Induced pluripotent stem (iPS) cells are a discovery barely five-years old but they are one of the most compelling stories in biology. Many presumed these adult-derived cells would bypass embryos in stem cell science. New research suggests, however, that iPS cells are not as much like embryonic stem cells (ES) as first believed. They remain a transformative discovery, especially in disease modeling, but it will require a lot more study before iPS cells are as medically revolutionary as hoped.
iPS cells are adult cells, derived from skin or blood, for example, that have been back-programmed into an embryonic-like state. Induced cells look and act like remarkably like ES cells. They might be able, as an ES cell can, make all the other cells in the body.
The concept is fascinating: Take your own cell, morph it into an iPS cell which in turn can become a heart cell or nerve cell – a very nifty biology trick. Limitless replacement parts, no immune rejection. And of course the ethical bypass is obvious (no embryos, no Dickey Wicker). But according to a closer look by a group led by Joseph Ecker, a molecular geneticist at the Salk Institute, iPS cells have "hotspots" in their gene libraries that are not completely reprogrammed.
In other words, the Ecker paper (Nature) and two others last year from Harvard tell us that mouse iPS cells retain an "epigenetic memory" of the cell type from which they came. If you think of genes as cellular software, this means the iPS cells contain old code that can’t be overwritten and may therefore limit the ability of the new cell to transition cleanly to a new lineage. An ES cell, by contrast, has no code or memory until it is directed toward its fate.
Ecker et al looked at patterns of DNA methylation as a way to map gene exchange across the genomes of four human ES cell lines, five iPS cell lines and the tissues from which they were derived, plus a batch of differentiated cells made from both kinds of stem cells. "If you look with blinders on, they look fairly similar," said Ecker. "But if you zoom in you find different signatures of what an iPS cell is."
It shouldn’t come as a surprise that there are genetic aberrations in iPS cells, considering how their fate is manipulated. There are several ways to create iPS cells but the most common inserts a set of transcription factors into cells to recode them. This sort of thing has been going on since 1987 when scientists forced expression of genes in fruit flies that caused them to grow an additional set of legs instead of antennae. They used the same forced transcription factors to create functional eyes on the legs of flies.
In the much less ghastly iPS work of late, it only takes overexpression of four transcription factors to turn back the clock so certain cells seem new -- embryonic, unfated.
The fact that iPS cells are different than ES cells is not by any means throwing the iPS train off the tracks. Indeed, iPS cells that have a genetic vestige of their original programming might even be better as a therapy: for example, an iPS cell derived from blood might engender better new blood cells.
What’s more, iPS cells remain a critical tool for studying developmental biology. How did we wire up the first time, what are the codes, how do cells lock in to their fate? And importantly, how do cells go haywire and cause cancers? If only a few transcription factors can so dramatically change cell fate to make an iPS cell, might that mean there are simple breaks in the code that cause cancer cells? Scientists note that there are remarkable similarities between tumorigenesis and cellular reprogramming.
Meanwhile, what’s possibly the most exciting thing about iPS cells is the dawning of personalized medicine – therapies might be tailor-made from pluripotent stem cells from specific patients. It’s too still soon for that but for studying disease, iPS looks to be an extraordinary new tool. The metaphor scientists use is that of the flight data recorder: diseased tissues from patient-derived iPS cells permit a replay of the disease process in vitro. Perhaps it will be possible to predict or visualize destructive process. It may also be possible to screen chemical arrays to restore normal function and promote drug development.
That brings us to Fred Gage, a professor in the Salk's Laboratory of Genetics, whose lab is one of the Reeve Foundation’s elite International Research Consortium on Spinal Cord Injury. His lab has been using stem cells to study disease, and that includes spinal cord injury. Take a couple of minutes to see this video
about how iPS cells can help understand what goes wrong.
Last week Gage received a $2.3 million grant from the California Institute for Regenerative Medicine (CIRM) to develop a stem cell based therapy for Parkinson's disease. His group will study iPS cells derived from people with the disease to replicate the disorder in the lab. They will investigate the role of inflammation and nerve degeneration that characterizes the disease. Until now, scientists were limited; they could study Parkinson's disease using imaging technologies or cadaver brain tissues. Now, iPS cells from patient skin cells, reprogrammed into neurons, will offer a model to study the pathology of Parkinson's in a human system. Ultimately, they hope to identify key molecular events in the early stages of the disease, with an eye on therapeutic intervention.
By Sam Maddox