Almost every disease-causing pathogen has its own specific sequences of DNA, but detecting foreign pathogens or minute mutations of DNA against a sea of benign DNA is a difficult technical challenge. David Yu Zhang's Nucleic Acid Bioengineering Laboratory (NABLab) seeks to understand the biophysics of nucleic acid hybridization, develop novel genome and transcriptome profiling technologies, and translate these technologies into non-invasive cancer diagnostics.
Zhang is the principal investigator on two five-year research projects grants (RO1) from the National Institutes of Health (NIH), totaling $5.5 million, to develop new diagnostics. The first R01 from the National Cancer Institute involves the development of polymerase chain reaction (PCR) techniques and instruments for the rapid and sensitive detection of driver mutations in cell-free DNA. Significant progress has been made through the lab’s development of the Blocker Displacement Amplification (BDA) technology, a temperature-robust PCR method that selectively amplifies all sequence variants within a roughly 20 nt window by 1000-fold over wildtype sequences, allowing easy detection and quantitation of hundreds of potentials variants originally at <0.1% allele frequency. The lab validated BDA on over 100 clinical blood samples from lung cancer patients and is scaling up BDA to even higher multiplex and integrating with NGS readout to allow discovery of rare mutations not previously detectable from clinical FF and FFPE tissue samples.
The second R01, funded by the National Human Genome Research Institute, focuses on target sequencing based on allele-specific hybrid-capture panels, as well as biophysical studies of DNA kinetics to better guide the probe design process. Zhang’s group has successfully demonstrated a 114-plex non-pathogenic SNP panel capable of detecting variants with 0.3% allele frequency using a library of only 60,000 reads, as compared to roughly 2 million reads needed to achieve similar variant sequencing depth without allele-specific enrichment. Steps are being taken to optimize a 130-plex cancer driver mutation panel based on National Comprehensive Cancer Network guidelines.
Hybridization is a key molecular process in biology and biotechnology, but so far there is no predictive model for accurately determining hybridization rate constants based on sequence information. NABLab specializes in hybridization kinetics studies, in order to predict rate constants in highly multiplexed settings typical for NGS hybrid-capture panels.
Prior to joining the Rice bioengineering program in 2013, Zhang worked as a postdoctoral scholar in the laboratory of Assistant Professor Peng Yin at the Wyss Institute for Biologically Inspired Engineering and Harvard Medical School. While at Harvard, he developed versatile and ultra-specific bio-imaging tools from DNA and RNA for biomedical application through two nationally competitive research fellowships: a K99/R00 Pathway to Independence Award by the National Institutes of Health (2012), and a Life Sciences Research Foundation award from the Howard Hughes Medical Institute (2010).
Zhang is the author of 24 peer-reviewed journal publications, and his work has led to four awarded U.S. patents and 12 pending U.S. and international patents. His research in molecular engineering and efforts to pinpoint rare genetic DNA variants helped catalyze the launch of NuProbe, a venture-funded startup company in Boston, MA that recently raised over $10M in a Series A offering.
The Nucleic Acid Bioengineering Laboratory (NABLab) is currently pursuing three main lines of research: