Instrumentation and cell-based assays.The increased usage of cell-based assays in the drug discovery process beginning in the 1990s has influenced the market for many types of analytical instrumentation, including automation, detection and imaging techniques. In fact, instruments with higher throughput, increased sensitivity and more sophisticated software have been important technology developments for facilitating the use of cell-based assays in all stages of drug discovery and the advancement of assay development. The growing markets for cell-based assays and for instrumentation, consumables and software for the preparation, manipulation and analysis of such assays helped establish new companies, fed merger and acquisition activities, and prompted increased investments by instrument companies seeking to increase their share of the market. In this article, IBO Ibo: see Igbo. takes a look at how the use of cell-based assays in the pharmaceutical industry has affected product introductions and business strategies at four companies. Although cell-based assays are not new, their routine use as part of all stages of the pharmaceutical discovery and development is. The emerging market for detection and automation techniques for cell-based assays holds a number of opportunities as instrumentation will be an important component of lower cost, easier to use and higher throughput cell-based analysis.
In the 1990s, drug makers began using cell-based assays earlier in the drug discovery cycle, including primary screening. The major advantages of cell-based functional assays are that they provide a more biologically relevant context for testing drug targets and compounds than biochemical assays. In addition, cell-based assays provide valuable information on cytotoxicity cytotoxicity /cy·to·tox·ic·i·ty/ (si?to-tok-sis´i-te) the degree to which an agent possesses a specific destructive action on certain cells or the possession of such action. , membrane permeability and stability, Image-based cellular assays can provide multiparametric data, such as spatial and temporal information, as well as enable subcellular sub·cel·lu·lar
1. Situated or occurring within a cell: subcellular organelles.
2. Smaller in size than ordinary cells: subcellular organisms.
3. analyses. Cell-based assays are also vital to developing drugs for orphan GPCR GPCR Guanine Nucleotide-Binding Protein-Coupled Receptor
GPCR GTP-binding Protein-Coupled Receptor (G-protein-coupled receptors) and ion channel ion channel
See channel. targets. However, the development of cell-based assays is laborious la·bo·ri·ous
1. Marked by or requiring long, hard work: spent many laborious hours on the project.
2. Hard-working; industrious. , expensive and complex, and due to lack of specificity, cell-based assays often require additional testing.
When asked about the influence of cell-based assays on instrumentation, Jan Hughes, vice president of Worldwide Marketing for Molecular Devices Molecular Devices Corporation is a leading supplier of high-performance bioanalytical measurement systems that accelerate and improve drug discovery and other life sciences research. , told IBO, "In the case of high-throughput screens, it's the chicken and the egg," noting how each influences the other. The company's LIP microplate reader is used widely for high-throughput screening High-throughput screening (HTS), is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Purpose and method of GPCR targets. New developments for the FLIPR FLIPR Fluorometric Imaging Plate Reader
FLIPR Fluorescent Imaging Plate Reader Tetra will include modifications for use with the aequorin ae·quor·in
A protein secreted by certain jellyfish that interacts with seawater to produce bioluminescent light.
[New Latin Aequorea, jellyfish genus (from Latin aequoreus, luminescence luminescence, general term applied to all forms of cool light, i.e., light emitted by sources other than a hot, incandescent body, such as a black body radiator. assay, an assay's whose popularity for high-throughput screens is growing.
"One of the reasons that we're pursuing a modified Tetra is that we find that the current suppliers of readers for aequorin don't have the preferred features that our customers want. They want the features of our FLIPR and our competitors don't have the same features, [such as being able to integrate the reader] into an automated screening environment," he explained. And just as new assays prompt instrument modifications, instrumentation is important for assay usages. "If there was a FLIPR-like product that had every thing a FLIPR had, and could run in an automated screening environment and run aequorin assays, the adoption of aequorin luminescence assays would probably be at a steeper rate," he added. "It doesn't mean that people are not doing it, it's just that if there was the right instrument, more people would try it." And the company's SpectraMax M5 plate reader, he noted, "has five different modes of reading, one of which is luminescence, which we added because of aequorin assays."
Molecular Devices is one of the largest providers of instrumentation for cell-based analysis. "Outside of the plate reader market, we sell assays and instruments for doing GPCRs, kinases and ion channels: all three of those are cell-based assays and targets." The company's portfolio includes automated system for automated electrophysiology electrophysiology /elec·tro·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je)
1. the study of the mechanisms of production of electrical phenomena, particularly in the nervous system, and their consequences in the living organism.
2. and confocal- and laser-based imaging systems, which are used for secondary screening. Other instrumentation for cell-based assays now used in secondary screening could move into primary screening. In particular, Mr. Hughes foresees demand for Molecular Devices' high-throughput electrophysiology systems in primary screening. "The first generation of the IonWorks HT could only do about 600 data points per day, [so] you could only use it in lead optimization organizations. Our second generation that we commercialized last year does almost 4,000 data points per day. We want to develop something that goes to 10,000 to 12,000 data points per day." Assay development will be one factor making such a move possible. "What we' re hoping is that they use it in secondary screening and compound profiling, and as they develop the assays and get a better understanding of the ion channels, it'll ultimately drive demand to use a system in high-throughput screening," he explained.
Making assays more affordable is important to growing the market for cell-based analysis. With its purchase of the Transfluor assay technology last year (see IBO 3/15/05), Molecular Devices is making the assay more affordable, which can help spur instrumentation sales. "[Historically,] one of the issues with Transfluor was that it was so expensive to license that there were not a lot of pharma companies adopting it. Now we have a licensing arrangement that we believe makes it very inexpensive for companies to try to begin developing assays to see how Transfluor assays can be used in secondary screening." Transfluor assays can be used with the FIAPR in primary screening as well as with Molecular Devices' imaging systems in secondary screens.
In the pharmaceutical industry, cell-based assays are mainly used in lead selection and optimization, and target identification and validation. Thus, it is these areas where demand for new instrumentation and software to accommodate and facilitate new cellular assays by pharmaceutical companies has been the greatest. The development of higher throughput microscopy systems as well as reagents, image-based assays and software have led to the adoption of high-content imaging systems by pharmaceutical companies. Cellomics, which was acquired by Fisher Scientific Fisher Scientific, formally Fisher Scientific International, Inc. and colloquially Fisher was a biotechnology company that provided products and services to the global scientific research and United States clinical laboratory markets. last year (see IBO 8/15/05) offers the modular ArmyScan [V.sup.TI] of high-content imaging the KineticScan for live cell imaging and the CellWoRx, developed with Applied Precision, a easier-to-use, lower cost instrument. "High-content screening High Content screening is an automated cell biology method drawing on optics, chemistry, biology and image analysis to permit rapid, highly parallel biological research and drug discovery. is still relatively in its infancy. The first systems were launched in the late 1990s/early 2000s. So I would say we' re on the cusp right now of people actually publishing papers proving that they've shortened the drug discovery cycle," said Judy P. Masucci, Ph.D., director of Marketing and Sales Support for Cellomics.
In advancing the use of cell-based assays and instrumentation, Cellomics has developed new software tools and kits, both designed to make working with cell-based assays easier. The company offers assay developer software as well as BioApplication software focused on specific application, including a new Neuronal neu·ro·nal
Relating to a neuron.
pertaining to or emanating from a neuron.
see hereditary neuronal abiotrophy of Swedish Lapland dogs. Profiling BioApplication for analyzing neurite growth and neuronal differentiation. But, currently, the company is most focused on assay kits. "From the reagent reagent /re·a·gent/ (re-a´jent) a substance used to produce a chemical reaction so as to detect, measure, produce, etc., other substances.
n. perspective, that's an area where Cellomics is putting a lot of effort right now. We currently have a small portfolio of kits, that's one area where we' re expanding: to make that assay development easier for our customers," said Dr. Masucci. "We've got it covered from a software side, so where we're really doing the most expansion right now is on the kit side."
However, instrumentation remains an important component in the ability to accommodate new applications. "You can come up with completely new biologies through the addition of software, maybe, but through a kit, definitely, without having to make very few changes to your instrument," said Dr. Masucci. "Our instruments, especially the ArrayScan, are designed to be modular so you can add on. [For example,] if you have an application where you now need confocal-like capabilities, you can now add on a optical sectioning module." Cellomics has just introduced a live option for the array scan for live cell testing.
The complexity, labor and expense involved in cell imaging have limited the market, which is something Cellomics is trying to change. "We see high-content screening spreading laterally through the whole drug discovery process and even into basic research and academic research labs-areas where they are not necessarily doing drug discovery," she noted. "High-content screening got its initial start in secondary screening because of the logic of having it there, but it has spread into target identification and upstream into Tox and even into the academic world."
Another company providing imaging instruments for the analysis of cell-based assays is Evotec Technologies GmbH, a subsidiary of drug developer and services company Evotec. According to according to
1. As stated or indicated by; on the authority of: according to historians.
2. In keeping with: according to instructions.
3. Guenter Bauer, chief business officer at Evotec Technologies, the main driver for the development of the Opera confocal confocal
see confocal microscopy. microplate imager reader was "the lack of capability in the pharmaceutical industry to be able to run functional high-content analyses of high-content screening cell assays fully automated so that they were available for primary screening." The Opera is capable of the analysis of 100,000 samples per day. "Opera provides the opportunity to run "phenotypic phe·no·type
a. The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.
b. assays,' i.e. to target independent and multi-target interaction assays," said Dr. Bauer. Such assays can be used to study protein trafficking, protein phosphorylation phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts. states and morphological changes. A recently signed agreement with Cellomics will allow each company to cross market their products in order to provide instrumentation for cell-based assays for high-, medium- and low-throughput application.
Evotec also offers a product line of cell handling devices, which meet the needs for the automation of cell handling for assay development and analysis. "There's still a lot of repetitive work to do in the cell biology Cell biology
The study of the activities, functions, properties, and structures of cells. Cells were discovered in the middle of the seventeenth century after the microscope was invented. field, and with our CellProcessor systems, we think we can address this and make this easier," explained Dr. Bauer. "With the CellProcessors, we see an unmet need in cell biology to be able to automate processes for the separation, manipulation and analysis of cell samples, especially at the single-cell level," said Dr. Bauer. As Mr. Bauer explained, instruments and automation tools for cellular assay development is also an important part of the market. "We are also still in an emerging market, and in an emerging market, it is difficult to sell assays that are standardized.... In an emerging market, having tools which will help people develop assays--this can be a good business. [The market is] now in this immediate phase, which is the reason now we are carefully looking at opportunities," he said.
A company with a long history in cell-based analyses is Beckman Coulter This article needs sources or references that appear in reliable, third-party publications. Alone, primary sources and sources affiliated with the subject of this article are not sufficient for an accurate encyclopedia article. , which offers cell-based assays, antibodies, flow cytometers, cell sorters as well as lab automation system configured for the preparation and analysis of cell-based assays for research. "Cell-based assays are commonly used In high-throughput systems, like our FX and NX automated systems. One estimate is that 50% of the applications are cell based and 50% are cell free," said Brendan Yee, business manager for Beckman Coulter's Affordable Cytometry Solutions. Last year, the company hunched hunch
1. An intuitive feeling or a premonition: had a hunch that he would lose.
2. A hump.
3. A lump or chunk: "She . . . a research reagent initiative that includes new cell signaling Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as reagents and antibodies. Like other companies, Beckman Coulter is also seeking to make working with cells simpler and the associated instrumentation more accessible. "We've really broken out with the Quanta quan·ta
Plural of quantum. series into the market space of personal, affordable, easy-to-use and simple but very powerful flow cytometers," said Mr. Yee. In August, Beckman Coulter will introduce a new microplate handier and software for the Quanta to increase throughput. "We're going to be able to have five systems and be able to dump the data into a single database," he added. The company currently offers a MPL 1. (language) MPL - An early possible name for PL/I.
[Sammet 1969, p.542].
2. MPL - MasPar data-parallel version of C. See also ampl.
Compiler version 3.1.
3. MPL - Motorola Programming Language. multi-platform loader A program routine that copies a program into memory for execution. and MPX MPX - Multiplexor Channel software for its Cytomics FC 500 flow cytometer.