December 08, 2011
Quality Of Induced Pluripotent Stem Cells Increased

Some MIT Whitehead researchers have found thru subtle changes in methods for creating stem cells from adult cells that embryonic-like stem cells can be produced much more reliably.

FINDINGS: Tweaking the levels of factors used during the reprogramming of adult cells into induced pluriopotent stem (iPS) cells can greatly affect the quality of the resulting iPS cells, according to Whitehead Institute researchers. This finding explains at least in part the wide variation in quality and fidelity of iPS cells created through different reprogramming methods.

RELEVANCE: Like embryonic stem cells, iPS cells can become any cell type in the body, a characteristic that could make them well-suited for therapeutic cell transplantation or for creating cell lines to study such diseases as Parkinson's and Alzheimer's. Inconsistencies in iPS cell quality reported in a number of recent studies have tarnished their promise, dampened enthusiasm, and fueled speculation that they may never be used therapeutically.

Mixed results in producing iPS cells led to disappointment and doubt. But small changes resulted in much higher quality outcomes.

To Bryce Carey, first author of the Cell Stem Cell paper and a graduate student in Jaenisch's lab at the time, this death knell seemed premature. He repeated the experiment, changing a few details, including the order in which the reprogramming factors were placed on the inserted piece of DNA. Surprisingly, such small alterations had a profound effect—more adult cells were converted to high-quality iPS cells than in the earlier, nearly identical study.

"We are trying to show that the reprogramming process is not as flawed as some have thought, and that you can isolate these fully pluripotent iPS cells that have all of the developmental potential as embryonic stem cells at a pretty high frequency," says Carey, who is now a postdoctoral associate at Rockefeller University. "A lot of times these parameters are very difficult to control, so while the approach first described by [Shinya] Yamanaka back in 2006 is still the most reliable method for research purposes, we should be cautious in concluding there are inherent limitations. We show recovery of high-quality cells doesn't have to be the exception."

I think this points to a larger problem for scientists attempting to coax cells into states where they will do repairs and to grow into replacement organs. The problem is that cells are extremely sensitive to small differences. My worry here is that the use of stem cells to do repairs on the body may progress very slowly due to the size of the solution space that must be searched to find good solutions. Researchers need to search over wide ranges of variations in sequences of conditions along multiple dimensions in order to find just the right sequence if biochemical manipulations to get cells to do some desired repair.

How hard will it turn out to be to coax cells to, for example, coax cells to become kidney podocytes and then to very precisely fix the glomerulus filtering area in sick kidneys? It is difficult to know at this point how hard it will be to orchestra tissue repair with stem cells or how hard it will be to do tissue engineering to grow replacements for most organs. Do we have another decade to wait for a big surge in usable stem cell therapies? Or even two decades? Hard to tell from where I sit.

Share |      Randall Parker, 2011 December 08 10:50 PM  Biotech Stem Cells

P O said at December 11, 2011 9:13 AM:

It would be really useful in the future if you linked to the primary source in the paper:
That would definitely add value to this blog

Tim said at December 11, 2011 3:23 PM:

Lets see now..first we will use the induced IPS stem cells to repair damaged organs. Hearts, lungs livers etc. Then the next logical step will be growing body tissues & whole new organs from the patients own cells, no rejection problem. Then probably at some point body parts like lost fingers, hands even limbs. The eventually they will decide why keep repairing an ageing body with new parts, just grow a whole new body sans brain and do a brain transplant. But the brain wears out assuming they don't figure out how to download yourself into a new grown brain then what? Remove the brain place it in some kind of nutrient rich oxygenated water bath, feed sensory inputs into the brain so the patient is in some kind of VR heaven. Gradually replace the brains cells themselves slowly over a period of months, maybe years if necessary with new brain cells. Memory is redundant probably personality as well..would you even notice if say 10% of your brain cells were replaced over the course of a year?

amanda said at December 11, 2011 5:31 PM:

I am less skeptical than you are, given your last two paragraphs. My understanding is that a useable stem cell will have enough potency, that is, potential (pleuripotent) to develop into the type of cell needed once introduced into the region. The key stimulus for that development will be the host environment: stimuli from other cells, hormones, immune modulators, etc. This is what will cause the cell to differentiate. The goal is not to create new tissue in vitro, but in vivo. We have already seen great strides with auto-skin grafts, some heart tissue, liver and pancreatic repair, and possibly neural. (apologies for not digging up references) I think Tim is getting a little fantastical thinking that stem cells could provide the "eternal youth." Bodies are an integrated, interactive whole and the aging process is a long, complex chain reaction.

Tim said at December 13, 2011 10:37 PM:
Quoting from this link: "Question: Where will the field of bioengineering be in 2021?
By 2021 there should be thousands if not millions of IPS lines created from individuals. We won't simply be making cardiac cells in a petri dish, but will be actually growing organs such as hearts and livers. We aim to replace organ donors by having patients grow their own organs. Eventually, elderly patients will have their failing organs replaced by younger organs. It is not an exaggeration to say that stem cell technology will utterly transform the field of healthcare within the next several decades." 2021 is not that far off, even if does not happen by then clearly the idea of growing organs from your own IPS cells is not "fantastical"

Randall Parker said at December 14, 2011 8:27 PM:


Right now today we can create as many embryonic stem cell lines some lab animals as we want. No legal barriers. Yet scientists aren't yet growing hearts or kidneys for these animals. The bigger problem isn't how to create the cell lines. The bigger problem is to orchestrate the changing and very complex 3-D biochemical and physical environment that causes a heart or kidney to grow just right. Tissue engineering is hard.

The problem isn't just how to get cells into the right starter state, the right initial epigenetic state. The problem is how to sequence them thru a series of states in 3-D over a period of months and even years to create an adult-sized heart or kidney or other organ that has a complex 3-D structure.

Tim said at December 15, 2011 2:42 PM:

You are correct, I think the idea is to use some sort of scaffolding for the cells to grow around. For what it is worth if you follow the link I posted Cellular Dynamics Vice-President Chris Parker seems confident within a decade we (or at least they) will be making human organs. We shall see..I am north of 50, so the sooner the better.

dlr said at December 19, 2011 8:42 AM:

Dear Mr. Parker, I have to disagree with you on the difficulty of the task, and the size of the solution space that needs to be searched. Amphibians, etc, are already accomplishing the feat of de-differentiating their cells, in the process of re-growing limbs. Researchers could use microarrays to determine which signalling molecules are used, in which order, by the amphibians, and mimic that sequence in the test tube. That's not decades of open ended searching, but a year or two at most of good quality, turn the crank lab work.

After all, to re-grow an entire limb, you have to recreate everything from bone cells to muscle cells to skin cells. That sounds like pluripotent to me.

Here's hoping someone is busily investigating this right now.

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