Just how tumorigenic are iPS cells? The field really doesn’t know at this point.
However, a steady stream of papers have raised red flag after red flag about genomic and epigenomic alterations/mutations that are linked to cancer.
Of course, then there is the fact that all the genetic changes actually used to make reprogrammed cells in the first palce are linked to cancer: not just Myc, but also Nanog, KLF4, Sox2, loss of p53 function, etc.
We all first thought that making iPSCs without extra Myc (if possible) would be safer, but it turns out that in the real world making human IPSCs without Myc is very hard and unfortunately even leaving Myc out of the process doesn’t seem to make the cells have a definitively safer profile.
Then of course everyone thought making iPS cells in an entirely non-genetic manner would be safer, but it’s not clear that that is true either. Note that now in 2020, there are safer ways to make IPS cells and they are still very much in the news 9 years later.
So what is the secret recipe to making safe or at least safer iPS cells? Where can I find that cookbook?
A key factor in making iPS cells that have a better shot at making it into the clinic to help patients will be preserving genome integrity during and after the iPS cell production process. It’s no longer enough to use a method that makes iPS cells in a reasonably efficient manner or uses non-genetic methods, although those may help.
Researchers must add to their recipes methods that actively protect the cellular genomes and epigenomes.
A key question is whether the mutations and epi-mutations that scientists are consistently seeing in iPS cells are simply a byproduct of the harsh reprogramming process OR alternatively, are actually actively involved in reprogramming, perhaps even enhancing the process.
Thus, there may be a catch-22 situation here. Preserving genome integrity may reduce the efficiency of iPS cell production, but preserving the genomic and epigenomic integrity of cells is essential for producing clinically useful iPS cells that can go beyond disease modeling.
Stay tuned as papers start coming out focused on preserving genomic integrity in the process of making iPS cells.