Impact of high-throughput screening in biomedical research

Policy‐makers and scientists are increasingly worried about the declining productivity of the pharmaceutical industry. Despite growing levels of investment from governments and industry, the number of new medicines that are approved each year has declined slowly during the past three decades (Betz, 2005; Booth & Zemmel, 2004; Cuatrecasas, 2006). The increased costs of drug discovery and development can no longer be supported by healthcare systems, and regulators are implementing control mechanisms such as price control schemes and increased regulatory demands, which could ultimately affect the drug discovery process by altering the financial and regulatory landscapes for new research programmes (Ess et al , 2003; Miller & Henderson, 2007). > The increased costs of drug discovery and development can no longer be supported by healthcare systems… Over the years, the industry has relied on various technologies to improve drug discovery. However, despite the use of structure‐based drug design, high‐throughput screening, combinatorial chemistry and the various ‘‐omics’ technologies, productivity continues to decline. The various explanations for this lack of success include increasing regulatory requirements, the depletion of therapeutic opportunities and ‘druggable’ targets, competition and organizational inefficiencies (Booth & Zemmel, 2004; Cuatrecasas, 2006; Dickson & Gagnon, 2004; Garnier, 2008). Although each of these explanations rings true, at the heart of the problem is a lack of proper scientific understanding of human biology and disease mechanisms. This is ultimately manifested in the high fraction of clinical programmes that fail owing to a lack of efficacy or safety, often in spite of excellent pre‐clinical data (Fingleton, 2008; Kola & Landis, 2004). Without a doubt, improved drug‐target validation would improve the success rate of drug discovery programmes, but this necessitates a better understanding of fundamental biological processes and the biological role of the drug target—usually a protein—under investigation. Paradoxically, …

A major bottleneck to the early stages of drug discovery is the absence of integration of high throughput screening (HTS) with smarter assays that screen “hits” from HTS to identify leads (High content screening, HCS). We propose a solution using novel fluorescent engineered protein biosensors integrated into a miniaturized live-cell-based screening platform (CellChip™ System) that markedly shortens the early drug discovery process. Microarrays of selectively localized living cells, containing engineered fluorescent biosensors, serve to integrate HTS and HCS onto a single platform. HTS “hits” are identified using one biosensor while reading the whole chip array of cells. The high-biological content information is then obtained from probing target activity at inter-cellular, sub-cellular and molecular levels in the “hit” wells. HCS assays yield temporal-spatial dynamic maps of the drug-target interaction within each living cell. We predict that a new platform incorporating HTS and HCS assays that are automated, miniaturized, and information-rich will dramatically improve the decision making process in the pharmaceutical industry and optimize lead compounds during the early part of the drug discovery process. There is an opportunity to establish a new paradigm for drug discovery based on integration of fluorescence technology, micropatterning of living cells, automated optical detection and data analysis, and a new generation of knowledge building bioinformatics approaches. The technology will have an expansive impact spanning the fields of drug discovery, biomedical research, environmental monitoring, life sciences, and clinical diagnostics. The integrated CellChip™ Platform with miniaturized tissue-specific microarrayed cells capable of providing inter-cellular and sub-cellular spatio-temporal information in response to drug-cell, toxin-cell, or pathogen-cell interactions will serve to enhance the decision making process in drug discovery, toxicology, and clinical diagnostics.

Statistics: Choosing the testHigh throughput technologies generate large datasets.To make all the data useful and convert them to meaningful results, the data need to be analyzed and statistically processed.The initial experimental hypothesis needs to be translated into a mathematical hypothesis which is then validated using an appropriate statistical test.But how to choose the right test?Jean-François

The 2020 SLAS Technology Ten: Translating Life Sciences Innovation.

In the fast-developing fields of pharmaceutical research and industry, the implementation of Raman spectroscopy and related technologies has been very well received due to the combination of chemical selectivity and the option for non-invasive analysis of samples. This chapter explores established and potential applications of Raman spectroscopy, confocal Raman microscopy and related techniques from the early stages of drug development research up to the implementation of these techniques in process analytical technology (PAT) concepts for large-scale production in the pharmaceutical industry. Within this chapter, the implementation of Raman spectroscopy in the process of selection and optimisation of active pharmaceutical ingredients (APIs) and investigation of the interaction with excipients is described. Going beyond the scope of early drug development, the reader is introduced to the use of Raman techniques for the characterization of complex drug delivery systems, highlighting the technical requirements and describing the analysis of qualitative and quantitative composition as well as spatial component distribution within these pharmaceutical systems. Further, the reader is introduced to the application of Raman techniques for performance testing of drug delivery systems addressing drug release kinetics and interactions with biological systems ranging from single cells up to complex tissues. In the last part of this chapter, the advantages and recent developments of integrating Raman technologies into PAT processes for solid drug delivery systems and biologically derived pharmaceutics are discussed, demonstrating the impact of the technique on current quality control standards in industrial production and providing good prospects for future developments in the field of quality control at the terminal part of the supply chain and various other fields like individualized medicine. On the way from the active drug molecule (API) in the research laboratory to the marketed medicine in the pharmacy, therapeutic efficacy of the active molecule and safety of the final medicine for the patient are of utmost importance. For each step, strict regulatory requirements apply which demand for suitable analytical techniques to acquire robust data to understand and control design, manufacturing and industrial large-scale production of medicines. In this context, Raman spectroscopy has come to the fore due to the combination of chemical selectivity and the option for non-invasive analysis of samples. Following the technical advancements in Raman equipment and analysis software, Raman spectroscopy and microscopy proofed to be valuable methods with versatile applications in pharmaceutical research and industry, starting from the analysis of single drug molecules as well as complex multi-component formulations up to automatized quality control during industrial production.

As a result of poor planning and inappropriate procedures for beneficiary selection, the land reform programme in Zimbabwe resulted in a drastic decline in production and productivity of the agricultural sector. At the same time, the perceived political agenda of the process sparked off a reaction in the investment climate that manifested in worsening balance of payments, reduction in industrial production, and growing unemployment. It is safe to conclude that the Zimbabwean land reform programme resulted in an economy-wide decline in effective demand occurring simultaneously with a sharp fall in physical agricultural output as appropriated farms lay idle and poor farm practices depressed productivity levels. A low-equilibrium trap thus ensued, culminating in the deterioration of livelihoods across the broad spectrum of society as a hyper-inflationary situation developed and assumed scandalous proportions. A situation such as this set off chain reactions that touched all segments of the economy and produced diverse effects, including the disappearance of markets, the emergence of informal exchange arrangements that represent adjustments to the aberrant phenomenon of hyper-inflation emerging in the absence of both cash and goods/services. To date, there has been no systematic assessment of this dimension of the land reform programme with the aim of drawing lessons that can provide some basis for developing strategies for revamping the economy now that clear signs are emerging that the long-running political crisis might soon end. To understand what might have happened, an initial broad appraisal of specific indicators of agricultural output and prices for the livestock and maize products has been conducted in one district and formed the basis for assessing any spatial and temporal patterns in markets and marketing relationships.

Introduction. The garment industry has always played a significant role in the state economy development and in everyone's life, as a factor in meeting consumer needs and a source of budget revenue, but in recent years there has been an extremely difficult situation - the garment industry has almost completely lost competitiveness in the consumer market. First, this situation arose due to fierce competition from imported goods, which saturate the market with their products of well-known brands, with a lower price, thereby displacing domestic goods. This encourages the need to study this industry, taking into account the specifics of working with toll raw materials, in order to identify problems and ways to overcome them in global competition. Purpose. Describe the current state of garment production; identify the features of the organization of sewing companies that use toll raw materials, analyze the main advantages and disadvantages of their operation; explore the accounting features; to consider the taxation of services for the processing of toll raw materials value added tax, the peculiarities of import duties calculation, other taxes and fees. Results. The peculiarities of the work organization of the sewing enterprises on the conditions of toll raw materials are covered. An indices analysis of light industry industrial products by activity type for 2015-2020 and revealed a decline in the industry production in 2018-2020. Ukrainian enterprises of the garment industry in 2010-2020 mainly used production on the terms of toll raw materials; full export; production for the domestic market. The main advantages and disadvantages of functioning of domestic garment productions with the use of toll raw materials are considered. A study of textile production indices, production of clothing, leather, leather products and other materials on a monthly basis in 2020 showed that starting from August 2020, the gradual decline in production stopped and there were trends of slight growth in production in the textile industry. The necessity of proper documentation of operations with toll raw materials for processing enterprises and creation of own package of primary forms by executing enterprises is substantiated, in order to simplify the complexity of the process of keeping accounting documentation. The interpretation of the category "toll raw materials" according to the Customs and Tax Codes of Ukraine is considered. A list of criteria in accordance with the current legislation on the recognition of transactions with toll raw materials, confirming the inability of the garment company to sell finished products made from toll raw materials, and therefore loses profits, most of which are sold by the owner of raw materials. The taxation of services on processing of toll raw materials by the value added tax, features of charge of import duty, other taxes and charges are considered. Prospects for further research are the development of virtual sales channels for garments.

Global world markets are often influenced by various macroeconomic factors that have both a positive and negative impact on their development. Recently, the whole world is experiencing, without exaggeration, a global economic catastrophe associated with the almost lightning-fast spread of a dangerous virus, the country of origin of which was China. The COVID-19 pandemic has caused unprecedented global upheavals that have had a major impact on societies in cities, countries, and regions. Most countries declared a nationwide lockdown in the first weeks of the pandemic, closing their borders to other countries. Moreover, at a time of global acute need for personal protective equipment, ALV and other medical devices and equipment, both air and sea transport were stopped, which separated the producing countries from the consumer countries. With soaring demand and the impact on supply chains, countries that had previously welcomed joint calls to fight the pandemic have entered a trade war in medical equipment. In the commodity market, the price of oil fell, leading to uncertainty about the future of oil-producing countries, as the end point of the pandemic was still unclear. Overall, the pandemic has been a severe test for the global economy. Due to the development of the pandemic, economists expect an unprecedented decline in industrial production and the percentage share of the stock exchange, rising commodity prices, as well as the possibility of reducing the GDP of a number of countries. While national Governments are trying to offset this drop in commodity prices, as well as for households, firms and financial markets, by providing economic assistance to affected groups, it is clear that such measures are not always viable. It is absolutely necessary to study the impact of COVID-19 on the global financial ecosystem in order to develop an effective trade policy. The danger of a pandemic is also exacerbated by the fact that a crisis in economic relations between countries can lead to political consequences that will cause an aggravation of the political situation in the world. The purpose of the work is to consider the development of world markets under the influence of various factors of uncertainty, the decline in production and trade under the influence of measures of national isolation.

The 2022 SLAS technology ten: Translating life sciences innovation.

There has been increased concern that the current "blockbuster" model of drug discovery and development practiced by "Big Pharma" are unsustainable in terms of cost (> $1 billion/approved drug) and time to market (10 - 15 years). The recent mergers and acquisitions (M&A), shuttering of internal research programs, closure of "redundant" sites of operations, senior management turnover and continued workforce reductions among the top 10 major pharmaceutical companies reflect draconian responses to reduce costs. However, the resultant exodus of intellectual capital, loss in motivation and momentum, and exit from early stage discovery programs by pharmaceutical companies has contributed to an "innovation deficit". Disease advocacy groups, investment communities and the government are calling for new innovative business models to address this deficit. In particular they are looking towards academia and clinical trials centers to catalyze new innovations in translational research. Indeed over the last decade many academic institutions have launched drug discovery centers largely comprising high-throughput screening (HTS) to accelerate "translational" research. A major impetus for this "open innovation" effort has been the National Institutes of Health (NIH) "Roadmap" and Molecular Libraries Initiative/Program (MLI/MLP), which is in its last year, and will be transitioned into the National Center for the Advancement of Translational Sciences (NCATS). With the end of Roadmap funding, general reduction in Federal government funding and its recent sequestration, academic drug discovery centers are being challenged to become selfsustaining, adding financial value, while remaining aligned with the missions of their respective academic non-profit institutions. We describe herein, a brief history of our bi-coastal Conrad Prebys Center for Chemical Genomics (Prebys Center) at the Sanford|Burnham Medical Research Institute (SBMRI), the key components of its infrastructure, core competencies of its fully integrated drug discovery expertise, best practices adopted in our day-to-day operations, and finally some of our current funding and collaboration and/or strategic alliance models for pre-competitive drug discovery with other academic/clinical partners, other governmental agencies, and with pharmaceutical and biotechnology companies.

High-throughput screening (HTS) is an established technology in the pharmaceutical industry (1). Over the past decade, there has been a logarithmic increase in the industry’s ability to screen large combinatorial libraries of compounds against target molecules (2). The technology to achieve this has come in the form of robotics, high-density microplates, small volume (microliter) liquid handling, and sophisticated detection schemes. Signifi cant effort has gone into the design of HTS workstations capable of screening tens of thousands of compounds in a 24-h period. However, these workstations come with a large price tag, ranging from several hundred thousand to millions of dollars. A considerable amount of work is necessary to optimize nascent microfl uidic devices for HTS applications. Stateof-the-art commercial microfl uidic devices are principally made by the micromachining of silicon (3) and glass and rely on electroosmotic fl ow (4,5) to drive liquid through the channels, requiring high salt concentrations and a voltage source. This process generates gas bubbles, creating ionic conditions that are far from ideal for assays measuring enzymatic activity or protein-protein interactions. Other problems with hard polymer microfl uidic devices include the need to build up layers to effi ciently seal the channel networks, making layer-layer adhesion a serious concern during the fabrication process, and the lack of a good compartmentalization technology for the large-scale analysis of chemical or biological libraries. In thinking about a generic design for microfl uidic HTS devices for catalytic screening applications that confi ne both enzyme and substrate to picoliter volumes, both serial and parallel approaches can be explored. Using a serial strategy, each compound of interest is screened sequentially using a common microfl uidic channel with a single detection element. Mechanically, throughput depends on factors such as fl ow speed, sample concentration, and the acquisition time of the detector. In contrast, parallel screening functions like an ultra-high density microplate, in which thousands of compounds are arrayed into individual picoliter-scale compartments, with a detector element that probes the entire matrix. Throughput is principally limited by the number of compartments in the array. We have designed and developed microfl uidic chips employing both serial and parallel screening strategies. Unlike in state-ofthe-art microfl uidic devices relying on electroosmotic fl ow, fltraffi cking and compartmentalization in our chips are pressure-based, using integrated elastomeric valves whose function is independent of solvent composition.

Enzymes enter the field of functional genomics

Medical research ethics in China

Ghostwriters, Data Manipulation and Dollar Diplomacy: How Drug Companies Pull the Strings in Clinical Research

The Society of Biomolecular Imaging and Informatics First Annual Conference