Current Research Areas

The Blainey lab addresses major challenges in single cell genomic and functional analysis, drug screening, and genomic screening by combining diverse molecular, optical, and microfluidic technologies. Many of our experimental efforts efficiently produce large multiparameter datasets from key biological models and primary human material that match well with advanced analytical methods.

Pooled optical genetic screening in human cells

The group is applying targeted in situ sequencing to determine the thousands of CRISPR perturbations in millions of cells by imaging, naturally linking large perturbation sets with rich image-based cellular phenotypes in powerful pooled formats. This capability reduces the cost for spatially and temporally-resolved screens by multiple orders of magnitude and extends large-scale pooled screening into new biological models and disease areas.

Key publications and resources:

Scalable combinatorial screening

We created a new, parallel-processing array format for manipulating hundreds of thousands of micro-droplets. The parallel format has strengths in robustness, compartmentalization of small-molecule solutes, and integration with imaging that enabled the first large-scale application of micro-droplets for drug screening. We applied this system to discover a half dozen known drugs and drug candidates that synergize to re-activate antibiotic drugs against Gram-negative bacterial pathogens. Versus existing approaches, our parallel-processing droplet system reduces costs by an order of magnitude and consumes two orders of magnitude less compound.

Key publications:

Accurate and sensitive measurement of somatic mutation flow across cells

Genetic changes in somatic cells are important in aging and cancer, yet difficult to detect – even with today’s advanced bulk and single-cell approaches. My group developed a concept to jointly analyze variants across samples related by a lineage prior (rather than one at a time) to improve the sensitivity and specificity of somatic mutation detection and resolve such events in individual related cells. We showed a major improvement in somatic variant calling performance and produced multiple lines of evidence that mutations arise across cells with non-Poissonian statistics and proposed a molecular mechanism by which individual chemical lesions on DNA can strongly couple somatic mutation events in mother and daughter cells.


Robust and accurate systems for single-cell genomics at scale

Single-cell genomics provides an increasingly important window into biology but depends heavily on specialized instrumentation and lacks the cellular throughput needed for many applications. The group developed one method based on a new microfluidics concept we call virtual microfluidics that eliminates the dependence on specialized equipment and a molecular enrichment method that makes a 100-fold improvement in sensitivity/throughput for rare target cells in pooled single-cell RNA-seq libraries.


Past Research Areas

Sample preparation for high-sample-throughput genomic science and medicine

With the ready availability of low-cost sequencing, sample preparation now limits the application of genomics in medicine. We demonstrated automated sample preparation from biomass to sequence libraries at the microscale in lab-on-a-chip systems – addressing total resource demand across labor, capital equipment, and consumables. We also showed how microfluidic workflows maintain quality and require 10-100-fold less sample quantity, enabling new genomic applications in analysis of bacterial pathogens and human primary cells.


Discovery and development of molecular sleds

We applied robust and higher-throughput experimental and analytical methods for the direct analysis of biomolecules sliding and hopping along DNA molecules at the single-molecule level. We discovered sliding activity among short basic peptide molecules and explored the chemical basis of this novel activity. These results implicate thousands of human proteins with likely DNA sliding activity. We also explored the activity of synthetic small molecules, finding that drug-like small molecules can be engineered to slide on DNA.