REVIEW: Nanobiotechnology: Cradle for revolution in drug carrier systems.

The role of nanobiotechnology in the treatment of diseases is limitless. In this review we tried to focus main aspects of nanotechnology in drug carrier systems for treatment and diagnosis of various diseases such as cancer, pulmonary diseases, infectious diseases, vaccine development, diabetes mellitus and the role of nanotechnology on our economy and its positive social impacts on our community. We discussed here about the different "Biotechnano Strategies" to develop new avenues and ultimately improve the treatment of multiple diseases.

Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity.

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

Danger in the Valley of Death: how the transition from preclinical research to clinical trials can impact valuations.

In drug development, a crucial step is the transition of a company from preclinical stages to human trials: the so-called 'Valley-of-Death' (VoD) that most efforts do not survive. Here, we analyzed how the valuations of biotech companies in the life science sector change as they cross this valley. Their average valuation increased significantly (87%) when crossing the VoD no later than their fourth funding round. However, companies that received more than four funding rounds saw significantly lower average valuations. Similarly, the volume of website traffic for companies that received no more than four preclinical funding rounds was significantly higher than companies receiving more than four preclinical funding rounds, whereas the number of patents was unrelated to the likelihood of a company of crossing the VoD.

Manufacturing MSCs for commercial application: an interview with Ross Macdonald.

Ross Macdonald is the CEO and Managing Director of Cynata Therapeutics Limited (Australia). He has over 30 years of experience and a track record of success in pharmaceuticals and biotechnology businesses. His career history includes positions as Vice President of Business Development for Sinclair Pharmaceuticals Ltd (now Sinclair IS Pharma), a UK-based specialty pharmaceuticals company, and Vice President of Corporate Development for Stiefel Laboratories, Inc., then the largest independent dermatology company in the world and acquired by GlaxoSmithKline in 2009 for £2.25 billion. He has also served as the CEO of Living Cell Technologies Ltd, Vice President of Business Development of Connetics Corporation and Vice President of Research and Development of F H Faulding & Co Ltd.

Bringing Stem Cell-Based Therapies for Type 1 Diabetes to the Clinic: Early Insights from Bioprocess Economics and Cost-Effectiveness Analysis.

Differentiation of pluripotent stem cells (PSCs) into ß cells could provide insulin independence for type 1 diabetes (T1D) patients. This approach would reduce the clinical complications that most patients managed on intensive insulin therapy (IIT) face. However, bottlenecks of PSC manufacturing and limited engraftment of encapsulated cells hinder the long-term effectiveness of these therapies. A bioprocess decision-support tool is combined with a disease state-transition model to evaluate the cost-effectiveness of the stem cell-based therapy against IIT. Clinical effectiveness is assessed in quality-adjusted life years (QALYs). Manufacturing costs per patient reduce from $430 000 to $160 000 with optimization of batch size and annual demand. For 96% of the patients, cell therapy improves the quality of life compared to IIT. Cost savings are achieved for 2% of the population through prevention of renal disease. The therapy is cost-effective for 3.4% of patients when a willingness to pay (WTP) of up to $150 000 per QALY is considered. A 75% cost reduction in the cell therapy price increases cost-effectiveness likelihood to 51% at $100 000 per QALY. This study highlights the need for scalable manufacturing platforms for stem cell therapies, as well as to prioritizing access to the therapy to patients with an increased likelihood of costly complications.

RNAi therapeutic and its innovative biotechnological evolution.

Recently, United States Food and Drug Administration (FDA) and European Commission (EC) approved Alnylam Pharmaceuticals' RNA interference (RNAi) therapeutic, ONPATTRO™ (Patisiran), for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. This is the first RNAi therapeutic all over the world, as well as the first FDA-approved treatment for this indication. As a milestone event in RNAi pharmaceutical industry, it means, for the first time, people have broken through all development processes for RNAi drugs from research to clinic. With this achievement, RNAi approval may soar in the coming years. In this paper, we introduce the basic information of ONPATTRO and the properties of RNAi and nucleic acid therapeutics, update the clinical and preclinical development activities, review its complicated development history, summarize the key technologies of RNAi at early stage, and discuss the latest advances in delivery and modification technologies. It provides a comprehensive view and biotechnological insights of RNAi therapy for the broader audiences.

Cost analysis of oil cake-to-biodiesel production in packed-bed micro-flow reactors with immobilized lipases.

Biodiesel production depends to a great extent on the use of cheap raw materials, since biodiesel itself is a mass product, not a high-value product. New processing methods, such as micro-flow continuous processing combined with enzymatic catalysis, open doors to the latter. As reported here, the window of opportunity in enzyme-catalyzed biodiesel production is the conversion of waste cooking oil. The main technological challenge for this is to obtain efficient immobilization of the lipase catalyst on beads. The beads can be filled into tubular reactors where designed packed-bed provide porous channels, forming micro-flow. It turns out, that in this way, the immobilization costs become the decisive economic factor. This paper reports a solution to that issue. The use of oil cake enables economic viability, which is not given by any of the commercial polymeric substrates used so far for enzyme immobilization. The costs of immobilization are mirrored in the earnings and cash flow of the new biotechnological process.

[Monoclonal antibodies at the forefront of health care economic analyses]. / Les anticorps monoclonaux à l'aune de l'économie de la santé - Les accords de l'industrie pharmaceutique.

Therapeutic antibodies have been used for several decades and their associated market (project numbers, approvals…) continues to grow. Remarkably, a new threshold was crossed in the early 2010's to make this decade the decade of immunotherapy. Over the past 10 years, 62 antibodies have been approved, the number of annual transactions between stakeholders has increased to more than 300 (three times more in 2018 than in 2009). The revolution of immunotherapy in cancer treatment and the recent use of antibodies as first-line treatment are the major turning points in oncology. Thus, the last three years alone represent two thirds of the most important deals of the decade involving immunotherapies. Immunotherapy is currently experiencing a golden age that has resulted in many successes, especially in France where biotechnology companies and large pharmaceutical companies have achieved impressive therapeutic and financial results.

TITLE: Les anticorps monoclonaux à l'aune de l'économie de la santé - Les accords de l'industrie pharmaceutique. ABSTRACT: Bien que les anticorps thérapeutiques existent depuis maintenant plusieurs décennies et que le marché associé (nombre de projets en développement, nombre d'anticorps mis sur le marché…) soit en croissance, un palier a été franchi au début des années 2010 pour faire de cette décennie celle de l'immunothérapie. Pendant ces 10 dernières années, 62 anticorps ont obtenu une autorisation de mise sur le marché et le nombre d'accords (acquisitions, participations, partenariats) annuels entre les différents acteurs a dépassé la barre des 300 (avec trois fois plus d'accords en 2018 qu'en 2009). La révolution de l'immunothérapie dans le traitement des cancers et la récente utilisation d'anticorps en première ligne thérapeutique dans celui-ci sont les tournants majeurs de l'oncologie. Les trois dernières années (2016-2019) regroupent d'ailleurs à elles seules les deux tiers des plus importants accords de la décennie impliquant des immunothérapies. L'immunothérapie connaît donc actuellement un âge d'or qui se traduit par de nombreuses success stories, notamment en France, où sociétés de biotechnologie et big pharma présentent des résultats très positifs au plan tant thérapeutique que financier.

Cost-effective production of tag-less recombinant protein in Nicotiana benthamiana.

Plants have recently received a great deal of attention as a means of producing recombinant proteins. Despite this, a limited number of recombinant proteins are currently on the market and, if plants are to be more widely used, a cost-effective and efficient purification method is urgently needed. Although affinity tags are convenient tools for protein purification, the presence of a tag on the recombinant protein is undesirable for many applications. A cost-effective method of purification using an affinity tag and the removal of the tag after purification has been developed. The family 3 cellulose-binding domain (CBM3), which binds to microcrystalline cellulose, served as the affinity tag and the small ubiquitin-related modifier (SUMO) and SUMO-specific protease were used to remove it. This method, together with size-exclusion chromatography, enabled purification of human interleukin-6 (hIL6) with a yield of 18.49 mg/kg fresh weight from leaf extracts of Nicotiana benthamiana following Agrobacterium-mediated transient expression. Plant-produced hIL6 (P-hIL6) contained less than 0.2 EU/µg (0.02 ng/mL) endotoxin. P-hIL6 activated the Janus kinase-signal transducer and activator of transcriptional pathways in human LNCaP cells, and induced expression of IL-21 in activated mouse CD4+ T cells. This approach is thus a powerful method for producing recombinant proteins in plants.

Tailor-made trees: engineering lignin for ease of processing and tomorrow's bioeconomy.

Lignocellulosic biomass represents an abundant source of cellulosic fibres and fermentable sugars. However, lignin, a polyphenolic constituent of secondary-thickened plant cell walls significantly contributes to biomass recalcitrance during industrial processing. Efforts to reduce plant total lignin content through genetic engineering have improved processing efficiency, but often incur an agronomic penalty. Alternatively, modifications that alter the composition of lignin and/or its interaction with other cell wall polymers display improved processing efficiency without compromising biomass yield. We propose that future efforts to improve woody feedstocks should focus on altering lignin composition and cell wall ultrastructure. Here, we describe potential future modifications to lignin and/or other cell wall characteristics that may serve as strategic targets in the production of trees that are tailor-made for specific pretreatments and end-product applications.

A framework for the identification of promising bio-based chemicals.

Recent progress in metabolic engineering and synthetic biology enables the use of microorganisms for the production of chemicals-"bio-based chemicals." However, it is still unclear which chemicals have the highest economic prospect. To this end, we develop a framework for the identification of such promising ones. Specifically, we first develop a genome-scale constraint-based metabolic modeling approach, which is used to identify a candidate pool of 209 chemicals (together with the estimated yield, productivity, and residence time for each) from the intersection of the high-production-volume chemicals and the KEGG and MetaCyc databases. Second, we design three screening criteria based on a chemical's profit margin, market volume, and market size. The total process cost, including the downstream separation cost, is systematically incorporated into the evaluation. Third, given the three aforementioned criteria, we identify 32 products as economically promising if the maximum yields can be achieved, and 22 products if the maximum productivities can be achieved. The breakeven titer that renders zero profit margin for each product is also presented. Comparisons between extracellular and intracellular production, as well as Escherichia coli and Saccharomyces cerevisiae systems are also discussed. The proposed framework provides important guidance for future studies in the production of bio-based chemicals. It is also flexible in that the databases, yield estimations, and criteria can be modified to customize the screening.

Alternative low-cost process for large-scale production of Bacillus thuringiensis in a simple and novel culture system.

An industrial-scale, profitable method for production of the most widely used bioinsecticide, Bacillus thuringiensis (Bt), is challenging because of its widespread application. The aim of this study is to present a strategy to develop a low-cost, large-scale bioprocess to produce Bt H14. This study was first focused on the design of a culture medium composed of economical and available components, such as glycerol and lysed Saccharomyces cerevisiae. The production goal of 1200 ITU was achieved using a medium composed of 20:20 g L-1of glycerol:lysed yeast in batch cultures. Efforts were subsequently focused on the design of an appropriate culture system, and an original two-stage culture system was proposed. First, yeast (the primary component of the culture medium) are cultivated using a minimal mineral medium and lysed, and in the second stage, Bt is cultivated in the same bioreactor using the lysed yeasts as culture medium (supplemented with a feeding pulse of 10 g L-1 glycerol). This system was called fed batch one pot (FOP). A new inoculation strategy is also presented in this study, since these Bt cultures were inoculated directly with heat pre-treated spores instead of vegetative bacteria to facilitate the bioprocess. This study was developed from the laboratory to production-scale bioreactors (measuring from 500 mL to 2500 L), and the efficiency of the proposed strategy was evident in LD50 tests results, achieving 1796 ITU in large-scale processes. Both the use of non-conventional sources and the process development for biomass production are important for cost-effective production of Bt-based insecticides in mosquito control projects.

Enhancement of fermentative hydrogen production from Spirogyra sp. by increased carbohydrate accumulation and selection of the biomass pretreatment under a biorefinery model.

In this work, hydrogen (H2) was produced through the fermentation of Spirogyra sp. biomass by Clostridium butyricum DSM 10702. Macronutrient stress was applied to increase the carbohydrate content in Spirogyra, and a 36% (w/w) accumulation of carbohydrates was reached by nitrogen depletion. The use of wet microalga as fermentable substrate was compared with physically and chemically treated biomass for increased carbohydrate solubilisation. The combination of drying, bead beating and mild acid hydrolysis produced a saccharification yield of 90.3% (w/w). The H2 production from Spirogyra hydrolysate was 3.9 L H2 L-1, equivalent to 146.3 mL H2 g-1 microalga dry weight. The presence of protein (23.2 ± 0.3% w/w) and valuable pigments, such as astaxanthin (38.8% of the total pigment content), makes this microalga suitable to be used simultaneously in both food and feed applications. In a Spirogyra based biorefinery, the potential energy production and food-grade protein and pigments revenue per cubic meter of microalga culture per year was estimated on 7.4 MJ, US $412 and US $15, respectively, thereby contributing to the cost efficiency and sustainability of the whole bioconversion process.

Oligosaccharide biotechnology: an approach of prebiotic revolution on the industry.

Oligosaccharides are polymers with two to ten monosaccharide residues which have sweetener functions and sensory characteristics, in addition to exerting physiological effects on human health. The ones called nondigestible exhibit a prebiotic behavior being fermented by colonic microflora or stimulating the growth of beneficial bacteria, playing roles in the immune system, protecting against cancer, and preventing cardiovascular and metabolic issues. The global prebiotics market is expected to grow around 12.7% in the next 8 years, so manufacturers are developing new alternatives to obtain sustainable and efficient processes for application on a large scale. Most studied examples of biotechnological processes involve the development of new strategies for fructooligosaccharide, galactooligosaccharide, xylooligosaccharide, and mannanooligosaccharide synthesis. Among these, the use of whole cells in fermentation, synthesis of microbial enzymes (ß-fructofuranosidases, ß-galactosidases, xylanases, and ß-mannanases), and enzymatic process development (permeabilization, immobilization, gene expression) can be highlighted, especially if the production costs are reduced by the use of agro-industrial residues or by-products such as molasses, milk whey, cotton stalks, corncobs, wheat straw, poplar wood, sugarcane bagasse, and copra meal. This review comprises recent studies to demonstrate the potential for biotechnological production of oligosaccharides, and also aspects that need more investigation for future applications in a large scale.

Bioenergetics potential of RR2 PRO transgenic soybean subjected to application of herbicides isolated and in combination

ABSTRACT In Brazil, there are several crops producing oil for biofuel production, such as canola, sunflower, peanut, cotton, castor bean, soybean, among others. There are parameters that indicate the energetic and economic viability for the production of biofuels, and that can be applied, for example, in transgenic soybeans. The present study aimed to evaluate the energetic viability of Intacta RR2 PROTM soybean for biofuel production.Experiments were conducted in the municipalities of Palotina and Marechal Cândido Rondon, both in the State of Paraná. Energy balance calculations were carried out from the production system, estimating energy expenditure, including the agricultural and industrial stages. The inputs used were considered as input of energy, while grain production, as output of energy. The energy balance of soybean biofuel showed positive values in the treatments with lower doses up to the recommended doses, highlighting the treatment glyphosate at 720 g.e.a. per hectare, which reached a positive energy balance (1: 1.11) for both municipalities. However, the Intacta RR2 PRO TM soybean was sensitive to treatments with high doses of glyphosate, which impaired productivity and consequently generated low economic returns.

Enrichment of highly settleable microalgal consortia in mixed cultures for effluent polishing and low-cost biomass production.

Microalgae cultivation is a promising technology for integrated effluent polishing and biofuel production, but poor separability of microalgal cells hinders its industrial application. This study intended to selectively enrich settleable microalgal consortia in mixed culture by applying "wash-out" pressure, which was realized by controlling settling time (ST) and volume exchange ratio (VER) in photo-SBRs. The results demonstrated that highly settleable microalgal consortia (settling efficiency>97%; SVI = 17-50 mL/g) could be enriched from indigenous algal cultures developed in WWTP's effluent. High VER was the key factor for the fast development of settleable microalgae. VER was also a controlling factor of the algal community structure. High VERs (0.5 and 0.7) resulted in the dominance of diatom, while low VER (0.2) facilitated the dominance of cyanobacteria. The settleable microalgal consortia were very efficient in phosphorus removal (effluent PO43--P<0.1 mg/L; removal efficiency>99%), which was largely attributed to intensive chemical precipitation of phosphate induced by high pH (8.5-10). However, the high pH decreased the bioavailable inorganic carbon, resulting in incomplete nitrate removal (effluent NO3--N = 2.2-4 mg/L; removal efficiency = 61-79%) under high VERs and low lipid content (up to 10%) in the settleable microalgae. This problem could be resolved by sparging CO2 or controlling pH. Overall, this study demonstrated a simple and effective method to overcome the separation challenge in scale-up of microalgae biotechnology for advanced wastewater purification and biofuel production.