Applying insect transgenic technology: Scientific and regulatory experiences*

Biotechnology affords opportunities to develop new tools to treat pest and disease problems. When a given pest or disease problem has no satisfactory cure or treatment, usually only a technological breakthrough can provide one, but the process whereby this happens can be undefined and unpredictable. Furthermore, it is difficult to predict which methods will work at the outset, meaning that it is also difficult for funding agencies to determine which proposals to support. When a proposed solution is new and may involve genetic manipulation, it may also be hard for the public, as represented by regulatory agencies, to accept. In addition, when the application market is small, funding is modest. When the problem is major but periodic, as in the case of migratory locusts, funding, interest and attention cannot be easily found, focused or sustained. It is only when a problem is severe and economically compelling, such as Pierce's Disease of grapevine in southern California, that it is possible to concentrate funding, attention and sustained interest long enough to have a chance of finding a lasting solution.     

Financing of U.S. Biomedical Research and New Drug Approvals across Therapeutic Areas

Background

We estimated U.S. biomedical research funding across therapeutic areas, determined the association with disease burden, and evaluated new drug approvals that resulted from this investment.

Methodology/Principal Findings

We calculated funding from 1995 to 2005 and totaled Food and Drug Administration approvals in eight therapeutic areas (cardiovascular, endocrine, gastrointestinal, genitourinary, HIV/AIDS, infectious disease excluding HIV, oncology, and respiratory) primarily using public data. We then calculated correlations between funding, published estimates of disease burden, and drug approvals.Financial support for biomedical research from 1995 to 2005 increased across all therapeutic areas between 43% and 369%. Industry was the principal funder of all areas except HIV/AIDS, infectious disease, and oncology, which were chiefly sponsored by the National Institutes of Health (NIH). Total (ρ = 0.70; P = .03) and industry funding (ρ = 0.69; P = .04) were correlated with projected disease burden in high income countries while NIH support (ρ = 0.80; P = .01) was correlated with projected disease burden globally. From 1995 to 2005 the number of new approvals was flat or declined across therapeutic areas, and over an 8-year lag period, neither total nor industry funding was correlated with future approvals.

Conclusions/Significance

Across therapeutic areas, biomedical research funding increased substantially, appears aligned with disease burden in high income countries, but is not linked to new drug approvals. The translational gap between funding and new therapies is affecting all of medicine, and remedies must include changes beyond additional financial investment.     

The case and opportunity for public-supported financial incentives to implement integrated pest management

Food, water, and worker protection regulations have driven availability, and loss, of pesticides for use in pest management programs. In response, public-supported research and extension projects have targeted investigation and demonstration of reduced-risk integrated pest management (IPM) techniques. But these new techniques often result in higher financial burden to the grower, which is counter to the IPM principle that economic competitiveness is critical to have IPM adopted. As authorized by the 2002 Farm Bill and administered by the U.S. Department of Agriculture (USDA) Natural Resources Conservation Service (NRCS), conservation programs exist for delivering public-supported financial incentives to growers to increase environmental stewardship on lands in production. NRCS conservation programs are described, and the case for providing financial incentives to growers for implementing IPM is presented. We also explored the opportunity and challenge to use one key program, the Environmental Quality Incentives Program (EQIP), to aid grower adoption of IPM. The EQIP fund distribution to growers from 1997 to 2002 during the last Farm Bill cycle totaled approximately 1.05 billion dollars with a portion of funds supporting an NRCS-designed pest management practice. The average percentage of allocation of EQIP funds to this pest management practice among states was 0.77 +/- 0.009% (mean +/- SD). Using Michigan as an example, vegetable and fruit grower recognition of the program's use to implement IPM was modest (25% of growers surveyed), and their recognition of its use in aiding implementation of IPM was improved after educational efforts (74%). Proposals designed to enhance program usefulness in implementing IPM were delivered through the NRCS advisory process in Michigan. Modifications for using the NRCS pest management practice to address resource concerns were adopted, incentive rates for pest management were adjusted, and an expanded incentive structure for IPM technique adoption was tabled for future consideration. The case is strong for using public-supported financial incentives offered by the EQIP to aid grower adoption of IPM as a means to address resource concerns, but current use of the EQIP for this purpose is modest to meager. With appropriate program adjustments and increased grower awareness, USDA NRCS conservation programs, and the EQIP in particular, may provide an important opportunity for growers to increase their use of IPM as a resource conservation and farm management tool.     

Applications of <Emphasis Type="Italic">in vitro</Emphasis> culture systems for commercial sugarcane production and improvement

Sugarcane breeding, while key to continued improvement of pest and disease resistance and to increasing sucrose and biomass yields, is constrained by the length of time taken to release a new cultivar (10–14 yr). Forty years of international research into sugarcane in vitro culture has delivered many well-developed systems that are routinely applied to research and commercial activities, namely: (a) micropropagation of genotypes; (b) production of disease-free material from excised apical meristems; (c) international germplasm exchange; (d) generation of somaclones; (e) rapid disease and pest resistance screening; and (f) germplasm conservation. This review outlines several in vitro techniques, discussing how protocols have been tailored to address pertinent research issues and exploring possible commercial applications in the sugar industry to reduce the time frame to release a new cultivar and decrease demands on resources such as land and labour.     

Genetically modified microbial symbionts as arthropod pest controllers: risk assessment through the European legislations

The genetic modification and applied use of microbial symbionts have been identified as novel tools to protect beneficial insects such as pollinators or parasitoids or to fight insects that constitute pests or are vectors of infectious diseases. The deliberate release of insect pest or disease vector control products containing genetically modified micro‐organisms (GMMs) can raise questions about health and environmental safety. Different national and international authorities have established legal requirements to ensure the safe use of conventional pesticides and insecticides as well as GMMs. A key requirement is to conduct a scientific risk assessment to determine whether the product is safe to be placed in the market. In this study, we address the legal framework, the regulatory requirements, and the criteria for the environmental risk assessment of GM symbionts that currently apply within the European Union.     

"It's at a Time in Your Life When You Are Most Vulnerable": A Qualitative Exploration of the Financial Impact of a Cancer Diagnosis and Implications for Financial Protection in Health

Although cancer patients may incur a wide range of cancer-related out-of-pocket costs and experience reduced income, the consequences of this financial burden are poorly understood. We investigated: financial adjustments needed to cope with the cancer-related financial burden; financial distress (defined as a reaction to the state of personal finances); and factors that increase risk of financial difficulties. Two sets of semi-structured face-to-face interviews were conducted with 20 patients with breast, lung and prostate cancer and 21 hospital-based oncology social workers (OSWs) in Ireland, which has a mixed public-private healthcare system. Participants were asked about: strategies to cope with the cancer-related financial burden; the impact of the financial burden on the family budget, other aspects of daily life, and wellbeing. OSWs were also asked about patient groups they thought were more likely to experience financial difficulties. The two interview sets were analysed separately using a thematic approach. Financial adjustments included: using savings; borrowing money; relying on family and friends for direct and indirect financial help; and cutting back on household spending. Financial distress was common. Financial difficulties were more likely for patients who were older or younger, working at diagnosis, lacked social support, had dependent children, had low income or had few savings. These issues often interacted with one another. As has been seen in predominantly publically and predominantly privately-funded healthcare settings, a complex mixed public-private healthcare system does not always provide adequate financial protection post-cancer. Our findings highlight the need for a broader set of metrics to measure the financial impact of cancer (and to assess financial protection in health more generally); these should include: out-of-pocket direct medical and non-medical costs; changes in income; financial adjustments (including financial coping strategies and household consumption patterns); and financial distress. In the interim, cancer patients require financial information and advice intermittently post diagnosis.     

The development, regulation and use of biopesticides for integrated pest management

Over the past 50 years, crop protection has relied heavily on synthetic chemical pesticides, but their availability is now declining as a result of new legislation and the evolution of resistance in pest populations. Therefore, alternative pest management tactics are needed. Biopesticides are pest management agents based on living micro-organisms or natural products. They have proven potential for pest management and they are being used across the world. However, they are regulated by systems designed originally for chemical pesticides that have created market entry barriers by imposing burdensome costs on the biopesticide industry. There are also significant technical barriers to making biopesticides more effective. In the European Union, a greater emphasis on Integrated Pest Management (IPM) as part of agricultural policy may lead to innovations in the way that biopesticides are regulated. There are also new opportunities for developing biopesticides in IPM by combining ecological science with post-genomics technologies. The new biopesticide products that will result from this research will bring with them new regulatory and economic challenges that must be addressed through joint working between social and natural scientists, policy makers and industry.     

The control of vertebrate pests by vertebrate predators

Carnivores can control mammalian pests for long periods, but only after pest numbers have been reduced by other means. In Australia, the cause is prolonged dry weather. The consequent low populations of rabbits can then be regulated by European foxes, feral cats and dingoes. Kangaroos, and probably feral goats and pigs, succumb to dingoes at the same time, as substitute prey for rabbits. In the general case, such regulatory predation may be triggered climatically, by disease or by human intervention. When predators are themselves pests to be controlled, integrated pest management may be required to avoid unwanted resurgences of other pests.     

RNAi在害虫防治中应用的重要进展及存在问题

RNAi是目前最有可能应用于害虫绿色防控的新技术。2017年6月,美国环境署(EPA)批准了国际上第一例表达昆虫双链RNA(dsRNA)的抗虫转基因玉米MON87411,掀起了利用RNAi技术进行害虫防治研究新的热潮。但是,目前RNAi在害虫防治中的应用还存在一些问题,例如有效靶标基因筛选和应用策略,鳞翅目昆虫对RNAi的敏感性以及双链RNA在环境中的稳定性等等。本文系统总结了RNA干扰现象发现20年来,该技术在害虫防治领域的研究及应用概况,并对RNAi技术应用的可行性、应用方法、存在问题和目前的一些解决办法进行了比较详细的综述。通过对近期研究结果的综合分析发现,dsRNA进入某些鳞翅目昆虫中肠或血淋巴后,被相关核酸酶降解可能是其RNAi效率较低的首要原因。通过对dsRNA进行脂质体修饰,纳米粒子包埋可以在一定程度上解决dsRNA降解的问题,进而提高RNAi效率。     

Synergizing biological control: Scope for sterile insect technique,induced plant defences and cultural techniques to enhance natural enemy impact

When used alone, only a minority of biological control programs succeed in bringing the target pest population under sufficient control. Biological control is, therefore, usually employed with chemical, cultural, genetic or other methods in an integrated pest management (IPM) strategy. The interactions between different pest management methods, especially conventional pesticides and host plant resistance, is an area of growing research interest but relatively little consideration is given to novel combinations. This paper reviews the interactions between biological control and other forms of pest management, especially induced plant defences and the novel, non-toxic plant protection compounds that may boost these defences; and sterile insect technique. We also cover the cultural methods that offer scope to support synergies between the aforementioned methodological combinations. We conclude that despite the sometimes negative consequences of other pest management techniques for biological control efficacy, there is great scope for new strategies to be developed that exploit synergies between biological control and various other techniques. Ultimately, however, we propose that future use of biological control will involve integration at a greater conceptual scale such that this important form of pest management is promoted as one of a suite of ecosystem services that can be engineered into farming systems and wider landscapes.     

Safety of Microorganisms Intended for Pest and Plant Disease Control: A Framework for Scientific Evaluation

Microorganisms are enormous but largely untapped natural resources for biological control of pests and diseases. There are two primary reasons for their underployment for pest or disease control: (1) the technical difficulties of using microorganisms for biological control, owing to a lack of fundamental information on them and their ecology, and (2) the costs of product development and regulatory approvals required for each strain, formulation, and use. Agriculture and forestry benefit greatly from the resident communities of microorganisms responsible for naturally occurring biological control of pest species, but additional benefits are achieved by introducing/applying them when or where needed. This can be done as (1) an inoculative release, (2) an augmentative application, or (3) an inundative application. Because of their specificity, different microbial biocontrol agents typically are needed to control different pests or the same pest in different environments. Four potential adverse effects are identified as safety issues (hazards) associated with the use of microorganisms for the biological control of plant pests and diseases. These are: (1) displacement of nontarget microorganisms, (2) allergenicity to humans and other animals, (3) toxigenicity to nontarget organisms, and (4) pathogenicity to nontarget organisms. Except for allergenicity, these are the same attributes that contribute to the efficacy of microbial biocontrol agents toward the target pest species. The probability of occurrence of a particular adverse nontarget effect of a microbial biocontrol agent may be a function of geographic origin or a specific trait genetically added or modified, but the safety issues are the still the same, including whether the microorganism intended for pest or disease control is indigenous, nonindigenous (imported and released), or genetically modified by traditional or recombinant DNA (rDNA) technology. Likewise, the probability of occurrence of a particular adverse nontarget effect may vary with method of application, e.g., whether as an aerosol, soil treatment, baits, or seed treatment, and may increase with increased scale of use, but the safety issues are still the same, including whether the microorganism is used for an inoculative release or augmentative or inundative application. Existing practices for managing microorganisms in the environment (e.g., plant pathogens,Rhizobium,plant inoculants) provide experience and options for managing the risks of microorganisms applied for pest and disease control. Moreover, experience to date indicates that any adverse nontarget effects, should they occur, are likely to be short-term or transitory effects that can, if significant, be eliminated by terminating use of the microbial biocontrol agent. In contrast, production agriculture as currently practiced, such as the use of tillage and crop rotations, has significant and long-term effects on nontarget organisms, including the intentional and unintentional displacement of microorganisms. Even the decision to leave plant pests and diseases unmanaged could have significant long-term environmental effects on nontarget organisms. Potential safety issues associated with the use of microbial biocontrol must therefore be properly identified and compared with the impact of other options for managing the pest or leaving the pest unmanaged. This paper provides a scientific framework for this process.     

Economic and practical challenges to the formulation of vaccines against endemic infectious diseases such as malaria

Herein, we analyze in general the current vaccine market and identify potential factors driving and modulating supply and demand for vaccines. An emphasis is placed on changes in regulation in the last 20 years which have led to increased indirect costs of production, and which can create a barrier against the timely use of technological advances to reduce direct costs. Other defining industry characteristics, such as firm numbers and sizes, cost and pricing strategies, nature extent and impact of Government involvement and international regulation are noted. These considerations, far from being removed from basic vaccine research, influence its ability to achieve aims that can be then progressed into effective vaccine products. We discuss specifically the development of particulate vaccines against malaria, a major lethal disease and health problem prevalent in Africa, including some key economic and methodological challenges and opportunities. We note some practical issues blocking the development of effective particulate vaccines for the Third World, mainly driven by the regulatory spiral noted above.     

跨区域森林生态补偿的演化博弈分析——基于主体功能区的视角

新常态下,我国的森林生态环境承载力已经达到或接近上限,森林资源存在乱砍乱伐现象和林区政府监管乏力问题,究其根源是缺乏森林保护和补偿的驱动机制。在中央政府投入大量物力和财力的同时,其他利益相关主体却存在不同利益诉求和行为导向冲突,跨区域森林生态补偿难以实现,因此利用演化博弈模型厘清森林生态环境保护与补偿行动中保护主体、受益主体和中央政府的关系,有助于突破跨区域森林生态保护补偿困境,形成良好的行动机制。分析主体功能区利益群体逻辑关系的基础上,构建保护地区政府和受益地区政府的演化博弈模型,分别研究未引入"约束-激励"机制和引入"约束-激励"机制下的主体行为特征及其影响因素,剖析不同情形地方政府间的博弈决策行为。研究结果表明,在未引入中央政府"约束-激励"机制的情况下,跨区域生态补偿无法实现,保护地区政府会通过权衡保护森林资源收益和机会成本进行策略选择,当保护森林资源的净收益为正时,即使没有受益地区生态补偿,保护地区政府仍然有足够的激励保护森林资源,当保护森林资源的净收益为负时,两类政府群体容易陷入森林生态治理的"囚徒困境",而"约束-激励"机制的引入可以实现森林生态保护补偿的帕累托改进,通过中央政府惩罚、奖励金额的限制能够实现最优稳定均衡策略。     

Cell based approaches for myocardial regeneration and artificial myocardium

Ischemic myocardial disease, the main cause of heart failure, is a major public health and economic problem. Given the aging population, heart failure is becoming an increasing clinical issue and a substantial financial burden. Thus, research in heart failure is of relevant interest and importance, involving specialties such as cellular and molecular biology, tissue engineering, genetics, biophysics and electrophysiology. Stem cell-based regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction or in patients presenting non-ischemic dilated cardiomyopathies. This biological approach is particularly attractive due to the potential for myocardial regeneration with a variety of myogenic and angiogenic cell types. The development of a bio-artificial myocardium using biological or synthetic matrix is a new challenge.     

Agrochemical Research and Development in the 21(st) Century: Bloom or Bust

Economic, environmental, and political issues arising in the last two decades have changed agricultural practice worldwide. While the agrochemical market has diminished, time and cost of R & D and regulatory restrictions have increased, thereby reducing profit margins dramatically. This has led to a change of strategy from screening whole organisms to screening diverse compounds, with high-throughput screening processes similar to those used in drug discovery. For large-scale high-throughput screening to efficiently facilitate storage, retrieval, preparation and tracking of compounds, the sample management process needs to be highly automated. The introduction of modern automated technology will help to address the problems faced by the agrochemical industry.     

DDoS avoidance strategy for service availability

Defending from DDoS attacks have become more difficult because they have evolved in many ways. Absence of a specific predetermined pattern, increase of number of attack devices, and distributed execution of the DDoS attack makes hard the recognition of the attack sources and thus application of countermeasures. When the DDoS attack is being executed, most of the cases, the target cannot provide its services normally; this is not a significant problem for non-critical application, but, for availability critical services such as stock financial, stock market, or governmental, the effect of the attack may involve huge damage. In this paper, we propose a DDoS avoidance strategy to provide service availability to those preregistered important users. In the proposed strategy, we divide the attack scenario in different time points and provide alternative access channels to already authenticated and other valid users.     

Understanding Financial Market States Using an Artificial Double Auction Market

The ultimate value of theories describing the fundamental mechanisms behind asset prices in financial systems is reflected in the capacity of such theories to understand these systems. Although the models that explain the various states of financial markets offer substantial evidence from the fields of finance, mathematics, and even physics, previous theories that attempt to address the complexities of financial markets in full have been inadequate. We propose an artificial double auction market as an agent-based model to study the origin of complex states in financial markets by characterizing important parameters with an investment strategy that can cover the dynamics of the financial market. The investment strategies of chartist traders in response to new market information should reduce market stability based on the price fluctuations of risky assets. However, fundamentalist traders strategically submit orders based on fundamental value and, thereby stabilize the market. We construct a continuous double auction market and find that the market is controlled by the proportion of chartists, P_c. We show that mimicking the real state of financial markets, which emerges in real financial systems, is given within the range P_c = 0.40 to P_c = 0.85; however, we show that mimicking the efficient market hypothesis state can be generated with values less than P_c = 0.40. In particular, we observe that mimicking a market collapse state is created with values greater than P_c = 0.85, at which point a liquidity shortage occurs, and the phase transition behavior is described at P_c = 0.85.     

Grand challenges in migration biology

Billions of animals migrate each year. To successfully reach their destination, migrants must have evolved an appropriate genetic program and suitable developmental, morphological, physiological, biomechanical, behavioral, and life-history traits. Moreover, they must interact successfully with biotic and abiotic factors in their environment. Migration therefore provides an excellent model system in which to address several of the "grand challenges" in organismal biology. Previous research on migration, however, has often focused on a single aspect of the phenomenon, largely due to methodological, geographical, or financial constraints. Integrative migration biology asks 'big questions' such as how, when, where, and why animals migrate, which can be answered by examining the process from multiple ecological and evolutionary perspectives, incorporating multifaceted knowledge from various other scientific disciplines, and using new technologies and modeling approaches, all within the context of an annual cycle. Adopting an integrative research strategy will provide a better understanding of the interactions between biological levels of organization, of what role migrants play in disease transmission, and of how to conserve migrants and the habitats upon which they depend.     

A Review of the Evidence to Support Influenza Vaccine Introduction in Countries and Areas of WHO's Western Pacific Region

Background

Immunization against influenza is considered an essential public health intervention to control both seasonal epidemics and pandemic influenza. According to the World Health Organization (WHO), there are five key policy and three key programmatic issues that decision-makers should consider before introducing a vaccine. These are (a) public health priority, (b) disease burden, (c) efficacy, quality and safety of the vaccine, (d) other inventions, (e) economic and financial issues, (f) vaccine presentation, (g) supply availability and (h) programmatic strength. We analyzed the body of evidence currently available on these eight issues in the WHO Western Pacific Region.

Methodology/Principal Findings

Studies indexed in PubMed and published in English between 1 January 2000 and 31 December 2010 from the 37 countries and areas of the Western Pacific Region were screened for keywords pertaining to the five policy and three programmatic issues. Studies were grouped according to country income level and vaccine target group. There were 133 articles that met the selection criteria, with most (90%) coming from high-income countries. Disease burden (n = 34), vaccine efficacy, quality and safety (n = 27) and public health priority (n = 27) were most frequently addressed by studies conducted in the Region. Many studies assessed influenza vaccine policy and programmatic issues in the general population (42%), in the elderly (24%) and in children (17%). Few studies (2%) addressed the eight issues relating to pregnant women.

Conclusions/Significance

The evidence for vaccine introduction in countries and areas in this Region remains limited, particularly in low- and middle-income countries that do not currently have influenza vaccination programmes. Surveillance activities and specialized studies can be used to assess the eight issues including disease burden among vaccine target groups and the cost-effectiveness of influenza vaccine. Multi-country studies should be considered to maximize resource utilization for cross-cutting issues such as vaccine presentation and other inventions.     

Challenges,achievements and opportunities in allelopathy research

Abstract

Allelopathy is defined as the suppression of any aspect of growth and/or development of one plant by another through the release of chemical compounds. Although allelopathic interference has been demonstrated many times using in vitro experiments, few studies have clearly demonstrated allelopathy in natural settings. This difficulty reflects the complexity in examining and demonstrating allelopathic interactions under field conditions. In this paper we address a number of issues related to the complexity of allelopathic interference in higher plants: These are: (i) is a demonstrated pattern or zone of inhibition important in documenting allelopathy? (ii) is it ecologically relevant to explain the allelopathic potential of a species based on a single bioactive chemical? (iii) what is the significance of the various modes of allelochemical release from the plant into the environment? (iv) do soil characteristics clearly influence allelopathic activity? (v) is it necessary to exclude other plant interference mechanisms?, and (vi) how can new achievements in allelopathy research aid in solving problems related to relevant ecological issues encountered in research conducted upon natural systems and agroecosystems? A greater knowledge of plant interactions in ecologically relevant environments, as well as the study of biochemical pathways, will enhance our understanding of the role of allelopathy in agricultural and natural settings. In addition, novel findings related to the relevant enzymes and genes involved in production of putative allelochemicals, allelochemical persistence in the rhizosphere, the molecular target sites of allelochemicals in sensitive plant species and the influence of allelochemicals upon other organisms will likely lead to enhanced utilization of natural products for pest management or as pharmaceuticals and nutraceuticals. This review will address these recent findings, as well as the major challenges which continue to influence the outcomes of allelopathy research.