Often when we dig a little into the science of stem cells, people get turned off by all the strange names of molecules and jargon. However, whether you are a scientist, patient, investor, reporter, etc. there are some aspects of stem cell science that are ‘musts’ to know about.
For example, you need to know about epigenetics and I recently did a post on that.
Another bit of stem cell science you need to know is about a molecular character called Myc.
What the heck is Myc and why do stem cell gurus need to know about it?
Myc was one of the first known cancer-causing genes and has turned out to be involved in a very high fraction of all human cancers. In fact, some people think Myc has one role or another in ALL human cancers. As such Myc is what is called an oncogene and a very dangerous one.
So if Myc is an oncogene, a bad guy, what does it have to do with stem cells?
Turns out that Myc is very much the Dr. Jekyll and Mr. Hyde of the cellular world. While it is Mr. Hyde as a cancer-causing gene, stem cells cannot do with the Dr. Jekyll side of Myc.
Around the year 2000 I started studying the role of Myc genes in stem cells. My theory was that if we could understand the normal function of Myc in cells that would help us understand how it causes cancer. In the process I realized that the normal function of Myc in stem cells is fascinating and important in its own right.
Myc comes in 3 forms, c-Myc, N-Myc, and L-Myc. All cause cancer, but also all have important normal roles in cell biology. In 2002, I published a paper in the journal Genes and Development knocking out (this means precisely eliminating the gene from the genome) N-Myc in neural stem cells.
The result? Mice survived the loss of N-Myc in their neural stem cells, but had a very tiny brain. Since N-Myc’s role in cancer often manifests as too much brain growth in the form of a tumor, our studies taking away N-Myc from neural stem cells made sense.
In 2004, Andreas Trumpp’s lab knocked out c-Myc from hematopoietic stem cells and found it was crucial for their function. Too much c-Myc often causes blood cancers so this also made sense.
Since that time Myc got a flood of new attention in 2006 when it was one of Yamanaka’s four superstar stem cell factors that can produce iPS cells. When Myc was combined with Oct4, Sox2, and Klf4 they together could transform ordinary cells such as fibroblasts into ESC-like iPS cells.
Since that time, Myc has been shown to not be formally essential for the iPS cell production process and in fact perhaps the only truly essential iPS cell factor is Oct4. However, although you in theory can leave Myc out of the iPS cell cocktail and still get iPS cells, without Myc the process is incredibly inefficient, up to 200 times less efficient. As a result, most researchers around the world still include Myc when they make iPS cells. The other thing is that even if you do not add extra Myc into your ingredients to make iPS cells, all the cells from which people make iPS cells are have some degree of their own natural levels of Myc (endogenous) that likely is essential to make iPS cells.
Why does Myc make normal stem cells happy? And why does Myc make it so much easier to make iPS cells?
The jury is somewhat still out, but we are starting to get a better idea.
One important thing is that Myc makes cells grow faster and when it comes to pluripotent stem cells, they like to grow fast. However, proliferation is not the whole story because fibroblasts grow pretty well, perhaps just a bit more slowly than iPS cells. Still, Myc may make cells more like to keep their stem-like properties as they proliferate and in this way Myc = self-renewal (the ability of stem cells to make more stem cells when they divide).
Myc has other functions that promote a stem-like state by shutting down almost all differentiation-related genes.
We have found that Myc is a potent blocker of differentiation both in mouse and also just now in a paper this month we found the same was true in human embryonic stem cells. In this way, Myc keeps embryonic stem cells and iPS cells in a non-differentiated state so that when the time comes that they are supposed to differentiate they still retain that function. You can boil it down to the equation Myc = pluripotency .
In part Myc tends to make cells more stem like by regulating the expression of other genes such as keeping differentiation genes in the OFF position. In addition, Myc appears to have a more global role in keeping the overall structure of DNA in the nucleus in a relatively ON state. In this way Myc may so to speak “set the table” in the genome for the subsequent action of factors like Oct4.
As with many things in our world, there can be too much of a good thing and that is true of Myc. Just a little too much Myc makes cells go beyond their normal stem cell functions and become cancer cells. Myc is also a likely culprit in the ability of ES and iPS cells to make teratoma. From an FDA perspective, I don’t believe cells with exogenous Myc will be allowed to be used in patients except under extraordinary circumstances such as in recurrent glioblastoma, where Karen Aboody’s lab is using neural stem cells with Myc to try to treat patients.
If you have any more questions about Myc, fire away in the comments section.