The human body is composed of many different cell types. Each of these cell types has a distinct identity and function, yet each cell contains the exact same DNA! Early in development stem cells have the ability to become any of the hundreds of cell types in the body. It is through careful regulation of which genes are turned-on, and which are turned-off that these cells can eventually become specialized.
In part I of our dance we can see a happy, healthy, human body made up of cells with distinct functions that are excitedly fulfilling their roles.
But then suddenly, tragedy strikes! Gene regulation in one cell is altered, causing that cell to change its identity and become a cancer cell. This BAAAD cell can quickly multiply. These cancer cells first attack the intestine but then later spread to the liver. The change in cell identity (from normal to cancer) results in tragedy, as the cancer cell population takes over and the body succumbs to the disease.
To understand this disease we need to investigate what early events cause that one rogue cell to become cancerous. Often cancer is detected late in the progression of the disease. This complicates the study of the early alterations that cause that cell to go bad. If only we could Turn Back Time and study the disease as it happens!
An exciting, cutting-edge technique provides us with a way to accomplish this goal. This technique (with the really fancy name, cellular reprogramming) allows us to turn one cell type into another!
By adding four factors (over-expressing the four ‘Yamanaka’ transcription factors to be precise) to a cell, you can alter the cell’s identity. These four factors have the ability to manipulate the way the DNA is organized in a cell, reverting it back to an earlier stage.
In part II these four factors, played by four graduate students, demonstrate how the organization of the DNA (epigenetic landscape for the genetically-inclined folks) can be changed and how this change results in new genes being turned-on and old genes being turned-off.
We do this for both healthy skin (fibroblast) cells and cancer cells…and BAM! we’ve coerced the cell back in time to an earlier stem cell-like state. We can now force these cells to specialize (differentiate) into the cell type we want to study, by adding goodies (signaling proteins and small molecules, if you’re uber-curious).
In part III, our newly-made cancer and healthy stem cells are represented by two men (our bosses) who are getting ready to jump into the job market, ready to specialize into any career that will take them.
As they try out different careers (akin to the stem cells turning into different cell types) the competence of the cancer-derived and healthy stem cells is evaluated by on looking scientists. What we see is that these crazy-funky-BAAAD cancer cells have alterations that make them unable to fulfill their job (i.e. as rockstars instead of a real instrument the cancer cell has a rubber-band guitar; as chefs, instead a roasted chicken, a rubber chicken and as police officers instead of a gun, a super-soaker.)
All of these evaluations and comparisons yield a googolplex of data. This data must be carefully analyzed through intensive computational efforts. The final part represents the moving and shuffling of data that allows us to analyze the differences between cancer and healthy cells at a genetic level as these cells develop.
This project will provide the first glimpse into the aberrations driving the initiation and development of cancer cells within individual patients afflicted with this devastating disease. It is only through understanding the disease that we can truly beat it!!