Standardization as situation-specific achievement: regulatory diversity and the production of value in intercontinental collaborations in stem cell medicine

The article examines the role and challenges of scientific self-governance and standardization in inter-continental clinical research partnerships in stem cell medicine. The paper shows that – due to a high level of regulatory diversity – the enactment of internationally recognized standards in multi-country stem cell trials is a complex and highly situation-specific achievement. Standardization is imposed on a background of regulatory, institutional and epistemic-cultural heterogeneity, and implemented exclusively in the context of select clinical projects. Based on ethnographic data from the first trans-continental clinical trial infrastructure in stem cell medicine between China and the USA, the article demonstrates that locally evolved and international forms of experimental clinical research practices often co-exist in the same medical institutions. Researchers switch back and forth between these schemas, depending on the purposes of their research, the partners they work with, the geographic scale of research projects, and the contrasting demands for regulatory review, that result from these differences. Drawing on Birch’s analysis of the role of standardization in international forms of capital production in the biosciences, the article argues that the integration of local knowledge institutions into the global bioeconomy does not necessarily result in the shutting down of localized forms of value production. In emerging fields of medical research, that are regulated in highly divergent ways across geographical regions, the coexistence of distinct modes of clinical translation allows also for the production of multiple forms of economic value, at varying spatial scales. This is especially so in countries with lenient regulations. As this paper shows, the long-standing absence of a regulatory framework for clinical stem cell applications in China, permits the situation-specific adoption of internationally recognized standards in some contexts, while enabling the continuation of localized forms of value production in others

Selection of chromosomal DNA libraries using a multiplex CRISPR system.

The directed evolution of biomolecules to improve or change their activity is central to many engineering and synthetic biology efforts. However, selecting improved variants from gene libraries in living cells requires plasmid expression systems that suffer from variable copy number effects, or the use of complex marker-dependent chromosomal integration strategies. We developed quantitative gene assembly and DNA library insertion into the Saccharomyces cerevisiae genome by optimizing an efficient single-step and marker-free genome editing system using CRISPR-Cas9. With this Multiplex CRISPR (CRISPRm) system, we selected an improved cellobiose utilization pathway in diploid yeast in a single round of mutagenesis and selection, which increased cellobiose fermentation rates by over 10-fold. Mutations recovered in the best cellodextrin transporters reveal synergy between substrate binding and transporter dynamics, and demonstrate the power of CRISPRm to accelerate selection experiments and discoveries of the molecular determinants that enhance biomolecule function

Introducing Technology onto a Traditional Course: Turning the Classroom Upside Down

In: A.J. Kallenberg and M.J.J.M. van de Ven (Eds), 2002, The New Educational Benefits of ICT in Higher Education: Proceedings. Rotterdam: Erasmus Plus BV, OECR ISBN 90-9016127-9This paper reports on the integration of a wide range of information and communication technology (ICT) tools into an undergraduate module in biosciences. The aim of the integration was to shift the balance of talk during classroom sessions, away from the lecturer and to the students. Over the four-year period covered by the data presented two distinct approaches to achieving this aim were taken. One of these exploited the use of a web site to facilitate preparation for face-to-face discussion during classes. The other relied on the use of asynchronous threaded discussion boards to promote interaction outside of timetabled classes. In the latter approach classroom sessions were used mainly for group work and to provide one-to-one feedback to students. In both approaches traditional lecturing was reduced to virtually nil. Both approaches were on the whole welcomed by students and tutor. However it was clear that during the semester, the majority of students only made use of the electronic tools and materials provided when they were needed for the completion of assessed coursewor

Space Biosciences Division

In the Space Biosciences Division at NASA's Ames Research Center, we perform the biological research and technology development necessary to tackle the challenges of living in the extreme environments of space and to enable NASA's long-term human exploration mission. This brochure provides a broad overview for our research and development capabilities, several case study examples, and finally real-world applications and collaborative partnerships

Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells

Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells

Transcription activator like effector (TALE)-directed piggyBac transposition in human cells.

Insertional therapies have shown great potential for combating genetic disease and safer methods would undoubtedly broaden the variety of possible illness that can be treated. A major challenge that remains is reducing the risk of insertional mutagenesis due to random insertion by both viral and non-viral vectors. Targetable nucleases are capable of inducing double-stranded breaks to enhance homologous recombination for the introduction of transgenes at specific sequences. However, off-target DNA cleavages at unknown sites can lead to mutations that are difficult to detect. Alternatively, the piggyBac transposase is able perform all of the steps required for integration; therefore, cells confirmed to contain a single copy of a targeted transposon, for which its location is known, are likely to be devoid of aberrant genomic modifications. We aimed to retarget transposon insertions by comparing a series of novel hyperactive piggyBac constructs tethered to a custom transcription activator like effector DNA-binding domain designed to bind the first intron of the human CCR5 gene. Multiple targeting strategies were evaluated using combinations of both plasmid-DNA and transposase-protein relocalization to the target sequence. We demonstrated user-defined directed transposition to the CCR5 genomic safe harbor and isolated single-copy clones harboring targeted integrations