Single-Cell Sequencing Pioneer Wins AAAS Wachtel Cancer Research Award

The first method for sequencing the genome of an individual cell — which has given scientists a new view into the inner workings of tumors — started as a side project during Nicholas Navin's graduate career. "It was kind of a background project that I did in the lab mostly on weekends," said Navin. "This was really kind of a high-risk project for me and something I had never [initially] told my advisor about."

After a few years of trying various sequencing methods, Navin finally got his eureka moment. "I found that you can get the same [genomic] information from sequencing one cell that you can get from sequencing millions of cells." After this, his advisor gave him the green light to continue refining his technique, which he used to study the evolution of breast cancer. Today, Navin's work has helped establish the emerging field of single-cell genomics.

Single-cell sequencing technology has proven to be a powerful tool for understanding cancer evolution, the genomic diversity in tumors, and the mutations that fuel cancer progression. An assistant professor of genetics and bioinformatics at MD Anderson Cancer Center, Navin is currently applying this knowledge to help guide early detection, diagnosis, and targeted therapy for cancer patients.

Looking back on the early phase of his career, Navin said, "This just speaks to the kind of serendipitous and circuitous nature of research and the importance of always looking closely at things you might not expect."

For his pioneering work, Navin has won this year's AAAS Martin and Rose Wachtel Cancer Research Award, which recognizes leading early-career scientists in the field of cancer research. Now in its third year, the award, which includes a $25,000 prize and the publication of an essay in Science Translational Medicine, is made possible by the generosity of Martin and Rose Wachtel, who bestowed a $1 million endowment to AAAS. Navin was honored at a ceremony on 31 July at the U.S. National Institutes of Health (NIH) in Bethesda, Maryland.

The award selection committee chose Navin because of "his innovative ideas, including his creativity in developing his own methods when there were no existing techniques to address the scientific questions he was interested in," said Yevgeniya Nusinovich, associate editor of Science Translational Medicine, who oversaw the committee. "His work jump-started an entirely new and growing field of research: single-cell genomics."

"Single-cell analysis will be critical as we enter the era of precision medicine," said Lee Helman, scientific director for clinical research at the Center for Cancer Research, National Cancer Institute (NCI), which co-hosted the award ceremony. "Dr. Navin's work has already begun to provide insight into how a tumor's genotype [and] phenotype evolve in response to therapeutic interventions.  These insights will lay the foundation for more rational approaches for treatment over the lifetime of a patient."

Navin's essay, published in Science Translational Medicine, discusses his early interest in understanding the genomic diversity within a tumor, known as intratumor heterogeneity. Cancer starts with a single cell gaining a mutation that allows it to grow uncontrolled. As tumor cells evolve, they continue to acquire mutations, and the end result is a population of genetically diverse cells. Some of these mutations allow the cancer to invade other parts of the body, or metastasize, or resist and evade therapy.

Standard genomic techniques typically rely on a single tumor biopsy, which averages together mutations from a whole population of tumor cells. This fails to accurately capture the complex genetic diversity of a tumor. To do so, Navin realized that he needed to develop a new method to probe the single cell.

"At the time when I was trying to sequence single cells, it was really a tough technical challenge, because even the best methods still required…hundreds of thousands of cells," said Navin. "I've been building methods to go smaller and smaller and smaller and, ultimately, getting to the single-cell level."

As a postdoctoral fellow, Navin developed single-nucleus sequencing and, later on, an even more precise method called nuc-seq. These techniques are finding many applications in the clinic, from early detection and non-invasive monitoring, to prognostics and guiding targeted therapy.

For example, Navin is investigating ways to sequence single tumor cells in the blood to monitor patients' responses to treatment. Sequencing these cells during the course of therapy would allow doctors to track how tumors are evolving and whether they are acquiring drug resistance. "So you can quickly adjust the therapeutic strategy in real-time as the therapy progresses," said Navin.

Single-cell sequencing may also enable clinicians to pinpoint the exact mutations present and how they are distributed in a tumor. "You can get kind of a map of all the tumor cells in the tumor," said Navin. "So it can really guide therapeutic targeting."

"It will be fascinating to see his [Dr. Navin's] work expand into the study of clonal diversity in metastatic disease and drug resistance, which may have significant impact on clinical care," said Glenn Merlino, acting scientific director for basic research at the Center for Cancer Research, NCI.

Navin's team is further refining their methods in an effort to bring down cost. Beyond cancer, researchers are looking to apply single-cell sequencing techniques to prenatal genetic diagnosis.

"The field didn't exist really more than four years ago, and it's moving very fast," said Navin. "There's a lot of support from NIH and NCI, but also from industry. So there's certainly a big interest in getting it into the clinic, and I think really in the next five years or so we'll see that happening."