health is dedicated to creating a model of health care based on understanding the full spectrum of health. It includes the University of South Florida’s colleges of Medicine, Nursing, Public Health and Pharmacy, the School of Biomedical Sciences and the School Physical of Therapy and Rehabilitation Sciences; and the USF Physician’s Group.

Safer Way To Make Induced Pluripotent Stem Cells

Researchers at Johns Hopkins have found a better way to create induced pluripotent stem (iPS) cells—adult cells reprogrammed with the properties of embryonic stem cells—from a small blood sample. This new method, described last week in Cell Research, avoids creating DNA changes that could lead to tumor formation.

“These iPS cells are much safer than ones made with previous technologies because they don’t involve integrating foreign viruses that can potentially lead to uncontrolled, cancerous cell growth,” says Linzhao Cheng, Ph.D., an associate professor of medicine in the Division of Hematology and a member of the Johns Hopkins Institute of Cell Engineering. “This is important if iPS cells are to be used as therapies one day.”

Cheng says the higher-quality iPS cells will also be more reliable in research studies, “since we don’t have to worry about extra genetic changes associated with previous technologies interfering with study results.”

Johns Hopkins researchers created the safer iPS cells by transferring a circular piece of DNA into blood cells from anonymous donors to deliver the needed genetic components.

The traditional way is to use viruses to carry DNA into a cell’s genome. Unlike the viral methods, the circular DNA the Hopkins team used is designed to stay separate from the host cell’s genome. After the iPS cells formed, the circular DNA delivered into the blood cells was gradually lost.

Using about a tablespoon of human adult blood or umbilical cord blood, the researchers grew the blood cells in the lab for eight to nine days. The researchers then transferred the circular DNA into the blood cells, where the introduced genes turned on to convert the blood cells to iPS cells within 14 days.

The research group verified conversion from mature blood cells to iPS cells by testing their ability to behave like stem cells and differentiate into other cell types, such as bone, muscle or neural cells. They also looked at the DNA from a dozen iPS cell lines to make sure there were no DNA rearrangements.

Cheng says the new method is also more efficient than the traditional use of skin cells to make iPS cells. “After a skin biopsy, it takes a full month to grow the skin cells before they are ready to be reprogrammed into iPS cells, unlike the blood cells that only need to grow for eight or nine days,” says Cheng. “The time it takes to reprogram the iPS cells from blood cells is also shortened to two weeks, compared to the month it takes when using skin cells.”

Cheng says “this easy method of generating integration-free human iPS cells from blood cells will accelerate their use in both research and future clinical applications.”

This study was funded by The Johns Hopkins University, a New York Stem Cell grant and grants from the National Institutes of Health.

Other authors on this manuscript are Bin-Kuan Chou, Pashant Mali, Xiaosong Huang, Zhaohui Ye, Sarah Dowey, Linda Resar and Chunlin Zou of the Johns Hopkins University School of Medicine; Y. Alex Zhang of the Cell Therapy Center at Xuanwu Hospital and Capital Medical University in Beijing, China; and Jay Tong of All-Cells LLC in Emeryville, California.

TUESDAY February 2, 2011---------News Archive

Combating Childhood Heart Disease

When the body can’t distinguish its right side from its left during development, a child can develop a condition called heterotaxy in which the heart is severely malformed, leading to congenital heart disease.

To improve survival in these children, researchers at Yale School of Medicine sought to identify the genes that cause heterotaxy.

They have shown in a new study that patients with heterotaxy have considerably more copy number variations (CNVs) on their genomes than do control patients.

Mustafa Khokha, M.D., assistant professor of pediatrics and genetics at Yale, and co-authors studied over 200 patients with heterotaxy as well as a large number of control subjects.

They identified and analyzed genome-wide CNVs in humans and then tested these genes in a frog model called Xenopus tropicalis. Copy number variations are insertions or deletions of regions of the genome, so parts of the genome might be deleted or a region might be duplicated.

Khohka said that the frog is a good model for testing genes identified from patients with heterotaxy because the developmental program to establish the left-right axis is nearly identical in frogs compared to humans.

“Five of the seven genes we identified in heterotaxy patients also cause left-right axis abnormalities in frogs when CNV genes were reduced,” said Mustafa. “Therefore, we have shown that children with heterotaxy have a higher burden of CNVs that also cause abnormalities in frogs.”

Khokha explained that while humans may appear symmetric across our right and left sides externally, internally our organs are not symmetric.

For example, our heart sits on the left side of our body along with the stomach and spleen. Our liver sits on the right. Also, the left and right side of the heart perform very different functions; the right side pumps blood to lungs while the left pumps blood to the body.

In children with heterotaxy, because the body cannot properly place the organs on the left or right sides, the heart in particular is severely malformed and can lead to severe disease. In fact, about 90 percent of these children have complex congenital heart disease, which requires surgery to reconstruct their hearts for the child to survive.

“This study is a big step toward understanding what causes congenital heart disease and hopefully will give us some idea of which genes lead to better or worse outcomes,” said Khohka.

“We also hope to improve our understanding of the genes that affect left-right development and the mechanisms involved in determining your left side from your right side. We also believe our results show that combining human genetics with rapid model systems such as the frog will allow us to rapidly identify genes that affect embryonic development and better understand the causes of these childhood diseases.”

In this “bench to bassinet” program, the plan is to identify many more patients with congenital heart disease and identify the mutations that have caused their disease.

A better understanding of the mutations that cause congenital heart disease might allow physicians to tailor surgery and long-term care to improve patient outcomes, Brueckner says, adding that congenital heart disease is clearly a broad spectrum of diseases and identifying the causative genes will allow physicians to better define the specific disease for any one patient.

The findings are published January 31 in Proceedings of the National Academy of Sciences (PNAS) Early Edition.

Martin Brueckner, a senior author on this study has been awarded a U01 grant from the NHLBI of the NIH.

In addition to Khokha and Brueckner, other Yale authors on the study include Richard P. Lifton, Khalid Fakhro, Murim Choi, Stephanie M. Ware, John Belmont, and Jeffrey Towbin.

If Junk DNA Is Useful, Why Not Shared Equally?

Recently, it has become clear that junk DNA performs a wide range of important tasks. As a result, attention is shifting to asking why some organisms have so much of it and other organisms so little.

DNA was originally thought to have a single function: to help cells make proteins. Any DNA not immediately required to produce proteins was written off as “junk” and unworthy of study.

But a puzzle was posed by “introns,” those stretches of DNA that interrupt the sequence of genes. Ashley Farlow, Eshwar Meduri and Christian Schlötterer of the University of Veterinary Medicine, Vienna propose a mechanism to account for the range of intron numbers observed between different species.

Their theory is published in the current issue of the journal Trends in Genetics.

The presence of introns in genes requires cells to process "messenger RNA" molecules before synthesizing proteins. This process is costly in terms of the time it takes and is often error-prone. However, it was long believed that this was simply the price organisms paid for the ability to create new proteins.

But recent work has made it clear that introns have many important functions. And so attention now is focused on why some organisms have so few introns and others so many.

It seems likely that new introns are added to DNA when double-stranded DNA breaks occur. Breaks can arise from a variety of causes.

A "homologous" repair of a double strand break rejoins the DNA strands between two similar or identical strands.

A "non-homologous" repair typically uses short homologous DNA sequences called microhomologies to guide repair. Non-homologous reparis are often present in single-stranded overhangs at the ends of double-strand breaks. When the overhangs are perfectly compatible, a "non-homologous" repair usually repairs the break accurately. But imprecise repairs are much more common when the overhangs are not compatible, that is, they have non-homologous ends.

Farlow and colleagues at the Institute of Population Genetics of the University of Veterinary Medicine, Vienna reasoned that introns may be lost by a similar mechanism. An examination of areas of DNA where introns are known to have been lost in organisms such as worms and flies support their idea.

The "homologous" and "non-homologous" repair paths are essentially separate and compete with each other to correct DNA breaks. Scientists at the University of Veterinary Medicine, Vienna now believe that species-specific differences in the activity of these two repair paths might be a cause for variation in intron number.

This theory represents a fundamental change in the way we think about the evolution of DNA. Evolution has seen periods of large scale intron loss alternating with periods of intron gain which has been interpreted as resulting from changing selection pressure on a given species.

The new theory provides an alternative interpretation: changes in the activities of the “homologous” and “non-homologous” pathways for repairing DNA breaks could cause introns to be lost faster than they are gained, or vice versa.

This new idea is consistent with what we currently know about intron numbers, which range from a handful in some simple eukaryotes to more than 180,000 in the human genome.

“Linking intron gain and loss to the repair of DNA breaks offers a neat explanation for how intron number can change over time. This theory may account for the huge diversity we seen in intron number between different species” says Farlow.

The paper DNA double-strand break repair and the evolution of intron density by Ashley Farlow, Eshwar Meduri and Christian Schlötterer is published in the January issue of the journal Trends in Genetics (2011, Vol. 27, pp. 1-6).

MONDAY February 1, 2011---------News Archive

DNA Caught "Rock 'N Rollin"

DNA, that marvelous, twisty molecule of life, has an alter ego, research at the University of Michigan and the University of California, Irvine reveals.

On rare occasions, its building blocks "rock and roll," deforming the familiar double helix into a different shape.

"We show that the simple DNA double helix exists in an alternative form—for one percent of the time—and that this alternative form is functional," said Hashim M. Al-Hashimi, who is the Robert L. Kuczkowski Professor of Chemistry and Professor of Biophysics at U-M. "Together, these data suggest that there are multiple layers of information stored in the genetic code." The findings were published online Jan. 26 in the journal Nature.

It's been known for some time that the DNA molecule can bend and flex, something like a rope ladder, but throughout these gyrations its building blocks—called bases—remain paired up just the way they were originally described by James Watson and Francis Crick, who proposed the spiral-staircase structure in 1953. By adapting nuclear magnetic resonance (NMR) technology, Al-Hashimi's group was able to observe transient, alternative forms in which some steps on the stairway come apart and reassemble into stable structures other than the typical Watson-Crick base pairs.

The question was, what were these alternative stable structures?

"Using NMR, we were able to access the chemical shifts of this alternative form," said graduate student Evgenia Nikolova. "These chemical shifts are like fingerprints that tell us something about the structure." Through careful analysis, Nikolova realized the "fingerprints" were typical of an orientation in which certain bases are flipped 180 degrees.

"It's like taking half of the stairway step and flipping it upside down so that the other face now points up," said Al-Hashimi. "If you do this, you can still put the two halves of the step back together, but now what you have is no longer a Watson-Crick base pair; it's something called a Hoogsteen base pair."

"Using computational modeling, we further validated that individual bases can roll over inside the double helix to achieve these Hoogsteen base pairs," said Ioan Andricioaei, an associate professor of chemistry at the University of California, Irvine.

Hoogsteen base pairs have previously been observed in double-stranded DNA, but only when the molecule is bound to proteins or drugs or when the DNA is damaged. The new study shows that even under normal circumstances, with no outside influence, certain sections of DNA tend to briefly morph into the alternative structure, called an "excited state."

Previous studies of DNA structure have relied mainly on techniques such as X-ray and conventional NMR, which can't detect such fleeting or rare structural changes.

"These methods do not capture alternative DNA structural forms that may exist for only a millisecond or in very little abundance, such as one percent of the time," said Al-Hashimi. "We took new solution NMR methods that previously have been used to study rare deformations in proteins and adapted them so that they could be used to study rare states in nucleic acids. Now that we have the right tools to look at these so-called excited states, we may find other short-lived states in DNA and RNA."

Because critical interactions between DNA and proteins are thought to be directed by both the sequence of bases and the flexing of the molecule, these excited states represent a whole new level of information contained in the genetic code, Al-Hashimi said.

In addition to Al-Hashimi, Nikolova and Andricioaei, the paper's authors are undergraduate student Abigail Wise and assistant professor of biological chemistry Patrick O'Brien of U-M and postdoctoral researcher Eunae Kim of the University of California, Irvine.

The researchers received funding from the National Science Foundation, the National Institutes of Health and the University of Michigan.

Worm Infection May Protect Infant From Eczema

Exposure to worm infections in the womb may protect a newborn infant from developing eczema, a study funded by the Wellcome Trust suggests.

A large trial in Uganda showed that treating a pregnant woman for worm infections increased her child's chances of developing the allergic skin disease.

Published this week in the journal Pediatric Allergy and Immunology, the research supports the so-called 'hygiene hypothesis', which proposes that exposure to infections in early childhood can modify the immune system and protect the child from allergies later in life.

The World Health Organisation estimates that one in five of the world's population suffers from allergic diseases such as asthma and eczema, but this epidemic is no longer restricted to developed countries: more than four out of five deaths due to asthma occur in low and lower-middle income countries. The declining incidence and prevalence of infectious diseases – including chronic infection by worms known as helminths – is widely considered to be an important contributor to this increase.

Helminth infection can cause symptoms ranging from mild anaemia to stomach pain and vomiting, depending on how severe the infection. But, very often people have no symptoms at all. The parasitic worms tend to enter the body through contaminated food or water, mosquito bites or through walking in bare feet on contaminated soil.

A preliminary study carried out at the Uganda Research Unit on AIDS in Entebbe in 2005 showed a reduced risk of eczema among infants whose mothers had worms and suggested an increased incidence among infants of mothers who received albendazole – a commonly used drug to treat worm infection – during pregnancy compared to infants whose mothers received a placebo.

In a follow-up study, researchers carried out a randomised, double-blind trial on 2,507 pregnant women in Uganda, comparing those treated with either albendazole or praziquantel, against those administered a placebo, and watching how this affected their offspring's risk of developing eczema.

Harriet Mpairwe, first author of the new study, says: "Worm infections can adversely affect a person's health, but the evidence also suggests that exposure to infection early in a child's life can have a beneficial effect in terms of modifying its immune system and protecting against allergies. We wanted to examine in a large cohort what effect de-worming women during pregnancy has on their offspring."

The researchers showed for the first time that treatment of pregnant women with albendazole appeared to almost double the risk of eczema in their offspring (an increase by a factor of 1.8) and that treatment with praziquantel more than doubled (an increase by a factor of 2.6) the risk of eczema among infants of mothers infected by the Schistosoma mansoni worm (a parasite which causes the disease schistosomiasis).

The findings support the hypothesis that maternal worms during pregnancy, neonatal life and early breastfeeding, may protect against allergy in infancy and that treatment of these worms during pregnancy increases the risk of allergy.

Professor Alison Elliott from the London School of Hygiene and Tropical Medicine, senior author of the study, says: "Our study suggests that routine de-worming during pregnancy, in settings where most worm infections are mild, may not be beneficial for the children and may actually cause problems with allergy. However, before we recommend changes to treatment policy, we need to do more work to confirm these findings and better understand what is happening.

"The findings certainly support the so-called 'hygiene hypothesis'. What will be important for the eczema story will be to see whether there are long term effects on allergy, especially asthma, at school age. Our next step is to investigate this further."

The research comes as Wellcome Collection prepares to open a major exhibition Dirt: The Filthy Reality of Everyday Life, exploring our relationship to dirt and hygiene across the centuries. The exhibition opens on 24 March 2011.


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