Regulating biorisks: Developing a coherent policy logic (part I)

This is the first of two articles empirically detailing the working practices of regulators who are charged with overseeing biological research. Specifically, it considers how regulators from the Biological Agents Unit of the UK Health and Safety Executive review notifications and applications, carry out inspections of research centres, and enforce the law once breaches are uncovered. This first article focuses on the Unit's working practices before 9/11, and the second, forthcoming article focuses on the Unit's working practices after 9/11. I argue that an understanding of the implementation processes--that is, the strategies adopted by regulatory agencies and the styles employed by agency regulators in their interactions with those regulated--is critical to developing a coherent policy logic for the developing regulatory regime around biorisks.     

Biosimilars--global issues, national solutions

Biotechnology derived medicinal products are presently the best characterized biologicals with considerable production and clinical experience, and have revolutionized the treatment of some of the most difficult-to-treat diseases, prolonging and improving the quality of life and patient care. They are also currently one of the fastest growing segments of the pharmaceutical industry market. The critical challenge that the biopharmaceutical industry is facing is the expiry of patents for the first generation of biopharmaceuticals, mainly recombinant DNA derived products, such as interferons, growth hormone and erythropoetin. The question that immediately arose was how should such copies of the originator products be licensed, bearing in mind that they are highly complex biological molecules produced by equally complex biological production processes with their inherent problem of biological variability. Copying biologicals is much more complex than copying small molecules and the critical issue was how to handle the licensing of products if relying in part on data from an innovator product. Since 2004 there has been considerable international consultation on how to deal with biosimilars and biological copy products. This has led to a better understanding of the challenges in the regulatory evaluation of the quality, safety and efficacy of "biosimilars", to the exchange of information between regulators, as well as to the identification of key issues. The aim of this article is to provide a brief overview of the scientific and regulatory challenges faced in developing and evaluating similar biotherapeutic products for global use. It is intended as an introduction to the series of articles in this special issue of Biologicals devoted to similar biotherapeutic products.     

Regulation,necessity, and the misinterpretation of knockouts

Much contemporary biology consists of identifying the molecular components that associate to perform biological functions, then discovering how these functions are controlled. The concept of control is key to biological understanding, at least of the physiological kind; identifying regulators of processes underpins ideas of causality and allows complicated, multicomponent systems to be summarized in relatively simple diagrams and models. Unfortunately, as this article demonstrates by drawing on published articles, there is a growing tendency for authors to claim that a molecule is a ‘regulator’ of something on evidence that cannot support the conclusion. In particular, gene knockout experiments, which can demonstrate only that a molecule is necessary for a process, are all too frequently being misinterpreted as revealing regulation. This logical error threatens to blur the important distinction between regulation and mere necessity and therefore to weaken one of our strongest tools for comprehending how organisms work.     

Making way for molecular biology: institutionalizing and managing reform of biological science in a UK university during the 1980s and 1990s

Historians agree that the second half of the twentieth century saw widespread changes in the structure of biological science in universities. This shift was, and continues to be, characterized by the de-differentiation of nineteenth and early twentieth century disciplines, with increasing emphasis on the methods and authority of molecular fields. Yet we currently lack appreciation of the dynamics that underpinned these changes, and of their tangible effects on the working practices of those involved. In this article we examine the wholesale reform of biological science at the University of Manchester, England, that occurred in two successive steps in 1986 and 1993. We examine how reform was enabled by economic and political factors, as staff seized upon national pressures; in so doing, we emphasize how this reform was shaped by a generational view of the biological sciences as a one field, unified by molecular techniques. We assess how the success of these reforms was tied to new management policies that rewarded research activity in molecular fields, and refigured teaching as a punishment for research inactivity. We close by showing how our analysis fits amongst, and can contribute to, 'big picture' debates in the history and sociology of knowledge.     

Synthetic biology confronts publics and policy makers: challenges for communication, regulation and commercialization

The novelty of synthetic biology lies in the use of synthesized parts that can be arranged to make useful products. Such advanced, high-throughput genetic engineering projects redesign and fabricate existing biological systems as well as new biological parts, devices and systems that do not occur in nature. This Opinion discusses challenges raised by synthetic biology for public acceptance, regulation, commercialization and the emerging global issue of access to genetic resources and information. As with all new fields of research, maintaining the trust of the public and policy regulators is paramount. Hype and exaggerated claims are counterproductive to developing adaptive and ethically sound regulatory models responsive to stakeholder concerns.     

Thematic Minireview Series: New Directions in G Protein-coupled Receptor Pharmacology

Over the past half-century, The Journal of Biological Chemistry has been the venue for many landmark publications on the topic of G protein-coupled receptors (GPCRs, also known as seven-transmembrane receptors). The GPCR superfamily in humans is composed of about 800 members, and is the target of about one-third of all pharmaceuticals. Most of these drugs target a very small subset of GPCRs, and do so by mimicking or competing with endogenous hormones and neurotransmitters. This thematic minireview series examines some emerging trends in GPCR drug discovery. The first article describes efforts to systematically interrogate the human “GPCR-ome,” including more than 150 uncharacterized “orphan” receptors. The second article describes recent efforts to target alternative receptor binding sites with drugs that act as allosteric modulators of orthosteric ligands. The third article describes how the recent expansion of GPCR structures is providing new opportunities for computer-guided drug discovery. Collectively, these three articles provide a roadmap for the most important emerging trends in GPCR pharmacology.     

Grand challenges for biological engineering

Biological engineering will play a significant role in solving many of the world's problems in medicine, agriculture, and the environment. Recently the U.S. National Academy of Engineering (NAE) released a document "Grand Challenges in Engineering," covering broad realms of human concern from sustainability, health, vulnerability and the joy of living. Biological engineers, having tools and techniques at the interface between living and non-living entities, will play a prominent role in forging a better future. The 2010 Institute of Biological Engineering (IBE) conference in Cambridge, MA, USA will address, in part, the roles of biological engineering in solving the challenges presented by the NAE. This letter presents a brief outline of how biological engineers are working to solve these large scale and integrated problems of our society.     

WHO Study Group on cell substrates for production of biologicals, Geneva, Switzerland, 11–12 June 2007

For many years, the World Health Organization (WHO) has provided global leadership in defining technical specifications for quality assurance and safety of biological medicines produced in cell substrates. Current WHO requirements for the use of animal cells as substrates for production of vaccines and other biologicals were adopted by the WHO Expert Committee on Biological Standardization in 1996 (WHO TRS 878). Since then, significant progress especially in the development of vaccines in novel continuous cell lines of mammalian origin as well as in insect cells has been made and consequently there is an increasing need for the re-evaluation of existing criteria for the acceptability of such cell lines. In addition there is also a need to consider new issues in cell substrate safety arising from these new cell types and developments in technology and scientific knowledge. In response to these demands, the WHO Study Group on Cell Substrates was formed in 2006 to initiate revision of WHO requirements and to address the need for further research in this area. At its second meeting on 11-12 June 2007, the Study Group reviewed scientific data that would form the basis for new recommendations and made a number of proposals for further investigations. The Study Group is working on the preparation of a revised WHO document, and a broad consultation with regulators, manufacturers, and other relevant parties is planned for 2008.     

Sex,gender, and pharmaceutical politics: From drug development to marketing

Background: Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing.Objectives: This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials.Methods: The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals.Results: The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome.Conclusions: Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and gender.     

Problems of biochemical organization]

Biological organization has been defined as a unity of structure, function and regulation. Biological organization of hierarchical multilevel biological systems is represented by a hierarchy of functioning controllable structures. The hierarchy of levels of material organization predetermines the existence of a hierarchy of regulatory mechanisms. Biochemical organization involves the levels of material organization corresponding to biomacromolecules, supramolecular complexes and cellular organelles. The levels of biomacromolecules and supramolecular structures effectuating elementary functions and controlled by basic regulatory mechanisms occupy key positions in biological systems. These levels play the role of standard functional blocks; their combination leads to hierarchically higher structural levels (cell, tissue, organ, systems of organs, organism) performing more complex functions and controlled by hierarchically more important regulatory mechanisms. The peculiarities of regulation of biological systems that are due to the existence of a hierarchy of regulatory mechanisms are discussed.     

The regulation of genes and genomes by small RNAs

A recent Keystone Symposium on 'MicroRNAs and siRNAs: Biological Functions and Mechanisms' was organized by David Bartel and Shiv Grewal (and was held in conjunction with 'RNAi for Target Validation and as a Therapeutic', organized by Stephen Friend and John Maraganore). The 'MicroRNAs and siRNAs' meeting brought together scientists working on diverse biological aspects of small regulatory RNAs, including microRNAs, small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs and rasiRNAs). Among the themes discussed were the diversity of small regulatory RNAs and their developmental functions, their biogenesis, the identification of their regulatory targets, their mechanisms of action, and their roles in the elaboration of multicellular complexity.     

Left-wing politics,civil society and immigration in Italy: The case of Bologna

Immigration and multiculturalism are important and much debated questions in contemporary Europe. Whereas considerable scholarship has examined how political institutions and Right-wing organizations have responded to these questions, little research has focused on the Left. This article examines the multicultural politics of the latter by considering ethnographically the experience of Bologna, the showcase city of the Italian Left, in the second half of the 1990s. The Left is here examined in terms of ideology, party, public policy and civil society in the context of everyday governance and with special reference to the discourses and practices concerning a group of Rom refugees from the former Yugoslavia. This article argues that the mainstream Italian Left (in its civil societal as well as party and administrative components) is characterized by a politics that fails to “integrate” ethno-cultural recognition with material justice and that, partly because of such failure, contributes little to the “integration” of immigrants.     

Legislative aspects: an evaluation of the impact of COSHH schedule 9 for assessing biological risks

Exposure to biological agents in the workplace can cause infection, allergy or toxicosis. Health effects caused by biological agents in the workplace are related both to incidental exposure and to deliberate work with microorganisms. A small but significant percentage of occupational allergy is associated with biological agents in organic dusts, and a new reporting scheme recorded more than 1000 new cases of occupational infection in its first year. Assessing risks from workplace biological agents in the UK forms part of the Control of Substances Hazardous to Health (COSHH) regulations. Legislation (Schedule 9) and guidance which deals with biological agents were added to implement EC Biological Agents Directives and to emphasise the position of biological agents in COSHH.We evaluated the impact of COSHH Schedule 9 by interviewing representatives of workers in laboratories deliberately handling microorganisms and discussing in a Focus Group format with representatives from industries where incidental exposure to microorganisms could occur. This paper describes the outcome of that evaluation and examines the tools available to assess risks from exposure to workplace microorganisms.     

Ethnic and civic dealings with newcomers: naturalization policies and practices in twenty-six immigration countries

Over the last decade or so, the comparative study of nationalism has produced a large number of cogent critiques of classifying nations according to how ethnic or civic they are. In fact, these critiques have been so convincing that many scholars today seem to agree that any mention of the words ‘ethnic’ and ‘civic’ is unwarranted. This is unfortunate, because the distinction still offers a useful heuristic device to compare and classify different nation-building practices. This article analyses naturalization policies in twenty-six Western immigrant-receiving democracies in order to show that the distinction constitutes a valuable analytical tool to explore how different countries deal with newcomers. The naturalization policy index developed in this article proves to have a high degree of face validity, to be a good predictor of actual naturalization practices, and to match up well with previous classifications of ethnic and civic nation-building practices.     

Cost-Benefit Analysis in a Regulatory Setting

The purpose of requiring cost-benefit analysis is to produce better out-comes from regulatory processes. If implemented well, cost-benefit analysis and risk assessment can produce improvements at several levels, by encouraging regulators to consider unintended effects of regulations and thereby avoid making things worse, to find the least burdensome approach to a goal, and to balance the pluses and minuses involved in choosing a goal. Whether these improvements will occur depends in large part on how cost-benefit analysis is implemented. Guidelines for conducting cost-benefit analysis and procedures for considering evidence on costs and benefits play an important role. This article describes how guidelines and rules of process can affect outcomes, and the issues that cost-benefit guidelines need to cover. Guidelines can affect the bias of a regulatory process toward one set of stakeholders or another, make outcomes more predictable, define the information needed for decisions, and provide a basis for legal challenges. The questions that guidelines should address include: what are costs and benefits, what constitutes good economics, what are standards of proof, how should unquantified costs and benefits be treated, how should uncertainties of cost-benefit estimates be dealt with, and how should alternatives be generated? The article concludes with recommen dations about how the adoption of cost-benefit analysis can be made most effective and beneficial in regulatory processes.     

链霉菌次级代谢调控相关的双组分系统研究进展

链霉菌具有强大的次级代谢能力, 能够产生众多具有生物活性的次级代谢产物, 如目前广泛应用的抗生素、抗肿瘤药物以及免疫抑制剂等。在链霉菌中, 次级代谢产物的生物合成受到包括途径特异性、多效性以及全局性调控基因在内的多层次严格调控。关键调控基因的缺失或过表达可以显著影响次级代谢产物的生物合成, 提示对于链霉菌次级代谢重要调控基因的功能及其作用机制的研究具有巨大的潜在应用价值。其中, 作为细菌信号传导系统的双组分系统(Two-component system, TCS)一直是大家研究的关注点。越来越多的研究表明TCS在链霉菌次级代谢过程中发挥着全局性的调控功能。本文重点介绍链霉菌模式菌株——天蓝色链霉菌中TCS(包括典型TCS)、孤立的组氨酸蛋白激酶(HK)以及应答调控蛋白(RR)参与次级代谢调控的研究进展。这些TCS的功能鉴定及机制解析为工业链霉菌的定向遗传改造以提高重要次级代谢产物的含量提供了理论依据。     

A probabilistic methodology for integrating knowledge and experiments on biological networks.

Biological systems are traditionally studied by focusing on a specific subsystem, building an intuitive model for it, and refining the model using results from carefully designed experiments. Modern experimental techniques provide massive data on the global behavior of biological systems, and systematically using these large datasets for refining existing knowledge is a major challenge. Here we introduce an extended computational framework that combines formalization of existing qualitative models, probabilistic modeling, and integration of high-throughput experimental data. Using our methods, it is possible to interpret genomewide measurements in the context of prior knowledge on the system, to assign statistical meaning to the accuracy of such knowledge, and to learn refined models with improved fit to the experiments. Our model is represented as a probabilistic factor graph, and the framework accommodates partial measurements of diverse biological elements. We study the performance of several probabilistic inference algorithms and show that hidden model variables can be reliably inferred even in the presence of feedback loops and complex logic. We show how to refine prior knowledge on combinatorial regulatory relations using hypothesis testing and derive p-values for learned model features. We test our methodology and algorithms on a simulated model and on two real yeast models. In particular, we use our method to explore uncharacterized relations among regulators in the yeast response to hyper-osmotic shock and in the yeast lysine biosynthesis system. Our integrative approach to the analysis of biological regulation is demonstrated to synergistically combine qualitative and quantitative evidence into concrete biological predictions.     

Trends in biological control: public interest,international networking and research direction

We investigated trends in biological control to both capture its evolution and explore future opportunities. We examined recent changes in public interest, international networking and peer-reviewed research. A Google Trends analysis revealed that the popularity of biological control is decreasing in terms of search hits on the internet. This trend is potentially worrying for the biological control community, given that public interest tends to drive political decisions regarding regulatory processes and governmental funding of research. To examine patterns of international collaboration, we established the list of authors who published their work in the three main biological control journals from the early 1990s to 2016. International co-authorship has intensified and the biological control sector is increasingly characterized by multilateral collaboration. We surveyed papers published in BioControl and Biological Control over the last 25 years to identify research trends with respect to target pests, commodities, biological control agents and biological control approaches. Finally, we report that articles on biological control are published in the broad-based scientific journals Science and Nature on a regular basis. This reflects contributions that biological control research makes to scientific discussions in general. Our analyses revealed a thriving scientific discipline with several major research trends in arthropod, plant pathogen and weed biological control.