Daily Science Podcast

In reference to the article" Funders groan under growing review burden" by Jop de Vrieze.

Science 2017, Vol 357, p343

By Leroy Hood from the Institute of Systems Biology in Seattle, WA

Nature 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.

Direct optical lithography of functional inorganic nanomaterials

Science 2017, vol 357, p385-388

By Dmitri Talapin from Department of Chemistry, at the University of Chicago

Supported 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.

Nature Neuroscience 2017, Vol 20, p1122-1132

By Guang Yang at the Neuroscience Institute part of New York University School of Medicine

Funding 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 hyperactivity somatostatin-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:

1. 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.

2. 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.

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.2017.113

6. 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).

Gender discrimination lawsuit at Salk ignites controversy by Meredith Whadman

Science 2017, Vol 357, p237

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:

1. 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.

2. 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, p1096-1103

Matthew 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 256

By Carole Lee and David Moher

My opinions:

The 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 other 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 irrelavent 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 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 279-283

Jang Wook Choi from the Graduate school of energy, environment, water, and sustainability at Korea Advanced Institute of Science and Technology

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:

1. 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.

2. 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.