"To be or not to be – that is the question"
– Prince Hamlet, Hamlet Act III by Shakespeare (c. 1600)
The more that we study nature, it appears that nature never runs out of tricks that are up her sleeve. Perhaps the most wondrous sleight of hand that we've learned of lately is that cell identities are remarkably malleable. It's been known for decades that a class of cells, known as stem cells, can turn into several alternative cell types through a process known as differentiation. For example, embryonic stem cells (pluripotent stem cells) can give rise to all the hundreds of cell types in the mammalian body – in fact, in the embryo, we start out as a small clump of several dozen embryonic stem cells, which give rise to our whole bodies. Stem cells are also important in adult life. Muscle stem cells (sattelite cells) are located in adult muscle, and when muscle is injured, muscle stem cells are activated and produce new muscle cells to repair our muscles. Neural stem cells are located in our brains, and interestingly, they appear to steadily generate a trickle of new neurons that are necessary for properly capturing and storing memories in our adult lives.
Biologists used to think that stem cells were the only class of cells that were "plastic" – that is, that they could turn into other cells. For example, neural stem cells can turn themselves into specialized neurons, astrocytes, and oligodendrocytes (the major cell types that populate the central nervous system). But once these "differentiated" cell types are produced from stem cells, they are thought to be locked into their cellular identity, and instead adopt specialized roles designed to fulfill a specific bodily task – for example, neurons mediate our cognitive capabilities and allow for neural perception and bodily control.
But you don't want differentiated cells to be "plastic" and turn into other cell types. Imagine what would happen if all your blood cells turned into bone. Or if all your neurons suddenly turned into skin. In order to prevent these gruesome contingencies from ever happening, nature has installed several complex layers of cellular control systems to ensure that differentiated cells can't turn into other cell types. This is also especially important in preventing cancer. The body has many mechanisms to ensure that normal differentiated cells can't become plastic and turn into cancer cells.
Earlier we mentioned that it would be decidedly deleterious if all your neurons turned into skin. Thus, it's pretty shocking that the reverse has recently been found to be true – a group led by Marius Wernig at the Stanford School of Medicine has found that skin/connective tissue cells (fibroblasts) can be converted into neurons! Imagine what would happen if your skin just turned into neurons all at once (would it help exam scores?)
This remarkable process of turning fibroblasts into neurons requires only the overexpression of a single neuron-associated transcription factor, Ascl1, in fibroblasts. Overexpression of Ascl1 in fibroblasts converts them into neurons in vitro (in a petri dish), although co-expression of additional genes (Brn2 and Myt1l) enhances the process. These results were published in Nature, and I actually got a chance to speak with Marius Wernig at Stanford.
The transformation of stem cells into more differentiated cell types is known as differentiation, and is acknowledged as a natural developmental and physiological process in order to generate new cell types to create new tissues (during embryogenesis) or repair old tissues (after disease or damage). However, reprogramming – the conversion of a differentiated cell type directly into another differentiated cell type, or the conversion of a differentiated cell type into a less differentiated cell type (turning a differentiated cell into an undifferentiated stem cell) – is really a magical feat.
Recent studies in reprogramming have showed that development is in fact reversible – the developmental process of generating differentiated cells from stem cells isn't a one-way street. In fact, differentiated cells can be converted into stem cells. Or stem cells can be bypassed together, and differentiated cells can be reprogrammed directly into alternative differentiated cell types (like in the aforementioned fibroblast-to-neuron reprogramming study).
Although vastly more is known about differentiation compared to reprogramming, the list of reprogramming sightings is building up fast. Perhaps the most notable example is the finding that fibroblasts can be reprogrammed to embryonic stem cells/pluripotent stem cells (known as "induced pluripotent stem cells"; "iPS cells"). So during development, your pluripotent stem cells make the skin that you have today, and amazingly, you can turn that skin right back into the pluripotent stem cells that it came from. This finding has extraordinary therapeutic applications that will not be discussed in this article, though it has really taken the stem cell field by surprise and has quickly garnered much scientific and media attention (a recent Nature review article referred to this fibroblast-to-stem cell conversion as "The new world order of iPS cells"). I formerly worked on this fibroblast-to-stem cell switch at the Harvard Stem Cell Institute, where my colleagues and I showed a specific mechanism by which this reprogramming event occurs.
Other cool examples of reprogramming include: the reprogramming of fibroblasts to muscle, the reprogramming of immune B cells to T cells and macrophages, and the reprogramming of pancreatic α-cells or pancreatic exocrine cells to β-cells (discussed further in my other article, "Beta-Cells Wanted! Looking For … Alpha-Cells"). Reprogramming holds great therapeutic promise, as it is hoped that we could directly reprogram a patient's unneeded cells into a cell type that has been damaged or killed by disease.
"To be or not to be" has been previously described as biology's most notable soliliquoy. Through cellular sleights of hand, we are not only learning that stem cells are differentiated into specialized, differentiated cells, but that these differentiated cells can be "de-differentiated" back into stem cells, or that these differentiated cells can even be "trans-differentiated" directly into other differentiated cells. Further studies in differentiation and reprogramming will reveal more about cells decide "to be or not to be" – how cells choose what cell type to be.