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Yale Michaels completed his DPhil under the joint supervision of Associate Professors Tudor Fulga and Thomas Milne, where he developed technology that enables scientists and clinicians to predictably and precise tune gene expression levels.

Yale MichaelsI began my scientific career at the University of Manitoba as a high school researcher working under the supervision of Gunnar Valdimarsson, David Eisenstat and Geoff Hicks. I next undertook a Bachelor’s degree in Molecular and Cellular Biology at Harvard University where I conducted research on nucleic acid biochemistry in Jack Szostak’s lab.

Seeking to apply the principles of RNA biology to the challenge of treating human disease, I joined the Weatherall Institute of Molecular Medicine (WIMM) as a DPhil student in 2014. As a student at the WIMM, I was extremely fortunate to benefit from excellent scientific and career mentorship, not only from my Supervisor Tudor Fulga and co-supervisor Tom Milne, but also through informal guidance from Enzo Cerundolo, Tatjana Sauka-Spengler, Ahmed Ahmed, Marella de Bruijn, Paresh Vyas, Hal Drakesmith and many others. 

The focus of my DPhil research was developing a technology that enables scientists and clinicians to predictably and precisely tune gene expression levels. While methods such as knock-in/knock-out technology have been developed for achieving on/off control of gene expression, tools for engineering more precise changes in protein levels were previously lacking. As a collaborative team comprising members of the Fulga, Milne, Sheppard, Fritzsche and Cerundolo labs, we set out to address this unmet need. miRNAs are naturally occurring fine-tuners of gene expression. I reasoned that introducing synthetic miRNA target sites downstream of user-specified genes would allow researchers to artificially repress gene expression levels. By engineering the sequence of these synthetic miRNA target sites, we demonstrated that it is possible to predictably tune gene expression to within 1% of any specified level. We applied this technology to precisely tune the tumour suppressor BRCA1 as well as genes involved in the anti-tumour immune response such as PD-1 and PD-L1.

As a postdoctoral fellow in Peter Zandstra’s lab at UBC’s School of Biomedical Engineering, I am currently expanding on this technology with the aim of understanding and controlling T-cell development from pluripotent stem cells.  

 

List of publications and patents:

 

1. Michaels, Y.S., Barnkob, M.B., Barbosa, H., Baeumler, T.A., Thompson, M.K., Andre, V., Colin-York, H., Fritzsche, M., Gileadi, U., Sheppard, H.M., et al. (2019). Precise tuning of gene expression levels in mammalian cells. Nat Commun 10, 818.

2. Knapp, D., Michaels, Y.S., Jamilly, M., Ferry, Q.R.V., Barbosa, H., Milne, T.A., and Fulga, T.A. (2019). Decoupling tRNA promoter and processing activities enables specific Pol-II Cas9 guide RNA expression. Nat Commun 10, 1490.

3. Michaels, Y.S., Wu, Q., and Fulga, T.A. (2017). Interrogation of Functional miRNA-Target Interactions by CRISPR/Cas9 Genome Engineering. Methods Mol Biol 1580, 79-97.

4. Wu, Q., Ferry, Q.R.V., Baeumler, T.A., Michaels, Y.S., Vitsios, D.M., Habib, O., Arnold, R., Jiang, X., Maio, S., Steinkraus, B.R., et al. (2017). In situ functional dissection of RNA cis-regulatory elements by multiplex CRISPR-Cas9 genome engineering. Nat Commun 8, 2109.

5. Patent WO2018/011590 A method for precisely controlling endogenous gene expression in response to effector miRNAs. Inventors: Tudor Fulga, Yale Michaels, Thomas Milne.