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UCSB Researchers Discover the Processes Leading to Acute Myeloid Leukemia

admin — Wed, 01 Feb 2012 05:42:47 +0000

Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry.

The UCSB research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML). The researchers were prompted to study this process by another research team’s discovery that AML patients have a mutation in a certain enzyme, which was reported in the New England Journal of Medicine. The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or “tagged.” Norbert Reich, professor in the Department of Chemistry and Biochemistry at UCSB, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.

Reich explained that tagging is a way of reading DNA at the cellular level. This falls within an area of study called epigenetics, a process that occurs “on top” of genetics. Each person has approximately 200 types of cells, all with the same DNA, and these must be controlled in different ways. “There is an enzyme –– a protein –– that tags DNA and controls which of the genes in your cells, your DNA, gets turned on and off,” said Reich. “So you have 20,000 genes, and you have to control them differently in your brain than in your liver.”

Reich explained that there is current interest in this broader field of epigenetics as a direction for the treatment of cancer. “There’s definitely the idea that this may be a new way of developing therapeutics, because you don’t have to kill the cancer cell,” said Reich. “Almost every cancer therapy that’s out there works on the principle that a cancer cell needs to be killed.”

With epigenetics, instead of only having DNA sequence coding for certain genes, there is an epigenetic process, with another layer of information on top of the genetic process. In this case, that information is the tagging by the methyl groups.

Science Brief thanks to EurekAlert.

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Cancer Sequencing Initiative Discovers Mutations Tied to Aggressive Childhood Brain Tumors

admin — Tue, 31 Jan 2012 03:40:02 +0000

Researchers studying a rare, lethal childhood tumor of the brainstem discovered that nearly 80 percent of the tumors have mutations in genes not previously tied to cancer. Early evidence suggests the alterations play a unique role in other aggressive pediatric brain tumors as well.

The findings from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) offer important insight into a poorly understood tumor that kills more than 90 percent of patients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG), is found almost exclusively in children and accounts for 10 to 15 percent of pediatric tumors of the brain and central nervous system.

“We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies,” said Suzanne Baker, Ph.D., co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology. She is a corresponding author of the study published in the January 29 online edition of the scientific journal Nature Genetics.

DIPG is an extremely invasive tumor that occurs in the brainstem, which is at the base of the skull and controls such vital functions as breathing and heart rate. DIPG cannot be cured by surgery and is accurately diagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in the U.S. and little is known about it.

Cancer occurs when normal gene activity is disrupted, allowing for the unchecked cell growth and spread that makes cancer so lethal. In this study, investigators found 78 percent of the DIPG tumors had alterations in one of two genes that carry instructions for making proteins that play similar roles in packaging DNA inside cells. Both belong to the histone H3 family of proteins. DNA must be wrapped around histones so that it is compact enough to fit into the nucleus. The packaging of DNA by histones influences which genes are switched on or off, as well as the repair of mutations in DNA and the stability of DNA. Disruption of any of these processes can contribute to cancer.

Researchers said that the mutations seem unique to aggressive childhood brain tumors.

“It is amazing to see that this particular tumor type appears to be characterized by a molecular ‘smoking gun’ and that these mutations are unique to fast-growing pediatric cancers in the brain,” said Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis and one of the study’s corresponding authors. “This is exactly the type of result one hopes to find when studying the genomes of cancer patients.”

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Quantitative Imaging Application to Gut And Ear Cells are Reported in 2 Nature Papers

admin — Tue, 17 Jan 2012 07:25:21 +0000

From tracking activities within bacteria to creating images of molecules that make up human hair, several experiments have already demonstrated the unique abilities of the revolutionary imaging technique called multi-isotope imaging mass spectometry, or MIMS, developed by researchers at Brigham and Women’s Hospital (BWH). MIMS can produce high-resolution, quantitative three-dimensional images of stable isotope tags within subcellular compartments in tissue sections or cells.

With its use of stable isotopes as tracers, MIMS has opened the door for biomedical researchers to answer various biological questions, as two new studies have demonstrated. These studies looked at the use of MIMS in tracking cell division in intestinal stem cells, lipid turnover in Drosophila flies, protein turnover in ear cells, and opened the way to human application by detecting the formation of new white blood cells. Both studies published in Nature online on January 15, 2012 and in print on January 26, 2012.

In the first study, researchers used MIMS to test the much debated “immortal strand hypothesis” which claims that as stem cells divide, the older template DNA remains together in a stem cell, as the newer DNA is passed to cells that differentiate forming the digestive lining of the small intestine.

By tagging DNA with stable isotope tracers, researchers tracked DNA replication as cells divided. They found that in any situation DNA segregation was random, thereby disproving the immortal strand hypothesis.

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NIH Scientists Identify Novel Approach to View Inner Workings of Viruses

admin — Sat, 14 Jan 2012 07:42:45 +0000

Since the discovery of the microscope, scientists have tried to visualize smaller and smaller structures to provide insights into the inner workings of human cells, bacteria and viruses. Now, researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, have developed a new way to see structures within viruses that were not clearly seen before. Their findings are reported in the Jan. 13 issue of Science.

Cryo-electron microscopy (cryo-EM) is a technique that allows scientists to image very small particles, like structures on the surface of viruses. This method has been useful in helping researchers understand how vaccines work. But, despite the success of cryo-EM, scientists have been unable to clearly visualize structures inside of viruses, because radiation is used to image them. “With lower doses of radiation, it is not possible to see inside the organism,” said lead author Dr. Alasdair Steven of the NIAMS Laboratory of Structural Biology Research. “However, higher doses of radiation damage the virus, destroying the very structures that we would like to view.”

Working in collaboration with the group of Dr. Lindsay Black at the University of Maryland Medical School, Baltimore, Steven and his team were able to turn the problem of radiation damage into an asset. Viruses, one of the simplest life forms, are made up of nucleic acids (DNA or RNA) and the proteins encoded by the nucleic acid instruction manual. The researchers realized that proteins inside the virus are more sensitive to damage than DNA.

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University of Florida Study on Newly Formed Plants Could Lead to Improved Crop Fertility

admin — Tue, 10 Jan 2012 05:25:58 +0000

A new University of Florida study shows genomes of a recently formed plant species to be highly unstable, a phenomenon that may have far-reaching evolutionary consequences.

Published online this week in the Proceedings of the National Academy of Sciences, the study is the first to document chromosomal variation in natural populations of a recently formed plant species following whole genome doubling, or polyploidy. Because many agricultural crops are young polyploids, the data may be used to develop plants with higher fertility and yields. Polyploid crops include wheat, corn, coffee, apples, broccoli and some rice species.

“It could be occurring in other polyploids, but this sort of methodology just hasn’t been applied to many plant species,” said study co-author Pam Soltis, distinguished professor and curator of molecular systematics and evolutionary genetics at the Florida Museum of Natural History on the UF campus. “So it may be that lots of polyploids – including our crops – may not be perfect additive combinations of the two parents, but instead have more chromosomes from one parent or the other.”

Researchers analyzed about 70 Tragopogon miscellus plants, a species in the daisy family that originated in the northwestern U.S. about 80 years ago. The new species formed naturally when two plants introduced from Europe mated to produce a hybrid offspring, and hybridization was followed by polyploidy.

Using a technique called “chromosome painting” to observe the plants’ DNA, UF postdoctoral researcher and lead author Michael Chester discovered that while whole genome doubling initially results in a new species containing 12 chromosomes from each parent, numbers subsequently vary among many plants.

The paints are made by attaching different dyes to DNA of the two parent species. Once the dye is applied, there is a match between the DNA of the paint and of the chromosome. Under a microscope, the chromosomes appear in one color or the other (red vs. green) depending on the parent from which they originated. Sometimes chromosomes are a patchwork of both colors because DNA from the two parents has been swapped as a result of chromosomal rearrangements.

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A Lake Fauna in a Shot-glass

admin — Tue, 13 Dec 2011 07:41:23 +0000

Danish research team leads the way for future biodiversity monitoring using DNA traces in the environment to keep track of threatened wildlife – a lake water sample the size of a shot-glass can contain evidence of an entire lake fauna.

Global biodiversity is plummeting while biologists are fighting to keep score and reliable monitoring of threatened animals remains a major challenge. The biologist toolset has changed little on this area for a hundred years – still relying on expensive expert surveys basically finding and counting the animals. However, this situation is now set to change according to a recent study by researchers at the Natural History Museum of Denmark published as a cover story in the acclaimed scientific journal Molecular Ecology. The results of the study show that a new method can be used to monitor rare and threatened animal species from DNA traces in their freshwater environments.

The development of the innovative DNA species monitoring was accomplished by PhD student Philip Francis Thomsen and Master’s students Jos Kielgast and Lars L. Iversen at Centre for GeoGenetics headed by professor Eske Willerslev.

“We have shown that the DNA detection method works on a wide range of different rare species living in freshwater – they all leave DNA traces in their environment which can be detected in even very small water samples from their habitat. In the water samples we find DNA from animals as different as an otter and a dragonfly,” says Philip Francis Thomsen.

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A lake fauna in a shot-glass

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Video Game Players Advancing Genetic Research

admin — Thu, 08 Dec 2011 06:12:23 +0000

Thousands of video game players have helped significantly advance our understanding of the genetic basis of diseases such as Alzheimer’s, diabetes and cancer over the past year. They are the users of a web-based video game developed by Dr. Jérôme Waldispuhl of the McGill School of Computer Science and collaborator Mathieu Blanchette. Phylo is designed to allow casual game players to contribute to scientific research by arranging multiple sequences of colored blocks that represent human DNA. By looking at the similarities and differences between these DNA sequences, scientists are able to gain new insight into a variety of genetically-based diseases.

The researchers are releasing the results computed from the solutions collected over the last year today, together with an improved version of Phylo for tablets.

Over the past year, Phylo’s 17,000 registered users have been able to simply play the game for fun or choose to help decode a particular genetic disease. “A lot of people said they enjoyed playing a game which could help to trace the origin of a specific disease like epilepsy,” said Waldispuhl. “There’s a lot of excitement in the idea of playing a game and contributing to science at the same time,” Blanchette agreed. “It’s guilt-free playing; now you can tell yourself it’s not just wasted time.”

Waldispuhl and his students came up with the idea of using a video game to solve the problem of DNA multiple sequence alignment because it is a task that is difficult for computers to do well. “There are some calculations that the human brain does more efficiently than any computer can. Recognizing and sorting visual patterns fall in that category,” explained Waldispuhl. “Computers are best at handling large amounts of messy data, but where we require high accuracy, we need humans. In this case, the genomes we’re analyzing have already been pre-aligned by computers, but there are parts of it that are misaligned. Our goal is to identify these parts and transform the task of aligning them into a puzzle people will want to sort out.”

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Penn Geneticists Help Show Bitter Taste Perception is Not Just About Flavors

admin — Thu, 08 Dec 2011 04:13:41 +0000

Long the bane of picky eaters everywhere, broccoli’s taste is not just a matter of having a cultured palate; some people can easily taste a bitter compound in the vegetable that others have difficulty detecting. Now a team of Penn researchers has helped uncover the evolutionary history of one of the genes responsible for this trait. Beyond showing the ancient origins of the gene, the researchers discovered something unexpected: something other than taste must have driven its evolution.

The team was led by Penn researchers Sarah Tishkoff, a Penn Integrates Knowledge professor with appointments in the genetics department in Penn’s Perelman School of Medicine and the biology department in the School of Arts and Sciences, and Michael C. Campbell, a postdoctoral fellow in the genetics department at the medical school, and included undergraduate and postdoctoral researchers from both the genetics and biology departments. The team included their collaborator Paul Breslin from the Monell Chemical Senses Center in Philadelphia and Rutgers University and researchers from the Musée de L’Homme in France, the National Institutes of Health and several African universities and research institutes.

Their research was published in the journal Molecular Biology and Evolution.

The researchers were interested in the gene TAS2R38, which codes for a bitter taste receptor protein with the same name. People with a certain version of that gene can taste a compound, phenylthiocarbamide, or PTC, which is chemically similar to naturally occurring bitter compounds, called glucosinolates, present in many foods, including cruciferous vegetables like broccoli and Brussels sprouts. These “tasters” find such foods to have a bitter taste that people with a different version can’t detect. As a result, “nontasters” have been shown to consume fewer cruciferous vegetables.

Modern humans originated in Africa, and populations from that region have the highest levels of genetic diversity globally. Previous studies had looked at variations in the PTC-sensitivity gene, but none had ever studied a large sample of diverse African populations with different cultures, ethnicities or diets.

“Because there is more genetic variation in African populations, you’re likely to see unique variants you may not see elsewhere,” Tishkoff said. “Our study of variation at the TAS2R38 gene in Africa and correlations with taste perception and diet gives us a clue about the evolutionary history of the gene and how natural selection might be influencing the pattern of variation.”

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Powerful Mathematical Model Greatly Improves Predictions for Species Facing Climate Change

admin — Sun, 04 Dec 2011 07:45:12 +0000

UCLA life scientists and colleagues have produced the most comprehensive mathematical model ever devised to track the health of populations exposed to environmental change.

The research, federally funded by the National Science Foundation, published Dec. 2 in the journal Science.

The team’s groundbreaking integral projection model, or IPM, unites various sub-disciplines of population biology, including population ecology, quantitative genetics, population genetics, and life-span and offspring information, allowing researchers to link many different data sources simultaneously. Scientists can now change just a single variable, like temperature, and see how that affects many factors for a population.

“This is one of the most innovative and holistic models, because it unifies so many sub-fields of ecology and genetics into one predictive model,” said study co-author Robert Wayne, a UCLA professor of ecology and evolutionary biology, who led the UCLA research team. “Traditionally, we have studied just a few ecological parameters at a time, like how much food there is or how the environment will change over time, and how that relates to population size. Here, we are analyzing everything at once.”

Among the researchers’ major findings with the IPM is that gradual, sustained change in an environment over time — a gradual increase in temperature, for example — has a greater impact on the species in an ecosystem than fluctuating changes.

“If we change the total environment, such as temperature, we change a whole suite of characteristics for a species, including viability, fertility, population size, body size and generation length,” Wayne said.

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Controlling Gene Expression to Halt Cancer Growth

admin — Tue, 01 Nov 2011 02:28:30 +0000

NUT midline carcinoma (NMC) is a cancer without a cure, and one that affects all age groups. NMC is a rapid-growth disease with an average survival time of four and a half months after diagnosis, making the development of clinical trials for potential therapies or cures for this cancer difficult, to say the least.

But difficult doesn’t mean impossible, and Olaf Wiest, professor of chemistry and biochemistry at the University of Notre Dame, is one of a group of collaborators studying the effects of a specific molecule (JQ1) on the trigger that controls the growth of this form of cancer.

Most people are familiar with genetics and the role they play in our height, hair color, and even predisposition to various diseases. “But there is this whole other world called epigenetics that controls which genes are expressed and which aren’t,” says Wiest.

This epigenetic world is made up of three classes of proteins: writers, erasers and readers, collectively the “instruction manual” that tells a gene when to activate and when to cease activation. Writers will create the instruction for the gene while erasers will remove instructions. Readers control the group and issue the start and stop commands for genes to use their instructions.

“The reason NMC is so aggressive is because these cancer cells divide very fast,” says Wiest. This rapid-growth is caused by the protein BRD4, an epigenetic reader that interacts with another protein called a histone. Their interaction changes the instructions for the gene and keeps the growth trigger permanently activated.

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UC Davis Researchers Discover Complexities of DNA Repair

admin — Tue, 25 Oct 2011 06:25:43 +0000

An international team of scientists led by UC Davis researchers has discovered that DNA repair in cancer cells is not a one-way street as previously believed. Their findings show instead that recombination, an important DNA repair process, has a self-correcting mechanism that allows DNA to make a virtual u-turn and start over.

The study’s findings, which appear in the Oct. 23 online issue of the journal Nature, not only contribute new understanding to the field of basic cancer biology, but also have important implications for potentially improving the efficacy of cancer treatments.

“What we discovered is that the DNA repair pathway called recombination is able to reverse itself,” said Wolf-Dietrich Heyer, UC Davis professor of microbiology and of molecular and cellular biology and co-leader of Molecular Oncology at UC Davis Cancer Center. “That makes it a very robust process, allowing cancer cells to deal with DNA damage in many different ways. This repair mechanism may have something to do with why some cancer cells become resistant to radiation and chemotherapy treatments that work by inducing DNA damage.”

Heyer likens this self-correcting ability of the DNA repair system to driving in a modern city where u-turns and two-way streets make it easy to rectify a wrong turn. “How much harder would it be to re-trace your path if you were in a medieval Italian city with only one-way streets,” he said.

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Vast Hidden Network Regulates Gene Expression in Cancer

admin — Mon, 17 Oct 2011 06:41:03 +0000

Researchers at Columbia University Medical Center (CUMC) and two other institutions have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases. The studies appear in the online edition of Cell.

“The discovery of this regulatory network fills in a missing piece in the puzzle of cell regulation and allows us to identify genes never before associated with a particular type of tumor or disease,” said Andrea Califano, PhD, professor of systems biology, director of the Columbia Initiative in Systems Biology, and senior author of the CUMC research team.

For decades, scientists have thought that the primary role of messenger RNA (mRNA) is to shuttle information from the DNA to the ribosomes, the sites of protein synthesis. However, these new studies suggest that the mRNA of one gene can control, and be controlled by, the mRNA of other genes via a large pool of microRNA molecules, with dozens to hundreds of genes working together in complex self-regulating sub-networks.

The findings have the potential to broaden investigations into how tumors develop and grow, who is at risk for cancer, and how to identify and inactivate key molecules that encourage the growth and spread of cancer.

For example, in the case of the phosphatase and tensin homolog gene (PTEN), a major tumor suppressor, deletions of its mRNA network regulators in patients appear to be as damaging as mutations of the gene itself in several types of cancer, the studies show.

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Johns Hopkins Scientists Discover ‘fickle’ DNA Changes in Brain

admin — Mon, 03 Oct 2011 02:29:01 +0000

Johns Hopkins scientists investigating chemical modifications across the genomes of adult mice have discovered that DNA modifications in non-dividing brain cells, thought to be inherently stable, instead underwent large-scale dynamic changes as a result of stimulated brain activity. Their report, in the October issue of Nature Neuroscience, has major implications for treating psychiatric diseases, neurodegenerative disorders, and for better understanding learning, memory and mood regulation.

Specifically, the researchers, who include a husband-and-wife team, found evidence of an epigenetic change called demethylation — the loss of a methyl group from specific locations — in the non-dividing brain cells’ DNA, challenging the scientific dogma that even if the DNA in non-dividing adult neurons changes on occasion from methylated to demethylated state, it does so very infrequently.

“We provide definitive evidence suggesting that DNA demethylation happens in non-dividing neurons, and it happens on a large scale,” says Hongjun Song, Ph.D., professor of neurology and neuroscience and director of the Stem Cell Program in the Institute for Cell Engineering of the Johns Hopkins University School of Medicine. “Scientists have previously underestimated how important this epigenetic mechanism can be in the adult brain, and the scope of change is dramatic.”

DNA comprises the fixed chemical building blocks of each person or animal’s genome, but the addition or removal of a methyl group at the specific location chemically alters DNA and regulates gene expression, enabling cells with the same genetic code to acquire and activate separate functions.

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Shake Hands with the Invisible Man

admin — Wed, 21 Sep 2011 06:25:39 +0000

Adermatoglypia, which leaves some individuals without fingerprints, is an exceedingly rare condition. Now professor Eli Sprecher of Tel Aviv University has traced the cause of the condition to a genetic mutation that affects only four documented families in the world. Despite the mutation’s scarcity, his research provides unique insights into the most complex biological phenomena, such as the consequences of lacking a single protein.

Science Brief thanks to EurekAlert.

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Shake hands with the invisible man

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Iberian Lynx Not Doomed By Its Genetics

admin — Wed, 24 Aug 2011 04:30:54 +0000

The low genetic diversity of the Iberian lynx – the most endangered carnivore in Europe – may not decrease the species’ chance of survival, according to new research by geneticists.

Research looking at DNA from Iberian lynx fossils shows that they have had very little genetic variation over the last 50,000 years, suggesting that a small long-term population size is the ‘norm’ in the species and has not hampered their survival. The new study is published in the journal Molecular Ecology.

Conservationists previously thought that having low genetic diversity would doom a species to extinction, through inbreeding and reduced ability to adapt to changing environments.

Such a lack of genetic diversity, also seen in other cat species such as African cheetahs, lions of the Ngorongoro crater and the Florida panther, is usually thought to be the result of population bottlenecks. The effect of human activity or the dramatic ecosystem changes at the end of the last ice age caused by the Holocene warming around 10,000 years ago are common explanations for the phenomenon.

However, when researchers in Spain, Denmark and Sweden extracted DNA from the fossil bones and teeth of Iberian lynx, covering a period of at least the last 50,000 years, they found no genetic variation over that period. They were looking at mitochondrial DNA – a part of the genome that is usually very variable.

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