Dr Albert Cheng: exploring the potential of CRISPR-Cas9

22 July 2015

On 1st July 2015, Dr Albert Cheng, a 2007 Croucher Scholar, was appointed to the faculty of Jackson Laboratory of Genomic Medicine in Farmington, Connecticut, USA. After launching his own laboratory, Cheng will continue his work on the CRISPR-Cas9 system.

The CRISPR-Cas9 system, is a potentially revolutionary tool for editing DNA. Previous strategies for targeted genome alteration were problematic: it took a long time to generate the necessary reagents; the various approaches had low efficiencies, often required drug-selectable markers, and left behind scar sequences. The CRISPR-Cas9 mechanism appears to have evolved as a form of adaptive immunity used by microbes as a defence against viral infection. Using short sequences of RNA, Cas9 proteins are guided to very specific locations on the target gene where they make accurate double-stranded breaks.

Two years ago, Cheng and his colleagues at the Whitehead Institute used the CRISPR-Cas9 system to insert DNA directly into fertilised mice zygotes, a very significant advance given that in the past it was necessary to start the process using mouse embryonic stem cells in vitro requiring additional rounds of breeding to get the desired mutants.

Now Cheng is working with colleagues at the Jackson Laboratory, including Dr Wenning Qin and Dr Haoyi Wang and their research teams, on new applications of the CRISPR-Cas9 system.

Cheng identifies three major problems within CRISPR-Cas9 technology that require further research to resolve. The first of which involves the process of delivery. For example, it may be necessary to correct a diseased cell in the human body, targeting just one organ, rather than the entire body – how can the CRISPR-Cas9 be delivered to that target organ? The second: how to generate precise modification with near-perfect efficiency; for the technology to be useful for therapeutics, it is important that the gene is not randomly cut, as the aim is to correct specific, disease-causing mutations many of which involve single nucleotide changes. Currently, precise modification efficiency – although higher than in processed used in the past – is not very high. The third: to reduce undesired off-target mutations. Enzymes (in this case, Cas9) are not perfect – they sometimes cut at the desired site – but may also cut other sites. Through further research and engineering, Cas9 may be improved so that it cuts only at its on-target site.

It is hoped that CRISPR-Cas9 may soon be used to treat or prevent human diseases, one potential disease being the acquired immunodeficiency syndrome caused by the human immunodeficiency virus (HIV). The process would involve inactivating CCR5 receptor, a cell surface protein required for HIV invasion, by CRISPR-Cas9 in blood cells and then reintroducing them back to HIV patients by bone marrow transplantation. Cheng suggests that in the future, a number of other debilitating diseases, including cancers, myotonic dystrophy, Alzheimer’s, and Parkinson’s may also benefit from CRISPR-Cas9 targeting.

On the other hand, Cheng is building CRISPR-Cas9 -based enzymes for studying gene regulation. In this case, Cas9 is mutated to lack DNA-cutting activity and thus serve as an RNA-guided DNA binding protein. When tethered to a transcriptional activator domain, the CRISPR-on system can turn on silent genes by binding to their promoters. This technique offers versatility of gene activation and may serve as a complementary approach to RNA interference (RNAi)-mediated gene repression.

Cheng obtained his Bachelor of Science in Biochemistry (First Class Honors; Academic Achievement Medalist) from Hong Kong University of Science and Technology (HKUST) in 2005. He worked in the lab of Professor Hannah Xue Hong on designing bioinformatics tools as a student helper and in the lab of Professor Nancy Ip on Trk signalling as a final year project student. He then joined the lab of Professor King L. Chow as a graduate student and contributed to a genome-wide RNAi screen for regulators of C. elegans male sensory ray development and worked on his master thesis on the role of Iroquois (irx-1) transcription factor in sensory ray formation.

After receiving his MPhil in Biology from HKUST (2005-2007), Cheng continued his studies in the field of Computational & Systems Biology, completing a PhD at the Massachusetts Institute of Technology (MIT) (Cambridge, MA) (2007-2014), concentrating on Molecular Systems Biology (Gene Regulation: Epigenetics, Transcriptional, mRNA processing), Bioinformatics, Cancer and Metastasis, Stem Cell and Development, Somatic Cell Reprogramming, Synthetic Biology, and Genome Engineering at the Whitehead Institute of Biomedical Research in the labs of Professors Rudolf Jaenisch and Chris Burge. From 2014-July 2015, Cheng was a JAX Scholar Postdoctoral Associate at the Jackson Laboratory (Bar Harbor, ME), where he worked on: parameters affecting CRISPR/Cas-mediated genome editing efficiency; constructing novel nuclease for genome editing with improved specificity; and epigenetic editing of enhancers. In July 2015, Cheng was appointed to the position of Assistant Professor at the Jackson Laboratory of Genomic Medicine (Farmington, CT).

To view Dr Albert Cheng’s Croucher profile, please click here.
For more information on Croucher Scholarships, please click here.

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