Scientific fact : Development of gene therapy

Since the late 1980s, gene therapy, more than virtually any other type of therapy, has given rise not only to high expectations of treatment success but also great concerns regarding health risks. Since the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG) issued its first memorandum in 1995, this field of research has developed enormously.

Wide-ranging experiments have shown the therapeutic potential as well as the risks of gene therapy. The second memorandum, which has just been presented by the DFG Senate Commission on Genetic Research, makes it clear that gene therapy already shows signs of success in certain areas, such as severe hereditary immunodeficiency diseases, while in other areas there is still considerable need for research. Moreover, the clinical application of gene therapy requires careful risk/benefit assessment, although in this respect it does not differ substantially from other therapeutic approaches.

Gene therapy is defined as the introduction of genes into tissues or cells via gene transfer, with the purpose of deriving a therapeutic or preventative benefit from the function of these genes. Gene transfer is achieved using a vector – a kind of vehicle that carries the gene. Somatic gene transfer only targets body cells (somatic cells). Introducing genes into the germline is illegal in Germany. The first well-documented gene therapy studies were launched in the early 1990s. By 2005 it was estimated that more than 1,100 gene therapy studies had been conducted worldwide, one-third of them in Europe, and a significant number in Germany. The DFG is currently funding a Priority Programme for research groups, some of which are international leaders in their field, that examine the entry and persistence of gene therapy vectors in target cells.

In spite of continued great difficulties with technical implementation, initial successes in somatic gene therapy are on the horizon, for example in treating adenosine deaminase deficiency and chronic granulomatous disease. There are also initial indicators that point to the efficacy of gene therapy in treating chronic lymphatic leukaemia and haemophilia B. But successes in clinical testing come with their share of setbacks, such as the currently slight margin of therapeutic effectiveness over unwanted side effects. This underscores the necessity to carefully assess risks and benefits and also shows that there is still a dire need for more research on gene therapy. Basic research should be conducted in direct collaboration across disciplines, using animal models and clinical studies. An acute need for research exists, especially regarding the development of efficient and safe vectors for gene transfer.

Source : Deutsche Forschungsgemeinschaft

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The good, the bad and the 'green' -- harnessing the potential of bacteria

A diverse family of bacteria that can cause a potentially fatal illness in humans but could offer a greener alternative to petrol to power our cars will be the subject of a talk by a University of Nottingham academic at an international conference.

Professor Nigel Minton, one of the world's leading experts on the Clostridium bacteria, will be presenting at the Society for Applied Microbiology (SfAM) annual Winter Meeting, being held at the Royal Society in London on January 12. In his presentation Professor Minton will discuss the potential exploitation of the anaerobic, Gram-positive Clostridium bacteria — a few strains of which have given the genus a bad name.

Clostridium difficile infection is the most significant cause of hospital-acquired diarrhoea and is seven times more deadly than MRSA. The bacterium is present in the gut of up to three per cent of healthy adults and 66 per cent of infants. Usually it is kept in check by the healthy balance of bacteria in the gut but when this is disturbed by certain antibiotics, C.difficile can multiply rapidly and produce toxins that cause illness and death. The disease is spread through spores, usually from poor hygiene. The emergence of highly virulent clones means that cases and fatalities from the illness are on the increase.

In addition, there has been heightened public concern in recent years about the potential use by bioterrorists of the food-borne pathogen Clostridium botulinum, which causes the rare but serious paralytic illness botulism.M I B S I T B T

Being good moms couldn't save the woolly mammoth

New research from The University of Western Ontario leads investigators to believe that woolly mammoths living north of the Arctic Circle during the Pleistocene Epoch (approx. 150,000 to 40,000 years ago) began weaning infants up to three years later than modern day African elephants due to prolonged hours of darkness.

This adapted nursing pattern could have contributed to the prehistoric elephant's eventual extinction. The findings were published recently in the journal, Palaeogeography, Palaeoclimatology, Palaeoecology.

By studying the chemical composition of adult and infant mammoth teeth, Jessica Metcalfe, an Earth Sciences PhD student working with professor Fred Longstaffe, was able to determine woolly mammoths that once inhabited Old Crow, Yukon didn't begin eating plants and other solid foods before the age of two (and perhaps as late as three) and considers predatory mammals like saber-toothed cats and a lack of sufficient vegetation to be the secondary reasons for delayed weaning.

"In modern Africa, lions can hunt baby elephants but not adults. They can't kill adults. But they can kill babies and by and large, they tend to be successful when they hunt at night because they have adapted night vision," explains Metcalfe, who examined fossil specimens alongside Grant Zazula of the Yukon Paleontology Program. "In Old Crow, where you have long, long hours of darkness, the infants are going to be more vulnerable, so the mothers nursed longer to keep them close."

Metcalfe says delayed weaning by Old Crow mammoths may have further significance for understanding mammoth life histories and extinction. "Today, a leading cause of infant elephant deaths in Myanmar is insufficient maternal milk production," offers Metcalfe. "Woolly mammoths may have been more vulnerable to the effects of climate change and human hunting than modern elephants not only because of their harsher environment, but also because of the metabolic demands of lactation and prolonged nursing, especially during the longer winter months."

Metcalfe concludes that knowing more about the past, can only help researchers understand more about the present and the future. "Mammoths lived all over the world for thousands of years, even millions of years, and then became extinct about 10,000 years ago, which was around the time the climate started warming the last time," says Metcalfe. "Understanding their ecology, their adaptations and their behaviour not only gives us insight into why they became extinct but also, potentially, gives us a better understanding of modern day mammals and how they might respond to the current warming of the planet."

Source : University of Western OntarioM I B S I T B T

If junk DNA is useful, why is it not shared more equally?

The presence of introns in genes requires cells to process "messenger RNA" molecules before synthesizing proteins, a process that is costly and often error-prone. It was long believed that this was simply part of the price organisms paid for the flexibility to create new types of protein but recent work has made it clear that introns themselves have a number of important functions. And so attention is gradually shifting to asking 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 – which may arise from a variety of mechanisms – are not repaired "correctly" but the newly created ends are instead joined to other fragments of DNA. 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 provides support for their idea.

DNA breaks may be treated in one of two ways: correct repair (by a relatively time-consuming process known as "homologous recombination") or the rapid and error-prone joining of non-homologous ends. The two pathways are essentially separate and can compete with each other for DNA breaks to work with. The scientists at the University of Veterinary Medicine, Vienna now suggest that species-specific differences in the relative activity of these two pathways might underlie the observed variation in intron number.

The 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 and this has been interpreted as the result of changing selection pressure. However, the rates at which single species have gained and lost introns throughout evolution have been found to vary in parallel, consistent with Farlow's notion that the two processes are related. 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.

The 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. And as Farlow says, "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."

Source : University of Veterinary Medicine -- ViennaM I B S I T B T

Animal with the most genes? A tiny crustacean

Complexity ever in the eye of its beholders, the animal with the most genes -- about 31,000 -- is the near-microscopic freshwater crustacean Daphnia pulex, or water flea. By comparison, humans have about 23,000 genes. Daphnia is the first crustacean to have its genome sequenced.

The findings are part of a comprehensive report in this week's Science by members of the Daphnia Genomics Consortium, an international network of scientists led by the Center for Genomics and Bioinformatics (CGB) at Indiana University Bloomington and the U.S. Department of Energy's Joint Genome Institute. A bullet-point list of the Science paper's most important findings appears at the end of this release.

"Daphnia's high gene number is largely because its genes are multiplying, by creating copies at a higher rate than other species," said project leader and CGB genomics director John Colbourne. "We estimate a rate that is three times greater than those of other invertebrates and 30 percent greater than that of humans."

Scientists have studied Daphnia for centuries because of its importance in aquatic food webs and for its transformational responses to environmental stress. Predators signal some of the animals to produce exaggerated spines, neck-teeth or helmets in self-defense. And like the virgin nymph of Greek mythology that shares its name, Daphnia thrives in the absence of males -- by clonal reproduction, until harsh environmental conditions favor the benefits of sex."More than one-third of Daphnia's genes are undocumented in any other organism -- in other words, they are completely new to science," says Don Gilbert, coauthor and Department of Biology scientist at IU Bloomington.

Sequenced genomes often contain some fraction of genes with unknown functions, even among the most well-studied genetic model species for biomedical research, such as the fruit fly Drosophila. By using microarrays (containing millions of DNA strands affixed to microscope slides) that are made to measure the conditions under which these new genes are transcribed into precursors for proteins, experiments that subjected Daphnia to environmental stressors point to these unknown genes having ecologically significant functions.

"If such large fractions of genomes evolved to cope with environmental challenges, information from traditional model species used only in laboratory studies may be insufficient to discover the roles for a considerable number of animal genes," Colbourne said. Daphnia is emerging as a model organism for a new field of science -- Environmental Genomics -- that aims to better understand how the environment and genes interact. This includes a practical need to apply scientific developments from this field toward managing our water resources and protecting human health from chemical pollutants in the environment.

James E. Klaunig, professor and chair of the School of Health, Physical Education, and Recreation's Department of Environmental Health at IU Bloomington, predicts the present work will yield a more realistic and scientifically-based risk evaluation. "Genome research on the responses of animals to stress has important implications for assessing environmental risks to humans," Klaunig said. "The Daphnia system is an exquisite aquatic sensor, a potential high-tech and modern version of the mineshaft canary. With knowledge of its genome, and using both field sampling and laboratory studies, the possible effects of environmental agents on cellular and molecular processes can be resolved and linked to similar processes in humans."

The idea behind environmental genomics for risk assessment is fairly simple. Daphnia's gene expression patterns change depending on its environment, and the patterns indicate what state its cells are in. A water flea bobbing in water containing a chemical pollutant will express by tuning-up or tuning-down a suite of genes differently than its clonal sisters accustomed to water without the pollutant. Importantly, the health effects of most industrially produced compounds at relevant concentrations and mixtures in the environment are unknown, because current testing procedures are too slow, too costly, and unable to indicate the causes for their effects on animals, including human. The new findings suggest that Daphnia's research tools (like microarrays) and genome information can provide a higher-throughput and information-rich method of measuring the condition of our water supply.

A requisite for reaching model system status is a large research community that contributes to its growing body of knowledge and resources. Over the course of the project, the Daphnia Genomics Consortium has grown from a handful of founding members to more than 450 investigators distributed around the globe. Nearly 200 scientists have contributed published work resulting from the genome study, many in open-source journals published as a thematic series by BioMedCentral.M I B S I T B T

Out of Africa -- how the fruit fly made its way in the world

Fruit flies that moved from sub-Saharan Africa found themselves confronted by conditions very different from those to which they were accustomed. Most obviously, the average temperatures were considerably lower and so it is no surprise that the flies had to adapt to cope with life in the north. As a result of thousands of years of evolution, populations in sub-Saharan African and in Europe now differ dramatically in a number of characteristics known to relate to temperature (such as pigmentation, size and resistance to cold). Schlötterer's previous work had suggested that a single gene, interestingly known as cramped (crm), might be involved in helping the flies survive in a colder environment but conclusive proof was lacking.

The crm protein is a transcription factor, so Jean-Michel Gibert in Schlötterer's laboratory decided to investigate what genes it could regulate, continuing to work on the project following his move to the University of Geneva. Gibert and Schlötterer focused in particular on genes known to be involved in wing development, such as the so-called cubitus interruptus (ci) gene, the regulation of which is known to depend on temperature. Satisfyingly, they were able to show that crm is absolutely required for the inactivation of the ci gene.

M I B S I T B T

Where did flowers come from? New Research reveals

The University at Buffalo is a key partner in a $7.3 million, multi-institution collaboration to explore the origins of all flowers by sequencing the genome of Amborella, a unique species that one researcher has nicknamed the "platypus of flowering plants."

Amborella is an understory shrub or small tree found in only one place on the planet: the Pacific islands of New Caledonia. The plant, a direct descendant of the common ancestor of all flowering plants, is the single known living species on the earliest branch of the genetic tree of life of flowering plants. As such, Amborella is a molecular living fossil, said Victor Albert, UB Empire Innovation Professor in biological sciences and a co-principal investigator on the Amborella genome project.

In the same way that the DNA of the platypus, a mammal of ancient lineage, can help us study the evolution of all mammals, the DNA of Amborella can help us learn about the evolution of all flowers, Albert said. Specifically, by comparing the genetic make-up of Amborella to that of newer species, biologists will be able to study a diverse range of plant characteristics, from how flowers resist drought and how fruits mature to how critical crops might respond to global warming.

"This is work that's related to the human condition in various ways. We're talking about food, fiber, fuel and the future," said Albert, a faculty member in UB's New York State Center of Excellence in Bioinformatics and Life Sciences. "Most of our food comes from flowers. All the fruit crops and grains are flowering plants. Cotton fiber is from fruit, and fruits come from flowers. Soybeans are fruits. Rice comes from the seed of a flowering plant."

Albert's co-investigators include Claude W. dePamphilis at Pennsylvania State University, who is leading the research; Hong Ma and Stephan Schuster at Penn State; Douglas E. Soltis, Pamela S. Soltis and W. Brad Barbazuk at the University of Florida; Steven D. Rounsley at the University of Arizona; James Leebens-Mack at the University of Georgia; Jeffrey Palmer at Indiana University; and Susan Wessler at the University of California, Riverside. The National Science Foundation is funding the project.

The team plans to complete and publish a draft sequence of the Amborella genome this year, Albert said. To share results with scientists around the world, the group will make the genome available online. "The Amborella genome and the strategies we are using to obtain and analyze the genome will provide not only a unique scientific resource with broad impacts on plant biology, but it also will provide excellent opportunities to demonstrate the utility of an evolutionary perspective across the biological sciences," said Albert, who is also a member of teams sequencing the genomes of coffee and avocado.

The Amborella project builds on another floral genetics project that dePamphilis of Penn State led. In that earlier study, he and partners including Albert sought information on the origins of flowers by comparing active genes of flowering plants including Amborella and non-flowering plants called gymnosperms. The team published major findings in the Proceedings of the National Academy of Sciences in December, reporting that genetic programming found in gymnosperm cones gave rise to flowering plants.

The Amborella genome project is the natural next step: Now that we know more about how the first flowers evolved, what can we learn about how they diversified? With a fossil record dating to just over 130 million years ago, flowering plants now include as many as 400,000 species on land and in water. Sequencing a genome involves determining the order in which nucleotide bases -- adenine, guanine, cytosine and thymine -- appear in strands of DNA. To complete this task, the Amborella team is employing "shotgun" technology that breaks DNA into tiny bits, sequences those bits simultaneously and reassembles them into a long chain. The approach is cheaper and quicker than older methods that require scientists to sequence entire strands of DNA in order, beginning at one end and moving to the other.

At UB, Albert and fellow researchers will use visual mapping to check their colleagues' work, examining large pieces of sequenced DNA under a microscope to make sure those pieces fit correctly on Amborella chromosomes. (Though scientists do not know the exact sequence of the Amborella genome, they do already know how large chunks of DNA map to one another.) UB researchers will also compare Amborella's genetic material to that of other plants, including rice, the cucumber, the tomato and the potato.

The goal of these comparative studies is to learn more about whole-genome duplication, a commonplace process in flowers in which a new plant inherits an extra, duplicate copy of its parents' DNA. Because redundant copies of genes can evolve to develop new functions, scientists think that whole-genome duplication may be behind "Darwin's abominable mystery" -- the abrupt proliferation of new varieties of flowering plants in fossil records dating to the Cretaceous period. Amborella has relatively few chromosomes, leading biologists including Albert to conclude that the species may never have undergone such a doubling.

Besides research, the Amborella genome project also includes plans for creating education, training and mentoring opportunities for high school students, undergraduates, graduate students and postdoctoral researchers.

Source : University at BuffaloM I B S I T B T

Nerve cells can distinguish odors.............But How????? New Research Reveals

Whether different odors can be quickly distinguished depends on certain synapses in the brain that inhibit nerve stimulation. The researchers in Professor Dr. Thomas Kuner's team at the Institute of Anatomy and Cell Biology at Heidelberg University Medical School and Dr. Andreas Schäfer at the Max Planck Institute for Medical Research have shown that mice in which a certain receptor in the olfactory center is missing can distinguish similar smells more quickly than mice without genetic manipulation. This behavior was directly attributed to inhibitor loops between adjacent nerve cells.

The discovery of the activation principle of "lateral inhibition" in the eye 43 years ago by Haldan K. Hartline, George Wald, and Ragnar Granit was honored with a Nobel Prize. The Heidelberg researchers have for the first time succeeded in confirming the same mechanism for the olfactory system, from the molecular level to behavior. The results of the studies were published in the prestigious journal "Neuron".

Odors attach to receptors of olfactory cells in nasal mucosa, where they trigger nerve signals. These signals are processed in what is known as the olfactory bulb, a part of the brain. In the neuronal network, the incoming signal is converted to a specific electrical pattern that is transmitted to the cerebral cortex and other areas of the brain and is recognized there. Local inhibitor loops make recognizing smells more preciseM I B S I T B T

Fluorescent compounds make tumors glow....New research reveals.

A series of novel imaging agents could light up tumors as they begin to form – before they turn deadly – and signal their transition to aggressive cancers. The compounds – fluorescent inhibitors of the enzyme cyclooxygenase-2 (COX-2) – could have broad applications for detecting tumors earlier, monitoring a tumor's transition from pre-malignancy to more aggressive growth, and defining tumor margins during surgical removal.

"We're very excited about these new agents and are moving forward to develop them for human clinical trials," said Lawrence Marnett, Ph.D., the leader of the Vanderbilt University team that developed the compounds, which are described in the May 1 issue of Cancer Research. COX-2 is an attractive target for molecular imaging. It's not found in most normal tissues, and then it is "turned on" in inflammatory lesions and tumors, Marnett explained.

"COX-2 is expressed at the earliest stages of pre-malignancy – in pre-malignant lesions, but not in surrounding normal tissue – and as a tumor grows and becomes increasingly malignant, COX-2 levels go up," Marnett said. Compounds that bind selectively to COX-2 – and carry a fluorescent marker – should act as "beacons" for tumor cells and for inflammation.

Marnett and his colleagues previously demonstrated that fluorescent COX-2 inhibitors – which they have now dubbed "fluorocoxibs" – were useful probes for protein binding, but their early molecules were not appropriate for cellular or in vivo imaging. "It was a real challenge to make a compound that is COX-2 selective (doesn't bind to the related COX-1 enzyme), has desirable fluorescence properties, and gets to the tissue in vivo," Marnett said.

To develop such compounds, Jashim Uddin, Ph.D., research assistant professor of Biochemistry, started with the "core" chemical structure of the anti-inflammatory medicines indomethacin and celecoxib. He then tethered various fluorescent parts to the core structure, ultimately synthesizing more than 200 compounds. The group tested each compound for its interaction with purified COX-2 and COX-1 proteins and then assessed promising compounds for COX-2 selectivity and fluorescence in cultured cells and in animals. Two compounds made the cut.M I B S I T B T

Did You know ? 1 in 25 people have gene that causes heart failure in India

One in 25 people from India and other south Asian countries carries a mutated gene that causes heart failure.

Studying this gene, and the protein it encodes, could lead to new treatments for heart failure, Loyola University Health System researcher Sakthivel Sadayappan, PhD, wrote in a recent review article in the Journal of Molecular and Cellular Cardiology. Sadayappan has studied the gene and protein for 15 years. Investigating the protein could provide "a better understanding of the mechanics of heart function during health and disease," Sadayappan and first author David Barefield wrote. Barefield is a graduate student and Sadayappan is an assistant professor in the Department of Cell and Molecular Physiology at Loyola University Chicago Stritch School of Medicine.

Previous studies by Sadayappan and other researchers found that about 4 percent of people who live in India, Pakistan, Sri Lanka, Indonesia and Malaysia carry the mutation. Carriers have about a 90 percent chance of developing heart failure after age 45. About 60 million people worldwide, including about 40 million Indians, carry the mutation. (Sadayappan, who is from India, is not a carrier.) Sadayappan said the mutation likely arose in a single person roughly 33,000 years ago, and spread throughout south Asia.

The gene encodes for a protein, called cardiac myosin binding protein-C (cMyBP-C), that is critical for the normal functioning of the heart. In the mutated gene, 25 base pairs (DNA letters) are missing. As a result, the tail end of the protein is altered. Due to this modification, the protein is not properly incorporated into the functioning unit of cardiac muscle called sarcomere. Consequently, the heart does not contract properly. In younger carriers, the heart can compensate for this defect. But as the person ages, his or her heart is no longer able to compensate. Heart muscle becomes inflamed and does not work well, a condition called cardiomyopathy. The most common manifestation of cardiomyopathy is heart failure -- the heart can't pump enough blood to the rest of the body.M I B S I T B T