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  • richardmitnick 4:04 pm on April 16, 2015 Permalink | Reply
    Tags: , DNA, , ,   

    From Quanta: “How Structure Arose in the Primordial Soup” 

    Quanta Magazine
    Quanta Magazine

    Life’s first epoch saw incredible advances — cells, metabolism and DNA, to name a few. Researchers are resurrecting ancient proteins to illuminate the biological dark ages.

    April 16, 2015
    Emily Singer

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    Olena Shmahalo/Quanta Magazine

    About 4 billion years ago, molecules began to make copies of themselves, an event that marked the beginning of life on Earth. A few hundred million years later, primitive organisms began to split into the different branches that make up the tree of life. In between those two seminal events, some of the greatest innovations in existence emerged: the cell, the genetic code and an energy system to fuel it all. All three of these are essential to life as we know it, yet scientists know disappointingly little about how any of these remarkable biological innovations came about.

    “It’s very hard to infer even the relative ordering of evolutionary events before the last common ancestor,” said Greg Fournier, a geobiologist at the Massachusetts Institute of Technology. Cells may have appeared before energy metabolism, or perhaps it was the other way around. Without fossils or DNA preserved from organisms living during this period, scientists have had little data to work from.

    Fournier is leading an attempt to reconstruct the history of life in those evolutionary dark ages — the hundreds of millions of years between the time when life first emerged and when it split into what would become the endless tangle of existence.

    He is using genomic data from living organisms to infer the DNA sequence of ancient genes as part of a growing field known as paleogenomics. In research published online in March in the Journal of Molecular Evolution, Fournier showed that the last chemical letter added to the code was a molecule called tryptophan — an amino acid most famous for its presence in turkey dinners. The work supports the idea that the genetic code evolved gradually.

    Using similar methods, he hopes to decipher the temporal order of more of the code — determining when each letter was added to the genetic alphabet — and to date key events in the origins of life, such as the emergence of cells.

    Dark Origins

    Life emerged so long ago that even the rock formations covering the planet at that time have been destroyed — and with them, most chemical and geological clues to early evolution. “There’s a huge chasm between the origins of life and the last common ancestor,” said Eric Gaucher, a biologist at the Georgia Institute of Technology in Atlanta.

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    The stretch of time between the origins of life and the last universal common ancestor saw a series of remarkable innovations — the origins of cells, metabolism and the genetic code. But scientists know little about when they happened or the order in which they occurred. Olena Shmahalo/Quanta Magazine

    Scientists do know that at some point in that time span, living creatures began using a genetic code, a blueprint for making complex proteins. It is those proteins that carry out the vital functions of the cell. (The structure of DNA and RNA also enables genetic information to be replicated and passed on from generation to generation, but that’s a separate process from the creation of proteins.) The components of the code and the molecular machinery that assembles them “are some of the oldest and most universal aspects of cells, and biologists are very interested in understanding the mechanisms by which they evolved,” said Paul Higgs, a biophysicist at McMaster University in Hamilton, Ontario.

    How the code came into being presents a chicken-and-egg problem. The key players in the code — DNA, RNA, amino acids, and proteins — are chemically complicated structures that work together to make proteins. But in modern cells, proteins are used to make the components of the code. So how did a highly structured code emerge?

    Most researchers believe that the code began simply with basic proteins made from a limited alphabet of amino acids. It then grew in complexity over time, as these proteins learned to make more sophisticated molecules. Eventually, it developed into a code capable of creating all the diversity we see today. “It’s long been hypothesized that life’s ‘standard alphabet’ of 20 amino acids evolved from a simpler, earlier alphabet, much as the English alphabet has accumulated extra letters over its history,” said Stephen Freeland, a biologist at the University of Maryland, Baltimore County.

    The earliest amino acid letters in the code were likely the simplest in structure, those that can be made from purely chemical means, without the assistance of a protein helper. (For example, the amino acids glycine, alanine and glutamic acid have been found on meteorites, suggesting they can form spontaneously in a variety of environments.) These are like the letters A, E and S — primordial units that served as the foundation for what came later.

    Tryptophan, in comparison, has a complex structure and is comparatively rare in the protein code, like a Y or Z, leading scientists to theorize that it was one of the latest additions to the code.

    That chemical evidence is compelling, but circumstantial. Enter Fournier. He suspected that by extending his work on paleogenomics, he would be able to prove tryptophan’s status as the last letter added to the code.

    The Last Letter

    Scientists have been reconstructing ancient proteins for more than a decade, primarily to figure out how ancient proteins differed from modern ones — what they looked like and how they functioned. But these efforts have focused on the period of evolution after the last universal common ancestor (or LUCA, as researchers call it). Fournier’s work delves further back than any other previous efforts. To do so, he had to move beyond the standard application of comparative genomics, which analyzes the differences between branches on the tree of life. “By definition, anything pre-LUCA lies beyond the deepest split in the tree,” he said.

    Fournier started with two related proteins, TrpRS (tryptophanyl tRNA synthetase) and TyrRS (tyrosyl tRNA synthetase), which help decode RNA letters into the amino acids tryptophan and tyrosine. TrpRS and TyrRS are more closely related to each other than to any other protein, indicating that they evolved from the same ancestor protein. Sometime before LUCA, that parent protein mutated slightly to produce these two new proteins with distinct functions. Fournier used computational techniques to decipher what that ancestral protein must look like.

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    Greg Fournier, a geobiologist at MIT, is searching for the origins of the genetic code. Helen Hill

    He found that the ancestral protein has all the amino acids but tryptophan, suggesting that its addition was the finishing touch to the genetic code. “It shows convincingly that tryptophan was the last amino acid added, as has been speculated before but not really nailed as has been done here,” said Nigel Goldenfeld, a physicist at the University of Illinois, Urbana-Champaign, who was not involved in the study.

    Fournier now plans to use tryptophan as a marker to date other major pre-LUCA events such as the evolution of metabolism, cells and cell division, and the mechanisms of inheritance. These three processes form a sort of biological triumvirate that laid the foundation for life as we know it today. But we know little about how they came into existence. “If we understand the order of those basic steps, it creates an arrow pointing to possible scenarios for the origins of life,” Fournier said.

    For example, if the ancestral proteins involved in metabolism lack tryptophan, some form of metabolism probably evolved early. If proteins that direct cell division are studded with tryptophan, it suggests those proteins evolved comparatively late.

    Different models for the origins of life make different predictions for which of these three processes came first. Fournier hopes his approach will provide a way to rule out some of these models. However, he cautions that it won’t definitively sort out the timing of these events.

    Fournier plans to use the same techniques to figure out the order in which other amino acids were added to the code. “It really reinforces the idea that evolution of the code itself was a progressive process,” said Paul Schimmel, a professor of molecular and cell biology at the Scripps Research Institute, who was not involved in the study. “It speaks to the refinement and subtlety that nature was using to perfect these proteins and the diversity it needed to form this vast tree of life.”

    See the full article here.

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    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

     
  • richardmitnick 12:18 pm on April 10, 2015 Permalink | Reply
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    From LBL: “New target for anticancer drugs: RNA” 

    UC Berkeley

    UC Berkeley

    April 6, 2015
    Robert Sanders

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    DNA is transcribed into mRNA, which is then translated by ribosomes into proteins. UC Berkeley researchers demonstrated that dysregulation of the gene expression program governed by a ribosomal protein called eIF3 leads to increased cell growth and carcinogenesis. That makes this protein an ideal anticancer drug target. (Amy Lee graphic)

    Most of today’s anticancer drugs target the DNA or proteins in tumor cells, but a new discovery by University of California, Berkeley, scientists unveils a whole new set of potential targets: the RNA intermediaries between DNA and proteins.

    This RNA, called messenger RNA, is a blueprint for making proteins. Messenger RNA is created in the nucleus and shuttled to the cell cytoplasm to hook up with protein-making machinery, the ribosome. Most scientists have assumed that these mRNA molecules are, aside from their unique sequences, generic, with few distinguishing characteristics that could serve as an Achilles heel for targeted drugs.

    Jamie Cate, UC Berkeley professor of molecular and cell biology, and postdoctoral fellows Amy Lee and Philip Kranzusch have found, however, that a small subset of these mRNAs – most of them coding for proteins linked in some way to cancer – carry unique tags. These short RNA tags bind to a protein, eIF3 (eukaryotic initiation factor 3), that regulates translation at the ribosome, making the binding site a promising target.

    “We’ve discovered a new way that human cells control cancer gene expression, at the step where the genes are translated into proteins. This research puts on the radar that you could potentially target mRNA where these tags bind with eIF3,” Cate said. “These are brand new targets for trying to come up with small molecules that might disrupt or stabilize these interactions in such a way that we could control how cells grow.”

    These tagged mRNAs – fewer than 500 out of more than 10,000 mRNAs in a cell – seem to be special in that they carry information about specific proteins whose levels in the cell must be delicately balanced so as not to tip processes like cell growth into overdrive, potentially leading to cancer.

    Surprisingly, while some of the tags turn on the translation of mRNA into protein, others turn it off.

    “Our new results indicate that a number of key cancer-causing genes – genes that under normal circumstances keep cells under control – are held in check before the proteins are made,” Cate said. “This new control step, which no one knew about before, could be a great target for new anticancer drugs.

    “On the other hand,” he said, “the tags that turn on translation activate genes that cause cancer when too much of the protein is made. These could also be targeted by new anticancer drugs that block the activation step.”

    The new results will be reported April 6 in an advance online publication of the journal Nature. Cate directs the Center for RNA Systems Biology, a National Institutes of Health-funded group developing new tools to study RNA, a group of molecules increasingly recognized as key regulators of the cell.

    mRNA a messenger between DNA and ribosome

    While our genes reside inside the cell’s nucleus, the machinery for making proteins is in the cytoplasm, and mRNA is the messenger between the two. All the DNA of a gene is transcribed into RNA, after which nonfunctional pieces are snipped out to produce mRNA. The mRNA is then shuttled out of the nucleus to the cytoplasm, where a so-called initiation complex gloms onto mRNA and escorts it to the ribosome. The ribosome reads the sequence of nucleic acids in the mRNA and spits out a sequence of amino acids: a protein.

    “If something goes out of whack with a cell’s ability to know when and where to start protein synthesis, you are at risk of getting cancer, because you can get uncontrolled synthesis of proteins,” Cate said. “The proteins are active when they shouldn’t be, which over-stimulates cells.”

    The protein eIF3 is one component of the initiation complex, and is itself made up of 13 protein subunits. It was already known to regulate translation of the mRNA into protein in addition to its role in stabilizing the structure of the complex. Overexpression of eIF3 also is linked to cancers of the breast, prostate and esophagus.

    “I think eIF3 is able to drive multiple functions because it consists of a large complex of proteins,” Lee said. “This really highlights that it is a major regulator in translation rather than simply a scaffolding factor.”

    Lee zeroed in on mRNAs that bind to eIF3, and found a way to pluck them out of the 10,000+ mRNAs in a typical human cell, sequenced the entire set and looked for eIF3 binding sites. She discovered 479 mRNAS – about 3 percent of the mRNAs in the cell – that bind to eIF3, and many of them seem to share similar roles in the cell.

    “When we look at the biological functions of these mRNAs, we see that there is an emphasis on processes that become dysregulated in cancer,” Lee said. These involve the cell cycle, the cytoskeleton, and programmed cell death (apoptosis), along with cell growth and differentiation.

    “Therapeutically, one could screen for increased expression of eIF3 in a cancer tissue and then target the pathways that we have identified as being eIF3-regulated,” she said.

    Lee actually demonstrated that she could tweak the mRNA of two cancer-related genes, both of which control cell growth, to stop cells from becoming invasive.

    “We showed that we could put a damper on invasive growth by manipulating these interactions, so clearly this opens the door to another layer of possible anticancer therapeutics that could target these RNA-binding regions,” Cate said.

    The work was funded by a grant from NIH’s National Institute of General Medical Sciences to the Center for RNA Systems Biology.

    “A goal of systems biology is to map entire biological networks, such as genes and their regulatory mechanisms, to better understand how those complex networks function and can contribute to disease,” said Peter Preusch, chief of the biophysics branch of NIGMS. “This center is using cutting-edge technology to interrogate the structure and function of many RNAs at a time, which is helping piece together RNA’s regulatory components.”

    Lee is supported through the American Cancer Society Postdoctoral Fellowship Program.

    See the full article here.

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  • richardmitnick 4:16 pm on April 7, 2015 Permalink | Reply
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    From U Colorado Boulder: “New study hints at spontaneous appearance of primordial DNA” 

    U Colorado

    University of Colorado Boulder

    April 6, 2015
    Noel Clark, 303-492-6420
    noel.clark@colorado.edu
    Jim Scott, CU-Boulder media relations, 303-492-3114
    jim.scott@colorado.edu

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    The image shows a droplet of condensed nano-DNA and within it smaller drops of its liquid crystal phase which show up in polarized light on the left. The liquid crystal droplets act as “micro-reactors” where short DNA can join together into long polymer chains without the aid of biological mechanisms. Image courtesy Noel Clark, University of Colorado

    The self-organization properties of DNA-like molecular fragments four billion years ago may have guided their own growth into repeating chemical chains long enough to act as a basis for primitive life, says a new study by the University of Colorado Boulder and the University of Milan.

    While studies of ancient mineral formations contain evidence for the evolution of bacteria from 3.5 to 3.8 billion years ago — just half a billion years after the stabilization of Earth’s crust — what might have preceded the formation of such unicellular organisms is still a mystery. The new findings suggest a novel scenario for the non-biological origins of nucleic acids, which are the building blocks of living organisms, said CU-Boulder physics Professor Noel Clark, a study co-author.

    A paper on the subject led by Tommaso Bellini of the University of Milan was published in a recent issue of Nature Communications. Other CU-Boulder co-authors of the study include Professor David Walba, Research Associate Yougwooo Yi and Research Assistant Gregory P. Smith. The study was funded by the Grant PRIN Program of the Italian Ministries of Education, Universities and Research and by the U.S. National Science Foundation.

    The discovery in the 1980’s of the ability of RNA to chemically alter its own structure by CU-Boulder Nobel laureate and Distinguished Professor Tom Cech and his research team led to the development of the concept of an “RNA world” in which primordial life was a pool of RNA chains capable of synthesizing other chains from simpler molecules available in the environment. While there now is consensus among origin-of-life researchers that RNA chains are too specialized to have been created as a product of random chemical reactions, the new findings suggest a viable alternative, said Clark.

    The new research demonstrates that the spontaneous self-assembly of DNA fragments just a few nanometers in length into ordered liquid crystal phases has the ability to drive the formation of chemical bonds that connect together short DNA chains to form long ones, without the aid of biological mechanisms. Liquid crystals are a form of matter that has properties between those of conventional liquids and those of a solid crystal — a liquid crystal may flow like a liquid, for example, but its molecules may be oriented more like a crystal.

    “Our observations are suggestive of what may have happened on the early Earth when the first DNA-like molecular fragments appeared,” said Clark.

    For several years the research group has been exploring the hypothesis that the way in which DNA emerged in the early Earth lies in its structural properties and its ability to self-organize. In the pre-RNA world, the spontaneous self-assembly of fragments of nucleic acids (DNA and RNA) may have acted as a template for their chemical joining into polymers, which are substances composed of a large number of repeating units.

    “The new findings show that in the presence of appropriate chemical conditions, the spontaneous self assembly of small DNA fragments into stacks of short duplexes greatly favors their binding into longer polymers, thereby providing a pre-RNA route to the RNA world,” said Clark.

    The CU-Boulder authors are part of the Soft Materials Research Center (SMRC) headquartered on campus, one of 12 Materials Research and Science Engineering Centers selected by the National Science Foundation for funding in February 2015. The CU-Boulder center was founded with a $12 million NSF grant over six years. Clark is the SMRC center director and Walba is the associate director.

    Other paper co-authors include the University of Milan’s Tommaso P. Fraccia, Giuliano Zanchetta and Elvezia Paraboschi and the University of Parma’s Giorgio Dieci. Parma University is located in Parma, Italy.

    See the full article here.

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    As the flagship university of the state of Colorado, CU-Boulder is a dynamic community of scholars and learners situated on one of the most spectacular college campuses in the country. As one of 34 U.S. public institutions belonging to the prestigious Association of American Universities (AAU) – and the only member in the Rocky Mountain region – we have a proud tradition of academic excellence, with five Nobel laureates and more than 50 members of prestigious academic academies.

    CU-Boulder has blossomed in size and quality since we opened our doors in 1877 – attracting superb faculty, staff, and students and building strong programs in the sciences, engineering, business, law, arts, humanities, education, music, and many other disciplines.

    Today, with our sights set on becoming the standard for the great comprehensive public research universities of the new century, we strive to serve the people of Colorado and to engage with the world through excellence in our teaching, research, creative work, and service.

     
  • richardmitnick 8:11 am on March 16, 2015 Permalink | Reply
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    From AAAS: “Don’t edit embryos, researchers warn” 

    AAAS

    AAAS

    12 March 2015
    Gretchen Vogel

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    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.

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  • richardmitnick 11:42 am on March 8, 2015 Permalink | Reply
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    From NYT: “Is Most of Our DNA Garbage?” 

    New York Times

    The New York Times

    MARCH 5, 2015
    CARL ZIMMER

    T. Ryan Gregory’s lab at the University of Guelph in Ontario is a sort of genomic menagerie, stocked with creatures, living and dead, waiting to have their DNA laid bare. Scorpions lurk in their terrariums. Tarantulas doze under bowls. Flash-frozen spiders and crustaceans — collected by Gregory, an evolutionary biologist, and his students on expeditions to the Arctic — lie piled in beige metal tanks of liquid nitrogen. A bank of standing freezers holds samples of mollusks, moths and beetles. The cabinets are crammed with slides splashed with the fuchsia-stained genomes of fruit bats, Siamese fighting fish and ostriches.

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    Moths in the lab of T. Ryan Gregory at the University of Guelph. Credit Jamie Campbell for The New York Times

    Gregory’s investigations into all these genomes has taught him a big lesson about life: At its most fundamental level, it’s a mess. His favorite way to demonstrate this is through what he calls the “onion test,” which involves comparing the size of an onion’s genome to that of a human. To run the test, Gregory’s graduate student Nick Jeffery brought a young onion plant to the lab from the university greenhouse. He handed me a single-edged safety razor, and then the two of us chopped up onion stems in petri dishes. An emerald ooze, weirdly luminous, filled my dish. I was so distracted by the color that I slashed my ring finger with the razor blade, but that saved me the trouble of poking myself with a syringe — I was to supply the human genome. Jeffery raised a vial, and I wiped my bleeding finger across its rim. We poured the onion juice into the vial as well and watched as the green and red combined to produce a fluid with both the tint and viscosity of maple syrup.

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    T. Ryan Gregory in his lab at University of Guelph. Credit Jamie Campbell for The New York Times

    After adding a fluorescent dye that attaches to DNA, Jeffrey loaded the vial into a boxy device called a flow cytometer, which sprayed the onion juice and blood through a laser beam. Each time a cell was hit, its DNA gave off a bluish glow; bigger genomes glowed more brightly. On a monitor, we watched the data accumulate on a graph. The cells produced two distinct glows, one dim, one bright, which registered on the graph as a pair of peaks.

    One peak represented my genome, or the entirety of my DNA. Genomes are like biological books, written in genetic letters known as bases; the human genome contains about 3.2 billion bases. Print them out as letters on a page, and they would fill a book a thousand times longer than “War and Peace.” Gregory leaned toward the screen. At 39, with a chestnut-colored goatee and an intense gaze, he somewhat resembles a pre-Heisenberg Walter White. He pointed out the onion’s peak. It showed that the onion’s genome was five times bigger than mine.

    “The onion wins,” Gregory said. The onion always does.

    But why? Why does an onion carry around so much more genetic material than a human? Or why, for that matter, do the broad-footed salamander (65.5 billion bases), the African lungfish (132 billion) and the Paris japonica flower (149 billion)? These organisms don’t appear to be more complex than we are, so Gregory rejects the idea that they’re accomplishing more with all their extra DNA. Instead, he champions an idea first developed in the 1970s but still startling today: that the size of an animal’s or plant’s genome has essentially no relationship to its complexity, because a vast majority of its DNA is — to put it bluntly — junk.

    The human genome contains around 20,000 genes, that is, the stretches of DNA that encode proteins. But these genes account for only about 1.2 percent of the total genome. The other 98.8 percent is known as noncoding DNA. Gregory believes that while some noncoding DNA is essential, most probably does nothing for us at all, and until recently, most biologists agreed with him. Surveying the genome with the best tools at their disposal, they believed that only a small portion of noncoding DNA showed any evidence of having any function.

    But in the past few years, the tide has shifted within the field. Recent studies have revealed a wealth of new pieces of noncoding DNA that do seem to be as important to our survival as our more familiar genes. Many of them may encode molecules that help guide our development from a fertilized egg to a healthy adult, for example. If these pieces of noncoding DNA become damaged, we may suffer devastating consequences like brain damage or cancer, depending on what pieces are affected. Large-scale surveys of the genome have led a number of researchers to expect that the human genome will turn out to be even more full of activity than previously thought.

    In January, Francis Collins, the director of the National Institutes of Health, made a comment that revealed just how far the consensus has moved. At a health care conference in San Francisco, an audience member asked him about junk DNA. “We don’t use that term anymore,” Collins replied. “It was pretty much a case of hubris to imagine that we could dispense with any part of the genome — as if we knew enough to say it wasn’t functional.” Most of the DNA that scientists once thought was just taking up space in the genome, Collins said, “turns out to be doing stuff.”

    For Gregory and a group of like-minded biologists, this idea is not just preposterous but also perilous, something that could yield bad science. The turn against the notion of junk DNA, they argue, is based on overinterpretations of wispy evidence and a willful ignorance of years of solid research on the genome. They’ve challenged their opponents face to face at scientific meetings. They’ve written detailed critiques in biology journals. They’ve commented on social media. When the N.I.H.’s official Twitter account relayed Collins’s claim about not using the term “junk DNA” anymore, Michael Eisen, a professor at the University of California, Berkeley, tweeted back with a profanity.

    The junk DNA wars are being waged at the frontiers of biology, but they’re really just the latest skirmish in an intellectual struggle that has played out over the past 200 years. Before Charles Darwin articulated his theory of evolution, most naturalists saw phenomena in nature, from an orchid’s petal to the hook of a vulture’s beak, as things literally designed by God. After Darwin, they began to see them as designs produced, instead, by natural selection. But some of our greatest biologists pushed back against the idea that everything we discover in an organism had to be an exquisite adaptation. To these biologists, a fully efficient genome would be inconsistent with the arbitrariness of our genesis, with the fact that every species emerged through pure happenstance, over eons of false starts. Where some look at all those billions of bases and see a finely tuned machine, others, like Gregory, see a disorganized, glorious mess.

    In 1953, Francis Crick and James Watson published a short paper in the journal Nature setting out the double-helix structure of DNA. That brief note sent biologists into a frenzy of discovery, leading eventually to multiple Nobel Prizes and to an unprecedented depth of understanding about how living things grow and reproduce. To make a protein from DNA, they learned, a cell makes a single-stranded copy of the relevant gene, using a molecule called RNA. It then builds a corresponding protein using the RNA as a guide.

    This research led scientists to assume that the genome was mostly made up of protein-coding DNA. But eventually scientists found this assumption hard to square with reality. In 1964, the German biologist Friedrich Vogel did a rough calculation of how many genes a typical human must carry. Scientists had already discovered how big the human genome was by staining the DNA in cells, looking at the cells through microscopes and measuring its size. If the human genome was made of nothing but genes, Vogel found, it would need to have an awful lot of them — 6.7 million genes by his estimate, a number that, when he published it in Nature, he admitted was “disturbingly high.” There was no evidence that our cells made 6.7 million proteins or anything close to that figure.

    Vogel speculated that a lot of the genome was made up of essential noncoding DNA — possibly operating as something like switches, for example, to turn genes on and off. But other scientists recognized that even this idea couldn’t make sense mathematically. On average, each baby is born with roughly 100 new mutations. If every piece of the genome were essential, then many of those mutations would lead to significant birth defects, with the defects only multiplying over the course of generations; in less than a century, the species would become extinct.

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    Cells are gathered from spiders for DNA studies at the lab of T. Ryan Gregory at the University of Guelph. Credit Jamie Campbell for The New York Times

    Faced with this paradox, Crick and other scientists developed a new vision of the genome during the 1970s. Instead of being overwhelmingly packed with coding DNA, the genome was made up mostly of noncoding DNA. And, what’s more, most of that noncoding DNA was junk — that is, pieces of DNA that do nothing for us. These biologists argued that some pieces of junk started out as genes, but were later disabled by mutations. Other pieces, called transposable elements, were like parasites, simply making new copies of themselves that were usually inserted harmlessly back in the genome.

    Junk DNA’s recognition was part of a bigger trend in biology at the time. A number of scientists were questioning the assumption that biological systems are invariably “well designed” by evolution. In a 1979 paper in The Proceedings of the Royal Society of London, Stephen Jay Gould and Richard Lewontin, both of Harvard, groused that too many scientists indulged in breezy storytelling to explain every trait, from antlers to jealousy, as an adaptation honed by natural selection for some essential function. Gould and Lewontin refer to this habit as the Panglossian paradigm, a reference to Voltaire’s “Candide,” in which the foolish Professor Pangloss keeps insisting, in the face of death and disaster, that we live in “the best of all possible worlds.” Gould and Lewontin did not deny that natural selection was a powerful force, but they stressed that it was not the only explanation for why species are the way they are. Male nipples are not adaptations, for example; they’re just along for the ride.

    Gould and Lewontin called instead for a broader vision of evolution, with room for other forces, for flukes and historical contingencies, for processes unfolding at different levels of life — what Gould often called “pluralism.” At the time, geneticists were getting their first glimpses of the molecular secrets of the human genome, and Gould and Lewontin saw more evidence for pluralism and against the Panglosses. Any two people may have millions of differences in their genomes. Most of those differences aren’t a result of natural selection’s guiding force; they just arise through random mutations, without any effect for good or ill.

    When Crick and others began to argue for junk DNA, they were guided by a similar vision of nature as slipshod. Just as male nipples are a useless vestige of evolution, so, in their theory, is a majority of our genome. Far from the height of machine-like perfection, the genome is largely a palimpsest of worthless instructions, a den of harmless parasites. Crick and his colleagues argued that transposable elements were common in our genome not because they did something essential for us, but because they could exploit us for their own replication. Gould delighted at this good intellectual company, arguing that transposable elements behaved like miniature organisms, evolving to become better at adding new copies to their host genomes. Our genomes were their ocean, their savanna. “They are merely playing Darwin’s game, but at the ‘wrong level,’ ” Gould wrote in 1981.

    Soon after Gould wrote those words, scientists set out to decipher the precise sequence of the entire human genome. It wasn’t until 2001, shortly before Gould’s death, that they published their first draft. They identified thousands of segments that had the hallmarks of dead genes. They found transposable elements by the millions. The Human Genome Project team declared that our DNA consisted of isolated oases of protein-coding genes surrounded by “vast expanses of unpopulated desert where only noncoding ‘junk’ DNA can be found.” Junk DNA had started out as a theoretical argument, but now the messiness of our evolution was laid bare for all to see.

    If you want to see the genome in a fundamentally different way, the best place to go is the third floor of Harvard’s Department of Stem Cell and Regenerative Biology, in a maze of cluttered benches, sequencing machines and microscopes. This is the lab of John Rinn, a 38-year-old former competitive snowboarder who likes to ponder biological questions on top of a skateboard, which he rides from one wall of his office to the other and back. Rinn is overseeing more than a dozen research projects looking for pieces of noncoding DNA that might once have been classified as junk but actually are essential for life.

    5
    John Rinn in his lab at Harvard. Credit Jamie Campbell for The New York Times

    Rinn studies RNA, but not the RNA that our cells use as a template for making proteins. Scientists have long known that the human genome contains some genes for other types of RNA: strands of bases that carry out other jobs in the cell, like helping to weld together the building blocks of proteins. In the early 2000s, Rinn and other scientists discovered that human cells were reading thousands of segments of their DNA, not just the coding parts, and producing RNA molecules in the process. They wondered whether these RNA molecules could be serving some vital function.
    Continue reading the main story

    As a postdoctoral fellow at Stanford University, Rinn decided he would try to show that one of these new RNA molecules had some important role. After a couple years of searching, he and a professor there, Howard Chang, settled on an RNA molecule that, somewhat bizarrely, was produced widely by skin cells below the waist but not above. Rinn and Chang were well aware that this pattern might be meaningless, but they set out to investigate it nevertheless. They had to give their enigmatic molecule a name, so they picked one that was a joke at their own expense: hotair. (“If it ends up being hot air, at least we tried,” Rinn said.)

    Rinn ran a series of experiments on skin cells to figure out what, if anything, hotair was doing. He carefully pulled hotair molecules out of the cells and examined them to see if they had attached to any other molecules. They had, in fact: they were stuck to a protein called Polycomb.

    Polycomb belongs to a group of proteins that are essential to the development of animals from a fertilized egg. They turn genes on and off in different patterns, so that a uniform clump of cells can give rise to bone, muscle and brain. Polycomb latches onto a number of genes and muzzles them, preventing them from making proteins. Rinn’s research revealed that hotair acts as a kind of guide for Polycomb, attaching to it and escorting it through the jungle of the cell to the precise spots on our DNA where it needs to silence genes.

    When Rinn announced this result in 2007, other geneticists were stunned. Cell, the journal that released it, hailed it as a breakthrough, calling Rinn’s paper one of the most important they had ever published. In the years since, Chang and other researchers have continued to examine hotair, using even more sophisticated tools. They bred engineered mice that lack the hotair gene, for example, and found that the mice developed a constellation of deformities, like stunted wrists and jumbled vertebrae. It appears very likely that hotair performs important jobs throughout the body, not just in the skin but in the skeleton and in other tissues too.

    In 2008, having been lured to Harvard, Rinn set up his new lab entirely in hopes of finding more hotair-like molecules. The first day I visited, a research associate named Diana Sanchez was dissecting mouse embryos the size of pinto beans. In a bowl of ice next to her were tubes for the parts she delicately removed — liver, leg, kidney, lung — that would be searched for cells making RNA molecules. After Rinn and I left Sanchez to her dissections, we ran into Martin Sauvageau, a blue-eyed Quebecer carrying a case of slides, each affixed with a slice of a mouse’s brain, with stains revealing cells making different RNA molecules. I tagged along with Sauvageau as he headed to a darkened microscope room to look at the slides with a pink-haired grad student named Abbie Groff. On one slide, a mouse’s brain looked as if it wore a cerulean mustache. To Groff, every pattern comes as a surprise. She once discovered an RNA molecule that created thousands of tiny rings on a mouse’s body, each encircling a hair follicle. “You come in in the morning, and it’s like Christmas,” she said.

    In December 2013, Rinn and his colleagues published the first results of their search: three potential new genes for RNA that appear to be essential for a mouse’s survival. To investigate each potential gene, the scientists removed one of the two copies in mice. When the mice mated, some of their embryos ended up with two copies of the gene, some with one and some with none. If these mice lacked any of these three pieces of DNA, they died in utero or shortly after birth. “You take away a piece of junk DNA, and the mouse dies,” Rinn said. “If you can come up with a criticism of that, go ahead. But I’m pretty satisfied. I’ve found a new piece of the genome that’s required for life.”

    As the scientists find new RNA molecules that look to be important, they are picking out a few to examine in close molecular detail. “I’m totally in love with this one,” Rinn said, standing at a whiteboard wall and drawing a looping line to illustrate yet another RNA molecule, one that he calls “firre.” The experiments that Rinn’s team has run on firre suggest that it performs a spectacular lasso act, grabbing onto three different chromosomes at once and drawing them together. Rinn suspects that there are thousands of RNA molecules encoded in our genomes that perform similar feats: bending DNA, unspooling it, bringing it in contact with certain proteins and otherwise endowing it with a versatility it would lack on its own.

    “It’s genomic origami,” Rinn said about this theory. “In every cell, you have the same piece of paper. Stem cell, brain cell, liver cell, it’s all made from the same piece of paper. How you fold that paper determines if you get a paper airplane or a duck. It’s the shape that you fold it into that matters. This has to be the 3-D code of biology.”

    To some biologists, discoveries like Rinn’s hint at a hidden treasure house in our genome. Because a few of these RNA molecules have turned out to be so crucial, they think, the rest of the noncoding genome must be crammed with riches. But to Gregory and others, that is a blinkered optimism worthy of Dr. Pangloss. They, by contrast, are deeply pessimistic about where this research will lead. Most of the RNA molecules that our cells make will probably not turn out to perform the sort of essential functions that hotair and firre do. Instead, they are nothing more than what happens when RNA-making proteins bump into junk DNA from time to time.

    “You say, ‘I found it — America!’ ” says Alex Palazzo, a biochemist at the University of Toronto who co-wrote a spirited defense of junk DNA with Gregory last year in the journal PLOS Genetics. “But probably what you found is a little bit of noise.”

    Palazzo and his colleagues also roll their eyes at the triumphant declarations being made about recent large-scale surveys of the human genome. One news release from an N.I.H. project declared, “Much of what has been called ‘junk DNA’ in the human genome is actually a massive control panel with millions of switches regulating the activity of our genes.” Researchers like Gregory consider this sort of rhetoric to be leaping far beyond the actual evidence. Gregory likens the search for useful pieces of noncoding DNA to using a metal detector to find gold buried at the beach. “The idea of combing the beach is a great idea,” he says. But you have to make sure your metal detector doesn’t go off when it responds to any metal. “You’re going to find bottle caps and nails,” Gregory says.

    He expects that as we examine the genome more closely, we’ll find many bottle caps and nails. It’s a prediction based, he and others argue, on the deep evolutionary history of our genome. Over millions of years, essential genes haven’t changed very much, while junk DNA has picked up many harmless mutations. Scientists at the University of Oxford have measured evolutionary change over the past 100 million years at every spot in the human genome. “I can today say, hand on my heart, that 8 percent, plus or minus 1 percent, is what I would consider functional,” Chris Ponting, an author of the study, says. And the other 92 percent? “It doesn’t seem to matter that much,” he says.

    It’s no coincidence, researchers like Gregory argue, that bona fide creationists have used recent changes in the thinking about junk DNA to try to turn back the clock to the days before Darwin. (The recent studies on noncoding DNA “clearly demonstrate we are ‘fearfully and wonderfully made’ by our Creator God,” declared the Institute for Creation Research.) In a sense, this debate stretches back to Darwin himself, whose 1859 book, “On the Origin of Species,” set the course for our understanding natural selection as a natural “designer.” Later in his life, Darwin took pains to stress that there was more to evolution than natural selection. He was frustrated to see how many of his readers thought he was arguing that natural selection was the only force behind life’s diversity. “Great is the power of steady misrepresentation,” Darwin grumbled when he updated the book for its sixth edition in 1872. In fact, he wrote, he was quite open-minded about other forces that might drive evolution, like “variations that seem to us in our ignorance to arise spontaneously.”

    Darwin was certainly ignorant about genomes, as scientists would continue to be for decades after his death. But Gregory argues that genomes embody the very mix of adaptation and arbitrariness that Darwin had in mind. Over millions of years, the human genome has spontaneously gotten bigger, swelling with useless copies of genes and new transposable elements. Our ancestors tolerated all that extra baggage because it wasn’t actually all that heavy. It didn’t make them inordinately sick. Copying all that extra DNA didn’t require them to draw off energy required for other tasks. They couldn’t add an infinite amount of junk to the genome, but they could accept an awful lot. To subtract junk, meanwhile, would require swarms of proteins to chop out every single dead gene or transposable element — without chopping out an essential gene. A genome evolving away its junk would lose the race to sloppier genomes, which left more resources for fighting diseases or having children.

    The blood-drenched slides that pack Gregory’s lab with their giant genomes only make sense, he argues, if we give up thinking about life as always evolving to perfection. To him, junk DNA isn’t a sign of evolution’s failure. It is, instead, evidence of its slow and slovenly triumph.

    See the full article here.

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

    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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    FIU Campus

    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: , DNA, , , 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: , DNA, ,   

    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 2:25 pm on February 12, 2015 Permalink | Reply
    Tags: , , , DNA   

    From APS: “Viewpoint: Making Waves with DNA” 

    AmericanPhysicalSociety

    American Physical Society

    February 9, 2015
    Irving R. Epstein

    Strands of DNA can be used to generate waves of chemical reactions with programmable shape and velocity.

    1
    Figure 1 Schematic view of the system studied by Zadorin et al. A single-stranded DNA (A) binds to one of the two complementary ends of the DNA template T. The resulting A:T complex uses the polymerase enzyme (pol) to generate another molecule of A on the template. A second enzyme (nick) facilitates the splitting of the two A molecules and their detachment from T. The net result is an “autocatalytic” reaction in which A catalyzes its own production: A+T+monomers→2A+T. By varying the concentration of DNA strands and enzymes, the authors were able to generate waves of chemical reactions with controllable shape and velocity.

    Research in chemistry can be roughly divided into two categories: analysis—the measurement of existing objects and phenomena—and synthesis—the construction of those objects and phenomena from simpler pieces. Typically, synthesis lags behind analysis: one first determines the formula of a molecule (and often its structure) before attempting to make it. However, as chemistry advances, investigators are increasingly attempting to synthesize first, designing chemical systems that realize desired phenomena. A team led by André Estevez-Torres at CNRS in France and co-workers has demonstrated an experimental toolkit that could be used for the rational engineering of nonlinear chemical effects in solution. Using DNA strands moving in a narrow channel and reacting under the action of enzymes, the authors are able to create chemical waves whose shapes and velocity can be finely controlled. Their setup could be programmed to yield a broad spectrum of other nonlinear phenomena in systems governed by a combination of chemical reactivity and molecular diffusion (“reaction-diffusion” systems).

    Nonlinear chemical dynamics characterizes many natural and industrial processes and is a quintessential feature of living organisms: most of their chemistry occurs far from equilibrium, has a nonlinear dependence on parameters like molecular concentrations, and may exhibit temporal oscillations (many biological functions are, for instance, synchronized to a 24-hour cycle). Researchers have applied a number of algorithms to design systems featuring such nonlinear behavior, engineering chemical oscillators (reactions in which the concentration of one or more components exhibits periodic changes), propagating reaction fronts or “Turing patterns” —spatial patterns of concentrations that, as Alan Turing proposed, might be related to biological morphogenesis (e.g., the formation of leopard spots or zebra stripes).

    But design algorithms are severely limited by the realities imposed by nature. One may write down a set of equations that generates a desired phenomenon, e.g., spatiotemporal chaos, for a set of reaction rates and diffusion coefficients. There is, however, no guarantee that an actual collection of molecules can be found that realizes the theorized behavior. For example, over the past several decades, researchers have successfully engineered, through systematic studies, new chemical oscillators with desired parameters for a variety of applications. These efforts have resulted in the discovery of several oscillators, but none of these oscillators “by design” has attained the importance of the Belousov-Zhabotinsky (BZ) reactions, a family of oscillating reactions (discovered serendipitously) that remains the most versatile and reliable chemical oscillator for most applications.

    Most efforts to design reaction-diffusion phenomena have utilized small inorganic molecules, largely because these substances are cheap, easy to work with, and produce visible color changes when they undergo reduction and oxidation (redox) reactions. Unfortunately, these reaction mixtures are typically not biocompatible, and they cannot be used in applications that place them in contact with components of living systems like proteins. The BZ reaction, for example, only works at acidity levels lethal to most biological cells.

    A solution may be offered by oligonucleotides (short single strands of DNA or RNA), which have been utilized as versatile building blocks for oscillators, computational elements, and structures with arbitrary shapes. In their new work, Estevez-Torres et al. have focused on dynamical aspects: They demonstrated that DNA strands can be used to realize an experimental model for reaction-diffusion systems whose spatiotemporal dynamics is fully controllable by programming three key elements of the system: the reaction rates, the diffusion coefficients, and the topology of the chemical reaction network (i.e., which reactions are linked to each other in ways that generate positive or negative feedback).

    Figure 1 shows a schematic of the authors’ setup: a linear channel in which they are able to generate traveling waves of chemical concentrations whose velocity can be precisely controlled. A single strand of DNA (A) can attach to either half of a complementary strand (T) to form a complex (A:T). In the presence of an enzyme (pol), the A:T complex serves as a template for growth of an additional A strand from monomeric precursors in the solution. A second “nicking” enzyme (nick) causes the two A molecules to detach from the T strand. The net result is an “autocatalytic” reaction in which A acts as a catalyst of its own production: A+T+monomers→2A+T

    It is known that autocatalytic reactions can generate chemical waves that travel with a characteristic velocity (ν) depending on the effective rate constant (k) for the reaction and the diffusion coefficient (D) of the autocatalyst (A in this case): ν=(kD)1/2. This idea has been exploited to generate a family of propagating acidity fronts in inorganic reactions, where the hydrogen ion (H+) was the autocatalyst. It was not possible, however, to control the velocity of those fronts, because the reaction rate depends on diffusion and the diffusion coefficient of H+ in water is fixed. Here, the authors are instead able to tune the effective rate constant k by varying the concentration of either the template or the enzyme. They can also control D, the effective diffusion rate of A (which depends on the diffusion rate of A relative to the A:T complex). By binding a heavy but chemically inert group C to T, they can reduce its diffusion rate and that of the complex without affecting its affinity to A. In other words, by choosing the concentrations of T, C, and pol, they can act on the two independent “control knobs” of the diffusion coefficient and the reaction rate constant. In this way, they can generate reaction waves with velocities that vary by as much as 3 orders of magnitude.

    What is exciting about this approach is that it is not limited to the generation of chemical waves. The scheme could be extended to generate any desired reaction-diffusion phenomenon for which one can write a set of elementary reactions. Turing patterns, for example, could be produced, as suggested by a previous study, by picking a slightly different reaction network, including an activator (like A in this case) but also an inhibitor that diffuses 1 order of magnitude faster than A. The “toolbox” employed by Estevez-Torres’ team, in which the activator species (A) can be slowed down by the massive inert group (C), already contains all elements needed to achieve the necessary range for diffusion coefficients.

    Approaches like the one explored by the authors, building on eons of evolution in the ability to control nucleic acids, suggest a bright future for this research line. The fact that DNA-based reactions are inherently biocompatible makes them attractive for potential applications, in particular if the system can be coupled to mechanical forces, as has been done for the BZ reaction. For example, one could envision inserting an anticancer drug into a DNA shell designed to undergo a mechanical deformation and release the drug when it encounters a molecule with a characteristic shape on the tumor surface.

    This research is published in Physical Review Letters.

    See the full article here.

    For those who are interested, the original article has a complete list of references and a numeric key for those references.

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    Physicists are drowning in a flood of research papers in their own fields and coping with an even larger deluge in other areas of physics. How can an active researcher stay informed about the most important developments in physics? Physics highlights a selection of papers from the Physical Review journals. In consultation with expert scientists, the editors choose these papers for their importance and/or intrinsic interest. To highlight these papers, Physics features three kinds of articles: Viewpoints are commentaries written by active researchers, who are asked to explain the results to physicists in other subfields. Focus stories are written by professional science writers in a journalistic style and are intended to be accessible to students and non-experts. Synopses are brief editor-written summaries.

     
  • richardmitnick 12:16 pm on November 30, 2014 Permalink | Reply
    Tags: , , , , , DNA   

    From Daily Galaxy: “DNA’s Ability to Survive Extreme Conditions of Space –‘Has Implications in Search for Extraterrestrial Life'” 

    Daily Galaxy
    The Daily Galaxy

    November 30, 2014
    via University of Zurich

    DNA can survive a flight through space and re-entry into Earth’s atmosphere — and still pass on genetic information. A team of scientists from the University of Zurich obtained these astonishing results during an experiment on the TEXUS-49 research rocket mission. Various scientists believe that DNA could certainly reach us from outer space as Earth is not insulated: in extraterrestrial material made of dust and meteorites, for instance, around 100 tons of which hits our planet every day.
    “This study provides experimental evidence that the DNA’s genetic information is essentially capable of surviving the extreme conditions of space and the re-entry into Earth’s dense atmosphere,” says study head Oliver Ullrich from the University of Zurich’s Institute of Anatomy.

    dna
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    This extraordinary stability of DNA under space conditions also needs to be factored into the interpretion of results in the search for extraterrestrial life: “The results show that it is by no means unlikely that, despite all the safety precautions, space ships could also carry terrestrial DNA to their landing site. We need to have this under control in the search for extraterrestrial life,” points out Ullrich.

    Applied to the outer shell of the payload section of a rocket using pipettes, small, double-stranded DNA molecules flew into space from Earth and back again. After the launch, space flight, re-entry into Earth’s atmosphere and landing, the so-called plasmid DNA molecules were still found on all the application points on the rocket from the TEXUS-49 mission. And this was not the only surprise: For the most part, the DNA salvaged was even still able to transfer genetic information to bacterial and connective tissue cells.

    The experiment called DARE (DNA atmospheric re-entry experiment) resulted from a spontaneous idea: UZH scientists Dr. Cora Thiel and Ullrich were conducting experiments on the TEXUS-49 mission to study the role of gravity in the regulation of gene expression in human cells using remote-controlled hardware inside the rocket’s payload. During the mission preparations, they began to wonder whether the outer structure of the rocket might also be suitable for stability tests on so-called biosignatures.

    “Biosignatures are molecules that can prove the existence of past or present extraterrestrial life,” explains Dr. Thiel. And so the two UZH researchers launched a small second mission at the European rocket station Esrange in Kiruna, north of the Arctic Circle.

    The quickly conceived additional experiment was originally supposed to be a pretest to check the stability of biomarkers during spaceflight and re-entry into the atmosphere. Dr. Thiel did not expect the results it produced: “We were completely surprised to find so much intact and functionally active DNA.” The study reveals that genetic information from the DNA can essentially withstand the most extreme conditions..

    Two types of biomolecules serve as the genetic information carriers for all Earthly biota. RNA on its own suffices for the business of life for simpler creatures, such as some viruses. Complex life, like humans, however, relies on DNA as its genetic carrier. Extremophiles have been discovered in recent decades thriving in strongly acidic hot springs, within liquid asphalt, and in other eyebrow-raising niches. Salt-tolerant bacteria and archaea, like H. volcanii, have been found to survive in deserts, and simulated Mars conditions. We should not be surprised, perhaps, if life has managed to take hold on formidable worlds.

    See the full article here.

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