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, p759

Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

By Weiping Zou from China and the University of Michigan

Funding through China

1. What is the most important rule in chemistry?

1. 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 environment

* Recent 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 production

* A 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. nucleatum

* Given the role of the autophagy pathway in cellular survival, our data suggest that F. nucleatum may cause autophagy pathway activation and potentially support cancer chemoresistance

* Moreover, F. nucleatum had no protective effect on HCT116 cells and HT29 cells treated with Doxorubicin

* We found that the F. nucleatum-induced chemoresistant effect was abolished by CQ treatment in HCT116 cells (Figures 3A and 3B) and HT29 cells

* The data indicate that F. nucleatum may induce autophagy activation via increasing ULK1 and ATG7 expression

* To explore the mechanism by which F. nucleatum induced upregulation of pULK1, ULK1, and ATG7 at both the mRNA and protein level

* Capecitabine (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 immunotherapy

* Furthermore, 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 twist

by Ray Baughmann of the Alan MacDiarmid NanoTech Institute at the University of Texas, Dallas

Funded by the Air Force office of Science Grants, NASA, and the Office of Naval Research

Science 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 scale

* They 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 variables

* Energy harvesters showed no loss in performance following 30,000 cycles

* Their 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.

I narrated an article by Christopher Coons, a US senator from Delaware.

Written in Science 2017, vol 357, p431

Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells

Nature Medicine 2017, vol 23, p938

by 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 understood

* Chronic inflammatory diseases include:

* Arthritis

* Alzheimers

* Asthma

* Atherosclerosis

* Crohn’s

* Colitis

* Irritable bowel syndrome

* Ulcerative colitis

* Current arthritis treatments include lifelong immunosuppressive treatment

* Current treatments strategies seek to prevent further inflammation instead of promoting its reversal

* They 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 concentrations

* Final 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

Multivalent bi-specific nanobioconjugate engagerfor targeted cancer immunotherapy

Nature Nanotechnology 2017, Vol 12, p763

by Betty Kim from the Mayo Clinic

Supported 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 response

Adaptive 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, p522

by Charles Hoogstraten from Michigan State University

In situ programming of leukaemia-specific T cellsusing synthetic DNA nanocarriers

Nature Nanotechnology 2017, Vol 12, p813

by 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.

Tough adhesives for diverse wet surfaces

Science 2017, vol 357, p378-381

by Dr. Mooney from the John Paulson School of Engineering and Applied Sciences at Harvard University

Funded 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 snails 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.

by Ashley Stevens. She is President of Focus IP Group

Nature Biotechnology 2017, Vol 35, p608