Posted: August 29, 2011

RESEARCHER PROFILE: How Phlebotomy and the Amish Paved the Way for this Leader in Cancer Genomics

Catherine Evans

Image: Dr. Stacey Gabriel

Stacey Gabriel, Ph.D. realized she wanted to be a geneticist one summer in college as she drew blood from an Amish farmer in a chicken coop. She had taken a summer job as a phlebotomist at the University of Pittsburgh Medical Center, but what she thought would be routine blood-drawing for a lab studying recessive diseases in the Amish became something much more intriguing. For the first time during her microbiology studies, genes became more to her than the strings of As, Ts, Cs and Gs illustrated in the pages of her undergraduate textbooks. For once, says Dr. Gabriel, she saw the research proceed from “the families into blood samples into DNA into actually making a scientific discovery.”  The research process came to life, literally, as she witnessed for the first time the human element of genetics.

At the time, she was working for Aravinda Chakravarti, Ph.D. who was studying a rare, inherited bowel disease called Hirschsprung’s disease. Because Hirschsprung’s more commonly appears in isolated populations like the Amish, and because the Amish keep very detailed family pedigrees, Dr. Chakravarti reasoned that it would be easier to track the Hirschsprung's gene inheritance in Amish families. Dr. Gabriel says witnessing a disease gene affecting the families she came to know diminished the opaque nature of genetics for her. Her experience made such an impact on her that she abandoned her original plans to attend medical school and instead, pursued a Ph.D. in genetics. She joined Dr. Chakravarti in his lab, eventually completing her thesis on Hirschsprung’s disease.

The Beginnings of Large-Scale Genetics

Dr. Gabriel came of age as a geneticist in the late 1990s; an era where new technologies were shifting the field of genetics into the fast lane. It was in this ripe environment where she finished her degree and first approached Eric Lander, Ph.D., of The Whitehead Institute for Biomedical Research, about a job. He had just published a paper detailing the use of a microchip technology that allowed the simultaneous genotyping of thousands of common DNA variations in the human genome. These new technologies promised radically faster and cheaper mapping of the human genome. Dr. Gabriel was immediately hooked. In 1998 she began work at The Whitehead Institute Center for Genome Research, which would soon become the Broad Institute.

In 2003, Dr. Gabriel, along with her colleague David Altschuler, M.D., Ph.D., led her first large scale genomics project using the microchip technology that had initially piqued her interest. The undertaking was called the International HapMap Project. The HapMap project mapped blocks of linked DNA variations along each chromosome in human populations spread all over the world. Building a public catalog of these blocks would enable researchers to more efficiently link diseases to genetic variation. Because of The Broad Institute’s state-of-the-art genomics capabilities, it was an ideal host for large-scale collaborations like HapMap. When the HapMap project was completed, its high-profile status put the Broad Institute and Dr. Gabriel’s Genetic Analysis Platform on the map in the genomics world. Soon after, the Broad Institute began its work with The Cancer Genome Atlas (TCGA).

The Broad Takes on Cancer Genomics

The Broad Institute is the only center to serve as a Genome Sequencing Center (GSC), Genome Characterization Center (GCC), and a Genomic Data Analysis Center (GDAC). Dr. Gabriel directs the GCC, along with her co-principal investigator, Matthew Meyerson, M.D., Ph.D. She leads a team of 10 project managers and 20 analysts who are responsible for the Broad’s contribution to TCGA and other large disease genetics initiatives at the National Institutes of Health (NIH).

Leading this large and complex team is a huge undertaking, with large numbers of tumor samples and even more massive amounts of data coming out the other side. But, says Dr. Gabriel, “when you’re at a genome center you get access to things earlier-- you’re using them before the rest of the world. I like seeing how cutting edge [technology] can be applied rapidly in a very efficient and large scale way to define a new problem in genetics or cancer.”

Being on the cutting edge also means having no precedents, no blueprints to follow. Dr. Gabriel has found herself wondering how her team will accomplish goals that can seem almost too ambitious given the learning curve with new technology and the scale of TCGA. When she began leading the Broad’s exome sequencing project she remembers thinking, “‘Sequencing all the exons?  Wow, that’s really hard when you’re trying to isolate just 1 percent of the genome – the part that encodes the genes – from the rest of the genome, all in a single reaction and put that onto a sequencer.’” Exome sequencing focuses just on the genome’s exons, the 1 percent of DNA that actually codes for genes. Exome sequencing requires sequencing only about thirty million bases, rather than the three billion bases in the whole genome. Since scientists estimate that 85 percent of all disease-causing mutations occur in the human exome, it presents an attractive approach to increase efficiency and save cost. Dr. Gabriel adds, “we hope this approach will allow more samples to be studied, hopefully leading to more conclusive and exciting results.”

Despite its advantages, exome sequencing is technically challenging.  

“I thought, ‘How will we ever do this for all these samples?’” she says. “But I turn around now, 18 months later we’ve done 20,000 exomes, and next year we’ll do twice that. The ability to do the exomes is changing the type of questions you can ask in cancer and human genetics.”

Dr. Gabriel’s experience with the roller-coaster of large-scale sequencing has prepared her well for a collaboration with TCGA. She and the Broad began work with TCGA in 2006. Their hands were full focusing on just two tumor types, glioblastoma and ovarian.  They were using so-called first generation sequencing, the same technology that they’d used for the last 15 years. Then, in 2009 the TCGA project scaled up. The number of tumor types to be studied went from two to 20. A new sequencing technology promised exponentially faster, cheaper and higher quality sequencing data. It replaced the familiar first generation standby. “All good things,” says Dr. Gabriel, “but there are growing pains and transition pains that come along with that.”

Given her track record with seemingly overwhelming projects, Dr. Gabriel is in a good position to lead the Broad’s TCGA effort. While its goals are ambitious, TCGA continues to deliver, thanks in part to the Broad’s sequencing efforts. Her experience at Broad will help her predict what the future holds for comprehensive projects like TCGA. TCGA’s greatest contribution to cancer genomics will be “the availability of the depth of data on such a wide collection of individuals in a given tumor type. The impact will be to show us that we have to do way more,” says Dr. Gabriel.    

The Future of Cancer Genomics  

The data available from the completed glioblastoma characterization is already fueling research that has shed more light on glioblastoma’s inner workings. So although the early data is already generating findings, more tumor samples will bring much brighter illumination to the cancers being studied. “A couple hundred tumors is a great place to start,” says Dr. Gabriel, “But I think what we’ll find is that to really know the frequency of these events, and to really characterize how the frequency of certain mutational events correlates with outcome or with ethnicity or environment, you’re going to have to do a much deeper study.”  However, she says, TCGA’s strength lies in its already sturdy foundation. “I think the richness of that information from all the types of molecular analysis is what the real foundation is,” Dr. Gabriel says.  It’s a strong start for the depth of study required to complete the TCGA project.

Despite leaving small-scale lab research behind for the Broad’s brand of large-scale genomics, Dr. Gabriel still collaborates with her former mentor, Dr. Chakravarti. They continue to work on Hirshsprung’s, the disease she encountered in the Pennsylvania Amish in her phlebotomy days so many years ago. It was, after all, the disease that gave her entree into the genetics world and that put her on the path to where she is now. She and Dr. Chakravarti’s group eventually found the mutation that causes Hirshsprung’s, and today, that finding has led to a better understanding of the disease’s underlying biology. Dr. Gabriel may have an already-full plate, but her continued work on this rare disease is not so surprising. Because for her, genetics at its core, whether large or small scale, is about the human element: accessing the microscopic workings of human diseases, pinpointing targets, and finding cures.