Tagged: Biology Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 4:04 pm on September 29, 2014 Permalink | Reply
    Tags: , Biology, ,   

    From LBL: “MaxBin: Automated Sorting Through Metagenomes” 

    Berkeley Logo

    Berkeley Lab

    September 29, 2014
    Lynn Yarris (510) 486-5375

    Microbes – the single-celled organisms that dominate every ecosystem on Earth – have an amazing ability to feed on plant biomass and convert it into other chemical products. Tapping into this talent has the potential to revolutionize energy, medicine, environmental remediation and many other fields. The success of this effort hinges in part on metagenomics, the emerging technology that enables researchers to read all the individual genomes of a sample microbial community at once. However, given that even a teaspoon of soil can contain billions of microbes, there is a great need to be able to cull the genomes of individual microbial species from a metagenomic sequence.

    Enter MaxBin, an automated software program for binning (sorting) the genomes of individual microbial species from metagenomic sequences. Developed at the U.S. Department of Energy (DOE)’s Joint BioEnergy Institute (JBEI), under the leadership of Steve Singer, who directs JBEI’s Microbial Communities Group, MaxBin facilitates the genomic analysis of uncultivated microbial populations that can hold the key to the production of new chemical materials, such as advanced biofuels or pharmaceutical drugs.

    cd
    MaxBin, an automated software program for binning the genomes of individual microbial species from metagenomic sequences, is available on-line through JBEI.

    “MaxBin automates the binning of assembled metagenomic scaffolds using an expectation-maximization algorithm after the assembly of metagenomic sequencing reads,” says Singer, a chemist who also holds an appointment with Berkeley Lab’s Earth Sciences Division. “Previous binning methods either required a significant amount of work by the user, or required a large number of samples for comparison. MaxBin requires only a single sample and is a push-button operation for users.”

    three
    JBEI researchers Yu-Wei Wu, Steve Singer and Danny Tang developed MaxBin to automatically recover individual genomes from metagenomes using an expectation-maximization algorithm. (Photo by Roy Kaltschmidt)

    The key to the success of MaxBin is its expectation-maximization algorithm, which was developed by Yu-Wei Wu, a post-doctoral researcher in Singer’s group. This algorithm enables the classification of metagenomic sequences into discrete bins that represent the genomes of individual microbial populations within a sample community.

    “Using our expectation-maximization algorithm, MaxBin combines information from tetranucleotide frequencies and scaffold coverage levels to organize metagenomic sequences into the individual bins, which are predicted from an initial identification of marker genes in assembled sequences,” Wu says.

    MaxBin was successfully tested on samples from the Human Microbiome Project and from green waste compost. In these tests, which were carried out by Yung-Tsu Tang, a student intern from the City College of San Francisco, MaxBin proved to be highly accurate in its ability to recover individual genomes from metagenomic datasets with variable sequencing coverages.

    “Applying MaxBin to an enriched cellulolytic consortia enabled us to identify a number of uncultivated cellulolytic bacteria, including a myxobacterium that possesses a remarkably reduced genome and expanded set of genes for biomass deconstruction compared to its closest sequenced relatives,” Singer says. “This demonstrates that the processes required for recovering genomes from metagenomic datasets can be applied to understanding biomass breakdown in the environment”.

    MaxBin is now being used at JBEI in its efforts to use microbes for the production of advanced biofuels – gasoline, diesel and jet fuel – from plant biomass. MaxBin is also available for downloading. To date, more than 150 researchers have accessed it.

    A paper describing MaxBin in detail has been published in the journal Microbiome. The paper is titled MaxBin: an automated binning method to recover individual genomes from metagenomes using an expectation-maximization algorithm. Co-authoring this paper in addition to Singer, Wu and Tang, were Susannah Tringe of the Joint Genome Institute, and Blake Simmons of JBEI.

    • See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

    University of California Seal

    DOE Seal

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 8:54 pm on September 28, 2014 Permalink | Reply
    Tags: , Biology, , ,   

    From MIT: “Biologists find an early sign of cancer” 


    MIT News

    September 28, 2014
    Anne Trafton | MIT News Office

    Patients show boost in certain amino acids years before diagnosis of pancreatic cancer.

    Years before they show any other signs of disease, pancreatic cancer patients have very high levels of certain amino acids in their bloodstream, according to a new study from MIT, Dana-Farber Cancer Institute, and the Broad Institute.

    cancer
    Christine Daniloff/MIT

    This finding, which suggests that muscle tissue is broken down in the disease’s earliest stages, could offer new insights into developing early diagnostics for pancreatic cancer, which kills about 40,000 Americans every year and is usually not caught until it is too late to treat.

    The study, which appears today in the journal Nature Medicine, is based on an analysis of blood samples from 1,500 people participating in long-term health studies. The researchers compared samples from people who were eventually diagnosed with pancreatic cancer and samples from those who were not. The findings were dramatic: People with a surge in amino acids known as branched chain amino acids were far more likely to be diagnosed with pancreatic cancer within one to 10 years.

    “Pancreatic cancer, even at its very earliest stages, causes breakdown of body protein and deregulated metabolism. What that means for the tumor, and what that means for the health of the patient — those are long-term questions still to be answered,” says Matthew Vander Heiden, an associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the paper’s senior authors.

    The paper’s other senior author is Brian Wolpin, an assistant professor of medical oncology at Dana-Farber. Wolpin, a clinical epidemiologist, assembled the patient sample from several large public-health studies. All patients had their blood drawn when they began participating in the studies and subsequently filled out annual health questionnaires.

    Working with researchers at the Broad Institute, the team analyzed blood samples for more than 100 different metabolites — molecules, such as proteins and sugars, produced as the byproducts of metabolic processes.

    “What we found was that this really interesting signature fell out as predicting pancreatic cancer diagnosis, which was elevation in these three branched chain amino acids: leucine, isoleucine, and valine,” Vander Heiden says. These are among the 20 amino acids — the building blocks for proteins — normally found in the human body.

    Some of the patients in the study were diagnosed with pancreatic cancer just one year after their blood samples were taken, while others were diagnosed two, five, or even 10 years later.

    “We found that higher levels of branched chain amino acids were present in people who went on to develop pancreatic cancer compared to those who did not develop the disease,” Wolpin says. “These findings led us to hypothesize that the increase in branched chain amino acids is due to the presence of an early pancreatic tumor.”

    Early protein breakdown

    Vander Heiden’s lab tested this hypothesis by studying mice that are genetically programmed to develop pancreatic cancer. “Using those mouse models, we found that we could perfectly recapitulate these exact metabolic changes during the earliest stages of cancer,” Vander Heiden says. “What happens is, as people or mice develop pancreatic cancer, at the very earliest stages, it causes the body to enter this altered metabolic state where it starts breaking down protein in distant tissues.”

    “This is a finding of fundamental importance in the biology of pancreatic cancer,” says David Tuveson, a professor at the Cancer Center at Cold Spring Harbor Laboratory who was not involved in the work. “It really opens a window of possibility for labs to try to determine the mechanism of this metabolic breakdown.”

    The researchers are now investigating why this protein breakdown, which has not been seen in other types of cancer, occurs in the early stages of pancreatic cancer. They suspect that pancreatic tumors may be trying to feed their own appetite for amino acids that they need to build cancerous cells. The researchers are also exploring possible links between this early protein breakdown and the wasting disease known as cachexia, which often occurs in the late stages of pancreatic cancer.

    Also to be answered is the question of whether this signature could be used for early detection. The findings need to be validated with more data, and it may be difficult to develop a reliable diagnostic based on this signature alone, Vander Heiden says. However, he believes that studying this metabolic dysfunction further may reveal additional markers, such as misregulated hormones, that could be combined to generate a more accurate test.

    The findings may also allow scientists to pursue new treatments that would work by targeting tumor metabolism and cutting off a tumor’s nutrient supply, Vander Heiden says.

    MIT’s contribution to this research was funded by the Lustgarten Foundation, the National Institutes of Health, the Burroughs Wellcome Fund, and the Damon Runyon Cancer Research Foundation.

    See the full article here.

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 10:11 pm on September 25, 2014 Permalink | Reply
    Tags: , , Biology,   

    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.

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 3:24 pm on September 23, 2014 Permalink | Reply
    Tags: , , Biology, ,   

    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.
    i1
    i2
    i3

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 3:50 pm on September 22, 2014 Permalink | Reply
    Tags: , , Biology, ,   

    From Caltech: “Variability Keeps The Body In Balance” 

    Caltech Logo
    Caltech

    09/22/2014
    Jessica Stoller-Conrad

    Although the heart beats out a very familiar “lub-dub” pattern that speeds up or slows down as our activity increases or decreases, the pattern itself isn’t as regular as you might think. In fact, the amount of time between heartbeats can vary even at a “constant” heart rate—and that variability, doctors have found, is a good thing.

    runner

    Reduced heart rate variability (HRV) has been found to be predictive of a number of illnesses, such as congestive heart failure and inflammation. For athletes, a drop in HRV has also been linked to fatigue and overtraining. However, the underlying physiological mechanisms that control HRV—and exactly why this variation is important for good health—are still a bit of a mystery.

    By combining heart rate data from real athletes with a branch of mathematics called control theory, a collaborative team of physicians and Caltech researchers from the Division of Engineering and Applied Sciences have now devised a way to better understand the relationship between HRV and health—a step that could soon inform better monitoring technologies for athletes and medical professionals.

    The work was published in the August 19 print issue of the Proceedings of the National Academy of Sciences.

    To run smoothly, complex systems, such as computer networks, cars, and even the human body, rely upon give-and-take connections and relationships among a large number of variables; if one variable must remain stable to maintain a healthy system, another variable must be able to flex to maintain that stability. Because it would be too difficult to map each individual variable, the mathematics and software tools used in control theory allow engineers to summarize the ups and downs in a system and pinpoint the source of a possible problem.

    Researchers who study control theory are increasingly discovering that these concepts can also be extremely useful in studies of the human body. In order for a body to work optimally, it must operate in an environment of stability called homeostasis. When the body experiences stress—for example, from exercise or extreme temperatures—it can maintain a stable blood pressure and constant body temperature in part by dialing the heart rate up or down. And HRV plays an important role in maintaining this balance, says study author John Doyle, the Jean-Lou Chameau Professor of Control and Dynamical Systems, Electrical Engineering, and Bioengineering.

    “A familiar related problem is in driving,” Doyle says. “To get to a destination despite varying weather and traffic conditions, any driver—even a robotic one—will change factors such as acceleration, braking, steering, and wipers. If these factors suddenly became frozen and unchangeable while the car was still moving, it would be a nearly certain predictor that a crash was imminent. Similarly, loss of heart rate variability predicts some kind of malfunction or ‘crash,’ often before there are any other indications,” he says.

    To study how HRV helps maintain this version of “cruise control” in the human body, Doyle and his colleagues measured the heart rate, respiration rate, oxygen consumption, and carbon dioxide generation of five healthy young athletes as they completed experimental exercise routines on stationary bicycles.

    By combining the data from these experiments with standard models of the physiological control mechanisms in the human body, the researchers were able to determine the essential tradeoffs that are necessary for athletes to produce enough power to maintain an exercise workload while also maintaining the internal homeostasis of their vital signs.

    Because monitors in hospitals can already provide HRV levels and dozens of other signals and readings, the integration of such mathematical analyses of control theory into HRV monitors could, in the future, provide a way to link a drop in HRV to a more specific and treatable diagnosis. In fact, one of Doyle’s students has used an HRV application of control theory to better interpret traditional EKG signals.

    Control theory could also be incorporated into the HRV monitors used by athletes to prevent fatigue and injury from overtraining, he says.

    “Physicians who work in very data-intensive settings like the operating room or ICU are in urgent need of ways to rapidly and acutely interpret the data deluge,” says Marie Csete, MD (PhD, ’00), chief scientific officer at the Huntington Medical Research Institutes and a coauthor on the paper. “We hope this work is a first step in a larger research program that helps physicians make better use of data to care for patients.”

    “For example, the heart, lungs, and circulation must deliver sufficient oxygenated blood to the muscles and other organs while not raising blood pressure so much as to damage the brain,” Doyle says. “This is done in concert with control of blood vessel dilation in the muscles and brain, and control of breathing. As the physical demands of the exercise change, the muscles must produce fluctuating power outputs, and the heart, blood vessels, and lungs must then respond to keep blood pressure and oxygenation within narrow ranges.”

    Once these trade-offs were defined, the researchers then used control theory to analyze the exercise data and found that a healthy heart must maintain certain patterns of variability during exercise to keep this complicated system in balance. Loss of this variability is a precursor of fatigue, the stress induced by exercise. Today, some HRV monitors in the clinic can let a doctor know when variability is high or low, but they provide little in the way of an actionable diagnosis.

    Because monitors in hospitals can already provide HRV levels and dozens of other signals and readings, the integration of such mathematical analyses of control theory into HRV monitors could, in the future, provide a way to link a drop in HRV to a more specific and treatable diagnosis. In fact, one of Doyle’s students has used an HRV application of control theory to better interpret traditional EKG signals.

    See the full article here.

    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.”
    Caltech buildings
    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 9:39 am on September 17, 2014 Permalink | Reply
    Tags: , Biology, , Stem Cell Research   

    From New Scientist: “Stem cells used in landmark therapy for failing sight” 

    NewScientist

    New Scientist

    17 September 2014
    Andy Coghlan

    A woman in Japan has received the first medical treatment based on induced pluripotent stem cells, eight years after they were discovered.

    The iPS cells were made by reprogramming skin cells from the woman’s arm, then transformed into specialised eye cells to treat age-related macular degeneration (AMD) ´ a condition that affects millions of elderly people worldwide, and often results in blindness. Last week, the woman, who is in her 70s, had a patch of the cells measuring 1.3 by 3 millimetres grafted into her eye in a two-hour operation.

    eye
    Grafts derived from stem cells could keep the retina in good working order (Image: Science Source/Science Photo Library)

    She is the first of six people lined up for the landmark treatment, developed by Masayo Takahashi and her colleagues at the RIKEN Center for Developmental Biology in Kobe, Japan. In a pilot study to test the safety of putting iPS-derived cells into humans, the six are all receiving a graft of new retinal pigment epithelial (RPE) cells, which serve to maintain the eye’s light-sensing cells.

    No embryos needed

    Since iPS cells can be made from adult tissue samples, the technique does not require the destruction of embryos, unlike stem-cell-based AMD treatments that are also being worked on – one such treatment is being trialled in the US and UK.

    “It’s an exciting development, and we await the outcome over the next year to see how well these cells integrate, and if there are any potential adverse reactions,” says Mike Cheetham of the Institute of Ophthalmology at University College London, one site which is also researching a human embryonic stem-cell treatment for AMD. “If it goes well, it could be the start of a new era in personalised medicine,” he says.

    Shinya Yamanaka and his colleagues at Kyoto University in Japan discovered iPS cells in 2006. In 2012, Yamanaka was awarded the Nobel prize for the work.

    See the full article here.

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 2:12 pm on September 15, 2014 Permalink | Reply
    Tags: , Biology, Harvard University,   

    From NOVA: “‘Biospleen Device’ Uses Magnetic Nanoparticles to Filter Pathogens from Blood” 

    PBS NOVA

    NOVA

    Mon, 15 Sep 2014
    Tim De Chant

    When a patient succumbs to an infection, it’s not the mere presence of the pathogen that kills them, but rather the sheer quantity of it. With many deadly diseases, the immune system simply can’t keep up. So bioengineers figured that outsourcing some of those duties could help keep patients alive.

    A team of bioengineers led by Donald Ingber at Harvard’s Wyss Institute devised a device to filter pathogens from a patient’s blood. Inspired by the spleen, an organ which filters antibody-coated pathogens from the bloodstream, the “biospleen” works by first injecting specially treated, magnetic nanoparticles into the blood flowing through it. The nanoparticles have a protein attached to their surfaces which adheres to bacteria, viruses, and fungi; the protein-coated nanoparticles work like antibodies, which glom onto foreign objects. The biospleen then uses a magnet to pull out the nanoparticles and the pathogens they’re attached to.

    bio
    The filtering section of the biospleen

    The biospleen is similar in concept to dialysis, which mimics the function of the kidneys, but works on pathogens instead of typical bodily waste.

    Sara Reardon, reporting for Nature News, has more details:

    To test the device, Ingber and his team infected rats with either E. coli or Staphylococcus aureus and filtered blood from some of the animals through the biospleen. Five hours after infection, 89% of the rats whose blood had been filtered were still alive, compared with only 14% of those that were infected but not treated. The researchers found that the device had removed more than 90% of the bacteria from the rats’ blood. The rats whose blood had been filtered also had less inflammation in their lungs and other organs, suggesting they would be less prone to sepsis.

    Ingber and his team also tested the device using human volumes of blood, and they found that it took about five hours to filter most pathogens from five liters of blood.

    If the device makes it into trials, which could happen in just a few years, it could give doctors the upper hand in a number of intractable infections, including HIV and Ebola. The biospleen could reduce the pathogen load in a patient’s blood, leaving the drugs that normally treat the infection to clear the virus or bacteria from the patient’s organs. In acute infections, like Ebola, it would also buy doctors valuable time in their efforts to eliminate the virus before the patient succumbs.

    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.

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 8:15 pm on September 14, 2014 Permalink | Reply
    Tags: , Biology,   

    From Caltech: “Slimy Fish and the Origins of Brain Development” 

    Caltech Logo
    Caltech

    09/14/2014
    Jessica Stoller-Conrad

    Lamprey—slimy, eel-like parasitic fish with tooth-riddled, jawless sucking mouths—are rather disgusting to look at, but thanks to their important position on the vertebrate family tree, they can offer important insights about the evolutionary history of our own brain development, a recent study suggests.

    eel
    A sea lamprey held by postdoctoral scholar Stephen Green in the Caltech Zebrafish/Xenopus/Lamprey Facility. Credit: Lance Hayashida/Caltech Marketing and Communications

    The work appears in a paper in the September 14 advance online issue of the journal Nature.

    “Lamprey are one of the most primitive vertebrates alive on Earth today, and by closely studying their genes and developmental characteristics, researchers can learn more about the evolutionary origins of modern vertebrates—like jawed fishes, frogs, and even humans,” says paper coauthor Marianne Bronner, the Albert Billings Ruddock Professor of Biology and director of Caltech’s unique Zebrafish/Xenopus/Lamprey facility, where the study was done.

    mb
    Marianne Bronner, the Albert Billings Ruddock Professor of Biology, with the tanks where the sea lamprey are kept during their time at Caltech.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    The facility is one of the few places in the world where lampreys can be studied in captivity. Although the parasitic lamprey are an invasive pest in the Great Lakes, they are difficult to study under controlled conditions; their lifecycle takes up to 10 years and they only spawn for a few short weeks in the summer before they die.

    Each summer, Bronner and her colleagues receive shipments of wild lamprey from Michigan just before the prime of breeding season. When the lamprey arrive, they are placed in tanks where the temperature of the water is adjusted to extend the breeding season from around three weeks to up to two months. In those extra weeks, the lamprey produce tens of thousands of additional eggs and sperm, which, via in vitro fertilization, generate tens of thousands of additional embryos for study. During this time, scientists from all over the world come to Caltech to perform experiments with the developing lamprey embryos.

    tank
    Lamprey embryos are sorted for observation at a microscope in the Caltech Zebrafish/Xenopus/Lamprey facility.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    In the current study, Bronner and her collaborators—who traveled to Caltech from Stower’s Institute for Medical Research in Kansas City, Missouri—studied the origins of the vertebrate hindbrain.

    The hindbrain is a part of the central nervous system common to chordates—or organisms that have a nerve cord like our spinal cord. During the development of vertebrates—a subtype of chordates that have backbones—the hindbrain is compartmentalized into eight segments, each of which becomes uniquely patterned to establish networks of neuronal circuits. These segments eventually give rise to adult brain regions like the cerebellum, which is important for motor control, and the medulla oblongata, which is necessary for breathing and other involuntary functions.

    br
    A lamprey embryo expressing the Hox gene Hoxb3 (green). In the study, Bronner and her colleagues found that Hox genes are important for hindbrain segmentation during lamprey development.
    Credit: Hugo Parker

    However, this segmentation is not present in so-called “invertebrate chordates”—a grouping of chordates that lack a backbone, such as sea squirts and lancelets.

    “The interesting thing about lampreys is that they occupy an intermediate evolutionary position between the invertebrate chordates and the jawed vertebrates,” says Hugo Parker, a postdoc at Stower’s Institute and first author on the study. “By investigating aspects of lamprey embryology, we can get a picture of how vertebrate traits might have evolved.”

    hp
    Hugo Parker, a postdoctoral scholar from the Stowers Institute for Medical Research, works with lamprey embryos at a microscope in the Caltech Zebrafish/Xenopus/Lamprey facility.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    In the vertebrates, segmental patterning genes called Hox genes help to determine the animal’s head-to-tail body plan—and those same Hox genes also control the segmentation of the hindbrain. Although invertebrate chordates also have Hox genes, these animals don’t have segmented hindbrains. Because lampreys are centered between these two types of organisms on the evolutionary tree, the researchers wanted to know whether or not Hox genes are involved in patterning of the lamprey hindbrain.

    To their surprise, the researchers discovered that the lamprey hindbrain was not only segmented during development but the process also involved Hox genes—just like in its jawed vertebrate cousins.

    “When we started, we thought that the situation was different, and the Hox genes were not really integrated into the process of segmentation as they are in jawed vertebrates,” Parker says. “But in actually doing this project, we discovered the way that lamprey Hox genes are expressed and regulated is very similar to what we see in jawed vertebrates.” This means that hindbrain segmentation—and the role of Hox genes in this segmentation—happened earlier on in evolution than was once thought, he says.

    Parker, who has been spending his summers at Caltech studying lampreys since 2008, is next hoping to pinpoint other aspects of the lamprey hindbrain that may be conserved in modern vertebrate information that will help contribute to a fundamental understanding of vertebrate development. And although those investigations will probably mean following the lamprey for a few more summers at Caltech, Parker says his time in the lamprey facility continually offers a one-of-a-kind experience.

    “The lamprey system here is unique in the world—and it’s not just the water tanks and how we’ve learned to maintain the animals. It’s the small nucleus of people who have particular skills, people who come in from all over the world to work together, share protocols, and develop the field together,” he says. “That’s one of the things I’ve liked ever since I first came here. I really felt like I was a part of something very special.

    These results were published in a paper titled A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates. Robb Krumlauf, a scientific director at the Stower’s Institute and professor at the Kansas University Medical Center, was also a coauthor on the study. The Zebrafish/Xenopus/Lamprey facility at Caltech is a Beckman Institute facility.

    See the full article here.

    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.”
    Caltech buildings
    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 10:10 am on September 14, 2014 Permalink | Reply
    Tags: , Biology, , , New Technology,   

    From Rutgers- “Novel Local Morphologic Scale: Applications in Disease Diagnosis and Prognosis” 

    Rutgers University
    Rutgers University

    Rutgers Technology

    Invention Summary

    Timely and accurate diagnosis of disease pathologies is critical to providing effective treatment to patients. Rutgers scientists have developed a novel local morphologic scale (LMS) to rapidly and automatically select, quantify and classify tissue/specimen topologies using parallelized computations. This unique tool has the ability to define features for every special image location and generate subsequent scene segmentation and classification for each location. Further this technology is free from shape constraints and generates output based on local structure attributes of complex histological images. This innovation has been successfully utilized in discriminating tumor versus stromal regions by classifying oncogenic tumor infiltrating lymphocytes (biomarker) in ovarian cancer tissue microarrays. Additionally, this technology has been applied across 3 other domains (prostate, breast) under two different stains illustrating its robustness to domain selection. This technology can be immensely useful to identify regions of interest, model heterogeneity of the underlying topology and generate digital signatures. It can also be used to train supervised classifiers to identify similar structural signatures in an image and therefore reduce or eliminate and observer variability.

    Market Application

    Disease Diagnosis, Digital Pathology, Histopathology, Computer Aided Diagnosis (CAD), Tissue Classification, Disease Monitoring and Prognosis, Lymphocyte Infiltration, Cancer.

    Advantages

    Signatures derived from cancerous versus non-cancerous tissues differ greatly. This tool can be highly instrumental in classifying cancerous versus non-cancerous tissue, can reliably and accurately account for cell shape and phenotypes, and provide accurate tissue classification, enabling pathologists to visually discern the two regions.

    Intellectual Property & Development Status
    Patent pending.

    Select Publication
    Janowczyk, A, Chandran S, Feldman MD, Madabhushi A. (2011). Local morphologic scale: Application to segmenting tumor infiltrating lymphocytes in ovarian cancer TMAs. SPIE http://lcib.rutgers.edu/publications/ Andrew/SPIE2011.pdf

    See the full articled here.

    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

    Rutgers Seal

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
  • richardmitnick 9:43 am on September 14, 2014 Permalink | Reply
    Tags: , , Biology, , ,   

    From M.I.T Tech Review: “Gene-Silencing Drugs Finally Show Promise” 

    MIT Technology Review
    M.I.T Technology Review

    September 14, 2014
    Kevin Bullis

    After more than a decade of disappointment, a startup leads the development of a powerful new class of drugs based on a Nobel-winning idea.

    The disease starts with a feeling of increased clumsiness. Spilling a cup of coffee. Stumbling on the stairs. Having accidents that are easy to dismiss—everyone trips now and then.

    But it inevitably gets worse. Known as familial amyloid polyneuropathy, or FAP, it can go misdiagnosed for years as patients lose the ability to walk or perform delicate tasks with their hands. Most patients die within 10 to 15 years of the first symptoms.

    There is no cure. The disease is caused by malformed proteins produced in the liver, so one treatment is a liver transplant. But few patients can get one—and it only slows the disease down.

    Now, after years of false starts and disappointment, it looks like an audacious idea for helping these patients finally could work.

    In 1998, researchers at the Carnegie Institution and the University of Massachusetts made a surprising discovery about how cells regulate which proteins they produce. They found that certain kinds of RNA—which is what DNA makes to create proteins—can turn off specific genes. The finding, called RNA interference (RNAi), was exciting because it suggested a way to shut down the production of any protein in the body, including those connected with diseases that couldn’t be touched with ordinary drugs. It was so promising that its discoverers won the Nobel Prize just eight years later.

    Inspired by the discovery, another group of researchers—including the former thesis supervisor of one of the Nobel laureates—founded Alnylam in Cambridge, Massachusetts, in 2002. Their goal: fight diseases like FAP by using RNAi to eliminate bad proteins (see “The Prize of RNAi” and “Prescription RNA”). Never mind that no one knew how to make a drug that could trigger RNAi. In fact, that challenge would bedevil the researchers for the better part of a decade. Along the way, the company lost the support of major drug companies that had signed on in a first wave of enthusiasm. At one point the idea of RNAi therapy was on the verge of being discredited.

    But now Alnylam is testing a drug to treat FAP in advanced human trials. It’s the last hurdle before the company will seek regulatory approval to put the drug on the market. Although it’s too early to tell how well the drug will alleviate symptoms, it’s doing what the researchers hoped it would: it can decrease the production of the protein that causes FAP by more than 80 percent.

    This could be just the beginning for RNAi. Alnylam has more than 11 drugs, including ones for hemophilia, hepatitis B, and even high cholesterol, in its development pipeline, and has three in human trials —progress that led the pharmaceutical company Sanofi to make a $700 million investment in the company last winter. Last month, the pharmaceutical giant Roche, an early Alnylam supporter that had given up on RNAi, reversed its opinion of the technology as well, announcing a $450 million deal to acquire the RNAi startup Santaris. All told, there are about 15 RNAi-based drugs in clinical trials from several research groups and companies.

    “The world went from believing RNAi would change everything to thinking it wouldn’t work, to now thinking it will,” says Robert Langer, a professor at MIT, and one of Alnylam’s advisors.

    Delivering Drugs

    Alnylam started with high hopes. Its founders, among them the Nobel laureate and MIT biologist Philip Sharp, had solved one of the biggest challenges facing the idea of RNAi therapies. When RNAi was discovered, the process was triggered by introducing a type of RNA, called double stranded RNA, into cells. This worked well in worms and fruit flies. But the immune system in mammals reacted violently to the RNA, causing cells to die and making the approach useless except as a research tool. The Alnylam founders figured out that shorter strands, called siRNA, could slip into mammalian cells without triggering an immune reaction, suggesting a way around this problem.

    Yet another huge problem remained. RNA interference depends upon delivering RNA to cells, tricking the cells into allowing it through the protective cell membrane, and then getting the cells to incorporate it into molecular machinery that regulates proteins. Scientists could do this in petri dishes but not in animals.

    Alnylam looked everywhere for solutions, scouring the scientific literature, collaborating with other companies, considering novel approaches of its own. It focused on two options. One was encasing RNA in bubbles of fat-like nanoparticles of lipids. They are made with the same materials that make up cell membranes—the thought was that the cell would respond well to the familiar substance. The other approach was attaching a molecule to the RNA that cells like to ingest, tricking the cell into eating it.

    And both approaches worked, sort of. Researchers were able to block protein production in lab animals. But getting the delivery system right wasn’t easy. The early mechanisms were too toxic at the doses required to be used as drugs.

    As a result, delivering RNA through the bloodstream like a conventional drug seemed a far-off prospect. The company tried a shortcut of injecting chemically modified RNA directly into diseased tissue —for example, into the retina to treat eye diseases. That approach even got to clinical trials. But it was shelved because it didn’t perform as well as up-and-coming drugs from other companies.

    By 2010, some of the major drug companies that were working with and investing in Alnylam lost patience. Novartis decided not to extend a partnership with Alnylam; Roche gave up on RNAi altogether. Alnylam laid off about a quarter of its workers, and by mid-2011, its stock price had plunged by 80 percent from its peak.

    But Alnylam and partner companies, notably the Canadian startup Tekmira, were making steady progress in the lab. Researchers identified one part of the lipid nanoparticles that was keeping them from delivering its cargo of RNA to the right part of a cell. That was “the real eureka moment,” says Rachel Meyers, Alnylam’s vice president of research. Better nanoparticles improved the potency of a drug a hundredfold and its safety by about five times, clearing the way for clinical trials for FAP—a crucial event that kept the company alive.

    Even with that progress, Alnylam needed more. The nanoparticle delivery mechanism is costly to make and requires frequent visits to the hospital for hour-long IV infusions—something patients desperate to stay alive will put up with, but likely not millions of people with high cholesterol.

    So Alnylam turned to its second delivery approach—attaching molecules to RNA to trick cells into ingesting it. Researchers found just the right inducement—attaching a type of sugar molecule. This approach allows for the drug to be administered with a simple injection that patients could give themselves at home.

    In addition to being easier to administer, the new sugar-based drugs are potentially cheaper to make. The combination of low cost and ease-of-use is allowing Alnylam to go after more common diseases—not just the rare ones that patients will go to great lengths to treat. “Because we’ve made incredible improvements in the delivery strategy,” Meyers says, “we can now go after big diseases where we can treat millions of patients potentially.”

    The Next Frontier

    In a sixth-floor lab on the MIT campus, postdoctoral researcher James Dahlman takes down boxes from a high shelf. They contain hundreds of vials, each containing a unique type of nanoparticle that Dahlman synthesized painstakingly, one at a time. “It turns out we have a robot in the lab that can do that,” he says. “But I didn’t know about it at the time.”

    Dahlman doesn’t work for Alnylam; he had been searching for the next great delivery mechanism, one that could greatly expand the diseases that can be treated by RNAi. Some of the materials look like clear liquids. Some are waxy, some like salt crystals. He points to a gap in the rows of vials, where a vial is conspicuously missing. “That’s the one that worked. That’s the miracle material,” he says.

    For all of their benefits, the drug delivery mechanisms Alnylam uses have one flaw—they’re effective only for delivering drugs to liver cells. For a number of reasons, the liver is a relatively easy target—that’s where all kinds of nanoparticles tend to end up. Alnylam sees the potential for billions of dollars in revenue from liver-related diseases. Yet most diseases involve other tissues in the body.

    Dahlman and his colleagues at MIT are some of the leaders in the next generation of RNAi delivery—targeting delivery to places throughout the body. Last month, in two separate articles, they published the results of studies showing that Dahlman’s new nanoparticles are a powerful way to deliver RNAi to blood vessel cells, which are associated with a wide variety of diseases. The studies showed that the method could be used to reduce tumor growth in lung cancer, for example.

    Treating cancer is one area where RNAi’s particular advantages are expected to shine. Conventional chemotherapy affects more than just the target cancer cells—it also hurts healthy tissue, which is why it makes people feel miserable. But RNAi can be extremely precise, potentially shutting down only proteins found in cancer cells. And Dahlman’s latest delivery system makes it possible to simultaneously target up to 10 proteins at once, which could make cancer treatments far more effective. Lab work like this is far from fruition, but if it maintains its momentum, the drugs currently in clinical trials could represent just a small portion of the benefits of the discovery of RNAi.

    See the full article here.

    The mission of MIT Technology Review is to equip its audiences with the intelligence to understand a world shaped by technology.

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
    Dell

     
c
Compose new post
j
Next post/Next comment
k
Previous post/Previous comment
r
Reply
e
Edit
o
Show/Hide comments
t
Go to top
l
Go to login
h
Show/Hide help
shift + esc
Cancel
Follow

Get every new post delivered to your Inbox.

Join 332 other followers

%d bloggers like this: