Creating parts that allow for rational design: Synthetic biology and the problem of context-sensitivity

The parts-based engineering approach in synthetic biology aims to create pre-characterised biological parts that can be used for the rational design of novel functional systems. Given the context-sensitivity of biological entities, a key question synthetic biologists have to address is what properties these parts should have so that they give a predictable output even when they are used in different contexts. In the first part of this paper I will analyse some of the answers that synthetic biologists have given to this question and claim that the focus of these answers on parts and their properties does not allow us to tackle the problem of context-sensitivity. In the second part of the paper, I will argue that we might have to abandon the notions of parts and their properties in order to understand how independence in biology could be achieved. Using Robert Cummins’ account of functional analysis, I will then develop the notion of a capacity and its condition space and show how these notions can help to tackle the problem of context-sensitivity in biology.     

Epitope-driven DNA vaccine design employing immunoinformatics against B-cell lymphoma: a biotech's challenge

DNA vaccination has been widely explored to develop new, alternative and efficient vaccines for cancer immunotherapy. DNA vaccines offer several benefits such as specific targeting, use of multiple genes to enhance immunity and reduced risk compared to conventional vaccines. Rapid developments in molecular biology and immunoinformatics enable rational design approaches. These technologies allow construction of DNA vaccines encoding selected tumor antigens together with molecules to direct and amplify the desired effector pathways, as well as highly targeted vaccines aimed at specific epitopes. Reliable predictions of immunogenic T cell epitope peptides are crucial for rational vaccine design and represent a key problem in immunoinformatics. Computational approaches have been developed to facilitate the process of epitope detection and show potential applications to the immunotherapeutic treatment of cancer. In this review a number of different epitope prediction methods are briefly illustrated and effective use of these resources to support experimental studies is described. Epitope-driven vaccine design employs these bioinformatics algorithms to identify potential targets of vaccines against cancer. In this paper the selection of T cell epitopes to develop epitope-based vaccines, the need for CD4(+) T cell help for improved vaccines and the assessment of vaccine performance against tumor are reviewed. We focused on two applications, namely prediction of novel T cell epitopes and epitope enhancement by sequence modification, and combined rationale design with bioinformatics for creation of new synthetic mini-genes. This review describes the development of epitope-based DNA vaccines and their antitumor effects in preclinical research against B-cell lymphoma, corroborating the usefulness of this platform as a potential tool for cancer therapy. Achievements in the field of DNA vaccines allow to overcome hurdles to clinical translation. In a scenario where the vaccine industry is rapidly changing from a mostly empirical approach to a rational design approach, these new technologies promise to discover and develop high-value vaccines, creating a new opportunity for future markets.     

The top five "game changers" in vaccinology: toward rational and directed vaccine development

Despite the tremendous success of the classical "isolate, inactivate, and inject" approach to vaccine development, new breakthroughs in vaccine research are increasingly reliant on novel approaches that incorporate cutting edge technology and advances in innate and adaptive immunology, microbiology, virology, pathogen biology, genetics, bioinformatics, and many other disciplines in order to: (1) deepen our understanding of the key biological processes that lead to protective immunity, (2) observe vaccine responses on a global, systems level, and (3) directly apply the new knowledge gained to the development of next-generation vaccines with improved safety profiles, enhanced efficacy, and even targeted utility in select populations. Here we highlight five key components foundational to vaccinomics efforts: applied immunogenomics, next generation sequencing and other cutting-edge "omics" technologies, advanced bioinformatics and analysis techniques, and finally, systems biology applied to immune profiling and vaccine responses. We believe these "game changers" will play a critical role in moving us toward the rational and directed development of new vaccines in the 21st century.     

Translating innate immunity into immunological memory: implications for vaccine development

Vaccination is the most effective means of preventing infectious diseases. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. Recent advances in immunology are beginning to provide an intellectual framework with which to address fundamental questions about how the innate immune system shapes adaptive immunity. In this review, we summarize current knowledge about how the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. In addition, we point out unanswered questions and identify critical challenges, the solution of which, we believe, will greatly facilitate the rational design of novel vaccines against a multitude of emerging infections.     

基于设计的生物大分子成药性优化策略研究进展

目前生物药物正处在高速发展阶段,但生物大分子的一些固有特性限制了其成药性,使得很多具有良好治疗潜能的生物大分子 最终不能开发成药物,因而严重制约了生物药物的发展。生物药物开发的瓶颈已从“新分子的产生”转向“如何获得具有优良生理特性 和预期治疗效果的有效药物”。近年来,通过合理设计改造生物大分子高级结构以优化其成药性的研究获得了快速发展。综述基于设计 的生物大分子成药性优化策略研究进展。     

Vaccines: From Empirical Development to Rational Design

Infectious diseases are responsible for an overwhelming number of deaths worldwide and their clinical management is often hampered by the emergence of multi-drug-resistant strains. Therefore, prevention through vaccination currently represents the best course of action to combat them. However, immune escape and evasion by pathogens often render vaccine development difficult. Furthermore, most currently available vaccines were empirically designed. In this review, we discuss why rational design of vaccines is not only desirable but also necessary. We introduce recent developments towards specifically tailored antigens, adjuvants, and delivery systems, and discuss the methodological gaps and lack of knowledge still hampering true rational vaccine design. Finally, we address the potential and limitations of different strategies and technologies for advancing vaccine development.     

Regulation of antiviral immune response by African swine fever virus (ASFV)

African swine fever (ASF) is a highly contagious and acute hemorrhagic viral disease with a high mortality approaching 100% in domestic pigs. ASF is an endemic in countries in sub-Saharan Africa. Now, it has been spreading to many countries, especially in Asia and Europe. Due to the fact that there is no commercial vaccine available for ASF to provide sustainable prevention, the disease has spread rapidly worldwide and caused great economic losses in swine industry. The knowledge gap of ASF virus (ASFV) pathogenesis and immune evasion is the main factor to limit the development of safe and effective ASF vaccines. Here, we will summarize the molecular mechanisms of how ASFV interferes with the host innate and adaptive immune responses. An in-depth understanding of ASFV immune evasion strategies will provide us with rational design of ASF vaccines.     

Identifying and classifying biomedical perturbations in text

Molecular perturbations provide a powerful toolset for biomedical researchers to scrutinize the contributions of individual molecules in biological systems. Perturbations qualify the context of experimental results and, despite their diversity, share properties in different dimensions in ways that can be formalized. We propose a formal framework to describe and classify perturbations that allows accumulation of knowledge in order to inform the process of biomedical scientific experimentation and target analysis. We apply this framework to develop a novel algorithm for automatic detection and characterization of perturbations in text and show its relevance in the study of gene–phenotype associations and protein–protein interactions in diabetes and cancer. Analyzing perturbations introduces a novel view of the multivariate landscape of biological systems.     

Vaccine design: future possibilities and potentials

Recent developments in the understanding of the structure and replications of a wide range of pathogens, including viruses, bacteria and parasites have opened up ways of designing novel vaccines which should both improve the quality and extend the range and value of vaccines as major prophylactic and therapeutic tools of the future. Two main strategies have emerged, one involving the development of synthetic vaccines which are essentially composed of selected epitopes of the pathogenic agent that will elicit neutralising antibodies. The other strategy attempts to make use of chimeric agents that will allow live virus or bacteria to be used as vectors for carrying appropriate epitopes of the target pathogen. Current knowledge about the immunology and improvements in the presentation of antigen to the immune system will also play an important role in the rational design of vaccines. This review summarises present methods of producing vaccines and considers the development of more rational methods of vaccine design that will greatly influence the production of vaccines in the future.     

Executable cell biology

Computational modeling of biological systems is becoming increasingly important in efforts to better understand complex biological behaviors. In this review, we distinguish between two types of biological models--mathematical and computational--which differ in their representations of biological phenomena. We call the approach of constructing computational models of biological systems 'executable biology', as it focuses on the design of executable computer algorithms that mimic biological phenomena. We survey the main modeling efforts in this direction, emphasize the applicability and benefits of executable models in biological research and highlight some of the challenges that executable biology poses for biology and computer science. We claim that for executable biology to reach its full potential as a mainstream biological technique, formal and algorithmic approaches must be integrated into biological research. This will drive biology toward a more precise engineering discipline.     

SARS及其病原体研究进展

严重急性呼吸道综合症(SARS)的病原体己被认定为一种新的冠状病毒-SARS冠状病毒。关于SARS冠状病毒的基因组和蛋白组研究也已取得重要进展,这为探索SARS病毒的来源与进化、研制SARS诊断试剂、开发SARS疫苗和治疗药物奠定了坚实基础。本文对严重急性呼吸道综合症病原学研究取得的一些进展进行了综述。     

Population biology and biological control of nematodes.

We studied the population biology of the nematophagous fungus Hirsutella rhossiliensis to understand its potential as a biological control agent. Because the fungus is an infectious and transmissible parasite, we framed our study within an epidemiological context. Field observations, theory, and experiments demonstrated that (i) parasitism of nematodes by H. rhossiliensis is dependent on nematode density, (ii) local populations of the fungus will go extinct unless supplied with some minimum number of nematodes (the host threshold density), and (iii) natural epidemics of this fungus in populations of nematodes develop slowly and only after long periods of high host density. Additional in-depth research on population biology is needed to explain other biological control systems and to guide future research. The most effective research will combine field observation, theory, and experimentation.     

Structural analysis of the epitope of the anti-HIV antibody 2F5 sheds light into its mechanism of neutralization and HIV fusion

Inhibition of human immunodeficiency virus (HIV) fusion with the host cell has emerged as a viable therapeutic strategy, and rational design of inhibitors and vaccines, interfering with this process, is a prime target for antiviral research. To advance our knowledge of the structural biology of HIV fusion, we have studied the membrane-proximal region of the fusogenic envelope subunit gp41, which includes the epitope ELDKWA of the broadly neutralizing human antibody 2F5. The structural evidence available for this region is contradictory, with some studies suggesting an overall helical conformation, while the X-ray structure of the ELDKWAS peptide bound to the antibody shows it folded in a type I beta turn. We used a two-step strategy: Firstly, by a competition binding assay, we identified the proper boundaries of the domain recognized by 2F5, which we found considerably larger than the ELDKWAS hexapeptide. Secondly, we studied the structure of the resulting 13 amino acid residue peptide by collecting NMR data and analyzing them by our previously developed statistical method (NAMFIS). Our study revealed that the increase in binding affinity goes in parallel with stabilization of specific local and global conformational propensities, absent from the shorter epitope. When compounded with the available biological evidence, our structural analysis allows us to propose a specific role for the membrane-proximal region during HIV fusion, in terms of a conformational transition between the turn and the helical structure. At the same time, our hypothesis offers a structural explanation for the mechanism of neutralization of mAb 2F5.     

Designing recombinant vaccines with viral properties: a rational approach to more effective vaccines

One of the great demands and challenges for vaccination is to successfully target the pathogens responsible for much of mankind's chronic disease burden including: AIDS, infectious hepatitis, tuberculosis and malaria. Another is realizing the potential of therapeutic immunization to cure diseases such as cancer, allergy and inflammatory autoimmunity. To achieve these objectives, the fundamental insights gained from immunology, genomics, molecular-cellular biology and vaccinology must be implemented in order to develop more effective, better defined and safer vaccines. As an illustrative example of this we examine the key features of viruses that are known to be responsible for eliciting superb host immune responses. These insights have formed a basis for understanding the effectiveness of existing vaccines and provide a framework for designing and developing new vaccines better able to meet pressing unmet medical needs. The key immunogenic properties of viruses that are understood to date and are currently being applied include: their particulate nature, their highly repetitive and ordered structures, their ability to induce innate immunity with consequent conditioning of adaptive responses and the kinetics and distribution of viral antigens during infection. Vaccines and vaccine-formulations recently registered for use in humans already incorporate some of these elements. Of great anticipation is the progress of the next-generation vaccines now advancing through the various stages of research and development. Vaccines which, by way of rational design, incorporate viral properties to induce tailored responses and thus have the potential to provide safer and more effective prophylaxis and therapies.     

Inference of biological S-system using the separable estimation method and the genetic algorithm

Reconstruction of a biological system from its experimental time series data is a challenging task in systems biology. The S-system which consists of a group of nonlinear ordinary differential equations (ODEs) is an effective model to characterize molecular biological systems and analyze the system dynamics. However, inference of S-systems without the knowledge of system structure is not a trivial task due to its nonlinearity and complexity. In this paper, a pruning separable parameter estimation algorithm (PSPEA) is proposed for inferring S-systems. This novel algorithm combines the separable parameter estimation method (SPEM) and a pruning strategy, which includes adding an l? regularization term to the objective function and pruning the solution with a threshold value. Then, this algorithm is combined with the continuous genetic algorithm (CGA) to form a hybrid algorithm that owns the properties of these two combined algorithms. The performance of the pruning strategy in the proposed algorithm is evaluated from two aspects: the parameter estimation error and structure identification accuracy. The results show that the proposed algorithm with the pruning strategy has much lower estimation error and much higher identification accuracy than the existing method.     

用模块化分子元件调控和编程生物系统

合成生物学的目标包括“通过合成来理解生命”以及用现代工程学方法设计合成复杂生物系统．其工程学目标的实现依赖于可集成、可调控、可重用、功能多样的蛋白质、RNA、DNA等基本分子元件．以分子机制为基础,合理设计与实验室进化相结合,改造和创建生物分子的相互作用特异性、调控方式、定量活性等,是实现生物系统人工调控与编程的重要策略,同时为自下而上设计合成日益复杂的人工生物系统奠定基础．     

Vaccinomics and a new paradigm for the development of preventive vaccines against viral infections

In this article we define vaccinomics as the integration of immunogenetics and immunogenomics with systems biology and immune profiling. Vaccinomics is based on the use of cutting edge, high-dimensional (so called "omics") assays and novel bioinformatics approaches to the development of next-generation vaccines and the expansion of our capabilities in individualized medicine. Vaccinomics will allow us to move beyond the empiric "isolate, inactivate, and inject" approach characterizing past vaccine development efforts, and toward a more detailed molecular and systemic understanding of the carefully choreographed series of biological processes involved in developing viral vaccine-induced "immunity." This enhanced understanding will then be applied to overcome the obstacles to the creation of effective vaccines to protect against pathogens, particularly hypervariable viruses, with the greatest current impact on public health. Here we provide an overview of how vaccinomics will inform vaccine science, the development of new vaccines and/or clinically relevant biomarkers or surrogates of protection, vaccine response heterogeneity, and our understanding of immunosenescence.