Adult stem cell research hits a snag

Reprogrammed stem cells on Dipity.

Babies can be anything when they grow up, but it's a lot harder for a 45-year-old accountant to start a new life as a firefighter. Likewise, embryonic stem cells can become any kind of cell in the human body, but it's another thing entirely to force a specialized adult cell out of its comfort zone. For instance, scientists can strip an adult blood cell of its programming, and make it act like a stem cell again. But the results aren't perfect. And, now, it looks like these "induced pluripotent stem cells" (or iPSCs) are even more flawed than researchers previously realized. Science blogger extraordinaire Ed Yong explains:

The history of iPSCs is written in molecular marks that annotate its DNA. These 'epigenetic' changes can alter the way a gene behaves even though its underlying DNA sequence is still the same. They are like Post-It notes - you can stick them to a book to point out parts to read or ignore, without editing the underlying text. Epigenetic marks separate different types of cells from one another, influencing which genes are switched on and which are switched off. And according to Kim, they're not easy to remove, even when the cell has apparently been reprogrammed into a stem-like state.

He focused on one such marker - the presence of methyl groups on DNA, which typically serve to switch off genes. They're like Post-it notes that say "Ignore this". Kim found that iPSCs have very different methylation patterns depending on the cells they came from. Those that come from brain or connective cells have methyl groups at genes that are necessary for making blood cells, and vice versa. The iPSCs even have distinctive methyl marks if they come from slightly different lineages of blood cells.

Now, Ryan Lister and Mattia Pelizzola from The Salk Institute have found the same reprogramming errors in human iPSCs, and to a much greater extent than even Kim had suspected.

At first, the iPSCs seemed to have a spread of methyl marks that looked superficially similar to those of embryonic cells. But when Lister and Pelizzola looked more closely, the cracks started to appear in this tidy picture. The duo found plenty of hotspots around the iPSC genomes that were unusually ridden with methyl marks. None of these marks existed in true embryonic stem cells, and some sat in places that could switch off important genes.

That's a problem. There might be ways around it, Ed says. And there are other ways to turn adult cells into stem cells. Trouble is, none of those technologies are as well-developed, and they're more likely to spark ethical debates. If we're going to be able to use stem cells in a really productive, wide-spread way, this is a big hurdle that will have to be cleared.

Why didn't we know this earlier? Because the path of research is long, winding, and bumpy. To get an idea of what it took to get to this point, check out the awesome interactive timeline Ed made to accompany this story.

Not Exactly Rocket Science: Reprogrammed stem cells are loaded with errors

• [Anonymous]

  I am confused – I thought there was a fair number of true stem cells – unprogrammed, floating around in blood or bone marrow. Is that not true? Why do they have to reprogram differentiated cells to create new stem cells?

• [WileyDogg]

  There is ongoing research using adult stem cells. One company, Aangstrom Biosciences (ASTM), is in the process of FDA approval for a process that extracts bone marrow, generates stem cells, grows the population of stem cells and then injects them back into the donor patient for specific medical issues. http://www.aastrom.com/technology.cfm — disclaimer, I own a small (less than $1,000 worth) amount of stock in this company

• [Ardreeves]

  Just a quick refresher on stem cells… All organs of the body have stem cells. “Stem cell” simply refers to the fact that it is capable of turning into one or more other types of cells as well a create another copy of itself. There are stem cells in the skin that can turn into the different layers of skin, there are stem cells in the blood that can turn into various types of blood cells, and there are stem cells in the stroma of the bone marrow that can turn into a whole lot of different tissue types. Those are adult stem cells and they are multipotent.

  Embryonic stem cells, as the name implies, are pluripotent and can turn into all cell types of the adult including all the various types of adult stem cells.

  Anyway, a question I have is how much do the differing epigenetic states of DNA matter in iPS cells versus ESCs? After all, mouse iPS cells are capable of generating a completely new mouse that is itself capable of reproducing. I don’t think experiments carrying out long term breeding from iPS generated mice has been done, but I have a feeling that these cells are, or can be, essentially equivalent to ESCs in their potential, even if their DNA methylation status is slightly different in culture.

  Only time will tell I guess, but it’s an exciting field of study!

• [glaborous immolate]

  That’s too bad. Guess we’ll have to go back to sticking fetuses in blenders

  • [benher]

    I can’t believe you! I was about to post the exact same thing to the letter! Now I have been robbed forever of my commenting glory!!! Although, I was going to say “cuisinart.”

  • [Brainspore]

    I’m pretty sure that was a joke but just in case anybody out there is still under the surprisingly common misconception:

    Embryonic stem cell research does not involve fetuses. Embryos aren’t the developing babies that grace the graphic picket signs of anti-abortion protesters, they are undifferentiated balls of cells which have yet to develop into distinct body parts. That’s precisely what makes them valuable for this research.

• [Anonymous]

  I thought recent research was showing transcription was full of ‘errors’ – far more than thought.

  http://www.sciencenews.org/view/generic/id/65063/title/Central_dogma_of_genetics_maybe_not_so_central

• [Mad King George]

  I’m surprised there’s no mention of the October, 2010 Wired article on extracting stem cells from adult adipose tissue.

  http://www.wired.com/magazine/2010/10/ff_futureofbreasts/

• [Anonymous]

  Or as Dr. Eldon Tyrell so eloquently put it:

  “The facts of life… to make an alteration in the evolvement of an organic life system is fatal. A coding sequence cannot be revised once it’s been established.”

• [Anonymous]

  The most important point, in my opinion, it that these embryos come from in vitro fertilization. IVF produces zygotes (fertilized female ‘eggs’) and not all zygotes are implanted. The zygotes that are NOT implanted are disposed of. Embryonic stem cell lines all came from what amounts to medical waste. Scientists take this tissue OUT OF THE TRASH and do research on it.

  Tell this to EVERYONE who thinks that babies are killed to research embryonic stem cells. Embryonic stem cells are cells that would be thrown away anyway. Why not conduct research?

  • [glaborous immolate]

    Some think that the generation and discarding of embryonic humans in IVF is the first immoral step that then continues with using them for medical research. And while the USA may allow the generation and discarding of them, it doesn’t, generally pay for it with tax money (nor is it covered by all insurances. Cali and NY prohibit insurance from covering IVF, interestingly).

    There are even institutions which seek to adopt the frozen embryonic humans rather than allow them to be put in the trash.

    http://www.slate.com/id/2119845/

• [Pablito]

  I wrote an essay years ago about stem cell research.

  I was amazed to discover a major ethical problem regarding embryonic stem cell research that had never (AFAIK) been reported in the mainstream media: the source of ova to produce the embryo.

  As someone mentioned earlier, they often come from discarded zygotes from IVF treatments. But it is not as simple as that.

  To farm ova, the woman is given large amounts of hormones in order to overproduce eggs. This can actually be very dangerous as there is a risk that the woman’s ovaries can increase in size causing internal bleeding, or (from memory) actually burst. The figures for women who die from this complication are hard to collate, because the cause of death is often labelled internal haemorrhaging.

  The more eggs that are farmed, the more dangers there are (including, again from memory, cysts on the ovaries). In the UK, women undergoing IVF treatment could sell their unused zygotes to mitigate the cost (NHS does not, or only partly, covers IVF). The more they sell, the less their treatment costs, the more dangerous it is to them. All of this with questionable informed consent on the part of the woman as the dangers are not properly understood/known/explained by the doctors involved.

  In South Korea, women not undergoing IVF were being paid outright for their eggs to be farmed.

  So, particularly vulnerable women (read poor and/or desperate to reproduce) are being enticed to undergo dangerous hormone treatment for money. The actual research (unbelievably) into the dangers of such high amounts of hormone treatment on women is incredibly thin.

  How often do we hear about these issues?

  • [Anonymous]

    I was under the impression that women normally chose to and paid to receive hormone therapy in an attempt to become pregnant. Certainly if the NHS does not cover the cost of IVF then a British woman had better have a significant amount of money to choose that option over, say, adoption.

    The rest of your argument seems like a pretty solid case of [citation needed]. If the mainstream media wasn’t reporting these issues, where did you get your information? Possibly from a source with a stake in the issue (e.g. a biased one)? Please substantiate those claims. I would love to be more informed about this issue, but I don’t believe random posters on web boards who just say “trust me”.

• [Anonymous]

  http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016816