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Updates found with 'delivery bots'

New DNA nanorobots successfully target and kill off cancerous tumorsBY SARAH BUHRFeb 12, 2018Science fiction no more — in an article out today in Nature Biotechnology, scientists were able to show tiny autonomous bots have the potential to function as intelligent delivery vehicles to cure cancer in mice.These DNA nanorobots do so by seeking out and injecting cancerous tumors with drugs that can cut off their blood supply, shriveling them up and killing them.“Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth, ” the paper explains.DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.DNA nanorobots, Nature Biotechnology 2018The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor’s vessels and cutting off their blood supply, leading to their death.Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they’d been programmed to target, according to the paper.The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.The goal, say the scientists behind the paper, is to eventually prove these bots can do the same thing in humans. Of course, more work will need to be done before human trials begin.Regardless, this is a huge breakthrough in cancer research. The current methods of either using chemotherapy to destroy every cell just to get at the cancer cell are barbaric in comparison. Using targeted drugs is also not as exact as simply cutting off blood supply and killing the cancer on the spot. Should this new technique gain approval for use on humans in the near future it could have impressive affects on those afflicted with the disease
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Clog Resistance of non-Pressure Based Flow CytometersBy Greg Kaduchak, PhD10.25.2017Flow cell clogs have been a long standing issue in flow cytometry. The small dimensions of the flow cell and fluidic path are susceptible to clogs especially when using larger or ‘sticky’ cells. In addition, historically, flow cytometer systems have been pressure-based which compounds this issue even more.In pressure-based systems, the particles are transported through the system by applying pressure to the fluid. It is a straightforward method to move the fluids through the small channels. To ensure a smooth delivery of fluids and particles through the flow cell without fluctuations, the systems employ pressure regulators. For those that have used these systems, it is a proven design to deliver particles in a flow cytometer and has been successful over the years. But, in the event of a clog, there is not much these systems can do.Figure 1(a) and (b) show what happens when a clog is encountered in a pressure-based fluidic system. When the system is in normal operation (a), the fluid is pushed through the system a specified pressure. For this example, we have used 7 psi. But, as seen in (b), when a clog is encountered the regulator keeps the system at 7 psi. No additional pressure is exerted to move the clog through the flow cell and the flow stops.Figure 1In contrast, in systems that employ positive displacement to drive the fluidic system (e.g. syringe pumps), the pressure is not held constant. These systems operate by a principle of constant volumetric flow. They are designed for fluid to flow with a specified volume delivery rate regardless of the pressure. An example of such a system facing a potential clog is shown in Figs. 1(c) and (d). As seen, the system operates at the same pressure as the pressure-based system when all is fine. But, once a clog is encountered, the system will build pressure to maintain the volumetric delivery rate. Pressure will build until the clog is displaced.The fluidic system in the Attune NxT Acoustic Focusing Flow Cytometers is based on positive displacement fluid delivery. For the purpose of robust clog removal, the system is outfit with a sensor that monitors the system pressure. When a potential clog is encountered, the pressure is allowed to build all the way up to 60 psi before safely shutting down the system. An additional benefit is used by the Attune NxT Flow Cytometer to keep the flow cell clean: a rinse cycle automatically runs between samples, this clears the sample in the flow cell with excess sheath fluid to prevent any cellular buildup.This feature has made the Attune flow cytometer platforms extremely clog resistant. Its install base has grown considerably since its initial launch more than two years ago, but still only a few clogs have been encountered by users of properly maintained instruments. Due to this resistance to clog, positive displacement systems are great from applications where cells are large and sticky, especially for tissue-based samples.
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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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A breakthrough in our understanding of how red blood cells developPosted on March 15, 2018 by Kat J. McAlpine Posted in People, Science, Therapeutics By taking a deep dive into the molecular underpinnings of Diamond-Blackfan anemia, scientists have made a new discovery about what drives the development of mature red blood cells from the earliest form of blood cells, called hematopoietic (blood-forming) stem cells.For the first time, cellular machines called ribosomes — which create proteins in every cell of the body — have been linked to blood stem cell differentiation. The findings, published today in Cell, have revealed a potential new therapeutic pathway to treat Diamond-Blackfan anemia. They also cap off a research effort at Boston Children’s Hospital spanning nearly 80 years and several generations of scientists.Diamond-Blackfan anemia — a severe, rare, congenital blood disorder — was first described in 1938 by Louis Diamond, MD, and Kenneth Blackfan, MD, of Boston Children’s. The disorder impairs red blood cell production, impacting delivery of oxygen throughout the body and causing anemia. Forty years ago, David Nathan, MD, of Boston Children’s determined that the disorder specifically affects the way blood stem cells become mature red blood cells.Then, nearly 30 years ago, Stuart Orkin, MD, also of Boston Children’s, identified a protein called GATA1 as being a key factor in the production of hemoglobin, the essential protein in red blood cells that is responsible for transporting oxygen. Interestingly, in more recent years, genetic analysis has revealed that some patients with Diamond-Blackfan have mutations that block normal GATA1 production.Now, the final pieces of the puzzle — what causes Diamond-Blackfan anemia on a molecular level and how exactly ribosomes and GATA1 are involved — have finally been solved by another member of the Boston Children’s scientific community, Vijay Sankaran, MD, PhD, senior author of the new Cell paper.“Much of the history of how this disorder works was written at Boston Children’s, ” says Sankaran, who is a hematologist/oncologist and a principal investigator at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “Now, we can move on to the next era of research — what we can do to treat it.”Learning from an error of naturePrevious studies have found that many patients with Diamond-Blackfan anemia have mutated ribosomal protein genes. But the question has remained: Do these mutations have something to do with GATA1 and why do they only impair the maturation of red blood cells? In Diamond-Blackfan, other mature blood cells — such as platelets, T cells and B cells — still fare well despite mutations of ribosomal protein or GATA1 genes.EPO molecule which is linked to production of red blood cellsLast year, Sankaran’s research on Diamond-Blackfan anemia led to a discovery that saved an infant’s life.“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes, ” Sankaran says. “We know now that it is the latter.”By closely examining human cell samples from patients with Diamond-Blackfan anemia, Sankaran and his team of collaborators found that the quantity of ribosomes within blood cell precursors directly influences their ability to produce effective levels of GATA1, which, if you remember, is needed for hemoglobin production and also for red blood cell production.Now, finally tying all the pieces together, Sankaran and his team have definitively found that a reduced number of ribosomes slashes the output of GATA1 proteins inside blood stem cells, therefore impairing their differentiation into mature red blood cells.An opportunity for gene therapyTheir finding supports the hypothesis that the presence of GATA1 proteins in early blood stem cells helps prime them for differentiation into red blood cells. Without enough ribosomes to produce enough GATA1 proteins, these early cells simply never receive the signal to become red blood cells.“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency, ” Sankaran says. “We now have a tremendous interest in this approach and believe it can be done.”Although a bone marrow transplant from a matched donor can treat Diamond-Blackfan anemia, Sankaran says that a gene therapy would be advantageous since it would use a patient’s own engineered cells, avoiding dangerous risks associated with graft versus host disease.“I think what’s great is that we can learn about developmental biology just by looking at our own patients very carefully, ” says Sankaran. “Genetic errors can give us the chance to pick apart the complex pieces of health and discover how they relate to one another.”In addition to Sankaran, additional authors of the new paper are Rajiv K. Khajuria, Mathias Munschauer, Jacob C. Ulirsch, Claudia Fiorini, Leif S. Ludwig, Sean K. McFarland, Nour J. Abdulhay, Harrison Specht, Hasmik Keshishian, D.R. Mani, Marko Jovanovic, Steven R. Ellis, Charles P. Fulco, Jesse M. Engreitz, Sabina Schütz, John Lian, Karen W. Gripp, Olga K. Weinberg, Geraldine S. Pinkus, Lee Gehrke, Aviv Regev, Eric S. Lander, Hanna T. Gazda, Winston Y. Lee, Vikram G. Panse and Steven A. Carr.This research was supported by the National Institutes of Health (DK103794, R33 HL120791 and T32 HL007574), a Manton Center Endowed Scholar Award, a DBA Foundation and March of Dimes Basil O’Connor Scholar Award, a Boehringer Ingelheim MD Fellowship, the Swiss National Science Foundation, Novartis Foundation, Olga Maybenfisch Stiftung and the European Research Council (EURIBIO260676).
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Gene editing can help treat congenital disease before birthUpdated Oct 09, 2018 | 20:02 IST | IANSPrenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.Representational imagePhoto Credit: ThinkstockRepresentational Image New York: In a first, a team of scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory mice, offering the potential to treat human congenital diseases before birth. The study led by research from Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania used both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools and reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels.They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1).AdvertisingAdvertisingHT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders."Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy, " said William H. Peranteau, a paediatric and foetal surgeon at CHOP."We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants, " he added. In the study, published in the journal Nature Medicine, the team used BE3, joined it with a modified CRISPR-associated protein 9.After birth, the mice carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bio-engineered to model HT1, BE3 improved liver function and preserved survival.However, "a significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach", said Peranteau.He added: "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."
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