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  • richardmitnick 5:18 pm on August 13, 2016 Permalink | Reply
    Tags: , Biology, , , ,   

    From Rosetta@home: “Designed Protein Containers Push Bioengineering Boundaries” 

    Rosetta@home

    Rosetta@home

    Rosetta@home has posted in their forum a new (July 21, 2016) article, Designed Protein Containers Push Bioengineering Boundaries
    from U Washington’s Institute for Protein Design which I highly recommend for anyone interested in Protein Studies.

    3

    This forum article cites Designed Protein Containers Push Bioengineering Boundariess which goes on to cite Icosahedral protein nanocage – new paper and podcast published in Nature, and “Accurate design of megadalton-scale multi-component icosahedral protein complexes”, published in Science.

    Of this second paper, they write, “In this paper, former Baker lab graduate student Jacob Bale, Ph.D. and collaborators describe the computational design and experimental characterization of ten two-component protein complexes that self-assemble into nanocages with atomic-level accuracy. These nanocages are the largest designed proteins to date with molecular weights of 1.8-2.8 megadaltons and diameters comparable to small viral capsids. The structures have been confirmed by X-ray crystallography (see figure). The advantage of a multi-component protein complex is the ability to control assembly by mixing individually prepared subunits. The authors show that in vitro mixing of the designed subunits occurs rapidly and enables controlled packaging of negatively charged GFP by introducing positive charges on the interior surfaces of the two copmonents.

    The ability to design, with atomic-level precision, these large protein nanostructures that can encapsulate biologically relevant cargo and that can be genetically modified with various functionalities opens up exciting new opportunities for targeted drug delivery and vaccine design.”

    Also referenced in the forum is an article in Science, Jul. 21, 2016 by Robert F. Service This protein designer aims to revolutionize medicines and materials, about Dr David Baker.

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    From this Science article, David Baker shows off models of some of the unnatural proteins his team has designed and made.© Rich Frishman

    included also is this video from Science.

    See the full article here.

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    Rosetta@home needs your help to determine the 3-dimensional shapes of proteins in research that may ultimately lead to finding cures for some major human diseases. By running the Rosetta program on your computer while you don’t need it you will help us speed up and extend our research in ways we couldn’t possibly attempt without your help. You will also be helping our efforts at designing new proteins to fight diseases such as HIV, Malaria, Cancer, and Alzheimer’s (See our Disease Related Research for more information). Please join us in our efforts! Rosetta@home is not for profit.

    About Rosetta

    One of the major goals of Rosetta is to predict the shapes that proteins fold up into in nature. Proteins are linear polymer molecules made up of amino acid monomers and are often refered to as “chains.” Amino acids can be considered as the “links” in a protein “chain”. Here is a simple analogy. When considering a metal chain, it can have many different shapes depending on the forces exerted upon it. For example, if you pull its ends, the chain will extend to a straight line and if you drop it on the floor, it will take on a unique shape. Unlike metal chains that are made of identical links, proteins are made of 20 different amino acids that each have their own unique properties (different shapes, and attractive and repulsive forces, for example), and in combination, the amino acids exert forces on the chain to make it take on a specific shape, which we call a “fold.” The order in which the amino acids are linked determines the protein’s fold. There are many kinds of proteins that vary in the number and order of their amino acids.

    To predict the shape that a particular protein adopts in nature, what we are really trying to do is find the fold with the lowest energy. The energy is determined by a number of factors. For example, some amino acids are attracted to each other so when they are close in space, their interaction provides a favorable contribution to the energy. Rosetta’s strategy for finding low energy shapes looks like this:

    Start with a fully unfolded chain (like a metal chain with its ends pulled).
    Move a part of the chain to create a new shape.
    Calculate the energy of the new shape.
    Accept or reject the move depending on the change in energy.
    Repeat 2 through 4 until every part of the chain has been moved a lot of times.

    We call this a trajectory. The end result of a trajectory is a predicted structure. Rosetta keeps track of the lowest energy shape found in each trajectory. Each trajectory is unique, because the attempted moves are determined by a random number. They do not always find the same low energy shape because there are so many possibilities.

    A trajectory may consist of two stages. The first stage uses a simplified representation of amino acids which allows us to try many different possible shapes rapidly. This stage is regarded as a low resolution search and on the screen saver you will see the protein chain jumping around a lot. In the second stage, Rosetta uses a full representation of amino acids. This stage is refered to as “relaxation.” Instead of moving around a lot, the protein tries smaller changes in an attempt to move the amino acids to their correct arrangment. This stage is regarded as a high resolution search and on the screen saver, you will see the protein chain jiggle around a little. Rosetta can do the first stage in a few minutes on a modern computer. The second stage takes longer because of the increased complexity when considering the full representation (all atoms) of amino acids.

    Your computer typically generates 5-20 of these trajectories (per work unit) and then sends us back the lowest energy shape seen in each one. We then look at all of the low energy shapes, generated by all of your computers, to find the very lowest ones. This becomes our prediction for the fold of that protein.

    To join this project, download and install the BOINC software on which it runs. Then attach to the project. While you are at BOINC, look at some of the other projects to see what else might be of interest to you.

    Rosetta screensaver

    BOINC

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  • richardmitnick 11:50 am on August 12, 2016 Permalink | Reply
    Tags: , Biology, , , Todd Hyster   

    From Princeton: “Professor explores new territory by bridging chemistry, biology” 

    Princeton University
    Princeton University

    August 11, 2016
    Tien Nguyen, Department of Chemistry

    In any given year, a synthetic chemist may set up several hundred chemical reactions. Many of these reactions will fail, so chemists temper their expectations.

    But not Todd Hyster, a Princeton University assistant professor who joined the Department of Chemistry last summer.

    1
    Todd Hyster (right), a Princeton University assistant professor of chemistry, focuses his research on novel reactions in an area just emerging among American chemists — the merger of classic organic synthesis and biocatalysis. As one of the few synthetic chemists who understands biological systems, he is uniquely equipped to identify the reactions that would be most impactful for organic synthesis and make them happen. He encourages researchers in his lab, such as chemistry graduate student Braddock Sandoval (left), to harness chemistry and biology to bring about seemingly unlikely reactions. (Photos by C. Todd Reichart, Department of Chemistry)

    “Todd gets really excited about these crazy ideas and he’s always confident that it’s going to work, even if we think it’s a long shot,” said Braddock Sandoval, a graduate researcher in Hyster’s lab.

    Hyster focuses his research on novel reactions at the merger of two areas in which he has extensive experience: classic organic synthesis, which uses small molecules that perform an expansive range of reactions, and biocatalysis, which uses large biological systems such as enzymes to execute only specific reactions, but does so very efficiently. Researchers at the intersection of these fields propose to modify powerful enzymes so that they can be used in more organic reactions.

    The majority of the work in this area has come from biology labs that are well acquainted with wrangling complex biological systems, but the field hasn’t seen the same level of engagement from chemists, especially in the United States. Essentially, chemists can have difficulty dealing with biological systems because they must learn how to grow cells and work with complicated enzymes. Yet, biologists may not know which of the thousands of possible reactions organic chemists would find most valuable and useful.

    Hyster, however, can do both. As one of the few synthetic chemists who also understands biological systems, he is uniquely equipped to identify the reactions that would be most impactful for organic synthesis and make them happen.

    “Todd has the ability to connect these enzymes to reaction mechanisms people aren’t even thinking about,” said David MacMillan, the James S. McDonnell Distinguished University Professor of Chemistry at Princeton. “He’s at the vanguard of something new in biocatalysis and I think it’s going to be incredibly exciting.”

    Building up to biocatalysis

    As a graduate student under the direction of Tomislav Rovis at Colorado State University, Hyster began research in transition-metal catalysis and, at the time, wanted nothing to do with biology. “I remember saying that I was ‘repulsed’ by biology,” Hyster said with a laugh, “probably one of the most naïve things I’ve ever said.”

    It wasn’t until his third year of graduate school that his attitude began to shift. He became intrigued by a conference presentation on using mutated proteins to catalyze a specific reaction and even chose the general topic — directed evolution — for his departmental seminar. Then Rovis went on sabbatical in France and presented Hyster with the opportunity to collaborate with a research group working at the interface of biology and organometallic chemistry at the University of Basel in Switzerland, opening a new area of research for the Rovis lab in biocatalysis.

    Rovis recalled emailing Hyster late at night from Europe to pitch him the collaboration idea. The usual strategy to improve the reaction is to change the small molecule known as the ligand. Instead, Rovis suggested keeping the ligand constant and changing the reaction environment using a biological system developed by the group in Basel. Hyster replied the next morning that he loved the idea and was game to try it.

    “He’s someone who had the vision to see the real impact and potential of the idea, and who certainly doesn’t pay attention at all to how hard it might be. That’s the kind of researcher he is,” Rovis said.

    In order to make the collaboration work, Hyster spent four months in Basel in Professor of Chemistry Thomas Ward’s laboratory learning how to work with proteins, ultimately bringing those skills back to the lab in Colorado.

    “His fearlessness is his best quality,” Rovis said. “It’s what allowed him to embrace this new field that he had no prior experience with and successfully tackle the problem.”

    The resulting work — published in the journal Science in 2012 — was the first example of a biological environment that could be engineered to promote the formation of new bonds. The reaction took advantage of the extremely strong binding affinity between the large protein streptavidin and the compound biotin, which is referred to as “molecular Velcro.” By attaching the ligand-metal complex to biotin, the researchers could lock the metal catalyst into the highly controlled binding pocket of streptavidin.

    For his postdoctoral study, Hyster began to shift his focus onto biocatalysis. He joined the laboratory of one of the pioneers of biocatalysis, Frances Arnold, professor of chemical engineering, bioengineering and biochemistry at the California Institute of Technology.

    In a 2014 paper published in the Journal of the American Chemical Society during his time in the Arnold lab, Hyster developed variants of the enzyme P450 — one of the most well-known enzymes that break down organic molecules in the liver — to catalyze a particularly unfavorable bond connection. In this type of reaction, known as an amination reaction, the catalyst typically breaks the weakest existing carbon-hydrogen bond to form the new bond. The specially designed P450 mutant, however, adopts a specific shape that favors the bond disconnection at the neighboring carbon, giving the researchers access to a reaction that would be difficult to accomplish by organic catalysis.

    Focusing on the puzzles

    At Princeton, Hyster is applying what he learned from his time in Rovis’ and Arnold’s labs in terms of both the science and mentorship. Their relaxed styles and flexibility in letting students follow their own interests were really effective, he said, and he hopes to emulate them.

    Hyster is hands-off, but always available to answer questions, Sandoval said. The whole group works long hours in the lab and is eager to establish themselves in the research community. Hyster is very driven, Sandoval said, and his confidence and excitement for the work has inspired them to set up reactions that they may not have tried otherwise.

    “If you pursue what you’re most passionate about, I think that’s when you can do your greatest possible amount of good,” Hyster said. Pursuing his own passion is already starting to pay off. Since starting up less than a year ago, the Hyster lab is already preparing to publish research about an enzyme-mediated light-based reaction that hasn’t been seen before.

    Though pleased about these initial successes, for Hyster, the real satisfaction comes from the research process.

    “I just like thinking about these problems. When I wake up, at home, all the time, it’s what I enjoy thinking about and that’s rewarding enough for me,” Hyster said. “It’s just an added bonus that these reactions might be valuable.”

    See the full article here .

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    Princeton University Campus

    About Princeton: Overview

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

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

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

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  • richardmitnick 1:43 pm on August 9, 2016 Permalink | Reply
    Tags: , Biology, ,   

    From Hopkins: ” Brain’s ‘physics engine’ allows us to catch, dodge, and react on the fly” 

    Johns Hopkins
    Johns Hopkins University

    8.8.16
    Jill Rosen


    Video: Len Turner

    Researchers find brain region that helps us predict how the world around us will behave

    Whether or not they aced the subject in high school, human beings are physics masters when it comes to understanding and predicting how objects in the world will behave. A Johns Hopkins University cognitive scientist has found the source of that intuition, the brain’s “physics engine.”

    This engine, which comes alive when people watch physical events unfold, is not in the brain’s vision center, but in a set of regions devoted to planning actions, suggesting the brain performs constant, real-time physics calculations so people are ready to catch, dodge, hoist, or take any necessary action, on the fly. The findings, which could help scientists design more nimble robots, are set to be published this week in the journal Proceedings of the National Academy of Sciences.

    “We run physics simulations all the time to prepare us for when we need to act in the world,” said lead author Jason Fischer, an assistant professor of psychological and brain sciences in JHU’s Krieger School of Arts and Sciences. “It is among the most important aspects of cognition for survival. But there has been almost no work done to identify and study the brain regions involved in this capability.”

    Fischer, along with researchers at Massachusetts Institute of Technology, conducted a series of experiments to find the parts of the brain involved in physical inference. First they had 12 subjects look at videos of Jenga-style block towers. While monitoring brain activity, the team asked the subjects either to predict where the blocks would land should the tower topple, or guess if the tower had more blue or yellow blocks. Predicting the direction of falling blocks involved physics intuition, while the color question was merely visual.

    Next, the team had other subjects watch a video of two dots bouncing around a screen. They asked subjects to predict the next direction the dots would head, based either on physics or social reasoning.

    With both the blocks and dots, the team found, when subjects attempted to predict physical outcomes, the most responsive brain regions included the premotor cortex and the supplementary motor area—the brain’s action planning areas.

    “Our findings suggest that physical intuition and action planning are intimately linked in the brain,” Fischer said. “We believe this might be because infants learn physics models of the world as they hone their motor skills, handling objects to learn how they behave. Also, to reach out and grab something in the right place with the right amount of force, we need real-time physical understanding.”

    In the last part of the experiment, the team asked subjects to look at short movie clips—just to look; they received no other instructions—while having their brain activity monitored. Some of the clips had a lot of physics content, others very little. The team found that the more physical content in a clip, the more the key brain regions activated.

    “The brain activity reflected the amount of physical content in a movie, even if people weren’t consciously paying attention to it,” Fischer said. “This suggests that we are making physical inferences all the time, even when we’re not thinking about it.”

    The findings could offer insight into movement disorders such as apraxia, as it’s very possible that people with damage to the motor areas of the brain also have what Fischer calls “a hidden impairment”—trouble making physical judgments.

    A better understanding of how the brain runs physics calculations might also enrich robot design. A robot built with a physics model, constantly running in its programming almost like a video game, could navigate the world more fluidly, Fischer said.

    See the full article here .

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    Johns Hopkins Campus

    The Johns Hopkins University opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”

    The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”

    What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.

     
  • richardmitnick 6:48 am on July 29, 2016 Permalink | Reply
    Tags: , Biology, , , Team of Proteins Works Together to Turn on T Cells   

    From Caltech: “Team of Proteins Works Together to Turn on T Cells” 

    Caltech Logo

    Caltech

    07/15/2016
    Whitney Clavin
    (626) 395-1856
    wclavin@caltech.edu

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    Researchers imaged cells to identify proteins that affect the expression of a genetic switch for T cells. On the right, T cells where the switch is activated glow in yellow. On the left, the rainbow pattern, a hierarchical cluster analysis, tells researchers which genes are controlled by the switch. The horizontal stripes are the genes. If they stripes turn red going from left to right, it means they are turning on; if they turn blue, the genes are turning off. Credit: Caltech

    The fates of various cells in our bodies—whether they become skin or another type of tissue—are controlled by genetic switches. In a new study, Caltech scientists investigate the switch for T cells, which are immune cells produced in the thymus that destroy virus-infected cells and cancers. The researchers wanted to know how cells make the choice to become T cells.

    “We already know which genetic switch directs cells to commit to becoming T cells, but we wanted to figure out what enables that switch to be turned on,” says Hao Yuan Kueh, a postdoctoral scholar at Caltech and lead author of a Nature Immunology report about the work, published on July 4.

    The study found that a group of four proteins, specifically DNA-binding proteins known as transcription factors, work in a multi-tiered fashion to control the T-cell genetic switch in a series of steps. This was a surprise because transcription factors are widely assumed to work in a simultaneous, all-at-once fashion when collaborating to regulate genes.

    The results may ultimately allow doctors to boost a person’s T-cell population. This has potential applications in fighting various diseases, including AIDS, which infects mature T cells.

    “In the past, combinatorial gene regulation was thought to involve all the transcription factors being required at the same time,” says Kueh, who works in the lab of Ellen Rothenberg, Caltech’s Albert Billings Ruddock Professor of Biology. “This was particularly true in the case of the genetic switch for T-cell commitment, where it was thought that a quorum of the factors working simultaneously was needed to ensure that the gene would only be expressed in the right cell type.”

    The authors report that a key to their finding was the ability to image live cells in real-time. They genetically engineered mouse cells so that a gene called Bcl11b—the key switch for T cells—would express a fluorescent protein in addition to its own Bcl11b protein. This caused the mouse cells to glow when the Bcl11b gene was turn on. By monitoring how different transcription factors, or proteins, affected the activation of this genetic switch in individual cells, the researchers were able to isolate the distinct roles of the proteins.

    The results showed that four proteins work together in three distinct steps to flip the switch for T cells. Kueh says to think of the process as a team of people working together to get a light turned on. He says first two proteins in the chain (TCF1 and GATA3) open a door where the main light switch is housed, while the next protein (Notch) essentially switches the light on. A fourth protein (Runx1) controls the amplitude of the signal, like sliding a light dimmer.

    “We identify the contributions of four regulators of Bcl11b, which are all needed for its activation but carry out surprisingly different functions in enabling the gene to be turned on,” says Rothenberg. “It’s interesting—the gene still needs the full quorum of transcription factors, but we now find that it also needs them to work in the right order. This makes the gene respond not only to the cell’s current state, but also to the cell’s recent developmental history.”

    Team member Kenneth Ng, a visiting student from California Polytechnic State University, says he was surprised by how much detail they could learn about gene regulation using live imaging of cells.

    “I had read about this process in textbooks, but here in this study we could pinpoint what the proteins are really doing,” he says.

    The next step in the research is to get a closer look at precisely how the T cell genetic switch itself works. Kueh says he wants to “unscrew the panels” of the switch and understand what is physically going on in the chromosomal material around the Bcl11b gene.

    The Nature Immunology paper, titled, Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment, includes seven additional Caltech coauthors: Mary Yui, Shirley Pease, Jingli Zhang, Sagar Damle, George Freedman, Sharmayne Siu, and Michael Elowitz; as well as a collaborator at the Fred Hutchinson Cancer Research Center, Irwin Bernstein. The work at Caltech was funded by a CRI/Irvington Postdoctoral Fellowship, the National Institutes of Health, the California Institute for Regenerative Medicine, the Al Sherman Foundation, and the Louis A. Garfinkle Memorial Laboratory Fund.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 5:44 am on July 23, 2016 Permalink | Reply
    Tags: , Biology, ,   

    From U Wisconsin: “New UW-Madison center offers ultra-speed protein analysis” 

    U Wisconsin

    University of Wisconsin

    July 22, 2016
    David Tenenbaum
    djtenenb@wisc.edu

    1
    UW-Madison undergraduate Kyle Connors operates a mass spectrometer in the new NIH National Center for Quantitative Biology at UW–Madison. Photo: Nick Wilkes

    Three University of Wisconsin—Madison researchers have won a prestigious, five-year grant to establish the National Center for Quantitative Biology of Complex Systems, which will develop next-generation protein measurement technologies and offer them to biologists nationwide.

    It is proteins that do the work in the body: Hemoglobin, for example, holds oxygen for transport in the blood stream, while insulin helps regulate sugar in the blood. Knowing which protein forms are present in what quantities, their subcellular location and their function is critical to understanding health and disease.

    The scientific technique of mass spectrometry, or mass spec, can already recognize proteins, but the researchers are eying a speed-up akin to that which revolutionized genetics research over the past 20 years.

    Genes are vital carriers of information and templates for proteins, says co-investigator David Pagliarini, a UW–Madison professor of biochemistry. But genes alone don’t explain everything.

    There is lot of action between the gene, the protein it patterns, and the actual biological result,” he explains. “Mass spec technology allows you to measure the proteins, which are closer to action, and we plan to push the limits on pace, depth, throughput.”

    The center, funded at $6 million by the National Institutes of Health (NIH), will develop and make available advanced protein measurement technologies, says Josh Coon, a UW–Madison professor of biomolecular chemistry and an expert in mass spec. “These are complicated, high-end instruments that hundreds or thousands of biomedical researchers who are funded by the NIH need access to. There are many problems that are not solved with current technology, and that high-throughput mass spec can address.”

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    A modified orbitrap mass spectrometer in the Coon Laboratory. The modifications illuminate trapped protein ions with infrared photons, providing the basis of a new protein sequencing technology. Photo: Nick Wilkes

    Two among the many areas of interest concern lung cancer and diabetes, Coon says. “We have researchers who want to examine proteins related to the function — or failure — of the pancreatic cells that make insulin.”

    The center will serve as a training ground in mass spec and a laboratory to invent new techniques and equipment. One tactic to be explored relies on parallel processing, an approach like the one that fed a revolution in gene sequencing.

    Co-investigator Lingjun Li, a UW–Madison professor of pharmacy, will develop chemical markers to identify individual samples after they are mixed for mass spec analysis. In a similar vein, Coon will explore “metabolic tags” composed of amino acids that enter proteins after being eaten by lab animals.

    “We are not developing technology in a vacuum,” says Li, “but with specific biomedical needs in mind. Our methods will be broadly available to NIH researchers, and they will be the test bed that validates our methods.”

    Pagliarini says he will serve as “a bridge between technology development and biological applications. Our future collaborators have told us there are certain problem out there waiting for a solution in new technology.”

    “The NIH wants the center to invent and disseminate technologies,” says Coon. “We hope to do for proteins what high-throughput sequencing has done for genomic studies.”

    See the full article here .

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    In achievement and prestige, the University of Wisconsin–Madison has long been recognized as one of America’s great universities. A public, land-grant institution, UW–Madison offers a complete spectrum of liberal arts studies, professional programs and student activities. Spanning 936 acres along the southern shore of Lake Mendota, the campus is located in the city of Madison.

     
  • richardmitnick 7:54 am on May 19, 2016 Permalink | Reply
    Tags: , , Biology, Hypoxia and cognitive decline   

    From AAAS: “Medical complications cut Everest research expedition short” 

    AAAS

    AAAS

    May. 17, 2016
    Patrick Monahan

    1
    Richard Parks undergoing tests on Island Peak in Nepal during his acclimatization period.

    Earlier this month, U.K. mountaineer Richard Parks prematurely abandoned his team’s expedition to the summit of Mount Everest in Nepal. He planned to ascend the peak without supplemental oxygen as part of Project Everest Cynllun, and take the highest-elevation blood sample and muscle biopsy ever collected. The project’s original goal was to examine the link between hypoxia and cognitive decline by examining human performance in low-oxygen environments, but its abrupt end has sparked questions of a different sort.

    The team had for several weeks been climbing smaller peaks to acclimatize to high altitude, and Parks was about to start his second rotation up the mountain: a 2-week stay above the Khumbu Icefall (5486 meters). Damian Bailey, a physiologist at the University of South Wales in the United Kingdom and the lead scientist on the project, decided to perform a blood test on Parks earlier than scheduled. When he drew the blood, he immediately knew something was wrong. “His blood was extraordinarily thick,” Bailey says. “It was actually clotting as I was taking a sample.”

    Testing revealed that Parks had exceptionally high levels of red blood cells and a high hematocrit, the percentage of the blood’s mass made up of red blood cells. On one hand, this was a clue to Parks’s ability to function in low-oxygen conditions: “His brain was actually getting more oxygen than it would get at sea level,” Bailey says, despite the thin alpine atmosphere containing half the amount of oxygen found at lower elevations. But such high cell densities also put him at increased risk of a stroke or a heart attack. For this reason, the team decided to end the expedition on 3 May despite Parks outwardly seeming in perfectly good health.

    The project still managed to collect data for its original goal of examining the link between hypoxia and cognitive decline. Plus, Bailey hopes to plan a follow-up expedition at some point. But for now, there is more testing to be done back in the lab—and Parks’s unusual physiology has turned out to have implications not just for cognitive decline, but also more directly for would-be Everest climbers.

    Parks’s exceptionally strong response to altitude suggests that climbers could “overacclimatize,” Bailey says, or put themselves and others in danger by spending too much time at high altitudes in preparation for an ascent. That runs against the prevailing wisdom that thorough acclimatization is a necessity for any ascent without supplemental oxygen.

    And given Parks’s outward signs of good health, it’s difficult to know how widespread the problem might be: How many climbers are already experiencing these symptoms without knowing it? And should high-altitude specialists be testing for this on the mountain? These aren’t the questions the team meant to provoke—but that doesn’t mean they’re unwelcome. “This is the dynamic of science,” Bailey says. “You can stumble across some findings … that can be just as profound as the original question you wanted to answer.”

    See the full article here .

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

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  • richardmitnick 7:59 pm on May 16, 2016 Permalink | Reply
    Tags: , Biology, , , Scientists Built a Giant Molecule That Could Fight Nearly Any Viral Infection   

    From NOVA: “Scientists Built a Giant Molecule That Could Fight Nearly Any Viral Infection” 

    PBS NOVA

    NOVA

    16 May 2016
    Allison Eck

    1
    Simian virus 40, a virus found in both monkeys and humans. No image credit.

    2
    The influenza virus. CDC/ Dr. Erskine. L. Palmer; Dr. M. L. Martin via Flickr

    Viruses have eluded our best efforts to fight them off. They mutate much more quickly than bacteria, and most anti-viral drugs that do keep symptoms at bay need to be administered for the rest of a patient’s life.

    But now, researchers may have discovered a workaround: a macromolecule that’s swift and nimble enough to tackle virtually any virus that crosses its path. The scientists, from both IBM and the Institute of Bioengineering and Nanotechnology in Singapore, recently published their findings* in the journal Macromolecules.

    The team concentrated their efforts on the similarities between viruses. Here’s Claire Maldarelli, writing for Popular Science:

    A group of researchers at IBM and the Institute of Bioengineering and Nanotechnology in Singapore sought to understand what makes all viruses alike.

    For their study, the researchers ignored the viruses’ RNA and DNA, which could be key areas to target, but because they change from virus to virus and also mutate, it’s very difficult to target them successfully.

    Instead, the researchers focused on glycoproteins, which sit on the outside of all viruses and attach to cells in the body, allowing the viruses to do their dirty work by infecting cells and making us sick. Using that knowledge, the researchers created a macromolecule, which is basically one giant molecule made of smaller subunits. This macromolecule has key factors that are crucial in fighting viruses. First, it’s able to attract viruses towards itself using electrostatic charges. Once the virus is close, the macromolecule attaches to the virus and makes the virus unable to attach to healthy cells. Then it neutralizes the virus’ acidity levels, which makes it less able to replicate.

    The researchers found that the molecules did in fact latch onto the a number of viruses’ glycoproteins (including those of the Ebola and dengue viruses) and reduced the number of viruses in their lab experiments. A sugar in the molecules was also able to bind to healthy immune cells that, in turn, destroyed the virus more efficiently.

    If the technique plays out as expected in further experiments, this lone molecule could someday be responsible for ridding humankind of the worst viral infections—from Ebola, to Zika, to the flu. That will take a while, though, and some scientists caution that universal antivirals may be dangerous, anyway—they could upset our immune systems in ways we don’t currently anticipate. Still, this macromolecule is a proof of concept that powerful antiviral drugs are not completely out of reach.

    *Science paper:
    Cooperative Orthogonal Macromolecular Assemblies with Broad Spectrum Antiviral Activity, High Selectivity, and Resistance Mitigation

    See the full article here .

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

     
  • richardmitnick 2:26 pm on May 13, 2016 Permalink | Reply
    Tags: , Biology, , Look, Ma! No Mitochondria, ,   

    From NPR: “Look, Ma! No Mitochondria” 

    NPR

    National Public Radio (NPR)

    May 12, 2016
    Nell Greenfield Boyce
    1
    These mitochondria, in red, are from the heart muscle cell of a rat. Mitochondria have been described as “the powerhouses of the cell” because they generate most of a cell’s supply of chemical energy. But at least one type of complex cell doesn’t need ’em, it turns out.
    Science Source

    Scientists have found a microbe that does something textbooks say is impossible: It’s a complex cell that survives without mitochondria.

    Mitochondria are the powerhouses inside eukaryotic cells, the type of complicated cell that makes up people, other critters and plants and fungi. All eukaryotic cells contain a nucleus and little organelles — and one of the most famous was the mitochondrion.

    “They were considered to be absolutely indispensable components of the eukaryotic cell and the hallmark of the eukaryotic cell,” says Anna Karnkowska, a researcher in evolutionary biology at the University of British Columbia in Vancouver. Karnkowska and her colleagues describe their new find in a study published* online Thursday in the journal Current Biology.

    1
    This is a light micrograph of the microbe that evolutionary biologists say lives just fine without any mitochondria.
    Naoji Yubuki/Current Biology

    Mitochondria have their own DNA, and scientists believe they were once free-living bacteria that got engulfed by primitive, ancient cells that were evolving to become the complex life forms we know and love today.

    For decades, researchers have tried to find eukaryotic cells that don’t have mitochondria — and for a while they thought they’d found some. One example is Giardia, a human gut parasite that causes diarrhea. It was considered to be a kind of living fossil because it had a nucleus but didn’t seem to have acquired mitochondria. But additional studies on Giardia and other microbes showed that actually, the mitochondria were there.

    “It turned out that all of them actually had some kind of remnant mitochondrion,” says Karnkowska, who notes that mitochondria perform key jobs in the cell beyond just generating power.

    A biggie is assembling iron-sulfur clusters for certain proteins, which is thought to be a mitochondrial function that’s really essential. So even if a microbe powers itself in a different way and has a limited form of the organelle that isn’t the same as the mitochondria found in people, Karnkowska says, “it’s still a mitochondrion and it has some important function for the cell.”

    That kind of vestigial mitochondrion is what she expected to find when she was a researcher at Charles University in Prague and started investigating a particular gut microbe that had been isolated from a researcher’s pet chinchilla.

    After she and her colleagues sequenced the gut microbe’s genome, however, they found no trace that it made any mitochondrial proteins at all. “So that’s a great surprise for us,” she says. “That should theoretically kill the cell — it shouldn’t exist.”

    What they learned is that instead of relying on mitochondria to assemble iron-sulfur clusters, these cells use a different kind of machinery. And it looks like they acquired it from bacteria.

    The researchers say this is the first example of any eukaryote that completely lacks mitochondria.

    Michael Gray, a biochemist at Dalhousie University in Halifax, Nova Scotia, says the researchers have made a “compelling” case that they have a bona fide eukaryote without any vestige of a mitochondrion; he calls the finding “unprecedented.”

    “The observation is significant, in that it clearly demonstrates that a eukaryote can still be a eukaryote without having a mitochondrion,” he tells Shots via email.

    However, the results do not negate the idea that the acquisition of a mitochondrion was an important and perhaps defining event in the evolution of eukaryotic cells, he adds.

    That’s because it seems clear that this organism’s ancestors had mitochondria that were then lost after the cells acquired their non-mitochondrial system for making iron-sulfur clusters.

    “This is not the missing link of eukaryotic evolution,” agrees Mark Van Der Giezen, a researcher in evolutionary biochemistry at the University of Exeter in the United Kingdom.

    Still, he says, it is an example of how flexible life is.

    “It lives in an area without oxygen and therefore can get rid of a lot of biochemistry that you and I would need in our cells to survive,” says Van Der Giezen. “This organism managed to adapt in such a way that it could lose an organelle, which every textbook will tell you is an essential feature of eukaryotes. That’s pretty amazing. It shows you that life is extremely creative in finding a way to eke out an existence.”

    *Science paper:
    A Eukaryote without a Mitochondrial Organelle

    See the full article here.

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  • richardmitnick 10:48 am on March 29, 2016 Permalink | Reply
    Tags: , Biology, , Foetus, or placenta   

    From EMBL: “Foetus, or placenta?” 

    EMBL European Molecular Biology Laboratory bloc

    European Molecular Biology Laboratory

    24 March 2016
    Mary Todd Bergman

    1
    New study on embryonic development by EMBL-EBI’s Marioni group sheds light on early cell-fate decisions. IMAGE: Zernicka-Goetz lab, University of Cambridge

    2

    New research in Cell shows subtle differences between seemingly identical cells at a very early stage of development

    When exactly does an embryonic cell decide whether it will become part of the foetus, or part of the placenta? Scientists at the University of Cambridge and EMBL-EBI shed light on this important question by studying the development of mice embryos only four cells in size. The findings, published in Cell, have implications for the understanding of mammalian development.

    When an embryo first starts to develop, genetic factors influence whether its cells will become part of the supporting structure around a new organism, or part of the organism itself. Today’s study shows that seemingly identical cells in a two-day-old mouse embryo already begin to display subtle differences.

    Once an egg has been fertilised by a sperm, it divides several times to become a free-floating ball of stem cells. At first, these cells are ‘totipotent’, able to divide and give rise into any type of cell, placental or organismal. Some of those cells then switch to a ‘pluripotent’ state, in which their development is restricted to generating the cells of the whole body, rather than the placenta. Understanding that switching mechanism, and when it occurs, is the subject of intense research.

    “We know that life starts when a sperm fertilises an egg, but we’re interested in when the important decisions that determine our future development occur,” says Magdalena Zernicka-Goetz from the Department of Physiology, Development and Neuroscience at the University of Cambridge. “We now know that even as early as the four-cell stage – just two days after fertilisation – the mouse embryo is being guided in a particular direction and its cells are no longer identical.”

    The team used the latest sequencing technologies to understand embryo development in mice, looking at the activity of individual genes at a single-cell level. They showed that some genes in each of the four cells behaved differently. The activity of several genes in particular differed the most between cells. These genes form part of the ‘pluripotency network’: they are targeted by key pluripotency factors, including Sox2 and Oct4. The team showed that when activity of such genes is reduced, the activity of a master regulator, which directs cells to develop into the placenta, was increased.

    John Marioni of EMBL-EBI, the Wellcome Trust Sanger Institute and CRUK-CI, adds: “We can make use of powerful sequencing tools to deepen our understanding of the molecular mechanisms that drive development in individual cells. Because of these high-resolution techniques, we are now able to see the genetic and epigenetic signatures that indicate the direction in which early embryonic cells will tend to travel.”

    The research was funded by the Wellcome Trust, the European Molecular Biology Laboratory and Cancer Research UK.

    The science team:
    Mubeen Goolam
    , Antonio Scialdone
    , Sarah J.L. Graham
    , Iain C. Macaulay
    , Agnieszka Jedrusik
    , Anna Hupalowska
    , Thierry Voet
    , John C. Marionicorrespondenceemail
    , Magdalena Zernicka-Goetzcorrespondenceemail

    See the full article here .

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    EMBL European Molecular Biology Laboratory campus

    EMBL is Europe’s flagship laboratory for the life sciences, with more than 80 independent groups covering the spectrum of molecular biology. EMBL is international, innovative and interdisciplinary – its 1800 employees, from many nations, operate across five sites: the main laboratory in Heidelberg, and outstations in Grenoble; Hamburg; Hinxton, near Cambridge (the European Bioinformatics Institute), and Monterotondo, near Rome. Founded in 1974, EMBL is an inter-governmental organisation funded by public research monies from its member states. The cornerstones of EMBL’s mission are: to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in the member states; to develop new instruments and methods in the life sciences and actively engage in technology transfer activities, and to integrate European life science research. Around 200 students are enrolled in EMBL’s International PhD programme. Additionally, the Laboratory offers a platform for dialogue with the general public through various science communication activities such as lecture series, visitor programmes and the dissemination of scientific achievements.

     
  • richardmitnick 6:58 pm on March 23, 2016 Permalink | Reply
    Tags: , , Biology, , 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.

    1
    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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