Friday, 29 February 2008

MIT Researchers Show That iPS Cells Are Fully Pluripotent

MIT Researchers Show That iPS Cells Are Fully Pluripotent Friday, 29 February 2008 In this month's issue of Cell Stem Cell, scientists at MIT's Whitehead Institute for Biomedical Research continue their groundbreaking work on pluripotent stem cells. The team headed by Rudolf Jaenisch shows that a specific sequence of biochemical manipulations can reprogram a skin cell into a pluripotent stem cell. Results showed that when expressing the reprogramming genes, a minimum of 16 days is required to fully reprogram skin cells to pluripotent cells, with one pluripotency marker arising first at three days, followed by another marker at nine days, and the fully reprogrammed cell at 16 days or later. This final stage of reprogramming was also the time in which the expression of the four genes could be removed. Any time point before then, the cells could not be reprogrammed. The cells thus go through a sequential, not random, process of reprogramming. Jaenisch concludes that there is a specific sequence of events required for reprogramming a cell to a pluripotent state. Also, silencing of the four reprogramming genes is necessary for differentiation of the iPS. The results will help future researchers to define what a cell needs to reprogram itself without using a virus or cancer-causing genes.

Reference: Sequential Expression of Pluripotency Markers during Direct Reprogramming of Mouse Somatic Cells Cell Stem Cell, Vol 2, 151-159, 07 February 2008 ......... ZenMaster

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Wednesday, 27 February 2008

Human Nerve Cell Tissue

Penn researchers engineer first system of human nerve cell tissue Implications for nerve repair and implantation Wednesday, 27 February 2008 Researchers at the University of Pennsylvania School of Medicine have demonstrated that living human nerve cells can be engineered into a network that could one day be used for transplants to repair damaged to the nervous system. They report their findings in the February issue of the Journal of Neurosurgery. “We have created a three-dimensional neural network, a mini nervous system in culture, which can be transplanted en masse,” explains senior author Douglas H. Smith, MD, Professor, Department of Neurosurgery and Director of the Center for Brain Injury and Repair at Penn. Although neuron transplantation to repair the nervous system has shown promise in animal models, there are few sources of viable neurons for use in the clinic and insufficient approaches to bridge extensive nerve damage in patients. The Stretch Test In previous work, Smith’s group showed that they could induce tracts of nerve fibers called axons to grow in response to mechanical tension. They placed neurons from rat dorsal root ganglia (clusters of nerves just outside the spinal cord) on nutrient-filled plastic plates. Axons sprouted from the neurons on each plate and connected with neurons on the other plate. The plates were then slowly pulled apart over a series of days, aided by a precise computer-controlled motor system, creating long tracts of living axons.

Four individual human DRG neurons that survived for months in culture. Differing colors indicate different neuron-specific stains. Bottom: Center region of an engineered human nervous tissue construct showing stretch-grown axon bundles. Credit: Douglas H. Smith, MD, University of Pennsylvania School of Medicine
These cultures were then embedded in a collagen matrix, rolled into a form resembling a jelly roll, and then implanted into a rat model of spinal cord injury. After the four-week study period, the researchers found that the geometry of the construct was maintained and that the neurons at both ends and all the axons spanning these neurons survived transplantation. More importantly, the axons at the ends of the construct adjacent to the host tissue extended through the collagen barrier to connect with the host tissue as a sort of nervous tissue bridge. The Next Step Now, the researchers have taken the next step and are applying this technique to living human nerve cells. Smith and his team obtained human dorsal root ganglia neurons (due to their robustness in culture) to engineer into transplantable nervous tissue. The root ganglia neurons were harvested from 16 live patients following elective ganglionectomies, and four thoracic neurons were harvested from organ donors. The neurons were purified and placed in a specially designed growth chamber. Using the stretch growth technique, the axons were slowly pulled in opposite directions over a series of days until they reached a desired length. The neurons survived at least three months in culture while maintaining the ability to generate action potentials, the electrical signals transmitted along nerve fibers. The axons grew at about 1 millimeter per day to a length of 1 centimeter, creating the first engineered living human nervous tissue constructs. “This study demonstrates the promise of adult neurons as an alternative transplant material due to their availability, viability, and capacity to be engineered,” says Smith. “We’ve also shown the feasibility of obtaining neurons from living patients as a source of neurons for autologous, or self, transplant as well as from organ donors for allografts.” ......... ZenMaster
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Tuesday, 26 February 2008

Lemurs' evolutionary history may shed light on our own

Lemurs' evolutionary history may shed light on our own Tuesday, 26 February 2008 After swabbing the cheeks of more than 200 lemurs and related primates to collect their DNA, researchers at the Duke Institute for Genome Sciences & Policy (IGSP) and Duke Lemur Center now have a much clearer picture of their evolutionary family tree. Found in nature only on the island nation of Madagascar, off Africa’s south-eastern coast, lemurs and their close relatives the lorises represent the sister lineage to all other primates. And that makes lemurs key to understanding what distinguishes us and the rest of our primate cousins from all other animals, according to Julie Horvath, a post-doctoral researcher in the IGSP. “If we find a trait or characteristic shared between lemurs and other primates, it can tell us what is or isn’t primate-specific and when those traits arose,” said Horvath, who works in the laboratory of IGSP director Huntington Willard. The new “phylogenomic toolkit” the researchers developed will also play into conservation efforts aimed to save the critically endangered lemurs, by helping to define the number of existing species, said David Weisrock, a post-doctoral researcher working with Duke Lemur Center Director Anne Yoder. The researchers report their findings in the March 1 issue of Genome Research. Scientists uncover evolutionary relationships among species based on similarities and differences in their genetic codes. The increasing number of fully sequenced genomes available for major evolutionary groups has allowed resolution of relationships that had been considered unmanageable before. But except for humans’ close evolutionary ties to chimpanzees, many of the relationships among other apes, monkeys and pre-monkeys called prosimians have remained somewhat murky, according to Horvath. To find out where Madagascar’s lemurs fit in, the Duke team first needed to develop the tools for comparing sequences from the many lemur species to one another, and to those of other primates including humans. The researchers identified stretches of DNA sequence held in common between the genomes of the human, the ring-tailed lemur and the mouse lemur. These "conserved sequences" served as primers, allowing them to sample comparable bits of sequence across the genomes of the various primate species. Their analysis confirmed that the first to branch off from the rest of the lemurs, some 66 million years ago, was the aye-aye — a nocturnal primate that taps on trees with its fingers to listen for insects inside, making it Madagascar’s version of a woodpecker. They also resolved the relationships among species within the remaining four evolutionary lineages, which includes a diverse cast of characters: the sifakas, named for the hissing “shee-fak” sound they make; the sportive lemurs, which are strictly nocturnal; the mouse lemurs, the smallest of all living primates; and the many so-called “true lemurs,” including the blue-eyed black lemur (one of only three blue-eyed primates in the world) and the ring-tailed lemur, which is often found in zoos. “By throwing this much data at the problem, we have absolutely confirmed, beyond any statistical doubt, that the spectacular array of lemurs all descended from a single ancestral species,” said Yoder, noting that lemurs account for about 20 percent of primate species and live on less than one percent of the earth’s surface. “It further highlights the importance of Madagascar as a cradle for biodiversity.” The study lays the groundwork for doing future studies of lemurs and other primates. The methods the group developed for this study can also be applied to understanding evolutionary relationships among other animal groups for which genomic sequences are hard to come by. ......... ZenMaster

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Thursday, 21 February 2008

Human Genetic Variation

U-M researchers release most detailed global study of genetic variation Wednesday, 20 February 2008 University of Michigan scientists and their colleagues at the National Institute on Aging have produced the largest and most detailed worldwide study of human genetic variation, a treasure trove offering new insights into early migrations out of Africa and across the globe. Like astronomers who build ever-larger telescopes to peer deeper into space, population geneticists like U-M's Noah Rosenberg are using the latest genetic tools to probe DNA molecules in unprecedented detail, uncovering new clues to humanity's origins. The latest study characterizes more than 500,000 DNA markers in the human genome and examines variations across 29 populations on five continents. "Our study is one of the first in a new wave of extremely high-resolution genome scans of population genetic variation," said Rosenberg, an assistant research professor at U-M's Life Sciences Institute and co-senior author of the study, to be published in the Feb. 21 edition of Nature. "Now that we have the technology to look at thousands, or even hundreds of thousands, of genetic markers, we can infer human population relationships and ancient migrations at a finer level of resolution than has previously been possible." The new study, led by Rosenberg and National Institute on Aging colleague Andrew Singleton, produced genetic data nearly 100 times more detailed than previous worldwide assessments of human populations. It shows that:

  • A recently discovered type of human genetic variation, known as a copy-number variant or CNV, is a reliable addition to the toolkit of population geneticists and should speed the discovery of disease-related genes. Rosenberg and his colleagues discovered 507 previously unknown CNVs, which are large chunks of DNA — up to 1,000,000 consecutive "letters" of the genetic alphabet — that are either repeated or deleted entirely from a person's genome. Various diseases can be triggered by an abnormal gain or loss in the number of gene copies.
  • It's sometimes possible to trace a person's ancestry to an individual population within a geographic region. While previous studies have found that broad-scale geographic ancestry could be successfully traced, the new results indicate "it's becoming increasingly possible to use genomics to refine the geographic position of an individual's ancestors with more and more precision," Rosenberg said.
  • Human genetic diversity decreases as distance from Africa — the cradle of humanity — increases. People of African descent are more genetically diverse than Middle Easterners, who are more diverse than Asians and Europeans. Native Americans possess the least-diverse genomes. As a result, searching for disease-causing genes should require the fewest number of genetic markers among Native Americans and the greatest number of markers among Africans.

The results are being made available on publicly shared databases. "I hope the study will be an invaluable resource for understanding genomic variability and investigating genetic association with disease," said the NIA's Singleton.

A schematic of worldwide human genetic variation, with colours representing different genetic types. The figure illustrates the great amount of genetic variation in Africa. Illustration by Martin Soave/University of Michigan.

The researchers analyzed DNA from 485 people. They examined three types of genetic variation: single-nucleotide polymorphisms, or SNPs; haplotypes; and CNVs. If the human genome is viewed as a 3-billion-letter book of life, then SNPs represent single-letter spelling changes, haplotype variations equate to word changes, and CNVs are wholesale deletions or duplications of full pages. The patterns revealed by the new study support the idea that humans originated in Africa, then spread into the Middle East, followed by Europe and Asia, the Pacific Islands, and finally to the Americas. The results also bolster the notion of "serial founder effects," meaning that as people began migrating eastward from East Africa about 100,000 years ago, each successive wave of migrants carried a subset of the genetic variation held by previous groups. "Diversity has been eroded through the migration process," Rosenberg said. In addition to his position at the Life Sciences Institute, Rosenberg is an assistant professor of human genetics, biostatistics, and ecology and evolutionary biology, as well as an assistant research professor of bioinformatics. "This data set is so rich. It provides a much more comprehensive, cross-sectional snapshot of the human genome than previous studies," said Paul Scheet, a post-doctoral researcher in the U-M Department of Biostatistics and one of the lead authors. "The next step for these studies is to sequence whole genomes," said Mattias Jakobsson, a post-doctoral researcher at the U-M Center for Computational Medicine and Biology and another lead author. "You would take 500 individuals, and you would just completely sequence everything, and then you'd have almost every important variant that's out there." The work was supported in part by National Institutes of Health grants, the U-M Center for Genetics in Health and Medicine, the Alfred P. Sloan Foundation, the Burroughs Wellcome Fund, the National Center for Minority Health and Health Disparities, and the Intramural Program of the National Institute on Aging. Reference: Genotype, haplotype and copy-number variation in worldwide human populations Nature 451, 998-1003 (21 February 2008) doi:10.1038/nature06742 .........

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Wednesday, 20 February 2008

Human Stem Cells Aid Stroke Recovery In Rats

Human Stem Cells Aid Stroke Recovery In Rats Wednesday, 20 February 2008 Neural cells derived from human embryonic stem cells helped repair stroke-related damage in the brains of rats and led to improvements in their physical abilities, according to a new study by researchers at the Stanford University School of Medicine. This study, to be published in the Feb. 20 issue of the journal PLoS ONE, marks the first time researchers have used human embryonic stem cells to generate neural cells that grow well in the lab, improve a rat’s physical abilities and consistently don’t form tumours when transplanted. Though the author’s caution that the study is small and that more work is needed to determine whether a similar approach would work in humans, they said they believe it shows the potential for using stem cell therapies in treating strokes. Senior author Gary Steinberg, MD, PhD, the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences, said that with 750,000 people having strokes in the United States each year, the disease creates a massive burden for people, their families and the medical system. “Human embryonic stem cell-based therapies have the potential to help treat this complex disease,” Steinberg said, adding that he hopes the cells from this study can be used in human stroke trials within five years. Human embryonic stem cells are able to form any cell type in the body. Pushing those cells to form neurons rather than other types of cells has been a substantial hurdle, as has avoiding the cells’ tendency to form tumours when transplanted. Because embryonic stem cells are still immature and retain the ability to renew themselves and produce all tissue types, they tend to grow uncontrollably into tumours consisting of a mass of different cells. First author Marcel Daadi, PhD, a senior scientist in Steinberg’s lab, said the team overcame both obstacles by growing the embryonic stem cells in a combination of growth factors that nudged the cells to mature into stable neural stem cells. After six months in a lab dish, those neural stem cells continued to form only the three families of neural cells — neurons, astrocytes and oligodendrocytes — and no tumours. Convinced that the cells appeared safe, Daadi and co-author Anne-Lise Maag, a former Stanford medical student, transplanted those cells into the brains of 10 rats with an induced form of stroke. At the end of two months, the cells had migrated to the damaged brain region and incorporated into the surrounding tissue. None of those transplanted cells formed tumours. Once in place, the replacement cells helped repair damage from the induced stroke. The researchers mimicked a stroke in a region of the brain that left one forelimb weak. This model parallels the kinds of difficulties people experience after a stroke. Testing at four weeks and again at eight weeks after the stem cell transplants showed the animals were able to use their forelimbs more normally than rats with similarly damaged brain regions that had not received the transplants. “The great thing about these cells is that they are in unlimited supply and are very versatile,” Daadi said. The neural cells the group generated grew indefinitely in the lab and could be an ongoing source of cells for treating stroke or other injuries, he added. In previous studies, Steinberg and others have implanted cells from cord blood, bone marrow, foetal and adult brain tissue or derived from mouse embryonic stem cells into stroke-damaged rats, but none of those cell types appear as promising as the cells in this study, the researchers said. Those cells are not as easy to produce in large scale for the appropriate quality assurance program to meet a sufficient patient population for multi-centre clinical trials. Before researchers can begin testing these neural cells in human stroke patients, Steinberg and Daadi said they need to verify that the cells are effective in other animal stroke models and don’t form tumours. They are working with industry groups to grow the cells in accordance with U.S. Food and Drug Administration guidelines, which would be necessary before they could move on to human trials. Reference: Adherent Self-Renewable Human Embryonic Stem Cell-Derived Neural Stem Cell Line: Functional Engraftment in Experimental Stroke Model. Daadi MM, Maag A-L, Steinberg GK PLoS ONE 3(2), (2008): e1644. doi:10.1371/journal.pone.0001644 ......... ZenMaster

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Saturday, 16 February 2008

The bioengineering challenge: From stem cells to organs

The bioengineering challenge: From stem cells to organs Saturday, 16 February 2008 For more than a decade, Peter Zandstra has been working at the University of Toronto to rev up the production of stem cells and their descendants. The raw materials are adult blood stem cells and embryonic stem cells. The end products are blood and heart cells – lots of them. Enough mouse heart cells that they form beating tissue. To do this, he has been applying engineering principles to stem cell research – work that has just earned him recognition by the American Association for the Advancement of Science (AAAS). The society will induct him as a Fellow during its Annual Conference, being held in Boston from February 14 to 18. Starting with computer models of stem cell growth and differentiation (the process by which a stem cell matures into its final form), Zandstra has moved on to develop more sophisticated culture methods that fine-tune the microenvironments to guide the generation of the different cells types that make up the mature cells in our tissues: heart cells for the heart or blood cells for blood. "If you describe something mathematically, you have a much better understanding of it than if you just observe it," he says. "And it's also a powerful way to test many different hypotheses ‘in silico’ before going into the lab and doing the much more difficult experiments in vitro." Dr. Zandstra, the Canada Research Chair in Stem Cell Bioengineering, also held a prestigious NSERC Steacie Fellowship. The Steacie prize - which goes to six select Canadian professors annually – allowed Zandstra to extend his work from mouse to man. “There's only so much we can do with mouse cells,” notes Dr. Zandstra. “Now if we can also figure out how to get human embryonic stem cells to differentiate on command to generate functional adult-like cells, you can begin to think about the kinds of medical conditions you could treat with them.” ......... ZenMaster

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Friday, 15 February 2008

Mitochondrial DNA mutations can cause degenerative heart and muscle disease

UCI study provides insights into age-related diseases and proof that mitochondrial DNA is central to health 
Friday, 15 February 2008

A single change in the DNA of mitochondria – the cellular power plants that generate energy in all human cells – has been found to cause degenerative heart and muscle disease, according to University of California, Irvine researchers. The study provides new insights into age-related disease and further proof that the mitochondria play a central role in human health. Study results appear in the Feb. 15 issue of Science. (More about mitochondria, see below.) 

Douglas Wallace, director of the Center for Molecular and Mitochondrial Medicine and Genetics at UC Irvine and study leader, says the findings also address a core dilemma facing efforts to cure and treat inherited degenerative diseases, including chronic heart and muscle disease. 

“While these diseases traditionally have been assumed to result from mutations in the genes encoded by DNA in the cell’s nucleus,” he said, “most common degenerative diseases frequently do not exhibit inheritance patterns wholly consistent with our understanding of these nuclear DNA genetics. Our demonstration that mutations in the mitochondrial DNA can also cause the same diseases means that both nuclear and mitochondrial DNA genes that affect mitochondrial function can contribute to disease risk.” 

A complete understanding of the importance of mitochondrial defects caused by either mitochondrial or nuclear DNA mutations could lead to treatments effective for age-related diseases that affect millions worldwide, Wallace added. To prove the importance of mitochondrial DNA mutations for health, the UC Irvine researchers generated a relatively mild mitochondrial DNA mutation in mouse cells, which reduced a key enzyme of mitochondrial energy production by 50 percent. They then used female mouse embryonic stem cells to create mice in which this mitochondrial DNA energy deficiency mutation was inherited through the female germ line, which is the reproductive cells and other genetic material passed to offspring. Mice harbouring the mutant mitochondrial DNA appeared normal early in life, but by one year they developed marked muscle and heart disease, similar to disease that can develop in humans. 

“Consequently, mitochondrial DNA mutations and their related energy defects are sufficient to cause age-related disease,” said Wallace, the Donald Bren Professor of Biological Sciences and Molecular Medicine and a National Academy of Sciences member. 

“Therefore, mitochondrial energy deficiency may be a common factor in these diseases.” 

Weiwei Fan, Katrina Waymire, Navneet Narula, Peng Li, Christophe Rocher, Pinar Coskun, Mani Vannan, Jaget Narula and Grant MacGregor of UC Irvine also participated in this study, which is supported by the National Institutes of Health and the California Institute of Regenerative Medicine.

About mitochondria: Mitochondria exist in all human cells and have their own DNA. They generate energy by burning the calories that we eat with the oxygen that we breathe, much like a coal-burning power plant. In addition to energy, mitochondrial combustion generates “smoke” in the form of oxygen radicals. These oxygen radicals damage the mitochondrial DNA giving it a very high mutation rate, both in the tissues of our bodies and also in the cells of the female germ line. Since the mitochondrial DNA is outside of the cell’s nucleus and not associated with its DNA, it is inherited exclusively from the mother and is present in thousands of copies per cell. As the mitochondrial DNA of our cells accumulates damage with age, the blueprints required to sustain energy production are lost, the body’s equivalent of a brownout. The resulting age-related decline in cellular energy production ultimately leads to tissue and organ failure and the development of clinical disease or illness. Thus the accumulation of mtDNA damage may explain aging and the delayed-onset and progressive course of age-related diseases and aging. 


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Genome of marine organism tells of humans' unicellular ancestors

Choanoflagellates, a type of nanoplankton, are closest living one-celled relatives of animals Friday, 15 February 2008 The newly sequenced genome of a one-celled, planktonic marine organism, reported Thursday, Feb. 14 in the journal Nature, is already telling scientists about the evolutionary changes that accompanied the jump from one-celled life forms to multicellular animals like ourselves. In the Nature paper and a complementary Science paper also released this week, University of California, Berkeley, biologists Nicole King, Daniel Rokhsar and their colleagues present their first draft of the genome of a choanoflagellate (ko AN oh FLA je let) called Monosiga brevicollis, and their first comparisons with the genes of multicellular animals, the so-called metazoans. The sequencing and analysis was performed by the Department of Energy Joint Genome Institute (JGI) in Walnut Creek, California, in collaboration with researchers from UC Berkeley and eight other institutions.

Choanoflagellates are aquatic microbial eukaryotes that are distinguished by an apical flagellum (green), which is used for swimming and feeding, surrounded by a collar of microvilli or tentacles (red) against which bacterial prey are trapped. The nucleus is highlighted in blue. Credit: Nicole King laboratory, UC Berkeley.

According to King, biologists know almost nothing about these organisms, aside from the fact that they are an important food for krill, which are the main source of food for baleen whales, and that, by consuming large quantities of bacteria, choanoflagellates play a major role in the carbon cycle of the oceans. Yet, because choanoflagellates and animals shared a common ancestor between 600 million and a billion years ago, they hold a key to understanding the origins and evolution of animals. "Choanoflagellates are the closest living unicellular relatives of animals and, as such, can help us learn about our history and the history of life on Earth, which has been dominated by one-celled organisms," said King, an assistant professor of integrative biology and of molecular and cell biology, and a 2005 MacArthur "genius" Award winner. "They help shed light on the biology and genome content of the unicellular organisms from which we evolved." One finding confirmed by the sequencing is that choanoflagellates have many genes that, in animals, produce proteins essential to cell-to-cell signalling and in determining which cells stick to one another. Since Monosiga does not form colonies as do some other choanoflagellates, these proteins' roles are a mystery, King said. "In animals, some of these proteins, called cadherins, evolved for linking cells together; they are the glue that prevents clumps of cells from falling apart," King said. "Choanoflagellates show no hint of multicellularity, but they have 23 genes for cadherin proteins, about the same as the fruit fly or the mouse." In the Science paper, King and graduate student Monika Abedin report that some of these proteins are found around the base of the choanoflagellate cell, where the choanoflagellate attaches to surfaces, and around the tentacles, where bacteria are captured and ingested. Perhaps, they argue, the last single-celled ancestor of all animals (including humans) employed these ancient cadherin proteins to bind and eat bacteria, while more complex metazoans adopted these proteins for gluing cells into a larger, many-celled creature. "The transition to multicellularity likely rested upon the co-option of diverse transmembrane and secreted proteins to new functions in intercellular signalling and adhesion," they wrote in Science. "Choanoflagellates really are a unique window back in time to the origin of animals and humans. They are our best way of triangulating on that last unicellular ancestor of animals, because the fossil record is not there," said Dan Rokhsar, UC Berkeley professor of molecular and cell biology and program head for computational genomics at JGI. King and Rokhsar also are members of UC Berkeley's Center for Integrative Genomics. Choanoflagellates are found abundantly in salt and fresh water around the world, where they gorge on bacteria. At about 10 microns across, they're about the size of another one-celled eukaryote, yeast. While yeast are well known to genetics researchers, however, choanoflagellates are not – a situation King hopes will change now that the genome is sequenced. The cells are egg-shaped with a single long tail or flagellum at one end surrounded at its base by a collar of tentacles – choano comes from the Greek word for collar - that capture bacteria. The flagellum propels the choanoflagellate through the water and also washes bacteria towards the tentacles. Because choanoflagellates resemble the feeding cells of sponges, which are among the most primitive of animals, biologists 165 years ago proposed that these organisms were very distant ancestors of multicelled animals. King and Rokhsar successfully proposed the choanoflagellate for sequencing several years ago as part of the Department of Energy's Microbial Genome Program, and in the intervening years, King worked on isolating enough uncontaminated DNA for sequencing. The draft genome, completed and annotated in 2007, consists of about 9,200 genes. It is similar in size to the genomes of fungi and diatoms, but much smaller than the genomes of metazoans. Humans, for example, have about 25,000 genes. Interestingly, the choanoflagellate has nearly as many introns – non-coding regions once referred to as "junk" DNA – in its genes as humans do in their genes, and often in the same spots. Introns have to be snipped out before a gene can be used as a blueprint for a protein and have been associated mostly with higher organisms. The choanoflagellate genome, like the genomes of many seemingly simple organisms sequenced in recent years, shows a surprising degree of complexity, King said. Many genes involved in the central nervous system of higher organisms, for example, have been found in simple organisms that lack a centralized nervous system. Likewise, choanoflagellates have five immunoglobulin domains, though they have no immune system; collagen, integrin and cadherin domains, though they have no skeleton or matrix binding cells together; and proteins called tyrosine kinases that are a key part of signalling between cells, even though Monosiga is not known to communicate, or at least does not form colonies. These findings are helping King and her colleagues assemble a picture of what the original common ancestor of humans and choanoflagellates looked like and also get hints about the first animals. "It remarkable to what extent we can figure out how those animal ancestors must have been able to stick together and communicate with each other, at least in ways that allow you to make hypotheses about what those first steps toward animals looked like," Rokhsar said. Nevertheless, it is not always easy determining which genes were in the last common ancestor of choanoflagellates and humans, and which are new. Choanoflagellates and humans have been evolving for the same length of time, so differences between the genomes may reflect genes that have been lost by choanoflagellates as much as genes gained by humans. Comparison of the Monosiga genome to that of other organisms, including another choanoflagellate – a colony-former called Proterospongia, whose genome is due to be sequenced by the National Institutes of Health - may answer such questions. King has hopes that the Monosiga genome will answer many questions of animal evolution and illuminate the biology of this poorly understood aquatic creature. "This is a new era, where we start with a genome to understand the biology of an organism," King said, noting a similar situation with the starlet sea anemone, Nematostella vectensis, sequenced in 2007. "The genome is the toehold." ......... ZenMaster
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BMP signalling, skin stem cells and hair formation

BMP signalling, skin stem cells and hair formation Friday, 15 February 2008 The February 15th cover story of G&D reports on the recent discovery by Dr. Elaine Fuchs and colleagues at the Rockefeller University Laboratory of Mammalian Cell Biology and Development that BMP signalling in dermal papilla cells is important for hair follicle formation. The dermal papilla (DP) is a small cluster of mesenchymal cells that exist at the base of the hair follicle, and instruct nearby epithelial stem cells to induce hair follicle growth. But because DP cells are so few in number, and loose their hair-inducing potential in culture, the details of this molecular conversation have remained elusive. Dr. Fuchs’ team developed a clever genetic strategy to delete specific genes of interest in DP cells, and then graft these genetically engineered cells onto the backs of immunocompromised (and bald) mice, to study the effect of gene deficiency on hair growth. The researchers found that deletion of the receptor for the bone morphogenetic protein 1a (BMPR1a) in DP cells prevented the formation of hair follicles in engrafted mice. However, if BMPR1a is intact in DP cells, and a bit more BMP protein is added to the cells, then the DP-stem cell cross-talk is prolonged, and recipient mice grow a tuft of hair on their otherwise bald backs. “Several years ago, we devised a method to purify the cells and characterize the genes expressed by the DP and its neighbouring cells that make hair,” says Fuchs. “This gave us clues that BMP signalling might be important in specifying the unique hair-inducing properties of DP cells. We’ve now succeeded in testing this possibility and our findings are important not only for our understanding of the mesenchymal-epithelial crosstalk that is so critical for hair production, but also for developing new and improved methods for stimulating hair growth.” ......... ZenMaster

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Wednesday, 13 February 2008

Location matters, even for genes

Location matters, even for genes Wednesday, 13 February 2008 Moving an active gene from the interior of the nucleus to its periphery can inactivate that gene report scientists from the University of Chicago Medical Center in an article to be published early online Feb.13, 2008, in the journal Nature. Attachment to the inner nuclear membrane, they show, can silence genes, preventing their transcription — a novel form of gene regulation. "Several years ago, we and others described the correlation between nuclear positioning and gene activation," said study author Harinder Singh, Louis Block Professor of Molecular Genetics and Cell Biology and an Investigator in the Howard Hughes Medical Institute at the University of Chicago. "With that in mind, we wanted to take the next step, to design an experiment that could test causality. Could we move a gene from the center of the nucleus to the periphery, we asked, and then measure the consequences of such repositioning?" In mammalian nuclei, chromatin — a complex of DNA and associated proteins — is organized into structural domains through interactions with distinct nuclear compartments. In this study, the authors developed the molecular tools to take specific genes from these interior compartments, move them to the periphery and attach them to the nuclear membrane — which turned those genes off. Not only were selected "test" genes that served as markers turned off after being attached to the inner nuclear membrane, but also nearby "real" genes. Singh’s laboratory had become interested in studying the role of nuclear positioning in the control of gene activity based on work analyzing immunoglobulin heavy-chain genes. These genes are assembled by DNA recombination and code for proteins that are a crucial part of antibodies, produced in antibody-secreting lymphocytes or B-cells. "In cells that don’t produce antibodies, like fibroblasts or T-cells, these antibody genes are attached to the inner nuclear membrane and are not recombined or expressed," said Singh. On the other hand, antibody genes are actively transcribed and recombined in developing B-cells, and therefore positioned in the nuclear interior, far away from the periphery. Five years ago, Singh and colleagues reported in Science that even in developing B cells, antibody genes start off at the nuclear periphery. As young cells mature and prepare to produce antibodies, however, these genes move to the interior of the nuclei. The exact ways in which positioning at the outer edge of the nucleus prevents gene expression are still unclear. The likely suspects, said Singh, are some of proteins that reside in the inner nuclear membrane. These proteins may be involved in blocking transcription, he said. They accumulate at sites of attachment and come in contact with parts of certain silenced genes. "So we think that these proteins are part of the molecular machinery that is used for positioning genes at the inner nuclear membrane, as well as potentially for repressing them,” he said. In their Nature paper, Singh's team also showed for the first time that this transcriptional repression was dependent on breakdown and reformation of the nuclear membrane during cell division. The reorganizing of chromosomes occurs when cells divide. "This suggests that cell division is used not only to transmit the genetic information into daughter cells and create two equivalent cells," he said, "but it is also an opportunity for cells to reorganize their genomes in 3D space, sequestering parts of the genome at the nuclear periphery and rendering it inaccessible to transcription.” Singh and colleagues are now looking for examples of striking reorganization of the genome separated by one cell division — in which active genes, that will not be active after the cell divides, get pushed away from the interior to the periphery. The lead author, Karen Reddy, a postdoctoral fellow in the Singh laboratory, proposes that, such compartmentalization "implies the existence of DNA segments that encode for ‘nuclear addresses’ acting like a nuclear zip code to direct or predispose genes to associate with specific regions within the nucleus. This could be tremendously important," she said, "for understanding the underlying cause of some diseases that result from mutations in genes encoding inner nuclear membrane proteins." Additional authors of the paper include J.M. Zullo and E. Bertolino of the University of Chicago. Reference: Transcriptional repression mediated by repositioning of genes to the nuclear lamina Nature advance online publication 13 February 2008 doi:10.1038/nature06727 ......... ZenMaster

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Tuesday, 12 February 2008

MicroRNAs Makes Vertebrates

Evolving complexity out of 'junk DNA' Tuesday, 12 February 2008 The study, published today in Proceedings of the National Academy of Sciences, USA, claims to have solved this scientific riddle by analysing the genomics of primitive living fishes such as sharks and lampreys and their spineless relatives, such as the sea squirts. Vertebrates - animals such as humans that possess a backbone - are the most anatomically and genetically complex of all organisms, but explaining how they achieved this complexity has vexed scientists since the conception of evolutionary theory. Alysha Heimberg of Dartmouth College and her colleagues showed that microRNAs, a class of tiny molecules only recently discovered residing within what has usually been considered ‘junk DNA’, are hugely diverse in even the most lowly of vertebrates, but relatively few are found in the genomes of our invertebrate relatives. She explained: “There was an explosive increase in the number of new microRNAs added to the genome of vertebrates and this is unparalleled in evolutionary history.” Co-author, Dr Philip Donoghue of Bristol University’s Department of Earth Sciences continued: “Most of these new genes are required for the growth of organs that are unique to vertebrates, such as the liver, pancreas and brain. Therefore, the origin of vertebrates and the origin of these genes is no coincidence.” Dr Kevin Peterson of Dartmouth College said: “This study not only points the way to understanding the evolutionary origin of our own lineage, but it also helps us to understand how our own genome was assembled in deep time.” Reference: MicroRNAs and the advent of vertebrate morphological complexity Alysha M. Heimberg, Lorenzo F. Sempere, Vanessa N. Moy, Philip C. J. Donoghue and Kevin J. Peterson PNAS online, February 11, doi/10.1073/pnas.0712259105 ......... ZenMaster

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One More Group Reprogram Fibroblasts to Stem Cells

UCLA stem cell scientists reprogram human skin cells into embryonic stem cells Tuesday, 12 February 2008 UCLA stem cell scientists have reprogrammed human skin cells into cells with the same unlimited properties as embryonic stem cells without using embryos or eggs. Led by scientists Kathrin Plath and William Lowry, UCLA researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells. The UCLA study confirms the work first reported in late November of researcher Shinya Yamanaka at Kyoto University and James Thompson at the University of Wisconsin. The UCLA research appears Feb. 11, 2008, in an early online edition of the journal Proceedings of the National Academy of the Sciences. The implications for disease treatment could be significant. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient’s skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types – beta islet cells to treat diabetes, hematopoietic cells to create a new blood supply for a leukaemia patient, motor neuron cells to treat Parkinson’s disease. “Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells,” said Plath, an assistant professor of biological chemistry, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and lead author of the study. “Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications.” The UCLA work was completed at about the same time the Yamanaka and Thomson reports were published. Taken together, the studies demonstrate that human iPS cells can be easily created by different laboratories and are likely to mark a milestone in stem cell-based regenerative medicine, Plath said. These new techniques to develop stem cells could potentially replace a controversial method used to reprogram cells, somatic cell nuclear transfer (SCNT), sometimes referred to as therapeutic cloning. To date, therapeutic cloning has not been successful in humans. However, top stem cell scientists worldwide stress that further research comparing these reprogrammed cells with stem cells derived from embryos, considered the gold standard, is necessary. Additionally, many technical problems, such as the use of viruses to deliver the four genes for reprogramming, need to be overcome to produce safe iPS cells that can be used in the clinic. “Reprogramming normal human cells into cells with identical properties to those in embryonic stem cells without SCNT may have important therapeutic ramifications and provide us with another valuable method to develop human stem cell lines,” said Lowry, an assistant professor of molecular, cell and developmental biology, a Broad Stem Cell Center researcher and first author of the study. “It is important to remember that our research does not eliminate the need for embryo-based human embryonic stem cell research, but rather provides another avenue of worthwhile investigation.” The combination of four genes used to reprogram the skin cells regulate expression of downstream genes and either activate or silence their expression. The reprogrammed cells were not just functionally identical to embryonic stem cells. They also had identical biological structure, expressed the same genes and could be coaxed into giving rise to the same cell types as human embryonic stem cells. The UCLA research team included four young scientists recruited to UCLA’s new stem cell center in the wake of the passage of Proposition 71 in 2004, which created $3 billion in funding for embryonic stem cell research. The scientists were drawn to UCLA in part because of California’s stem cell research friendly atmosphere and the funding opportunities created by Proposition 71. In addition to Plath and Lowry, the team included Amander Clarke, an assistant professor of molecular, cell and developmental biology, and April Pyle, an assistant professor of microbiology, immunology and molecular genetics. The creation of the human iPS cells is an extension of Plath’s work on mouse stem cell reprogramming. Plath headed up one of three research teams that were able to successfully reprogram mouse skin cells into mouse embryonic stem cells. That work appeared in the inaugural June 2007 issue of the journal Cell Stem Cell. ......... ZenMaster

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Friday, 8 February 2008

Cheap Genome Sequencing?

Cheap Genome Sequencing? Friday, 08 February 2008 Today the company Illumina, based in San Diego, California, announced that they had sequenced a person’s DNA for $100,000, although this has yet to be confirmed (see Company claims to have sequenced man's genome cheaply). This compares with last year’s announcement that 454 Life Sciences in Branford, Connecticut, had sequenced the genome of Nobel Prize winner James Watson in two months for under $1 million. In October, Chinese officials also announced they had sequenced an Asian man's genome for about $1 million. It is not clear how Illumina’s $100,000 price tag compares with 454’s $1 million tally, because neither company has explained what labour, reagents or analysis were included in these totals. Reference: Company claims to have sequenced man's genome cheaply Published online 8 February 2008 Nature doi:10.1038/news.2008.563 More about the State-of-the-Art of Genome Sequencing: The Race to Read Genomes on a Shoestring, Relatively Speaking NY Times - February 9, 2008 ......... ZenMaster

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Thursday, 7 February 2008

Ancient Bacteria Efficiently Adapted to Changing Temperature on Earth

Scientists Rebuild Ancient Proteins to Reveal Primordial Earth's Temperature Thursday, 07 February 2008 Using the genetic equivalent of an ancient thermometer, a team of scientists has determined that the Earth endured a massive cooling period between 500 million and 3.5 billion years ago. Reporting today in the journal Nature, researchers from the University of Florida, the Foundation for Applied Molecular Evolution and the biotechnology company DNA2.0 describe how they reconstructed proteins from ancient bacteria to measure the Earth’s temperature over the ages. “By studying proteins encoded by these primordial genes, we are able to infer information about the environmental conditions of the early Earth,” said Eric Gaucher, Ph.D., president of scientific research at the Foundation for Applied Molecular Evolution in Gainesville and the study’s lead scientist. “Genes evolve to adapt to the environmental conditions in which an organism lives. Resurrecting these since long-extinct genes gives us the opportunity to analyze and dissect the ancient surroundings that have been recorded in the gene sequence. The genes essentially behave as dynamic fossils.” The team wanted to measure Earth’s temperature billions of years ago to learn more about life on Earth during the Precambrian period. But instead of taking the traditional route — analyzing rock formations or measuring isotopes in fossils — they opted to do what they knew best: protein reconstruction. “We’ve analyzed the temperature stability of proteins inside organisms that were around during those times,” said Omjoy Ganesh, a structural biologist in the University of Florida College of Medicine’s department of biochemistry and molecular biology. “The ancient oceans were warmer. For ocean organisms living during that time to survive, the proteins within them had to be stable at high temperatures.” After scanning multiple databases, the scientists struck gold with a protein called elongation factor, which helps bacteria string together amino acids to form other proteins. Each bacterial species has a slightly different form of the protein: Bacteria that live in warmer environments have resilient elongation factors, which can withstand high temperatures without melting. The opposite is true for bacteria that live in cold environments. Armed with information about when bacterial species evolved, the scientists rebuilt 31 elongation factors from 16 ancient species. By comparing the heat sensitivity of the reconstructed proteins, they were able to discern how Earth’s temperature changed over the ages. “Although the concept of ancestral gene resurrection was proposed more than 40 years ago, the development of efficient gene synthesis has only recently enabled the synthesis of ancestral genes,” said Sridhar Govindarajan, Ph.D., co-author of the paper and vice president of informatics at DNA2.0, a California-based company that constructed the genes. “Gene synthesis allows for a direct route from a calculated gene sequence to a protein that can be tested for function in the laboratory.” Almost all bacteria are related if you go back far enough, the scientists said. Even organisms that like extreme heat are related to organisms that are very sensitive to temperature change. The key is determining when, during Earth’s history, each type of bacteria came into existence. “Remarkably, our results are nearly identical to geologic studies that estimate the temperature trend for the ancient ocean over the same time period. The convergence of results from biology and geology show that Earth’s environment has continuously been changing since life began, and life has adapted appropriately to survive,” Gaucher said. Reference: Palaeotemperature trend for Precambrian life inferred from resurrected proteins Nature 451, 704-707 (7 February 2008) doi:10.1038/nature06510; ......... ZenMaster

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Tuesday, 5 February 2008

Three Parent Embryos Created

Three Parent Embryos Created - Again! Tuesday, 05 February 2008 Ten human embryos each containing the DNA from one man and two women have been created in a project that within three years could lead to the first genetically altered babies being born in Britain. The aim is to treat mitochondrial disorders, inherited diseases that can include fatal liver failure, stroke-like episodes, mental retardation with intractable epilepsy, muscle weakness, diabetes and deafness. All cells of the body have many (typically 1000-10,000) mitochondria. Mitochondria are tiny energy-producing structures ('organelles', the cell's equivalent to organs of the body) vital to cell function. If they malfunction then organs will eventually fail. The mitochondria are transmitted to the next generation through eggs, but not via the sperm, so mitochondrial defects are only inherited from the mother. The Newcastle team would take a one-day old IVF embryo from a couple at risk of mitochondrial disease, when the DNA cargoes from the sperm and egg are still separate and sit in structures called pronuclei. Then they would remove these pronuclei and insert them into an emptied egg from a second woman, which contains healthy mitochondria. The resulting early embryo would contain DNA from the parents in the nucleus, plus the mitochondria from the egg donor. If implanted back into the mother and a girl were born in this way, the inserted mitochondria would be passed to future generations to free them of potentially deadly disorders, too. Boys would not pass on the implanted mitochondria, because sperm do not contain mitochondria. Professor Patrick Chinnery, a member of the Newcastle team, said: "We believe that from this work, and work we have done on other animals that in principle we could develop this technique and offer treatment in the foreseeable future that will give families some hope of avoiding passing these diseases to their children." This procedure has been performed successfully previously (see Three Parent Embryo’s Created, CellNEWS - Wednesday, 15 October 2003). Articles: Transplant creates embryos with three parents Telegraph - Last Updated: 12:01am GMT 05/02/2008 Three-parent embryo formed in lab BBC - Last Updated: Tuesday, 5 February 2008, 11:13 GMT Scientists create three-parent embryos Reuters - Tue Feb 5, 2008 11:17am EST ......... ZenMaster
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2 Genes Play Crucial Role in Embryonic Cell Survival

2 Genes Play Crucial Role in Embryonic Cell Survival Tuesday, 05 February 2008 New research suggests that two recently discovered genes are critically important for controlling cell survival during embryonic development. The genes, called E2F7 and E2F8, are the least understood members of a family of genes that play a fundamental role in animal development. Members of this family are also involved in cancers of the breast, bladder, stomach and colon. This animal study showed that complete loss of the two genes causes massive cell death and is lethal in developing embryos. It also showed that the two genes prevent this cell death largely by suppressing the activity of another member of the family, called E2f1. This third gene is known to play an important role in triggering programmed cell death, or apoptosis, in embryos. The findings by researchers at the Ohio State University Comprehensive Cancer Center are published in the Jan. 15 issue of the journal Developmental Cell, with an accompanying commentary. “Until now, almost nothing was known about the function of these two genes in animals,” says principal investigator Gustavo Leone, an associate professor of molecular virology, immunology and medical genetics at Ohio State’s Comprehensive Cancer Center. “Our study not only shows that both these genes are critical for embryonic development, but also how members of this gene family work together to regulate cell survival and proliferation.” Leone and his colleagues used mice that were missing either E2f7 or E2f8, or both genes, and mice missing both genes and the E2f1 gene. Their experiments showed that embryos survived, and massive cell death was prevented, if they had at least one copy (of the normal two) of either of the two genes. When the two genes were entirely missing, however, massive cell death and other problems occurred that were lethal before birth. On the other hand, embryos that were completely missing both genes and missing the E2f1 gene, did not show the massive cell death, although they also died before birth. “This of course means that E2f7 and E2f8 are doing more than just regulating cell death, and we are now exploring new avenues of their function,” Leone says. “Overall,” he says, “our findings indicate that these two genes are essential for embryonic development and for preventing widespread cell death, mainly by targeting the E2f1 gene.” Reference: Synergistic Function of E2F7 and E2F8 Is Essential for Cell Survival and Embryonic Development Developmental Cell, Vol 14, 62-75, 15 January 2008 ......... ZenMaster

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Monday, 4 February 2008

China’s new Great Leap Forward — in drug discovery

China’s new Great Leap Forward — in drug discovery Monday, 04 February 2008 In a modern-day counterpart to Mao Zedong’s program to modernize the Chinese economy, China’s pharmaceutical industry is quietly taking its own Great Leap Forward — as a major force in drug discovery and development, according to an article scheduled for the Feb. 4 issue of Chemical & Engineering News, ACS’ weekly newsmagazine. China already is an important source of active ingredients that large pharmaceutical companies in the United States and other countries use to make prescription and over-the-counter drugs Chemical & Engineering News’s cover story, by Senior Correspondent Jean-Fran├žois Tremblay, notes that China is playing an increasingly important, yet mostly unrecognized role in drug discovery. Companies based in China that undertake research projects on behalf of foreign companies have in the past three years beefed up their range of services. From Shanghai to Beijing, new companies are being launched with research capabilities that, in terms of the time it takes to produce results, exceed those of Western pharmaceutical companies. A growing number of Chinese firms offer a full range of drug research and development services, including synthesis, process research and scale up, and animal testing, the article states. Within two years, the first drug to be mostly developed in China could begin human trials in the U.S., Tremblay says. The growth in pharmaceutical services in China seems to be part of a major trend. “Last century, we saw the pharmaceutical industry move from Europe to the United States,” Chemical & Engineering News quotes a manager at one drug discovery company. “Now, it’s perhaps moving to China and India.” Article: China’s Pharma Leaps into Discovery Chemical & Engineering News ......... ZenMaster

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Sunday, 3 February 2008

Targeting astrocytes slows disease progression in ALS

Targeting astrocytes slows disease progression in ALS Sunday, 03 February 2008 In what the researchers say could be promising news in the quest to find a therapy to slow the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, scientists at the University of California, San Diego (UCSD) School of Medicine have shown that targeting neuronal support cells called astrocytes sharply slows disease progression in mice. The study, conducted in the laboratory of Don Cleveland, Ph.D., UCSD Professor of Medicine, Neurosciences and Cellular and Molecular Medicine and member of the Ludwig Institute for Cancer Research, will appear in the advance online publication on Nature Neuroscience's website on February 3rd. “Mutant genes that cause ALS are expressed widely, not just in the motor neurons,” Cleveland explained. “Targeting the partner cells like astrocytes, which live in a synergistic environment with the neuron cells, helps stop the ‘cascade of damage.’ Therapeutically, this is the big news.” ALS is a progressive disease that attacks the motor neurons, long and complex nerve cells that reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body, which act to control voluntary movement. Degeneration of the motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely death. Estimated to affect some 30,000 Americans, most people are diagnosed with ALS between the ages of 45 and 65. Typically, ALS patients live only one to five years after initial diagnosis. In findings published in Science in June 2006, Cleveland and his colleagues showed that in early stages of inherited ALS, small immune cells called microglia are damaged by mutations in the SOD1 protein, and that these immune cells then act to significantly accelerate the degeneration of the motor neurons. The new study demonstrates that much the same thing happens to astrocytes, support cells that are essential to neuronal function, and whose dysfunction is implicated in many diseases. The researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment. As with microglia, the helper role of astrocytes is altered due to mutations in the SOD1 protein. “We tested what would happen if we removed the mutant gene from astrocytes in mouse models,” said Cleveland. “What happened was it doubled the lifespan of the mouse after the onset of ALS.” Astrocytes are key components in balancing the neurotransmitter signals that neurons use to communicate. To examine whether mutant SOD1 damage to the astrocytes contributes to disease progression in ALS, researchers in the Cleveland lab used a genetic trick to excise the mutant SOD1 gene, but only in astrocytes. Reduction of the disease-causing mutant SOD1 in astrocytes did not slow disease onset or early disease; however, the late stage of the disease was extended, nearly doubling the normal life expectancy of a mouse with ALS. “Silencing the mutant gene in the astrocytes not only helps protect the motor neuron, but delays activation of mutant microglia that act to accelerate the progression of ALS,” said Cleveland. The findings show that mutant astrocytes are likely to be viable targets to slow the rate of disease spread and extend the life of patients with ALS. Cleveland added that this may prove especially important news to researchers in California and elsewhere working with stem cells. “This gives scientists a good idea of what cells should be replaced using stem cell therapy. Astrocytes are very likely much easier to replace than the slow-growing motor neuron.” Additional contributors to the study include Koji Yamanaka, Seung Joo Chun and Severine Boillee, Ludwig Institute for Cancer Research and UCSD Department of Medicine and Neuroscience; Noriko Fujimore-Tonou and Hirofumi Yamashita, Yamanaka Research Unit, RIKEN Brain Science Institute, Saitama, Japan; David H. Gutmann, Department of Neurology, Washington University, St. Louis; Ryosuke Takahashi, Department of Neurology, Kyoto University, Japan; and Hidemi Misawa, Department of Pharmacology, Kyoritsu University of Pharmacy, Tokyo. ......... ZenMaster

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Friday, 1 February 2008

Carbohydrate Regulating Stem Cell Potency

Carbohydrate Regulating Stem Cell Potency Friday, 01 February 2008 Heparan sulfate, a carbohydrate molecule that coats certain proteins on the cell surface, is critical for the proper proliferation and potency of embryonic stem cells, researchers report. Stem cells’ tremendous therapeutic potential arises from their ability to continually self-renew and turn into any adult cell type. Researchers have long been trying to uncover the basis of these abilities, but while several proteins and growth factors are known to play a role both inside and outside the cell, the molecular mechanisms remain largely unknown. Many of the stem cell associated can attach to heparan sulphate (HS) molecules, so Shoko Nishihara and colleagues, Laboratory of Cell Biology, Department of Bioinformatics, Faculty of Engineering, Soka University, Tokyo, Japan, examined what would happen to mouse stem cells in cell culture if heparan sulphate production was reduced or blocked. They discovered that three of the major external factors promoting stem cell renewal (proteins called Wnt, FGF, and BMP) could not induce the proper signals inside the cell without HS. As a result, HS deficient cells grew more slowly, and also spontaneously differentiated into other cells more often, at rates that correlated with the level of inhibition. Nishihara and colleagues propose that heparan sulphate might be the cell-surface component that mediates the external and internal signals promoting stem cell renewal, and could be an important target for stem cell engineering.

Caption: Model displays external factors that act to block stem cells from differentiating into different types of adult tissue. LIF activates STAT3 and blocks non-neural differentiation by induction of Myc, while BMP/Smad signalling through HS chains blocks neural differentiation by induction of Id. Wnt/b-catenin signalling through HS chains blocks primitive endodermal differentiation by induction of Nanog. FGF may contribute to proliferation through HS chains. HS chain dependent signalling by unknown factors may regulate proliferation and Oct3/4 expression. Credit: Shoko Nishihara.


Heparan Sulfate Regulates Self-renewal and Pluripotency of Embryonic Stem Cells J. Biol. Chem., Vol. 283, Issue 6, 3594-3606, February 8, 2008 ......... ZenMaster

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Human Genetic Recombination Studied II

Gene variants may help to distribute the work of evolution between men and women Thursday, 31 January 2008 Scientists from deCODE genetics today report the discovery of two common, single-letter variants in the sequence of the human genome (SNPs) that regulate one of the principle motors of evolution. Versions of the two SNPs, located on chromosome 4p16, have a genome-wide impact on the rate of recombination — the reshuffling of the genome that occurs in the formation of eggs and sperm. Recombination is largely responsible for generating human diversity, the novel configurations of the genome that enable the species to adapt and evolve in an ever-changing environment. Yet remarkably, the versions of the SNPs that increase recombination in men decrease it in women, and vice versa. This highly unusual characteristic may enable the variants to help to maintain a fundamental tension crucial for evolutionary success: promoting the generation of significant diversity within a portion of the population but keeping the pace of this change within certain bounds, maintaining it relatively constant overall and so supporting the stability of the genome and the cohesiveness of the species. “This is the latest in a series of landmark papers from deCODE in which we have utilized our unique capabilities in human genetics to elucidate some of the key mechanisms driving human evolution,” said Kari Stefansson, CEO of deCODE. “We are also excited that we can now immediately enable individuals to see if they carry such variants, by folding the findings announced today — and others we expect to publish in the near future — into our deCODEme™ personal genome analysis service.” The deCODE team identified the SNPs through a genome-wide analysis of more than 300,000 SNPs in approximately 20,000 participants in the company’s gene discovery programs. The SNPs, referred to as rs3796619 and rs1670533, are within the RNF212 gene, and are estimated to account for approximately 22% of paternal variability in recombination and 6.5% of maternal variability. Little is known about RNF212, though it is a mammalian homolog of a gene called ZHP-3 known to be crucial for the success of recombination in other organisms. The paper, entitled ‘Sequence Variants in the RNF212 Gene Associate with Genomewide Recombination Rate,’ is published today in the online edition of Science. deCODE has made a number of breakthrough discoveries in the understanding of recombination, fertility and human evolution. In 2002, deCODE published the most detailed recombination map to date of the genome, demonstrating that there are hotspots and coldspots for recombination in all chromosomes, and that these are very different in women and men. This map provided a template for completing the final assembly of the sequence of the human genome. deCODE scientists then showed that recombination rate varies between families and between women; that recombination rate increases with the age of the mother; and that higher recombination rate correlates with fertility, indicating that evolution appears to place a premium on the generation of human diversity. In 2005, deCODE identified a genetic variant that correlates with higher recombination rate, the first genetic variant ever demonstrated to be under positive evolutionary selection in human populations in real time. References for these and all deCODE’s major discoveries can be found at About deCODE deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of drugs and diagnostics for common diseases. deCODE is a global leader in gene discovery — our population approach and resources have enabled us to isolate key genes contributing to major public health challenges from cardiovascular disease to cancer, genes that are providing us with drug targets rooted in the basic biology of disease. deCODE is also leveraging its expertise in human genetics and integrated drug discovery and development capabilities to offer innovative products and services in DNA-based diagnostics, bioinformatics, genotyping, structural biology, drug discovery and clinical development. deCODE is delivering on the promise of the new genetics. ......... ZenMaster

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Human Genetic Recombination Studied I

Inherited individual variations influence patterns of gene shuffling Thursday, 31 January 2008 The first large-scale, high-resolution study of human genetic recombination has found remarkably high levels of individual variation in genetic exchange, the process by which parents pass on a mosaic-like mixture of their genes. In an article appearing February 1, 2008, in Science Express, the online version of Science, researchers from the University of Chicago locate nearly 25,000 recombination events that occurred in the transmission of the parental genomes to 364 offspring. The high-resolution of their maps allows them to provide the precise location of where these genetic exchanges occur, and to assess the differences in recombination rates between individuals. "Genetic recombination is a fundamental process, at the core of reproduction and evolution," said study author Graham Coop, PhD, post-doctoral fellow in the Department of Human Genetics at the University of Chicago, "yet we know very little about where it occurs or why there is so much variation among individuals in this important process." "Now," he said, "we know where it occurs. Understanding where it happens provides us with important clues as to how it happens, how it is regulated and what the mechanisms are that control this essential biological phenomenon." Recombination occurs during meiosis, a special kind of cell division that takes place only in the testicles and ovaries. In the process of making sperm or egg cells, the parent-to-be takes the chromosomes inherited from each of his or her parents and reshuffles them, swapping parts of one chromosome for the matching segments of the other version of that same chromosome. The result is a reproductive cell with a mosaic, or patchwork, of genes, about half from each parent, but shuffled together into entirely new combinations. This process leads to offspring having different combinations of genes than their parents and is thought to have many advantages. Errors in this recombination process during the production of sperm or egg cells underlie a variety of chromosomal abnormalities and can cause deletions of regions of the genome, miscarriage, or genetic disorders such as Down syndrome. The research team focused on the Hutterites, a genetically similar population of European immigrants who settled in the Dakotas in the 19th century and have maintained a communal agricultural lifestyle. One member of the research team, Carole Ober, PhD, professor of human genetics and of obstetrics and gynaecology at the University of Chicago, has been working closely with this group for many years on health and inheritance issues. The researchers collected DNA samples from 725 volunteers, representing 82 overlapping nuclear families, most of which included four or more children. These families are part of a larger 1650-person, 13-generation pedigree of the Hutterites in the US. They used 500,000 markers of genetic variation (SNPs) to determine, along each chromosome, whether the genetic material transmitted from the mother (or father) came from the child's maternal (or paternal) grandmother or grandfather. The large number of markers allowed the researchers to map out at high resolution the locations in the genome where ancestry shifts from one grandparent to another, which are known as recombination events. Chromosomes from the mother (not including the X chromosome) averaged around 40 recombination events per gamete. Those from the father had only 26. The authors confirm a previous finding that older mothers have more recombination events in the transmission of their genome to their offspring, while the father's age has no such effect. For both sexes, the majority of crossovers occur at genetic "hotspots," small regions where genetic exchanges are unusually common. Although the overall rate of hotspot use was similar between the two sexes, a subset of hotspots, "seems to be used mainly by one sex of the other," the authors note. Strikingly the pattern of hotspot used varied among individuals, but seemed to be passed on from generation to generation — a heritable difference potentially pointing to differences in the recombination machinery among individuals. The study uncovered "tremendous variation in recombination rates over all genomic scales considered and in particular heritable variation in hotspot use," the authors conclude. Their ongoing efforts to map this variation should offer insights into the "genetic basis of recombination-rate variation and the selective forces governing the evolution of recombination rates." The National Institutes of Health funded the research. Additional authors include Molly Przeworski, Jonathan Pritchard and Xiaoquan Wen of the Department of Human Genetics at the University of Chicago. ......... ZenMaster

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