Science tends not to be a series of “eureka” moments but rather, if one is lucky, the odd eureka interspersed with a lot of hard slogging.
In the mid ‘90s my group made the rather startling discovery that we could stimulate the expansion of blood-forming stem cells by engineering the overexpression of a single gene. By 2002 we had advanced this discovery to show that it was possible to expand stem cells in the laboratory. These discoveries were based on ten years of previous work (the hard slogging bit) by which we developed and optimized methods of genetically modifying stem cells with specialized viruses; and almost as many years trying to identify the right genes to tinker with in the hopes of increasing the expansion of stem cells.
While this particular method was not easily applicable to the clinic, it provided proof that expansion of blood stem cells was possible and helped to stimulate efforts in many laboratories to find user-friendly methods to achieve the result that we had obtained with genetic modification. These efforts bore fruit in the last two years with the identification of small molecules (drugs) that appear to stimulate expansion of very primitive blood-forming cells, and hopefully stem cells. We are now involved in a major team grant with investigators in Montreal, Toronto, Vancouver and Seattle, to bring such drug agents to the clinic in an effort to increase the safety and efficacy of stem cell transplantation for leukemia and in the future for gene therapy of diseases such as thalassemia and sickle cell anemia.
Other stories of a similar nature have unfolded in my lab in the context of leukemia: at the moment we are particularly excited about our discovery that a gene called Meis1 appears to play a major role in the self-renewal function of leukemic stem cells. Now comes the hard slogging: figuring out precisely what this gene controls in the cells and finding some way to block its effects. Again, our ability to genetically modify blood-forming cells in the lab is paying dividends as we now have ways to engineer leukemic cell directly from normal human blood cells. This gives a controlled setting to really delve deeply into what the overexpression of Meis1 is doing.
My vision of the future is that increasingly we will need to focus on “gene function” and to exploit ever more complex models to fully understand the altered functions associated with the myriad of gene mutations being discovered in leukemias and other cancers. The eureka moment of discovering a frequent mutation in a particular type of cancer will necessarily be followed by the heavy slogging to see what this mutation actually does. But the pace is quickening and I suspect that the next ten years will see a huge increase in the number of so called “targeted” therapies informed by basic gene function studies such as are the focus in my lab.
Thanks for reading,