By Mikkael A. Sekeres, MD, MS

2009-12-08

As a postdoctoral fellow at the Ontario Cancer Institute in the mid-1980s, Dr. John E. Dick learned two important lessons: first, to always look back to the past to guide the directions of the future, so as to not “reinvent the wheel”; and second, that the drive to do research should come from the intrinsic value and importance of the question being asked and not from looking over one’s shoulder to stay ahead of the competition. Yesterday, as he delivered this year’s honorary E. Donnall Thomas Lecture, Prof. Dick demonstrated how the purity of his focus — learning from the past and letting solid science, not politics or evanescent trends, guide research — could lead to a transformation in our understanding of stem cell biology and carcinogenesis.

In part because of Prof. Dick’s ground-breaking work, cancer stem cells (CSCs) are now recognized as being responsible for long-term maintenance of tumor growth in a variety of malignancies, particularly acute leukemias. CSCs have a high capacity for self-renewal, proliferation, and differentiation. CSCs are distinct from the rest of the tumor, which itself retains a hierarchical organization defined by a maturation process, similar to normal tissue, with stem cells at the apex of that hierarchy. 

The CSC concept provides a powerful explanation for the phenotypic and functional heterogeneity within tumors with respect to everything from cell morphology to cell proliferation kinetics. Perhaps even more compelling, the CSC model also explains clinically why some tumor cells respond to chemotherapy while others do not, even within the same person, and why most patients (such as those with acute leukemia) relapse following standard cytotoxic chemotherapy — i.e., because the distinct CSCs (in the case of leukemia, leukemia stem cells, or LSCs) may lie dormant for weeks and survive the drug assault to sustain tumor growth again. The key to eradicating cancer lies in identifying the “wooden stake” (or combinations of stakes) to kill CSCs – for example, by developing anti-CD123 monoclonal antibodies — in effect destroying tumors at their root.

Sounds easy, right? Prof. Dick made it seem that way as he reviewed some of the seminal work coming from his and other labs, leading to the current understanding of CSCs. Critical developments have included development of the xenotransplant model for normal cells and for leukemia, particularly involving the mixed-lineage leukemia (MLL) gene; purification of hematopoietic stem cells (HSCs) and LSCs; defining the biological properties of CSCs; and identifying the intrinsic heterogeneity of self-renewal potential among CSCs using clonal tracking. Prof. Dick then provided a glimpse into ongoing studies, in which his lab has purified human HSCs to a single cell and isolated and characterized the entire human hematopoietic progenitor hierarchy, and demonstrated that the heterogeneous genetic signatures of LSCs can be predictive of clinical outcome.

To what does Prof. Dick credit his remarkable accomplishments? “Time and place are essential,” he said. “Pick your postdoctoral project carefully — it may become the basis for your life’s work.” He took advantage of technologies that came of age as his research developed, and a remarkable group of colleagues in Toronto who set high standards and collaborated without competition. And, he adds, “trainees drive research.” Teaching may be its own reward, but learning is bi-directional.

Dr. Sekeres indicated no relevant conflicts of interest.

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