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  • richardmitnick 2:49 pm on July 31, 2016 Permalink | Reply
    Tags: , Biochemistry, ,   

    From Technion: “Lethal Sequences” 

    Technion bloc

    Technion

    31/07/2016
    No writer credit found

    1
    Underrepresented sequences (URSs) inhibit protein translation and can be lethal. Top, The genetic information is transferred to the protein synthesis machine, the ribosome, by messenger RNA. Amino acids (colored circles) are added one by one and the newly synthesized protein is pushed out of the ribosome. On the left is a normal sequence. On the right is a sequence with the strong URS – CMYW, which slows translation and prevents ribosome recycling. Middle, left, proteins fold and assemble correctly. On the right, fewer full-length proteins are produced and truncated proteins are also produced due to the URS effect on the ribosome. Bottom, E. coli cells grown on plates in the absence (-) or presence (+) of the protein translation signal molecule IPTG. On the left, cells grow normally with or without IPTG. On the right, cells grow normally when the URS containing protein is not synthesized (no IPTG). When IPTG is added, the URS containing protein synthesis is initiated (+), ribosomes are inhibited, and fewer colonies of the bacteria grow. No image credit

    2
    Prof. Noam Adir, Dean of the Schulich Faculty of Chemistry.

    A study from the lab of Prof. Noam Adir of the Schulich Faculty of Chemistry at Technion – Israel Institute of Technology: natural evolutionary processes prevent the presence of dangerous and potentially lethal molecular interactions by avoiding the presence of specific protein sequences in microorganisms. They found these sequences by a novel method – looking for what is missing in biological data sets. The group then experimentally showed that when these sequences are present in a protein, bacterial growth is indeed inhibited. The study was recently published in the Proceedings of the National Academy of Sciences, USA.

    Evolution is an ongoing process, whereby those individuals of species that are the most fit for their environment have more offspring and thus out-compete less fit individuals. The individual’s fitness is a product of the quality of its cellular biochemistry, made possible by the thousands of enzymes that allow its physiology to perform all of the necessary chemical reactions that allow the cell to live. Deficiency in these molecular functions can lead to disease, loss of adaptability to environmental changes, or weakness against other organisms. The molecular machines that make life possible are large polymers made up of linear sequences of building blocks that contain different chemical functions: proteins, DNA, and RNA. Biological variety is a result of the evolutionary changes in these polymers, first and foremost the result of the astronomic number of possible permutations in the order of the 20 naturally occurring amino acid (AA) residues that are the building blocks of proteins. There are 8,000 possible sequences of three AAs, 160,000 sequences of four AAs, over 3 million sequences of five AAs and so on. Since proteins can contain between hundreds to thousands of AAs, the possibilities are endless.

    The millions of different protein sequences found in all organisms determine the three-dimensional structures that give proteins the ability to function correctly. Proteins in cells can work alone or associate correctly with other cellular components, while avoiding incorrect and harmful associations with other components. Changes to the sequences naturally occur due to mutations (single site, or larger changes due to more dramatic sequence shuffling) of an organism’s DNA – the genetic material. Changes due to mutations can lead to new positive characteristics, or they may have negative consequences to the organism’s viability. A mutation that has a negative effect may prevent the organism from competing with other organisms in its environment, eventually leading to its demise. One could predict that over time, evolutionary pressure would work against the presence of organisms containing these internally lethal sequences and they would disappear.

    Over the past few years, there has been a world-wide effort to obtain the entire DNA sequences (the entire genomes) of many organisms. These data have given us the ability to predict all of the possible protein sequences (the proteome) that might exist in organisms as simple as bacteria or as complicated as humans. Prof. Adir and his students, Dr. Sharon Penias-Navon and Ms. Tali Schwartzman, hypothesized that the huge amount of data made available by modern genomics would allow them to look for short sequences that occur less often than expected or are completely missing in the organism’s proteome. They developed a computer program that searched the many existing data sets to identify short sequences that are underrepresented (URSs). While they found that most of the sequences of three or four AAs indeed do exist at their expected frequency in the proteins of different organisms, URSs do exist. They used the program to search for URSs in the proteomes of many different organisms (especially pathogenic microorganisms) and found that different organisms have different URSs. Adir and Penias-Navon wanted to prove that these URSs are indeed harmful, and they hypothesized that protein synthesis (translation) by the ribosome is the function that URSs might harm.

    They embedded bacterial URSs (identified in the proteome of the gut bacterium E. coli) comprised of three or four AAs in a normal protein sequence, and showed that no matter where they put the URS, protein translation was inhibited. They showed that these same E. coli URSs had no effect on protein translation in human cells, showing that the effect is species specific. They further showed that one four-AA URS was powerful enough to inhibit translation completely to the point where the growth of the bacterial cells was significantly reduced: these are indeed lethal sequences. Adir and Navon suggested that URSs could be used as highly specific anti-microbial agents, and a patent, together with the Technion, was submitted.

    In order to obtain even more precise molecular details on the action of the URS, they initiated a collaboration with Prof. Joseph Puglisi and his student Dr. Guy Kornberg of Stanford University, who are experts in following protein translation in single ribosomes, thereby obtaining direct information on the translation reaction mechanism. Using these single molecule methods, the inhibitory effect of the existence of a URS on translation was confirmed. Their methods enabled a precise determination of the site of inhibition. They found that as soon as the URS AAs enter the entrance to the ribosomal nascent protein exit tunnel, translation is inhibited.

    See the full article here .

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  • richardmitnick 11:48 am on April 15, 2016 Permalink | Reply
    Tags: , Biochemistry,   

    From Princeton: “Chemical tracers reveal oxygen-dependent switch in cellular pathway to fat (Nature Chemical Biology)” 

    Princeton University
    Princeton University

    April 15, 2016
    Tien Nguyen, Department of Chemistry

    Using tracer compounds, scientists have been able to track the cellular production of NADPH, a key coenzyme for making fat, through a pathway that has never been measured directly before.

    By tracking this pathway, known as malic enzyme metabolism, which is one of a few recognized routes to make NADPH, researchers from Rabinowitz lab discovered a novel switch in the way fat cells make NADPH depending on the presence of oxygen. The findings were published* in Nature Chemical Biology.

    “No one had ever shown an environmental dependent switch in any NADPH production pathway,” said Joshua Rabinowitz, Professor of Chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton and principal investigator of the work. “No one had the tools to look,” he said.

    NADPH is critical to not only fat synthesis, but also protein and DNA synthesis, and antioxidant defense, implicating it in many diseases such as cancer and diabetes. By understanding and monitoring the pathways through which NADPH is made, scientists can work towards influencing these processes using therapeutic compounds.

    The Rabinowitz lab first applied their tracer method in 2014* to study the most well known NADPH production pathway, the oxidative pentose phosphate pathway (oxPPP). The method relied on compounds labeled with deuterium atoms, hydrogen’s heavier cousin, which can be deployed in the cell and measured by a technique called mass spectrometry.

    In this work, the researchers extended their method to probe the lesser-known malic enzyme pathway by developing two new, orthogonal tracer compounds specific to this pathway. One tracer, a deuterated succinate compound, enters the cycle more directly but is somewhat challenging for the cell to uptake, while the other, a deuterated glucose molecule, is taken up by the cell readily but takes an extra step to enter the pathway.

    The research team investigated the malic enzyme pathway under various concentrations of oxygen. Low oxygen environments, which are found in fat cells in obesity, are of particular clinical interest. They found that in a low oxygen environment, the oxidative pentose phosphate pathway produced more NADPH than the malic enzyme pathway, but in a higher oxygen environment, the pathway contributions completely flipped.

    “It’s like the cells are quite clever. They choose the pathway depending on what they want to make, and what nutrients they can access,” said Ling Liu, a graduate student in the Rabinowitz lab and lead author on the work.

    One advantage of this method is that it tracks NADPH made specifically in the cytosolic compartment of the cell, whereas the previous leading technique, which relied on tracer compounds with carbon-13 atoms, is unable to differentiate between malic enzyme activity in the cytosol and mitochondria.

    NADPH involvement in essential cellular processes has a direct impact on diseases such as diabetes, obesity and cancer. “All of these central biomedical questions depend on an understanding of NADPH pathways, and if you can’t quantify how a metabolite is made and used, you can’t understand what’s going on,” Rabinowitz said. “Ultimately, we’re trying to understand the fundamental chemistry that’s leading to these important biological outcomes,” he said.

    *[Article’s subject paper] Read the full article or abstract:

    Liu, L.; Shah, S.; Fan, J.; Park, J. O.; Wellen, K. E.; Rabinowitz, J. D. Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage. Nat. Chem. Bio. Published online March 21, 2016.

    Science team and affiliations:

    Affiliations

    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
    Ling Liu, Jing Fan, Junyoung O Park & Joshua D Rabinowitz
    Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
    Ling Liu, Jing Fan & Joshua D Rabinowitz
    Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA.
    Junyoung O Park
    Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
    Supriya Shah & Kathryn E Wellen
    Diabetes Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
    Ling Liu, Supriya Shah, Kathryn E Wellen & Joshua D Rabinowitz

    Contributions

    J.D.R., K.E.W., L.L. and J.F. conceived the project. L.L. performed and analyzed most experiments. L.L., J.O.P., J.F. and J.D.R. conducted the flux analysis. S.S. performed electroporation experiments and analyzed the data. J.D.R. and L.L. wrote the manuscript.

    This work was supported by the US National Institutes of Health grants R01CA163591, R01AI097382 and P30DK019525 (to the University of Pennsylvania Diabetes Research Center).

    *2014 Science paper:
    Quantitative flux analysis reveals folate-dependent NADPH production

    Science team and affiliations:
    These authors contributed equally to this work.
    Jing Fan & Jiangbin Ye

    Affiliations

    Department of Chemistry and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA
    Jing Fan, Jurre J. Kamphorst, Tomer Shlomi & Joshua D. Rabinowitz
    Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Jiangbin Ye & Craig B. Thompson
    Department of Computer Science, Technion – Israel Institute of Technology, Haifa 32000, Israel
    Tomer Shlomi

    Contributions

    J.F. and J.D.R. conceived the study. J.F., J.Y., C.B.T. and J.D.R. designed the experiments. J.F., J.Y. and J.J.K. performed the experiments. T.S. and J.F. conducted the computational analyses. J.D.R. and J.F., assisted by J.Y., T.S. and C.B.T., wrote the manuscript.

    See the full article here .

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  • richardmitnick 6:58 pm on March 23, 2016 Permalink | Reply
    Tags: , Biochemistry, , , Phages   

    From NOVA: “The Virus That Could Cure Alzheimer’s, Parkinson’s, and More” 

    PBS NOVA

    NOVA

    23 Mar 2016
    Jon Palfreman

    In 2004, the British chemist Chris Dobson speculated that there might be a universal elixir out there that could combat not just alpha-synuclein for Parkinson’s but the amyloids caused by many protein-misfolding diseases at once. Remarkably, in that same year an Israeli scientist named Beka Solomon discovered an unlikely candidate for this elixir, a naturally occurring microorganism called a phage.

    Solomon, a professor at Tel Aviv University, made a serendipitous discovery one day when she was testing a new class of agents against Alzheimer’s disease. If it pans out, it might mark the beginning of the end of Alzheimer’s, Parkinson’s, and many other neurodegenerative diseases. It’s a remarkable story, and the main character isn’t Solomon or any other scientist but a humble virus that scientists refer to as M13.

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    Alzheimer’s disease can cause brain tissues to atrophy, seen here in blue. No image credit.

    Among the many varieties of viruses, there is a kind that only infects bacteria. Known as bacteriophages, or just phages, these microbes are ancient (over three billion years old) and ubiquitous: they’re found everywhere from the ocean floor to human stomachs. The phage M13’s goal is to infect just one type of bacteria, Escherichia coli, or E. coli, which can be found in copious amounts in the intestines of mammals. Like other microorganisms, phages such as M13 have only one purpose: to pass on their genes. In order to do this, they have developed weapons to enable them to invade, take over, and even kill their bacterial hosts. Before the advent of antibiotics, in fact, doctors occasionally used phages to fight otherwise incurable bacterial infections.

    To understand Solomon’s interest in M13 requires a little background about her research. Solomon is a leading Alzheimer’s researcher, renowned for pioneering so-called immunotherapy treatments for the disease. Immunotherapy employs specially made antibodies, rather than small molecule drugs, to target the disease’s plaques and tangles. As high school students learn in biology class, antibodies are Y-shaped proteins that are part of the body’s natural defense against infection. These proteins are designed to latch onto invaders and hold them so that they can be destroyed by the immune system. But since the 1970s, molecular biologists have been able to genetically engineer human-made antibodies, fashioned to attack undesirable interlopers like cancer cells. In the 1990s, Solomon set out to prove that such engineered antibodies could be effective in attacking amyloid-beta plaques in Alzheimer’s as well.

    In 2004, she was running an experiment on a group of mice that had been genetically engineered to develop Alzheimer’s disease plaques in their brains. She wanted to see if human-made antibodies delivered through the animals’ nasal passages would penetrate the blood-brain barrier and dissolve the amyloid-beta plaques in their brains. Seeking a way to get more antibodies into the brain, she decided to attach them to M13 phages in the hope that the two acting in concert would better penetrate the blood-brain barrier, dissolve more of the plaques, and improve the symptoms in the mice—as measured by their ability to run mazes and perform similar tasks.

    Solomon divided the rodents into three groups. She gave the antibody to one group. The second group got the phage-antibody combination, which she hoped would have an enhanced effect in dissolving the plaques. And as a scientific control, the third group received the plain phage M13.

    Because M13 cannot infect any organism except E. coli, she expected that the control group of mice would get absolutely no benefit from the phage. But, surprisingly, the phage by itself proved highly effective at dissolving amyloid-beta plaques and in laboratory tests improved the cognition and sense of smell of the mice. She repeated the experiment again and again, and the same thing happened. “The mice showed very nice recovery of their cognitive function,” Solomon says. And when Solomon and her team examined the brains of the mice, the plaques had been largely dissolved. She ran the experiment for a year and found that the phage-treated mice had 80% fewer plaques than untreated ones. Solomon had no clear idea how a simple phage could dissolve Alzheimer’s plaques, but given even a remote chance that she had stumbled across something important, she decided to patent M13’s therapeutic properties for the University of Tel Aviv. According to her son Jonathan, she even “joked about launching a new company around the phage called NeuroPhage. But she wasn’t really serious about it.”

    The following year, Jonathan Solomon—who’d just completed more than a decade in Israel’s special forces, during which time he got a BS in physics and an MS in electrical engineering—traveled to Boston to enroll at the Harvard Business School. While he studied for his MBA, Jonathan kept thinking about the phage his mother had investigated and its potential to treat terrible diseases like Alzheimer’s. At Harvard, he met many brilliant would-be entrepreneurs, including the Swiss-educated Hampus Hillerstrom, who, after studying at the University of St. Gallen near Zurich, had worked for a European biotech venture capital firm called HealthCap.

    Following the first year of business school, both students won summer internships: Solomon at the medical device manufacturer Medtronic and Hillerstrom at the pharmaceutical giant AstraZeneca. But as Hillerstrom recalls, they returned to Harvard wanting more: “We had both spent…I would call them ‘weird summers’ in large companies, and we said to each other, ‘Well, we have to do something more dynamic and more interesting.’ ”

    In their second year of the MBA, Solomon and Hillerstrom took a class together in which students were tasked with creating a new company on paper. The class, Solomon says, “was called a field study, and the idea was you explore a technology or a new business idea by yourself while being mentored by a Harvard Business School professor. So, I raised the idea with Hampus of starting a new company around the M13 phage as a class project. At the end of that semester, we developed a mini business plan. And we got on so well that we decided that it was worth a shot to do this for real.”

    In 2007, with $150,000 in seed money contributed by family members, a new venture, NeuroPhage Pharmaceuticals, was born. After negotiating a license with the University of Tel Aviv to explore M13’s therapeutic properties, Solomon and Hillerstrom reached out to investors willing to bet on M13’s potential therapeutic powers. By January 2008, they had raised over $7 million and started hiring staff.

    Their first employee—NeuroPhage’s chief scientific officer—was Richard Fisher, a veteran of five biotech start-ups. Fisher recalls feeling unconvinced when he first heard about the miraculous phage. “But the way it’s been in my life is that it’s really all about the people, and so first I met Jonathan and Hampus and I really liked them. And I thought that within a year or so we could probably figure out if it was an artifact or whether there was something really to it, but I was extremely skeptical.”

    Fisher set out to repeat Beka Solomon’s mouse experiments and found that with some difficulty he was able to show the M13 phage dissolved amyloid-beta plaques when the phage was delivered through the rodents’ nasal passages. Over the next two years, Fisher and his colleagues then discovered something totally unexpected: that the humble M13 virus could also dissolve other amyloid aggregates—the tau tangles found in Alzheimer’s and also the amyloid plaques associated with other diseases, including alpha-synuclein (Parkinson’s), huntingtin (Huntington’s disease), and superoxide dismutase (amyotrophic lateral sclerosis). The phage even worked against the amyloids in prion diseases (a class that includes Creutzfeldt-Jakob disease). Fisher and his colleagues demonstrated this first in test tubes and then in a series of animal experiments. Astonishingly, the simple M13 virus appeared in principle to possess the properties of a “pan therapy,” a universal elixir of the kind the chemist Chris Dobson had imagined.

    This phage’s unique capacity to attack multiple targets attracted new investors in a second round of financing in 2010. Solomon recalls feeling a mix of exuberance and doubt: “We had something interesting that attacks multiple targets, and that was exciting. On the other hand, we had no idea how the phage worked.”
    The Key

    That wasn’t their only problem. Their therapeutic product, a live virus, it turned out, was very difficult to manufacture. It was also not clear how sufficient quantities of viral particles could be delivered to human beings. The methods used in animal experiments—inhaled through the nose or injected directly into the brain—were unacceptable, so the best option available appeared to be a so-called intrathecal injection into the spinal canal. As Hillerstrom says, “It was similar to an epidural; this was the route we had decided to deliver our virus with.”

    While Solomon and Hillerstrom worried about finding an acceptable route of administration, Fisher spent long hours trying to figure out the phage’s underlying mechanism of action. “Why would a phage do this to amyloid fibers? And we really didn’t have a very good idea, except that under an electron microscope the phage looked a lot like an amyloid fiber; it had the same dimensions.”

    Boston is a town with enormous scientific resources. Less than a mile away from NeuroPhage’s offices was MIT, a world center of science and technology. In 2010, Fisher recruited Rajaraman Krishnan—an Indian postdoctoral student working in an MIT laboratory devoted to protein misfolding—to investigate the M13 puzzle. Krishnan says he was immediately intrigued. The young scientist set about developing some new biochemical tools to investigate how the virus worked and also devoured the scientific literature about phages. It turned out that scientists knew quite a lot about the lowly M13 phage. Virologists had even created libraries of mutant forms of M13. By running a series of experiments to test which mutants bound to the amyloid and which ones didn’t, Krishnan was able to figure out that the phage’s special abilities involved a set of proteins displayed on the tip of the virus, called GP3. “We tested the different variants for examples of phages with or without tip proteins, and we found that every time we messed around with the tip proteins, it lowered the phage’s ability to attach to amyloids,” Krishnan says.

    Virologists, it turned out, had also visualized the phage’s structure using X-ray crystallography and nuclear magnetic resonance imaging. Based on this analysis, those microbiologists had predicted that the phage’s normal mode of operation in nature was to deploy the tip proteins as molecular keys; the keys in effect enabled the parasite to “unlock” E. coli bacteria and inject its DNA. Sometime in 2011, Krishnan became convinced that the phage was doing something similar when it bound to toxic amyloid aggregates. The secret of the phage’s extraordinary powers, he surmised, lay entirely in the GP3 protein.

    As Fisher notes, this is serendipitous. Just by “sheer luck, M13’s keys not only unlock E. coli; they also work on clumps of misfolded proteins.” The odds of this happening by chance, Fisher says, are very small. “Viruses have exquisite specificity in their molecular mechanisms, because they’re competing with each other…and you need to have everything right, and the two locks need to work exactly the way they are designed. And this one way of getting into bacteria also works for binding to the amyloid plaques that cause many chronic diseases of our day.”

    Having proved the virus’s secret lay in a few proteins at the tip, Fisher, Krishnan, and their colleagues wondered if they could capture the phage’s amyloid-busting power in a more patient friendly medicine that did not have to be delivered by epidural. So over the next two years, NeuroPhage’s scientists engineered a new antibody (a so-called fusion protein because it is made up of genetic material from different sources) that displayed the critical GP3 protein on its surface so that, like the phage, it could dissolve amyloid plaques. Fisher hoped this novel manufactured product would stick to toxic aggregates just like the phage.

    By 2013, NeuroPhage’s researchers had tested the new compound, which they called NPT088, in test tubes and in animals, including nonhuman primates. It performed spectacularly, simultaneously targeting multiple misfolded proteins such as amyloid beta, tau, and alpha-synuclein at various stages of amyloid assembly. According to Fisher, NPT088 didn’t stick to normally folded individual proteins; it left normal alpha-synuclein alone. It stuck only to misfolded proteins, not just dissolving them directly, but also blocking their prion-like transmission from cell to cell: “It targets small aggregates, those oligomers, which some scientists consider to be toxic. And it targets amyloid fibers that form aggregates. But it doesn’t stick to normally folded individual proteins.” And as a bonus, it could be delivered by intravenous infusion.
    The Trials

    There was a buzz of excitement in the air when I visited NeuroPhage’s offices in Cambridge, Massachusetts, in the summer of 2014. The 18 staff, including Solomon, Hillerstrom, Fisher, and Krishnan, were hopeful that their new discovery, which they called the general amyloid interaction motif, or GAIM, platform, might change history. A decade after his mother had made her serendipitous discovery, Jonathan Solomon was finalizing a plan to get the product into the clinic. As Solomon says, “We now potentially have a drug that does everything that the phage could do, which can be delivered systemically and is easy to manufacture.”

    Will it work in humans? While NPT088, being made up of large molecules, is relatively poor at penetrating the blood-brain barrier, the medicine persists in the body for several weeks, and so Fisher estimates that over time enough gets into the brain to effectively take out plaques. The concept is that this antibody could be administered to patients once or twice a month by intravenous infusion for as long as necessary.

    NeuroPhage must now navigate the FDA’s regulatory system and demonstrate that its product is safe and effective. So far, NPT088 has proved safe in nonhuman primates. But the big test will be the phase 1A trial expected to be under way this year. This first human study proposed is a single-dose trial to look for any adverse effects in healthy volunteers. If all goes well, NeuroPhage will launch a phase 1B study involving some 50 patients with Alzheimer’s to demonstrate proof of the drug’s activity. Patients will have their brains imaged at the start to determine the amount of amyloid-beta and tau. Then, after taking the drug for six months, they will be reimaged to see if the drug has reduced the aggregates below the baseline.

    “If our drug works, we will see it working in this trial,” Hillerstrom says. “And then we may be able to go straight to phase 2 trials for both Alzheimer’s and Parkinson’s.” There is as yet no imaging test for alpha-synuclein, but because their drug simultaneously lowers amyloid-beta, tau, and alpha-synuclein levels in animals, a successful phase 1B test in Alzheimer’s may be acceptable to the FDA. “In mice, the same drug lowers amyloid beta, tau, and alpha-synuclein,” Hillerstrom says. “Therefore, we can say if we can reduce in humans the tau and amyloid-beta, then based on the animal data, we can expect to see a reduction in humans in alpha-synuclein as well.”

    Along the way, the company will have to prove its GAIM system is superior to the competition. Currently, there are several drug and biotech companies testing products in clinical trials for Alzheimer’s disease, against both amyloid-beta (Lilly, Pfizer, Novartis, and Genentech) and tau (TauRx) and also corporations with products against alpha-synuclein for Parkinson’s disease (AFFiRiS and Prothena/Roche). But Solomon and Hillerstrom think they have two advantages: multi-target flexibility (their product is the only one that can target multiple amyloids at once) and potency (they believe that NPT088 eliminates more toxic aggregates than their competitors’ products). Potency is a big issue. PET imaging has shown that existing Alzheimer’s drugs like crenezumab reduce amyloid loads only modestly, by around 10%. “One weakness of existing products,” Solomon says, “is that they tend to only prevent new aggregates. You need a product potent enough to dissolve existing aggregates as well. You need a potent product because there’s a lot of pathology in the brain and a relatively short space of time in which to treat it.”
    Future Targets

    NeuroPhage’s rise is an extraordinary example of scientific entrepreneurship. While I am rooting for Solomon, Hillerstrom, and their colleagues, and would be happy to volunteer for one of their trials (I was diagnosed with Parkinson’s in 2011), there are still many reasons why NeuroPhage has a challenging road ahead. Biotech is a brutally risky business. At the end of the day, NPT088 may prove unsafe. And it may still not be potent enough. Even if NPT088 significantly reduces amyloid beta, tau, and alpha-synuclein, it’s possible that this may not lead to measurable clinical benefits in human patients, as it has done in animal models.

    But if it works, then, according to Solomon, this medicine will indeed change the world: “A single compound that effectively treats Alzheimer’s and Parkinson’s could be a twenty billion-dollar-a-year blockbuster drug.” And in the future, a modified version might also work for Huntington’s, ALS, prion diseases like Creutzfeldt-Jakob disease, and more.

    I asked Jonathan about his mother, who launched this remarkable story in 2004. According to him, she has gone on to other things. “My mother, Beka Solomon, remains a true scientist. Having made the exciting scientific discovery, she was happy to leave the less interesting stuff—the engineering and marketing things for bringing it to the clinic—to us. She is off looking for the next big discovery.”

    See the full article here .

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  • richardmitnick 1:19 pm on July 22, 2015 Permalink | Reply
    Tags: , Biochemistry, ,   

    From SLAC: “Long-sought Discovery Fills in Missing Details of Cell ‘Switchboard'” 


    SLAC Lab

    July 22, 2015

    SLAC’s X-ray Laser Lends New Insight into Key Target for Drug Development

    A biomedical breakthrough, published today in the journal Nature, reveals never-before-seen details of the human body’s cellular switchboard that regulates sensory and hormonal responses. The work is based on an X-ray laser experiment at the Department of Energy’s SLAC National Accelerator Laboratory.

    The much-anticipated discovery, a decade in the making, could have broad impacts on development of more highly targeted and effective drugs with fewer side effects to treat conditions including high blood pressure, diabetes, depression and even some types of cancer.


    This video shows a 3-D rendering of a tiny signaling switch found in cells that involves arrestin (magenta), an important signaling protein, while docked with rhodopsin (green), a light-sensitive protein that is a type of G protein-coupled receptor (GPCR) found in the retina of our eyes. The cyan structure at the top is a protein called lysozyme that scientists added to more easily preserve and study the arrestin and rhodopsin structures. An experiment at SLAC’s Linac Coherent Light Source, an X-ray laser, provided this first-ever atomic-scale map of arrestin coupled to a GPCR. (SLAC National Accelerator Laboratory)

    The study has been hailed by researchers familiar with the work as one of the most important scientific results to date using SLAC’s Linac Coherent Light Source (LCLS), a DOE Office of Science User Facility that is one of the brightest sources of X-rays on the planet. The LCLS X-rays are a billion times brighter than those from synchrotrons and produce higher-resolution images while allowing scientists to use smaller samples.

    2
    In crystallography experiments at the Coherent X-ray Imaging experimental station at LCLS, a liquid jet delivers nanoscale crystals into this chamber, where X-ray laser pulses strike them. (SLAC National Accelerator Laboratory)

    1
    This illustration shows arrestin (yellow), an important type of signaling protein, while docked with rhodopsin (orange), a G protein-coupled receptor. GPCRs are embedded in cell membranes and serve an important role in a cellular signaling network. An experiment conducted at SLAC’s Linac Coherent Light Source X-ray laser provided an atomic-scale 3-D map of this joined structure. (SLAC National Accelerator Laboratory)

    These ultrabright X-rays enabled the research team to complete the first 3-D atomic-scale map of a key signaling protein called arrestin while it was docked with a cell receptor involved in vision. The receptor is a well-studied example from a family of hundreds of G protein-coupled receptors, or GPCRs, which are targeted by about 40 percent of drugs on the market. Its structure while coupled with arrestin provides new insight into the on/off signaling pathways of GPCRs.

    The research, led by scientists at the Van Andel Research Institute in Michigan in collaboration with dozens of other scientists from around the globe, represents a major milestone in GPCR structural studies, said Dr. Jeffrey L. Benovic, a biochemistry and molecular biology professor at Thomas Jefferson University in Philadelphia who specializes in such research but was not a part of this study.

    “This work has tremendous therapeutic implications,” Benovic said. “The study is a critical first step and provides key insight into the structural interactions in these protein complexes.”

    Decoding the Body’s Cellular ‘Switchboard’

    Arrestins and another class of specialized signaling proteins called G proteins take turns docking with GPCRs. Both play critical roles in the body’s communications “switchboard,” sending signals that the receptors translate into cell instructions. These instructions are responsible for a range of physiological functions.

    Until now, only a G protein had been seen joined to a receptor at this scale, one of the discoveries recognized with the 2012 Nobel Prize in Chemistry. Before the study at SLAC, little was known about how arrestins – which serve a critical role as the “off” switch in cell signaling, opposite the “on” switch of G proteins – dock with GPCRs, and how this differs from G protein docking. The latest research helps scientists understand how a docked arrestin can block a G protein from docking at the same time, and vice versa.

    Many of the available drugs that activate or deactivate GPCRs block both G proteins and arrestins from docking.

    “The new paradigm in drug discovery is that you want to find this selective pathway – how to activate either the arrestin pathway or the G-protein pathway but not both — for a better effect,” said Eric Xu, a scientist at the Van Andel Research Institute in Michigan who led the experiment. The study notes that a wide range of drugs would likely be more effective and have fewer side effects with this selective activation.

    X-ray Laser Best Tool for Tiny Samples

    Xu said he first learned about the benefits of using SLAC’s X-ray laser for protein studies in 2012. The microscopic arrestin-GPCR crystals, which his team had painstakingly produced over years, proved too difficult to study at even the most advanced type of synchrotron, a more conventional X-ray source.

    In the LCLS experiments, Xu’s team used samples of a form of human rhodopsin – a GPCR found in the retina whose dysfunction can cause night blindness – fused to a type of mouse arrestin that is nearly identical to human arrestin. Measuring just thousandths of a millimeter, the crystals – which had been formed in a toothpaste-like solution – were oozed into the X-ray pulses at LCLS, producing patterns that when combined and analyzed allowed researchers to reconstruct a complete 3-D map of the protein complex

    “While this particular sample serves a specific function in the body, people may start to use this research as a model for how GPCRs, in general, can interact with signaling proteins,” Xu said. His team had been working toward this result since 2005.

    SLAC Director Chi-Chang Kao said of the research milestone, “This important work is a prime example of how SLAC’s unique combination of cutting-edge scientific capabilities, including its expertise in X-ray science and structural biology, are playing key roles in high-impact scientific discoveries.”

    Data Analysis Helps Fill in Missing Piece

    Qingping Xu, a scientist in the Joint Center for Structural Genomics at SLAC’s Stanford Synchrotron Radiation Lightsource who helped to solve the 3-D structure, said it took many hours of computer modeling and data analysis to help understand and refine its details.

    “This structure is especially important because it fills in a missing piece about protein-binding pathways for GPCRs,” he said. Even so, he noted that much work remains in determining the unique structures and docking mechanisms across the whole spectrum of GPCRs and associated signaling proteins.

    Eric Xu said his group hopes to conduct follow-up studies at LCLS with samples of GPCRs bound to different types of signaling proteins.

    In addition to scientists from SLAC, including LCLS and SSRL’s Joint Center for Structural Genomics, and the Van Andel Research Institute, the study also included researchers from: Arizona State University, University of Southern California, DESY lab’s Center for Free Electron Laser Science in Germany, National University of Singapore, New York Structural Biology Center, The Scripps Research Institute, University of California, Los Angeles, University of Toronto, Vanderbilt University, Beijing Computational Science Research Center in China, the University of Wisconsin-Milwaukee, Chinese Academy of Sciences, Paul Scherrer Institute in Switzerland, Trinity College in Ireland, University of Chicago, University of Konstanz in Germany, Chinese Academy of Sciences, Center for Ultrafast Imaging in Germany, and University of Toronto.

    See the full article here.

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    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 4:42 pm on October 21, 2014 Permalink | Reply
    Tags: , , Biochemistry, ,   

    From astrobio.net: “Scientists create possible precursor to life” 

    Astrobiology Magazine

    Astrobiology Magazine

    Oct 21, 2014
    University of Southern Denmark
    Contact Professor, Head of FLINT Center, Steen Rasmussen. Email: steen@sdu.dk. Mobile: +45 60112507

    How did life originate? And can scientists create life? These questions not only occupy the minds of scientists interested in the origin of life, but also researchers working with technology of the future. If we can create artificial living systems, we may not only understand the origin of life – we can also revolutionize the future of technology.

    pro
    Model of a protocell. Image by Janet Iwasa

    Protocells are the simplest, most primitive living systems, you can think of. The oldest ancestor of life on Earth was a protocell, and when we see, what it eventually managed to evolve into, we understand why science is so fascinated with protocells. If science can create an artificial protocell, we get a very basic ingredient for creating more advanced artificial life.

    However, creating an artificial protocell is far from simple, and so far no one has managed to do that. One of the challenges is to create the information strings that can be inherited by cell offspring, including protocells. Such information strings are like modern DNA or RNA strings, and they are needed to control cell metabolism and provide the cell with instructions about how to divide.

    Essential for life

    If one daughter cell after a division has a slightly altered information (maybe it provides a slightly faster metabolism), they may be more fit to survive. Therefore it may be selected and an evolution has started.

    Now researchers from the Center for Fundamental Living Technology (FLINT), Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, describe in the journal Europhysics Letters, how they, in a virtual computer experiment, have discovered information strings with peculiar properties.

    Professor and head of FLINT, Steen Rasmussen, says: “Finding mechanisms to create information strings are essential for researchers working with artificial life.”

    auto
    An autocatalytic network is a network of molecules, which catalyze each other’s production. Each molecule can be formed by at least one chemical reaction in the network, and each reaction can be catalyzed by at least one other molecule in the network. This process will create a network that exhibits a primitive form of metabolism and an information system that replicates itself from generation to generation. Credit University of Southern Denmark.

    Steen Rasmussen and his colleagues know they face two problems:

    Firstly long molecular strings are decomposed in water. This means that long information strings “break” quickly in water and turn into many short strings. Thus it is very difficult to maintain a population of long strings over time.

    Secondly, it is difficult to make these molecules replicate without the use of modern enzymes, whereas it is easier to make a so-called ligation. A ligation is to connect any combination of two shorter strings into a longer string, assisted by another matching longer string. Ligation is the mechanism used by the SDU-researchers.

    “In our computer simulation – our virtual molecular laboratory – information strings began to replicate quickly and efficiently as expected. However, we were struck to see that the system quickly developed an equal number of short and long information strings and further that a strong pattern selection on the strings had occurred. We could see that only very specific information patterns on the strings were to be seen in the surviving strings. We were puzzled: How could such a coordinated selection of strings occur, when we knew that we had not programmed it. The explanation had to be found in the way the strings interacted with each other”, explains Steen Rasmussen.

    It is like society

    According to Steen Rasmussen, a so-called self-organizing autocatalytic network was created in the virtual pot, into which he and his colleagues poured the ingredients for information strings.

    “An autocatalytic network works like a community; each molecule is a citizen who interacts with other citizens and together they help create a society”, explains Steen Rasmussen.

    This autocatalytic set quickly evolved into a state where strings of all lengths existed in equal concentrations, which is not what is usually found. Further, the selected strings had strikingly similar patterns, which is also unusual.

    “We might have discovered a process similar to the processes that initially sparked the first life. We of course don’t know if life actually was created this way – but it could have been one of the steps. Perhaps a similar process created sufficiently high concentrations of longer information strings when the first protocell was created”, explains Steen Rasmussen.

    Basis for new technology

    The mechanisms underlying the formation and selection of effective information strings are not only interesting for the researchers who are working to create protocells. They also have value to researchers working with tomorrow’s technology, like they do at the FLINT Center.

    “We seek ways to develop technology that’s based on living and life-like processes. If we succeed, we will have a world where technological devices can repair themselves, develop new properties and be re-used. For example a computer made of biological materials poses very different – and less environmentally stressful – requirements for production and disposal”, says Steen Rasmussen.

    Ref: http://epljournal.edpsciences.org/articles/epl/abs/2014/14/epl16388/epl16388.html

    See the full article here.

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  • richardmitnick 2:18 pm on October 10, 2014 Permalink | Reply
    Tags: , Biochemistry, ,   

    From BNL: “Researchers Pump Up Oil Accumulation in Plant Leaves” 

    Brookhaven Lab

    October 7, 2014
    Karen McNulty Walsh, (631) 344-8350 or Peter Genzer, (631) 344-3174

    Increasing the oil content of plant biomass could help fulfill the nation’s increasing demand for renewable energy feedstocks. But many of the details of how plant leaves make and break down oils have remained a mystery. Now a series of detailed genetic studies conducted at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory and published in The Plant Cell reveals previously unknown biochemical details about those metabolic pathways—including new ways to increase the accumulation of oil in leaves, an abundant source of biomass for fuel production.

    Using these methods, the scientists grew experimental Arabidopsis plants whose leaves accumulated 9 percent oil by dry weight, which represents an approximately 150-fold increase in oil content compared to wild type leaves.

    “This is an unusually high level of oil accumulation for plant vegetative tissue,” said Brookhaven Lab biochemist Changcheng Xu, who led the research team. “In crop plants, whose growth time is longer, if the rate of oil accumulation is the same we could get much higher oil content—possibly as high as 40 percent by weight,” he said.

    And when it comes to growing plants for biofuels, packing on the calories is the goal, because energy-dense oils give more “bang per bushel” than less-energy-dense leaf carbohydrates.
    Deciphering biochemical pathways

    The key to increasing oil accumulation in these studies was to unravel the details of the biochemical pathways involved in the conversion of carbon into fatty acids, the storage of fatty acids as oil, and the breakdown of oil in leaves. Prior to this research, scientists did not know that these processes were so intimately related.

    “Our method resulted in an unusually high level of oil accumulation in plant vegetative tissue.”
    — Brookhaven Lab biochemist Changcheng Xu

    “We previously thought that oil storage and oil degradation were alternative fates for newly synthesized fatty acids—the building blocks of oils,” said Brookhaven biochemist John Shanklin, a collaborator on the studies.

    To reveal the connections, Brookhaven’s Jillian Fan and other team members used a series of genetic tricks to systematically disable an alphabet soup of enzymes—molecules that mediate a cell’s chemical reactions—to see whether and how each had an effect in regulating the various biochemical conversions. They also used radiolabeled versions of fatty acids to trace their paths and learn how quickly they move through the pathway. They then used the findings to map out how the processes take place inside different subcellular structures, some of which you might recognize from high school science classes: the chloroplast, endoplasmic reticulum, storage droplets, and the peroxisome.

    team
    Brookhaven researchers Jilian Fan, John Shanklin, and Changcheng Xu have developed a method for getting experimental plants to accumulate more leaf oil. Their strategy could have a significant impact on the production of biofuels.

    “Our goal was to test and understand all the components of the system to fully understand how fatty acids, which are produced in the chloroplasts, are broken down in the peroxisome,” Xu said.

    Key findings

    syn
    Details of the oil synthesis and breakdown pathways within plant leaf cells: Fatty acids (FA) synthesized within chloroplasts go through a series of reactions to be incorporated into lipids (TAG) within the endoplasmic reticulum (ER); lipid droplets (LD) store lipids such as oils until they are broken down to release fatty acids into the cytoplasm; the fatty acids are eventually transported into the peroxisome for oxidation. This detailed metabolic map pointed to a new way to dramatically increase the accumulation of oil in plant leaves — blocking the SDP1 enzyme that releases fatty acids from lipid droplets in plants with elevated fatty acid synthesis. If this strategy works in biofuel crops, it could dramatically increase the energy content of biomass used to make biofuels.

    The research revealed that there is no direct pathway for fatty acids to move from the chloroplasts to the peroxisome as had previously been assumed. Instead, many complex reactions occur within the endoplasmic reticulum to first convert the fatty acids through a series of intermediates into plant oils. These oils accumulate in storage droplets within the cytoplasm until another enzyme breaks them down to release the fatty acid building blocks. Yet another enzyme must transport the fatty acids into the peroxisome for the final stages of degradation via oxidation. The amount of oil that accumulates at any one time represents a balance between the pathways of synthesis and degradation.

    Some previous attempts to increase oil accumulation in leaves have focused on disrupting the breakdown of oils by blocking the action of the enzyme that transports fatty acids into the peroxisome. The reasoning was that the accumulation of fatty acids would have a negative feedback on oil droplet breakdown. High levels of fatty acids remaining in the cytoplasm would inhibit the further breakdown of oil droplets, resulting in higher oil accumulation.

    That idea works to some extent, Xu said, but the current research shows it has negative effects on the overall health of the plants. “Plants don’t grow as well and there can be other defects,” he said.

    Based on their new understanding of the detailed biochemical steps that lead to oil breakdown, Xu and his collaborators explored another approach—namely disabling the enzyme one step back in the metabolic process, the one that breaks down oil droplets to release fatty acids.

    “If we knock out this enzyme, known as SDP1, we get a large amount of oil accumulating in the leaves,” he said, “and without substantial detrimental effects on plant growth.”

    “This research points to a new and different way to accumulate oil in leaves from that being tried in other labs,” Xu said. “In addition, the strategy differs fundamentally from other strategies that are based on adding genes, whereas our strategy is based on disabling or inactivating genes through simple mutations. This work provides a very promising platform for engineering oil production in a non-genetically modified way.”

    “This work provides another example of how research into basic biochemical mechanisms can lead to knowledge that has great promise to help solve real world problems,” concluded Shanklin.

    This research was conducted by Xu in collaboration with Jilian Fan and Chengshi Yan and John Shanklin of Brookhaven’s Biosciences Department, and Rebecca Roston, now at the University of Nebraska, Lincoln. The work was funded by the DOE Office of Science and made use of a confocal microscope at Brookhaven Lab’s Center for Functional Nanomaterials, a DOE Office of Science user facility.

    See the full article here.

    BNL Campus

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
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  • richardmitnick 10:11 pm on September 25, 2014 Permalink | Reply
    Tags: , Biochemistry, ,   

    From NOVA: “Genetically Engineering Almost Anything” 

    PBS NOVA

    NOVA

    Thu, 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.

    dna repair
    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.”
    “There’s a lot to be done still, but on the scale of years, not months or decades.”

    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.

    gene drive
    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%.

    gene drive
    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. 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.
    “What is to stop us from potentially doing it for almost anything that is sexually reproducing?”

    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.
    There’s little in the way of precedent that we can use as a guide.

    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.

    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.

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  • richardmitnick 7:25 am on September 25, 2014 Permalink | Reply
    Tags: , Biochemistry,   

    From DG: “Electricity at the Quantum Level -‘Played a Strong Role in the Creation of Life'” 

    Daily Galaxy
    The Daily Galaxy

    September 23, 2014
    No Writer Credit

    In 1953, American chemist Stanley Miller had famously electrified a mixture of simple gas and water to simulate lightning and the atmosphere of early Earth. The revolutionary experiment—which yielded a brownish soup of amino acids—offered a simple potential scenario for the origin of life’s building blocks. Miller’s work gave birth to modern research on pre-biotic chemistry and the origins of life.

    fire

    For the past 60 years, scientists have investigated other possible energy sources for the formation of life’s building blocks, including ultra violet light, meteorite impacts, and deep sea hydrothermal vents. Now. for the first time, researchers have reproduced the results of the [Stanley] Miller-[Harold] Urey experiment in a computer simulation, yielding new insight into the effect of electricity on the formation of life’s building blocks at the quantum level.

    In this new study, Antonino Marco Saitta, of the Université Pierre et Marie Curie, Sorbonne, in Paris, France and his colleagues wanted to revisit Miller’s result with electric fields, but from a quantum perspective. Saitta and study co-author Franz Saija, two theoretical physicists, had recently applied a new quantum model to study the effects of electric fields on water, which had never been done before. After coming across a documentary on Miller’s work, they wondered whether the quantum approach might work for the famous spark-discharge experiment.

    The method would also allow them to follow individual atoms and molecules through space and time—and perhaps yield new insight into the role of electricity in Miller’s work.

    “The spirit of our work was to show that the electric field is part of it,” Saitta said, “without necessarily involving lightning or a spark.”

    As in the original Miller experiment, Saitta and Saija subjected a mixture of molecules containing carbon, nitrogen, oxygen and hydrogen atoms to an electric field. As expected, the simulation yielded glycine, an amino acid that is one of the simplest building blocks for proteins, and one the most abundant products in the original Miller experiment.

    A typical intermediate in the formation of amino acids is the small molecule formaldehyde.
    Formaldehyde – A typical intermediate in the formation of amino acids.

    But their approach also yielded some unexpected results. In particular, their model suggested that the formation of amino acids in the Miller scenario might have occurred via a more complex chemical pathway than previously thought.

    A typical intermediate in the formation of amino acids is the small molecule formaldehyde. But their simulation showed that when subjected to an electric field, the reaction favored a different intermediate, the molecule formamide.

    It turns out, formamide could have not only played a crucial role in the formation of life’s building blocks on Earth, but also elsewhere.

    “We weren’t looking for it, or expecting it,” Saitta said. “We only learned after the fact, by reviewing the scientific literature, that it’s an important clue in prebiotic chemistry.”

    For instance, formamide has recently been shown to be a key ingredient in making some of the building blocks of RNA, notably guanine, in the presence of ultra violet light.

    Formamide has also recently been observed in space—notably in a comet and in a solar-type proto star. Earlier research has also shown that formamide can form when comets or asteroids impact the Earth.

    “The possibility of new routes to make amino acids without a formaldehyde intermediate is novel and gaining ground, especially in extraterrestrial contexts,” the authors wrote. “The presence of formamide might be a most telling fingerprint of abiotic terrestrial and extraterrestrial amino acids.”

    However, Jeff Bada, who was a graduate student of Miller’s in the 1960s and spent his career working of the origin of life, remains skeptical about their results and theoretical approach. “Their model might not meaningfully represent what happens in a solution,” he says. “We know there’s a lot of formaldehyde made in the spark discharge experiment. I don’t think the formamide reaction would be significant in comparison to the traditional reaction.”

    But Saitta points out that formamide is very unstable, so it may not last long enough to be observed in real Miller experiments. “In our simulation, formamide always formed spontaneously. And it was some sort of crucible—it would either break up into water and hydrogen cyanide, or combine with other molecules and form the amino acid glycine.”

    Another key insight from their study is that the formation of some of life’s building blocks may have occurred on mineral surfaces, since most have strong natural electric fields.

    “The electric field of mineral surfaces can be easily 10 or 20 times stronger than the one in our study,” Saitta said. “The problem is that it only acts on a very short range. So to feel the effects, molecules would have to be very close to the surface.”

    “I think that this work is of great significance,” said François Guyot, a geochemist at the French Museum of Natural History. “Regarding the mineral surfaces, strong electric fields undoubtedly exist at their immediate proximity. And because of their strong role on the reactivity of organic molecules, they might enhance the formation of more complex molecules by a mechanism distinct from the geometrical concentration of reactive species, a mechanisms often proposed when mineral surfaces are invoked for explaining the formation of the first biomolecules.”

    One of the leading hypotheses in the field of life’s origin suggests that important prebiotic reactions may have occurred on mineral surfaces. But so far scientists don’t fully understand the mechanism behind it. “Nobody has really looked at electric fields on mineral surfaces,” Saitta said. “My feeling is that there’s probably something to explore there.”

    Their results are published this week in the scientific journal Proceedings of the National Academy of Sciences.

    See the full article here.

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    • Atul Gupta 9:15 am on September 25, 2014 Permalink | Reply

      Adding on, I think I read this in Hawking’s book, life as we know it is organic, but maybe at some other location or conditions in the universe, life didn’t have to depend on Oxygen, maybe there were other forms of life that didn’t need Earth like conditions!

      -Metaphysicien

      Like

  • richardmitnick 3:46 pm on September 23, 2014 Permalink | Reply
    Tags: , Biochemistry,   

    From SLAC: “Research Pinpoints Role of ‘Helper’ Atoms in Oxygen Release” 


    SLAC Lab

    September 22, 2014

    System Studied at SLAC’s Synchrotron Mimics Steps in Photosynthesis

    Experiments at the Department of Energy’s SLAC National Accelerator Laboratory solve a long-standing mystery in the role calcium atoms serve in a chemical reaction that releases oxygen into the air we breathe. The results offer new clues about atomic-scale processes that drive the life-sustaining cycle of photosynthesis and could help forge a foundation for producing cleaner energy sources by synthesizing nature’s handiwork.

    The research is detailed in a paper published Sept. 14 in Nature Chemistry. X-ray experiments at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science User Facility, played a key role in the study, led by Wonwoo Nam at Ewha Womans University in Korea in a joint collaboration with Riti Sarangi, an SSRL staff scientist.

    SLAC SSRL
    SLAC SSRL

    “For the first time, we show how calcium can actually tune this oxygen-releasing reaction in subtle but precise ways,” said Sarangi, who carried out the X-ray work and supporting computer simulations and calculations. “The study helps us resolve the question, ‘Why does nature choose calcium?'”

    Photosynthesis is one of many important biological processes that rely on proteins with metal-containing centers, such as iron or manganese. The chemistry carried out in such centers is integral to their function. Scientists have known that the presence of calcium is necessary for the oxygen-releasing stages of photosynthesis, but they didn’t know how or why.

    The SSRL experiment used a technique known as X-ray absorption spectroscopy to explore the chemical and structural details of sample systems that mimic of the oxygen-releasing steps in photosynthesis. The basic oxygen-releasing system contained calcium and was centered around an iron atom.

    Researchers found that charged atoms, or ions, of calcium and another element, strontium, bind to the oxygen atoms in a way that precisely tunes the chemical reaction at the iron center. This, in turn, facilitates the bond formation between two oxygen atoms. The study also revealed that calcium and strontium do not obstruct the release of these bound oxygen atoms into the air as an oxygen molecule — the final step in this reaction.

    “We saw that unless you use calcium or strontium, this sample system will not release oxygen,” Sarangi said. “Calcium and strontium bind at just the right strength to facilitate the oxygen release. Anything that binds too strongly would impede that step.”

    While the sample system studied is not biological, the chemistry at work is considered a very good analogue for the oxygen-releasing steps carried out in photosynthesis, she said, and could assist in constructing artificial systems that replicate these steps. The next step will be to study more complex samples that perform more closely to the actual chemistry in photosynthesis.

    Other participants in this research were from Osaka University in Japan and the Japan Science Technology Agency. The research was supported by the National Research Foundation of Korea and the Ministry of Education, Culture, Sports, Science and Technology in Japan. SSRL’s Structural Molecular Biology program is supported by the National Institutes of Health and the Office of Biological and Environmental Research of the U.S. Department of Energy.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 3:24 pm on September 23, 2014 Permalink | Reply
    Tags: , Biochemistry, ,   

    From Sandia Lab: “Sandia researchers find clues to superbug evolution” 


    Sandia Lab

    September 23, 2014
    Patti Koning, pkoning@sandia.gov, (925) 294-4911

    Imagine going to the hospital with one disease and coming home with something much worse, or not coming home at all.

    With the emergence and spread of antibiotic-resistance pathogens, healthcare-associated infections have become a serious threat. On any given day about one in 25 hospital patients has at least one such infection and as many as one in nine die as a result, according to the Centers for Disease Control and Prevention.

    Consider Klebsiella pneumoniae, not typically a ferocious pathogen, but now armed with resistance to virtually all antibiotics in current clinical use. It is the most common species of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. As carbapenems are considered the antibiotic of last resort, CREs are a triple threat for their resistance to nearly all antibiotics, high mortality rates and ability to spread their resistance to other bacteria.

    But there is hope. A team of Sandia National Laboratories microbiologists for the first time recently sequenced the entire genome of a Klebsiella pneumoniae strain, encoding New Delhi Metallo-beta-lactamase (NDM-1). They presented their findings in a paper published in PLOS One, Resistance Determinants and Mobile Genetic Elements of an NDM-1 Encoding Klebsiella pneumoniae Strain.

    image
    Sandia National Laboratories’ researchers Kelly Williams, left, and Corey Hudson look at the mosaic pattern of one of the Klebsiella pneumoniae plasmids and discuss mechanisms that mobilize resistance genes. (Photo by Dino Vournas)

    The Sandia team of Corey Hudson, Zach Bent, Robert Meagher and Kelly Williams is beginning to understand the bacteria’s multifaceted mechanisms for resistance. To do this, they developed several new bioinformatics tools for identifying mechanisms of genetic movement, tools that also might be effective at detecting bioengineering.

    “Once we had the entire genome sequenced, it was a real eye opener to see the concentration of so many antibiotic resistant genes and so many different mechanisms for accumulating them,” explained Williams, a bioinformaticist. “Just sequencing this genome unlocked a vault of information about how genes move between bacteria and how DNA moves within the chromosome.”

    Meagher first worked last year with Klebsiella pneumoniae ATCC BAA-2146 (Kpn2146), the first U.S. isolate found to encode NDM-1. Along with E.coli, it was used to test an automatic sequencing library preparation platform for the RapTOR Grand Challenge, a Sandia project that developed techniques to allow discovery of pathogens in clinical samples.

    “I’ve been interested in multi-drug-resistant organisms for some time. The NDM-1 drug resistance trait is spreading rapidly worldwide, so there is a great need for diagnostic tools,” said Meagher. “This particular strain of Klebsiella pneumoniae is fascinating and terrifying because it’s resistant to practically everything. Some of that you can explain on the basis on NDM-1, but it’s also resistant to other classes of antibiotics that NDM-1 has no bearing on.”

    Unlocking Klebsiella pneumoniae

    Assembling an entire genome is like putting together a puzzle. Klebsiella pneumoniae turned out to have one large chromosome and four plasmids, small DNA molecules physically separate from and able to replicate independently of the bacterial cell’s chromosomal DNA. Plasmids often carry antibiotic resistant genes and other defense mechanisms.

    The researchers discovered their Klebsiella pneumoniae bacteria encoded 34 separate enzymes of antibiotic resistance, as well as efflux pumps that move compounds out of cells, and mutations in chromosomal genes that are expected to confer resistance. They also identified several mechanisms that allow cells to mobilize resistance genes, both within a single cell and between cells.

    “Each one of those genes has a story: how it got into this bacteria, where it has been, and how it has evolved,” said Williams.

    Necessity leads to development of new tools

    Klebsiella pneumoniae uses established mechanisms to move genes, such as “jumping genes” known as transposons, and genomic islands, mobile DNA elements that enable horizontal gene transfer between organisms. However, the organism has so many tricks and weapons that the research team had to go beyond existing bioinformatics tools and develop new ways of identifying mechanisms of genetic movement.

    Williams and Hudson detected circular forms of transposons in movement, which has never been shown this way, and discovered sites within the genome undergoing homologous recombination, another gene mobilization mechanism. By applying two existing bioinformatics methods for detecting genomic islands, they found a third class of islands that neither method alone could have detected.

    “To some extent, every extra piece of DNA that a bacteria acquires comes at some cost, so the bacteria doesn’t usually hang onto traits it doesn’t need,” said Hudson. “The further we dug down into the genome, the more stories we found about movement within the organism and from other organisms and the history of insults, like antibiotics, that it has faced. This particular bacteria is just getting nastier over time.”

    Applying findings to future work

    The findings are being applied to a Laboratory Directed Research and Development project led by Sandia microbiologist Eric Carnes, who is examining alternative approaches for treating drug-resistant organisms. “Instead of traditional antibiotics, we use a sequence-based approach to silence expression of drug-resistant genes,” said Meagher.

    The researchers also are applying their understanding of Klebsiella pneumoniae’s mechanisms of resistance and their new bioinformatics tools to developing diagnostic tools to detect bioengineering. Looking across 10 related but distinct strains of Klebsiella pneumoniae, they pinpointed regions that were new to their strain, and so indicate genetic movement.

    “By studying the pattern of movement, we can better characterize a natural genomic island,” said Hudson. “This leads down the path of what does an unnatural island look like, which is an indication of bioengineering. We hope to apply the knowledge we gained from sequencing Klebsiella pneumoniae to developing diagnostic tools that could detect bioengineering.”

    See the full article here.

    Sandia National Laboratories is a multiprogram laboratory operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy’s National Nuclear Security Administration. With main facilities in Albuquerque, N.M., and Livermore, Calif., Sandia has major R&D responsibilities in national security, energy and environmental technologies, and economic competitiveness.
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