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Design and implementation of synthetic circuits for research and therapeutic applications

Fulga group genome engineering and synthetic biology

 

About the Research

We aim to decipher the logic of post-transcriptional gene regulation, harness this knowledge to create synthetic systems capable of rewiring or enhancing naturally evolved cellular behaviours, and use the emerging principles to advance the scope of somatic and stem cell engineering for basic research and therapeutic applications. Using an integrated approach, we currently endeavour to develop programmable signalling pathways and gene networks responsive to exogenous cues and/or endogenous metabolites. This research paves the way for the design of more sophisticated regulatory circuits enabling de novo implementation of custom cellular functions. Our scientific program is inspired by advances in miRNA biology, synthetic biology and genome engineering.

The recent breakthrough in genome engineering technologies (CRISPR/Cas9) marked the beginning of a new era of scientific discovery and molecular medicine applications. The relatively straightforward design and streamlined construction protocols developed for these technologies, together with continuous improvements to increase on-target efficiency and reduce off-target effects, now offer a realistic opportunity for genome engineering-based therapeutic applications. Most notably, the astonishing wave of innovations in this field has radically expanded the scope of ex vivo somatic and stem cell engineering from simple viral transgene expression to site-specific knock-ins, controlled gene disruption, and direct correction of disease-causing mutations. These groundbreaking studies have not only redefined the promise of cell-based interventions for multiple disease indications, but have also set the stage for the implementation of more sophisticated regulatory programs aiming to modulate cellular behavior and function.

The goal of this research project is to develop CRISPR-based synthetic devices suitable for gene and cell therapy applications in acquired and inherited human diseases. Achieving spatial‐temporal control over endogenous gene expression will be instrumental for understanding gene pathway architectures, as well as changes and choices in transcriptional programs operating during differentiation, development, and disease. Ultimately, our aim is to establish new experimental frameworks for programmed regulation and correction of protein levels, and apply these systems to develop cell-based therapies for blood disorders and cancer. Adding to a growing toolkit of standardised components, this conceptual framework will play a pivotal role in synthetic biology, empowering scientists to create complex systems able to challenge or reprogram cells upon sensing a disease state

 

Training Opportunities

The proposed project will be undertaken at University of Oxford’s MRC Weatherall Institute of Molecular Medicine, in a highly dynamic and competitive environment. The project will involve a broad range of cutting-edge technologies including CRISPR-Cas9/Cas13 genome engineering, digital PCR, next generation sequencing, advanced molecular biology, RNA biochemistry, FACS, lentiviral-mediated delivery, and computational biology. In addition, the student will be trained to develop writing and presentation skills, will have opportunities to present their work at conferences and attend at least one advanced training course.

 

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

Publications

Wu Q, Ferry QRV, et al. (2017) In situ functional dissection of RNA cis-regulatory elements by multiplex CRISPR-Cas9 genome engineering. Nature Comm. Dec 13;8(1):2109.

Baeumler TA, Ahmed AA and Fulga TA. (2017) Engineering synthetic signalling pathways with programmable dCas9-based chimeric receptors. Cell Reports. Sept 20(11):2639-2653.

Ferry QR, Lyutova R and Fulga TA. (2017) Rational design of inducible CRISPR guide RNAs for de novo assembly of transcriptional programs. Nature Comm. Mar 3;8:14633.

Michaels YS, et al. (2018) Precise tuning of gene expression output levels in mammalian cells. bioRxiv, https://doi.org/10.1101/352377

Knapp DJHF, et al. (2018) Decoupling tRNA promoter and processing activities enables specific Pol-II Cas9 guide RNA expression. bioRxiv, https://doi.org/10.1101/342485


 

Supervisors