Genetic Engineering & Biotechnology News

JUL 2017

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14 | JULY 2017 | GENengnews.com | Genetic Engineering & Biotechnology News See Roundup on page 16 possibilities using patient cells for personal- ized medicine. Finally, these platforms may enable therapeutic applications with stem cell spheroids in regenerative medicine. Mrs. Hussain The focus for 3D cell culture methods is still the drug-safety testing that occurs before in vivo testing. Recently, there has been a renewed interest in phenotypic drug screening to discover new drug targets. With this shift, there is growing emphasis on bridging the gap between phenotypic screens and 3D methods. Phenotypic screens, in vi- tro, were traditionally carried out using 2D methods that do not take into account the complexity of the in vivo environment. 3D methods are now sought to build biological- ly relevant models that are more predictive of phenotypic response to new drug targets. Dr. Bulpin Applications continue to expand for 3D models, including the development of specific disease models and complex tissue models that can be used for basic research as well as drug discovery. Another promising area for 3D models is personalized medicine. Several types of cells can be used in these models including "immortalized" cells, ge- netically engineered cells, induced pluripo- tent stem cell–derived cells, primary human cells, and patient-derived cells (including pa- tient-derived xenografts). Another potential research avenue is engineering 3D tissues for organ transplants. Dr. Joore Over the past year, we observed a growing interest in 3D tissue models that could be used in studies of disease processes, whether the studies emphasized screening or efficacy analysis. These are, I think, two sides of the same coin. Once researchers re- alize they need better predictive models for safety testing, they start to see that improved models would also have potential for discov- ery and development. Molecule-to-molecule screens have generated lots of very specific inhibitors, but not so many therapies. Re- searchers are now starting to appreciate the richness of 3D model data, especially in com- bination with the throughput of our organ- on-a-chip platforms. Ms. Floyd Cancer researchers and develop- mental biologists have certainly benefitted from 3D cell culture models, which are more physiologically relevant than are 2D systems to the study of cellular differentiation. Fur- ther, 3D in vitro systems are well positioned to obtain approvals from authorities such as the Organization for Economic Co-operation and Development (OECD). The OECD and other bodies are considering alternatives to whole-animal testing, including alternatives that can accomplish skin-sensitization studies for the safety assessment of chemicals. Prof. Przyborski What has changed more re- cently is the ease of access to innovative tech- nologies on the market that enable research- ers to more readily practice 3D cell culture routinely. 3D cell culture has had impact in multiple areas in basic research, drug screen- ing, and safety assessment. Researchers are now looking to 3D technologies to create more sophisticated models that are repre- sentative of real human tissues. Investment in more advanced in vitro assays at an early stage will improve predictions of drug action and inform the decision-making process as to whether to further invest in a particular drug candidate. Dr. Kennedy 3D cell cultures continue to be extensively explored for drug-safety screen- ing; however, there is a growing interest in expanding the use of more complex 3D mod- els into areas such as disease modeling and precision medicine. For example, preclinical hepatic research is now looking to exploit the benefits of spheroid cultures by building 3D co-culture models that consist of multiple primary liver cell types to create new models of hepatic and biliary disease. Likewise, stem cell–derived organoids are opening the pos- sibility of tailoring therapeutic regimens to patients' genetic makeups and to identify the best treatment options. GEN Is there technology on the horizon that will significantly impact 3D cell culture models? Dr. Aho We believe that new tissue model systems will address many current pain points of 3D cell culture. One such system is based on technology developed by the Multiclonal Therapeutics research team of Wa Xian, Ph.D., and Frank McKeon, Ph.D. It allows for the derivation and expansion of ground-state stem cells from adult tissue. These cells can then be differentiated back into the host tissue, which then maintains its native architecture, regional specificity, and (if isolated from diseased tissue) disease phe- notype. This system is robust across samples, provides better 3D model standardization and accessibility, and removes the structural inconsistencies seen in cell clustering methods. Dr. Banks Recently, we have been working with a 3D magnetic bioprinting technology for applications such as migration and pro- liferation. We have also successfully used the technology for complete "walkaway" auto- mation of mesenchymal stem cell differentia- tion into chondrocytes. During the two-week differentiation period, chondrocyte function in 3D models was far superior to that in typi- cal microplate models. Dr. Eglen In a rapidly evolving field such as 3D cell culture, technologies continue to evolve that provide increasingly easier adop- tion to 3D models, and simpler, more robust protocols. These technologies include microti- ter plates for culturing and high-throughput screening assays of spheroids; natural and synthetic hydrogels for the development of extracellular matrices upon which a variety of cells can be grown; and permeable supports that facilitate complex cell-culture models, in- cluding multilayered tissues, migration/inva- sion assays, and co-culture applications. Further out on the horizon may be appli- cations such as organs-on-chips, hydrostatic flow technologies, microfluidics, and 3D bio- printing. To the latter point, printing an in- tact organ remains elusive, but 3D-bioprinted bladders, tracheal grafts, bone, and cartilage have proven to be functional. Potentially, 3D models will allow observations of cellular re- sponsiveness to drug candidates in real time; that is, 3D culture may move to 4D culture! Dr. Trezise Improvements in the 3D cell cul- ture toolkit include cell-imaging modalities, cell biomatrices, and stem-cell harvesting and differentiation protocols. In addition, 3D cell cultures are incorporating continu- ous live-cell analysis and imaging, raising hopes that researchers will gain the ability to follow the development, maturation, and functional properties of 3D cell cultures over time, and to do so without resorting to meth- ods that introduce perturbing influences. Only when 3D cell cultures can be created, manipulated, and analyzed as readily as can 2D cell cultures, will the true promise of 3D biology be realized. Dr. Klette New spheroid creation technolo- gies continue to expand the field. For exam- Roundup Continued from page 13 Drug Discovery Drug discovery today is mostly based on parameter research, i.e., to measure indi- vidual factors like gene-expression levels, protein levels, protein activity, and localiza- tion, and then try to extrapolate this into in vivo function for treatment in humans. The extrapolation of the effect in a 2D cell culture to the in vivo human situation has often resulted in less favorable downstream effects of limited efficacy or toxicological side effects. One example is the screening of anticancer drugs performed in oxygen-rich 2D cell culture in which high-specific metabolism gives very different chemical hits compared to the screening on hypoxic 3D cell cultures. The oxygen-starved situa- tion will be a closer match to the situation in solid tumors in vivo. Performing a me- tabolism-based screening with phenotype- based readout provides the possibility to screen closer to the real-life situation. Technology like the calScreener calorimetry-based assay provides a direct measurement of the cell activity without labels or additions of any kind, according to Magnus Jansson, CSO, Symcel, who adds that it is not measured via a proxy measurement; it is a direct measurement of the energy release. "Direct metabolic readout (DMR) pro- vided by the technology gives the scien- tist access to an unbiased assay where the effects of treatment are studied in a cor- rect biological context resulting in greater predictive value for cost-effective and rap- id drug development," says Jansson. "The technology can be used to bridge the gap between screening isolated components to 2D cell cultures to 3D tissue to the in vivo human situation, thus increasing the predictive power of the scientific hypothesis in drug development." The extension of 3D-based drug dis- covery would be to apply the same assay principle on actual patient tissue samples to evaluate the best possible treatment based on the real patient response in phe- notype response based and personalized medicine, continues Jansson, who predicts a resurgence of calorimetry cell-based assays in drug discovery and personalized medicine. n 3D Phenotypic Assays for Personalized Medicine Phenotypic screens, in vitro, were traditionally carried out using 2D methods that do not take into account the complexity of the in vivo environment. —Lubna Hussain, Lonza

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