Induced stem cells can’t replace embryonic ones

Science|Business Senior Editor, Nuala Moran.

It has been suggested that these induced pluripotent stem (iPS) cells offer greater therapeutic promise than embryonic stem cells, since it should be possible to use a patient’s own skin cells to produce iPS cells, and then differentiate these to the required replacement cells, thus avoiding immune rejection.

As yet, no one is suggesting specific cells derived from iPS cells are ready for use in human therapies. But they are proving to be very useful tools for understanding the biology of disease.

Among examples that were discussed at the American Association for the Advancement of Science annual meeting in San Diego this week, Lawrence Goldstein, Director of the Stem Cell Research Programme at the University of California San Diego, described how they are becoming important in research into Alzheimer’s disease.

Since it is not easy to get samples of diseased brain, most current research is carried out in animal models. “The problem is that genetically modified animals only develop some symptoms of the disease,” Goldstein said.

Now he is developing true human models using iPS cells. While most cases of Alzheimer’s are sporadic and have multiple genetic and environmental causes, there is a rare form of the disease that is inherited. Some of the genes involved in these cases are known. Goldstein has produced iPS cell lines from patients with the inherited form of Alzheimer’s and used these to generate brain cells or neurons. “We can then ask the question, do the neurons develop any Alzheimer’s disease phenotypes, knock mutations in and out, and silence particular genes,” Goldstein said.

There have been several technical difficulties to overcome, including a high level of variation in the neurons that are generated. However, Goldstein said neurons derived from iPS cells are now yielding insights into the biochemistry of Alzheimer’s disease.

In another example, Rudy Jaenisch of the Massachusetts Institute of Technology is using iPS cells derived from patients with Parkinson’s disease to derive the dopaminergic neurons that are undermined in this disease.

Jaenisch and others agree that eventually iPS cells will be used in therapies. “They could be customised for the needs of specific patients: that’s what’s so attractive about them,” Jaenisch said.

But this promise lies far in the future, and getting there requires the continued use of existing human embryonic stem cell lines and the derivation of new lines, according to George Daley of the Children’s Hospital at Harvard Medical School. The use of viruses to deliver the genes that reprogramme skin cells to iPS cells, and other complicating factors, raises fundamental questions about how equivalent iPS cells are to their embryonic counterparts.

There is a “complex, emerging sense” that there are practical difficulties, based on a variety of variables, Daley said. Evidence is mounting of consistent differences between the two types of cell, some of which are related to the conditions under which they are derived.

“When you look at the genes expressed in fibroblasts and iPS cells, and compare these to human embryonic stem cells there are differences,” Daley said.

Daley noted also that not all diseases can be modelled in iPS cells. An example is the inherited disorder Fanconi’s anaemia, which is caused by a fault in the DNA repair pathway.

So while iPS cells are very exciting, it is necessary to better define and standardise methods for reprogramming cells, and build a deeper understanding of how the process works. Doing the research will require continued work on human embryonic stem cells.

One of the most critical reasons for this is the need to find out what the “ground state” of pluripotency is in human embryonic stem cells, to provide a reference for showing iPS cells are truly equivalent.

“We still need to define what is a good human embryonic stem cell line,” Jaenisch agreed. The 1,000 or so human embryonic stem lines world-wide were generated under different conditions. This early handling can have an influence many years later. “Where you went to school influences you for life,” Jaenisch said.

And so, in short, iPS cells may represent an alternative to human embryonic stem cells that is ethically more acceptable and clinically more valuable. But far more research is needed, and human embryonic stem cells are a crucial element of that. As Daley put it, “You can’t say ignore all these issues as long as we can make a liver cell: we don’t understand enough to make it safe.”