d-mannose induces regulatory T cells and suppresses immunopathologyby WanJun Chen from the Mucosal Immunology Section of NIHFunded by NIH Abstract: d-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of d-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of d-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, d-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-b activation, which in turn was mediated by upregulation of integrin avb8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of d-mannose may have clinical applications for immunopathology. Notes:Fruits containing Mannose: cranberries, tomatoes, apples, peaches, and blueberriesVegetables containing mannose: green beans, cabbage, broccoli, and eggplant“d-mannose is a C-2 epimer of glucose and occurs naturally in many plants and fruits, especially cranberries.”“For example, a d-mannose supplement has been shown to be an effective therapy for congenital disorders of glycosylation type Ib2,4. It has also been used as a non-antibiotic treatment for bacterial urinary tract infection in animals5 and humans6, with a proposed mechanism of binding to the type 1 pili of enteric bacteria and thereby blocking their adhesion to uroepithelial cells7.”“However, it is unknown whether d-mannose has any effect on T cells and immune responses. Here we show that oral administration of d-mannose suppressed immunopathology in models of autoimmune diabetes and airway inflammation.”“We administered d-mannose in drinking water to BALB/cJ mice for 2 weeks,”“hus, as in mouse T cells, d-mannose also drove Treg cell generation in human naive CD4+ T cells via a TGF-β-dependent mechanism.”“TGF-β is produced as a latent form in complex with latent associated protein (LAP)28,29”“We next determined whether d-mannose has beneficial effects in autoimmunity, using as a type 1 diabetes model non-obese diabetic (NOD) mice, in which pathology involves Treg cell defects40. NOD mice received d-mannose in their drinking water starting at 7.5 weeks of age, when the mice are considered prediabetic, and at which point the inflammatory process has just been initiated but blood glucose levels are still within the normal range40 (Supplementary Fig. 11a). As expected, control (non-d-mannose-treated) NOD mice started to develop diabetes at about 12–13 weeks of age, and 80–90% became diabetic by the age of 23 weeks (Fig. 4a). However, most of the NOD mice supplemented with d-mannose were diabetes-free through 23 weeks of age (Fig. 4a).”“Moreover, treatment of NOD mice with d-mannose once they had reached prediabetic blood glucose levels of 140–160 mg/dL (Supplementary Fig. 11e) or new-onset diabetic levels of 200–230 mg/dL (refs. 41,42) (Supplementary Fig. 12a) suppressed the progression of diabetes (Fig. 4h–k, Supplementary Fig. 12b–d).”“We next tested d-mannose function in a model of lung airway inflammation.”“Indeed, we found that d-mannose treatment prevented the development of airway inflammation in the lungs, as demonstrated by considerably less infiltration of inflammatory cells and reduced mucus production in the airways compared with that in control mice (Fig. 6a,b).”“To investigate whether d-mannose can be effective in a clinically relevant setting, we first induced airway inflammation in the mice and then treated them with d-mannose in drinking water (Supplementary Fig. 15a). We found that d-mannose treatment significantly ameliorated airway inflammation (Fig. 6g–i).”“Here we have outlined a previously unrecognized ability of d-mannose, a hexose sugar, to suppress experimental type 1 diabetes and lung airway inflammation.”“Of note, long-term supplementation with d-mannose had no obvious side-effects in the NOD mice—a finding that might have implications for the development of a similar clinical therapy for type 1 diabetes in humans49.”“However, it should be noted that the reasons for the lack of an increased frequency of Treg cells among the polyclonal nontransgenic CD4+ T cells remain unknown and require further investigation.”“A previous study showed that a high concentration of glucose (for example, >25 mM) can activate TGF-β and may be involved in the growth of epithelial and mesenchymal cells46.”“Notably, we replicated and confirmed this immunoregulatory effect of d-mannose in an ovalbumin-induced airway inflammation model, which indicates broader efficacy of mannose-mediated therapeutic effects on immunopathology.”“The physiological level of d-mannose in the blood of humans and mice is approximately 100 μM. However, it has been reported that the amount of circulating d-mannose increases up to ninefold (from 100 to 900 μM) in mice receiving d-mannose in drinking water, with no adverse consequences49.”“In humans, stable serum d-mannose levels of up to 2 mM can be reached and are well tolerated, without signs of liver or renal toxicity51.”“Moreover, the possible connection between the consumption of fruits rich in d-mannose (for example, cranberries) and autoimmunity may be an interesting and important issue.”
I’m writing this week’s blog in response to a couple of recent articles published in Science addressing quality control in academic labs. Step up for quality research in Science 2017, vol 357, p531 and Fostering reproducibility in industry-academia research in Science 2017, vol 356, p759Referencing publications:Step up for quality research in Science 2017, vol 357, p531Fostering reproducibility in industry-academia research in Science 2017, vol 356, p759Quality Time in Nature 2016, vol 529, p456
Necroptosis activation in Alzheimer’s diseaseNature Neuroscience 2017, vol 20, p1236-1246By Salvatore Oddo from Arizona State University, Banner Neurodegenerative Disease Research CenterFunded primarily by Arizona Alzheimer’s Consortium and the NIH Abstract: Alzheimer’s disease is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human Alzheimer’s Disease brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent Alzheimer’s Disease transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in Alzheimer’s Disease. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of Alzheimer’s Disease. We anticipate that our findings will spur a new area of research in the Alzheimer’s Disease field focused on developing new therapeutic strategies aimed at blocking its activation. Notes:“AD is the sixth leading cause of death in the United States, where there are currently more than 5 million cases1. Given that there are no effective therapeutic approaches to treat or slow down the progression of the disease, it is estimated that the number of cases in the United States alone will reach 20 million by 2050 (ref. 1). Clinically, AD is characterized by progressive memory loss, personality disturbances and general cognitive decline2,3. Neuropathological, AD is characterized by the accumulation of tau, amyloid-β (Aβ) and marked neuroinflammation. Tau is a microtubule-binding protein that is hyperphosphorylated and mislocalized in AD5. Aβ derives from a larger precursor, amyloid precursor protein (APP), which is ubiquitously expressed throughout the brain4. Marked neuronal loss is another constant feature of AD.”“Classically, cell death has been classified into two main groups: apoptosis and necrosis. Apoptosis is a programmed form of cell death, whereas necrosis is an uncontrolled lysis of the cell8.”“Necroptosis was first identified as a result of inflammation11; however, it is now clear that many micro-environmental factors activate this pathway9,10. There are three key proteins involved in the execution of necroptosis: RIPK1, RIPK3 and MLKL12.”“We found for the first time, to the best of our knowledge, that necroptosis is also activated in AD, thereby providing a plausible mechanism underlying neuronal loss in this insidious disorder.”“The changes in solubility of the necrosome have also been confirmed in the cortex of people with multiple sclerosis13.”“During necroptosis activation, RIPK1 binds to and activates RIPK3, which then binds to and activates MLKL9,10.”“These findings indicate that inducing necroptosis exacerbates cognitive decline in APP/PS1 mice to a greater degree than in NonTg mice.”“The lack of changes in Aβ and tau suggest that inducing necroptosis does not contribute to Aβ and tau accumulation.”“Neuronal loss is a cardinal feature of AD and invariably affects multiple brain regions. Notably, brain atrophy is evident in asymptomatic individuals 10 years before the onset of dementia30. Despite this indisputable evidence, the precise mechanism by which neurons die remains unknown31–33.”“However, the vast majority of ongoing clinical trials are designed to reduce a toxic insult (for example, removal of Aβ from the brain).”“From a basic biology perspective, it will be essential to dissect the mechanisms underlying necroptosis induction in AD; such studies may reveal new insights into the pathogenesis of this disorder. From a therapeutic perspective, our data strongly suggest that reducing necroptosis may be a valid therapeutic target for AD.”“In summary, we report, to the best of our knowledge, the first direct evidence of necroptosis activation in AD. These findings may serve as a springboard for future evaluation of triggers of necroptosis in AD. Moreover, these findings may open up a new phase of drug discovery for AD focused on identifying small molecule inhibitors of RIPK1, RIPK3 and/or MLKL.”Used GWAS to identify necrotic genes that would be upregulated in AD patients. Dinner party tag line: Researchers just figured out that dying brain cells are the cause of Alzheimer’s Disease effects and not necessarily the buildup of tau and amyloid-B proteins in the brain. Since this is a new finding identifying the cause, big pharma can now develop drug targets to prevent this from happening. So much of science really is knowing the right question to ask. The answer is often right in front of our noses, but we don’t know what question to ask to yield the answers we have been looking for.
Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy By Weiping Zou from China and the University of MichiganFunding through China What is the most important rule in chemistry?Never lick the spoon. Abstract: Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium(F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinico-pathological characteristics. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, micro-RNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes. Notes:Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. In advanced CRC patients, the purpose of chemotherapy is to shrink tumor size, reduce tumor growth, and inhibit tumor metastasis. In general, active cytotoxic drugs, including 5-fluorouracil (5-FU) and capecitabine, inhibit the enzyme activity of thymidylate synthase during DNA replication. Oxaliplatin, another chemotherapy drug, inhibits tumor cell growth and causes cell G2 phase arrest by covalently binding DNA and forming platinum-DNA adducts. The combination of these chemotherapeutic agents is widely used in the treatment of CRCs. The majority of patients with advanced CRC are initially responsive to the combined chemotherapy. However, the patients eventually experience tumor recurrence due to drug resistance, and the 5 year survival rate is lower than 10% in advanced CRC patients. Unfortunately, colon cancer patients are generally not responsive to novel immune checkpoint therapy. Thus, it is of paramount importance to elucidate the mechanism of chemotherapy resistance in CRC patients. Cancer chemoresistance results from a complex interplay between gene regulation and the environmentRecent mouse studies have shown that the gut microbiota may modulate local immune responses and in turn affect chemotherapy and immunotherapy. Human gut microbiota are linked to inflammatory cytokine productionA high amount of F. nucleatum was strongly associated with shorter recurrence free survival (RFS) (Figure 1D). The five-year recurrence survival was substantially shorter in the F. nucleatum-high group than the F. nucleatumlow group. Receiver operating characteristic (ROC) curve analysis was conducted to predict the potential CRC recurrence using either AJCC stage or the amount of F. nucleatumGiven the role of the autophagy pathway in cellular survival, our data suggest that F. nucleatum may cause autophagy pathway activation and potentially support cancer chemoresistanceMoreover, F. nucleatum had no protective effect on HCT116 cells and HT29 cells treated with DoxorubicinWe found that the F. nucleatum-induced chemoresistant effect was abolished by CQ treatment in HCT116 cells (Figures 3A and 3B) and HT29 cellsThe data indicate that F. nucleatum may induce autophagy activation via increasing ULK1 and ATG7 expressionTo explore the mechanism by which F. nucleatum induced upregulation of pULK1, ULK1, and ATG7 at both the mRNA and protein levelCapecitabine (and 5-FU) in combination with platinum-based chemotherapy has been widely used to treat different types of cancer including CRC. Although CRC patients’ initial responses to surgical debulking and chemotherapy is often effective, relapse with drug-resistant cancer usually occurs and patients succumb to disease. Unfortunately, CRC patients are generally not responsive to novel immune checkpoint therapy. Conventional chemotherapy remains the first line therapy for patients with CRC. Thus, understanding the mechanisms of chemoresistance in CRC is essential to optimizing current therapeutic strategies.Recent mouse studies have shown that the gut microbiota may modulate local immune responses and in turn affect chemotherapy and immunotherapyFurthermore, our data raise an important clinical question: are conventional chemotherapeutic regimens including Capecitabine plus Oxaliplatin suitable for CRC patients with a high amount of F. nucleatum? Alternatively, we suggest that CRC patients with a high amount of F. nucleatum may be treated with conventional chemotherapy in combination with anti-F. nucleatum treatment and/or an autophagy inhibitor. Thus, it is important to detect F. nucleatum and its associated pathway and differentially manage patients with different levels of F. nucleatum. Dinner Party Tag Line: Researchers from China figured out that one of the reasons colorectal cancer recurrence is so high is because of an imbalance in patients gut microbiota. Basically, one bacteria species in your gut is protecting colorectal cancer from common chemotherapeutics.
If the Silver Surfer and Iron Man team up, they would be alloys.Harvesting electrical energy from carbon nanotube yarn twistby Ray Baughmann of the Alan MacDiarmid NanoTech Institute at the University of Texas, DallasFunded by the Air Force office of Science Grants, NASA, and the Office of Naval ResearchScience 2017, vol 357, p773 Abstract: Mechanical energy harvesters are needed for diverse applications, including self-powered wireless sensors, structural and human health monitoring systems, and the extraction of energy from ocean waves. We report carbon nanotube yarn harvesters that electrochemically convert tensile or torsional mechanical energy into electrical energy without requiring an external bias voltage. Stretching coiled yarns generated 250 watts per kilogram of peak electrical power when cycled up to 30 hertz, as well as up to 41.2 joules per kilogram of electrical energy per mechanical cycle, when normalized to harvester yarn weight. These energy harvesters were used in the ocean to harvest wave energy, combined with thermally driven artificial muscles to convert temperature fluctuations to electrical energy, sewn into textiles for use as self-powered respiration sensors, and used to power a light-emitting diode and to charge a storage capacitor. Notes:"The importance of using mechanical energy as electrical energy motivates the search for new technologies”Current energy generating technologies do not scale well to the millimeter scaleThey previously worked on incorporating carbon nanotubes into yarn for to generate energy, but the system was not realistic for commercial use.They figured out that creating functional energy harvester depended greatly on how the yarn was fabricated; cone spinning is better than the standard dual archimedean Power generation was optimized for spring index, and stretching frequency, among other variablesEnergy harvesters showed no loss in performance following 30,000 cyclesTheir products demonstrate among the highest peak power and peak power/frequency among competitor technologies while remaining low cost.They demonstrated real products for generating energy from waves, gloves, and monitoring breathing with shirts. Dinner party tag line: I heard about this new way researchers are using nanotechnology for making energy generating yarn. They demonstrated that they can harvest energy from the ocean, light up a light bulb, and monitor breathing using their core technology. Commercial perspective: A patent has been submitted for this technology, but many questions remain that I would have. Specifically around scalable manufacturing. However, product integration and targeting the easiest market would be an interesting question to get answered. Here is a platform technology that could be applied to many applications. What I would do is push to build a demo product and try to find a strong strategic partner to help with commercialization.
Narrating an article by Christopher Coons, a United States Senator from DelawarePublished in Science 2017, Vol 357, p431
Multivalent bi-specific nanobioconjugate engagerfor targeted cancer immunotherapyNature Nanotechnology 2017, Vol 12, p763by Betty Kim from the Mayo ClinicSupported almost entirely by internally funding through the Mayo Clinic Abstract: Tumour-targeted immunotherapy offers the unique advantageof specific tumouricidal effects with reduced immune-associated toxicity. However, existing platforms suffer from low potency, inability to generate long-term immune memory anddecreased activities against tumour-cell subpopulations withlow targeting receptor levels. Here we adopted a modular design approach that uses colloidal nanoparticles as substrates to create a multivalent bi-specific nanobioconjugate engager (mBiNE) to promote selective, immune-mediated eradicationof cancer cells. By simultaneously targeting the human epidermal growth factor receptor 2 (HER2) expressed by cancer cells and pro-phagocytosis signalling mediated by calreticulin, the mBiNE stimulated HER2-targeted phagocytosis and produceddurable antitumour immune responses against HER2-expressing tumours. Interestingly, although the initial immune acti-vation mediated by the mBiNE was receptor dependent, thesubsequent antitumour immunity also generated protectiveeffects against tumour-cell populations that lacked the HER2 receptor. Thus, the mBiNE represents a new targeted, nanomaterial-immunotherapy platform to stimulate innate and adaptive immunity and promote a universal antitumour response. Innate immunity: macrophage responseAdaptive immunity: T-cell response and generation Summary: Kim has developed and confirmed the development of a novel method to treat cancer tumors via the general immunotherapy method. They activated both the innate and adaptive immune response of the body using their nanoparticles to promote both quick cancer removal by macrophage cell engulfment and by immune cell recognition and long term removal. The novelty here is the activation of both responses in mice using a versatile nanoparticle formulation. Business Development: While they demonstrated excellent efficacy in a mouse breast cancer model, there are so many major hurdles to overcome. I would anticipate, based on how they are preparing and delivering their formulation, that manufacturing and safety profiles will be the next items to work on. As with all nanoparticle formulations used for medical applications, excessive particle characterization will be required. Since the authors have already patented their nanoparticle formulation, I would anticipate that they will begin conducting these tests internally until which time they can remove more of the risk and spin out a company.
Original article: Science 2017, Vol 357, p522By Charles Hoogstraten from Michigan State UniversityI wrote a companion article titled "Depression in Science is more Common than many Think"
In situ programming of leukaemia-specific T cellsusing synthetic DNA nanocarriersNature Nanotechnology 2017, Vol 12, p813by Matthias Stephan in the Clinical Research Division of the Fred Hutchinson Cancer Research Center in Seattle, WA. With funding from the Fred Hutchinson Cancer Research Center’s Immunotherapy Initiative with funds provided by the Bezos Family Foundation. Additional funds from the Leukemia and Lymphoma Society, the NSF, and the NIH. Abstract: An emerging approach for treating cancer involves programming patient-derived T cells with genes encoding disease-specific chimeric antigen receptors (CARs), so that they can combat tumour cells once they are reinfused. Although trials of this therapy have produced impressive results, the in vitro methods they require to generate large numbers of tumour-specific T cells are too elaborate for widespread application to treat cancer patients. Here, we describe a method to quickly program circulating T cells with tumour-recognizing capabilities, thus avoiding these complications. Specifically, we demonstrate that DNA-carrying nanoparticles can efficiently introduce leukaemia-targeting CAR genes into T-cell nuclei, thereby bringing about long-term disease remission. These polymer nanoparticles are easy to manufacture in a stable form, which simplifies storage and reduces cost. Our technology may therefore provide a practical, broadly applicable treatment that can generate anti-tumour immunity ‘on demand’ for oncologists in a variety of settings. Dinner party tag line: I just read a new article out of Seattle where scientists were able to turn on immune cells in your body to fight and eliminate leukemia in mice using there DNA modifying nanoparticles. This new formulation would avoid chemotherapeutic pre-treatment for people with leukemia while maintaining and/or exceeding current efficacy rates. Future Business Potential: The results from this paper are truly amazing considering the response they are achieving through uptake of their nanoparticles by T-cells and the reduction in off-site deposition of their nanoparticles. Mechanistically, I think there is a lot of potential for this immunotherapeutic approach to treating specific leukemia patients. However, there are still many many hurdles they will need to overcome before ever even reaching first-in-human trials. Such as future detailed characterization of the particles, their stability in dry and wet form, the potential toxicity of broken, pieces of the nanoparticles, the effect of different sized particles. This list goes on and on from their. Then, they will need to move to larger animal models to prove efficacy and safety there as well. Finally, human clinical trials tend to offer a whole host of new problems. Therefore, while this is a great mechanistic finding, I think it will be a very long time before we see these particles or this approach used in humans.
Highlights from Daily Science Podcasts in July, 2017.The inaugural month as host of Daily Science Podcast presented some great research articles from around the US and the world. As a scientist, we are trained to take massive amounts of seemingly unrelated information and put them together into a coherent story. So, I will do my best to summarize and tie together the articles that I narrated this month. I have tried to structure the Daily Science Podcast around 5 main themes: Medicine, Neuroscience, Nutrition, Energy & Computing, and Policy. During the course of the first month of podcasting, I have transitioned from providing simple takeaway summaries of each article to providing reflection on how the published research can someday lead to a real product. My goal is to transition this podcast into an entrepreneurial resource for screening new technologies at the highest levels of science.The hot topics this month revolved around batteries and immunotherapy improvement. For example, Meng proved that using liquefied difluoromethane (a gas at room temperature) as the electrolyte solvent in lithium ion batteries lead to a 23% increased energy density and wider operating temperature range1. Additionally, Choi identified a unique method to stabilize the silicon microparticle anodes using an old organic molecule, polyrotaxanes. This minor adjustment to anode assembly yielded batteries capable of maintaining their energy density over 400+ tested charge/discharge cycles2. Based on these two improvements, I would envision quickly being able to build a small company around manufacturing small to large batteries for electric cars, solar energy storage, and mobile devices.Actually, I’m willing to bet that these batteries could power the new data storage drives in the laptops of the future based on the 3D nanotechnology integrated devices built by Shulaker3. These drives can read/write at a speed of up to 10 Tbits/sec and store 1,000 time more data per volume3. Someday, the information on these drives will be reading information stored on DNA using CRISPR-Cas9 genome editing technology4, based on a report by George Church. However, I don’t expect these technologies to be commercialized anytime soon because they would need to overcome manufacturing and infrastructure related hurdles.In medicine, personalized cancer immunotherapy received a boost with Wang’s demonstration that using protein capturing nanoparticles in conjunction with radiotherapy lead to a drastic improvement of immunotherapeutic efficacy5. Again, these studies are only in small animals and have a long pathway to commercialization. Similarly, Moon used nanodisks modified with personalized peptides found using genome sequencing to treat cancer tumors6. I will be following Moon’s company centered around this technology in hopes it leads to promising clinical results. Both groups stress the need for personalized treatment of tumors; with Wang letting the nanoparticles dress themselves with cancer antigens and Moon dressing their nanoparticles prior to delivery. Both strategies are based on previously well-studied nanoparticle platforms; but will take many years to commercialize due to the rigorous regulatory process.I am also very interested in the future direction of gut microbiome control. This month, Silver engineered bacteria that can survive and remain in the gut for 6 months while maintaining their function; paving the way for diagnostic and therapeutic gut bacteria7. Similarly, Daly et. al. used genome wide associated studies to identify a potential therapeutic target for inflammatory bowel disease8. Ideally, they could combine forces to engineer bacteria for controlled release of therapeutics to treat or control inflammatory bowel diseases.Top Two Potential Companies from July’s Research:1. Build better Li-ion batteries using polyrotaxane modified silicon microparticle anodes and using liquid difluoromethane as the electrolyte.2. Engineer bacteria to remain in the gut to controllably release (or make and release) therapeutics to treat life-long gut and gastrointestinal problems. Titles of Articles that I narrated:· Liquefied gas electrolytes for electrochemical energy storage devices· Highly elastic binders integrating polyrotaxanes for silicon microparticle anodes in lithium ion batteries· Three-dimensional integration of nanotechnologies for computing and data storage on a single chip· 3D Printed Stretchable Tactile Sensors· CRISPR–Cas encoding of a digital movie into the genomes of a population of living bacteria· Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy· Designer vaccine nanodiscs for personalized cancer immunotherapy· Global analysis of protein folding using massively parallel design, synthesis, and testing· Thalamic projections sustain prefrontal activity during working memory maintenance (mental disorder therapy target)· Decreased alertness due to sleep loss increases pain sensitivity in mice· Fine-mapping inflammatory bowel disease loci to single-variant resolution (GWAS)· Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation· Diet-Microbiome interactions in health are controlled by intestinal nitrogen source constraints· Cortex-dependent recovery of unassisted hindlimb locomotion after complete spinal cord injury in adult rats· Climate scientists flock to France’s call and US lawmakers seek extra $1.1 billion for the NIH· Trump’s science shop is small and waiting for leadership Bibliography: 1. Rustomji, C. S. et al. Liquefied gas electrolytes for electrochemical energy storage devices. Science 356, (2017).2. Choi, S., Kwon, T.-W., Coskun, A. & Choi, J. W. Highly elastic binders integrating polyrotaxanes for silicon microparticle anodes in lithium ion batteries. Science 357, 279–283 (2017).3. Shulaker, M. M. et al. Three-dimensional integration of nanotechnologies for computing and data storage on a single chip. Nature Publishing Group 547, 74–78 (2017).4. Shipman, S. L., Nivala, J., Macklis, J. D. & Church, G. M. CRISPR–Cas encoding of a digital movie into the genomes of a population of living bacteria. Nature Publishing Group 547, 345–349 (2017).5. Min, Y. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nature Nanotech 1–8 (2017). doi:10.1038/nnano.2017.1136. Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nature Materials 16, 489–496 (2016).7. Riglar, D. T. et al. Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation. Nature Publishing Group 35, 653–658 (2017).8. Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature Publishing Group 547, 173–178 (2017).
Nature 2017, Vol 547, p413-418By Nicholas Haining and John Doench of Department of Pediatric Oncology at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MITFunding primarily through awards from Broad Institute. Abstract:Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR–Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signaling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signaling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression.In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways. My Takeaways:The potential of immunotherapy has been proven highly effective in animal models over and over again, however, transition to its efficacy in humans has been limited with little to no understanding of why. The researchers use CRISPR gene editing, along with various other biological techniques, to tease out a specific protein that is interfering with immune therapy. The scientists identify a single target, PTPN2, that caused significant changes in the efficacy of standard immunotherapy treatment regimes. A company can easily be built around the translation of a therapeutic to block production of this Ptpn2 protein. The hurdles will be in the identification of such therapeutic, it’s safety profile, and the really big hurdle will be the proof in human clinical studies. While the researchers seem to identify one protein that’s blocking immunotherapy efficacy, they did not prove that there are other potential roadblocks to immunotherapy success in humans. Therefore, while exciting, the science is still risky.
Nature Neuroscience, 2017, Vol 20, p1096-1103Matthew Poy of the Max Delbruk Center for Molecular Medicine in Germany along with a team of 28 other researchers from various institutions around Europe and the US. Abstract: Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis.Genome wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects.Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles forCadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity. My takeaways:This team of researchers used the established genome wide associated studies system to identify a possible target protein responsible for regulation of body metabolism, and therefore obesity. This research establishes a pathway forward for a company to build a true weight loss product. Additionally, it allows doctors the ability to diagnose obesity as a genetic disorder for some. Obviously, there is a lot of research still to be done here, but the fact that the researchers were able to show that selectively turning off this one protein lead to reduction in weight is promising. They did this in both genetically engineered mice and by injecting an adenosine virus into the hippocampus of the brain and both showed promising results.
Science 2017, vol 357, p 256By Carole Lee and David MoherThe importance of ethics and transparency in scientific data reporting is a growing increasingly important for a number of reasons. For example, why are some good papers getting rejected and others squeaking through the cracks. And why are scientists having so much trouble reproducing published results. After spending 11 years in an academic lab researching various topics and publishing 14 first author papers, I understand the challenges associated with organizing and presenting a high quality paper as quickly as possible. Research is hard and when you finally have enough results to present the answer to a scientific question, you want to do so as quickly and efficiently as possible. The peer review process is established to ensure that any published scientific finding can be reproduced based on what is reported in the paper. There is a certain amount of responsibility on the scientists to report all the details and specifics of their published research, but since it is not required by many journals to have extensive supporting data and methods sections, scientists often will not include them. So, while there is a responsibility on the scientists to present clear data, there is also a responsibility on the journal to adequately screen publications. I think that implementation of more transparency in the peer review process would be a great idea, but I also think it is going to take a long time as it is a cultural shift in an extremely opaque industry. One short term solution to improving the process has been adopted by the organic chemistry journal, SynLett. They are trying a new model of peer review wherein submitted research articles can be reviewed using a crowdsourcing method. Here, in a pilot study, researchers will submit their journal article, then Synlett will release the submitted paper to a database of over a 100 scientist peer reviewers. Reviewers will have 3-5 days to read and add their comments on the publication. Only reviewers with the most relevant experience are expected to comment. Additionally, the peer reviewers will be able to comment on the comments of other peer reviewers. The peer reviewers are held to a higher standard because if they are inappropriate or include irrelevant comments, then they are out of the pool. The comments are more relevant and in depth because it is getting viewed by more scientists. And the authors of the article are happy because they get their paper back in days instead of weeks. In summary, the article published by Lee and Moher cited numerous structural changes that would improve the transparency of the journal article review and publication process leading to a higher quality of the scientific publication, however, these changes will take many years to implement due to the current culture that is established across the world. It will take a few brave leaders in the largest publishing houses to truly change how science is communicated.
Science, 2017, Vol 357, p 279-283Jang Wook Choi from the Graduate school of energy, environment, water, and sustainability at Korea Advanced Institute of Science and Technology Abstract: Lithium-ion batteries with ever-increasing energy densities are needed for batteries for advanced devices and all-electric vehicles. Silicon has been highlighted as a promising anode material because of its superior specific capacity. During repeated charge-discharge cycles, silicon undergoes huge volume changes. This limits cycle life via particle pulverization and an unstable electrode-electrolyte interface, especially when the particle sizes are in the micrometer range. We show that the incorporation of 5 weight % polyrotaxane to conventional polyacrylic acid binder imparts extraordinary elasticity to the polymer network originating from the ring sliding motion of polyrotaxane. This binder combination keeps even pulverized silicon particles coalesced without disintegration, enabling stable cycle life for silicon microparticle anodes at commercial-level areal capacities. My takeaways:This is unique approach to an old problem: the anode in batteries degrades over time. This is the reason that batteries get progressively worse. The researchers found a method to incorporate molecular rubber bands to keep the anode from degrading over time. They were able to show minimal decrease in battery capacity over 400 cycles.While this technology is another exciting upgrade to Li ion batteries, commercializing rotaxane synthesis and incorporation will likely have unexpected challenges. However, due to the impending size of the battery market, a promising business could be built around this technology in the American market. Additionally, it’s my opinion that the concept of incorporating polyrotaxanes into various materials would be a viable pathway to creating materials that didn’t crack or degrade over time. This could have impacts in the solar cell industry, rocket material industry, and medical implants industry where the goal is to create a material that will last a very long time under significant stresses.
Nature, 2017, Vol 547, p345-349By George Church out of the Department of Genetics and the Wyss Institute for Biologically Inspired Engineering at Harvard UniversityThis project was funded primary by multiple NIH grants DNA is an excellent medium for archiving data. Recent effortshave illustrated the potential for information storage in DNAusing synthesized oligonucleotides assembled in vitro1–6. Arelatively unexplored avenue of information storage in DNA isthe ability to write information into the genome of a living cellby the addition of nucleotides over time. Using the Cas1–Cas2integrase, the CRISPR–Cas microbial immune system storesthe nucleotide content of invading viruses to confer adaptiveimmunity7. When harnessed, this system has the potential towrite arbitrary information into the genome8. Here we use theCRISPR–Cas system to encode the pixel values of black and whiteimages and a short movie into the genomes of a population ofliving bacteria. In doing so, we push the technical limits of thisinformation storage system and optimize strategies to minimizethose limitations. We also uncover underlying principles of theCRISPR–Cas adaptation system, including sequence determinantsof spacer acquisition that are relevant for understanding boththe basic biology of bacterial adaptation and its technologicalapplications. This work demonstrates that this system can captureand stably store practical amounts of real data within the genomesof populations of living cells. My takeaways:While the application they demonstrated in the main manuscript is cool, the real value of this paper is in the details of how they were able to achieve data reading and writing using DNA. They conducted many more control and mechanistic experiments than the actual reading and writing of data experiments. They identified a viable pathway to using bacteria and DNA to store information. This will have many obvious applications in data storage and protection. While the technology is exciting, it is still very much in its infancy. I don’t expect to see this technology hit the markets for at least a decade.
Nature Materials, 2017, Vol16, p 489-496 James Moon and Anna Schwendeman of the Department of Pharmaceutical Sciences and Biointerfaces Institute at the University of MichiganThey were funded by the NIH, AHA, the UM MTRAC for Life Sciences, and the UM College of Pharmacy faculty start-up fund. Additionally, they found funding from the DoD Congressionally directed medical research program peer reviewed cancer research program and the NSF. Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signaled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lackingHere we demonstrate that high-density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cellsStrikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine. My takeaways:The researchers leverage the two successful developing cancer treatment strategies - immunotherapy and personalized medicine - to demonstrate excellent cancer treatment and prevention in mice. I like how they used an established nanoparticle, the synthetic HDL particles - that are currently under investigation by CSL limited for preventing the recurrence of cardiovascular events. By doing this they avoid developing their own good manufacturing practices and safety profiles required for regulatory approval. I’m excited to hear about the startup that the researchers formed for this product in 2016: EVOQ Therapeutics. They have a long pathway ahead of them with fundraising, pre-clinical efficacy, and safety testing, and establishing their own GMP manufacturing methods. And that is just to get to first-in-human testing. The company CSL demonstrated that HDL-ApoA1 particles have received positive results from a clinical trial on recurrence of cardiovascular events in a phase 2 clinical trial recently. Competing financial interestsA patent application for nanodisc vaccines has been filed, with J.J.M., A.S. and R.K. as inventors, and J.J.M. and A.S. are co-founders of EVOQ Therapeutics, LLC., that develops the nanodisc technology for vaccine applications.Found EVOQ Therapeutics in 2016.
The first article is by Nature, the second is by Lauren Morelloboth articles are published in Nature vol 547 My opinions:Public funding for science is critical to the development of promising technologies and products. Highly targeted funding of areas of science, like what is being done in France with climate change, are integral in making rapid progress in those areas. The US has many programs similar to the one highlighted by France; such as the cancer moonshot seeking to make progress quicker on cancer prevention, detection and treatment; the BRAIN initiative seeking to treat, cure, and prevent brain disorders, the CRAN initiative focusing on addition; and the precision medicine initiative, among many other successful programs in the past. It may appear to be a significant win for science with the House of Representatives rejecting President Trump’s proposed 18% reduction in the NIH budget; However, the reality is that the new budget proposed by the house will only increase the NIH budget by 3.2%. My hope is that the minor increase in funding combined with the presidents vision of a more efficient and less wasteful government will lead to more innovations within the NIH framework. Here, it is important for the long term success of science and research public programs to place everything into context; such as the France initiative where they are creating this fund for climate change, but at the same time significantly reducing their overall science and research budget. So my final opinion is that it is great that the US House of representatives and the world supports scientific research, however, we need to continuously market and publicize scientific measures of success and why the scientific community affects the US and the global economy through these successes. This in turn will continue to build confidence in scientific funding.
eLife science, vol 6, e23532 Karen Moxon in the School of Biomedical Engineering at Drexel University and the Department of Biomedical Engineering at UC DavisHer work was funded by the National Science Foundation, National Institute of Health, and Shriners Hospital for Children After paralyzing spinal cord injury the adult nervous system has little ability to ‘heal’ spinal connections, and it is assumed to be unable to develop extra-spinal recovery strategies to bypass the lesion. We challenge this assumption, showing that completely spinalized adult rats can recover unassisted hindlimb weight support and locomotion without explicit spinal transmission of motor commands through the lesion. This is achieved with combinations of pharmacological and physical therapies that maximize cortical reorganization, inducing an expansion of trunk motor cortex and forepaw sensory cortex into the deafferented hindlimb cortex, associated with sprouting of corticospinal axons. Lesioning the reorganized cortex reverses the recovery. Adult rat scan thus develop a novel cortical sensorimotor circuit that bypasses the lesion, probably through biomechanical coupling, to partly recover unassisted hindlimb locomotion after complete spinal cord injury. My takeaways:This early basic research demonstrates a method for paralyzed individuals to recover function in their limbs following spinal cord injury.
by Jeffrey Mervis Summary and highlights from the article: The Trump administration has not built up their Office of Science and Technology Policy (OSTP) after taking over 6 months ago. It currently has 35 staffers with no defined leadership. The previous administration anticipated this sluggishness and According to previous Director of OSTP, John Holdren, says the plunge in staff levels is normal during a presidential transition. “But what’s shocking is that, this far into the new administration, the numbers haven’t gone back up”. "Holdren says his staff - substantially larger than OSTP’s under Bush and twice its previous peak under former President Bill Clinton - reflected Obama’s desire to elevate science and technology in his administration. “The president was so interested in knowing what science could do to advance his agenda, be it on economic recovery, energy and climate change, or national security,” Holdren says. In contrast, Holdren says, “right now I think OSTP is just hanging on.”” My opinion as a scientist is that it saddens me that the priority of this administration is to cut the budgets of scientists across all disciplines and research development level (basic vs applied). I think that advancements in science and technology have been and will be the greatest drivers of US economic success in the future years and decades to come. The hardest part for short term politicians is that science and technology progress takes a lot of time, often spanning multiple administrations from the tops of the government down to mayors of cities. Please, if you would like to continue this discussion, please comment below. Podcast RSS
Nature 2017, Vol 547, pp 173-178By Mark Daly of Massachusetts General Hospital, Harvard Medical School, and the Broad Institute of MIT and Harvard and 46 of his fellow scientists from Belgium, Denmark, Sweden, Spain, Germany, Australia, UK, Canada, and the Netherlands The American scientists were supported primarily by NIH, and the Crohn’s & Colitis Foundation of America, Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide.Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms. My takeaways:The many authors show that by using this powerful method of genome wide associated studies, scientists can elucidate the underlying mechanism for disease development. Especially in complicated diseases such as inflammatory bowel disease. This has a huge impact for all the other diseases that are not well understood; which are most of the diseases that affect our lives because they have no cures or good treatments.