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Updates found with 'international team'

Sequencing Human Genome with Pocket-Sized “Nanopore” DeviceDr. Francis CollinsMinION sequencing deviceIt’s hard to believe, but it’s been almost 15 years since we successfully completed the Human Genome Project, ahead of schedule and under budget. I was proud to stand with my international colleagues in a celebration at the Library of Congress on April 14, 2003 (which happens to be my birthday), to announce that we had stitched together the very first reference sequence of the human genome at a total cost of about $400 million. As remarkable as that achievement was, it was just the beginning of our ongoing effort to understand the human genome, and to use that understanding to improve human health.That first reference human genome was sequenced using automated machines that were the size of small phone booths. Since then, breathtaking progress has been made in developing innovative technologies that have made DNA sequencing far easier, faster, and more affordable. Now, a report in Nature Biotechnology highlights the latest advance: the sequencing and assembly of a human genome using a pocket-sized device [1]. It was generated using several “nanopore” devices that can be purchased online with a “starter kit” for just $1, 000. In fact, this new genome sequence—completed in a matter of weeks—includes some notoriously hard-to-sequence stretches of DNA, filling several key gaps in our original reference genome.For most sequencing methods, DNA must be broken into smaller, more manageable fragments. That means all of the nucleotide “letters”— the As, Cs, Gs, and Ts—in the DNA code must be pieced back together in their correct order like a complex puzzle. While many methods are incredibly accurate at reassembling many parts of the puzzle, it’s much trickier to do this in highly repetitive stretches of DNA. When broken up, they produce puzzle pieces that are essentially identical.To get around that problem, some newer sequencing technologies are able to read out much longer stretches of DNA. In this latest report, an international team including Nicholas Loman at the University of Birmingham in the United Kingdom (U.K.), Matthew Loose at the University of Nottingham, U.K., and Adam Phillippy at NIH’s National Human Genome Research Institute, Bethesda, MD, relied on one such device: the hand-held MinION nanopore sequencer, produced by Oxford Nanopore Technologies.In fact, nanopore sequencing was named one of Science magazine’s “Breakthroughs of the Year” in 2016. The method involves threading single DNA strands through many tiny protein pores, i.e., nanopores, set in an electrically resistant polymer membrane. Inside the device, an ionic current is passed through the nanopore. When a single-stranded DNA molecule passes through the charged nanopore, it alters the current. In fact, the current is altered in different ways depending on which of DNA’s four unique nucletoides—adenine (A), cytosine (C), guanine (G), or thymine (T)—is passing through the pore. As a result, it’s possible to “read” off the DNA sequence, letter by letter!The nanopore sequencer was initially used primarily for sequencing smaller microbial genomes. In fact, Loman was part of a team that used the portable nanopore device to track Ebola and Zika viruses during the recent outbreaks in Africa and Brazil [2, 3]. The nanopore sequencer was also used on the International Space Station to do the very first DNA sequencing in zero gravity [4].The larger, more complex human genome represents a much stiffer challenge. But Loman and colleagues took on the challenge, betting that MinION was now up to the task based on recent improvements in its sequencing speed, computer software, and sample prep.The team, which included five labs in three countries, sequenced the complete genome of a well-studied human cell line in a matter of weeks. The researchers generated 91.2 gigabytes of DNA data, enough to cover the genome 30 times over, which helps to put the pieces together accurately. Most notably, they also generated ultra-long “reads” up to 882, 000 bases of contiguous DNA sequence. The researchers report that they have since read individual DNA molecules over a million bases long! Though the final cost ran about $23, 000 to sequence one human genome, further refinements should continue to drop the price.The real trick to getting such long reads is to prepare the DNA in such a way that the molecules don’t get cut or otherwise broken into small fragments, which the team has learned to do well. In fact, the team reports that in principle there may be no limit to the read-lengths that are possible using nanopore-based sequencing, including possibly entire chromosomes. The challenge will be getting the DNA molecules into the sequencing device without damaging them. Once a DNA molecule is threaded into a pore, there’s really no reason for it to stop until its passed all the way through.Despite those longer, easier-to-assemble reads, the researchers still required some big computers, including the high-performance computational resources in NIH’s Biowulf system, to make sense of the data, correct for errors, and piece together portions of the genome that had been impossible to assemble previously. For example, they resolved several highly repetitive genomic regions, including the sequences of some essential genes in immunity. They were also able to accurately estimate the lengths of highly repetitive telomeres, which act like “caps” at the tips of chromosomes. Telomere lengths are of great research interest for their implications in aging and cancer.Just as capabilities once only available through huge supercomputers can today be accessed though apps on smartphones, DNA sequencers continue to get better, smaller, and more portable. And as this study demonstrates, there’s no doubt that we’re pushing ever closer to a time when it may become both feasible and practical to sequence individual human genomes to bring greater precision to the delivery of health care for everyone.References:[1] Nanopore sequencing and assembly of a human genome with ultra-long reads. Jain M, Koren S, Miga KH, Quick J, Rand AC, Sasani TA, Tyson JR, Beggs AD, Dilthey AT, Fiddes IT, Malla S, Marriott H, Nieto T, O’Grady J, Olsen HE, Pedersen BS, Rhie A, Richardson H, Quinlan AR, Snutch TP, Tee L, Paten B, Phillippy AM, Simpson JT, Loman NJ, Loose M. Nature Biotech. 2018 Jan. 29. [Epub ahead of print][2] Real-time, portable genome sequencing for Ebola surveillance. Quick J, Loman NJ, Duraffour S, Simpson JT, Severi E, Cowley L, et al..Nature. 2016 Feb 11;530(7589):228-232.[3] Establishment and cryptic transmission of Zika virus in Brazil and the Americas. Faria NR, Quick J, Claro IM, Thézé J, de Jesus JG, et al. Nature. 2017 Jun 15;546(7658):406-410.[4] Nanopore DNA Sequencing and Genome Assembly on the International Space Station. Castro-Wallace SL, Chiu CY, John KK, Stahl SE, Rubins KH, McIntyre ABR, Dworkin JP, Lupisella ML, Smith DJ, Botkin DJ, Stephenson TA, Juul S, Turner DJ, Izquierdo F, Federman S, Stryke D, Somasekar S, Alexander N, Yu G, Mason CE7, Burton AS. Sci Rep. 2017 Dec 21;7(1):18022.Links:DNA Sequencing (National Human Genome Research Institute/NIH)Loman Lab (University of Birmingham, United Kingdom)Matt Loose (University of Nottingham, U.K.)Adam Phillippy (National Human Genome Research Institute/NIH)MinION (Oxford Nanopore Technologies, U.K.)NIH Support: National Human Genome Research Institute; National Cancer Institute
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In the future we won’t edit genomes—we’ll just print out new onesWhy redesigning the humble yeast could kick off the next industrial revolution.by Bryan Walsh February 16, 2018At least since thirsty Sumerians began brewing beer thousands of years ago, Homo sapiens has had a tight relationship with Saccharomyces cerevisiae, the unicellular fungus better known as brewer’s yeast. Through fermentation, humans were able to harness a microscopic species for our own ends. These days yeast cells produce ethanol and insulin and are the workhorse of science labs.That doesn’t mean S. cerevisiae can’t be further improved—at least not if Jef Boeke has his way. The director of the Institute for Systems Genetics at New York University’s Langone Health, Boeke is leading an international team of hundreds dedicated to synthesizing the 12.5 million genetic letters that make up a yeast’s cells genome.In practice, that means gradually replacing each yeast chromosome—there are 16 of them—with DNA fabricated on stove-size chemical synthesizers. As they go, Boeke and collaborators at nearly a dozen institutions are streamlining the yeast genome and putting in back doors to let researchers shuffle its genes at will. In the end, the synthetic yeast—called Sc2.0—will be fully customizable.“Over the next 10 years synthetic biology is going to be producing all kinds of compounds and materials with microorganisms, ” says Boeke. “We hope that our yeast is going to play a big role in that.”Think of the project as something like Henry Ford’s first automobile—hand built and, for now, one of a kind. One day, though, we may routinely design genomes on computer screens. Instead of engineering or even editing the DNA of an organism, it could become easier to just print out a fresh copy. Imagine designer algae that make fuel; disease-proof organs; even extinct species resurrected.Jef Boeke leads an effort to create yeast with a man-made genome.“I think this could be bigger than the space revolution or the computer revolution, ” says George Church, a genome scientist at Harvard Medical School.Researchers have previously synthesized the genetic instructions that operate viruses and bacteria. But yeast cells are eukaryotic—meaning they confine their genomes in a nucleus and bundle them in chromosomes, just as humans do. Their genomes are also much bigger.That’s a problem because synthesizing DNA is still nowhere near as cheap as reading it. A human genome can now be sequenced for $1, 000, with the cost still falling. By comparison, to replace every DNA letter in yeast, Boeke will have to buy $1.25 million worth of it. Add labor and computer power, and the total cost of the project, already under way for a decade, is considerably more.Along with Church, among others, Boeke is a leader of GP-write, an organization advocating for international research to reduce the cost of designing, engineering, and testing genomes by a factor of a thousand over the next decade. “We have all kinds of challenges facing ourselves as a species on this planet, and biology could have a huge impact on them, ” he says. “But only if we can drive down costs.”Bottom upA scientist named Ronald Davis at Stanford first suggested the possibility of synthesizing the yeast genome at a conference in 2004—though initially, Boeke didn’t see the point. “Why would anyone want to do this?” he recalls thinking.But Boeke came around to the idea that manufacturing a yeast genome might be the best way to comprehend the organism. By replacing each part, you might learn which genes are necessary and which the organism can live without. Some team members call the idea “build to understand.”“It’s a different take on trying to understand how living things work, ” says Leslie Mitchell, a postdoctoral fellow in the NYU lab and one of the main designers of the synthetic yeast. “We learn what gaps in our knowledge exist in a bottom-up genetic approach.”Joel Bader, a computer scientist at Johns Hopkins, signed on to develop software that let scientists see the yeast chromosomes on a screen and keep track of versions as they changed, like a Google Docs for biology. And in 2008, to make the DNA, Boeke launched an undergraduate course at Hopkins called “Build a Genome.” Students would learn basic molecular biology as each one assembled a continuous stretch of 10, 000 DNA letters that would go toward the synthetic-yeast project. Later, several institutions in China joined to share the workload, along with collaborators in Britain, Australia, and Japan.“We assign chromosomes to individual teams, like assigning a chapter of a book, and they have the freedom to decide how to do it, as long as it’s based 100 percent on what we design, ” says Patrick Cai, a synthetic biologist at the University of Manchester and the yeast project’s international coordinator.Next stepsIt took Boeke and his team eight years before they were able to publish their first fully artificial yeast chromosome. The project has since accelerated. Last March, the next five synthetic yeast chromosomes were described in a suite of papers in Science, and Boeke says that all 16 chromosomes are now at least 80 percent done. These efforts represent the largest amount of genetic material ever synthesized and then joined together.It helps that the yeast genome has proved remarkably resilient to the team’s visions and revisions. “Probably the biggest headline here is that you can torture the genome in a multitude of different ways, and the yeast just laughs, ” says Boeke.
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Decoding the chemistry of fearSalk team charts pathway for fear in worms to reveal more about human anxietyLA JOLLA—Ask a dozen people about their greatest fears, and you’ll likely get a dozen different responses. That, along with the complexity of the human brain, makes fear—and its close cousin, anxiety—difficult to study. For this reason, clinical anti-anxiety medicines have mixed results, even though they are broadly prescribed. In fact, one in six Americans takes a psychiatric drug.A team of investigators from the Salk Institute uncovered new clues about the mechanisms of fear and anxiety through an unlikely creature: the tiny nematode worm. By analyzing the responses of worms exposed to chemicals secreted by its natural predator and studying the underlying molecular pathways, the team uncovered a rudimentary fear-like response that has parallels to human anxiety. Such insights may eventually help refine prescriptions for current anti-anxiety drugs and enable the development of new drugs to treat conditions like PTSD and panic disorder.In this illustration, a C. elegans worm (lower right) exposed to sulfolipid chemicals from one of its natural predators, a worm called P. pacificus, quickly reverses direction in a response analogous to human fear.“For the past 30 or 40 years, scientists have used simpler animals to figure out how fear might work in humans, ” says Sreekanth Chalasani, associate professor in Salk’s Molecular Neurobiology Laboratory and senior author of the paper, published in Nature Communications on March 19, 2018. “The idea has been that if you could figure out which underlying signals in the brain are related to fear and anxiety, you could develop better drugs to block them.”The team at Salk started with a simple creature, the microscopic worm called Caenorhabditis elegans. C. elegans, which contains only 302 neurons, has a natural predator—another worm called Pristionchus pacificus, which bites and kills C. elegans. The researchers discovered that by exposing C. elegans to chemicals that are excreted by P. pacificus, they could elicit a fear-like response. When it encounters these predator-excreted chemicals, C. elegans rapidly reverses direction and crawls away.They found that this fear-inducing chemical, a new class of molecules called sulfolipids, could activate four redundant brain circuits that led to this behavior. Additionally, C. elegans continued to change its behavior even after the fear-chemical was removed. This is analogous to behavior in mice, who express fear when exposed to the scent of cat urine, even if a cat is nowhere nearby.“For years, we thought that only advanced brains like those of mammals would have this complex reaction, ” Chalasani says. “But our study is showing that a simple animal expresses something very much like fear.”In the experiment, coauthor and UC San Diego graduate student Amy Pribadi soaked C. elegans in a solution containing the sulfolipid for 30 minutes. The worms failed to lay eggs, even for an hour after they had been removed from the solution—an indicator of acute stress as well as a longer-term response akin to anxiety. Further research showed that the signaling pathways activated during the worms’ response are similar to the pathways activated when more complex animals experience fear.When the worms were soaked in a solution containing Zoloft (a human anti-anxiety drug), however, these fear- and anxiety-like responses were not observed. This suggested that at least some of the pathways that the drug acts on to eliminate anxiety in mammals have been preserved by evolution.Also intriguingly, the team found that Zoloft acted on the worms’ GABA signaling in a neuron that affects the animal’s sleep. Whether this is also the case in humans is not yet known, but points to a potential pathway to understand why Zoloft works in some people and not others. The research eventually could lead to a change in how these drugs are prescribed.“We hope the findings from this paper will contribute to the field by providing a broader picture of some of these signaling activities, ” Chalasani says. “Our findings suggest that fear and anxiety are ancient and evolved much earlier than we originally thought. The pathways, nerves, circuits and genes that we’ll now be able to study in the worm should inform us about this process in humans.”In addition, he says, understanding which chemicals may repel nematodes could have implications for developing new kinds of pesticides, potentially ones that are even nontoxic. “C. elegans is not a pathogen, but many other types of nematodes can do severe damage to crops, ” he explains. “Biology research can go in many different directions, and you never know what you’re going to uncover.”The paper’s other authors were Zheng Liu, Maro J. Kariya, Christopher D. Chute, Sarah G. Leinwand, Ada Tong, and Kevin P. Curran of Salk; Neelanjan Bose and Frank C. Schroeder of Cornell University; and Jagan Srinivasan of Worcester Polytechnic Institute.This work was funded by the W. M. Keck Foundation, the National Institutes of Health and a Salk Alumni Fellowship.PUBLICATION INFORMATION JOURNALNature CommunicationsTITLEPredator-secreted sulfolipids induce defensive responses in C. elegansAUTHORSZheng Liu, Maro J. Kariya, Christopher D. Chute, Amy K. Pribadi, Sarah G. Leinwand, Ada Tong, Kevin P. Curran, Neelanjan Bose, Frank C. Schroeder, Jagan Srinivasan and Sreekanth H. Chalasani
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A tool that tracks and stops bacterial blight outbreaks in ricericetoday.irri.org/a-tool-that-tracks-and-stops-bacterial-blight-outbreaks-in-rice/A new, faster, and more accurate way of identifying infectious organisms—down to their genetic fingerprint—could finally put farmers a step ahead of bacterial blight. Severe bacterial blight infection in a susceptible rice variety from West Java, Indonesia. (Photo by R. Oliva)Severe bacterial blight infection in a susceptible rice variety from West Java, Indonesia. (Photo by R. Oliva)A revolutionary tool called the PathoTracer has been developed at the International Rice Research Institute (IRRI) and it can identify the exact strain of the bacterium that causes bacterial blight present in a field in a matter of days instead of several months of laboratory work.“It’s like a paternity test that uses DNA profiling, ” said Ricardo Oliva, a plant pathologist at IRRI. “It will not only tell you that you have bacterial blight in your plant. It will tell you the particular strain of the pathogen so that we can recommend varieties resistant to it.”For more than four years, Dr. Oliva and his team worked on deciphering the genetic code of Xanthomonas oryzae pv. oryzae, the pathogen that causes bacterial blight, to develop the test. Bacterial blight is one of the most serious diseases of rice. The earlier the disease occurs, the higher the yield loss—which could be as much as 70% in vulnerable varieties.“Bacterial blight is a persistent disease in rice fields, ” said Dr. Oliva. “The epidemic builds up every season when susceptible varieties are planted. The problem is that the bacterial strains vary from one place to another and farmers don’t know which are the resistant varieties for that region. We were always behind because the pathogens always moved and evolved faster.”Identifying the strains of bacterial blight present in the field requires a lot of labor and time. You need people to collect as many samples as they can over large areas to accurately monitor the pathogen population. In addition, isolating the pathogens in the lab is laborious and it typically takes several months or even a year to determine the prevalent strains in a region.The PathoTracer can identify the local bacteria in the field using small leaf discs as samples. The samples will be sent to a certified laboratory to perform the genetic test and the results will be analyzed by IRRI.The team that developed PathoTracer. Left row: Maritess Carillaga, Cipto Nugroho, Ian Lorenzo Quibod, and Genelou Grande. Right row: Veronica Roman-Reyna, Sapphire Thea Charlene Coronejo, and Dr. Oliva. Not in photo: Eula Gems Oreiro, EiEi Aung, and Marian Hanna Nguyen. (Photo by Isagani Serrano, IRRI)The team that developed PathoTracer. Left row (front to back): Maritess Carillaga, Cipto Nugroho, Ian Lorenzo Quibod, and Genelou Grande. Right row: Veronica Roman-Reyna, Sapphire Thea Charlene Coronejo, and Dr. Oliva. Not in photo: Eula Gems Oreiro, EiEi Aung, Epifania Garcia, Ismael Mamiit, and Marian Hanna Nguyen. (Photo by Isagani Serrano, IRRI)“It takes only a few days to analyze the samples, ” Dr. Oliva explained. “With the PathoTracer, we can bring a year’s work down to probably two weeks. Because the tool can rapidly and efficiently monitor the pathogen present in each season, the information can be available before the cropping season ends.”It’s like knowing the future, and predicting what would happen the next season can empower the farmers, according to Dr. Oliva.“Recognizing the specific local bacteria present in the current season can help us plan for the next, ” he added. “We can come up with a list of recommended rice varieties that are resistant to the prevalent pathogen strains in the locality. By planting the recommended varieties, farmers can reduce the risk of an epidemic in the next season and increase their profits.”The PathoTracer was pilot tested in Mindanao in the southern part of the Philippines in April 2017. The rains came early in the region, just after the peak of the dry season, and that triggered an outbreak of bacterial blight.“We went there and took samples from different fields, ” Dr. Oliva said. “By the end of April, we had the results and we were able to come up with a list of resistant varieties that could stop the pathogen. We submitted our recommendation to give farmers a choice in reducing the risk. If the farmers planted the same rice varieties in the succeeding rainy seasons, I am 100% sure the results would be very bad.”The PathoTracer can run thousands of samples and can, therefore, easily cover large areas, making it an essential tool for extension workers of agriculture departments and private-sector rice producers, or it can be incorporated into monitoring platforms such as the Philippine Rice Information System (PRiSM) or Pest and Disease Risk Identification and Management (PRIME) to support national or regional crop health decision-making.“National breeding programs could also make more informed decisions, ” Dr. Oliva said. “If you know the pathogen population in the entire Philippines, for example, the country’s breeding program could target those strains.”IRRI is interested in expanding the genetic testing tool to include rice blast and, further down the road, all bacteria, viruses, and fungi that infect rice.The speed at which PathoTracer can identify the strains of bacterial blight present in the field can be used for recommending resistant rice varieties to farmers for planting in the next cropping season. (Photo: IRRI)The speed at which PathoTracer can identify the strains of bacterial blight present in the field can be used for recommending resistant rice varieties to farmers for planting in the next cropping season. (Photo: IRRI)The PathoTracer has been tested in other Asian countries and IRRI expects to roll it out early in 2018. When it becomes available, the expected potential impact of the PathoTracer on a devastating disease that affects rice fields worldwide would be huge.“Imagine if this tool prevented bacterial blight outbreaks every season across Asia, ” said Dr. Oliva. “It’s super cool!”For more information about bacterial blight, see Section II, Chapter 2 of IRRI’s Rice Diseases Online Resource
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IGIB researchers partially reverse a rare disorderThe HinduR. Prasad10 FEBRUARY 2018 18:13 ISTUPDATED: 10 FEBRUARY 2018 18:14 IST The syndrome also affects about one in one lakh people, causing a range of defectResearchers at Delhi’s Institute of Genomics & Integrative Biology (CSIR-IGIB) have for the first time used zebra fish to model the rare genetic disorder — Rubinstein Taybi Syndrome (RSTS) — seen in humans. They have also used two small molecules to partially reverse some of the defects caused by the disorder in zebrafish, thus showing them to be an ideal animal model for screening drug candidates. There is currently no cure or treatment for the disorder.The Rubinstein Taybi Syndrome has a frequency of about one in one lakh people, and causes intellectual disability, growth retardation (short stature), craniofacial deformities, heart defects and broad thumbs and toes. The results were published in the journal Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.Close to human genomeSince zebrafish genome has very close similarity to human genome and the embryonic developmental is very similar in the two, the team led by Dr. Chetana Sachidanandan at IGIB went about checking if EP300, one of the two genes that cause the disorder is present in the fish and if mutations in this gene result in a RSTS-like disease in fish.Using chemicals, the researchers inhibited the activity of the protein Ep300 to see if this resulted in the manifestation of the disorder in the brain, heart, face and pectoral fins (equivalent to forearm in humans). “Like in the case of humans, the same organs were affected in the fish when the functioning of the protein was stopped. This helped in confirming that the protein in question does the same functions in fish and humans, ” she says.Since zebrafish commonly has two copies of many human genes, the researchers first checked if one or both the genes were functional and equivalent to the human gene that causes the disorder. “We found Ep300a gene was active and functional while Ep300b was not, ” says Prof. Tapas K. Kundu from the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, the other corresponding author. The Ep300a gene is responsible for producing a protein (Ep300) that opens up the DNA.“The protein Ep300 is evolutionarily conserved from fish to humans. Though the Ep300 gene has been earlier identified in fish, its function was not known, ” says Prof. Kundu.Reversal of effectsLike in the case of fish treated with chemicals manifesting the disorder, fish mutants that lacked the Ep300a gene too exhibited defects very similar to those seen in humans.“When we introduced excess amount of a tiny portion of the Ep300a protein in the mutants, the craniofacial deformities became less severe [mutants had severed craniofacial deformities] and pectoral fins in the fish became normal, ” she says.But neuronal defects were not reversed, even partially. “It might be because only a portion of the protein was put into the fish. Probably, that potion isn’t sufficient to compensate for the loss of the whole protein, ” she explains.“It’s proof-of-concept that just a piece of the protein is sufficient to reverse some defects, even if only partially, in zebrafish, ” Dr. Sachidanandan says.Alternatively, the researchers used two small molecules to reverse the defects. If the protein Ep300 is responsible for opening the DNA, there are other proteins that are responsible for closing the DNA.The two molecules were found from a screen of compounds well known for their ability to inhibit proteins responsible for closing the DNA.Like in the case when excess amount of Ep300 protein was introduced, both the molecules could partially restore facial defects but not the neuronal defects.“Introducing excess amount of a portion of the ep300 protein showed greater rescue of deformities than the small molecules, ” says Aswini Babu from IGIB and first author of the paper. “But rescuing the deformities using small molecules is a relatively easier and better option.”
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HUMAN DEVELOPMENTHow to build a human brainSome steps for growing mini versions of human organs are easier than othersBY INGFEI CHEN 3:30PM, FEBRUARY 20, 2018SHARE ARTICLEorganoid brainBRAIN-MAKING 101 As blobs of two types of brainlike tissue fuse, interneurons (green) migrate from the left clump to the right, linking with neurons (not stained) in the right blob. On both sides, neural support cells called glia appear in purple.PAŞCA LAB/STANFORD UNIV.Magazine issue: Vol. 193, No. 4, March 3, 2018, p. 22SPONSOR MESSAGEIn a white lab coat and blue latex gloves, Neda Vishlaghi peers through a light microscope at six milky-white blobs. Each is about the size of a couscous grain, bathed in the pale orange broth of a petri dish. With tweezers in one hand and surgical scissors in the other, she deftly snips one tiny clump in half.When growing human brains, sometimes you need to do some pruning.The blobs are 8-week-old bits of brainlike tissue. While they wouldn’t be mistaken for Lilliputian-sized brains, some of their fine-grained features bear a remarkable resemblance to the human cerebral cortex, home to our memories, decision making and other high-level cognitive powers.Vishlaghi created these “minibrains” at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, where she’s a research assistant. First she immersed batches of human pluripotent stem cells — which can morph into any cell type in the body — in a special mix of chemicals.The free-floating cells multiplied and coalesced into itty-bitty balls of neural tissue. Nurtured with meticulously timed doses of growth-supporting ingredients, the cell clumps were eventually transferred to petri dishes of broth laced with Matrigel, a gelatin-like matrix of proteins.On day 56, the blobs display shadowy clusters of neural “rosettes.” Under a laser scanning microscope, razor-thin slices of those rosettes reveal loose-knit layers of a variety of dividing neural stem cells and the nerve cells, or neurons, they give rise to. The layered structures look similar to the architecture of a human fetal brain at 14 weeks of gestation.By eight weeks, brainlike clumps (top) show neural clusters called rosettes. Within one cluster (red box, expanded at bottom), stem cells (blue and teal) churn out layers of neural precursor cells (pink) and neurons (not stained).BOTH: M. WATANABE ET AL/CELL REPORTS 2017Across the globe, labs such as this one, led by UCLA developmental biologist and neuroscientist Bennett Novitch, are cultivating thousands of these brainy clumps for research. Less than five years ago, a team of biologists in Austria and the United Kingdom and one in Japan wowed the world when they announced they had made rudimentary bits of 3-D human cerebral cortex in a dish. Since then, researchers have been eagerly tinkering with techniques for producing these miniature brain models, like chefs obsessively refining their favorite recipes.“It’s like making a cake: You have many different ways in which you can do it, ” says Novitch, who prefers using the Japanese method with a few tweaks. “There are all sorts of little tricks that people have come up with to overcome some of the common challenges.”For instance, because the brain blobs lack a built-in blood supply, they must absorb enough oxygen and nutrients from the tissue-culture broth to remain healthy. To help, some labs circulate the broth around the tissue clumps. The UCLA researchers choose instead to grow theirs at higher oxygen levels and chop the blobs at the 35-day mark, when they are as wide as three millimeters, and then about every two weeks after. Sounds radical, but the slicing gives cells on the inside — some of which start dying — exposure to much-needed oxygen and nutrients. Those divided bits then continue growing separately. But cutting can be done only so many times before the expanding rosette structures inside are damaged.With all the experimenting, researchers have cooked up a lot of innovations, including some nifty progress reported in just the last year. Scientists have concocted tiny versions of several brain regions ranging from the hypothalamus, which regulates body temperature, thirst and hunger, to the movement-controlling basal ganglia. Electrical chatter among neurons, reflecting active brain circuits, has been detected. And research groups have recently begun linking bits of specific regions like Legos. Scientists have even observed some early developmental processes as they happen within the human brain blobs.Stem cell payoffThe work is part of a broader scientific bonanza that comes from coaxing human stem cells to self-assemble into balls of organlike tissue, known as organoids, that are usually no bigger than a lentil. Although the organoids don’t grow enough to replicate entire human organs, these mini-versions can mimic the 3-D cellular infrastructure of everything from our guts to our lungs. That’s something you can’t get from studies of rodents, which have different biology than humans do.Mini-organ models promise enormous advantages for understanding basic human biology, teasing apart human disease processes, and offering an accurate testing ground for finding or vetting drug therapies. And by creating personalized organoids from the reprogrammed cells of patients, scientists could study disease in a very individualized way — or maybe even use organoid structures to replace certain damaged tissues, such as in the liver or spinal cord.“Organoids offer an unprecedented level of access into the inner workings of the human brain, ” Novitch says, noting that our brains are largely off-limits to poking and cutting into for research. If scientists can study accurate models of working neural circuits in these brain bits, he and others say, researchers might finally get a handle on uniquely human neurological conditions. Such disorders, which include epilepsy and, experts theorize, schizophrenia and autism (SN Online: 7/17/15), can arise when the brain’s communication networks develop off-kilter.
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MISSION CRITICALHEALTH, CANCER, MICROBIOLOGYHuman skin bacteria have cancer-fighting powersThe microbes make a compound that disrupts DNA formation in tumor cellsBY AIMEE CUNNINGHAM 3:49PM, FEBRUARY 28, 2018Staphylococcus epidermidis petri dishSKIN WIN Staphylococcus epidermidis, a species of bacteria that lives on human skin, grows here in a dish. Strains of this bacteria make a cancer-fighting compound that stops DNA synthesis.R. GALLO AND TERUAKI NAKATSUJI/UC SAN DIEGOSPONSOR MESSAGECertain skin-dwelling microbes may be anticancer superheroes, reining in uncontrolled cell growth. This surprise discovery could one day lead to drugs that treat or maybe even prevent skin cancer.The bacteria’s secret weapon is a chemical compound that stops DNA formation in its tracks. Mice slathered with one strain of Staphylococcus epidermidis that makes the compound developed fewer tumors after exposure to damaging ultraviolet radiation compared with those treated with a strain lacking the compound, researchers report online February 28 in Science Advances.The findings highlight “the potential of the microbiome to influence human disease, ” says Lindsay Kalan, a biochemist at the University of Wisconsin–Madison.Staphylococcal species are the most numerous of the many bacteria that normally live on human skin. Richard Gallo and his colleagues were investigating the antimicrobial powers of these bacteria when the team discovered a strain of S. epidermidis that made a compound — 6-N-hydroxyaminopurine, or 6-HAP for short — that looked a lot like one of the building blocks of DNA. “Because of that structure, we wondered if it interfered with DNA synthesis, ” says Gallo, a physician scientist at the University of California, San Diego. In a test tube experiment, 6-HAP blocked the enzyme that builds DNA chains and prevented the chains from growing.Mice treated with a strain of S. epidermidis that does not make the compound 6-HAP and then exposed to ultraviolet rays developed UV-induced tumors (left). The skin of mice who got a strain with the compound remained largely normal (right). T. NAKATSUJI ET AL/SCI ADV 2018Cancer cells have runaway growth, so the researchers thought the compound might inhibit those cells. Sure enough, 6-HAP stopped DNA formation in different tumor cells grown in the lab. But the compound was not able to do so in normal skin cells. Certain enzymes in normal skin cells deactivated 6-HAP, the researchers found, and the tumor cells tested appeared to lack those enzymes.Gallo and colleagues found that the compound had an effect both when injected and when applied topically. Among mice injected with skin cancer cells, some received a shot of 6-HAP while others got a dummy shot. Tumors grew in all the mice, but the tumors in mice given the compound were about half the size of those in mice without the compound.The researchers then spread S. epidermidis on the backs of hairless mice subjected to UV rays. Some mice got a strain that makes 6-HAP; others got a strain that does not. After 12 weeks of being exposed periodically to UV rays, the first group of mice developed only one tumor each, while mice in the second group were saddled with four to six tumors.S. epidermidis strains might have gained the ability to stop DNA synthesis to prevent other bacteria from growing, Gallo says. In that way, the bacteria protect their homestead from other invading pathogens. “Perhaps we evolved to provide a safe haven for these organisms because they also benefit us when they’re doing this.” The researchers did a small study of existing genetic data from the human skin microbiome and estimate that 20 percent of the human population have S. epidermidis strains that make 6-HAP on their skin, Gallo says.More work needs to be done to understand how S. epidermidis makes 6-HAP and how much of the compound is on the skin, Kalan says. “It is important to understand how the microbiome interacts with its human host before we can begin to manipulate it for disease treatment.” One approach could be to develop probiotics for the skin — adding helpful bacteria to ward off infection or maybe even prevent cancer, she says.Along with skin cancer cells, 6-HAP was also able to block DNA synthesis in lymphoma cells, cancerous immune system cells. It’s too early to say, but there is potential for this secret weapon to slay more than one villain.
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