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  • richardmitnick 4:01 am on March 21, 2015 Permalink | Reply
    Tags: , , Genetics,   

    From NOVA: “Genetically Engineering Almost Anything” 2014 and Very Important 

    PBS NOVA

    NOVA

    17 Jul 2014
    Tim De Chant and Eleanor Nelsen

    When it comes to genetic engineering, we’re amateurs. Sure, we’ve known about DNA’s structure for more than 60 years, we first sequenced every A, T, C, and G in our bodies more than a decade ago, and we’re becoming increasingly adept at modifying the genes of a growing number of organisms.

    But compared with what’s coming next, all that will seem like child’s play. A new technology just announced today has the potential to wipe out diseases, turn back evolutionary clocks, and reengineer entire ecosystems, for better or worse. Because of how deeply this could affect us all, the scientists behind it want to start a discussion now, before all the pieces come together over the next few months or years. This is a scientific discovery being played out in real time.

    1
    Scientists have figured out how to use a cell’s DNA repair mechanisms to spread traits throughout a population.

    Today, researchers aren’t just dropping in new genes, they’re deftly adding, subtracting, and rewriting them using a series of tools that have become ever more versatile and easier to use. In the last few years, our ability to edit genomes has improved at a shockingly rapid clip. So rapid, in fact, that one of the easiest and most popular tools, known as CRISPR-Cas9, is just two years old. Researchers once spent months, even years, attempting to rewrite an organism’s DNA. Now they spend days.

    Soon, though, scientists will begin combining gene editing with gene drives, so-called selfish genes that appear more frequently in offspring than normal genes, which have about a 50-50 chance of being passed on. With gene drives—so named because they drive a gene through a population—researchers just have to slip a new gene into a drive system and let nature take care of the rest. Subsequent generations of whatever species we choose to modify—frogs, weeds, mosquitoes—will have more and more individuals with that gene until, eventually, it’s everywhere.

    Cas9-based gene drives could be one of the most powerful technologies ever discovered by humankind. “This is one of the most exciting confluences of different theoretical approaches in science I’ve ever seen,” says Arthur Caplan, a bioethicist at New York University. “It merges population genetics, genetic engineering, molecular genetics, into an unbelievably powerful tool.”

    We’re not there yet, but we’re extraordinarily close. “Essentially, we have done all of the pieces, sometimes in the same relevant species.” says Kevin Esvelt, a postdoc at Harvard University and the wunderkind behind the new technology. “It’s just no one has put it all together.”

    It’s only a matter of time, though. The field is progressing rapidly. “We could easily have laboratory tests within the next few months and then field tests not long after that,” says George Church, a professor at Harvard University and Esvelt’s advisor. “That’s if everybody thinks it’s a good idea.”

    It’s likely not everyone will think this is a good idea. “There are clearly people who will object,” Caplan says. “I think the technique will be incredibly controversial.” Which is why Esvelt, Church, and their collaborators are publishing papers now, before the different parts of the puzzle have been assembled into a working whole.

    “If we’re going to talk about it at all in advance, rather than in the past tense,” Church says, “now is the time.”

    “Deleterious Genes”

    The first organism Esvelt wants to modify is the malaria-carrying mosquito Anopheles gambiae. While his approach is novel, the idea of controlling mosquito populations through genetic modification has actually been around since the late 1970s. Then, Edward F. Knipling, an entomologist with the U.S. Department of Agriculture, published a substantial handbook with a chapter titled “Use of Insects for Their Own Destruction.” One technique, he wrote, would be to modify certain individuals to carry “deleterious genes” that could be passed on generation after generation until they pervaded the entire population. It was an idea before its time. Knipling was on the right track, but he and his contemporaries lacked the tools to see it through.

    The concept surfaced a few more times before being picked up by Austin Burt, an evolutionary biologist and population geneticist at Imperial College London. It was the late 1990s, and Burt was busy with his yeast cells, studying their so-called homing endonucleases, enzymes that facilitate the copying of genes that code for themselves. Self-perpetuating genes, if you will. “Through those studies, gradually, I became more and more familiar with endonucleases, and I came across the idea that you might be able to change them to recognize new sequences,” Burt recalls.

    Other scientists were investigating endonucleases, too, but not in the way Burt was. “The people who were thinking along those lines, molecular biologists, were thinking about using these things for gene therapy,” Burt says. “My background in population biology led me to think about how they could be used to control populations that were particularly harmful.”

    In 2003, Burt penned an influential article that set the course for an entire field: We should be using homing endonucleases, a type of gene drive, to modify malaria-carrying mosquitoes, he said, not ourselves. Burt saw two ways of going about it—one, modify a mosquito’s genome to make it less hospitable to malaria, and two, skew the sex ratio of mosquito populations so there are no females for the males to reproduce with. In the following years, Burt and his collaborators tested both in the lab and with computer models before they settled on sex ratio distortion. (Making mosquitoes less hospitable to malaria would likely be a stopgap measure at best; the Plasmodium protozoans could evolve to cope with the genetic changes, just like they have evolved resistance to drugs.)

    Burt has spent the last 11 years refining various endonucleases, playing with different scenarios of inheritance, and surveying people in malaria-infested regions. Now, he finally feels like he is closing in on his ultimate goal. “There’s a lot to be done still,” he says. “But on the scale of years, not months or decades.”

    Cheating Natural Selection

    Cas9-based gene drives could compress that timeline even further. One half of the equation—gene drives—are the literal driving force behind proposed population-scale genetic engineering projects. They essentially let us exploit evolution to force a desired gene into every individual of a species. “To anthropomorphize horribly, the goal of a gene is to spread itself as much as possible,” Esvelt says. “And in order to do that, it wants to cheat inheritance as thoroughly as it can.” Gene drives are that cheat.

    Without gene drives, traits in genetically-engineered organisms released into the wild are vulnerable to dilution through natural selection. For organisms that have two parents and two sets of chromosomes (which includes humans, many plants, and most animals), traits typically have only a 50-50 chance of being inherited, give or take a few percent. Genes inserted by humans face those odds when it comes time to being passed on. But when it comes to survival in the wild, a genetically modified organism’s odds are often less than 50-50. Engineered traits may be beneficial to humans, but ultimately they tend to be detrimental to the organism without human assistance. Even some of the most painstakingly engineered transgenes will be gradually but inexorably eroded by natural selection.

    Some naturally occurring genes, though, have over millions of years learned how to cheat the system, inflating their odds of being inherited. Burt’s “selfish” endonucleases are one example. They take advantage of the cell’s own repair machinery to ensure that they show up on both chromosomes in a pair, giving them better than 50-50 odds when it comes time to reproduce.

    2
    A gene drive (blue) always ends up in all offspring, even if only one parent has it. That means that, given enough generations, it will eventually spread through the entire population.

    Here’s how it generally works. The term “gene drive” is fairly generic, describing a number of different systems, but one example involves genes that code for an endonuclease—an enzyme which acts like a pair of molecular scissors—sitting in the middle of a longer sequence of DNA that the endonculease is programmed to recognize. If one chromosome in a pair contains a gene drive but the other doesn’t, the endonuclease cuts the second chromosome’s DNA where the endonuclease code appears in the first.

    The broken strands of DNA trigger the cell’s repair mechanisms. In certain species and circumstances, the cell unwittingly uses the first chromosome as a template to repair the second. The repair machinery, seeing the loose ends that bookend the gene drive sequence, thinks the middle part—the code for the endonuclease—is missing and copies it onto the broken chromosome. Now both chromosomes have the complete gene drive. The next time the cell divides, splitting its chromosomes between the two new cells, both new cells will end up with a copy of the gene drive, too. If the entire process works properly, the gene drive’s odds of inheritance aren’t 50%, but 100%.

    3
    Here, a mosquito with a gene drive (blue) mates with a mosquito without one (grey). In the offspring, one chromosome will have the drive. The endonuclease then slices into the drive-free DNA. When the strand gets repaired, the cell’s machinery uses the drive chromosome as a template, unwittingly copying the drive into the break.

    Most natural gene drives are picky about where on a strand of DNA they’ll cut, so they need to be modified if they’re to be useful for genetic engineering. For the last few years, geneticists have tried using genome-editing tools to build custom gene drives, but the process was laborious and expensive. With the discovery of CRISPR-Cas9 as a genome editing tool in 2012, though, that barrier evaporated. CRISPR is an ancient bacterial immune system which identifies the DNA of invading viruses and sends in an endonuclease, like Cas9, to chew it up. Researchers quickly realized that Cas9 could easily be reprogrammed to recognize nearly any sequence of DNA. All that’s needed is the right RNA sequence—easily ordered and shipped overnight—which Cas9 uses to search a strand of DNA for where to cut. This flexibility, Esvelt says, “lets us target, and therefore edit, pretty much anything we want.” And quickly.

    Gene drives and Cas9 are each powerful on their own, but together they could significantly change biology. CRISRP-Cas9 allows researchers to edit genomes with unprecedented speed, and gene drives allow engineered genes to cheat the system, even if the altered gene weakens the organism. Simply by being coupled to a gene drive, an engineered gene can race throughout a population before it is weeded out. “Eventually, natural selection will win,” Esvelt says, but “gene drives just let us get ahead of the game.”

    Beyond Mosquitoes

    If there’s anywhere we could use a jump start, it’s in the fight against malaria. Each year, the disease kills over 200,000 people and sickens over 200 million more, most of whom are in Africa. The best new drugs we have to fight it are losing ground; the Plasmodium parasite is evolving resistance too quickly.

    3
    False-colored electron micrograph of a Plasmodium sp. sporozoite.

    And we’re nowhere close to releasing an effective vaccine. The direct costs of treating the disease are estimated at $12 billion, and the economies of affected countries grew 1.3% less per year, a substantial amount.

    Which is why Esvelt and Burt are both so intently focused on the disease. “If we target the mosquito, we don’t have to face resistance on the parasite itself. The idea is, we can just take out the vector and stop all transmission. It might even lead to eradication,” Esvelt says.

    Esvelt initially mulled over the idea of building Cas9-based gene drives in mosquitoes to do just that. He took the idea to to Flaminia Catteruccia, a professor who studies malaria at the Harvard School of Public Health, and the two grew increasingly certain that such a system would not only work, but work well. As their discussions progressed, though, Esvelt realized they were “missing the forest for the trees.” Controlling malaria-carrying mosquitoes was just the start. Cas9-based gene drives were the real breakthrough. “If it let’s us do this for mosquitos, what is to stop us from potentially doing it for almost anything that is sexually reproducing?” he realized.

    In theory, nothing. But in reality, the system works best on fast-reproducing species, Esvelt says. Short generation times allow the trait to spread throughout a population more quickly. Mosquitoes are a perfect test case. If everything were to work perfectly, deleterious traits could sweep through populations of malaria-carrying mosquitoes in as few as five years, wiping them off the map.

    Other noxious species could be candidates, too. Certain invasive species, like mosquitoes in Hawaii or Asian carp in the Great Lakes, could be targeted with Cas9-based gene drives to either reduce their numbers or eliminate them completely. Agricultural weeds like horseweed that have evolved resistance to glyphosate, a herbicide that is broken down quickly in the soil, could have their susceptibility to the compound reintroduced, enabling more farmers to adopt no-till practices, which help conserve topsoil. And in the more distant future, Esvelt says, weeds could even be engineered to introduce vulnerabilities to completely benign substances, eliminating the need for toxic pesticides. The possibilities seem endless.

    The Decision

    Before any of that can happen, though, Esvelt and Church are adamant that the public help decide whether the research should move forward. “What we have here is potentially a general tool for altering wild populations,” Esvelt says. “We really want to make sure that we proceed down this path—if we decide to proceed down this path—as safely and responsibly as possible.”

    To kickstart the conversation, they partnered with the MIT political scientist Kenneth Oye and others to convene a series of workshops on the technology. “I thought it might be useful to get into the room people with slightly different material interests,” Oye says, so they invited regulators, nonprofits, companies, and environmental groups. The idea, he says, was to get people to meet several times, to gain trust and before “decisions harden.” Despite the diverse viewpoints, Oye says there was surprising agreement among participants about what the important outstanding questions were.

    As the discussion enters the public sphere, tensions are certain to intensify. “I don’t care if it’s a weed or a blight, people still are going to say this is way too massive a genetic engineering project,” Caplan says. “Secondly, it’s altering things that are inherited, and that’s always been a bright line for genetic engineering.” Safety, too, will undoubtedly be a concern. As the power of a tool increases, so does its potential for catastrophe, and Cas9-based gene drives could be extraordinarily powerful.

    There’s also little in the way of precedent that we can use as a guide. Our experience with genetically modified foods would seem to be a good place to start, but they are relatively niche organisms that are heavily dependent on water and fertilizer. It’s pretty easy to keep them contained to a field. Not so with wild organisms; their potential to spread isn’t as limited.

    Aware of this, Esvelt and his colleagues are proposing a number of safeguards, including reversal drives that can undo earlier engineered genes. “We need to really make sure those work if we’re proposing to build a drive that is intended to modify a wild population,” Esvelt says.

    There are still other possible hurdles to surmount—lab-grown mosquitoes may not interbreed with wild ones, for example—but given how close this technology is to prime time, Caplan suggests researchers hew to a few initial ethical guidelines. One, use species that are detrimental to human health and don’t appear to fill a unique niche in the wild. (Malaria-carrying mosquitoes seem fit that description.) Two, do as much work as possible using computer models. And three, researchers should continue to be transparent about their progress, as they have been. “I think the whole thing is hugely exciting,” Caplan says. “But the time to really get cracking on the legal/ethical infrastructure for this technology is right now.”

    Church agrees, though he’s also optimistic about the potential for Cas9-based gene drives. “I think we need to be cautious with all new technologies, especially all new technologies that are messing with nature in some way or another. But there’s also a risk of doing nothing,” Church says. “We have a population of 7 billion people. You have to deal with the environmental consequences of that.”

    See the full article here.

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    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

     
  • richardmitnick 10:50 am on March 19, 2015 Permalink | Reply
    Tags: , Genetics, ,   

    From Rockefeller: “Scientists pinpoint molecule that controls stem cell plasticity by boosting gene expression” 

    Rockefeller U bloc

    Rockefeller University

    March 19, 2015
    Zach Veilleux | 212-327-8982

    1
    Glowing and growing: Researchers made stem cells fluoresce green (at the base of hair follicles above) by labeling their super-enhancers, regions of the genome bound by gene-amplifying proteins. It appears one such protein, Sox9, leads the activation of super-enhancers that boost genes associated with stem cell plasticity.No mage credit

    Stem cells can have a strong sense of identity. Taken out of their home in the hair follicle, for example, and grown in culture, these cells remain true to themselves. After waiting in limbo, these cultured cells become capable of regenerating follicles and other skin structures once transplanted back into skin. It’s not clear just how these stem cells — and others elsewhere in the body — retain their ability to produce new tissue and heal wounds, even under extraordinary conditions.

    New research at Rockefeller University has identified a protein, Sox9, that takes the lead in controlling stem cell plasticity. In a paper published Wednesday (March 18) in Nature, the team describes Sox9 as a “pioneer factor” that breaks ground for the activation of genes associated with stem cell identity in the hair follicle.

    “We found that in the hair follicle, Sox9 lays the foundation for stem cell plasticity. First, Sox9 makes the genes needed by stem cells accessible, so they can become active. Then, Sox9 recruits other proteins that work together to give these “stemness” genes a boost, amplifying their expression,” says study author Elaine Fuchs, Rebecca C. Lancefield Professor, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. “Without Sox9, this process never happens, and hair follicle stem cells cannot survive.”

    Sox9 is a type of protein called a transcription factor, which can act like a volume dial for genes. When a transcription factor binds to a segment of DNA known as an enhancer, it cranks up the activity of the associated gene. Recently, scientists identified a less common, but more powerful version: the super-enhancer. Super-enhancers are much longer pieces of DNA, and host large numbers of cell type-specific transcription factors that bind cooperatively. Super-enhancers also contain histones, DNA-packaging proteins, that harbor specific chemical groups — epigenetic marks — that make genes they are associated with accessible so they can be expressed.

    Using an epigenetic mark associated specifically with the histones of enhancers, first author Rene Adam, a graduate student in the lab, and colleagues, identified 377 of these high-powered gene-amplifying regions in hair follicle stem cells. The majority of these super-enhancers were bound by at least five transcription factors, often including Sox9. Then, they compared the stem cell super-enhancers to those of short-lived stem cell progeny, which have begun to choose a fate, and so lost the plasticity of stem cells. These two types of cells shared only 32 percent of their superenhancers, suggesting these regions played an important role in skin cell identity. By switching off super-enhancers associated with stem cell genes, these genes were silenced while new super-enhancers were being activated to turn on hair genes.

    To better understand these dynamics, the researchers took a piece of a super-enhancer, which they called an “epicenter,” where all the stem cell transcription factors bind, and they linked it to a gene that glowed green whenever the transcription factors were present. In living mice, all the hair follicle stem cells glowed green, but surprisingly, the green gene turned off when the stem cells were taken from the follicle and placed in culture. When they put the cells back into living skin, the green glow returned.

    Another clue came from experiments performed by Hanseul Yang, another student in the lab. By examining the new super-enhancers that were gained when the stem cells were cultured, they learned that these new super-enhancers bound transcription factors that were known to be activated during wound-repair. When they used one of these epicenters to drive the green gene, the green glow appeared in culture, but not in skin. When they wounded the skin, then the green glow switched on.

    “We were learning that some super-enhancers are specifically activated in the stem cells within their native niche, while other super-enhancers specifically switch on during injury,” explained Adam. “By shifting epicenters, you can shift from one cohort of transcription factors to another to adapt to different environments. But we still needed to determine what was controlling these shifts.”

    The culprit turned out to be Sox9, the only transcription factor expressed in both living tissue and culture. Further experiments confirmed Sox9’s importance by showing, for example, that removing it spelled death for stem cells, while expressing it in the epidermis gave the skin cells features of hair follicle stem cells. These powers seemed to be special to Sox9, placing it atop the hierarchy of transcription factors in the stem cells. Sox9 is one of only a few pioneer factors known in biology which can initiate such dramatic changes in gene expression.

    “Importantly, we link this pioneer factor to super-enhancer dynamics, giving these domains a ‘one-two punch’ in governing cell identity. In the case of stem cell plasticity, Sox9 appears to be the lead factor that activates the super-enhancers that amplify genes associated with stemness,” Fuchs says. “These discoveries offer new insights into the way in which stem cells choose their fates and maintain plasticity while in transitional states, such as in culture or when repairing wounds.”

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 8:11 am on March 16, 2015 Permalink | Reply
    Tags: , , , Genetics   

    From AAAS: “Don’t edit embryos, researchers warn” 

    AAAS

    AAAS

    12 March 2015
    Gretchen Vogel

    1

    Scientists should refrain from studies that alter the genome of human embryos, sperm, or egg cells, researchers warn in a commentary published today in Nature.

    In it, they sound the alarm about new genome-editing techniques known as CRISPR and zinc-finger nucleases that make it much easier for scientists to delete, add, or change specific genes. These tools have made it possible to make better animal models of disease and more easily study the role of individual genes. They also hold the promise of correcting gene mutations in patients, whether in blood cells, muscle cells, or tumor cells.

    But scientists have also used the technology to make genetically altered monkeys. And there are rumors that some researchers are trying the same technique on human embryos, MIT Technology Review reports.

    That is unsafe and unethical, say Edward Lanphier and four other researchers in their commentary. Ethically justifiable applications “are moot until it becomes possible to demonstrate safe outcomes and obtain reproducible data over multiple generations,” they write. They call for a moratorium on any experiments that would edit genes in sperm cells, egg cells, or embryos while scientists publicly debate the scientific and ethical consequences of such experiments. The recent discussion of mitochondrial DNA replacement therapy in the United Kingdom could be a model, they suggest.

    They hope that such a discussion would help the public understand the difference between genome editing in a person’s somatic cells—cells other than sperm and egg cells—and editing in cells that could pass the changes on to future generations, says Lanphier, who is president and CEO of Sangamo BioSciences in Richmond, California, a company that hopes to use gene-editing technology to treat patients. “There’s an important and clear ethical boundary between genome editing in somatic cells versus in the germ line.”

    George Daley, a stem cell researcher at Boston Children’s Hospital and Harvard Medical School, agrees that a public debate is important. Among scientists, he says, there is broad consensus that at the moment “it’s far too premature and we know far too little about the safety to make any attempts” at modifying germ cells or embryos. But that will eventually change, he says. “There needs to be broad public debate and discussion about what, if any, are the permissible uses of the technology.

    See the full article here.

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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  • richardmitnick 8:21 am on March 7, 2015 Permalink | Reply
    Tags: , , FIU, Genetics   

    From FIU: “Scientists unlock tangled mysteries of DNA” 

    FIU bloc

    Florida International University

    03/06/2015
    JoAnn Adkins

    Chromosomal proteins hold the key to our DNA and they are changing, according to Jose Eirin-Lopez, marine sciences professor in the FIU Department of Biological Sciences.

    While today’s human body contains a variety of these proteins, Eirin-Lopez believes they evolved from a single ancestor millions of years ago. This finding, published recently in Molecular Biology and Evolution, is pivotal in unraveling the mysteries of DNA organization and regulation, and could someday lead to innovative biomonitoring strategies and therapies targeting a variety of diseases including cancer.

    DNA is the recipe for all living things. Each of our cells has a DNA molecule enclosed within its nucleus, containing the entirety our genetic information. However, like a recipe book, not all that information is required at the same time. Most DNA remains tightly packaged in chromosomes until specific pieces of information are needed to do a job.

    It is up to a group of proteins known as chromosomal proteins to unlock the information required to trigger a function in a given cell — to form a bone, determine eye color, metabolize food, fight infections or any other function. While significant information is available about the structure and functions of chromosomal proteins, very little is known about their origin and evolution. The team of researchers is the first to explain the mechanisms responsible for the evolutionary diversification of a specific group of chromosomal proteins known as High Mobility Group Nucleosome-binding (HMG-N) proteins.

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    Each of our cells contains a genetic message encoded in a DNA molecule which is almost 6 feet long. The packing and regulation of the DNA (represented in the figure above using sticks) is possible thanks to its wrapping around chromosomal proteins (represented here by yellow, red, blue and green dots)

    “In the early stages of life on earth, cells were rudimentary yet still able to perform their jobs. But evolution, through mutations, drift and natural selection, has led these proteins (along with our cells) to evolve into higher performers,” said Eirin-Lopez who co-authored the study with Rodrigo Gonzalez-Romero from FIU and Juan Ausio from the University of Victoria in Canada.

    The research unveils the mechanisms responsible for the functional specialization of this group of proteins, from a common ancestor directing a variety of activities to the actual HMG-N lineages working in concert in vertebrate organisms including humans. However, along with a better cell performance, a higher number of chromosomal proteins also provide more potential targets for harmful mutations. If one or more of these proteins are altered or mutated they will target wrong genes in the DNA, giving erroneous instructions to cells. The potential health consequences of such mistakes are massive, often causing cells to grow uncontrollably and resulting in cancer.

    “The only way we can alleviate the negative effects of these alterations is by getting an exhaustive knowledge about these proteins and their function, helping us to develop therapies to reinstate the correct communication with DNA and the cell,” Eirin-Lopez said. “Nonetheless, our knowledge about chromosomal proteins will never be complete until we determine how they came to be and to fulfill their current roles in the cell. Only evolutionary analyses can answer that question. Understanding this better prepares us to take action in the future.”

    See the full article here.

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    As Miami’s first and only public research university, offering bachelor’s, master’s, and doctoral degrees, FIU is worlds ahead in its service to the academic and local community.

    Designated as a top-tier research institution, FIU emphasizes research as a major component in the university’s mission. The Herbert Wertheim College of Medicine and the School of Computing and Information Sciences’ Discovery Lab, are just two of many colleges, schools, and centers that actively enhance the university’s ability to set new standards through research initiatives.

     
  • richardmitnick 7:51 pm on March 3, 2015 Permalink | Reply
    Tags: , , Genetics, , WYSS Institute   

    From Wyss Institute at Harvard: “Activating genes on demand” 

    Harvard University

    Harvard University

    Harvard Wyss Institute

    Mar 3, 2015
    Wyss Institute for Biologically Inspired Engineering at Harvard University
    Kat J. McAlpine, katherine.mcalpine@wyss.harvard.edu, +1 617-432-8266

    Harvard Medical School
    David Cameron, david_cameron@hms.harvard.edu, +1 617-432-0441

    New mechanism for engineering genetic traits governed by multiple genes paves the way for various advances in genomics and regenerative medicine

    When it comes to gene expression – the process by which our DNA provides the recipe used to direct the synthesis of proteins and other molecules that we need for development and survival – scientists have so far studied one single gene at a time. A new approach developed by Harvard geneticist George Church, Ph.D., can help uncover how tandem gene circuits dictate life processes, such as the healthy development of tissue or the triggering of a particular disease, and can also be used for directing precision stem cell differentiation for regenerative medicine and growing organ transplants.

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    In these images, the ability of the new Cas9 approach to differentiate stem cells into brain neuron cells is visible. On the left, a previous attempt to direct stem cells to develop into neuronal cells shows a low level of success, with limited red–colored areas indicating low growth of neuron cells. On the right, the new Cas9 approach shows a 40–fold increase in the number of neuronal cells developed, visible as red-colored areas on the image. Credit: Wyss Institute at Harvard University

    The findings, reported by Church and his team of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School in Nature Methods, show promise that precision gene therapies could be developed to prevent and treat disease on a highly customizable, personalized level, which is crucial given the fact that diseases develop among diverse pathways among genetically–varied individuals.

    The approach leverages the Cas9 protein, which has already been employed as a Swiss Army knife for genome engineering, in a novel way. The Cas9 protein can be programmed to bind and cleave any desired section of DNA – but now Church’s new approach activates the genes Cas9 binds to rather than cleaving them, triggering them to activate transcription to express or repress desired genetic traits. And by engineering the Cas9 to be fused to a triple–pronged transcription factor, Church and his team can robustly manipulate single or multiple genes to control gene expression.

    “In terms of genetic engineering, the more knobs you can twist to exert control over the expression of genetic traits, the better,” said Church, a Wyss Core Faculty member who is also Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and MIT. “This new work represents a major, entirely new class of knobs that we could use to control multiple genes and therefore influence whether or not specific genetics traits are expressed and to what extent – we could essentially dial gene expression up or down with great precision.”

    Such a capability could lead to gene therapies that would mitigate age–related degeneration and the onset of disease; in the study, Church and his team demonstrated the ability to manipulate gene expression in yeast, flies, mouse and human cell cultures.

    “We envision using this approach to investigate and create comprehensive libraries that document which gene circuits control a wide range of gene expression,” said one of the study’s lead authors Alejandro Chavez, Ph.D., Postdoctoral Fellow at the Wyss Institute. Jonathan Schieman, Ph.D, of the Wyss Institute and Harvard Medical School, and Suhani Vora, of the Wyss Institute, Massachusetts Institute of Technology, and Harvard Medical School, are also lead co–authors on the study.

    In this technical animation, Wyss Institute researchers instruct how they engineered a Cas9 protein to create a powerful and robust tool for activating gene expression. The novel method enables Cas9 to switch a gene from off to on and has the potential to precisely induce on-command expression of any of the countless genes in the genomes of yeast, flies, mice, or humans. Credit: Wyss Institute at Harvard University

    The new Cas9 approach could also potentially target and activate sections of the genome made up of genes that are not directly responsible for transcription, and which previously were poorly understood. These sections, which comprise up to 90% of the genome in humans, have previously been considered to be useless DNA “dark matter” by geneticists. In contrast to translated DNA, which contains recipes of genetic information used to express traits, this DNA dark matter contains transcribed genes which act in mysterious ways, with several of these genes often having influence in tandem.

    But now, that DNA dark matter could be accessed using Cas9, allowing scientists to document which non-translated genes can be activated in tandem to influence gene expression. Furthermore, these non-translated genes could also be turned into a docking station of sorts. By using Cas9 to target and bind gene circuits to these sections, scientists could introduce synthetic loops of genes to a genome, therefore triggering entirely new or altered gene expressions.

    The ability to manipulate multiple genes in tandem so precisely also has big implications for advancing stem cell engineering for development of transplant organs and regenerative therapies.

    “In order to grow organs from stem cells, our understanding of developmental biology needs to increase rapidly,” said Church. “This multivariate approach allows us to quickly churn through and analyze large numbers of gene combinations to identify developmental pathways much faster than has been previously capable.”

    To demonstrate this point, the researchers used it to grow brain neuron cells from stem cells and found that using the approach to program development of neuronal cells was 40–fold more successful than prior established methods. This is the first time that Cas9 has been leveraged to efficiently differentiate stem cells into brain cells.

    The new approach is also compatible to be used in combination with other gene editing technologies. Church and his team have previously made breakthroughs by developing a gene editing mechanism for therapeutic applications and gene drives for altering traits in plant and animal species.

    “This newest tool in the Cas9 genome engineering arsenal offers a powerful new way to control cell and tissue function that could revolutionize virtually all areas of science and medicine, ranging from gene therapy to regenerative medicine and anti–aging,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital and Professor of Bioengineering at Harvard SEAS.

    See the full article here.

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

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  • richardmitnick 5:34 am on February 24, 2015 Permalink | Reply
    Tags: , , Genetics,   

    From NYT: “I’ve Just Seen a (DNA-Generated) Face” 

    New York Times

    The New York Times

    1
    Predictions of what people look like using a DNA analysis tool compared with photos of the actual people. Credit The New York Times; Images and renderings by Mark D. Shriver/Penn State University

    The faces here, which look a bit like video game avatars, are actually portraits drawn from DNA.

    Each rendering was created by plugging an individual genetic profile into a predictive tool created by Mark D. Shriver, a professor of anthropology and genetics at Penn State University. Dr. Shriver and his colleagues have studied the ways that genes influence facial development.

    Their software yields an image in a matter of minutes, rapidly drawing connections beween genetic markers and points on the face. In less time than it takes to make a cup of coffee, a sketch emerges inferred solely from DNA.

    How accurate or useful are these predictions? That is something that Dr. Shriver is still researching – and that experts are still debating. Andrew Pollack writes about the issues in an article on genetic sleuthing in Science Times.

    On The New York Times’s science desk, we wondered whether it would be possible to identify our colleagues based on the formula that Dr. Shriver has developed. So we tried a somewhat unscientific experiment.

    2
    We asked New York Times employees if they could identify their colleagues based on these DNA renderings, explaining that these were not adjusted for age. Credit Mark D. Shriver/Penn State University

    John Markoff, a reporter, and Catherine Spangler, a video journalist, each volunteered to share their genetic profile, downloaded from 23andMe, a consumer DNA-testing company. The files we sent to Dr. Shriver did not include their names or any information about their height, weight or age.

    Dr. Shriver processed the genotype data and sent us renderings of the donors’ faces.

    We distributed the images to colleagues via email and a private Facebook group, and asked them if they could identify these individuals. We told them that because age and weight could not be determined from DNA, the person might be older or younger, heavier or lighter than the image suggested. At least a dozen people immediately responded that they could not guess because the images felt too generic. Among the 50 or so people who did venture guesses, none identified the man as Mr. Markoff, who is 65.

    The man who received the most votes was Andrew Ross Sorkin, a business columnist and editor of Dealbook. A number of other possibilities were suggested, too — mostly white men who work on the science desk.

    3
    The correct answer — that no one guessed — was John Markoff. New York Times employees were shown the face, top right. Dr. Shriver’s team later adjusted for age and height and the bottom right image emerged.

    When it came to the computer’s DNA portrait of Ms. Spangler, 31, staffers had more luck. About 10 people correctly identified her.

    Although there was no close second, participants put forth the names of nearly 10 other women. About half of them were of European ancestry, half of Asian ancestry.

    To build his model, Dr. Shriver measured 7,000 three-dimensional coordinates on the face and analyzed their links to thousands of genetic variants. Though sex and ancestral mix are not the only predictor of face shape in this model, they are the primary influencers — something that has raised concerns about the potential for racial profiling.

    4
    About ten employees correctly guessed Catherine Spangler. Employees were shown the top right image. The face, bottom right, was adjusted for age, weight and height

    Ms. Spangler’s ancestry is half Korean and half northern European. Mr. Markoff’s is almost entirely Ashkenazi Jewish, with a tenth of a percent Asian, according to his 23andMe analysis.

    Using DNA portraiture, would every male or female with these genetic percentages wind up looking exactly the same? Dr. Shriver says no.

    “People with same ancestry levels can come out looking different,” he said. But just how different — and how much like the actual flesh-and blood-person — is something he and his team are still testing.

    See the full article here.

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  • richardmitnick 4:54 am on February 23, 2015 Permalink | Reply
    Tags: , Genetics,   

    From NOVA: “In Once-Mysterious Epigenome, Scientists Find What Turns Genes On” 

    PBS NOVA

    NOVA

    19 Feb 2015
    R.A. Becker

    1
    A handful of new studies provide epigenetic roadmaps to understanding the human genome in action.(No image credit)

    Over a decade ago, the Human Genome Project deciphered the “human instruction book” of our DNA, but how cells develop vastly different functions using the same genetic instructional text has remained largely a mystery.

    As of yesterday, it became a bit less mysterious. A massive NIH consortium called the Roadmap Epigenomics Program published eight papers in the journal Nature which report on their efforts to map epigenetic modifications, or the changes to DNA that don’t alter its code. These subtle modifications make genes more or less likely to be expressed, and the collection of epigenetic modifications is called the epigenome.

    One of the eight studies mapped over 100 epigenomes characterizing every epigenetic modification occurring in human tissue cells. “These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types,” Roadmap researcher Bing Ren, a professor of cellular and molecular medicine at the University of California, San Diego, said in a news release. “These maps are like snapshots of the human genome in action.”

    This kind of mapping has challenged the field because of the huge amount of data needed to make sense of the chaotic arrangements of genes and their regulators. “The genome hasn’t nicely arranged the regulatory elements to be cheek by jowl with the elements they regulate,” Broad Institute director Eric Lander told Gina Kolata at The New York Times. “It can be very hard to figure out which regulator lines up with which genes.”

    Here’s how Lander described the detective process used to Kolata:

    If you knew when service on the Red Line was disrupted and when various employees were late for work, you might be able to infer which employees lived on the Red Line, he said. Likewise, when a genetic circuit was shut down, certain genes would be turned off. That would indicate that those genes were connected, like the employees who were late to work when the Red Line shut down.

    Diseases can be linked to epigenetic variations as well. For example, another of the eight papers published yesterday proposed that the roots of Alzheimer’s disease lie in immune cell genetic dysfunction and epigenetic alterations in brain cells.

    Creating an epigenetic road map is a huge step, but it’s just a first step. As Collins wrote in 2001 when the human genome had been mostly mapped, “This is not even the beginning of the end. But it may be the end of the beginning.”

    See the full article here.

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    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

     
  • richardmitnick 3:32 am on February 20, 2015 Permalink | Reply
    Tags: , Genetics,   

    From NYT: “A New Theory on How Neanderthal DNA Spread in Asia” 

    New York Times

    The New York Times

    FEB. 19, 2015
    Carl Zimmer

    1
    Chinese passengers wait on a train platform at the Beijing Railway Station. Researchers have discovered that Neanderthals interbred with the ancestors of Asians at two points in history, giving this population an extra infusion of Neanderthal DNA. Credit European Pressphoto Agency

    In 2010, scientists made a startling discovery about our past: About 50,000 years ago, Neanderthals interbred with the ancestors of living Europeans and Asians.

    Now two teams of researchers have come to another intriguing conclusion: Neanderthals interbred with the ancestors of Asians at a second point in history, giving them an extra infusion of Neanderthal DNA.

    The findings are further evidence that our genomes contain secrets about our evolution that we might have missed by looking at fossils alone. “We’re learning new, big-picture things from the genetic data, rather than just filling in details,” said Kirk E. Lohmueller, a geneticist at the University of California, Los Angeles, and co-author of one of the new studies.

    The oldest fossils of Neanderthals date back about 200,000 years, while the most recent are an estimated 40,000 years old. Researchers have found Neanderthal bones at sites across Europe and western Asia, from Spain to Siberia.

    Some of those bones still retain fragments of Neanderthal DNA. Scientists have pieced those DNA fragments together, reconstructing the entire Neanderthal genome. It turns out that Neanderthals had a number of distinct genetic mutations that living humans lack. Based on these differences, scientists estimate that the Neanderthals’ ancestors diverged from ours 600,000 years ago.

    Our own ancestors remained in Africa until about 60,000 years ago, then expanded across the rest of the Old World. Along the way, they encountered Neanderthals. And our DNA reveals that those encounters led to children.

    Today, people who are not of African descent have stretches of genetic material almost identical to Neanderthal DNA, comprising about 2 percent of their entire genomes. These DNA fragments are the evidence that Neanderthals interbred with the early migrants out of Africa, likely in western Asia.

    Researchers also have found a peculiar pattern in non-Africans: People in China, Japan and other East Asian countries have about 20 percent more Neanderthal DNA than do Europeans.

    Last year, Sriram Sankararaman, a postdoctoral researcher at Harvard Medical School, and his colleagues proposed that natural selection was responsible for the difference. Most Neanderthal genes probably had modestly bad effects on the health of our ancestors, Dr. Sankararaman and other researchers have found. People who inherited a Neanderthal version of any given gene would have had fewer children on average than people with the human version.

    As a result, Neanderthal DNA became progressively rarer in living humans. Dr. Sankararaman and his colleagues proposed that it disappeared faster in Europeans than in Asians. The early Asian population was small, the researchers suggested, and natural selection eliminates harmful genes more slowly in small groups than in large populations. Today, smaller ethnic groups, like Ashkenazi Jews and the Amish, can have unusually high rates of certain genetic disorders.

    Joshua M. Akey, a geneticist at the University of Washington, and the graduate student Benjamin Vernot recently set out to test this hypothesis. They took advantage of the fact that only some parts of our genome have a strong influence on health. Other parts — so-called neutral regions — are less important.

    A mutation in a neutral region won’t affect our odds of having children and therefore won’t be eliminated by natural selection. If Dr. Sankararaman’s hypothesis were correct, you would expect Europeans to have lost more harmful Neanderthal DNA than neutral DNA. In fact, the scientists did not find this difference in the DNA of living Europeans.

    Dr. Akey and Mr. Vernot then tested out other possible explanations for the comparative abundance of Neanderthal DNA in Asians. The theory that made the most sense was that Asians inherited additional Neanderthal DNA at a later time.

    In this scenario, the ancestors of Asians and Europeans split, the early Asians migrated east, and there they had a second encounter with Neanderthals. Dr. Akey and Mr. Vernot reported their findings in the American Journal of Human Genetics.

    Dr. Lohmueller and the graduate student Bernard Y. Kim approached the same genetic question, but from a different direction. They constructed a computer model of Europeans and Asians, simulating their reproduction and evolution over time. They added some Neanderthal DNA to the ancestral population and then watched as Europeans and Asian populations diverged genetically.

    The scientists ran the model many times over, trying out a range of likely conditions. But no matter which variation they tried, they couldn’t find one explaining why Asians today have extra Neanderthal DNA.

    But when they ran a model that included a second interbreeding, another “pulse” of Neanderthal genes into the Asian population, the researchers had better luck. “We find that the two-pulse model can fit the data really well,” Dr. Lohmueller said. He and Mr. Kim published their results in a separate paper in the American Journal of Human Genetics.

    Dr. Akey is pleased that the two studies reached the same conclusion. “Together, they tell the same story, just from different perspectives,” he said.

    Dr. Sankararaman agreed that the new research cast doubt on his proposal that natural selection stripped Neanderthal DNA from Europeans more quickly than from Asians. “The analysis from both papers gives strong support to the two-pulse model in Asians,” he said.

    But the two-pulse hypothesis also poses a puzzle of its own.

    If Neanderthals became extinct 40,000 years ago, they may have disappeared before Europeans and Asian populations genetically diverged. How could there have been Neanderthals left to interbreed with Asians a second time?

    It’s conceivable that the extinction of the Neanderthals happened later in Asia. If that is true, there might yet more recent Neanderthal fossils waiting to be discovered there.

    Or perhaps Asians interbred with some other group of humans that had interbred with Neanderthals and carried much of their DNA. Later, that group disappeared.

    “That’s a paradox the field needs to address,” Dr. Lohmueller said.

    See the full article here.

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  • richardmitnick 4:04 pm on February 11, 2015 Permalink | Reply
    Tags: , Genetics,   

    From Princeton: “A gene that shaped the evolution of Darwin’s finches” 

    Princeton University
    Princeton University

    February 11, 2015
    Catherine Zandonella, Office of the Dean for Research

    Researchers from Princeton University and Uppsala University in Sweden have identified a gene in the Galápagos finches studied by English naturalist Charles Darwin that influences beak shape and that played a role in the birds’ evolution from a common ancestor more than 1 million years ago.

    The study illustrates the genetic foundation of evolution, including how genes can flow from one species to another, and how different versions of a gene within a species can contribute to the formation of entirely new species, the researchers report in the journal Nature. The study was published online Feb. 11, one day before the birthday of Darwin, who studied the finches during the 1835 voyage that would lead him to publish the seminal work on evolution, On the Origin of Species, in 1859.

    1
    New research from Princeton University and Uppsala University in Sweden reveals a gene associated with beak shape in Darwin’s finches in the Galápagos islands. Evolutionary biologists Peter and Rosemary Grant (above) provided DNA samples collected during 40 years of field work on the islands. The team in Uppsala led by Leif Andersson provided the whole-genome sequencing that resulted in detection of the gene. The findings illustrate several aspects of the genetic foundation of evolution. (Photo by Denise Applewhite, Office of Communications)

    “We now know more about the genetic basis for our evolutionary studies, and this is a highly satisfactory, very exciting discovery after all these years,” said Peter Grant, Princeton’s Class of 1877 Professor of Zoology, Emeritus, and a professor of ecology and evolutionary biology, emeritus. Along with co-author and wife B. Rosemary Grant, a senior biologist in ecology and evolutionary biology, Grant has studied the finches for 40 years on the arid, rocky islands of Daphne Major and Genovesa in the Galápagos archipelago.

    The latest study reveals how evolution occurs in halting and disordered steps, with many opportunities for genes to spread in different species and create new lineages. Given the right conditions, such as isolation from the original population and an accumulation of genetic differences, these lineages can eventually evolve into entirely new species.

    Working with DNA samples collected by the Grants, researchers at Uppsala identified the gene that influences beak shape by comparing the genomes of 120 birds, all members of the 15 species known as “Darwin’s finches.” They spotted a stretch of DNA that looked different in species with blunt beaks, such as the large ground finch (Geospiza magnirostris), versus species with pointed beaks, such as the large cactus finch (G. conirostris).

    Within that stretch of DNA, the researchers found a gene known as ALX1, which has previously been identified in humans and mice as being associated with the formation of facial features. Mutations that inactivate this gene cause severe birth defects in humans.

    2
    The large ground finch (Geospiza magnirostris) on Daphne Major Island, Galápagos archipelago. (Photo B.R. Grant, Department of Ecology and Evolutionary Biology. Reproduced with the permission of Princeton University Press)

    “This is an interesting example where mild mutations in a gene that is critical for normal development leads to phenotypic [observable] evolution,” said lead researcher Leif Andersson, a professor of functional genomics at Uppsala University, the Swedish University of Agricultural Sciences, and Texas A&M University.

    But the most exciting and interesting finding of the study, Andersson said, was that the gene also varied among individuals from the same species. For example, the medium ground finch (G. fortis) species includes some birds with blunt beaks and others with pointed ones.

    This finding is significant because it shows how evolution can happen, Peter Grant said. Within a species, when some individuals have a trait that aids their survival — such as a blunt beak that allows them to crack open tough seed coverings — they will pass on the genes for that trait to their offspring, whereas individuals with pointed beaks will have died. “This is the genetic variation upon which natural selection can work,” he said.

    The shape and size of the beak are crucial for finch survival on the islands, which periodically experience extreme droughts, El Niño-driven rains and volcanic activity. The birds use their beaks as tools to crack open the hard and woody outer coverings of seeds, pry insects from twigs, and sip nectar from cactus flowers. In times of drought, a bird that can extract food from multiple sources will survive whereas other birds will not.

    During the past four decades, the Grants and their research team have found that beak shape and size played a significant role in the evolution of finch species via natural selection when droughts hit Daphne Major in 1977, 1985 and 2004. “Now we have a genetic underpinning of something we have seen three times during the last 40 years,” Rosemary Grant said.

    4
    The medium ground finch (Geospiza fortis) on Daphne Major Island, Galápagos archipelago. (Photo B.R. Grant, Department of Ecology and Evolutionary Biology. Reproduced with the permission of Princeton University Press)

    The Nature study also adds to what is known about how genes are transferred from one species to another when individuals from two closely related species mate. Although in many species of birds the resulting chicks would be sterile, the hybrid offspring of Galápagos finches can mate with an individual from either of the two parental species. The resulting chicks will identify with one or the other of the parent species through song and appearance, but they will carry genes from both parents.

    Through this process, known as gene flow, or introgression, genetic material can move between species and contribute to the development of new species. The Grants had shown that gene flow has occurred in the finches of Daphne Major during the past 40 years, but the new study found extensive evidence for gene flow throughout the roughly 1 million years that the birds have occupied the archipelago, which has helped the researchers update their understanding of how the lineages diverged over time.

    “We’ve been able to get a much more confident estimate,” Peter Grant said, “of which species are old and which are young, and the time course over which evolution happened.”

    The article, Evolution of Darwin’s finches and their beaks revealed by genome sequencing, was published online Feb. 11 by Nature. The study was supported by the Knut and Alice Wallenberg Foundation, Uppsala University and Hospital, SciLifeLab and Swedish Research Council. The collection of samples was funded by the National Science Foundation under permits from the Galápagos and Costa Rica National Parks Services.

    See the full article here.

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 10:25 am on February 3, 2015 Permalink | Reply
    Tags: , Genetics,   

    From U Maryland: “New Mechanism of Epigenetic Inheritance Could Advance Study of Evolution and Disease Treatment” 

    U Maryland bloc

    University of Maryland

    February 2, 2015
    Matthew Wright, 301-405-9267, mewright@umd.edu

    Results show that gene silencing can last for 25+ generations

    For more than a century, scientists have understood the basics of inheritance: if good genes help parents survive and reproduce, the parents pass those genes along to their offspring. And yet, recent research has shown that reality is much more complex: genes can be switched off, or silenced, in response to the environment or other factors, and sometimes these changes can be passed from one generation to the next.

    1
    UMD scientists have discovered a mechanism for transgenerational gene silencing in the roundworm Caenorhabditis elegans. Special fluorescent dyes help to visualize neurons (magenta) and germ cells (green) in the roundworm’s body. Photo: Sindhuja Devanapally

    The phenomenon has been called epigenetic inheritance, but it is not well understood. Now, UMD geneticist Antony Jose and two of his graduate students are the first to figure out a specific mechanism by which a parent can pass silenced genes to its offspring. Importantly, the team found that this silencing could persist for multiple generations—more than 25, in the case of this study.

    The research, which was published in the Feb. 2, 2015 online early edition of the Proceedings of the National Academy of Sciences, could transform our understanding of animal evolution. Further, it might one day help in the design of treatments for a broad range of genetic diseases.

    “For a long time, biologists have wanted to know how information from the environment sometimes gets transmitted to the next generation,” said Jose, an assistant professor in the UMD Department of Cell Biology and Molecular Genetics. “This is the first mechanistic demonstration of how this could happen. It’s a level of organization that we didn’t know existed in animals before.”

    Jose and graduate students Sindhuja Devanapally and Snusha Ravikumar worked with the roundworm Caenorhabditis elegans, a species commonly used in lab experiments. They made the worms’ nerve cells produce molecules of double-stranded RNA (dsRNA) that match a specific gene. (RNA is a close relative of DNA, and has many different varieties, including dsRNA.) Molecules of dsRNA are known to travel between body cells (any cell in the body except germ cells, which make egg or sperm cells) and can silence genes when their sequence matches up with the corresponding section of a cell’s DNA.

    2
    This schematic illustrates how the gene silencing mechanism works in C. elegans. Neurons (magenta) can export double-stranded RNA (orange arrow) that match a gene (green) in germ cells. Import of RNA into germ cells results in silencing of the gene (black) within germ cells. This silencing can persist for more than 25 generations. Photo: Antony Jose

    The team’s biggest finding was that dsRNA can travel from body cells into germ cells and silence genes within the germ cells. Even more surprising, the silencing can stick around for more than 25 generations. If this same mechanism exists in other animals—possibly including humans—it could mean that there is a completely different way for a species to evolve in response to its environment.

    “This mechanism gives an animal a tool to evolve much faster,” Jose said. “We still need to figure out whether this tool is actually used in this way, but it is at least possible. If animals use this RNA transport to adapt, it would mean a new understanding of how evolution happens.”

    The long-term stability of the silencing effect could prove critical in developing treatments for genetic diseases. The key is a process known as RNA interference, more commonly referred to as RNAi. This process is how dsRNA silences genes in a cell. The same process has been studied as a potential genetic therapy for more than a decade, because you can target any disease gene with matching dsRNA. But a main obstacle has been achieving stable silencing, so that the patient does not need to take repeated high doses of dsRNA.

    “RNAi is very promising as a therapy, but the efficacy of the treatment declines over time with each new cell division,” Jose said. “This particular dsRNA, from C. elegans nerve cells, might have some chemical modifications that allow stable silencing to persist for many generations. Further study of this molecule could help solve the efficacy problem in RNAi therapy.”

    Jose acknowledges the large gap between roundworms and humans. Unlike simpler animals, mammals have known mechanisms that reprogram silenced genes every generation. On the surface, it would seem as though this would prevent epigenetic inheritance from happening. And yet, previous evidence suggests that the environment may be able to cause some sort of transgenerational effect in mammals as well. Jose believes that his team’s work provides a promising lead in the search for how this happens.

    3
    The roundworm C. elegans, seen here, is commonly used in laboratory studies because it reproduces quickly and has a simple body. Photo: Hai Le

    “This is a fertile research field that will keep us busy for 10 years or more into the future,” Jose said. “The goal is to achieve a very clear understanding—in simple terms—of all the tools an animal can use to evolve.”

    This research was supported by the National Institute of General Medical Sciences of the National Institutes of Health. The content of this article does not necessarily reflect the views of this organization.

    The research paper, Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing, Sindhuja Devanapally, Snusha Ravikumar and Antony M. Jose, was published online in the Feb. 2, 2015 early edition of the journal Proceedings of the National Academy of Sciences.

    See the full article here.

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    U Maryland Campus

    Driven by the pursuit of excellence, the University of Maryland has enjoyed a remarkable rise in accomplishment and reputation over the past two decades. By any measure, Maryland is now one of the nation’s preeminent public research universities and on a path to become one of the world’s best. To fulfill this promise, we must capitalize on our momentum, fully exploit our competitive advantages, and pursue ambitious goals with great discipline and entrepreneurial spirit. This promise is within reach. This strategic plan is our working agenda.

    The plan is comprehensive, bold, and action oriented. It sets forth a vision of the University as an institution unmatched in its capacity to attract talent, address the most important issues of our time, and produce the leaders of tomorrow. The plan will guide the investment of our human and material resources as we strengthen our undergraduate and graduate programs and expand research, outreach and partnerships, become a truly international center, and enhance our surrounding community.

    Our success will benefit Maryland in the near and long term, strengthen the State’s competitive capacity in a challenging and changing environment and enrich the economic, social and cultural life of the region. We will be a catalyst for progress, the State’s most valuable asset, and an indispensable contributor to the nation’s well-being. Achieving the goals of Transforming Maryland requires broad-based and sustained support from our extended community. We ask our stakeholders to join with us to make the University an institution of world-class quality with world-wide reach and unparalleled impact as it serves the people and the state of Maryland.

     
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