Research Overview
The development of new measurement techniques has often opened new avenues in science. My group is interested in the application of principles of physics and physical measurement to biology. Our early work in single molecule biophysics provided a springboard to the development of the first single molecule DNA sequencing technology, which helped usher in the personal genome era. We have continued to pursue novel applications of next-generation sequencing technologies, including their application to non-invasive diagnostics, immune repertoire analysis, and de novo genome sequencing.
Single-cell sequencing
The development of new measurement techniques has often opened new avenues in science. My group is interested in the application of principles of physics and physical measurement to biology. Our early work in single molecule biophysics provided a springboard to the development of the first single molecule DNA sequencing technology, which helped usher in the personal genome era. We have continued to pursue novel applications of next-generation sequencing technologies, including their application to non-invasive diagnostics, immune repertoire analysis, and de novo genome sequencing.
Immune repertoire sequencing
We have also been interested in using next-generation sequencing technologies to monitor the status of the immune system by sequencing the repertoire of expressed antibodies. This provides a direct window into the clonal structure of the immune system and provides a detailed picture of the various processes of immune defense which are impossible to measure with conventional approaches. We have explored the use of this sort of measurement both in model systems such as zebrafish, and also in humans. Influenza vaccination provides a particularly compelling example in which humans receive a defined antigen and by taking longitudinal blood samples we have been able to study the response to such stimuli.
Cell-free nucleic acid sequencing
Our work in non-invasive diagnostics uses next-generation sequencers as molecular counters to explore a phenomenon called circulating cell free DNA (cfDNA). When cells die, their genome gets digested into small nucleosome-sized pieces of DNA that circulate in the blood. Nearly all organs of the body contribute such DNA, as well as RNA. In particular, the blood of pregnant women contains DNA from their fetus. We used this phenomenon to develop the first non-invasive diagnostic for Down syndrome and other aneuploidies, and versions of this test are now offered worldwide. In 2014, approximately one million women were able to avoid dangerous invasive tests, such as amniocentesis, by using a simple blood test based on our approach – thereby saving thousands of lives. Our research in this area has enabled us to measure many other aspects of the fetus non-invasively – including sequencing its genome and monitoring its developmental gene expression program.
Another area in which we have combined cfDNA and high throughput sequencing is in the care of organ transplant recipients. Heart transplant patients are constantly monitored for rejection, in which their immune system recognizes the transplanted heart as a foreign object and attacks it. These patients must take strong immunosuppressant drugs and are monitored for rejection by invasive biopsies. We realized that the heart transplant should be thought of as a genome transplant, since each cell in the donor heart has a different genome than the recipient. Monitoring the quantity of this distinct DNA in the blood provides a direct window into the health of the transplanted organ, since when more cells die more DNA is contributed to the blood. Finally, not all of the DNA in one’s blood is human – a small fraction of it derives from the microbiome of the individual. We have been exploring this phenomenon as a tool to monitor the microbiome and as a diagnostic for infectious disease.