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Daily Science Podcast
6 minutes | Sep 21, 2017
Mannose suppresses immunopathology; preventing diabetes and airway inflammation
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.”
14 minutes | Sep 10, 2017
Quality Control in Academic Labs
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
15 minutes | Sep 6, 2017
September 6, 2017 - The Future of Alzheimer's Disease Treatment
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.
11 minutes | Aug 31, 2017
August 31, 2017 - Gut bacteria protecting cancer
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.
9 minutes | Aug 29, 2017
August 29, 2017 - Energy harvesting yarn
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.
13 minutes | Aug 26, 2017
August 26, 2017 - Science Advocacy is for Everyone
Narrating an article by Christopher Coons, a United States Senator from DelawarePublished in Science 2017, Vol 357, p431
9 minutes | Aug 23, 2017
August 23, 2017 - A mechanism to reverse rheumatoid arthritis
Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cellsNature Medicine 2017, vol 23, p938by Andreas Ramming from the Department of Internal Medicine at the Friedrich Alexander University in Germany Abstract: Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired type 2 innate lymphoid cell proliferation and activation of regulatory T (Treg) cells, resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted type 2 innate lymphoid cell-dependent regulatory T cell activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ type 2 innate lymphoid cells in joints and the circulation. Hence, fostering IL-9-mediated type 2 innate lymphoid cell activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses. Key points from the Intro and Conclusion:Reversal of inflammation is incompletely understoodChronic inflammatory diseases include:ArthritisAlzheimersAsthmaAtherosclerosisCrohn’sColitisIrritable bowel syndromeUlcerative colitisCurrent arthritis treatments include lifelong immunosuppressive treatmentCurrent treatments strategies seek to prevent further inflammation instead of promoting its reversalThey identified the cytokine, IL-9, and type 2 innate lymphoid cells, that produce IL-9, are responsible for reversing arthritis in a mouse animal model.They did this by using a mouse model where you can give the mouse a shot and it will develop arthritis, which then goes away spontaneously.This study is a great example of how to identify a new therapeutic pathway. They were very thorough. They compared their results in mice with synovial tissue of humans with rheumatoid arthritis and found similar correlation of IL-9 and type 2 innate lymphoid cell concentrationsFinal lines from their conclusions: These findings are remarkable, as resolution of inflammation has thus far been preferentially attributed to lipid mediators such as resolving and little was known about innate/adaptive immune system interactions in orchestrating the resolution process. IL-9 and the function of type 2 innate lymphoid cells in this process provide strong support for the existence of immune pathways that primarily foster the resolution of inflammation and restore immune homeostasis in chronic inflammatory diseases. Dinner part tag line: I heard that researchers figured out a way to treat arthritis by reversing the disease, instead of just preventing it from progressing further. They said this could have broad implications for other inflammation diseases like heart disease, inflammatory bowel diseases, and alzheimers disease. Business perspective:Interesting mechanistic research will still require several more years before an initial therapeutic will even be tested in the lab. I’m discussing this paper more because of my general interest in reversing inflammatory diseases than for its potential business applications
11 minutes | Aug 21, 2017
August 21, 2017 - A new cancer immunotherapy nanoparticle
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.
20 minutes | Aug 19, 2017
August 19, 2017 - Depression in Science
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"
19 minutes | Aug 16, 2017
August 16, 2017 - Nanoparticle immune activation to treat leukemia
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.
11 minutes | Aug 14, 2017
August 14, 2017 - New biomimetic bandages
Tough adhesives for diverse wet surfacesScience 2017, vol 357, p378-381by Dr. Mooney from the John Paulson School of Engineering and Applied Sciences at Harvard UniversityFunded by NIH Abstract: Adhesion to wet and dynamic surfaces, including biological tissues, is important in many fields but has proven to be extremely challenging. Existing adhesives are cytotoxic, adhere weakly to tissues, or cannot be used in wet environments. We report a bioinspired design for adhesives consisting of two layers: an adhesive surface and a dissipative matrix.The former adheres to the substrate by electrostatic interactions, covalent bonds, and physical interpenetration. The latter amplifies energy dissipation through hysteresis. The two layers synergistically lead to higher adhesion energies on wet surfaces as compared with those of existing adhesives. Adhesion occurs within minutes, independent of blood exposure and compatible with in vivo dynamic movements. This family of adhesives may be useful in many areas of application, including tissue adhesives, wound dressings, and tissue repair. My takeaways:This seems like a great adaptation of adhesives nature was able to optimize over time. They took the structure of the material snail's use for adhesion, simplified it, and optimized the formulation for other applications. They demonstrate a few obvious applications in adhering plastic material to blood soaked tissue. If you have access, I would suggest watching the videos they created in the supporting information for this paper. They show strong adhesion to a live pig heart soaked in blood. They also indicate that their tough adhesive is 8 times stronger at adhesion than current products on the market. Naturally, the authors have patented this technology. If I were them, I would focus on bringing a consumer product to market first, then target the medical applications such as large external wounds that need rapid sealing, internal wounds, or other applications like nerve adhesives. My expectation would be that revenue in conjunction with federal funding through SBIRs and DoD grants could mostly fund the development of these class 2 or 3 devices. This biggest hurdle that I would anticipate would be establishing a scalable and reproducible manufacturing process.
27 minutes | Aug 13, 2017
August 13, 2017 - How to establish academic technology transfer
An emerging model for life sciences commercializationby Ashley Stevens. He is President of Focus IP GroupNature Biotechnology 2017, Vol 35, p608
19 minutes | Aug 11, 2017
August 11, 2017 - Funding Agency Peer Reviewer Fatigue
"Funders groan under growing review burden" by Jop de Vrieze in AmsterdamGranting agencies want research on how to reduce pressure and maintain qualityScience 2017, Vol 357, p343See my accompanying article in the blog page
11 minutes | Aug 10, 2017
August 10, 2017 - A longitudinal wellness study using full body scans
A wellness study of 108 individuals using personal, dense, dynamic data cloudsBy Leroy Hood from the Institute of Systems Biology in Seattle, WANature Biotechnology 2017, vol 35, p747-756 Abstract: Personal data for 108 individuals were collected during a 9-month period, including whole genome sequences; clinical tests,metabolomes, proteomes, and microbiomes at three time points; and daily activity tracking. Using all of these data, we generateda correlation network that revealed communities of related analytes associated with physiology and disease. Connectivity withinanalyte communities enabled the identification of known and candidate biomarkers (e.g., gamma-glutamyltyrosine was denselyinterconnected with clinical analytes for cardiometabolic disease). We calculated polygenic scores from genome-wide associationstudies (GWAS) for 127 traits and diseases, and used these to discover molecular correlates of polygenic risk (e.g., genetic riskfor inflammatory bowel disease was negatively correlated with plasma cystine). Finally, behavioral coaching informed by personaldata helped participants to improve clinical biomarkers. Our results show that measurement of personal data clouds over time canimprove our understanding of health and disease, including early transitions to disease states. My summary: I presented this article because I think it is going to open the door to a more scientific approach to health and wellness tracking and optimization. New generations of the population are get more interested and invested in optimizing their own health and wellness because they are seeing the payoffs it has on the quality of their life; whether it be personally or professionally. Now these authors have already established a spinoff company to conduct the work, Arivale, but I can envision many diagnostic and wellness tracking companies being created to monitor key biomarkers on a daily or weekly basis based on the results they find. The scientists were able to identify a handful of impactful biomarkers simply based on screening and tracking 100 individuals for 9 months. I can’t even imagine what they will find when they hit their 100,000 mark and track those individuals for years and being correlating all this data to disease development. This will truly be a herculean task. I will be keeping my eye out for future reports when new enrollment milestones are hit.
9 minutes | Aug 9, 2017
August 9, 2017 - New Thin Film Manufacturing
Direct optical lithography of functional inorganic nanomaterialsScience 2017, vol 357, p385-388By Dmitri Talapin from Department of Chemistry, at the University of ChicagoSupported by DoD Air Force Office of Scientific Research, and the NSF Abstract: Photolithography is an important manufacturing process that relies on using photoresists, typically polymer formulations, that change solubility when illuminated with ultraviolet light. Here, we introduce a general chemical approach for photoresist-free, direct optical lithography of functional inorganic nanomaterials. The patterned materials can be metals, semiconductors, oxides, magnetic, or rare earth compositions. No organic impurities are present in the patterned layers, which helps achieve good electronic and optical properties.The conductivity, carrier mobility, dielectric, and luminescence properties of optically patterned layers are on par with the properties of state-of-the-art solution-processed materials. The ability to directly pattern all-inorganic layers by using a light exposure dose comparable with that of organic photoresists provides an alternate route for thin-film device manufacturing. My takeaways:This new way to thin film print nanomaterials and conductive films will help revolutionize the manufacturing applications the author's reference; optoelectronic devices like light emitting diodes, field effect transistors, near- and mid-infrared photodetectors, and solar cells. In the end, this will lead to cheaper electronic displays, like TVs, tablets, and phones. Additionally, this new, nondestructive thin film deposition technology presents a possibly much better method to manufacture flexible and wearable electronics and sensors.Therefore, the next steps that I would see for this technology would be to identify the biggest and/or quickest to enter the market and focus on building a consumer product using these methods. Since this is a manufacturing method they developed, there are many applications that one could get distracted with; here, the new company would need to establish that they can create competitive products for less price than current methods.
11 minutes | Aug 8, 2017
August 8, 2017 - Preventing and understanding chronic pain
Activation of cortical somatostatin interneurons prevents the development of neuropathic painNature Neuroscience 2017, Vol 20, p1122-1132By Guang Yang at the Neuroscience Institute part of New York University School of MedicineFunding by the Ralph French Charitable Foundation Trust, and the NIH Abstract: Neuropathic pain involves long-lasting modifications of pain pathways that result in abnormal cortical activity. How cortical circuits are altered and contribute to the intense sensation associated with allodynia is unclear. Here we report a persistent elevation of layer V pyramidal neuron activity in the somatosensory cortex of a mouse model of neuropathic pain. This enhanced pyramidal neuron activity was caused in part by increases of synaptic activity and NMDA-receptor-dependent calcium spikes in apical tuft dendrites. Furthermore, local inhibitory interneuron networks shifted their activity in favor of pyramidal neuron hyperactivitysomatostatin-expressing and parvalbumin-expressing inhibitory neurons reduced their activity, whereas vasoactive intestinal polypeptide–expressing interneurons increased their activity. Pharmacogenetic activation of somatostatin-expressing cells reduced pyramidal neuron hyperactivity and reversed mechanical allodynia. These findings reveal cortical circuit changes that arise during the development of neuropathic pain and identify the activation of specific cortical interneurons as therapeutic targets for chronic pain treatment. My takeaways:These researchers conducted deep mechanistic studies into how chronic pain is occurring in a spared nerve injury mouse model. They then demonstrated using numerous interesting techniques how the nerves adapted to this damage. Finally, they identify potential nerve targets to reduce or even eliminate chronic pain. This could be life-changing for individuals with epilepsy, schizophrenia, general pain, and depression. The biggest roadblocks ahead will not be identifying a small molecule inhibitor to block this chronic pain, but proving efficacy on in larger animal models (and humans) quantitatively.
7 minutes | Aug 7, 2017
August 7, 2017 - Summary of July, 2017 Podcasts
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).
18 minutes | Aug 4, 2017
August 4, 2017 - Gender Bias in Science
Gender discrimination lawsuit at Salk ignites controversy: Institute’s critique of plaintiffs’ science comes under fireScience 2017, vol 357, p237By Meredith WhadmanAnd, Gender Discrimination in Science is the Responsibility of Scientific Leadership by Michael Bruckman
13 minutes | Aug 3, 2017
August 3, 2017 - In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
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.
10 minutes | Aug 1, 2017
August 1, 2017 - Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
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.
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