Discovery could help bring down price of DNA sequencing

Discovery could help bring down price of DNA sequencing June 29, 2007 In May, Nobel Laureate James D. Watson, the scientist who co-discovered the structure of DNA, became the first person to receive his own complete personal genome - all three billion base pairs of his DNA code sequenced. The cost was $1 million, and the process took two months. A million dollars for a map of all your genes is way out of reach for most people. The National Institutes of Health would like to bring it down to $1,000 by the year 2014, but plenty of technological hurdles remain before you’ll be able to secure your genetic blueprint for this more affordable price. One promising method for speeding up DNA sequencing, and thus reducing its cost, is nanopore sequencing, where DNA moves through a tiny hole, much like thread going through a needle. The technique can detect individual DNA molecules, but the DNA gallops through so fast that it is impossible to read the individual letters, or bases, and determine the sequence. (The four letters of the genomic alphabet are A, T, G and C, each representing one of the base nucleotides that make up DNA.) Using a theory based on classical hydrodynamics, a Northwestern University researcher now has explained the nature of the resistive force that determines the speed of the DNA as it moves through the nanopore, which is just five to 10 nanometers wide. (One nanometer is a billionth of a meter.) This understanding could help scientists figure out how to slow the DNA down enough to make it readable and usable - for medical and biotechnology applications, in particular. Sandip Ghosal, associate professor of mechanical engineering in Northwestern’s McCormick School of Engineering and Applied Science, is the first to apply classical hydrodynamics to the interaction of DNA with a nanopore. The findings, an important step toward achieving single-base resolution in nanopore sequencing, were published in the June 8 issue of the journal Physical Review Letters (PRL). “DNA is pulled through the nanopore’s channel by an electric force, but there also is a resistive force,” said Ghosal, sole author of the PRL paper. “My idea was that the resistance was coming from fluid friction, which could explain the speed measurements taken in experimental studies.” In Ghosal’s explanation, the DNA pulls some of the fluid surrounding the molecule through the channel with it. The lubrication forces arising in this fluid layer create the resistance that opposes the electrical pulling force. Ghosal’s calculations in the PRL paper show that his theoretical model is consistent with experimental results and explains the DNA’s speed. “Understanding the mechanics of DNA translocation will allow scientists to make alterations, to figure out how to apply more friction,” said Ghosal, who has proposed using a coating on the channel walls to slow down the flow of the DNA. ......... ZenMaster

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Cloned pigs help scientists towards a breakthrough in Alzheimer's

Cloned pigs help scientists towards a breakthrough in Alzheimer's June 29, 2009 The first pigs containing genes responsible for Alzheimer's disease will be born in Denmark in August. This event is a landmark achivement in the effort towards finding a cure for the disease. Scientists from the universities of Copenhagen and Århus, Denmark are once again at the cutting edge of biotechnology. This time with cloned pigs that have been genetically modified so that they may function as animal models for the notorious Alzheimer’s disease. "In the light of the intense focus on medical research at the University of Copenhagen and the continuous expansion of the pharmaceutical industry in Denmark, the ability to produce transgenic pig models for human diseases is a major prerequisite for future progress in this area," says Professor Ingrid Brück Bøgh from the Department of Large Animal Sciences, University of Copenhagen. "The upcoming birth of these transgenic pig models constitutes a fantastic success for us. It is also a demonstration of the excellent cross-disciplinary collaboration between the experts at both universities," she continues. "We now have evidence that our system is very well suited for the task of making disease models for human medicine," says Professor Gábor Vajta from the Department of Genetics and Biotechnology, Faculty of Agricultural Sciences, University of Aarhus. Associate Professor Arne Lund Jorgensen, Institute of Human Genetics, Aarhus University and his group have made the gene construct with the putative Alzheimer gene and inserted into the somatic cells. These somatic cells were used for the nuclear transfer experiments performed at the Faculty of Agricultural Sciences, Aarhus University. ......... ZenMaster

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New Regulations Needed For Xenotransplantations

New Regulations Needed For Patients Receiving Animal Tissue Donation June 29, 2007 A new article in the Journal of Law, Medicine and Ethics calls for a change in the regulations surrounding xenotransplantation, the transplanting of animal cells, tissues or organs into humans. Although few xenotransplantation procedures have been done to this time, there appears to be a lack of awareness among potential xenotransplant patients about the risk of the procedures, and the required lifetime of infectious disease monitoring that come with it. ......... ZenMaster

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Next Step Towards Artificial Life

Whole Genome Transplantation Achieved in Mycobacteria June 28, 2007 Researchers at the J. Craig Venter Institute (JCVI) today announced the results of work on genome transplantation methods allowing them to transform one type of bacteria into another type dictated by the transplanted chromosome. The work, published online in the journal Science, by JCVI’s Carole Lartigue, Ph.D. and colleagues, outlines the methods and techniques used to change one bacterial species, Mycoplasma capricolum into another, Mycoplasma mycoides Large Colony (LC), by replacing one organism’s genome with the other one’s genome. “The successful completion of this research is important because it is one of the key proof of principles in synthetic genomics that will allow us to realize the ultimate goal of creating a synthetic organism,” said J. Craig Venter, Ph.D., president and chairman, JCVI. “We are committed to this research as we believe that synthetic genomics holds great promise in helping to solve issues like climate change and in developing new sources of energy.” Methods and techniques The JCVI team devised several key steps to enable the genome transplantation. First, an antibiotic selectable marker gene was added to the M. mycoides LC chromosome to allow for selection of living cells containing the transplanted chromosome. Then the team purified the DNA or chromosome from M. mycoides LC so that it was free from proteins (called naked DNA). This M. mycoides LC chromosome was then transplanted into the M. capricolum cells. After several rounds of cell division, the recipient M. capricolum chromosome disappeared having been replaced by the donor M. mycoides LC chromosome, and the M. capricolum cells took on all the phenotypic characteristics of M. mycoides LC cells. As a test of the success of the genome transplantation, the team used two methods — 2D gel electrophoresis and protein sequencing, to prove that all the expressed proteins were now the ones coded for by the M. mycoides LC chromosome. Two sets of antibodies that bound specifically to cell surface proteins from each cell were reacted with transplant cells, to demonstrate that the membrane proteins switch to those dictated by the transplanted chromosome not the recipient cell chromosome. The new, transformed organisms show up as bright blue colonies in images of blots probed with M. mycoides LC specific antibody. The group chose to work with these species of mycoplasmas for several reasons — the small genomes of these organisms which make them easier to work with, their lack of cell walls, and the team’s experience and expertise with mycoplasmas. The mycoplasmas used in the transplantation experiment are also relatively fast growing, allowing the team to ascertain success of the transplantation sooner than with other species of mycoplasmas. According to Dr. Lartigue, “While we are excited by the results of our research, we are continuing to perfect and refine our techniques and methods as we move to the next phases and prepare to develop a fully synthetic chromosome.”Genome transplantation is an essential enabling step in the field of synthetic genomics as it is a key mechanism by which chemically synthesized chromosomes can be activated into viable living cells. The ability to transfer the naked DNA isolated from one species into a second microbial species paves the way for next experiments to transplant a fully synthetic bacterial chromosome into a living organism and if successful, “boot up” the new entity. There are many important applications of synthetic genomics research including development of new energy sources and as means to produce pharmaceuticals, chemicals or textiles. Background and Ethical Considerations The work described by Lartigue et al. has its genesis in research begun by Dr. Venter and colleagues in the mid-1990’s after sequencing Mycoplasma genitalium and beginning work on the minimal genome project. This area of research, trying to understand the minimal genetic components necessary to sustain life, underwent significant ethical review by a panel of experts at the University of Pennsylvania (Cho et al, Science December 1999:Vol. 286. no. 5447, pp. 2087 – 2090). The bioethical group's independent deliberations, published at the same time as the scientific minimal genome research, resulted in a unanimous decision that there were no strong ethical reasons why the work should not continue as long as the scientists involved continued to engage public discussion. In 2003 Drs. Venter, Smith and Hutchison made the first significant strides in the development of a synthetic genome by their work in assembling the 5,386 base pair bacteriophage φX174 (phi X). They did so using short, single strands of synthetically produced, commercially available DNA (known as oligonucleotides) and using an adaptation of polymerase chain reaction (PCR), known as polymerase cycle assembly (PCA), to build the phi X genome. The team produced the synthetic phi X in just 14 days.Dr. Venter and the team at JCVI continue to be concerned with the societal implications of their work and the field of synthetic genomics generally. As such, the Institute’s policy team, along with the Center for Strategic & International Studies (CSIS), and the Massachusetts Institute of Technology (MIT), were funded by a grant from the Alfred P. Sloan Foundation for a 15-month study to explore the risks and benefits of this emerging technology, as well as possible safeguards to prevent abuse, including bioterrorism. After several workshops and public sessions the group is set to publish a report in summer 2007 outlining options for the field and its researchers. About the J. Craig Venter Institute The J. Craig Venter Institute is a not-for-profit research institute dedicated to the advancement of the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, Ph.D., the JCVI is home to approximately 500 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The legacy organizations of the JCVI are: The Institute for Genomic Research (TIGR), The Center for the Advancement of Genomics (TCAG), the Institute for Biological Energy Alternatives (IBEA), the Joint Technology Center (JTC), and the J. Craig Venter Science Foundation. The JCVI is a 501 (c)(3) organization. For additional information, please visit http://www.jcvi.org/. Genome Transplantation in Bacteria - Science, 29/06/2007 Also read: Venter Attempt a Minimalistic Approach of Creating ‘Artificial’ Life ......... ZenMaster

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Non-coding RNA may play larger role in cell's gene activity

RNA may play larger role in cell's gene activity June 28, 2007 Large, seemingly useless pieces of RNA - a molecule originally considered only a lowly messenger for DNA - play an important role in letting cells know where they are in the body and what they are supposed to become, researchers at Stanford University School of Medicine have discovered. The finding implies that ancient RNA molecules can orchestrate gene activity across vast portions of the human genome - a cell's genetic blueprint. It also suggests they may be important in cancer development and stem cell maintenance. Overall, the work adds another brick to the growing wall of evidence suggesting that RNA is more than a mere genomic servant. RNA is best known for ferrying protein-coding instructions from DNA, once thought to be the master molecule of the genome, to the cell's assembly factories. But cracks in this theory began to appear when it became evident that many RNA molecules aren't capable of making protein. While more recent research has shown that small bits of RNA can silence individual genes by interfering with their expression - a la Stanford professor Andrew Fire's recent Nobel work - longer pieces, called non-coding RNAs, have been more perplexing. ......... ZenMaster

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microRNA suppresses genes that trigger cancer progression

microRNA suppresses genes that trigger cancer progression June 26, 2007 Levels of a small non-coding RNA molecule called let-7 appear to define different stages of cancer better than some of the "classical" markers for tumor progression, researchers from the University of Chicago report in the June 25, 2007, early online edition of the Proceedings of the National Academy of Sciences. By suppressing genes that are active in the developing embryo, silenced just before birth, and re-activated years later in many advanced cancers, the let-7 family of "microRNAs"—tiny snippets of RNA that can put the brakes on expression of selected genes—appears to prevent human cancer cells from reasserting their prenatal capacity to divide rapidly, travel and spread. ......... ZenMaster

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Synthetic Biology

Scientists call for global push to advance research in synthetic biology June 25, 2007 With research backgrounds ranging from materials engineering to molecular biophysics, seventeen leading scientists issued a statement today announcing that, much as the discovery of DNA and creation of the transistor revolutionized science, there is a new scientific field on the brink of revolutionizing our approach to problems ranging from eco-safe energy to outbreaks of malaria: synthetic biology. ......... ZenMaster

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British trial will test stem cells capacity to repair heart muscle

Stem cells to repair damaged heart muscle First ever-surgical trial gets the go-ahead 22 June 2007 In the first trial of its kind in the world, 60 patients who have recently suffered a major heart attack will be injected with selected stem cells from their own bone marrow during routine coronary bypass surgery. The Bristol trial will test whether the stem cells will repair heart muscle cells damaged by the heart attack, by preventing late scar formation and hence impaired heart contraction. ......... ZenMaster

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Again Bush Vetoes Stem Cell Research Bill

Today Bush, as expected, again vetoed the stem cell bill. In a lame attempt to cover-up the stupidity, he at the same time issued an executive order, urging more research for other types of stem cell research than embryonic. Of course, there are no money or no plan for this. Here are some links to comments about the veto: Obama Statement on Bush Veto of Stem Cell Bill – CattleNetwork, KS, 06/20/2007 Sen. Feinstein response to stem cell veto – The Desert Sun, CA, 06/20/2007 Sen. Boxer response to stem cell veto – The Desert Sun, CA, 06/20/2007 Pelosi: Bush Veto of Stem Cell Bill Says ‘No’ to the Hopes – GEN, NY, 06/20/2007 Corzine, Menendez bash Bush's stem-cell veto – Newark Star Ledger, NJ, 06/20/2007 Edwards on Stem Cell Bill Veto – Campaigns & Elections, 06/20/2007 Corzine deems Bush stem cell veto misguided – Newsday, NY, 06/20/2007 President Bush Has Turned His Back on the American People – Earthtimes, 06/20/2007 DeGette's response to Bush veto – Rocky Mountain News, CO, 06/20/2007 ......... ZenMaster

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AAAS comments on stem cell veto and Executive Order

AAAS comments on stem cell veto and Executive Order June 20, 2007 "The American Association for the Advancement of Science released the following statement on President Bush's decision today to veto a stem cell research funding bill The President has again vetoed the Stem Cell Research Enhancement Act, which would expand federal support for embryonic stem cell research. AAAS, the world’s largest general scientific society, stands with a broad coalition of Americans spanning all parties and faiths that supports this bill. The scientific consensus is that embryonic stem cell research is an extremely promising approach to developing more effective treatments for devastating conditions like diabetes, spinal cord injuries, and Parkinson’s disease. The bill would mandate that such research be allowed to compete for federal funding while following strict ethical guidelines. The Executive Order is not a substitute for the Stem Cell Research Enhancement Act. The new approaches addressed by the order are still in the early stages of development and appear to already be eligible for NIH funding. AAAS strongly believes that it is only through federal support of diverse avenues of stem cell research that we may better understand the potential value and limitations of each approach. During his tenure the President has acknowledged that it is a critical time for the American scientific enterprise, therefore it is disappointing that he has chosen to maintain restrictions on such a promising area of research. AAAS will continue to support the interests of scientists and patients in fostering medical progress." ......... ZenMaster -------------------------------------------------------------------------------- For more on stem cells and cloning, go to CellNEWS at http://www.geocities.com/giantfideli/index.html --------------------------------------------------------------------------------

Genetic themes key to keeping stem cells in a flexible state

Study identifies 5 genetic themes key to keeping stem cells in a primitive, flexible state June 19, 2007 For more than 25 years, stem cells have been defined based on what they can become: more of themselves, as well as multiple different specialized cell types. But as genetic techniques have become increasingly powerful, many scientists have sought a more molecular definition of stem cells, based on the genes they express. Now, a team of Canadian scientists has identified 1,155 genes under the control of a gene called Oct4 considered to be the master regulator of the stem cell state. A comprehensive molecular definition of stem cells is emerging: according to this research, stem cells are cells that keep their DNA packaged in a flexible format, keep cell division tightly controlled, prevent signals that might trigger death, repair DNA very effectively, and reinforce all of these characteristics by tightly controlling how molecules can move within the nucleus. The study will be published in the June 20 edition of the online, open-access journal PLoS ONE. “You could call this a ‘theory-of-everything’ for stem cells,” said senior author Dr. Michael Rudnicki, referring to the often-cited theory of everything for physics. Dr. Rudnicki is a Senior Scientist and Professor at the Ottawa Health Research Institute and the University of Ottawa. He also leads the Sprott Centre for Stem Cell Research in Ottawa and Canada’s Stem Cell Network. While previous studies have tried to compare gene expression in different types of stem cells, the strategy used in this study was unique. Rather than simply searching for any genes expressed by stem cells, the researchers looked for genes whose expression was also correlated with the master stem cell regulator gene Oct4. They also applied very rigorous analysis methods, using data from StemBase, the largest stem cell gene expression database in the world. Designed by bioinformaticist Dr. Miguel Andrade, the database includes data from thousands of DNA microarrays submitted mainly by scientists in Canada’s Stem Cell Network. All data is freely available at http://www.stembase.ca/. Lead author Ms. Pearl Campbell noted that understanding how stem cells maintain their identity is key to the emerging field of regenerative medicine. “These findings may help us to understand how the key genes which control cell fate are regulated, and how, when dysregulated, they can lead to disease. This may ultimately allow us to develop targeted therapies to stimulate adult stem cells within our own bodies to repair damaged tissues, and may provide further areas of exploration for the treatment of cancer.” ......... ZenMaster

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Monkey cloning

Monkey cloning Wednesday, 20 June 2007 In a world first Shoukhart Mitalipov of the Oregon National Primate Research Centre in Beaverton, USA, have provided evidence that he successfully achieved somatic cell nuclear transfer (SCNT) in a primate. Mitalipov talked of his latest potentially groundbreaking discovery: an efficient and reliable method for cloning primate embryos from adult cells, at an unscheduled talk at the end of Monday’s session of the 5th International Society for Stem Cell Research Meeting held in Cairns, Australia, this week. He managed to clone rhesus monkey embryos from adult cells and generate embryonic stem cells from them. Previously it has proved impossible to derive embryonic cells from cloned embryos in primates. Mitalipov made two batches of embryonic stem cells from 20 cloned embryos. Human cloning closer than ever before Cosmos Online - Tuesday, 19 June 2007 ......... ZenMaster

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Batten Disease Clinical Trial

Batten Disease StemCells, Inc. Announces Important Milestone in Batten Disease Clinical Trial Business Wire, CA - Jun 18, 2007 StemCells, Inc. today announced that the Phase I clinical trial of its proprietary HuCNS-SC™ product candidate (purified human neural stem cells) has successfully completed enrollment of the low-dose cohort and will proceed to the high-dose cohort. This trial is designed to evaluate the safety and preliminary efficacy of the HuCNS-SC product candidate as a treatment for infantile and late infantile neuronal ceroid lipofuscinosis (NCL), also often referred to as Batten disease. To date, three patients out of a planned total of six have been transplanted with HuCNS-SC cells. A review of the trial data to date, conducted by an independent Data Safety Monitoring Committee comprised of experts in pediatric neurosurgery, pediatric neurology, solid organ transplantation, and genetics, has identified no safety issues that would preclude advancing the trial to the next dose level. "This is a significant milestone for the trial and StemCells, Inc. We are halfway through the planned enrollment in the first FDA-approved clinical investigation of purified human neural stem cells. The first patient enrolled in the trial has now reached the halfway point of the study and completed a number of important assessments. To date, all three patients have tolerated the transplantation and have returned home," said Stephen Huhn, M.D., F.A.C.S., F.A.A.P., Vice President and Head of the Neural Program of StemCells, Inc. "We are encouraged by the progress of the trial, but remain mindful of the difficult challenges involved with the development of novel therapeutics. We are also grateful for the participation of the families in this study and the commitment of the research staff at OHSU. Batten disease is a terrible affliction and this trial is the first step on the path toward a treatment for this devastating disease and potentially other lysosomal storage disorders." The clinical trial is being led by co-principal investigator Robert Steiner, Vice Chairman of Pediatric Research at Doernbecher Children's Hospital, and Professor of Pediatrics and Molecular & Medical Genetics in the OHSU School of Medicine; co-principal investigator Nathan Selden, Campagna Associate Professor of Pediatric Neurological Surgery and Head of the Division of Pediatric Neurological Surgery, Doernbecher and OHSU School of Medicine; co-investigator Thomas K. Koch, M.D., F.A.A.P., F.A.A.N., Director of Pediatric Neurology and Professor of Pediatrics and Neurology at Doernbecher, OHSU School of Medicine; and co-investigator Amira Al-Uzri, M.D., M.C.R., associate professor of pediatrics (pediatric nephrology and hypertension), and director of the pediatric kidney transplant program at Doernbecher Children's Hospital, OHSU School of Medicine. About Neuronal Ceroid Lipofuscinosis (Batten Disease) Neuronal ceroid lipofuscinosis is a fatal neurodegenerative disorder brought on by inherited genetic mutations. The disorder afflicts infants and young children, and the three most common forms of NCL—infantile, late infantile and juvenile onset—are often referred to as Batten disease. All forms have the same basic cause—lack of a lysosomal enzyme—and have similar progression and outcome. Children with NCL suffer seizures, progressive loss of motor skills, sight and mental capacity, eventually becoming blind, bedridden and unable to communicate. Infantile or late infantile NCL is brought on by inherited mutations in the CLN1 gene, which codes for palmitoyl-protein thioesterase 1 (PPT1) or in the CLN2 gene, which codes for tripeptidyl peptidase I (TPP-I), respectively. The consequence of these gene mutations is either a defective or missing enzyme that leads to accumulation of lipofuscin-like fluorescent inclusions in various cell types. These non-degraded lysosomal inclusions accumulate to the point of interference with normal cellular function and ultimately lead to the pathological manifestations of the disease. One way to treat the disease is to provide the brain with a replacement source of functional enzyme that can be taken up by the enzyme-deficient cells. About HuCNS-SC™ Cell-Based Therapeutic StemCells' HuCNS-SC cell-based therapeutic product candidate is purified human neural stem cells prepared under controlled conditions. When HuCNS-SC cells are transplanted into the brain of a mouse model developed to mimic the human form of infantile NCL, the cells spread throughout the brain and produce the missing lysosomal enzyme. The enzyme level increases and continues to do so over time after the transplant. Thus, placement of HuCNS-SC cells in appropriate places in the brain provides the prospect of long-term delivery of the missing lysosomal enzyme. In laboratory studies, HuCNS-SC cells also produce the lysosomal enzyme missing in late infantile NCL, the other subtype being studied in the clinical trial. The production of both enzymes by HuCNS-SC cells provides a scientific rationale for enzyme replacement and cellular rescue in these two subtypes of NCL. About StemCells, Inc. StemCells, Inc. is a clinical-stage biotechnology company focused on the discovery, development and commercialization of cell-based therapeutics to treat diseases of the nervous system, liver and pancreas. The Company's programs seek to repair or repopulate neural, liver or other tissue that has been damaged or lost as a result of disease or injury. StemCells has pioneered the discovery and development of HuCNS-SC cells, its highly purified population of human neural stem cells. The cells are expandable into cell banks for therapeutic use, which offers the potential of using normal, non-genetically modified cells as cell-based therapeutics. StemCells owns or has exclusive rights to more than 50 issued or allowed U.S. patents and more than 150 granted or allowed non-U.S. patents. Further information about the Company is available on its Web site at http://www.stemcellsinc.com/. About OHSU and Doernbecher Children's Hospital Oregon Health & Science University is the state's only health and research university, and Oregon's only academic health center. OHSU is Portland's largest employer and the fourth largest in Oregon (excluding government), with more than 12,000 employees. OHSU's size contributes to its ability to provide many services and community support activities not found anywhere else in the state. It serves 189,000 patients annually, and is a conduit for learning for more than 3,400 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to every county in the state. As a leader in research, OHSU earned $294 million in research funding in fiscal year 2006. OHSU serves as a catalyst for the region's bioscience industry and is an incubator of discovery, averaging one new breakthrough or innovation every three days, with more than 3,500 research projects currently under way. OHSU disclosed 116 inventions in 2006 alone, and OHSU research resulted in 28 new spinoff companies since 2000, most of which are based in Oregon. Doernbecher Children's Hospital, a division of Oregon Health & Science University, is a world-class academic health center that each year cares for more than 56,000 patients from across the United States. In the most patient- and family-centered environment, children receive outstanding cancer treatment, specialized neurology care, highly sophisticated heart surgery, and care in many other pediatric specialties. In addition to several locations in the Portland metropolitan area, Doernbecher's pediatric experts travel throughout Oregon and southwest Washington providing pediatric specialty care at 13 outreach clinics. ......... ZenMaster

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Illuminating the dark matter of the genome

Illuminating the dark matter of the genome Nature Reviews Genetics 8, 490-491 (July 2007) doi:10.1038/nrg2139 Although much of the eukaryotic genome is transcribed, the function of most of this transcriptome remains unknown. Therefore, in a parallel to cosmology, it has been dubbed the dark matter of the genome. Kapranov et al. now shed light on its possible function by identifying new classes of RNAs that might have an important role in regulating gene transcription, and showing that many long transcripts might function as precursors for shorter RNAs. .........

ZenMaster

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Mutating the entire genome

Mutating the entire genome New way to hunt for illness-causing mutants in non-gene DNA June 17 2007 Genes account for only 2.5 percent of DNA in the human genetic blueprint, yet diseases can result not only from mutant genes, but from mutations of other DNA that controls genes. University of Utah researchers report in the journal Nature Genetics that they have developed a faster, less expensive technique for mutating those large, non-gene stretches of DNA. “Diseases are known to occur as a consequence of deleting non-gene DNA sequences, and this new method allows us to evaluate what these sequences do,” says Mario Capecchi, distinguished professor and co-chair of human genetics at the University of Utah and an investigator for the Howard Hughes Medical Institute (HHMI). The new method “is significant because it makes it practical to do this for a vast amount of the total genome,” he adds. Because mice are used to study human disease, “we want to know the function of every piece of DNA in the mouse genome,” says Sen Wu, a postdoctoral fellow in human genetics at the University of Utah and HHMI. “The best way to know the function of the genetic blueprint is by removing part of the DNA and seeing what goes wrong. We have found a way to do this job on a large scale that is simple and practical.” Capecchi says: “We developed a method for deleting any piece of DNA from the mouse genetic blueprint very efficiently.” The new method for mutating large, non-gene stretches of DNA is outlined in this week’s online edition of Nature Genetics. Capecchi and Wu conducted the research with two other University of Utah human geneticists: Guoxin Ying, a postdoctoral fellow, and Qiang Wu, an assistant professor (and no relation to Sen Wu). In the journal paper, the University of Utah scientists report:

• They found a way to delete or duplicate moderately long to very long pieces of DNA and make those mutations happen much more frequently than other methods can. That makes it easier to find out what defects or diseases arise due to such mutations, and thus what the DNA does normally.
• They devised a much more efficient method for mixing and recombining pieces of two chromosomes, making it easier to breed mice with human cancers. Such mice are needed to develop new treatments.

Vast, Non-Gene Stretches of the Genetic Blueprint. The genome is the genetic blueprint of a living organism. It is made of deoxyribonucleic acid, or DNA, a twisting, double ladder-shaped molecule made from numerous “base pairs” of four building blocks: nucleic acids designated A, C, G and T. DNA in each human cell has about 3 billion base pairs, arranged into 23 pairs of chromosomes. Those chromosomes include roughly 20,000 genes, which carry the code needed for cells to produce the proteins used to make body parts and carry out most functions in living organisms. Genes typically have 50,000 base pairs but can range in size from a few thousand to 300,000 base pairs, Capecchi says. The genes include only about 2.5 percent to 3 percent of human DNA. In between the genes are vast stretches of “non-coding” or non-gene DNA. Some pieces of non-gene DNA are “regulatory sequences” that turn genes on or off, or turn their activity up or down like a dimmer switch. Other DNA sequences are responsible for folding and packing DNA into the nucleus of each cell. Five percent to 50 percent of DNA is considered useless junk, “depending on who you ask, although probably at least half of the ‘junk’ DNA is going to end up having a pretty important function,” Capecchi says. Capecchi is known for developing gene targeting, in which mice are bred with a gene disabled or “knocked out” to see what goes wrong, thus revealing the gene’s normal function and how disease makes it malfunction. But DNA regulatory sequences between genes also can mutate to cause disease by making the genes they control malfunction. “We know how to knock out genes, and that technology is very good at changing any given gene in a designed manner,” Capecchi says. “The negative side is, it takes work and money to do that.” The new method is “a cheaper way of knocking out a gene as well as regulatory sequences.” Capecchi says it now costs about $10,000 to genetically engineer a mouse with a particular gene or other DNA sequence knocked out. So using existing technology to knock out the estimated 20,000 mouse genes would cost $200 million, and knocking out the roughly 300,000 non-gene DNA sequences in mice would cost $3 billion, he adds. The new method is a faster, cheaper way of mutating DNA, costing $200 to create each mouse with a mutant gene or other DNA sequence, although the savings are not proportionate because more mutant mice must be bred to obtain desired mutants, he says. Capecchi says the new technique could speed a National Institutes of Health effort to mutate all mouse genes in cell culture and create 900 new lines of mutant mice by 2010 – an effort NIH says “will be extremely useful for the study of human disease.” Simpler, Faster Mutations in the Whole Mouse Genome Existing gene-targeting methods for deleting large segments of DNA are time-consuming and expensive because they require researchers to make multiple manipulations in mouse embryonic stem cells, which means those cells are less likely to yield mice with the desired stretch of DNA disabled, Capecchi says. To quickly, cheaply mutate genes or none-gene DNA, Wu and Capecchi used short pieces of DNA known as loxP. Pieces of loxP act like signposts saying, “Cut the DNA between these two signposts.” In the new method, loxP is inserted in a chromosome on one mouse, and in a different position on the same chromosome in a second mouse, which also has a gene named Cre in its cells. When the mice are bred, an offspring mouse has loxP DNA on two sites on the same chromosome and also has the Cre gene. The protein made by Cre acts like a knife, cutting the DNA wherever loxP is found. The offspring mouse, in turn, is bred with a normal mouse. In a “remarkably high” average of 10 percent of the offspring, the desired large stretch of DNA is either deleted or duplicated so scientists can see what goes wrong in the mutant mouse and thus learn the normal job of that piece of DNA. Capecchi says the same method also can be used to make two chromosomes break and recombine, with each new chromosome containing a piece of each of the two old ones. The process, “translocation,” also can create new genes from two other genes. Many cancers – certain sarcomas, leukemias and lymphomas – start with translocation. Existing methods result in the desired translocation of two chromosomes in one of every 1 million to 10 million cells cultured, Capecchi says, while the new method produces the desired result in one of every 100 cells. So it is 10,000-100,000 times better. That is important, because multiple molecular steps are needed for a mouse to develop a human cancer – and such mice are used to learn how to treat or prevent cancers, says Capecchi. In many cancers, translocation of two chromosomes is the first step, and if it occurs only in one of every million cells, not enough cells are present in which subsequent steps can occur so that cancer develops. “If we now improve that 10,000-fold, the pool of cells [with translocated chromosomes] may be large enough to create a mouse that develops the cancer,” so the new method makes it easier to breed mice with human cancers, Capecchi says. ‘Jumping Genes’ Help Make More Mutant DNA Wu and Capecchi improved their new method by using it in combination with a “transposon” or so-called “jumping gene” named piggyBac, which comes from a moth. They used piggyBac to insert pieces of loxP DNA randomly into numerous spots on the mouse genome. So scientists easily can breed multiple generations of mice with loxP surrounding various large stretches of DNA. Then the first part of the new method is used: The mice are bred with mice that carry the Cre gene so any large stretch of DNA that is located between two short pieces of loxP DNA can be mutated. Because the whole mouse genome has been sequenced – the order and location of base pairs determined in detail – scientists can identify locations in individual mice where the jumping genes have carried pieces of loxP DNA. Then, they can select a mouse with loxP on both sides of the large piece of DNA they want to mutate and study. If the jumping gene carrying loxP hops into the middle of a gene, then the gene will be mutated. So while the method began as a way to delete large stretches of non-gene DNA, it has the bonus of also being able to disable genes more easily and inexpensively than existing knockout techniques, Wu says. In their study, Wu and Capecchi demonstrated that by using a jumping gene to mutate a mouse gene involved in bone formation, resulting in mutant mice with abnormally short limbs and tail (see photo with this news release).

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ZenMaster

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Human genetic 'deserts' are teeming with significant life

Human genetic 'deserts' are teeming with significant life June 18 2007 Many of the areas of the human genome previously thought to be deserts are in fact teeming with life, a scientist will tell the annual conference of the European Society of Human Genetics today (Tuesday 19 June). Most known human genes in the genome map are still incompletely annotated, says Professor Alexandre Reymond, from the Centre for Integrative Genomics, University of Lausanne, Switzerland and the Department of Genetic Medicine, University of Geneva, Geneva, Switzerland. “We found that the vast majority of the protein coding genes we studied utilised often in a tissue-specific manner previously unknown set of exons [the regions of DNA within a gene that are transcribed to messenger RNA] outside the current boundaries of the annotated genes ”, Professor Reymond will say. He and his team are among the many international collaborators working together on a pilot project to use as a ‘reference set’ by the ENCODE consortium, launched in 2003 by the National Human Genome Research Institute, part of the US National Institutes of Health, with the aim of identifying all functional elements in the human genome sequence. The pilot phase is focusing on 44 regions, totalling approximately 1% of the human genome. By testing and comparing existing methods for annotating the human genome the consortium members hope to find the most effective ways of analysing it in its entirety. Although the finished sequence of the human genome announced in 2003 was a great achievement, it left a number of questions unanswered. Before the information contained in the sequence can be used to its best effect, the identity and precise location of all the protein-encoding and non protein-encoding genes in the genome will have to be determined. “The notion that mammalian transcriptomes [the set of all messenger RNA molecules produced in a population of cells] are made of a swarming mass of different overlapping transcripts, together with our findings that suggest we have only uncovered a portion of its complexity, has important implications for medicine," says Professor Reymond. “They increase the size of the genomic regions that might harbour disease-causing mutations, and they could impair cloning strategies that try to find genes implicated in these pathologies.” They also suggest that extra caution should be used when associating a genetic phenotype with a gene knock-out or knock-in, where genes are added or deleted from a model organism in order to study the effect of therapies, he says. “It appears that the same nucleotide [the structural unit of DNA and RNA] on the genome can carry out a number of different, sometimes simultaneous, functions.” Professor Reymond’s team, in collaboration with other laboratories in Switzerland, the UK, the US and Spain, now intends to carry out the same kind of analysis for two complete human chromosomes. “I will be surprised if we do not find the same kind of variety in these structures”, he says. “Our work has shown that the human genome is far more complex than anyone could have imagined, even ten years ago. Understanding these complexities is essential to the development of effective and safe genetic medicine in the future.”

Changes in chromosomal constitution of preimplantation embryos suggest caution in genetic screening

Changes in chromosomal constitution of preimplantation embryos suggest caution in genetic screening June 18 2007 Embryos that are selected out as abnormal can undergo chromosomal modifications, a scientist will tell the annual conference of the European Society of Human Genetics today. Ms Tsvia Frumkin, from the Racine IVF unit, LIS Maternity Hospital, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel, will tell the conference that her team’s findings meant that the results of preimplantation genetic screening (PGS) for chromosomal abnormalities were not always reliable and should be interpreted with caution. PGS is offered to women with recurrent IVF failures as well as repeated miscarriages. It is based on the concept that the entire chromosomal constitution of an embryo can be represented by a single cell, which is removed from the embryo. If one biopsied cell is found to be abnormal, there is a 90% chance that the rest of the embryo is also abnormal or mosaic, where two or more cells with different chromosomal constitution exist in a single embryo. Ms Frumkin analysed 8 cell embryos at day 3 of development using the FISH (fluorescence in situ hybridization) technique. Two cells from each embryo were analysed, and between 5 and 9 chromosomes were investigated. The abnormal embryos were re-analysed on day 5, using the same method. “By comparing FISH results of day 5 embryos to the abnormal results of the same embryos on day 3, we could elucidate the origin of the chromosomal aberrations and follow different chromosomal modifications as they occurred during preimplantation period. The timing is significant because embryos used in IVF are normally transferred at between 3 and 5 days old”, says Ms Frumkin. “We found that embryos which were abnormal on day 3 demonstrated a high rate of mosaicism However, on day 5 some of them had undergone ‘self-correction’ into normal embryos. Others kept the same abnormalities, while some had acquired additional chromosomal abnormalities”, she says. Following the research, Ms Frumkin’s hospital has decided to offer PGS only to patients after they have undergone more than 6 previous failed IVF cycles, been checked for and found to have normal chromosomal make-up, and produced more than 6 good quality embryos. “Even in cases that fulfil these conditions, we nevertheless prefer transferring more embryos back to the uterus rather than carrying out PGS biopsies for them on day 3, assuming that natural selection will usually favour the normal embryos for implantation,” she says. “Our results can explain why PGS would not be able to increase pregnancy potential but rather can serve as a prognostic tool in a limited number of cases”, says Ms Frumkin. “It can also help us make optimal decisions about the value of switching to a different assisted reproduction technique, for example egg donation.” .........

ZenMaster

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Biologics Rapidly Becoming New Frontier in Drug Arena

Biologics Rapidly Becoming New Frontier in Drug Arena, FDLJ Article Concludes Monday, 18 June 2007 Dolly was cloned only adecade ago. Since then, there's been an almost cataclysmic revolution in our understanding of biologics, with potentially significant implications for every facet of the health care delivery system in the United States. This awareness of new types of biologics, which now range from universal vaccines for possibly curing cancer, to genetically engineered plants and animals that produce biologics for human or veterinary use, is raising thorny issues for agency regulators, Congressional lawmakers and biotech representatives, such as:

• How should FDA and Congress define biologics as part of new legislation under consideration that will allow the marketing of "generic"or "follow on" versions and does it really matter?
• Do we need a whole new statutory or regulatory scheme for defining human and veterinary biologics?
• How or why do cells, tissues and cloning qualify as biologics?
• What's the best way to define biologics to accommodate rapid and complex technological advances in the development of new medicines?

In the current issue of the Food and Drug Law Journal (Vol. 62, No. 2), published by the Food and Drug Law Institute, attorney and scientist Edward L. Korwek helps policymakers address these and other issues by offering the most comprehensive, historical analysis to date of the major changes in the statutory and regulatory definitions of human and veterinary biologics in the last 100 years. The FDLJ article analyzes and compares in-depth the criteria for human and veterinary biological product status related to the treatment of infectious diseases, gene and cell therapies, tissue engineering and cloning, among other products of both new and older technologies. Korwek, a senior partner with the law firm of Hogan & Hartson, LLP, in Washington, D.C., notes that while the "regulatory recipes" for human and animal biologics differ in several key aspects, neither covers two critical areas in the drug arena: antibiotics and hormones. The bottom line,according to the article: Regulating innovative technical applications of human and other animal medicines as biologics has become one of the most important challenges facing the drug industry today. .........

ZenMaster

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Spain approves therapeutic cloning

Spain's parliament approves therapeutic cloning 15 June 2007 MADRID - The lower house of the Spanish Parliament voted in favour of a bill on biomedical research that authorizes therapeutic cloning.The measure, which expressly prohibits reproductive cloning, was supported by all the parties in that chamber with the exception of the main opposition conservative Popular Party. ………….. ZenMaster

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Turning adult cells embryonic

Turning adult cells embryonic Friday, 08 June 2007 Embryonic stem cells are unique because they can develop into virtually any kind of tissue type, an attribute called pluripotency. Somatic cell nuclear transfer (“therapeutic cloning”) offers the hope of one day creating customized embryonic stem cells with a patient’s own DNA. Here, an individual’s DNA would be placed into an egg, resulting in a blastocyst that houses a supply of stem cells. But to access these cells, researchers must destroy a viable embryo.Now, scientists at Kyoto University, Whitehead Institute, Harvard University and UCLA have all demonstrated that embryonic stem cells can be created without eggs. By genetically manipulating mature skin cells taken from a mouse, the scientists have transformed these cells back into a pluripotent state, one that appears identical to an embryonic stem cell in every way. Read all at: Turning adult cells embryonic CellNEWS - Friday, 08 June 2007 ………….. ZenMaster

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