[Source ASU, Skip Derra] - Eight Arizona State University faculty members are among the 486 newly elected Fellows of the American Association for the Advancement of Science (AAAS), a prestigious international scientific society. AAAS is the world's largest general scientific society.
Brad Allenby, Richard Creath, James Elser, Patricia Gober, Nancy Grimm, Sudhir Kumar, Thomas Moore and John Spence will be recognized Feb. 14 at the Fellows forum, during the 2009 AAAS annual meeting in Chicago.
This year's election brings the total number of AAAS Fellows at Arizona State University to 54.
Becoming a Fellow is in recognition of efforts toward advancing science applications that are deemed scientifically or socially distinguished. Within that general framework, each awardee is honored for contributions to a specific field.
Braden Allenby is cited by the AAAS for "distinguished contributions to earth systems engineering and management, design for environment, industrial ecology and science and technology policy." He is a professor in ASU's Department of Civil and Environmental Engineering, as well as a professor of law and of engineering and ethics with the Joan and David Lincoln Center for Applied Ethics. Recognized as a pioneer of modern industrial ecology, Allenby is co-director of the Center for Sustainable Engineering and is helping establish a new Center of Earth Systems Engineering and Management. He recently was named as one of the U.S. Professors of the Year for 2008 by the Carnegie Foundation for the Advancement of Teaching and the Council for Advancement and Support of Higher Education.
Richard Creath is cited by AAAS for "achievements in archiving and interpreting key documents in the historical development of scientific philosophy and demonstrating their relevance to current problems." Creath, a professor in the School of Life Sciences, is a philosopher of science and epistemologist who uses historical methods to illuminate fundamental questions about the nature of scientific reasoning and knowledge. He is one of the world's foremost authorities on philosophers Rudolf Carnap and W.V.O. Quine. As general editor of the multi-volume Carnap Project, he leads an international team of two dozen leading researchers.
James Elser is cited by AAAS for "pioneering work in developing the theories of ecological and biological stoichiometry to integrate levels of biology from the genome to the biosphere and thereby improve our management of renewable resources." Elser, a professor in the School of Life Sciences, has built a career asking questions about evolutionary biology and energy and material flows in ecosystems, traveling from Antarctica to alpine lakes of Norway and Colorado to the Mongolian grasslands of China, to find answers. Understanding the balance of carbon, nitrogen and phosphorus in systems forms the backbone of Elser's worldview, known as "stoichiometric theory." He has taught more than 10,000 students and his pioneering studies have shaped young minds and jumpstarted new research approaches, as well as provided insights into nutrient limitation, trophic dynamics, and biogeochemical cycling, evolution and integrated levels of organization from molecules to cells to ecosystems.
Patricia Gober, a human geographer and demographer, is co-director of the National Science Foundation's Decision Center for a Desert City, part of ASU's Global Institute of Sustainability, and a professor in the School of Geographical Sciences. A former president of the Association of American Geographers, Gober's research focuses on the use of science and visualization for real-world decision-making, particularly in tackling the difficult water management decisions necessary in the face of growing climatic uncertainty in metropolitan Phoenix. Gober is cited by AAAS for her "outstanding record of scholarship and disciplinary leadership" and because she "clearly established herself as a leader within the discipline and has left a permanent mark within American geography."
Nancy Grimm is cited by AAAS for "pioneering studies of urban social-ecological systems that conceptually expand urban resource management, and for innovative contributions in stream ecology and biogeochemistry that have stimulated decades of research." Grimm, a professor in ASU's School of Life Sciences, has for the past 10 years led the Central Arizona-Phoenix Long-Term Ecological Research project. CAP-LTER is centered on the analysis of urban-semi-arid ecosystem relationships. Through her collaborative work, Grimm has established a conceptual basis for including human choice and action in theory of urban ecosystem dynamics. The work on biogeochemistry, species distribution and abundance, and designed aquatic ecosystems in cities has revealed that many ecological features are best explained by combinations of social and biophysical drivers.
Sudhir Kumar directs the Center for Evolutionary Functional Genomics in ASU's Biodesign Institute and is a professor of biology in the School of Life Sciences. He is cited by AAAS for "exemplary contributions in evolutionary bioinformatics, particularly in developing high-impact comparative analysis software for biologists and in illuminating the evolutionary dynamics of mutations and species through comparative genomics." Among his pioneering efforts was the software analysis of gene expression patterns from early gene expression patterns of fruit fly development, advanced work using protein molecular clocks to illuminate the Evolutionary Timescale of Life and the Molecular Evolutionary Genetics Analysis (MEGA) software package that makes useful methods of comparative sequence analysis easily accessible to the scientific community for research and education. Kumar also has received an Innovation Award in Functional Genomics from the Burroughs Wellcome Fund in 2000.
Thomas Moore, a biochemist, is cited by AAAS for "pioneering research in artificial photosynthesis including the design of artificial reaction centers, antenna and assembling an energy-converting artificial photosynthetic membrane." Moore is a professor in ASU's chemistry and biochemistry department and director of the Center for Bioenergy and Photosynthesis. Most recently, he served on the U.S. Department of Energy Basic Energy Sciences Grand Challenges Committee, which produced "Directing Matter and Energy: Five Challenges for Science and the Imagination," outlining research priorities for the foreseeable future. Moore and colleagues collaborate on research in artificial photosynthesis, which is aimed at providing a deeper understanding of natural photosynthesis and the design, synthesis and assembly of bio-inspired constructs capable of sustainable energy production and conversion for human use.
John C.H. Spence is a Regents Professor in ASU's Department of Physics. He was cited by the AAAS for "distinguished contributions to diffraction physics, especially atomic-resolution electron microscopy, electron diffraction studies of the chemical bond and diffractive (lens-less) x-ray imaging." Spence undertakes experiments in condensed matter physics based around the use of electron beams for imaging, spectroscopy and diffraction. The work requires Spence's group to build or modify advanced instruments in order to do their experiments. Spence is currently working with others to get femtosecond "snapshots" of individual proteins using the first hard x-ray laser facility in the U.S., which will begin operation next year.
Showing posts with label genomics. Show all posts
Showing posts with label genomics. Show all posts
Tuesday, December 23, 2008
UA losing major bioscience researcher
[Source: Aaron Mackey, ARizona Daily Star] - The leader of the UA's top research institute — whom colleagues hail as a key architect of the region's burgeoning bioscience industry — is leaving to head a San Francisco-based non-profit's scientific endeavors, the university announced Monday.
Vicki Chandler, director of the University of Arizona's Bio5 Institute, played a critical role in establishing the collaborative research center, which has brought tens of millions of grant dollars to the UA, including a $50 million award thought to be the largest grant in Arizona history.
The second high-profile professor with ties to Bio5 to leave the UA this year, Chandler will become chief program officer for the Gordon and Betty Moore Foundation's science efforts in February.
In July, Bio5 founder Thomas Baldwin left the UA to become dean of UC-Riverside's College of Natural and Agricultural Sciences. Baldwin founded the program, which at the time was known as the Institute for Biomedical Science and Biotechnology, in 2001.
Besides being one of the UA's premier scientists, Chandler has become a regional ambassador for bioscience research, lobbying for state money to build research facilities while striving to tell the public about the importance of the work.
"She had a vision for Bio5 that was about much more than just scientific research," said Leslie Tolbert, the UA's vice president for research. "She has an enthusiasm for outreach and the role a university can play in community development."
Taking over Bio5 in 2002, Chandler led several efforts that culminated in the UA's landing a $50 million grant in January to establish the iPlant Collaborative, a research program aimed at unlocking the secrets of plant biology. That alone accounted for roughly 10 percent of the UA's overall $500 million research budget.
The project, co-led by Chandler, was seeded by state support in research funding and new buildings — both of which Chandler lobbied for, Tolbert said.
Chandler "has been a strong spokesperson with the Legislature and with private donors as well," Tolbert said. "She gets them to see that it isn't just about the institute in the abstract, but the people doing the science and getting results."
The Bio5 Institute is the UA's most prominent interdisciplinary research center, blending researchers from five fields —agriculture, medicine, pharmacy, basic science and engineering — with industry leaders to find solutions to common problems, such as disease.
The institute has been a pipeline for grants and also has proved successful at creating a number of spin-off companies that use technologies developed in UA laboratories.
Managing the complex relationships between business leaders and researchers, Chandler was integral in convincing several bioscience companies to either expand in or move to Tucson, said Joe Snell, president and CEO of Tucson Regional Economic Opportunities Inc.
"Her leadership has been incredibly valuable in helping to position Tucson as the next bioscience hub," he said.
"I don't think we would be where we're at or where we're going without her efforts."
Chandler also has helped build interest in science among high school students and UA undergraduates. She holds summer programs that get high schoolers in laboratories with researchers and often touts how half the Bio5 researchers are undergrads.
She also has narrated the UA-produced PBS show "WaveLengths," which provides a 30-minute snapshot of some of the research produced on campus.
On top of that, Chandler maintains a full-time lab and conducts field research as a Regents Professor in both the plant science and molecular and cellular biology departments. She also holds the Weiler Endowed Chair for Excellence in Agriculture and Life Sciences.
Chandler, who has been at the UA since 1997, said she has mixed emotions about her new role.
"It's always exciting to take on a new challenge, but I poured my heart and soul into the University of Arizona and really care deeply for it," she said.
The move will take her back to her roots. She grew up in Northern California and studied at the University of California-Berkeley and UC-San Francisco while later working at Stanford after earning her Ph.D.
The foundation she is joining invests $300 million each year in projects, including science and environmental conservation research around San Francisco.
Even with her new job, Chandler will be in Tucson often. She plans to retain her endowed chair and conduct research as part of the iPlant Collaborative, a process she says will take up about 20 percent of her time.
"The university has been incredibly gracious to allow me to continue to research," she said. "By keeping my feet squarely planted in science, it will hopefully help me in my new position."
The UA will name an interim director of Bio5 early next year and plans to conduct a national search for a permanent replacement, Tolbert said.
Vicki Chandler, director of the University of Arizona's Bio5 Institute, played a critical role in establishing the collaborative research center, which has brought tens of millions of grant dollars to the UA, including a $50 million award thought to be the largest grant in Arizona history.
The second high-profile professor with ties to Bio5 to leave the UA this year, Chandler will become chief program officer for the Gordon and Betty Moore Foundation's science efforts in February.
In July, Bio5 founder Thomas Baldwin left the UA to become dean of UC-Riverside's College of Natural and Agricultural Sciences. Baldwin founded the program, which at the time was known as the Institute for Biomedical Science and Biotechnology, in 2001.
Besides being one of the UA's premier scientists, Chandler has become a regional ambassador for bioscience research, lobbying for state money to build research facilities while striving to tell the public about the importance of the work.
"She had a vision for Bio5 that was about much more than just scientific research," said Leslie Tolbert, the UA's vice president for research. "She has an enthusiasm for outreach and the role a university can play in community development."
Taking over Bio5 in 2002, Chandler led several efforts that culminated in the UA's landing a $50 million grant in January to establish the iPlant Collaborative, a research program aimed at unlocking the secrets of plant biology. That alone accounted for roughly 10 percent of the UA's overall $500 million research budget.
The project, co-led by Chandler, was seeded by state support in research funding and new buildings — both of which Chandler lobbied for, Tolbert said.
Chandler "has been a strong spokesperson with the Legislature and with private donors as well," Tolbert said. "She gets them to see that it isn't just about the institute in the abstract, but the people doing the science and getting results."
The Bio5 Institute is the UA's most prominent interdisciplinary research center, blending researchers from five fields —agriculture, medicine, pharmacy, basic science and engineering — with industry leaders to find solutions to common problems, such as disease.
The institute has been a pipeline for grants and also has proved successful at creating a number of spin-off companies that use technologies developed in UA laboratories.
Managing the complex relationships between business leaders and researchers, Chandler was integral in convincing several bioscience companies to either expand in or move to Tucson, said Joe Snell, president and CEO of Tucson Regional Economic Opportunities Inc.
"Her leadership has been incredibly valuable in helping to position Tucson as the next bioscience hub," he said.
"I don't think we would be where we're at or where we're going without her efforts."
Chandler also has helped build interest in science among high school students and UA undergraduates. She holds summer programs that get high schoolers in laboratories with researchers and often touts how half the Bio5 researchers are undergrads.
She also has narrated the UA-produced PBS show "WaveLengths," which provides a 30-minute snapshot of some of the research produced on campus.
On top of that, Chandler maintains a full-time lab and conducts field research as a Regents Professor in both the plant science and molecular and cellular biology departments. She also holds the Weiler Endowed Chair for Excellence in Agriculture and Life Sciences.
Chandler, who has been at the UA since 1997, said she has mixed emotions about her new role.
"It's always exciting to take on a new challenge, but I poured my heart and soul into the University of Arizona and really care deeply for it," she said.
The move will take her back to her roots. She grew up in Northern California and studied at the University of California-Berkeley and UC-San Francisco while later working at Stanford after earning her Ph.D.
The foundation she is joining invests $300 million each year in projects, including science and environmental conservation research around San Francisco.
Even with her new job, Chandler will be in Tucson often. She plans to retain her endowed chair and conduct research as part of the iPlant Collaborative, a process she says will take up about 20 percent of her time.
"The university has been incredibly gracious to allow me to continue to research," she said. "By keeping my feet squarely planted in science, it will hopefully help me in my new position."
The UA will name an interim director of Bio5 early next year and plans to conduct a national search for a permanent replacement, Tolbert said.
Thursday, December 18, 2008
Tissue samples collect, store and analyze
[Source: Luxemburger Wort (via Google Translate)] - (fh) - About 200 biobanks exist in Europe. The new Integrated biobank of Luxembourg (IBBL), which yesterday the press was presented, differs in two respects from other tissue banks: in addition to the collection and storage of biological samples (tissue, tumors, blood, urine, saliva ...) leads the IBBL also analyzes and stores this addition is a national project, which represents an independent unit. The samples or data of research made available. The IBBL is part of the biotechnology project in the field of molecular medicine, the 140 million euros over five years will cost and also the creation of a Center for Systems Biology and the implementation of a cancer research project covers. The goal of the biotech project is among other things, one day, drugs and therapies targeted to be able to treat patients more efficiently and reduce costs. Founded as the IBBL by CRPs Santé, Henri Tudor and Gabriel Lippmann and the University of Luxembourg. Has inspired a look at biobank model of the company "Translational Genomics Research Institute (TGen), by Dr. Jeffrey Trent, which, in Phoenix in the U.S. state of Arizona is located. The IBBL has the shape of a foundation. Your Board includes nine persons.Chairman of the Board is Dr. Jean-Claude Schmit, director of the CRP Santé. IBBL to include also a Board of Directors, an external ethics committee, a scientific project evaluation committee, a scientific council and a monitoring committee for the hospitals and the National Health Laboratory. Hospitals are important partners of the country and the wider region.
Strict conditions
The biobank itself has no research. It mainly manages data to interested researchers. If samples are made available, then only under very strict conditions. Each research project must be ethically tested and approved. The donations are voluntary, donors may withdraw their consent at any time.
If desired they can test for a special project available. The data of the donors are encrypted on several levels - the technology is called de-identification. It plays a so-called trusted third party, it still applies to define an important role. This alone can, if necessary, the data back together. This could for example be necessary if one for the health of the donor beneficial discovery is made.
In contact with the doctors
In Luxembourg, 200 people are annually diagnosed with lung cancer, but only a few surgery. These operations are carried out in two hospitals of the country. The IBBL is in contact with the concerned physicians, their patients about a possible use by the tissue biobank information. In addition, samples of healthy individuals to be collected. This is a call made via the press. Soon more information www.ibbl.lu available.
Strict conditions
The biobank itself has no research. It mainly manages data to interested researchers. If samples are made available, then only under very strict conditions. Each research project must be ethically tested and approved. The donations are voluntary, donors may withdraw their consent at any time.
If desired they can test for a special project available. The data of the donors are encrypted on several levels - the technology is called de-identification. It plays a so-called trusted third party, it still applies to define an important role. This alone can, if necessary, the data back together. This could for example be necessary if one for the health of the donor beneficial discovery is made.
In contact with the doctors
In Luxembourg, 200 people are annually diagnosed with lung cancer, but only a few surgery. These operations are carried out in two hospitals of the country. The IBBL is in contact with the concerned physicians, their patients about a possible use by the tissue biobank information. In addition, samples of healthy individuals to be collected. This is a call made via the press. Soon more information www.ibbl.lu available.
Just A Little Squeeze Lets Proteins Assess DNA
[Source: ScienceDaily] - To find its target, all a protein needs to do is give quick squeezes as it moves along the DNA strand, suggests new research from The University of Arizona in Tucson.
Scientists had thought DNA-binding proteins primarily used full-body hugs for accurate readings of the information coded in the DNA's sequence.
Even a protein known to use the hug method, called direct readout, can effectively pinpoint sites on DNA using indirect readout, found researcher Nancy C. Horton and her colleagues.
"It was a total surprise," said Horton, a UA associate professor of biochemistry and molecular biophysics. "No one had ever seen it before."
Doing the quick squeezes that scientists call indirect readout probably works faster than requiring full-body contact with all the DNA, the researchers suggest. Quick and accurate identification of key sites on DNA is important for the health of all kinds of cells, from bacteria to humans.
To detect the protein-DNA connection in such detail, Horton and her co-authors Elizabeth J. Little and Andrea C. Babic studied a DNA-binding protein that bacteria use to protect themselves from viral infections.
The finding has implications for the development of designer drugs.
"People have and are developing DNA-binding proteins to turn genes on and off," Horton said. Such designer proteins can be used to cut out the bad copy of a gene and help replace it with good copy.
"We found that indirect readout is important for finding the right sequence, and we now think indirect readout is also important for finding it quickly," she said.
The team published their paper, "Early Interrogation and Recognition of DNA Sequence by Indirect Readout," in the December issue of the journal Structure. First author Little and co-author Babic were postdoctoral research associates in Horton's laboratory when they did the research. The two are now senior scientists at Ventana Medical Systems, Inc. in Tucson, Ariz.
The National Institutes of Health funded the research.
Horton studies proteins that bind to DNA.
Seven years ago, she figured out the structure of a protein called HincII that snips up DNA. The protein is a type of enzyme called a restriction endonuclease and comes from Haemophilus influenzae bacteria.
Since that time, Horton has been trying to learn how HincII interrogates the DNA to find the right place to cut.
The protein protects bacteria by cutting up DNA from invading viruses. Without the protective protein, viral DNA would commandeer the bacterium's cellular machinery to produce viruses and ultimately kill the bacterial cell.
The HincII protein distinguishes between bacterial DNA and viral DNA by recognizing certain sequences on DNA. Such a defense requires speed to prevent the marauding virus from killing the cell and also accuracy so the protein doesn't accidentally hack up the bacterium's own DNA.
Horton knew from her previous work that the HincII protein used the direct readout method to find the particular sequence of DNA that corresponded to enemy DNA. The protein seemed to distort the DNA to read it.
Removing the direct readout contact between the protein and the DNA might show whether the DNA distortion or the contact itself was important, Horton said.
Therefore Little and Babic created a mutant protein that couldn't hug DNA closely and therefore couldn't use the direct readout method. Little described the mutant protein as missing the fingers the normal protein used to probe the DNA.
"If the finger was doing all the recognition, then the mutant should cut any DNA sequence," Horton said.
To see how the mutant interacted with DNA, the researchers crystallized the mutant protein-DNA complex in action.
Initially, Horton thought the assay had gone wrong and almost threw the results in the trash, she wrote in an e-mail.
The mutant protein had chosen the proper site on the DNA with 100 percent specificity, which was opposite from what she expected. In addition, the DNA was distorted, even though the mutant couldn't make the strong contact a normal protein would.
"I did a double-take. I was just taking a picture to have a record that it was non-specific," she said.
Understanding how endonucleases and other DNA binding-proteins recognize a particular DNA sequence provides insight into key cellular processes including the replication, transcription and repair of DNA.
Little said, "In every single one of your cells are proteins looking for the proper sequences in DNA in order to make the proteins you need to stay alive."
Horton added, "Understanding how these processes work helps in the understanding of diseases so that we could potentially cure the disease."
Scientists had thought DNA-binding proteins primarily used full-body hugs for accurate readings of the information coded in the DNA's sequence.
Even a protein known to use the hug method, called direct readout, can effectively pinpoint sites on DNA using indirect readout, found researcher Nancy C. Horton and her colleagues.
"It was a total surprise," said Horton, a UA associate professor of biochemistry and molecular biophysics. "No one had ever seen it before."
Doing the quick squeezes that scientists call indirect readout probably works faster than requiring full-body contact with all the DNA, the researchers suggest. Quick and accurate identification of key sites on DNA is important for the health of all kinds of cells, from bacteria to humans.
To detect the protein-DNA connection in such detail, Horton and her co-authors Elizabeth J. Little and Andrea C. Babic studied a DNA-binding protein that bacteria use to protect themselves from viral infections.
The finding has implications for the development of designer drugs.
"People have and are developing DNA-binding proteins to turn genes on and off," Horton said. Such designer proteins can be used to cut out the bad copy of a gene and help replace it with good copy.
"We found that indirect readout is important for finding the right sequence, and we now think indirect readout is also important for finding it quickly," she said.
The team published their paper, "Early Interrogation and Recognition of DNA Sequence by Indirect Readout," in the December issue of the journal Structure. First author Little and co-author Babic were postdoctoral research associates in Horton's laboratory when they did the research. The two are now senior scientists at Ventana Medical Systems, Inc. in Tucson, Ariz.
The National Institutes of Health funded the research.
Horton studies proteins that bind to DNA.
Seven years ago, she figured out the structure of a protein called HincII that snips up DNA. The protein is a type of enzyme called a restriction endonuclease and comes from Haemophilus influenzae bacteria.
Since that time, Horton has been trying to learn how HincII interrogates the DNA to find the right place to cut.
The protein protects bacteria by cutting up DNA from invading viruses. Without the protective protein, viral DNA would commandeer the bacterium's cellular machinery to produce viruses and ultimately kill the bacterial cell.
The HincII protein distinguishes between bacterial DNA and viral DNA by recognizing certain sequences on DNA. Such a defense requires speed to prevent the marauding virus from killing the cell and also accuracy so the protein doesn't accidentally hack up the bacterium's own DNA.
Horton knew from her previous work that the HincII protein used the direct readout method to find the particular sequence of DNA that corresponded to enemy DNA. The protein seemed to distort the DNA to read it.
Removing the direct readout contact between the protein and the DNA might show whether the DNA distortion or the contact itself was important, Horton said.
Therefore Little and Babic created a mutant protein that couldn't hug DNA closely and therefore couldn't use the direct readout method. Little described the mutant protein as missing the fingers the normal protein used to probe the DNA.
"If the finger was doing all the recognition, then the mutant should cut any DNA sequence," Horton said.
To see how the mutant interacted with DNA, the researchers crystallized the mutant protein-DNA complex in action.
Initially, Horton thought the assay had gone wrong and almost threw the results in the trash, she wrote in an e-mail.
The mutant protein had chosen the proper site on the DNA with 100 percent specificity, which was opposite from what she expected. In addition, the DNA was distorted, even though the mutant couldn't make the strong contact a normal protein would.
"I did a double-take. I was just taking a picture to have a record that it was non-specific," she said.
Understanding how endonucleases and other DNA binding-proteins recognize a particular DNA sequence provides insight into key cellular processes including the replication, transcription and repair of DNA.
Little said, "In every single one of your cells are proteins looking for the proper sequences in DNA in order to make the proteins you need to stay alive."
Horton added, "Understanding how these processes work helps in the understanding of diseases so that we could potentially cure the disease."
Monday, December 8, 2008
HTG SIGNS COLLABORATION AGREEMENT WITH HARVARD CATALYST LABORATORY FOR INNOVATIVE TRANSLATIONAL TECHNOLOGIES AT HARVARD MEDICAL SCHOOL
(Source: HTG] - HTG, Inc., provider of the quantitative Nuclease Protection Assay (qNPA™) system and service partner for the life sciences industry, today announced a collaboration agreement with researchers at Harvard Catalyst Laboratory for Innovative Translational Technologies (HC-LITT) at Harvard Medical School. Under the terms of the agreement, HTG and HC-LITT will collaborate to generate a novel microRNA biogenesis assay that can measure expression of both pre-microRNA (miRNA) precursors, mature-microRNAs and regulated RNA using HTG’s qNPA™ (quantitative Nuclease Protection Assay) technology.
Researchers at the HC-LITT are investigating the implications of differential microRNA expression in human diseases such as cancer. MicroRNAs are singlestranded functional RNA species encoded in the human genome that regulate protein expression of numerous gene products. HC-LITT will utilize HTG’s technology to evaluate regulation of miRNA biogenesis by established oncogenic cell signaling pathways in order to develop novel diagnostic markers and therapeutic targets for the molecular characterization and treatment of cancer.
“We selected HTG’s technology due to the high precision and sensitivity of the product platform,” said Winston Patrick Kuo, Director, Harvard Catalyst Laboratory for Innovative Translational Technologies at Harvard Medical School. “I’m looking forward to utilizing HTG’s gene expression assay technology and imagers for HC-LITT’s research initiatives.”
HTG’s qNPA technology is used to carry out quantitative, multiplexed gene-based drug discovery programs, including target validation, HTS lead optimization, metabolism, toxicology and clinical development. HTG’s platform is highly flexible and designed for high throughput automation; it allows scientists to test any sample, including fixed tissues, without RNA extraction or target amplification. The technology is ideal for detecting small yet important changes in gene expression levels which other gene expression platforms cannot reliably detect.
Researchers at the HC-LITT are investigating the implications of differential microRNA expression in human diseases such as cancer. MicroRNAs are singlestranded functional RNA species encoded in the human genome that regulate protein expression of numerous gene products. HC-LITT will utilize HTG’s technology to evaluate regulation of miRNA biogenesis by established oncogenic cell signaling pathways in order to develop novel diagnostic markers and therapeutic targets for the molecular characterization and treatment of cancer.
“We selected HTG’s technology due to the high precision and sensitivity of the product platform,” said Winston Patrick Kuo, Director, Harvard Catalyst Laboratory for Innovative Translational Technologies at Harvard Medical School. “I’m looking forward to utilizing HTG’s gene expression assay technology and imagers for HC-LITT’s research initiatives.”
HTG’s qNPA technology is used to carry out quantitative, multiplexed gene-based drug discovery programs, including target validation, HTS lead optimization, metabolism, toxicology and clinical development. HTG’s platform is highly flexible and designed for high throughput automation; it allows scientists to test any sample, including fixed tissues, without RNA extraction or target amplification. The technology is ideal for detecting small yet important changes in gene expression levels which other gene expression platforms cannot reliably detect.
Thursday, December 4, 2008
Ant Researcher Nets Collaborative Innovation Award
[Source: Margaret Coulombe, Imperial Valley News] - The Fountain of Youth to be found in an anthill? Aging - we are all doing it. It is relentless and terminal. Auguries and alchemists, mendicants and magicians, philosophers and science fiction writers, researchers and plastic surgeons have employed all their various arts in the pursuits of “turning back the clock.” Yet, we stand in modern times with a span of a century to our name, at most. Technological wizardry abounds, so why do the factors that determine life span still elude us?
If you ask Arizona State University researcher Juergen Liebig, he would point to his favorite study animal, the ant, to provide answers.
Liebig is one of a trio of scientists who are taking an audacious approach to studying gene regulation, using the ant to model human aging, with support from a Howard Hughes Medical Institute (HHMI) $40 million pilot program, The Collaborative Innovation Awards.
As its name suggests, the award will allow scientists to attack problems that one person can’t solve, according to Jack Dixon, HHMI vice president and chief scientific officer.
“We were looking for projects that could really represent breakthroughs and change the way we think,” says Dixon.
One of eight teams selected, Liebig, assistant professor in School of Life Sciences and member of the Center for Social Dynamics and Complexity in ASU’s College of Liberal Arts and Sciences, will partner with team leader Danny Reinberg, a Howard Hughes Medical Institute investigator at the New York University School of Medicine, and colleague Shelley Berger of the Wistar Institute, both top researchers in the field of epigenetics.
The eight collaborative projects collectively engage 33 researchers and 16 institutions in the United States and Chile. What can ants, not typically known for long life, tell us about human aging?
Potentially much, says Liebig. Ants in a colony are genetically closely related, yet these sisters’ body types, behavior and purpose can become specialized and vastly different. Queens typically arise as the single reproductive female in an ant colony, living for as long as 30 years in some species. As head of the colony they stay in the nest dedicated to perform one major task, egg-laying, for their whole life. Workers on the other hand perform brood care, colony maintenance, and complex foraging tasks. Among the workers additional behavioral and morphological differences may exist. Some individuals are larger and more robust with a focus on colony defense, which earned them the name soldiers. How can such big differences arise in each of these ant types’ longevity and behavior without some real differences in their DNA?
According to Liebig and his collaborators, the answer can be found in the rising field of epigenetics – the study of inherited changes in the activity of genes - for example, when they turned on or off; changes not caused by alterations in the DNA sequence. Epigenetic changes occur during normal development and tissue differentiation, and correlate with certain disease states in humans, such as cancer.
“But, little is known about the molecular basis for epigenetic changes that underlie aging or behavior,” Liebig says. “One advantage of using ants as models is that as individuals they follow very different behavioral and developmental trajectories, and these changes are plastic.”
It is this behavioral and developmental plasticity that drew the collaborators to work together.
Liebig studies three species of ants, each which allows the HHMI team to examine a different aspect of how epigenetic factors can influence outcomes in behavior, morphology, and longevity.
Harpegnathos saltator (literally meaning “jumping sickle jaw”) is a primitive species of ant where workers are able to perform either reproductive or helper tasks. A worker can become a reproductive functional queen, if the original queen dies or is removed. Such a trait is not found in “higher” order ants because these species have become structurally specialized. Carpenter ants, Camponotus floridanus, allow Liebig, Reinberg and Berger to examine what epigenetic factors or genes control longevity. Queens in this species are structurally specialized, growing large and also long-lived. Finally, using ants from the genus Pheidole, whose soldier caste development can be artificially induced, allows the researchers to closely examine (and potentially manipulate) what genes are expressed or repressed, and identify the factors regulating structural specialization and behavior.
The first task for the collaborative team will be to get the complete sequences of the genomes for these three ant species. Reinberg is currently identifying partners specialized to do this task. Then the group will examine the gene expression profiles of the different castes (worker, queen, soldier).
“This collaboration is fortuitous,” says Liebig. “Danny and Shelley were looking for a model system to study epigenetic factors of differences in ant behavior and development. They contacted my colleague Bert Hölldobler, who knew I was looking for geneticists interested in differential gene expression in behavior, aging, and development in ants.” Hölldobler is the Pulitzer Prize winning coauthor of “The Ants,” and leading expert in ant communication and social organization.
Liebig notes that the project is risky. For example, the complete sequence of the ant genome has never been achieved before.
“Often potential research partners are reluctant to cross barriers in scientific specialties and there is not funding for such risky ventures when there is interest to do them,” Liebig says.
“The beauty of this project is that the HHMI Collaborative Innovation Awards create the opportunity for us to blend our skills to develop a new approach and model system for the study of behavior and aging.”
Arizona State University has become the world leader in the study of social insects, and study of their levels of organization from organism to society, according to luminary Edward O. Wilson. Liebig believes that the study of social insects and using them as models for human systems has the potential to transform understanding about aging, sociobiology, neurobiology, learning and memory and behavior. Liebig believes his collaborators on the HHMI project would agree.
“Social insect societies are remarkable in that their specialization extends beyond the organism level, to function at the level of the ‘superorganism,’” Liebig notes. “In that way, the division of labor seen between reproductive and non-reproductive individuals is analogous to cellular specialization in different organs in a multicellular organism. The prediction is that epigenetic regulation may determine behavioural castes in ant colonies.”
“Who knows? Separating these effects may even give us the tools and understanding to look at what regulates longevity in humans,” Liebig adds.
If you ask Arizona State University researcher Juergen Liebig, he would point to his favorite study animal, the ant, to provide answers.
Liebig is one of a trio of scientists who are taking an audacious approach to studying gene regulation, using the ant to model human aging, with support from a Howard Hughes Medical Institute (HHMI) $40 million pilot program, The Collaborative Innovation Awards.
As its name suggests, the award will allow scientists to attack problems that one person can’t solve, according to Jack Dixon, HHMI vice president and chief scientific officer.
“We were looking for projects that could really represent breakthroughs and change the way we think,” says Dixon.
One of eight teams selected, Liebig, assistant professor in School of Life Sciences and member of the Center for Social Dynamics and Complexity in ASU’s College of Liberal Arts and Sciences, will partner with team leader Danny Reinberg, a Howard Hughes Medical Institute investigator at the New York University School of Medicine, and colleague Shelley Berger of the Wistar Institute, both top researchers in the field of epigenetics.
The eight collaborative projects collectively engage 33 researchers and 16 institutions in the United States and Chile. What can ants, not typically known for long life, tell us about human aging?
Potentially much, says Liebig. Ants in a colony are genetically closely related, yet these sisters’ body types, behavior and purpose can become specialized and vastly different. Queens typically arise as the single reproductive female in an ant colony, living for as long as 30 years in some species. As head of the colony they stay in the nest dedicated to perform one major task, egg-laying, for their whole life. Workers on the other hand perform brood care, colony maintenance, and complex foraging tasks. Among the workers additional behavioral and morphological differences may exist. Some individuals are larger and more robust with a focus on colony defense, which earned them the name soldiers. How can such big differences arise in each of these ant types’ longevity and behavior without some real differences in their DNA?
According to Liebig and his collaborators, the answer can be found in the rising field of epigenetics – the study of inherited changes in the activity of genes - for example, when they turned on or off; changes not caused by alterations in the DNA sequence. Epigenetic changes occur during normal development and tissue differentiation, and correlate with certain disease states in humans, such as cancer.
“But, little is known about the molecular basis for epigenetic changes that underlie aging or behavior,” Liebig says. “One advantage of using ants as models is that as individuals they follow very different behavioral and developmental trajectories, and these changes are plastic.”
It is this behavioral and developmental plasticity that drew the collaborators to work together.
Liebig studies three species of ants, each which allows the HHMI team to examine a different aspect of how epigenetic factors can influence outcomes in behavior, morphology, and longevity.
Harpegnathos saltator (literally meaning “jumping sickle jaw”) is a primitive species of ant where workers are able to perform either reproductive or helper tasks. A worker can become a reproductive functional queen, if the original queen dies or is removed. Such a trait is not found in “higher” order ants because these species have become structurally specialized. Carpenter ants, Camponotus floridanus, allow Liebig, Reinberg and Berger to examine what epigenetic factors or genes control longevity. Queens in this species are structurally specialized, growing large and also long-lived. Finally, using ants from the genus Pheidole, whose soldier caste development can be artificially induced, allows the researchers to closely examine (and potentially manipulate) what genes are expressed or repressed, and identify the factors regulating structural specialization and behavior.
The first task for the collaborative team will be to get the complete sequences of the genomes for these three ant species. Reinberg is currently identifying partners specialized to do this task. Then the group will examine the gene expression profiles of the different castes (worker, queen, soldier).
“This collaboration is fortuitous,” says Liebig. “Danny and Shelley were looking for a model system to study epigenetic factors of differences in ant behavior and development. They contacted my colleague Bert Hölldobler, who knew I was looking for geneticists interested in differential gene expression in behavior, aging, and development in ants.” Hölldobler is the Pulitzer Prize winning coauthor of “The Ants,” and leading expert in ant communication and social organization.
Liebig notes that the project is risky. For example, the complete sequence of the ant genome has never been achieved before.
“Often potential research partners are reluctant to cross barriers in scientific specialties and there is not funding for such risky ventures when there is interest to do them,” Liebig says.
“The beauty of this project is that the HHMI Collaborative Innovation Awards create the opportunity for us to blend our skills to develop a new approach and model system for the study of behavior and aging.”
Arizona State University has become the world leader in the study of social insects, and study of their levels of organization from organism to society, according to luminary Edward O. Wilson. Liebig believes that the study of social insects and using them as models for human systems has the potential to transform understanding about aging, sociobiology, neurobiology, learning and memory and behavior. Liebig believes his collaborators on the HHMI project would agree.
“Social insect societies are remarkable in that their specialization extends beyond the organism level, to function at the level of the ‘superorganism,’” Liebig notes. “In that way, the division of labor seen between reproductive and non-reproductive individuals is analogous to cellular specialization in different organs in a multicellular organism. The prediction is that epigenetic regulation may determine behavioural castes in ant colonies.”
“Who knows? Separating these effects may even give us the tools and understanding to look at what regulates longevity in humans,” Liebig adds.
TGen and international team identify gene that could put people at risk for age-related hearing loss
{Source: TGen] - Researchers at the Translational Genomics Research Institute, working with scientists from Los Angeles and Belgium, have identified a gene that could help explain why some people lose their hearing as they age.
In a study released online today in the journal Human Molecular Genetics, researchers identified a gene that could help lead to the treatment of presbycusis, or age-related hearing loss, which accounts for 30 percent of all deafness.
“Finding the genetic causes of age-related hearing loss could lead to treatments that would bring relief to millions of people worldwide who now suffer from social isolation, depression and even cognitive impairment as a result of not being able to properly understand what others are saying,’’ said Dr. Matthew Huentelman, an Investigator in TGen’s Neurogenomics Division and one of the scientific paper’s lead authors.
Researchers at TGen, the Los Angeles-based House Ear Institute, and the University of Antwerp, Belgium, said they believe the paper’s findings represent important and significant progress in the efforts to discover the origins of presbycusis.
“This is the first ever and largest genome-wide association study for age-related hearing loss,” said Dr. Rick Friedman, another lead author who also is a Principal Investigator at the House Ear Institute and surgeon at the House Clinic.
The study uncovered several genes, but one gene stands out and is believed to put people at risk for hearing loss as they age. The research team believes a common variant in the GRM7 gene may be associated with susceptibility to glutamate excitotoxicity and hearing loss. It is the overexpression of glutamate that causes damage to the inner and outer hair cells in the inner ear leading to age-related hearing loss.
“We have known for a long time that genes play an important role in presbycusis. But until now, genetic research has lagged behind compared to other important diseases,” said Guy Van Camp, director of the Hereditary Deafness Laboratory and professor, University of Antwerp, Belgium. “The identification of GRM7 is a very exciting result, as it may provide insights in the development of the disease.”
The study participants were Caucasian, ages 53 to 67, and the samples were collected at eight centers in six nations throughout Europe from population registries or audiological consultations. The team of investigators analyzed the samples and identified genetic risks. In the lab, the research team scored markers across the entire genome of more than 2,000 samples.
Friedman said the next step is developing a laboratory model to test pharmaceuticals for possible treatment of presbycusis in the future.
In a study released online today in the journal Human Molecular Genetics, researchers identified a gene that could help lead to the treatment of presbycusis, or age-related hearing loss, which accounts for 30 percent of all deafness.
“Finding the genetic causes of age-related hearing loss could lead to treatments that would bring relief to millions of people worldwide who now suffer from social isolation, depression and even cognitive impairment as a result of not being able to properly understand what others are saying,’’ said Dr. Matthew Huentelman, an Investigator in TGen’s Neurogenomics Division and one of the scientific paper’s lead authors.
Researchers at TGen, the Los Angeles-based House Ear Institute, and the University of Antwerp, Belgium, said they believe the paper’s findings represent important and significant progress in the efforts to discover the origins of presbycusis.
“This is the first ever and largest genome-wide association study for age-related hearing loss,” said Dr. Rick Friedman, another lead author who also is a Principal Investigator at the House Ear Institute and surgeon at the House Clinic.
The study uncovered several genes, but one gene stands out and is believed to put people at risk for hearing loss as they age. The research team believes a common variant in the GRM7 gene may be associated with susceptibility to glutamate excitotoxicity and hearing loss. It is the overexpression of glutamate that causes damage to the inner and outer hair cells in the inner ear leading to age-related hearing loss.
“We have known for a long time that genes play an important role in presbycusis. But until now, genetic research has lagged behind compared to other important diseases,” said Guy Van Camp, director of the Hereditary Deafness Laboratory and professor, University of Antwerp, Belgium. “The identification of GRM7 is a very exciting result, as it may provide insights in the development of the disease.”
The study participants were Caucasian, ages 53 to 67, and the samples were collected at eight centers in six nations throughout Europe from population registries or audiological consultations. The team of investigators analyzed the samples and identified genetic risks. In the lab, the research team scored markers across the entire genome of more than 2,000 samples.
Friedman said the next step is developing a laboratory model to test pharmaceuticals for possible treatment of presbycusis in the future.
Keeping Chromosomes From Cuddling Up
[Source: Mari N. Jensen, UA College of Science] - If chromosomes snuggle up too closely at the wrong times, the results can be genetic disaster.
Now University of Arizona researchers have found the molecular machines in fruit flies that yank chromosomes, the DNA-carrying structures, apart when necessary.
The machines, proteins called condensin II, separate chromosomes by twisting them into supercoils that kink up and therefore can no longer touch.
Scientists had known of condensin II but did not know how it functioned inside cells.
Keeping specific parts of chromosomes from touching can change how the instructions carried in the DNA are read, said BIO5 member Giovanni Bosco, a UA assistant professor of molecular and cellular biology.
"It's like picking up your favorite book and, depending on what chair you chose to sit in, it turned into a different story -- even though the printed words in the book never changed," research team leader Bosco wrote in an e-mail.
"This now changes the way we think about genetic information. Taking a literal reading of it is not what actually happens," he wrote. "Instead, context matters."
The team also found that condensin II plays a key role in making sure that fruit fly sperm cells each receive the proper number of chromosomes -- not too many, not too few.
Bosco suspects that condensin II plays the same role in the formation of human sperm and eggs.
Having too many or too few chromosomes in egg or sperm cells is the source of several important genetic disorders, including Down syndrome.
Abnormalities in chromosome number is also the cause of some miscarriages of early-term fetuses in humans.
The research is published in two separate papers. "Chromosome Alignment and Transvection are Antagonized by Condensin II," by Tom A. Hartl and Helen F. Smith, UA doctoral students, and Bosco is in the Nov. 28 issue of the journal Science.
Hartl, Sarah J. Sweeney, Peter J. Knepler and Bosco published their paper, "Condensin II Resolves Chromosomal Associations to Enable Anaphase I Segregation in Drosophila Male Meiosis," in the October 2008 issue of PLoS Genetics. Sweeney and Knepler, now doing research at UA, were UA undergraduates when they conducted the research.
The National Institutes of Health and the National Science Foundation funded the research.
Learning how cells control chromosomes and how DNA is transcribed will lead to better understanding of how an organism's DNA affects the organism's final form.
Scientists have known for about 50 years that when chromosomes are in direct contact, the transcription machinery can choose to transcribe either the gene from the mother or the gene from the father.
Many researchers investigated how the specific genes were brought close together so that process, known as transvection, could happen.
Bosco wondered, what if the chromosomes stayed stuck together?
To find something that separated chromosomes, he looked for female fruit flies that were sterile because chromosomes in their eggs had stuck together.
Once he had those fruit flies, Hartl isolated the gene that kept the chromosomes from coming apart. He found that the gene coded for condensin II, indicating that the sterile flies couldn't make condensin II.
To be able to watch how condensin II affects chromosomes, the researchers used the salivary glands from normal Drosophila melanogaster fruit flies. Fruit fly salivary glands are unusual, because they have many copies of the same chromosome coiled together like a rope.
Hartl said, "You can actually see chromosomes, because the cells are so huge and the chromosomes are so huge."
The team inserted an additional gene into the chromosomes that would turn the condensin II-producing gene off at 77 F (21 C) and on at 95 F (35 C). The researchers also marked one gene on the chromosomes with green fluorescent protein, or GFP, to be able to see changes in the chromosomes' positions.
The scientists then looked at the salivary glands at the two temperatures to see what happened when condensin II was present and when it was absent.
Bosco said, "Simply turning the condensin gene on or off, we could watch the chromosomes move right before our eyes, demonstrating that condensin was mostly likely the tiny machine that was ripping the chromosomes apart."
He said these findings are significant because more and more genetic tests to sequence people's DNA are becoming available, but the DNA sequence alone does not completely determine what diseases the person will have.
Even if it's in the genes, it might not show, he said. "It's what your cells are doing with your genes that's important."
To pull the chromosomes apart, condensin II changes its shape. Smith said the team's next step is figuring out how condensin II proteins are recruited to the chromosomes and how the condensin II proteins use the cellular energy packets known as ATP to change shape.
Now University of Arizona researchers have found the molecular machines in fruit flies that yank chromosomes, the DNA-carrying structures, apart when necessary.
The machines, proteins called condensin II, separate chromosomes by twisting them into supercoils that kink up and therefore can no longer touch.
Scientists had known of condensin II but did not know how it functioned inside cells.
Keeping specific parts of chromosomes from touching can change how the instructions carried in the DNA are read, said BIO5 member Giovanni Bosco, a UA assistant professor of molecular and cellular biology.
"It's like picking up your favorite book and, depending on what chair you chose to sit in, it turned into a different story -- even though the printed words in the book never changed," research team leader Bosco wrote in an e-mail.
"This now changes the way we think about genetic information. Taking a literal reading of it is not what actually happens," he wrote. "Instead, context matters."
The team also found that condensin II plays a key role in making sure that fruit fly sperm cells each receive the proper number of chromosomes -- not too many, not too few.
Bosco suspects that condensin II plays the same role in the formation of human sperm and eggs.
Having too many or too few chromosomes in egg or sperm cells is the source of several important genetic disorders, including Down syndrome.
Abnormalities in chromosome number is also the cause of some miscarriages of early-term fetuses in humans.
The research is published in two separate papers. "Chromosome Alignment and Transvection are Antagonized by Condensin II," by Tom A. Hartl and Helen F. Smith, UA doctoral students, and Bosco is in the Nov. 28 issue of the journal Science.
Hartl, Sarah J. Sweeney, Peter J. Knepler and Bosco published their paper, "Condensin II Resolves Chromosomal Associations to Enable Anaphase I Segregation in Drosophila Male Meiosis," in the October 2008 issue of PLoS Genetics. Sweeney and Knepler, now doing research at UA, were UA undergraduates when they conducted the research.
The National Institutes of Health and the National Science Foundation funded the research.
Learning how cells control chromosomes and how DNA is transcribed will lead to better understanding of how an organism's DNA affects the organism's final form.
Scientists have known for about 50 years that when chromosomes are in direct contact, the transcription machinery can choose to transcribe either the gene from the mother or the gene from the father.
Many researchers investigated how the specific genes were brought close together so that process, known as transvection, could happen.
Bosco wondered, what if the chromosomes stayed stuck together?
To find something that separated chromosomes, he looked for female fruit flies that were sterile because chromosomes in their eggs had stuck together.
Once he had those fruit flies, Hartl isolated the gene that kept the chromosomes from coming apart. He found that the gene coded for condensin II, indicating that the sterile flies couldn't make condensin II.
To be able to watch how condensin II affects chromosomes, the researchers used the salivary glands from normal Drosophila melanogaster fruit flies. Fruit fly salivary glands are unusual, because they have many copies of the same chromosome coiled together like a rope.
Hartl said, "You can actually see chromosomes, because the cells are so huge and the chromosomes are so huge."
The team inserted an additional gene into the chromosomes that would turn the condensin II-producing gene off at 77 F (21 C) and on at 95 F (35 C). The researchers also marked one gene on the chromosomes with green fluorescent protein, or GFP, to be able to see changes in the chromosomes' positions.
The scientists then looked at the salivary glands at the two temperatures to see what happened when condensin II was present and when it was absent.
Bosco said, "Simply turning the condensin gene on or off, we could watch the chromosomes move right before our eyes, demonstrating that condensin was mostly likely the tiny machine that was ripping the chromosomes apart."
He said these findings are significant because more and more genetic tests to sequence people's DNA are becoming available, but the DNA sequence alone does not completely determine what diseases the person will have.
Even if it's in the genes, it might not show, he said. "It's what your cells are doing with your genes that's important."
To pull the chromosomes apart, condensin II changes its shape. Smith said the team's next step is figuring out how condensin II proteins are recruited to the chromosomes and how the condensin II proteins use the cellular energy packets known as ATP to change shape.
Monday, November 17, 2008
UA Researchers Studying Little-Known Genetic Sequences
[Source University Arizona Communications] - University of Arizona researchers are among a group of scientists who have discovered a source of previously scarce small RNA molecules. Their finding, which was recently published in the Proceedings of the National Academy of Sciences, provides a valuable new tool for better understanding how plants grow and develop.
All living things contain small RNA molecules, said Vicki Chandler, a UA Regents' Professor and director of the UA's BIO5 Institute. Some small RNA molecules help the genes in cells carry out their instructions, others silence genes and prevent them from acting. In plants, two types of small RNA molecules have been studied, one of them 21 nucleotides long, the other 24 nucleotides long. Nucleotides are the atomic "building blocks" of all genetic material.
Working with a mutant strain of maize, Chandler and her colleagues have honed in on a distinct class of small RNA molecule that is 22 nucleotides long. The 21- and 22-nucleotide RNAs are scarce in most plants, including wild maize, but in the mutant strain, the researchers discovered that they were common because the 24-nucleotide RNAs are dramatically reduced.
Having a reliable source of the 21- and 22-nucleotide RNA means plant biologists can now study these molecules in depth, and work out the pathways they follow to regulate plant genes. "We don't yet know exactly what it (the 22-nucleotide RNA) is doing in the cells, so there'll be a whole new line of experiments as we try to figure it out," Chandler said.
She also said that there may well be other understudied small RNA molecules waiting to be looked at as well. "I think we've only seen the tip of the iceberg with these small regulatory RNAs. There's still a lot to learn, and that's exciting."
The information that results from studying "new" small RNAs will become doubly valuable as other plant biologists, including BIO5 member Rod Wing, finish refining the genetic sequence of maize. "The two together (the small RNA molecules and the sequenced maize genome) will provide a lot of new tools for better understanding plant growth and function," Chandler said.
That work could ultimately have implications for everything from environmental and ecological issues to agriculture and medicine. "Gene regulation is fundamental to so many issues," Chandler said. The 22-nucleotide RNA molecule, she said "is one example of a pathway that – once it's worked out – could be targeted to address them."
All living things contain small RNA molecules, said Vicki Chandler, a UA Regents' Professor and director of the UA's BIO5 Institute. Some small RNA molecules help the genes in cells carry out their instructions, others silence genes and prevent them from acting. In plants, two types of small RNA molecules have been studied, one of them 21 nucleotides long, the other 24 nucleotides long. Nucleotides are the atomic "building blocks" of all genetic material.
Working with a mutant strain of maize, Chandler and her colleagues have honed in on a distinct class of small RNA molecule that is 22 nucleotides long. The 21- and 22-nucleotide RNAs are scarce in most plants, including wild maize, but in the mutant strain, the researchers discovered that they were common because the 24-nucleotide RNAs are dramatically reduced.
Having a reliable source of the 21- and 22-nucleotide RNA means plant biologists can now study these molecules in depth, and work out the pathways they follow to regulate plant genes. "We don't yet know exactly what it (the 22-nucleotide RNA) is doing in the cells, so there'll be a whole new line of experiments as we try to figure it out," Chandler said.
She also said that there may well be other understudied small RNA molecules waiting to be looked at as well. "I think we've only seen the tip of the iceberg with these small regulatory RNAs. There's still a lot to learn, and that's exciting."
The information that results from studying "new" small RNAs will become doubly valuable as other plant biologists, including BIO5 member Rod Wing, finish refining the genetic sequence of maize. "The two together (the small RNA molecules and the sequenced maize genome) will provide a lot of new tools for better understanding plant growth and function," Chandler said.
That work could ultimately have implications for everything from environmental and ecological issues to agriculture and medicine. "Gene regulation is fundamental to so many issues," Chandler said. The 22-nucleotide RNA molecule, she said "is one example of a pathway that – once it's worked out – could be targeted to address them."
Monday, November 10, 2008
New Regulatory Mechanism Discovered For Cell Identity And Behavior In Forming Organs
[Source: ScienceDaily] - Two proteins interact in a previously unknown molecular mechanism that may have broad implications in future studies looking for the causes of defective organs in fetuses, metastatic cancers and other diseases, according to researchers at Cincinnati Children's Hospital Medical Center.
Reporting their work in the Oct. 15 Genes & Development, the researchers said the mechanism coordinates cell identity and behavior in the forming organs of embryos.
"Our study helps address the current challenge of finding out where cell specificity comes from, how cells do what they do in the context of disease and development, and how these activities are regulated," said Aaron Zorn, Ph.D., a researcher in the division of Developmental Biology at Cincinnati Children's and the study's corresponding author. "This helps inform research into how we tell early stem cells what to become. If someone has diabetes, for example, how do we tell a cell to become a pancreas cell so it will produce insulin?"
The study involved embryos of Xenopus frogs, a species indigenous to Africa often used in early biomedical studies. The scientists discovered a signaling protein very common in developmental biology, Wnt11 (Wingless), has to be inhibited by the modulating protein Sfrp5 (Secreted Frizzled Related Protein), a known antagonist of Wnt. Without this restriction, Wnt signaling runs amok and the frog's foregut, liver and pancreas form improperly from a cascade of disorganized cell growth.
"We point out that Wnt has two key roles here – one controlling the cell expression pathway to tell cells what they are supposed to be, and the other controlling the pathway for cell movement, behavior and adhesion," said Dr. Zorn, also associate professor of pediatrics at the University of Cincinnati (UC) College of Medicine. "Without Sfrp5 controlling what Wnt does in both pathways, things go horribly wrong in the developing foregut and its organs."
The Wnt signaling pathway is a complex network of proteins best known for their role in stimlating cell behavior during embryo development and in cancer. They also are involved in normal physiological processes in adult animals. Parts of the Wnt pathway have been conserved between species during the long course of evolution, all the way from simple roundworms to humans.
Previous research in Xenopus has established that a low level of activity from a molecule called B-catenin – which promotes cell-to-cell adhesion and is part of the Wnt pathway – is necessary to maintain accurate foregut formation and initiate liver and pancreas development. Unknown before the study by Dr. Zorn's team was which Wnt genes are involved and how Wnt and B-catenin activity are regulated along the frog's developing anterior-posterior body axis.
During the very early phases of embryo development – when the organism is still essentially flattened layers of cells called an endoderm – Dr. Zorn's team found Wnt's stimulation of B-catenin must be restricted in the anterior region so the tissue of forming foregut organs maintain its integrity. Their experiments showed that Sfrp5 steps in at the right time and place to repress Wnt signaling, allowing the cells to form an epithelial sheet, or lining – an essential step in organ development.
In one experiment, when researchers removed the Sfrp5 protein, the resulting Sfrp5-depleted Xenopus embryos had smaller foregut cavities filled with unorganized early-stage endoderm cells, which were incapable of properly forming liver and pancreatic organs.
Dr. Zorn and colleagues said their results have possible implications in metastatic cancer. For one, Sfrp proteins are already known to be tumor suppressors that are genetically inactivated in some cancers as they progress to aggressive carcinomas. Carcinomas typically originate in epithelial cells – which form linings surrounding the surfaces and cavities of many body structures – then spread into surrounding organs and tissues.
In cancer development, the research team is suggesting a loss of Sfrp function may unleash Wnt to trigger elevated B-catenin expression, allowing its stimulation of cell-to-cell adhesion to proliferate quickly. Rapid cell proliferation and adhesion are common in cancerous and pre-cancerous conditions. It could also let Wnt send improper signals that cause a loss of structural integrity in epithelial cells, allowing cancer to spread, or metastasize.
"We talked about this mechanism in the context of cancer because the control of cell specificity, and of movement and behavior, also occurs in cancer," Dr. Zorn said. "Cells will start to proliferate out of control and then, when a cancer starts to go metastatic, they will also start to change behavior. They become motile, moving spontaneously and actively, and they become invasive."
The early stage nature of the study means it would be premature to suggest the Wnt11-Sfrp5 mechanism might become the basis of diagnostic or therapeutic strategies for patients, Dr. Zorn said. The next step is to use these results as a basis for future studies, probably involving mice, to verify the mechanism's applicability to mammalian embryo development and see how it affects disease, he said.
Participating in the study were the Cincinnati Children's Research Foundation; Department of Pediatrics, UC College of Medicine; Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center and the State Key Laboratory of Phytochemistry and Plant Resources at the Kunming Institute of Botany, Kunming, China. Other researchers include lead author, Yan Li, and Scott A. Rankin, Debora Sinner, Alan P. Kenney and Paul A. Kreig.
Funding support came from the National Institutes of Health.
Reporting their work in the Oct. 15 Genes & Development, the researchers said the mechanism coordinates cell identity and behavior in the forming organs of embryos.
"Our study helps address the current challenge of finding out where cell specificity comes from, how cells do what they do in the context of disease and development, and how these activities are regulated," said Aaron Zorn, Ph.D., a researcher in the division of Developmental Biology at Cincinnati Children's and the study's corresponding author. "This helps inform research into how we tell early stem cells what to become. If someone has diabetes, for example, how do we tell a cell to become a pancreas cell so it will produce insulin?"
The study involved embryos of Xenopus frogs, a species indigenous to Africa often used in early biomedical studies. The scientists discovered a signaling protein very common in developmental biology, Wnt11 (Wingless), has to be inhibited by the modulating protein Sfrp5 (Secreted Frizzled Related Protein), a known antagonist of Wnt. Without this restriction, Wnt signaling runs amok and the frog's foregut, liver and pancreas form improperly from a cascade of disorganized cell growth.
"We point out that Wnt has two key roles here – one controlling the cell expression pathway to tell cells what they are supposed to be, and the other controlling the pathway for cell movement, behavior and adhesion," said Dr. Zorn, also associate professor of pediatrics at the University of Cincinnati (UC) College of Medicine. "Without Sfrp5 controlling what Wnt does in both pathways, things go horribly wrong in the developing foregut and its organs."
The Wnt signaling pathway is a complex network of proteins best known for their role in stimlating cell behavior during embryo development and in cancer. They also are involved in normal physiological processes in adult animals. Parts of the Wnt pathway have been conserved between species during the long course of evolution, all the way from simple roundworms to humans.
Previous research in Xenopus has established that a low level of activity from a molecule called B-catenin – which promotes cell-to-cell adhesion and is part of the Wnt pathway – is necessary to maintain accurate foregut formation and initiate liver and pancreas development. Unknown before the study by Dr. Zorn's team was which Wnt genes are involved and how Wnt and B-catenin activity are regulated along the frog's developing anterior-posterior body axis.
During the very early phases of embryo development – when the organism is still essentially flattened layers of cells called an endoderm – Dr. Zorn's team found Wnt's stimulation of B-catenin must be restricted in the anterior region so the tissue of forming foregut organs maintain its integrity. Their experiments showed that Sfrp5 steps in at the right time and place to repress Wnt signaling, allowing the cells to form an epithelial sheet, or lining – an essential step in organ development.
In one experiment, when researchers removed the Sfrp5 protein, the resulting Sfrp5-depleted Xenopus embryos had smaller foregut cavities filled with unorganized early-stage endoderm cells, which were incapable of properly forming liver and pancreatic organs.
Dr. Zorn and colleagues said their results have possible implications in metastatic cancer. For one, Sfrp proteins are already known to be tumor suppressors that are genetically inactivated in some cancers as they progress to aggressive carcinomas. Carcinomas typically originate in epithelial cells – which form linings surrounding the surfaces and cavities of many body structures – then spread into surrounding organs and tissues.
In cancer development, the research team is suggesting a loss of Sfrp function may unleash Wnt to trigger elevated B-catenin expression, allowing its stimulation of cell-to-cell adhesion to proliferate quickly. Rapid cell proliferation and adhesion are common in cancerous and pre-cancerous conditions. It could also let Wnt send improper signals that cause a loss of structural integrity in epithelial cells, allowing cancer to spread, or metastasize.
"We talked about this mechanism in the context of cancer because the control of cell specificity, and of movement and behavior, also occurs in cancer," Dr. Zorn said. "Cells will start to proliferate out of control and then, when a cancer starts to go metastatic, they will also start to change behavior. They become motile, moving spontaneously and actively, and they become invasive."
The early stage nature of the study means it would be premature to suggest the Wnt11-Sfrp5 mechanism might become the basis of diagnostic or therapeutic strategies for patients, Dr. Zorn said. The next step is to use these results as a basis for future studies, probably involving mice, to verify the mechanism's applicability to mammalian embryo development and see how it affects disease, he said.
Participating in the study were the Cincinnati Children's Research Foundation; Department of Pediatrics, UC College of Medicine; Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center and the State Key Laboratory of Phytochemistry and Plant Resources at the Kunming Institute of Botany, Kunming, China. Other researchers include lead author, Yan Li, and Scott A. Rankin, Debora Sinner, Alan P. Kenney and Paul A. Kreig.
Funding support came from the National Institutes of Health.
DNA Chunks, Chimps And Humans: Marks Of Differences Between Human And Chimp Genomes
[Source: ScienceDaily] - Researchers have carried out the largest study of differences between human and chimpanzee genomes, identifying regions that have been duplicated or lost during evolution of the two lineages. The study, published in Genome Research, is the first to compare many human and chimpanzee genomes in the same fashion.
The team show that particular types of genes - such as those involved in the inflammatory response and in control of cell proliferation - are more commonly involved in gain or loss. They also provide new evidence for a gene that has been associated with susceptibility to infection by HIV.
"This is the first study of this scale, comparing directly the genomes of many humans and chimpanzees," says Dr Richard Redon, from the Wellcome Trust Sanger Institute, a leading author of the study. "By looking at only one 'reference' sequence for human or chimpanzee, as has been done previously, it is not possible to tell which differences occur only among individual chimpanzees or humans and which are differences between the two species.
"This is our first view of those two important legacies of evolution."
Rather than examining single-letter differences in the genomes (so-called SNPs), the researchers looked at copy number variation (CNV) - the gain or loss of regions of DNA. CNVs can affect many genes at once and their significance has only been fully appreciated within the last two years. The team looked at genomes of 30 chimpanzees and 30 humans: a direct comparison of this scale or type has not been carried out before.
The comparison uncovered CNVs that are present in both species as well as copy number differences (CNDs) between the two species. CNDs are likely to include genes that have influenced evolution of each species since humans and chimpanzees diverged some six million years ago.
"Broadly, the two genomes have similar patterns and levels of CNVs - around 70-80 in each individual - of which nearly half occur in the same regions of the two species' genomes," continues Dr Redon. "But beyond that similarity we were able to find intriguing evidence for key sets of genes that differ between us and our nearest relative."
One of the genes affected by CNVs is CCL3L1, for which lower copy numbers in humans have been associated with increased susceptibility to HIV infection. Remarkably, the study of 60 human and chimpanzee genomes found no evidence for fixed CNDs between human and chimp and no within-chimp CNV. Rather, they found that a nearby gene called TBC1D3 was reduced in number in chimpanzee compared to human: typically, there were eight copies in human, but apparently only one in all chimpanzees.
The authors suggest that it might be evolutionary selection of CNDs in TBC1D3 that have driven the population differences. Consistent with this novel observation, TBC1D3 is involved in cell proliferation (favoured category) and is on a core region for duplication - a focal point for large regions of duplication in human genome.
"It is evident that there has been striking turnover in gene content between humans and chimpanzees, and some of these changes may have resulted from exceptional selection pressures," explains Dr George Perry from Arizona State University and Brigham and Women's Hospital, another leading author of the study. "For example, a surprisingly high number of genes involved in the inflammatory response - APOL1, APOL4, CARD18, IL1F7, IL1F8 - are completely deleted from chimp genome. In humans, APOL1 is involved in resistance to the parasite that causes sleeping sickness, while IL1F7 and CARD18 play a role in regulating inflammation: therefore, there must be different regulations of these processes in chimpanzees.
"We already know that inactivation of an immune system gene from the human genome is being positively selected: now we have an example of similar consequences in the chimpanzee."
CNVs in humans and chimpanzees often occur in equivalent genomic locations: most lie in regions of the genomes, called segmental duplications, that are particularly 'fragile'. However, one in four of the 355 CNDs that the team found do not overlap with CNVs within either species - suggesting that they are variants that are 'fixed' in each species and might mark significant differences between human and chimpanzee genomes.
DNA Samples and analysis
The project used DNA samples from 30 chimpanzees (29 from W Africa, one from E Africa): the chimpanzee reference was produced using DNA from Clint, the chimpanzee whose DNA was used for the genome sequence.
Human DNA samples were obtained from following participants: ten Yoruba (Ibadan, Nigeria), ten Biaka rainforest hunter-gatherers (Central African Republic) and ten Mbuti rainforest hunter-gatherers (Democratic Republic of Congo). The human reference is a European-American male from the HapMap Project (NA10852).
CNVs and CNDs were detected using a whole-genome tilepath of DNA clones spanning the human genome used previously to map human CNVs: this platform can reveal structural variants greater than around 10,000 base-pairs in size.
This work was funded by the Wellcome Trust, the LSB Leakey Foundation, the Wenner-Gren Foundation for Anthropological Research, the National Institutes of Health, The University of Louisiana at Lafayette-New Iberia Research Center and the Howard Hughes Medical Institute.
The authors thank the Human Genome Diversity Project, the Coriell Institute for Medical Research, the Integrated Primate Biomaterials and Information Resource, New Iberia Research Center, and the Primate Foundation of Arizona for samples.
The team show that particular types of genes - such as those involved in the inflammatory response and in control of cell proliferation - are more commonly involved in gain or loss. They also provide new evidence for a gene that has been associated with susceptibility to infection by HIV.
"This is the first study of this scale, comparing directly the genomes of many humans and chimpanzees," says Dr Richard Redon, from the Wellcome Trust Sanger Institute, a leading author of the study. "By looking at only one 'reference' sequence for human or chimpanzee, as has been done previously, it is not possible to tell which differences occur only among individual chimpanzees or humans and which are differences between the two species.
"This is our first view of those two important legacies of evolution."
Rather than examining single-letter differences in the genomes (so-called SNPs), the researchers looked at copy number variation (CNV) - the gain or loss of regions of DNA. CNVs can affect many genes at once and their significance has only been fully appreciated within the last two years. The team looked at genomes of 30 chimpanzees and 30 humans: a direct comparison of this scale or type has not been carried out before.
The comparison uncovered CNVs that are present in both species as well as copy number differences (CNDs) between the two species. CNDs are likely to include genes that have influenced evolution of each species since humans and chimpanzees diverged some six million years ago.
"Broadly, the two genomes have similar patterns and levels of CNVs - around 70-80 in each individual - of which nearly half occur in the same regions of the two species' genomes," continues Dr Redon. "But beyond that similarity we were able to find intriguing evidence for key sets of genes that differ between us and our nearest relative."
One of the genes affected by CNVs is CCL3L1, for which lower copy numbers in humans have been associated with increased susceptibility to HIV infection. Remarkably, the study of 60 human and chimpanzee genomes found no evidence for fixed CNDs between human and chimp and no within-chimp CNV. Rather, they found that a nearby gene called TBC1D3 was reduced in number in chimpanzee compared to human: typically, there were eight copies in human, but apparently only one in all chimpanzees.
The authors suggest that it might be evolutionary selection of CNDs in TBC1D3 that have driven the population differences. Consistent with this novel observation, TBC1D3 is involved in cell proliferation (favoured category) and is on a core region for duplication - a focal point for large regions of duplication in human genome.
"It is evident that there has been striking turnover in gene content between humans and chimpanzees, and some of these changes may have resulted from exceptional selection pressures," explains Dr George Perry from Arizona State University and Brigham and Women's Hospital, another leading author of the study. "For example, a surprisingly high number of genes involved in the inflammatory response - APOL1, APOL4, CARD18, IL1F7, IL1F8 - are completely deleted from chimp genome. In humans, APOL1 is involved in resistance to the parasite that causes sleeping sickness, while IL1F7 and CARD18 play a role in regulating inflammation: therefore, there must be different regulations of these processes in chimpanzees.
"We already know that inactivation of an immune system gene from the human genome is being positively selected: now we have an example of similar consequences in the chimpanzee."
CNVs in humans and chimpanzees often occur in equivalent genomic locations: most lie in regions of the genomes, called segmental duplications, that are particularly 'fragile'. However, one in four of the 355 CNDs that the team found do not overlap with CNVs within either species - suggesting that they are variants that are 'fixed' in each species and might mark significant differences between human and chimpanzee genomes.
DNA Samples and analysis
The project used DNA samples from 30 chimpanzees (29 from W Africa, one from E Africa): the chimpanzee reference was produced using DNA from Clint, the chimpanzee whose DNA was used for the genome sequence.
Human DNA samples were obtained from following participants: ten Yoruba (Ibadan, Nigeria), ten Biaka rainforest hunter-gatherers (Central African Republic) and ten Mbuti rainforest hunter-gatherers (Democratic Republic of Congo). The human reference is a European-American male from the HapMap Project (NA10852).
CNVs and CNDs were detected using a whole-genome tilepath of DNA clones spanning the human genome used previously to map human CNVs: this platform can reveal structural variants greater than around 10,000 base-pairs in size.
This work was funded by the Wellcome Trust, the LSB Leakey Foundation, the Wenner-Gren Foundation for Anthropological Research, the National Institutes of Health, The University of Louisiana at Lafayette-New Iberia Research Center and the Howard Hughes Medical Institute.
The authors thank the Human Genome Diversity Project, the Coriell Institute for Medical Research, the Integrated Primate Biomaterials and Information Resource, New Iberia Research Center, and the Primate Foundation of Arizona for samples.
Thursday, November 6, 2008
UA genomics lab tackles Holocaust puzzle
[Source: Tom Beal, Arizona Daily Star] - Genetic technology developed to identify the remains of those killed in the terror attacks of Sept. 11, 2001, will be enhanced in a University of Arizona genomics laboratory to solve a more complex puzzle — identification of families separated for generations after the Holocaust.
In addition to possibly reuniting families, the DNA Shoah Project will collect a database that will aid identification of remains yet to be discovered and will develop forensic tools for use in other acts of genocide.
The project, an effort of the UA's Human Origins Genotyping Laboratory, is also creating an educational component that will allow the story of the Holocaust to be taught in scientific curricula.
It's not possible today to match relatives three generations apart, but that doesn't deter UA researchers, who say they'll solve that puzzle once the data are collected.
In the meantime, the DNA Shoah Project is racing to spread the word to Holocaust survivors, whose numbers dwindle by the day.
Tucson survivor Bill Kugelman, 83, said he intends to give a simple oral swab sample of his DNA to the project, though he expects no benefit from it. Kugelman, a survivor of three Nazi concentration camps, lost most of the European branch of his family in the Holocaust.
"All of the family I have, I have," said Kugelman. "Whoever is gone, is gone."
Matches of living relatives are a long shot, said Matt Kaplan, research director for the DNA Shoah Project, but he's confident some will be made and says the project will have many other benefits.
In addition, it represents an intriguing scientific puzzle for Kaplan and the lab he runs in the University of Arizona's Bio5 Institute.
He calls the technology developed for remains-testing at Ground Zero "high quality work" but also says "it was easy. It matched you to you. We're trying to do this for the Holocaust — 6,000 people a day killed, 9 million overall."
In addition to the numbers, the passage of time makes the task more difficult.
"Your DNA is a shuffled deck of cards you get from your mom and your dad."
With each succeeding generation, that shuffling makes identification of similarities more difficult.
Most of our DNA is identical, said Kaplan. "That's what makes a wildebeest a wildebeest. Or a human being a human being."
What the computers are looking for are those random mutations that not only identify "you as you," but you as the son or daughter of your particular parents. That gets tougher with each successive generation because you're losing half of the original material each time your DNA deck is shuffled.
"The more markers we can identify, the deeper in time we're going to be able to go back," said Kaplan.
Kaplan says he'll need a fairly large group of DNA, at least 10,000 samples, to begin looking for markers and matches.
He can't do that today, but he's getting close, Kaplan said. "Most of the things I do today were impossible three or four years ago."
It's made simpler by the infrastructure built by Arizona Research Labs at the UA's Bio5 Institute, where the Human Origins Genotyping Laboratory installed the technology to handle large-scale genotyping after it signed on to do the sampling from 260,000 people who have so far participated in the Genographics Project, run by IBM and National Geographic.
"In 2000, we did 300 samples," said Kaplan. "Now it's 1,500 to 4,000 a day."
His lab and his collaborators at the Genomic Analysis and Technology Core and the Biotechnology Computing Facility, now offer large-scale DNA testing for the entire UA campus, in addition to the outside projects.
The first step for the DNA Shoah Project is not testing, but collecting samples. Holocaust survivors, the first target of the campaign, are dying.
"It's a numbers game," said Lynn Davis, information specialist for the project. "We need to get around the world and build the biggest database we can to make it possible."
Right now, the DNA Shoah Project has fewer than 1,000 participants. Its outreach is going first to Jewish congregations and Holocaust survivors groups.
Next, said Syd Mandelbaum, the project's founder, they'll concentrate on second- and third-generation descendants of those orphaned, killed or displaced.
Mandelbaum, who now runs a nonprofit organization to feed the hungry in New York, was a geneticist earlier in his career. He is also the son of two Holocaust survivors, who always wondered if some members of the families they thought were wiped out might have been displaced and are still living somewhere in the world.
He began searching for a scientific way to answer his parents' questions after reading accounts of a mass grave that had been disturbed in the excavation for an airport expansion in Stuttgart, Germany.
He discovered there was no genetic database for comparing those remains.
A former colleague directed him to Kaplan's boss, UA geneticist Michael Hammer. He visited and was impressed with the UA's setup.
Then, Mandelbaum had a call from another former colleague, James Watson, whose theoretical work with Francis Crick on the structure of DNA led to a Nobel Prize in 1953.
Watson directed him to Howard Cash, of Gene Code Forensics, who had developed the genetic matching system that identified Ground Zero victims during the excavation of the World Trade Center in Manhattan.
Cash became a part of the project and donated his company's software to it.
For Kugelman, the Tucson Holocaust survivor, the odds of anyone finding lost family seem high but not impossible.
"Who says no? You don't know. You never know. My extended family in Poland was more than 100 people. After the war there was a handful left, except for the family we had in America."
He is also certain there are mass graves yet to be discovered. He was forced to dig graves in a camp near Dachau in Bavarian Germany during the war — the camp where his brother perished.
Kugelman began speaking out about his experiences long after the war. "It took me about 30 years to open my mouth. For 30 years, you try to erase from your memory the horrible things."
To Mandelbaum, the genetic history he is helping to record is part of that total history that should never be forgotten. "It's another way to keep the memory alive."
He thinks the project's potential impact on the young is the most important part of it.
"They read 'The Diary of Anne Frank' right now, but how about a DNA lesson in a science class to talk about the Holocaust?"
Davis said the project has already developed the first module of a curriculum that will harness the current interest in forensic science to interest students in both science and the history of the Holocaust.
In addition to possibly reuniting families, the DNA Shoah Project will collect a database that will aid identification of remains yet to be discovered and will develop forensic tools for use in other acts of genocide.
The project, an effort of the UA's Human Origins Genotyping Laboratory, is also creating an educational component that will allow the story of the Holocaust to be taught in scientific curricula.
It's not possible today to match relatives three generations apart, but that doesn't deter UA researchers, who say they'll solve that puzzle once the data are collected.
In the meantime, the DNA Shoah Project is racing to spread the word to Holocaust survivors, whose numbers dwindle by the day.
Tucson survivor Bill Kugelman, 83, said he intends to give a simple oral swab sample of his DNA to the project, though he expects no benefit from it. Kugelman, a survivor of three Nazi concentration camps, lost most of the European branch of his family in the Holocaust.
"All of the family I have, I have," said Kugelman. "Whoever is gone, is gone."
Matches of living relatives are a long shot, said Matt Kaplan, research director for the DNA Shoah Project, but he's confident some will be made and says the project will have many other benefits.
In addition, it represents an intriguing scientific puzzle for Kaplan and the lab he runs in the University of Arizona's Bio5 Institute.
He calls the technology developed for remains-testing at Ground Zero "high quality work" but also says "it was easy. It matched you to you. We're trying to do this for the Holocaust — 6,000 people a day killed, 9 million overall."
In addition to the numbers, the passage of time makes the task more difficult.
"Your DNA is a shuffled deck of cards you get from your mom and your dad."
With each succeeding generation, that shuffling makes identification of similarities more difficult.
Most of our DNA is identical, said Kaplan. "That's what makes a wildebeest a wildebeest. Or a human being a human being."
What the computers are looking for are those random mutations that not only identify "you as you," but you as the son or daughter of your particular parents. That gets tougher with each successive generation because you're losing half of the original material each time your DNA deck is shuffled.
"The more markers we can identify, the deeper in time we're going to be able to go back," said Kaplan.
Kaplan says he'll need a fairly large group of DNA, at least 10,000 samples, to begin looking for markers and matches.
He can't do that today, but he's getting close, Kaplan said. "Most of the things I do today were impossible three or four years ago."
It's made simpler by the infrastructure built by Arizona Research Labs at the UA's Bio5 Institute, where the Human Origins Genotyping Laboratory installed the technology to handle large-scale genotyping after it signed on to do the sampling from 260,000 people who have so far participated in the Genographics Project, run by IBM and National Geographic.
"In 2000, we did 300 samples," said Kaplan. "Now it's 1,500 to 4,000 a day."
His lab and his collaborators at the Genomic Analysis and Technology Core and the Biotechnology Computing Facility, now offer large-scale DNA testing for the entire UA campus, in addition to the outside projects.
The first step for the DNA Shoah Project is not testing, but collecting samples. Holocaust survivors, the first target of the campaign, are dying.
"It's a numbers game," said Lynn Davis, information specialist for the project. "We need to get around the world and build the biggest database we can to make it possible."
Right now, the DNA Shoah Project has fewer than 1,000 participants. Its outreach is going first to Jewish congregations and Holocaust survivors groups.
Next, said Syd Mandelbaum, the project's founder, they'll concentrate on second- and third-generation descendants of those orphaned, killed or displaced.
Mandelbaum, who now runs a nonprofit organization to feed the hungry in New York, was a geneticist earlier in his career. He is also the son of two Holocaust survivors, who always wondered if some members of the families they thought were wiped out might have been displaced and are still living somewhere in the world.
He began searching for a scientific way to answer his parents' questions after reading accounts of a mass grave that had been disturbed in the excavation for an airport expansion in Stuttgart, Germany.
He discovered there was no genetic database for comparing those remains.
A former colleague directed him to Kaplan's boss, UA geneticist Michael Hammer. He visited and was impressed with the UA's setup.
Then, Mandelbaum had a call from another former colleague, James Watson, whose theoretical work with Francis Crick on the structure of DNA led to a Nobel Prize in 1953.
Watson directed him to Howard Cash, of Gene Code Forensics, who had developed the genetic matching system that identified Ground Zero victims during the excavation of the World Trade Center in Manhattan.
Cash became a part of the project and donated his company's software to it.
For Kugelman, the Tucson Holocaust survivor, the odds of anyone finding lost family seem high but not impossible.
"Who says no? You don't know. You never know. My extended family in Poland was more than 100 people. After the war there was a handful left, except for the family we had in America."
He is also certain there are mass graves yet to be discovered. He was forced to dig graves in a camp near Dachau in Bavarian Germany during the war — the camp where his brother perished.
Kugelman began speaking out about his experiences long after the war. "It took me about 30 years to open my mouth. For 30 years, you try to erase from your memory the horrible things."
To Mandelbaum, the genetic history he is helping to record is part of that total history that should never be forgotten. "It's another way to keep the memory alive."
He thinks the project's potential impact on the young is the most important part of it.
"They read 'The Diary of Anne Frank' right now, but how about a DNA lesson in a science class to talk about the Holocaust?"
Davis said the project has already developed the first module of a curriculum that will harness the current interest in forensic science to interest students in both science and the history of the Holocaust.
Monday, November 3, 2008
New Regulatory Mechanism Discovered For Cell Identity And Behavior In Forming Organs
[Source: ScienceDaily] - Two proteins interact in a previously unknown molecular mechanism that may have broad implications in future studies looking for the causes of defective organs in fetuses, metastatic cancers and other diseases, according to researchers at Cincinnati Children's Hospital Medical Center.
Reporting their work in the Oct. 15 Genes & Development, the researchers said the mechanism coordinates cell identity and behavior in the forming organs of embryos.
"Our study helps address the current challenge of finding out where cell specificity comes from, how cells do what they do in the context of disease and development, and how these activities are regulated," said Aaron Zorn, Ph.D., a researcher in the division of Developmental Biology at Cincinnati Children's and the study's corresponding author. "This helps inform research into how we tell early stem cells what to become. If someone has diabetes, for example, how do we tell a cell to become a pancreas cell so it will produce insulin?"
The study involved embryos of Xenopus frogs, a species indigenous to Africa often used in early biomedical studies. The scientists discovered a signaling protein very common in developmental biology, Wnt11 (Wingless), has to be inhibited by the modulating protein Sfrp5 (Secreted Frizzled Related Protein), a known antagonist of Wnt. Without this restriction, Wnt signaling runs amok and the frog's foregut, liver and pancreas form improperly from a cascade of disorganized cell growth.
"We point out that Wnt has two key roles here – one controlling the cell expression pathway to tell cells what they are supposed to be, and the other controlling the pathway for cell movement, behavior and adhesion," said Dr. Zorn, also associate professor of pediatrics at the University of Cincinnati (UC) College of Medicine. "Without Sfrp5 controlling what Wnt does in both pathways, things go horribly wrong in the developing foregut and its organs."
The Wnt signaling pathway is a complex network of proteins best known for their role in stimlating cell behavior during embryo development and in cancer. They also are involved in normal physiological processes in adult animals. Parts of the Wnt pathway have been conserved between species during the long course of evolution, all the way from simple roundworms to humans.
Previous research in Xenopus has established that a low level of activity from a molecule called B-catenin – which promotes cell-to-cell adhesion and is part of the Wnt pathway – is necessary to maintain accurate foregut formation and initiate liver and pancreas development. Unknown before the study by Dr. Zorn's team was which Wnt genes are involved and how Wnt and B-catenin activity are regulated along the frog's developing anterior-posterior body axis.
During the very early phases of embryo development – when the organism is still essentially flattened layers of cells called an endoderm – Dr. Zorn's team found Wnt's stimulation of B-catenin must be restricted in the anterior region so the tissue of forming foregut organs maintain its integrity. Their experiments showed that Sfrp5 steps in at the right time and place to repress Wnt signaling, allowing the cells to form an epithelial sheet, or lining – an essential step in organ development.
In one experiment, when researchers removed the Sfrp5 protein, the resulting Sfrp5-depleted Xenopus embryos had smaller foregut cavities filled with unorganized early-stage endoderm cells, which were incapable of properly forming liver and pancreatic organs.
Dr. Zorn and colleagues said their results have possible implications in metastatic cancer. For one, Sfrp proteins are already known to be tumor suppressors that are genetically inactivated in some cancers as they progress to aggressive carcinomas. Carcinomas typically originate in epithelial cells – which form linings surrounding the surfaces and cavities of many body structures – then spread into surrounding organs and tissues.
In cancer development, the research team is suggesting a loss of Sfrp function may unleash Wnt to trigger elevated B-catenin expression, allowing its stimulation of cell-to-cell adhesion to proliferate quickly. Rapid cell proliferation and adhesion are common in cancerous and pre-cancerous conditions. It could also let Wnt send improper signals that cause a loss of structural integrity in epithelial cells, allowing cancer to spread, or metastasize.
"We talked about this mechanism in the context of cancer because the control of cell specificity, and of movement and behavior, also occurs in cancer," Dr. Zorn said. "Cells will start to proliferate out of control and then, when a cancer starts to go metastatic, they will also start to change behavior. They become motile, moving spontaneously and actively, and they become invasive."
The early stage nature of the study means it would be premature to suggest the Wnt11-Sfrp5 mechanism might become the basis of diagnostic or therapeutic strategies for patients, Dr. Zorn said. The next step is to use these results as a basis for future studies, probably involving mice, to verify the mechanism's applicability to mammalian embryo development and see how it affects disease, he said.
Participating in the study were the Cincinnati Children's Research Foundation; Department of Pediatrics, UC College of Medicine; Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center and the State Key Laboratory of Phytochemistry and Plant Resources at the Kunming Institute of Botany, Kunming, China. Other researchers include lead author, Yan Li, and Scott A. Rankin, Debora Sinner, Alan P. Kenney and Paul A. Kreig.
Funding support came from the National Institutes of Health.
Reporting their work in the Oct. 15 Genes & Development, the researchers said the mechanism coordinates cell identity and behavior in the forming organs of embryos.
"Our study helps address the current challenge of finding out where cell specificity comes from, how cells do what they do in the context of disease and development, and how these activities are regulated," said Aaron Zorn, Ph.D., a researcher in the division of Developmental Biology at Cincinnati Children's and the study's corresponding author. "This helps inform research into how we tell early stem cells what to become. If someone has diabetes, for example, how do we tell a cell to become a pancreas cell so it will produce insulin?"
The study involved embryos of Xenopus frogs, a species indigenous to Africa often used in early biomedical studies. The scientists discovered a signaling protein very common in developmental biology, Wnt11 (Wingless), has to be inhibited by the modulating protein Sfrp5 (Secreted Frizzled Related Protein), a known antagonist of Wnt. Without this restriction, Wnt signaling runs amok and the frog's foregut, liver and pancreas form improperly from a cascade of disorganized cell growth.
"We point out that Wnt has two key roles here – one controlling the cell expression pathway to tell cells what they are supposed to be, and the other controlling the pathway for cell movement, behavior and adhesion," said Dr. Zorn, also associate professor of pediatrics at the University of Cincinnati (UC) College of Medicine. "Without Sfrp5 controlling what Wnt does in both pathways, things go horribly wrong in the developing foregut and its organs."
The Wnt signaling pathway is a complex network of proteins best known for their role in stimlating cell behavior during embryo development and in cancer. They also are involved in normal physiological processes in adult animals. Parts of the Wnt pathway have been conserved between species during the long course of evolution, all the way from simple roundworms to humans.
Previous research in Xenopus has established that a low level of activity from a molecule called B-catenin – which promotes cell-to-cell adhesion and is part of the Wnt pathway – is necessary to maintain accurate foregut formation and initiate liver and pancreas development. Unknown before the study by Dr. Zorn's team was which Wnt genes are involved and how Wnt and B-catenin activity are regulated along the frog's developing anterior-posterior body axis.
During the very early phases of embryo development – when the organism is still essentially flattened layers of cells called an endoderm – Dr. Zorn's team found Wnt's stimulation of B-catenin must be restricted in the anterior region so the tissue of forming foregut organs maintain its integrity. Their experiments showed that Sfrp5 steps in at the right time and place to repress Wnt signaling, allowing the cells to form an epithelial sheet, or lining – an essential step in organ development.
In one experiment, when researchers removed the Sfrp5 protein, the resulting Sfrp5-depleted Xenopus embryos had smaller foregut cavities filled with unorganized early-stage endoderm cells, which were incapable of properly forming liver and pancreatic organs.
Dr. Zorn and colleagues said their results have possible implications in metastatic cancer. For one, Sfrp proteins are already known to be tumor suppressors that are genetically inactivated in some cancers as they progress to aggressive carcinomas. Carcinomas typically originate in epithelial cells – which form linings surrounding the surfaces and cavities of many body structures – then spread into surrounding organs and tissues.
In cancer development, the research team is suggesting a loss of Sfrp function may unleash Wnt to trigger elevated B-catenin expression, allowing its stimulation of cell-to-cell adhesion to proliferate quickly. Rapid cell proliferation and adhesion are common in cancerous and pre-cancerous conditions. It could also let Wnt send improper signals that cause a loss of structural integrity in epithelial cells, allowing cancer to spread, or metastasize.
"We talked about this mechanism in the context of cancer because the control of cell specificity, and of movement and behavior, also occurs in cancer," Dr. Zorn said. "Cells will start to proliferate out of control and then, when a cancer starts to go metastatic, they will also start to change behavior. They become motile, moving spontaneously and actively, and they become invasive."
The early stage nature of the study means it would be premature to suggest the Wnt11-Sfrp5 mechanism might become the basis of diagnostic or therapeutic strategies for patients, Dr. Zorn said. The next step is to use these results as a basis for future studies, probably involving mice, to verify the mechanism's applicability to mammalian embryo development and see how it affects disease, he said.
Participating in the study were the Cincinnati Children's Research Foundation; Department of Pediatrics, UC College of Medicine; Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center and the State Key Laboratory of Phytochemistry and Plant Resources at the Kunming Institute of Botany, Kunming, China. Other researchers include lead author, Yan Li, and Scott A. Rankin, Debora Sinner, Alan P. Kenney and Paul A. Kreig.
Funding support came from the National Institutes of Health.
Judging genetic risks: Physicians often caught between what patients want and what science offers
[Source: Amy Lynn Sorrel, AMNews] - It's amazing what someone can get these days with a credit card and a spit sample. For a drop of saliva or blood and up to a few thousand dollars, more companies promise to unlock the mysteries of human health by profiling patients' genetic predisposition to a variety of common conditions.
Genetic testing is not just for rare diseases anymore. Clinical tests are available, through more traditional routes such as physicians, genetic counselors and labs, for more than 1,300 diseases, with several hundred more under research, according to the National Institutes of Health.
Such is the rapidly evolving world of so-called personalized medicine -- tailoring treatment options based on patients' genetic tendencies. While the trend can prompt awareness of genetic conditions and encourage patients to take charge of their health care, it also portends a world of potential legal liability for physicians, experts say.
"The standard of care -- medical and legal -- is changing, and there's a lot more to know these days about genetic technologies," said Lynn Fleisher, PhD, general counsel for the American College of Medical Genetics. "It's the duty of physicians to know about the information and communicate the results of that knowledge to patients."
But doctors may not be prepared. In an April study on the potential for increased regulatory oversight of genetic testing, the Dept. of Health & Human Services Secretary's Advisory Committee on Genetics, Health and Society suggested that many physicians and health professionals lack the training and expertise to facilitate and interpret tests. The panel, like many doctors, also questioned the validity and usefulness of some emerging technologies.
Some genetic tests -- such as those used in well-established newborn screenings and cancer diagnoses -- are regulated by the 1988 federal Clinical Laboratory Improvement Amendments. CLIA established quality standards for labs performing high-complexity tests and required supervision by a licensed doctor or certified geneticist. Only manufactured tests sold directly to labs are monitored by the Food and Drug Administration as medical devices.
But experts say federal regulations ignore the latest generation of testing that purports to predict a patient's susceptibility to health risks based on genetic markers. Despite increased research and awareness of such testing, its effectiveness and accuracy remain largely unconfirmed in science. Meanwhile, more of these tests are marketed directly to consumers and have raised concerns among the medical community, the FDA and the Federal Trade Commission that the tests are misleading.
It is in this milieu that physicians may find themselves vulnerable to liability risks, said Gail H. Javitt, JD, MPH, law and policy director at the Genetics and Public Policy Center at Johns Hopkins University. "In the absence of regulatory mechanisms for the introduction of new tests into clinical practice or clinical guidelines, it is difficult for physicians to discern when a test has reached the standard of care or whether it should," Javitt said.
Family physician Jacqueline A. Chadwick, MD, recently found herself facing such questions.
On two occasions, patients asked about genetic testing because a family member was diagnosed with a disease. After researching medical literature, Dr. Chadwick found that testing might be helpful in one of the cases and referred the patient to a genetic counselor. In the other case, however, Dr. Chadwick discovered little scientific support to show that testing would be beneficial and informed the patient.
"Now that the industry is recommending patients get genetic testing, they are going to expect physicians to use [their genetic profile] to define their entire health," said Dr. Chadwick, associate dean of clinical affairs at the University of Arizona College of Medicine. As access increases, "the question is what do we [as physicians] do with that information?"
American Medical Association policy recommends that genetic testing be carried out under the personal supervision of a qualified health care professional. The AMA is working to educate physicians and society about the lack of scientific validity of certain genetic tests and supports enhanced federal oversight, including oversight of direct-to-consumer tests.
Without firm guidelines on emerging technologies, the courts may be left to decide the standard of care.
Javitt pointed to a 2006 New Hampshire Supreme Court ruling in a case in which a couple sued Dartmouth-Hitchcock Medical Center for failing to detect their child's rare chromosomal disorder. Justices found that the doctors had adequately used routine screenings and informed the couple of the risk of congenital anomalies. Although additional genetic testing was available to detect this child's anomaly, the court declined to expand the standard of care.
Genetic advancements also could force courts to re-evaluate existing legal remedies, said Massachusetts attorney Susan L. Crockin, who focuses on reproductive genetics. "It's not clear what form claims are going to take and where we might see changes in the law," she said.
For example, case law in about 25 states recognizes wrongful birth claims. These claims allow parents of a child born with disabilities to argue that they lost their right to terminate the pregnancy after a doctor failed to detect and inform them of genetic anomalies. States that prohibit such actions still may allow plaintiffs to sue for medical negligence, or begin recognizing wrongful birth claims, Crockin said. As genetic testing proliferates, "state-by-state interpretation is going to be up for scrutiny," she said.
Among the first legal tests was a 2006 case in which a child was born in Maryland with a genetic anomaly, but the fetal test was interpreted in North Carolina. The Maryland Court of Appeals, the state's highest court, allowed the child's parents to sue the lab under Maryland's wrongful birth law, even though North Carolina law did not recognize the claim.
Pharmacogenomics also could pose legal concerns for doctors, said Gary E. Marchant, PhD, executive director at Arizona State University's Center for the Study of Law, Science and Technology.
More drug companies are investigating whether genetic testing can help determine a patient's response to medication. Last August the FDA allowed the manufacturers of the blood thinner Coumadin (warfarin) to change their labeling and advise physicians that genetic testing may help with dosing and reduce known drug complications.
Patients harmed by a drug could sue their doctor for failing to order such tests before prescribing, Marchant said.
Meanwhile, courts have varied in their opinions on whether doctors have an obligation to warn a patient's family members about discovered genetic risks, legal observers said.
And other ethical questions have yet to be tested in the courts.
For example, physicians who object to genetic testing in certain circumstances based on their personal beliefs may face challenges, said Denise M. Burke, vice president and legal director at the anti-abortion group Americans United for Life. Only three states -- Illinois, Mississippi and Washington -- have right-of-conscience laws protecting doctors who avoid genetic testing or any associated procedures for religious or moral reasons. Statutes in a majority of states apply only to abortion.
The role of regulation
A major step toward easing physicians' and patients' concerns over misuse of genetic test results was the Genetic Information Nondiscrimination Act, signed by President Bush in May. The AMA supported the measure, which prohibits health insurers and employers from using genetic data in coverage and employment decisions.
The statute is expected to speed demand for genetic testing. But regulations to implement the law still are under development and could face scrutiny in court, experts note.
Fleisher said the American College of Medical Genetics had received numerous calls from physicians about whether patients can pay out-of-pocket for genetic testing, fearing their insurers would abuse the information. While there's nothing wrong with having patients paying on their own, "the test results should go into the medical record," she said. State record laws vary, and in some circumstances federal laws, such as HIPAA, may be implicated. Patients also may have disclosure requirements in their insurance agreements.
Many physicians and legal experts alike agree that federal regulation that is aimed at ensuring high-quality, clinically useful genetic testing could help close some of the gaps that challenge doctors and patients alike as they try to keep abreast of the latest new developments.
"Genetic technology is rapidly advancing and has the potential to greatly impact patient care," AMA Executive Vice President and CEO Michael D. Maves, MD, MBA, wrote in a 2007 letter to the HHS Secretary's Advisory Committee on Genetics, Health and Society. "Properly regulating genetic tests used in the clinical setting will maximize benefit and reduce harm to patients." At the same time, such regulations "should not restrict a physician's diagnostic and therapeutic options," Dr. Maves wrote.
How oversight takes shape remains to be seen. Some medical specialty societies, such as the ACMG, offer educational programs and favor professional, not regulatory, supervision. The HHS committee made several recommendations, including increased quality standards for labs, greater FDA oversight, and ongoing evaluations of testing by public and private entities.
Until such changes are achieved, legal experts recommend that physicians disclose to patients what they know about genetic test options. When unsure, doctors can seek help from a genetic counselor.
But doctors are likely to play a much more direct role, said family physician W. Gregory Feero, MD, PhD, chief of the Genomic Healthcare Branch at the NIH's National Human Genome Research Institute. "We are now seeing applications and tests ... for things clinicians see on a daily basis," from asthma to diabetes to cancer, he said. As the standard of care evolves, "when you explain something to a patient, to leave [genetics] out of the discussion is to leave out fundamentals."
Genetic testing is not just for rare diseases anymore. Clinical tests are available, through more traditional routes such as physicians, genetic counselors and labs, for more than 1,300 diseases, with several hundred more under research, according to the National Institutes of Health.
Such is the rapidly evolving world of so-called personalized medicine -- tailoring treatment options based on patients' genetic tendencies. While the trend can prompt awareness of genetic conditions and encourage patients to take charge of their health care, it also portends a world of potential legal liability for physicians, experts say.
"The standard of care -- medical and legal -- is changing, and there's a lot more to know these days about genetic technologies," said Lynn Fleisher, PhD, general counsel for the American College of Medical Genetics. "It's the duty of physicians to know about the information and communicate the results of that knowledge to patients."
But doctors may not be prepared. In an April study on the potential for increased regulatory oversight of genetic testing, the Dept. of Health & Human Services Secretary's Advisory Committee on Genetics, Health and Society suggested that many physicians and health professionals lack the training and expertise to facilitate and interpret tests. The panel, like many doctors, also questioned the validity and usefulness of some emerging technologies.
Some genetic tests -- such as those used in well-established newborn screenings and cancer diagnoses -- are regulated by the 1988 federal Clinical Laboratory Improvement Amendments. CLIA established quality standards for labs performing high-complexity tests and required supervision by a licensed doctor or certified geneticist. Only manufactured tests sold directly to labs are monitored by the Food and Drug Administration as medical devices.
But experts say federal regulations ignore the latest generation of testing that purports to predict a patient's susceptibility to health risks based on genetic markers. Despite increased research and awareness of such testing, its effectiveness and accuracy remain largely unconfirmed in science. Meanwhile, more of these tests are marketed directly to consumers and have raised concerns among the medical community, the FDA and the Federal Trade Commission that the tests are misleading.
It is in this milieu that physicians may find themselves vulnerable to liability risks, said Gail H. Javitt, JD, MPH, law and policy director at the Genetics and Public Policy Center at Johns Hopkins University. "In the absence of regulatory mechanisms for the introduction of new tests into clinical practice or clinical guidelines, it is difficult for physicians to discern when a test has reached the standard of care or whether it should," Javitt said.
Family physician Jacqueline A. Chadwick, MD, recently found herself facing such questions.
On two occasions, patients asked about genetic testing because a family member was diagnosed with a disease. After researching medical literature, Dr. Chadwick found that testing might be helpful in one of the cases and referred the patient to a genetic counselor. In the other case, however, Dr. Chadwick discovered little scientific support to show that testing would be beneficial and informed the patient.
"Now that the industry is recommending patients get genetic testing, they are going to expect physicians to use [their genetic profile] to define their entire health," said Dr. Chadwick, associate dean of clinical affairs at the University of Arizona College of Medicine. As access increases, "the question is what do we [as physicians] do with that information?"
American Medical Association policy recommends that genetic testing be carried out under the personal supervision of a qualified health care professional. The AMA is working to educate physicians and society about the lack of scientific validity of certain genetic tests and supports enhanced federal oversight, including oversight of direct-to-consumer tests.
Without firm guidelines on emerging technologies, the courts may be left to decide the standard of care.
Javitt pointed to a 2006 New Hampshire Supreme Court ruling in a case in which a couple sued Dartmouth-Hitchcock Medical Center for failing to detect their child's rare chromosomal disorder. Justices found that the doctors had adequately used routine screenings and informed the couple of the risk of congenital anomalies. Although additional genetic testing was available to detect this child's anomaly, the court declined to expand the standard of care.
Genetic advancements also could force courts to re-evaluate existing legal remedies, said Massachusetts attorney Susan L. Crockin, who focuses on reproductive genetics. "It's not clear what form claims are going to take and where we might see changes in the law," she said.
For example, case law in about 25 states recognizes wrongful birth claims. These claims allow parents of a child born with disabilities to argue that they lost their right to terminate the pregnancy after a doctor failed to detect and inform them of genetic anomalies. States that prohibit such actions still may allow plaintiffs to sue for medical negligence, or begin recognizing wrongful birth claims, Crockin said. As genetic testing proliferates, "state-by-state interpretation is going to be up for scrutiny," she said.
Among the first legal tests was a 2006 case in which a child was born in Maryland with a genetic anomaly, but the fetal test was interpreted in North Carolina. The Maryland Court of Appeals, the state's highest court, allowed the child's parents to sue the lab under Maryland's wrongful birth law, even though North Carolina law did not recognize the claim.
Pharmacogenomics also could pose legal concerns for doctors, said Gary E. Marchant, PhD, executive director at Arizona State University's Center for the Study of Law, Science and Technology.
More drug companies are investigating whether genetic testing can help determine a patient's response to medication. Last August the FDA allowed the manufacturers of the blood thinner Coumadin (warfarin) to change their labeling and advise physicians that genetic testing may help with dosing and reduce known drug complications.
Patients harmed by a drug could sue their doctor for failing to order such tests before prescribing, Marchant said.
Meanwhile, courts have varied in their opinions on whether doctors have an obligation to warn a patient's family members about discovered genetic risks, legal observers said.
And other ethical questions have yet to be tested in the courts.
For example, physicians who object to genetic testing in certain circumstances based on their personal beliefs may face challenges, said Denise M. Burke, vice president and legal director at the anti-abortion group Americans United for Life. Only three states -- Illinois, Mississippi and Washington -- have right-of-conscience laws protecting doctors who avoid genetic testing or any associated procedures for religious or moral reasons. Statutes in a majority of states apply only to abortion.
The role of regulation
A major step toward easing physicians' and patients' concerns over misuse of genetic test results was the Genetic Information Nondiscrimination Act, signed by President Bush in May. The AMA supported the measure, which prohibits health insurers and employers from using genetic data in coverage and employment decisions.
The statute is expected to speed demand for genetic testing. But regulations to implement the law still are under development and could face scrutiny in court, experts note.
Fleisher said the American College of Medical Genetics had received numerous calls from physicians about whether patients can pay out-of-pocket for genetic testing, fearing their insurers would abuse the information. While there's nothing wrong with having patients paying on their own, "the test results should go into the medical record," she said. State record laws vary, and in some circumstances federal laws, such as HIPAA, may be implicated. Patients also may have disclosure requirements in their insurance agreements.
Many physicians and legal experts alike agree that federal regulation that is aimed at ensuring high-quality, clinically useful genetic testing could help close some of the gaps that challenge doctors and patients alike as they try to keep abreast of the latest new developments.
"Genetic technology is rapidly advancing and has the potential to greatly impact patient care," AMA Executive Vice President and CEO Michael D. Maves, MD, MBA, wrote in a 2007 letter to the HHS Secretary's Advisory Committee on Genetics, Health and Society. "Properly regulating genetic tests used in the clinical setting will maximize benefit and reduce harm to patients." At the same time, such regulations "should not restrict a physician's diagnostic and therapeutic options," Dr. Maves wrote.
How oversight takes shape remains to be seen. Some medical specialty societies, such as the ACMG, offer educational programs and favor professional, not regulatory, supervision. The HHS committee made several recommendations, including increased quality standards for labs, greater FDA oversight, and ongoing evaluations of testing by public and private entities.
Until such changes are achieved, legal experts recommend that physicians disclose to patients what they know about genetic test options. When unsure, doctors can seek help from a genetic counselor.
But doctors are likely to play a much more direct role, said family physician W. Gregory Feero, MD, PhD, chief of the Genomic Healthcare Branch at the NIH's National Human Genome Research Institute. "We are now seeing applications and tests ... for things clinicians see on a daily basis," from asthma to diabetes to cancer, he said. As the standard of care evolves, "when you explain something to a patient, to leave [genetics] out of the discussion is to leave out fundamentals."
Friday, October 31, 2008
Corn Researchers Discover Novel Gene Shut-off Mechanisms
[Source: ScienceDaily] - University of Delaware scientists, in collaboration with researchers from the University of Arizona and South Dakota State University, have identified unusual differences in the natural mechanisms that turn off, or “silence,” genes in corn.
The discovery, which was made by comparing the impact of inactivating a gene that occurs in both corn and in the much-studied laboratory plant Arabidopsis, provides new insight into how one of the world's most important crops protects itself from mutation-causing mobile DNA elements and viruses.
The research was led by Blake Meyers, associate professor of plant and soil sciences, and Pamela Green, Crawford H. Greenewalt Chair and professor of plant and soil sciences and marine bioscience, and their laboratory groups at the Delaware Biotechnology Institute, a major center for biotechnology and life sciences research at the University of Delaware.
Collaborating with the University of Delaware team were Vicki Chandler, the Carl E. and Patricia Weiler Endowed Chair for Excellence in Agriculture and Life Sciences Regents' Professor at the University of Arizona, and Yang Yen, a professor at South Dakota State University.
The results were published in the Proceedings of the National Academy of Sciences of the United States of America.
Studies of Arabidopsis thaliana, a small flowering plant of the mustard family that is easy to grow in the lab, have provided a lot of what scientists know about gene silencing in plants.
An important key to the process is short sequences of ribonucleic acids known as “small RNAs” which act like biochemical switches that shut off genes, thus playing a fundamental role in plant development. Understanding how small RNAs work is a continuing quest for geneticists seeking to breed plants with improved crop yields, disease resistance and other characteristics.
Previously, the Meyers and Green labs had studied Arabidopsis plants with nonfunctional versions of a gene known as RNA-dependent RNA polymerase 2 (RDR2). Without an active copy of this gene, the plants were unable to produce a major class of small RNAs, which act to stabilize and protect genes on the chromosomes.
In that prior work, Meyers and Green took advantage of the nonfunctional gene to study microRNAs, an interesting type of small RNA that is usually “masked” by the major class of small RNAs produced by RDR2.
Independently of the UD groups, Chandler and her team at the University of Arizona had identified from corn an orthologous gene--a gene that has the same function in different organisms. In corn, this gene, which the Chandler lab found, is called the mediator of paramutation (MOP1). Its equivalent in Arabidopsis is the RDR2 gene.
Because the RDR2 and MOP1 genes should both produce the “protective” set of small RNAs, the research groups decided to collaborate to see if the small RNAs in corn behave the same way they do in Arabidopsis. The hypothesis was that the result would be the same in the two plant species, and the lab groups could use the MOP1 corn plants to focus their studies on the harder-to-examine microRNAs, as they had done previously in Arabidopsis.
“Yet we found something that had not been observed before in this plant--an odd class of small RNAs,” Meyers said. “I think it's pretty neat to work in a more complex system like corn and see things that Arabidopsis hadn't shown us,” he noted.
Using a technique known as sequencing by synthesis (SBS), provided by Illumina in Hayward, Calif., coupled with state-of-the-art bioinformatics in Meyers' lab, the research team found that the MOP1 and RDR2 genes are not fully equivalent based on an assessment of small RNA complexity.
The researchers found that there are lots more RNAs of an unusual class known as “small interfering RNAs” in corn than there are in Arabidopsis.
“This class of RNAs mainly functions to repress repetitive sequences, including mobile DNA elements called transposons,” Meyers said. “Thus, small interfering RNAs act to protect the genome,” he noted.
“Corn contains an extra layer of protective small RNAs that had not been observed in Arabidopsis, so there must be additional genes other than MOP1 that produce this,” Meyers said.
The scientific community is sequencing the corn genome now, Meyers said. Once the genome is available, the work of matching up small RNAs to specific traits in corn will be much easier, he noted.
“This research is helping us to better understand the biology of corn--one of the most important plants in the world--and gives us new avenues for exploring a novel class of small RNAs,” Meyers said.
The discovery, which was made by comparing the impact of inactivating a gene that occurs in both corn and in the much-studied laboratory plant Arabidopsis, provides new insight into how one of the world's most important crops protects itself from mutation-causing mobile DNA elements and viruses.
The research was led by Blake Meyers, associate professor of plant and soil sciences, and Pamela Green, Crawford H. Greenewalt Chair and professor of plant and soil sciences and marine bioscience, and their laboratory groups at the Delaware Biotechnology Institute, a major center for biotechnology and life sciences research at the University of Delaware.
Collaborating with the University of Delaware team were Vicki Chandler, the Carl E. and Patricia Weiler Endowed Chair for Excellence in Agriculture and Life Sciences Regents' Professor at the University of Arizona, and Yang Yen, a professor at South Dakota State University.
The results were published in the Proceedings of the National Academy of Sciences of the United States of America.
Studies of Arabidopsis thaliana, a small flowering plant of the mustard family that is easy to grow in the lab, have provided a lot of what scientists know about gene silencing in plants.
An important key to the process is short sequences of ribonucleic acids known as “small RNAs” which act like biochemical switches that shut off genes, thus playing a fundamental role in plant development. Understanding how small RNAs work is a continuing quest for geneticists seeking to breed plants with improved crop yields, disease resistance and other characteristics.
Previously, the Meyers and Green labs had studied Arabidopsis plants with nonfunctional versions of a gene known as RNA-dependent RNA polymerase 2 (RDR2). Without an active copy of this gene, the plants were unable to produce a major class of small RNAs, which act to stabilize and protect genes on the chromosomes.
In that prior work, Meyers and Green took advantage of the nonfunctional gene to study microRNAs, an interesting type of small RNA that is usually “masked” by the major class of small RNAs produced by RDR2.
Independently of the UD groups, Chandler and her team at the University of Arizona had identified from corn an orthologous gene--a gene that has the same function in different organisms. In corn, this gene, which the Chandler lab found, is called the mediator of paramutation (MOP1). Its equivalent in Arabidopsis is the RDR2 gene.
Because the RDR2 and MOP1 genes should both produce the “protective” set of small RNAs, the research groups decided to collaborate to see if the small RNAs in corn behave the same way they do in Arabidopsis. The hypothesis was that the result would be the same in the two plant species, and the lab groups could use the MOP1 corn plants to focus their studies on the harder-to-examine microRNAs, as they had done previously in Arabidopsis.
“Yet we found something that had not been observed before in this plant--an odd class of small RNAs,” Meyers said. “I think it's pretty neat to work in a more complex system like corn and see things that Arabidopsis hadn't shown us,” he noted.
Using a technique known as sequencing by synthesis (SBS), provided by Illumina in Hayward, Calif., coupled with state-of-the-art bioinformatics in Meyers' lab, the research team found that the MOP1 and RDR2 genes are not fully equivalent based on an assessment of small RNA complexity.
The researchers found that there are lots more RNAs of an unusual class known as “small interfering RNAs” in corn than there are in Arabidopsis.
“This class of RNAs mainly functions to repress repetitive sequences, including mobile DNA elements called transposons,” Meyers said. “Thus, small interfering RNAs act to protect the genome,” he noted.
“Corn contains an extra layer of protective small RNAs that had not been observed in Arabidopsis, so there must be additional genes other than MOP1 that produce this,” Meyers said.
The scientific community is sequencing the corn genome now, Meyers said. Once the genome is available, the work of matching up small RNAs to specific traits in corn will be much easier, he noted.
“This research is helping us to better understand the biology of corn--one of the most important plants in the world--and gives us new avenues for exploring a novel class of small RNAs,” Meyers said.
Wednesday, October 29, 2008
NSF Grants Nearly $60M for Plant Genome Research Program Awards
Source: GenomeWeb News, a GenomeWeb staff reporter ] - The National Science Foundation has injected $57.3 million into plant genomics studies across the country, and to several international recipients, covering a wide variety of plant life, such as legumes, soil microbes, flower nectar, mutant plants, and other crops.
This round of Plant Genome Research Program studies, in the eleventh year of the program, range from $350,000 to $6.8 million, and vary from two to five years in duration.
These grants will support tool development to advance genomics studies, and the studies will use sequence and functional genomics resources to investigate gene function and interactions between genomes and the environment. These programs will emphasize studies of crop plants that are economically useful such as corn, soybean, wheat, and rice, NSF said.
"Plant biologists continue to make significant conceptual and theoretical advances in our understanding of basic biological processes using plants," James Collins, NSF assistant director for biological sciences, said in a statement. "The latest projects funded through the PGRP reflect this shift and will integrate innovative, cutting edge research with the training of the next generation of plant scientists at both research universities and small teaching colleges and universities.”
These awards will be spread out among a total of 45 institutions in 28 states, and they will support international scientists in Asia, Australia, Europe, and South America. The grants were focused on funding research partnerships between two or more institutions, for example: The University of California, Davis, Cold Spring Harbor Laboratory, and Kansas State University will use $6.8 million to conduct physical mapping of the Wheat D genome. The J. Craig Venter Institute and the University of Wisconsin-Madison will receive $3.8 million to curate the genome of the Medicago truncatula, a legume from the Mediterranean regions commonly used in biology. The University of Southern California and the University of California, Davis, will study the same legume, and will receive $3.2 million to conduct community genomics research into local adaptation of the plant. The University of Arizona and the University of Missouri, Columbia, will use $4.3 million to study comparative functional genomic and proteomic analysis of rhizome specificity across the plant kingdom.
A complete list of the NSF’s PGCSP funding recipients for 2008, and previous years, is available here.
This round of Plant Genome Research Program studies, in the eleventh year of the program, range from $350,000 to $6.8 million, and vary from two to five years in duration.
These grants will support tool development to advance genomics studies, and the studies will use sequence and functional genomics resources to investigate gene function and interactions between genomes and the environment. These programs will emphasize studies of crop plants that are economically useful such as corn, soybean, wheat, and rice, NSF said.
"Plant biologists continue to make significant conceptual and theoretical advances in our understanding of basic biological processes using plants," James Collins, NSF assistant director for biological sciences, said in a statement. "The latest projects funded through the PGRP reflect this shift and will integrate innovative, cutting edge research with the training of the next generation of plant scientists at both research universities and small teaching colleges and universities.”
These awards will be spread out among a total of 45 institutions in 28 states, and they will support international scientists in Asia, Australia, Europe, and South America. The grants were focused on funding research partnerships between two or more institutions, for example: The University of California, Davis, Cold Spring Harbor Laboratory, and Kansas State University will use $6.8 million to conduct physical mapping of the Wheat D genome. The J. Craig Venter Institute and the University of Wisconsin-Madison will receive $3.8 million to curate the genome of the Medicago truncatula, a legume from the Mediterranean regions commonly used in biology. The University of Southern California and the University of California, Davis, will study the same legume, and will receive $3.2 million to conduct community genomics research into local adaptation of the plant. The University of Arizona and the University of Missouri, Columbia, will use $4.3 million to study comparative functional genomic and proteomic analysis of rhizome specificity across the plant kingdom.
A complete list of the NSF’s PGCSP funding recipients for 2008, and previous years, is available here.
Monday, October 27, 2008
Arizona receives federal DNA grant
[Source: Judy Nichols, Sandra Day O’Connor College of Law] - The Arizona Justice Project and the Arizona Attorney General’s Office have been awarded a $1.4 million grant from the U.S. Justice Department through its National Institute of Justice. The grant will be used for post-conviction DNA testing in cases of forcible rape, murder, and non-negligent manslaughter to demonstrate actual innocence.
Under this grant, Arizona could become one of the first states in America to systematically and categorically identify inmates in which DNA might resolve questions about actual innocence, and then conduct the needed testing.
“This grant affords us a very exciting opportunity,” said Carrie Sperling, executive director of the Arizona Justice Project and a professor at the Sandra Day O'Connor College of Law, where the project is housed. “This is a huge and important undertaking and the opportunity to collaborate with all of the relevant agencies in the state is very exciting.”
Over the next 18 months, the Arizona Justice Project will identify and evaluate potential cases and, with the help of the Attorney General’s Office, will secure the relevant biological evidence and the necessary files.
Attorney General Terry Goddard said the grant will help make sure the right people are convicted.
“DNA testing is a powerful tool that benefits all involved in our criminal justice system, especially victims,” Goddard said. “This grant enables my office to support local prosecutors and ensure that those who have committed violent crimes are identified and behind bars.”
The Arizona Justice Project and the Attorney General’s Office will work with Arizona’s crime labs – both public and private –under the grant administration of the Arizona Criminal Justice Commission.
Arizona’s crime laboratories will make their resources available both for examination of samples and for conducting comparison testing through the national database of DNA profiles. Several private laboratories also have been identified to assist in the collaborative effort, including the Chromosomal Laboratories located in Phoenix.
The Project also will use private investigators through the Arizona Association of Licensed Private Investigators.
The Project will continue with its criminal justice endeavors and case evaluations in many other areas.
“We look forward to devoting special attention to this undertaking and the partnership with Arizona’s law enforcement and forensic communities,” Sperling said.
More than 200 exonerations in the United States have resulted from DNA evidence, two of them in Arizona. Most of these exoneration cases are brought forward by inmates through private attorneys or non-profit organizations, such as the national Innocence Project or state organizations such as the Arizona Justice Project. The principals of this grant-funded post-conviction DNA project will document the processes with the goal of making this a best practice to be replicated in other states that allow for post-conviction DNA testing.
The Arizona Justice Project, an innocence project, is now in its 11th year and is now centered at the College of Law, which enjoys a national reputation as a center for the study of forensic science and DNA research and evaluation. For many years the Project also has worked in concert with the James E. Rogers College of Law at the University of Arizona and with the Northern Arizona University Justice Project.
Under this grant, Arizona could become one of the first states in America to systematically and categorically identify inmates in which DNA might resolve questions about actual innocence, and then conduct the needed testing.
“This grant affords us a very exciting opportunity,” said Carrie Sperling, executive director of the Arizona Justice Project and a professor at the Sandra Day O'Connor College of Law, where the project is housed. “This is a huge and important undertaking and the opportunity to collaborate with all of the relevant agencies in the state is very exciting.”
Over the next 18 months, the Arizona Justice Project will identify and evaluate potential cases and, with the help of the Attorney General’s Office, will secure the relevant biological evidence and the necessary files.
Attorney General Terry Goddard said the grant will help make sure the right people are convicted.
“DNA testing is a powerful tool that benefits all involved in our criminal justice system, especially victims,” Goddard said. “This grant enables my office to support local prosecutors and ensure that those who have committed violent crimes are identified and behind bars.”
The Arizona Justice Project and the Attorney General’s Office will work with Arizona’s crime labs – both public and private –under the grant administration of the Arizona Criminal Justice Commission.
Arizona’s crime laboratories will make their resources available both for examination of samples and for conducting comparison testing through the national database of DNA profiles. Several private laboratories also have been identified to assist in the collaborative effort, including the Chromosomal Laboratories located in Phoenix.
The Project also will use private investigators through the Arizona Association of Licensed Private Investigators.
The Project will continue with its criminal justice endeavors and case evaluations in many other areas.
“We look forward to devoting special attention to this undertaking and the partnership with Arizona’s law enforcement and forensic communities,” Sperling said.
More than 200 exonerations in the United States have resulted from DNA evidence, two of them in Arizona. Most of these exoneration cases are brought forward by inmates through private attorneys or non-profit organizations, such as the national Innocence Project or state organizations such as the Arizona Justice Project. The principals of this grant-funded post-conviction DNA project will document the processes with the goal of making this a best practice to be replicated in other states that allow for post-conviction DNA testing.
The Arizona Justice Project, an innocence project, is now in its 11th year and is now centered at the College of Law, which enjoys a national reputation as a center for the study of forensic science and DNA research and evaluation. For many years the Project also has worked in concert with the James E. Rogers College of Law at the University of Arizona and with the Northern Arizona University Justice Project.
Diatom Genome Helps Explain Their Great Diversity and Success in Trapping Excess Carbon in Oceans
[Source: Deborah Daun, BIO5] - Diatoms, mighty microscopic algae, have profound influence on climate, producing 20 percent of the oxygen we breathe by capturing atmospheric carbon and in so doing, countering the greenhouse effect. Since their evolutionary origins these photosynthetic wonders have come to acquire advantageous genes from bacterial, animal and plant ancestors enabling them to thrive in today’s oceans. These findings, based on the analysis of the latest sequenced diatom genome, Phaeodactylum tricornutum, are published in the October 15, 2008 edition of the journal Nature by an international team of researchers led by the U.S. Department of Energy Joint Genome Institute (DOE JGI) and the Ecole Normale Supérieure of Paris. The research team includes Carolyn Napoli, PhD, a research professor with the BIO5 Institute; and Rich Jorgensen, PhD, professor of plant sciences at The University of Arizona.
The researchers compared Phaeodactylum with the diatom Thalassiosira pseudonana, previously sequenced by DOE JGI, revealing a wealth of information about diatom biology, particularly the rapid diversification among the hundreds of thousands of diatom species that exist today. Phaeodactylum was targeted for sequencing due to its value as a diatom model, given the ease with which it can be grown in the lab and the availability of tools to genetically transform it, and the comparisons with the previously sequenced diatom genome of Thalassiosira pseudonana.
“These organisms represent a veritable melting pot of traits—a hybrid of genetic mechanisms contributed by ancestral lineages of plants, animals, and bacteria, and optimized over the relatively short evolutionary timeframe of 180 million years since they first appeared,” says first author Chris Bowler of the Ecole Normale Supérieure. “Our findings show that gene transfer between diatoms and other organisms has been extremely common, making diatoms ‘transgenic by nature’,” he adds.
The wholesale acquisition of genetic material has provided food for thought to researchers bent on characterizing the diatom’s staying power and ability to cope with environmental change.
“We believe this is the first time bacterial horizontal gene transfer has been observed in eukaryotes at such scale,” says senior author Igor Grigoriev of DOE JGI. “This study gets us closer to explaining the dramatic diversity across the genera of diatoms, morphologically, behaviorally, but we still haven’t yet explained all the differences conferred by the genes contributed by the other taxa.”
From plants, the diatom inherited photosynthesis, and from animals the production of urea. Bowler speculates that the diatom uses urea to store nitrogen, not to eliminate it like animals do, because nitrogen is a precious nutrient in the ocean. What’s more, the tiny alga draws the best of both worlds—it can convert fat into sugar, as well as sugar into fat—extremely useful in times of nutrient shortage.
The team documented more than 300 genes sourced from bacteria and found in both types of diatoms, pointing to their ancient origin and suggesting novel mechanisms of managing nutrients—for example utilization of organic carbon and nitrogen—and detecting cues from their environment.
Diatoms, encapsulated by elaborate lacework-like shells made of glass, are only about one-third of a strand of hair in diameter. “The diatom genomes will help us to understand how they can make these structures at ambient temperatures and pressures, something that humans are not able to do. If we can learn how they do it, we could open up all kinds of new nanotechnologies, like for building miniature silicon chips or for biomedical applications,” says Bowler.
Diatoms reside in fresh or salt water and can be divided into two camps, centrics and pennates. The centric Thalassiosira resemble a round “Camembert” cheese box (only much smaller) and pennates like Phaeodactylum look more like a cross between a boomerang and a narrow three-cornered hat—hence the species name, tricornutum. Not only is their shape and habitat diverse, so too is their behavior; for instance, the former get around by floating, the latter by gliding through the water or on surfaces.
The lifestyle of diatoms can be characterized as “bloom or bust.” When light and nutrient conditions in the upper reaches of the ocean are favorable, particularly at the onset of spring, diatoms gain an edge and tend to dominate their phytoplankton brethren. When food is scarce, they die and sink, carrying their complement of carbon dioxide to the deeper recesses.
Bowler and his colleagues are also trying to understand the role that iron plays in the Phaeodactylum’s development. Iron is even more precious than nitrogen in the ocean and its absence in the southern hemisphere is likely a major cause of oceanic deserts of photosynthesis there. Bowler’s team has demonstrated that when iron deficiency occurs processes such as photosynthesis and nitrogen assimilation are suppressed. Other studies, which hail diatoms as champions in capturing carbon dioxide, suggest a bold strategy of using iron as a fertilizer to provoke massive diatom blooms. “Once they have feasted, the weight of their silicon shells, which resemble glass, causes the diatoms to sink to the bottom of the ocean when they die, and the carbon that they assimilated is trapped there for millennia,” says Bowler. “By sequestering carbon in this way we could reverse the damage from the burning of fossil fuels.”
Other DOE JGI authors on the Nature study include Alan Kuo, Robert Otillar, Asaf Salamov, Chris Detter, Erika Lindquist, Susan Lucas, Harris Shapiro, Daniel Rokhsar, and Igor Grigoriev as well as Jane Grimwood and Jeremy Schmutz of JGI at the HudsonAlpha Institute.
The U.S. Department of Energy Joint Genome Institute, supported by the DOE Office of Science, unites the expertise of five national laboratories -- Lawrence Berkeley, Lawrence Livermore, Los Alamos, Oak Ridge, and Pacific Northwest -- along with the HudsonAlpha Institute for Biotechnology -- to advance genomics in support of the DOE missions related to clean energy generation and environmental characterization and cleanup. DOE JGI’s Walnut Creek, CA, Production Genomics Facility provides integrated high-throughput sequencing and computational analysis that enable systems-based scientific approaches to these challenges.
The researchers compared Phaeodactylum with the diatom Thalassiosira pseudonana, previously sequenced by DOE JGI, revealing a wealth of information about diatom biology, particularly the rapid diversification among the hundreds of thousands of diatom species that exist today. Phaeodactylum was targeted for sequencing due to its value as a diatom model, given the ease with which it can be grown in the lab and the availability of tools to genetically transform it, and the comparisons with the previously sequenced diatom genome of Thalassiosira pseudonana.
“These organisms represent a veritable melting pot of traits—a hybrid of genetic mechanisms contributed by ancestral lineages of plants, animals, and bacteria, and optimized over the relatively short evolutionary timeframe of 180 million years since they first appeared,” says first author Chris Bowler of the Ecole Normale Supérieure. “Our findings show that gene transfer between diatoms and other organisms has been extremely common, making diatoms ‘transgenic by nature’,” he adds.
The wholesale acquisition of genetic material has provided food for thought to researchers bent on characterizing the diatom’s staying power and ability to cope with environmental change.
“We believe this is the first time bacterial horizontal gene transfer has been observed in eukaryotes at such scale,” says senior author Igor Grigoriev of DOE JGI. “This study gets us closer to explaining the dramatic diversity across the genera of diatoms, morphologically, behaviorally, but we still haven’t yet explained all the differences conferred by the genes contributed by the other taxa.”
From plants, the diatom inherited photosynthesis, and from animals the production of urea. Bowler speculates that the diatom uses urea to store nitrogen, not to eliminate it like animals do, because nitrogen is a precious nutrient in the ocean. What’s more, the tiny alga draws the best of both worlds—it can convert fat into sugar, as well as sugar into fat—extremely useful in times of nutrient shortage.
The team documented more than 300 genes sourced from bacteria and found in both types of diatoms, pointing to their ancient origin and suggesting novel mechanisms of managing nutrients—for example utilization of organic carbon and nitrogen—and detecting cues from their environment.
Diatoms, encapsulated by elaborate lacework-like shells made of glass, are only about one-third of a strand of hair in diameter. “The diatom genomes will help us to understand how they can make these structures at ambient temperatures and pressures, something that humans are not able to do. If we can learn how they do it, we could open up all kinds of new nanotechnologies, like for building miniature silicon chips or for biomedical applications,” says Bowler.
Diatoms reside in fresh or salt water and can be divided into two camps, centrics and pennates. The centric Thalassiosira resemble a round “Camembert” cheese box (only much smaller) and pennates like Phaeodactylum look more like a cross between a boomerang and a narrow three-cornered hat—hence the species name, tricornutum. Not only is their shape and habitat diverse, so too is their behavior; for instance, the former get around by floating, the latter by gliding through the water or on surfaces.
The lifestyle of diatoms can be characterized as “bloom or bust.” When light and nutrient conditions in the upper reaches of the ocean are favorable, particularly at the onset of spring, diatoms gain an edge and tend to dominate their phytoplankton brethren. When food is scarce, they die and sink, carrying their complement of carbon dioxide to the deeper recesses.
Bowler and his colleagues are also trying to understand the role that iron plays in the Phaeodactylum’s development. Iron is even more precious than nitrogen in the ocean and its absence in the southern hemisphere is likely a major cause of oceanic deserts of photosynthesis there. Bowler’s team has demonstrated that when iron deficiency occurs processes such as photosynthesis and nitrogen assimilation are suppressed. Other studies, which hail diatoms as champions in capturing carbon dioxide, suggest a bold strategy of using iron as a fertilizer to provoke massive diatom blooms. “Once they have feasted, the weight of their silicon shells, which resemble glass, causes the diatoms to sink to the bottom of the ocean when they die, and the carbon that they assimilated is trapped there for millennia,” says Bowler. “By sequestering carbon in this way we could reverse the damage from the burning of fossil fuels.”
Other DOE JGI authors on the Nature study include Alan Kuo, Robert Otillar, Asaf Salamov, Chris Detter, Erika Lindquist, Susan Lucas, Harris Shapiro, Daniel Rokhsar, and Igor Grigoriev as well as Jane Grimwood and Jeremy Schmutz of JGI at the HudsonAlpha Institute.
The U.S. Department of Energy Joint Genome Institute, supported by the DOE Office of Science, unites the expertise of five national laboratories -- Lawrence Berkeley, Lawrence Livermore, Los Alamos, Oak Ridge, and Pacific Northwest -- along with the HudsonAlpha Institute for Biotechnology -- to advance genomics in support of the DOE missions related to clean energy generation and environmental characterization and cleanup. DOE JGI’s Walnut Creek, CA, Production Genomics Facility provides integrated high-throughput sequencing and computational analysis that enable systems-based scientific approaches to these challenges.
Answering the Question: ‘Which Drug Therapy Is Right for Me?’
[Source: Karin Lorentzen, AHSC Office of Public Affairs] - In the world of pharmaceutical science, the question of why two very similar individuals can react differently to a drug is the subject of intense interest.
At The University of Arizona College of Pharmacy, researchers are striving to find answers to seemingly simple questions asked by patients, such as, "Why did I have to try three different high blood pressure medications before my doctor found one that worked for me?" and "Why did my cancer stay in remission with drug treatment, but my friend who had the same treatment was not so fortunate?"
At the basis of the answers to these questions is a field of study called pharmacogenomics, the analysis of how the expression of the human genome, the DNA code that instructs the making of the machinery of a cell, is key to the body's response to drugs.
"Importantly," said Walt Klimecki, assistant professor at UA College of Pharmacy, "pharmacogenomics helps us understand why two apparently similar individuals could have very different responses to the same drug. It holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own particular makeup."
In his lab at the UA's BIO5 Institute, Klimecki and Alicia Bolt, a graduate student in pharmacology and toxicology, are conducting pharmacogenomic research on a collection of white blood cells taken from about 200 healthy individuals from diverse global populations in the United States, China and Africa. The cells have been manipulated experimentally so that they can easily be grown in a plastic flask with growth media. Klimecki stores stocks of these individuals' cells in a lab freezer at the BIO5 Institute – a "town in a tube," he said.
This system allows Klimecki and Bolt to explore the diversity of individual variation in drug response in a much more controlled way than could be possible with the short-lived samples taken directly from human study participants.
In the lab, Klimecki and Bolt expose the white blood cells to arsenic trioxide, a relatively recent addition to the cancer-treatment arsenal in the United States, to measure how different expression patterns of the genome can predict response to this anti-cancer drug.
To measure differences in drug response, they use a technology called microarrays, a highly miniaturized analysis technology that allows scientists to measure the levels of each and every product contained in the master recipe book that is the human genome. For example, on one typical microscope slide, 44,000 such products can be measured four separate times.
Bolt reported he results of the research this month at the Mountain West Society of Toxicology meeting. In her abstract, Bolt states that a frequent observation in humans is the scenario of a relatively uniform toxicant exposure that is associated with a variable response. "The results are exciting," said Bolt. "Our observations suggest that this cell line model reproduces the inter-individual variation seen in arsenic-induced cell-killing observed in humans."
"Our research to date is encouraging," Klimecki said, "but these are complicated problems to solve. We need to study the effects of both genetics and the environment. The long-term solutions to these complex problems are going to involve multidisciplinary teams that include pharmacist-scientists, pharmacologists, toxicologists, chemists and computational/statistical scientists. But the results will be worth the work. These approaches and tools are an important part of the movement away from ‘trial-and-error' drug selection to the more individually targeted drug choices that are on the horizon."
At The University of Arizona College of Pharmacy, researchers are striving to find answers to seemingly simple questions asked by patients, such as, "Why did I have to try three different high blood pressure medications before my doctor found one that worked for me?" and "Why did my cancer stay in remission with drug treatment, but my friend who had the same treatment was not so fortunate?"
At the basis of the answers to these questions is a field of study called pharmacogenomics, the analysis of how the expression of the human genome, the DNA code that instructs the making of the machinery of a cell, is key to the body's response to drugs.
"Importantly," said Walt Klimecki, assistant professor at UA College of Pharmacy, "pharmacogenomics helps us understand why two apparently similar individuals could have very different responses to the same drug. It holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own particular makeup."
In his lab at the UA's BIO5 Institute, Klimecki and Alicia Bolt, a graduate student in pharmacology and toxicology, are conducting pharmacogenomic research on a collection of white blood cells taken from about 200 healthy individuals from diverse global populations in the United States, China and Africa. The cells have been manipulated experimentally so that they can easily be grown in a plastic flask with growth media. Klimecki stores stocks of these individuals' cells in a lab freezer at the BIO5 Institute – a "town in a tube," he said.
This system allows Klimecki and Bolt to explore the diversity of individual variation in drug response in a much more controlled way than could be possible with the short-lived samples taken directly from human study participants.
In the lab, Klimecki and Bolt expose the white blood cells to arsenic trioxide, a relatively recent addition to the cancer-treatment arsenal in the United States, to measure how different expression patterns of the genome can predict response to this anti-cancer drug.
To measure differences in drug response, they use a technology called microarrays, a highly miniaturized analysis technology that allows scientists to measure the levels of each and every product contained in the master recipe book that is the human genome. For example, on one typical microscope slide, 44,000 such products can be measured four separate times.
Bolt reported he results of the research this month at the Mountain West Society of Toxicology meeting. In her abstract, Bolt states that a frequent observation in humans is the scenario of a relatively uniform toxicant exposure that is associated with a variable response. "The results are exciting," said Bolt. "Our observations suggest that this cell line model reproduces the inter-individual variation seen in arsenic-induced cell-killing observed in humans."
"Our research to date is encouraging," Klimecki said, "but these are complicated problems to solve. We need to study the effects of both genetics and the environment. The long-term solutions to these complex problems are going to involve multidisciplinary teams that include pharmacist-scientists, pharmacologists, toxicologists, chemists and computational/statistical scientists. But the results will be worth the work. These approaches and tools are an important part of the movement away from ‘trial-and-error' drug selection to the more individually targeted drug choices that are on the horizon."
Thursday, October 16, 2008
Using Living Cells As Nanotechnology Factories
[Source: ScienceDaily] - In the tiny realm of nanotechnology, scientists have used a wide variety of materials to build atomic scale structures. But just as in the construction business, nanotechnology researchers can often be limited by the amount of raw materials. Now, Biodesign Institute at Arizona State University researcher Hao Yan has avoided these pitfalls by using cells as factories to make DNA based nanostructures inside a living cell.
The results were published in the early online edition of the Proceedings of the National Academy of Sciences.
Yan specializes in a fast-growing field within nanotechnology -- commonly known as structural DNA nanotechnology -- that uses the basic chemical units of DNA, abbreviated as C, T, A, or G, to self-fold into a number of different building blocks that can further self-assemble into patterned structures.
"This is a good example of artificial nanostructures that can be replicated using the machineries in live cells" said Yan. "Cells are really good at making copies of double stranded DNA and we have used the cell like a copier machine to produce many, many copies of complex DNA nanostructures."
DNA nanotechnologists have made some very exciting achievements during the past five to 10 years. But DNA nanotechnology has been limited by the need to chemically synthesize all of the material from scratch. To date, it has strictly been a test tube science, where researchers have developed many toolboxes for making different DNA nanostructures to attach and organize other molecules including nanoparticles and other biomolecules.
"If you need to make a single gram of a DNA nanostructure, you need to order one gram of the starting DNA materials. Scientists have previously used chemical methods to copy branched DNA structures, and there has also been significant work in using long-stranded DNA sequences replicated from cells or phage viruses to scaffold short helper DNA sequences to form 2-D or 3-D objects," said Yan, who is also a professor in the Department of Chemistry and Biochemistry at ASU.
"We have always dreamed of scaling up DNA nanotechnology. One way to scale that it up is to use the cellular system because simple DNA can be replicated inside the cell. We wanted to know if the cell's copy machine could tolerate single stranded DNA nanostructures that contain complicated secondary structures."
To test the nanoscale manufacturing capabilities of cells, Yan and his fellow researchers, Chenxiang Lin, Sherri Rinker and Yan Liu at ASU and their collaborators Ned Seeman and Xing Wang at New York University went back to reproducing the very first branched nanostructure made up of DNA- a cross-shaped, four-arm DNA junction and another DNA junction structure containing a different crossover topology.
To copy these branched DNA nanostructures inside a living cell, the ASU and NYU research team first shipped the cargo inside a bacteria cell. They cut and pasted the DNA necessary to make these structures into a phagemid, a virus-like particle that infects a bacteria cell. Once inside the cell, the phagemid used the cell just like a photocopier machine to reproduce millions of copies of the DNA. By theoretically starting with just a single phagemid infection, and a single milliliter of cultured cells, Yan found that the cells could churn out trillions of the DNA junction nanostructures.
The DNA nanostructures produced in the cells were also found to fold correctly, just like the previously built test tube structures. According to Yan, the results also proved the key existence of the DNA nanostructures during the cell's routine DNA replication and division cycles. "When a DNA nanostructure gets replicated, it does exist and can survive the complicated cellular machinery. And it looks like the cell can tolerate this kind of structure and still do its job. It's amazing," said Yan.
Yan acknowledges that this is just the first step, but foresees there are many interesting DNA variations to consider next. "The fact that the natural cellular machinery can tolerate artificial DNA objects is quite intriguing, and we don't know what the limit is yet."
Yan's group may be able to change and evolve DNA nanostructures and devices using the cellular system and the technology may also open up some possibilities for synthetic biology applications.
"I'm very excited about the future of DNA nanotechnology, but there is a lot of work to be done. An interesting research topic to pursue is the interface of DNA nanostructures with live cells; it is full of opportunities," said Yan.
The results were published in the early online edition of the Proceedings of the National Academy of Sciences.
Yan specializes in a fast-growing field within nanotechnology -- commonly known as structural DNA nanotechnology -- that uses the basic chemical units of DNA, abbreviated as C, T, A, or G, to self-fold into a number of different building blocks that can further self-assemble into patterned structures.
"This is a good example of artificial nanostructures that can be replicated using the machineries in live cells" said Yan. "Cells are really good at making copies of double stranded DNA and we have used the cell like a copier machine to produce many, many copies of complex DNA nanostructures."
DNA nanotechnologists have made some very exciting achievements during the past five to 10 years. But DNA nanotechnology has been limited by the need to chemically synthesize all of the material from scratch. To date, it has strictly been a test tube science, where researchers have developed many toolboxes for making different DNA nanostructures to attach and organize other molecules including nanoparticles and other biomolecules.
"If you need to make a single gram of a DNA nanostructure, you need to order one gram of the starting DNA materials. Scientists have previously used chemical methods to copy branched DNA structures, and there has also been significant work in using long-stranded DNA sequences replicated from cells or phage viruses to scaffold short helper DNA sequences to form 2-D or 3-D objects," said Yan, who is also a professor in the Department of Chemistry and Biochemistry at ASU.
"We have always dreamed of scaling up DNA nanotechnology. One way to scale that it up is to use the cellular system because simple DNA can be replicated inside the cell. We wanted to know if the cell's copy machine could tolerate single stranded DNA nanostructures that contain complicated secondary structures."
To test the nanoscale manufacturing capabilities of cells, Yan and his fellow researchers, Chenxiang Lin, Sherri Rinker and Yan Liu at ASU and their collaborators Ned Seeman and Xing Wang at New York University went back to reproducing the very first branched nanostructure made up of DNA- a cross-shaped, four-arm DNA junction and another DNA junction structure containing a different crossover topology.
To copy these branched DNA nanostructures inside a living cell, the ASU and NYU research team first shipped the cargo inside a bacteria cell. They cut and pasted the DNA necessary to make these structures into a phagemid, a virus-like particle that infects a bacteria cell. Once inside the cell, the phagemid used the cell just like a photocopier machine to reproduce millions of copies of the DNA. By theoretically starting with just a single phagemid infection, and a single milliliter of cultured cells, Yan found that the cells could churn out trillions of the DNA junction nanostructures.
The DNA nanostructures produced in the cells were also found to fold correctly, just like the previously built test tube structures. According to Yan, the results also proved the key existence of the DNA nanostructures during the cell's routine DNA replication and division cycles. "When a DNA nanostructure gets replicated, it does exist and can survive the complicated cellular machinery. And it looks like the cell can tolerate this kind of structure and still do its job. It's amazing," said Yan.
Yan acknowledges that this is just the first step, but foresees there are many interesting DNA variations to consider next. "The fact that the natural cellular machinery can tolerate artificial DNA objects is quite intriguing, and we don't know what the limit is yet."
Yan's group may be able to change and evolve DNA nanostructures and devices using the cellular system and the technology may also open up some possibilities for synthetic biology applications.
"I'm very excited about the future of DNA nanotechnology, but there is a lot of work to be done. An interesting research topic to pursue is the interface of DNA nanostructures with live cells; it is full of opportunities," said Yan.
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