大数据-模型混合驱动下生物过程优化与放大的新机遇与挑战

当前,生物制造技术和产业是世界关注的热点。然而,生物过程优化与放大过程中普遍面临以下几个难题,包括:过程检测手段缺乏,难以满足关键指标参数的监控;细胞代谢认知匮乏,无法理性实现过程最优化调控;反应器环境差异大,导致逐级放大效率低下。文中针对以上亟待解决的关键问题,通过案例分析介绍发酵过程实时检测-动态调控-理性放大全链条关键技术创新。在未来,生物过程设计将以集成细胞生理学(时空多尺度细胞代谢模型)和流体动力学(CFD模型)的全生命周期模型为指导,推进计算机辅助设计与开发,加速生物过程实现大规模智能化生产,开启绿色生物制造新时代。     

A special report on India's biotech scenario: Advancement in biopharmaceutical and health care sectors

India's biotechnology industry has been growing towards new heights in conjunction with the recent economic outburst. The country has the potential to revolutionize biopharmaceutical and healthcare sectors. In this review, we have highlighted the achievements of India's biotechnology industry, especially biopharmaceutical and healthcare sectors that include therapeutics, diagnostics, stem cell research, human healthcare related bioinformatics and animal health care. We have also described regulatory mechanisms involved in India's health care biotech including manpower development.     

Hubs and Authorities in the World Trade Network Using a Weighted HITS Algorithm

We investigate the economic hubs and authorities of the world trade network (WTN) from to , an era of rapid economic globalization. Using a well-defined weighted hyperlink-induced topic search (HITS) algorithm, we can calculate the values of the weighted HITS hub and authority for each country in a conjugate way. In the context of the WTN, authority values are large for countries with significant imports from large hub countries, and hub values are large for countries with significant exports to high-authority countries. The United States was the largest economic authority in the WTN from to . The authority value of the United States has declined since , and China has now become the largest hub in the WTN. At the same time, China''s authority value has grown as China is transforming itself from the “factory of the world” to the “market of the world.” European countries show a tendency to trade mostly within the European Union, which has decreased Europe''s hub and authority values. Japan''s authority value has increased slowly, while its hub value has declined. These changes are consistent with Japan''s transition from being an export-driven economy in its high economic growth era in the latter half of the twentieth century to being a more mature, economically balanced nation.     

Next issue (November 2007): Singapore Biotech Crossroads

Edited by Dr. Michael Entzeroth, Singapore Highlight articles: – Singapore's biomedical sciences landscape – Re-starting malaria research at NITD – CombinatoRx moves its molecular speed-dating to Singapore – UK-Singapore relationships in life sciences – AMRI and Singapore: Driving discovery in Asia – Function of SIRT1 Deacetylase in Oncology – The chakragati mouse: rapid in vivo antipsychotic drug screening – Neuroscience drug discovery in Singapore ... and much more: Read the next issue of BTJ!     

Biotech Crossroads: Singapore

Cover illustration: Singapore Biotech Crossroads, a BTJ special issue edited by Dr. Michael Entzeroth, Pharma Resources Asia Pte Ltd, Singapore. Highlights include articles about Singapore's biomedical sciences landscape, UK-Singapore relationships in life sciences, oncology and drug discovery, bioprocessing technology and much more. Image©Photodisc Inc.     

Upstream biomanufacturing of pharmaceutical colchicine

The plant-based colchicine potentially affects major diseases such as cardiovascular events, cancers and gout. Gloriosa superba seeds are a conventional pharmaceutical source of colchicine. The demand for pharmaceutical-grade colchicine has increased due to the shortage of feasible upstream manufacturing, encompassing all stages in the processes of biosynthesis and biomanufacturing before the raw material is ready for purification. Consequently, developing sustainable upstream industrial colchicine biofactories is imperative, especially in curtailing drug costs. A new upstream bioprocess has been established, using specialized biorhizomes with comprehensive specific-enzymes that catalyze the construction of biogenic functionalized intermediates that are converted into colchicine. This review emphasizes a novel biorhizome approach for biomanufacturing pharmaceutical-grade natural colchicine, a biosynthetic pathway elucidation and its challenges to synthetic biotechnology.     

全球生物产业发展现状及政策启示

生物经济时代正在引发人类新一波技术和产业革命,并已成为了全球主要发达国家和新兴经济体抢占的制高点。文中从生物医药产业、转基因作物种植产业、生物能源产业以及生物基化学品产业4个角度分析了全球生物产业发展的时空特征,概括总结了全球生物产业发展的主要特点,并进一步针对我国生物产业发展中存在的瓶颈问题提出政策建议,对我国生物经济的未来发展具有指导意义。     

全球生物制造产业市场与融资现状分析*

作为现代生物产业的核心,生物制造涵盖了从生物资源到生物技术,再到生物产业的价值链,集中体现了现代生物技术在医药、农业、能源、材料、化工、环保等多个工业领域的应用,对经济社会可持续发展进程有重要推动作用。当前,生物制造已成为世界主要发达经济体科技产业布局的重点领域之一,吸引了大量公共投资和社会资本,形成了价值数十亿美元级别的投资风口。调研统计2018~2019年全球150家生物制造相关企业201次融资事件,梳理生物制造产业的国内外发展环境和融资现状,为我国生物制造产业发展提出建议,以期引导领域科技成果转移转化、技术资本对接和行业繁荣发展,为我国经济社会可持续发展做出贡献。     

From observational to actionable: rethinking omics in biologics production

As the era of omics continues to expand with increasing ubiquity and success in both academia and industry, omics-based experiments are becoming commonplace in industrial biotechnology, including efforts to develop novel solutions in bioprocess optimization and cell line development. Omic technologies provide particularly valuable ‘observational’ insights for discovery science, especially in academic research and industrial R&D; however, biomanufacturing requires a different paradigm to unlock ‘actionable’ insights from omics. Here, we argue the value of omic experiments in biotechnology can be maximized with deliberate selection of omic approaches and forethought about analysis techniques. We describe important considerations when designing and implementing omic-based experiments and discuss how systems biology analysis strategies can enhance efforts to obtain actionable insights in mammalian-based biologics production.     

Chinese ethnicities in neoliberal Singapore? State designs and dialect(ical) struggles of community associations

Since the late 1990s, Singaporean state authorities have been increasingly marketing the city state as a knowledge-based hub between mainland China and western societies. Their focus on Mandarin-speaking mainlanders contrasts with Singapore's historical Chinese roots. By investigating the daily activities of Hokkien and Teochew community associations, I argue that these associations are finding ways to adapt to state initiatives that market a China-centric identity and target mainlanders. These dialect-based associations try to profit from state designs, while at the same time reclaiming their own historical distinctiveness. Drawing on qualitative work, I document the temporal practices of local dialect-based associations in reaction to neoliberal state initiatives that reduce Chineseness to a de-historicized skill set and stress how state–community interactions shape evolving Chinese ethnicities of the city state.     

甲醇生物转化合成化学品的研究进展

甲醇来源丰富、价格低廉,已成为生物制造行业极具吸引力的底物之一。构建微生物细胞工厂实现甲醇到增值化学品的生物转化,具有过程绿色、条件温和、产品体系多样等优势,不仅能拓展基于甲醇的产品链,还能缓解当前生物制造“与民争粮、与粮争地”的问题,是实现绿色生物制造的重要手段。因此,阐明不同天然甲基营养菌中涉及甲醇氧化、甲醛同化和异化途径对于后续基因工程改造工作至关重要,也更有利于构建新型非天然甲基营养菌。本文讨论了甲基营养菌中甲醇代谢途径的研究现状,并结合近年来天然和人工合成甲基营养菌在甲醇生物转化中的应用进展及面临的挑战。     

Cover Image,Volume 116, Number 9, September 2019

The new and rapid advancement in the complexity of biologics drug discovery has been driven by a deeper understanding of biological systems combined with innovative new therapeutic modalities, paving the way to breakthrough therapies for previously intractable diseases. These exciting times in biomedical innovation require the development of novel technologies to facilitate the sophisticated, multifaceted, high-paced workflows necessary to support modern large molecule drug discovery. A high-level aspiration is a true integration of “lab-on-a-chip” methods that vastly miniaturize cellulmical experiments could transform the speed, cost, and success of multiple workstreams in biologics development. Several microscale bioprocess technologies have been established that incrementally address these needs, yet each is inflexibly designed for a very specific process thus limiting an integrated holistic application. A more fully integrated nanoscale approach that incorporates manipulation, culture, analytics, and traceable digital record keeping of thousands of single cells in a relevant nanoenvironment would be a transformative technology capable of keeping pace with today's rapid and complex drug discovery demands. The recent advent of optical manipulation of cells using light-induced electrokinetics with micro- and nanoscale cell culture is poised to revolutionize both fundamental and applied biological research. In this review, we summarize the current state of the art for optical manipulation techniques and discuss emerging biological applications of this technology. In particular, we focus on promising prospects for drug discovery workflows, including antibody discovery, bioassay development, antibody engineering, and cell line development, which are enabled by the automation and industrialization of an integrated optoelectronic single-cell manipulation and culture platform. Continued development of such platforms will be well positioned to overcome many of the challenges currently associated with fragmented, low-throughput bioprocess workflows in biopharma and life science research.     

Expert systems in the control of animal cell culture processes: Potentials,functions, and perspectives

In recent years, the development of advanced systems for bioprocess monitoring and control has become an area of intensive research. Along with traditional techniques, there are several new approaches which are increasingly being applied to bioprocess operations. Among these, of special note is expert system technology, which provides possibilities for the design of efficient bioprocess control systems with new functional capabilities. This technology has been successfully applied to variety of microbial processes at laboratory and industrial scale. The present paper analyzes the possibility for application of expert systems to animal cell cultures processes whose high complexity is well suited to expert control. The discussion focuses on the organization and the functionality of the intelligent control systems, and covers some practical aspects of their design.     

动物细胞大规模培养技术

近年来,动物细胞大规模培养技术在生物技术领域成为最受关注的热点之一,并开始广泛应用于生物医药的研发和生产过程中。以生物反应器技术为基础的动物细胞大规模培养技术平台,正逐步被建立起来并日益走向成熟,成为推动生物医药产业快速发展的有力工具。结合该技术目前的应用水平和最新进展,分析了不同细胞培养工艺之间的内在差异,以探索这一技术的未来发展方向。     

Changing health policy in the post-Mao era.

A shift away from Mao Zedong''s concept of equality in the delivery of medical care is now taking place in The People''s Republic of China. This change is evident in the emphasis now placed upon high technology, basic research, and hospital care. All of these changes are occurring against the backdrop of extremely scarce medical resources. Medicine seemingly is viewed as one of many material incentives to be provided high productivity and leadership groups; the "modernization" of medicine is seen as one visible manifestation of the success of the broader modernization effort itself. As well, population policy has become more stringent, with rewards being given to one-child families and sanctions being applied against couples having three or more children. Although these policy changes offer bright prospects for Sino-American cooperation in the biomedical field, foreigners must remain sensitive to the controversial nature of these alterations in the Chinese political setting.     

生物医药产业发展态势与对策

当今许多国家政府已经把生物医药产业作为新的经济增长点来培育,通过采取不同政策和措施加速生物医药产业的发展。在我国政府相关利好政策的鼓励刺激和资金扶持下,我国生物医药产业有望加快走出经济危机的低谷,迎来快速发展期;在政府的引导下,构建生物产业技术创新战略联盟,推进资源整合和优势互补;多个高科技生物医药产业园区建设蓬勃,形成和集聚了一批具有较强实力的创新型企业,有力地带动了全国生物医药产业的发展和技术创新能力的提高。我国生物医药产业发展的重点要在产学研结合、前沿生物技术方面、市场准入政策和规范市场竞争秩序,以及高素质人才队伍的建设方面有所突破。根据市场导向,国家出台和制定相应的产业发展规划和政策,鼓励生物产业发展,加快国家生物医药产业基地建设;制定有关优惠政策,鼓励生物技术企业多种渠道和形式解产业发展资金问题;建立生物医药产业资源共享的机制,加强沟通与公共平台建设;发挥龙头企业的作用,支持大企业的收购兼并;加强相关法律法规建设,完善生物安全法和知识产权制度等一些措施来应对我国生物产业的快速发展。     

Recruitment constraints in Singapore's fluted giant clam (Tridacna squamosa) population—A dispersal model approach

Recruitment constraints on Singapore''s dwindling fluted giant clam, Tridacna squamosa, population were studied by modelling fertilisation, larval transport, and settlement using real-time hydrodynamic forcing combined with knowledge of spawning characteristics, larval development, behaviour, and settlement cues. Larval transport was simulated using a finite-volume advection-diffusion model coupled to a three-dimensional hydrodynamic model. Three recruitment constraint hypotheses were tested: 1) there is limited connectivity between Singapore''s reefs and other reefs in the region, 2) there is limited exchange within Singapore''s Southern Islands, and 3) there exist low-density constraints to fertilisation efficacy (component Allee effects). Results showed that connectivity among giant clam populations was primarily determined by residual hydrodynamic flows and spawning time, with greatest chances of successful settlement occurring when spawning and subsequent larval dispersal coincided with the period of lowest residual flow. Simulations suggested poor larval transport from reefs located along the Peninsular Malaysia to Singapore, probably due to strong surface currents between the Andaman Sea and South China Sea combined with a major land barrier disrupting larval movement among reefs. The model, however, predicted offshore coral reefs to the southeast of Singapore (Bintan and Batam) may represent a significant source of larvae. Larval exchange within Singapore''s Southern Islands varied substantially depending on the locations of source and sink reefs as well as spawning time; but all simulations resulted in low settler densities (2.1–68.6 settled individuals per 10,000 m²). Poor fertilisation rates predicted by the model indicate that the low density and scattered distribution of the remaining T. squamosa in Singapore are likely to significantly inhibit any natural recovery of local stocks.     

Determination of protein concentration in downstream biomanufacturing processes by in-line index of refraction

Protein concentration determination is a necessary in-process control for the downstream operations within biomanufacturing. As production transitions from batch mode to an integrated continuous bioprocess paradigm, there is a growing need to move protein concentration quantitation from off-line to in-line analysis. One solution to fulfill this process analytical technology need is an in-line index of refraction (IoR) sensor to measure protein concentration in real time. Here the performance of an IoR sensor is evaluated through a series of experiments to assess linear response, buffer matrix effects, dynamic range, sensor-to-sensor variability, and the limits of detection and quantitation. The performance of the sensor was also tested in two bioprocessing scenarios, ultrafiltration and capture chromatography. The implementation of this in-line IoR sensor for real-time protein concentration analysis and monitoring has the potential to improve continuous bioprocess manufacturing.     

化学品生物合成专刊序言

以酶及微生物细胞催化剂结合工程学方法将廉价、废弃原料进行高效生物转化可实现化学品的可持续生产。近年来,合成生物学、系统生物学及酶工程等技术的快速发展大大推动了化学品的可持续生物制造,既实现了多种新型化学品的生物合成,又显著提高化学品的生物合成效率。为展示化学品生物合成的最新进展并促进绿色生物制造的发展,《生物工程学报》特组织出版化学品生物合成专刊,从酶催化与生物合成机制、微生物细胞合成、一碳生物炼制以及关键核心技术等方面,介绍化学品生物合成的最新前沿、挑战以及潜在解决方案。