Circulating Cell-Free DNA

A large number of small fragments of cell-free DNA circulate in blood and urine. In healthy individuals, cfDNA is predominantly derived from apoptosis of normal cells of the hematopoietic lineage, with additional contributions from other tissues. 1,000 to 10,000 genome equivalents of cell-free DNA can be isolated from just one mL of plasma, including small fragments of chromosomal DNA and mitochondrial DNA, as well as fragments of viral, bacterial and fungal genomes. Cell-free DNA offers an information-rich window into human physiology, with rapidly expanding applications in prenatal testing, cancer diagnosis, and the monitoring of infection, rejection, and immunosuppression after solid-organ transplantation.

The lab develops assays to interrogate cell-free DNA via sequencing. This work requires innovation in both molecular biology and computational biology. We have recently developed an assay to sequence ultrashort molecules of cell-free DNA and we have described an algorithm to estimate donor cell-free DNA in absence of a donor genotype. We furthermore pursue new applications in medical diagnostics, in particular new approaches to the monitoring of solid organ transplant patients and blood and marrow transplant patients. 


Precision Monitoring of Solid-Organ and Hematopoietic Stem Cell Transplants


Transplant medicine offers an ideal test bed for precision and genomic medicine. A diverse range of complications that are of relevance for the general population arise with high frequency after transplantation, including malignancies, infections and immunological complications. Consequently, investigations of the utility of genomic medicine tools that target the transplant population require a much smaller sample size and follow-up time than those recruiting from the general population. Further, transplant recipients are followed very closely and frequently visit the hospital, which aids in designing and executing prospective studies and studies that require serial sampling. These factors provide significant opportunities for early success in precision medicine affecting not just transplant recipients, but development and optimization of precision medicine monitoring and treatment techniques for the general population. 

For more info on recent advances and outstanding opportunities for precision medicine in solid organ and hematopoeitic trasnplantation, check out our recent review here

Spatial Metagenomic Sequencing


Despite the centrality of microbes to life on earth, we know very little about how microbes interact with each other and their environment. This lack of understanding is due to fundamental limitations of the tools available to study microbiomes. Microbiome analyses primarily rely on DNA sequencing of microbial genetic material recovered from environmental samples (“meta-genomes”). Metagenomic sequencing enables access to the nucleic acid diversity and gene content of microbial populations from a diverse range environments, but metagenomic sequencing destroys all information about the spatial context of microbes and their functional interactions.

To better understand the complexity of microbial communities we must devise ways to perform high-throughput measurements of microbial genotypes while preserving nanoscale spatial information. Our lab is developing spatial metagenomic sequencing, an imaging methodology that enables identification of thousands of unique species in dense microbial communities with nanoscale spatial resolution. This technology opens up new avenues for investigating complex microbial populations.