Pharyngula

Stem cell breakthrough

Blogging on Peer-Reviewed Research

A recent discovery in stem cell research is no minor event: researchers have figured out how to reprogram adult cells into a state that is nearly indistinguishable from that of embryonic, pluripotent stem cells. This is huge news that promises to accelerate the pace of research in the field.

The problem has always been that cells exist in distinct states. A skin cell, for instance, has one set of genes essential for its specific function activated, and other sets of genes turned off; an egg cell has different patterns of gene activation and inactivation. Just taking the DNA from a skin cell and inserting it into the egg cell isn’t necessarily going to create a functional egg cell, because genes essential for egg cells may be switched off in the skin cell DNA, and we don’t know how to specifically switch them on. The process of somatic cell nuclear transfer has been hit or miss for that reason, with very high failure rates—scientists are basically trying to make the right configuration of genes switch on by giving the nucleus a good hard kick, and hoping that something in the cells will reconfigure the pattern of gene activation into something appropriate.

What the discovery by Takahashi et al. accomplishes is to reveal how to specifically switch on the right pattern of genes for a pluripotent stem cell. They have discovered the reset button for mammalian cells: a simple trigger that puts the cells in the right state to become anything else.

This reset button consists of four genes: Oct3/4, Sox2, Klf4, and c-Myc, together with maintenance of a specific extracellular environment. These genes are transcription factors, genes that regulate the expression of other genes, and they were suspected of being important because, among other things, they are differentially expressed in normal embryonic stem cells, something that wouldn’t be known if people hadn’t been doing research on embryonic stem cells. The c-Myc and Klf4 genes are thought to modify chromatin, changing patterns of DNA methylation and histone modifications, enabling Oct3/4 and Sox2 to slip in and bind to specific gene targets. These few genes acting in concert then trigger a whole series of downstream genetic events that switch the cell to the pluripotent state.

The results have been tested in several ways. A similar procedure in mice has been used to create whole mouse embryos that then go on to develop into adults, demonstrating totipotency. The human induced pluripotent stem cells have been subjected to a whole battery of assays that show gene expression similar to that of true embryonic stem cells. And colonies of these human induced stem cells have been injected into mice, where they form tumors — teratomas that differentiate into an array of different tissue types (but poorly organized—they do not form small human babies inside the mice, but only scattered bits). Gut, muscle, skin, cartilage, fat, and nervous tissue all form, as shown in the image below, demonstrating the pluripotency of these stem cells.

i-82e0860a723c97274f923529788981d0-teratoma.jpg
(click for larger image)

Hematoxylin and eosin staining of teratoma
derived from iPS cells (clone 201B7). Cells
were transplanted subcutaneously into four
parts of a SCID mouse. A tumor developed
from one injection site.

There is a catch. The way the four genes were activated in these cells is effective, but lacks a little finesse: constructs containing the genes with promoters we can control were inserted by retroviral transfection into the target cells. There are problems with this technique. Where the genes get inserted is random, and has the potential to create new mutations. In addition, they aren’t regulated in quite the same way as the normal genes are — this leaves the cells wide open for aberrant expression. The mice made from induced stem cells, for instance, are highly prone to cancer.

What the investigators have accomplished is to discover the reset button for the cell, but the way they currently press it is by hitting it hard with a ball peen hammer.

This is good enough for a start, and they’ve shown that these four genes do the necessary job, but eventually we’ll want to find a more elegant way of activating them. Rather than inserting extra copies of the genes, for instance, we’d like to find a way to turn on the signaling cascades that will activate the natural copies present in the genome; some combination of extracellular factors and injected small molecules that do the same job of putting the cell in the ES state.

This discovery is probably going to become a political football in short order, with the far right politicians who have restricted American research into embryonic stem cells claiming vindication. However, let’s point out some realities here. Americans did not make this discovery; Japanese researchers did. It required understanding of gene expression in embryonic stem cells, an understanding that was hampered in our country. It’s going to require much more confirmation and comparison between the induced pluripotent stem cells and embryonic stem cells as part of the process of making this technique useful — science doesn’t take just one result from a few labs and accept it as gospel truth. And we definitely need to figure out better ways of switching the four genes on. Figuring that out will require more research into how organisms switch cells into the ES state in situ &mdash we can’t figure that out from these cells with inserted, artificial gene constructs.

Another essential point is that scientists are excited about this work because it opens up avenues for basic research into development and differentiation. These cells are NOT useable for therapies…the immediate, practical applications that the electorate wants from stem cell research. They also cannot be used for reproductive cloning, although that won’t trouble most people. These are cells with retroviral infections, potential unknown mutations, and that have genetic modifications that make them prone to collapse into cancers. We are not going to be able to grow new organs and tissues for human beings from a few skin cells using this particular technique. It’s going to take more work on embryonic stem cells to figure out how to take any cell from your body, and cleanly and elegantly switch it to a stem cell state that can be molded into any organ you need. What this work says is that yes, we’ll be able to do that, it isn’t going to be that difficult, and that we ought to be supporting more stem cell research right now so we can work out the details.

Or we can just sit back and let the Japanese and Europeans and Koreans do it for us, which is OK, I suppose. Just keep in mind that ceding the research to others means giving them a head start on the development of all the subsequent breakthroughs, too, and that what we’re doing is willingly consigning US research in one of the most promising biomedical research fields ever to an also-ran, secondary status.


Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 131(4):1-12.

Comments

  1. #1 zer0
    November 21, 2007

    This is the most incredible thing I have ever read.

  2. #2 Engr Tony
    November 21, 2007

    Thank you, PZ, for the detailed post. Unfortunately, the news outlets that I read that initially wrote about this story were poorly lacking in details. I also expect the religious fanatics to latch on to this story and try to use it as a tool to limit federal funding of hESC research.

  3. #3 Kseniya
    November 21, 2007

    Yeah, this is interesting; I read about this in this morning’s NYT. One thing:

    the new method includes potentially risky steps, like introducing a cancer gene.

    Given the nature of the terrible infectious cancer afflicting Tasmanian Devils, do you think this technology runs any risk of inadvertently producing a pathogen that presents a similar danger to humans?

    (Aside: It’s fascinating to consider that the emergence of DFTD may be a speciation event.)

    Off-topic, but another headline in today’s Times that may be of interest:

    Polygamist Sentenced to 10 Years in Prison : Warren S. Jeffs was sentenced Tuesday to 10 years to life in prison for forcing a 14-year-old girl to “spiritually” marry her 19-year-old cousin and submit to sexual relations against her will.

  4. #4 Norman Doering
    November 21, 2007

    PZ wrote:

    This discovery is probably going to become a political football in short order, with the far right politicians who have restricted American research into embryonic stem cells claiming vindication.

    So, I guess we keep track of whatever simplistic lies they come up with and keep reminding them that:

    1) This isn’t yet ready to replace embryonic stem cell research.

    2) We wouldn’t know how to do this trick if we hadn’t done research on embryonic cells.

  5. #5 Cuttlefish
    November 21, 2007

    My son has diabetes;
    Diagnosed a year ago.
    There’s hope, within his lifetime,
    Pancreatic cells will grow!

    I know that this is early,
    They might not–but then, they might;
    There’s cause for celebration
    For the Cuttlefish tonight!

  6. #6 Shaggy Maniac
    November 21, 2007

    This really is exciting stuff. One can’t emphasize enough how important work with embryonic stem cells was in leading to this breakthrough and how important it will continue to be as this work proceeds and is refined.

  7. #7 Johnny Vector
    November 21, 2007

    Best. Cuttlefish. Poem. EVAR!

  8. #8 PZ Myers
    November 21, 2007

    It’s not a cancer gene. There are no cancer genes. There are genes that prevent cancer, and when broken, allow cancers to grow; there are also genes that promote a general proliferative state that are essential for normal development and that are coopted by cancers. c-Myc is one of the latter.

    Calling it a “cancer gene” is just a kind of scare tactic. Any process that encourages the formation of a pluripotent, proliferative cell has the potential to lead to cancer. What we need is a mechanism to enter that state that does not override the normal checks against cancer that a cell has — the Takahashi method is risky precisely because it removes the normal regulation of certain genes.

  9. #9 zer0
    November 21, 2007

    Cuttlefish, I share your optimism, and I love your Poem. On another note, why don’t Cuttlefish and Kseniya ever post as OM’s? Be proud of your orderism!

  10. #10 Nathaniel
    November 21, 2007

    This actually is really cool. It would also suggest that if we can figure out some way of creating stem cells inside the body that we could heal any wounds, repair nerve damage, create new blood vessels and pretty much anything we want simply by injecting some of these chemicals to modify nearby cells into being stem cells which would then run around and fill in gaps. Just imagine what this could do for longevity.

    The only way the retro-viral thing would work would be if the genes where inserted at specific locations, they didn’t cause crazy mutations, the virus died off (leaving the genes) and they cell could still properly regulate them… but good luck with that!

  11. #11 Colugo
    November 21, 2007

    Many across the political spectrum are prematurely proclaiming this as the end of the stem cell wars. They’re wrong. Some pundits, however, understand that the issue has not been settled.

    Ramesh Ponnuru, anti-ESC research conservative, National Review’s The Corner:

    “the political debate over whether the federal government should fund certain forms of embryo-destructive research or allow certain other forms of it would not be over under certain conditions. If, for example, these people believe that embryo-destructive research (or certain forms of it) still have advantages that the new research methods don’t have, or that it is still important to encourage research of all types, then the debate isn’t over, although it will change”

    Brandon Keim, Wired, 11/2/07:
    http://blog.wired.com/wiredscience/2007/11/too-soon-to-giv.html

    “Lanza noted that gene expression in the new stem cells wasn’t equivalent to that in embryonic cells. Even ESCs, he said, “all have personalities. Some can do certain tricks better than others. There’s no reason to believe it’s going to be any different with these.”

    It’s quite possible, then, that the new cells will end up being useful in many ways, but embryonic stem cells — not to mention various types of adult stem cells — will still be required … If research funding suddenly dries up for everything except de-differentiation, those cures will never arise.”

    I have followed this issue for a long time and been dismayed by embryonic stem cell research advocates dismissing adult stem cell research and anti-ESC activists dismissing ESC research, as if it were a zero sum game (politically, I suppose it is). The overhype on both sides is also unedifying. This new technique is a big advance. But it does not herald the end of the political conflict, just a new stage.

  12. #12 Kseniya
    November 21, 2007

    Thanks, Dr. Myers, I understand now.

    I hesitate to accuse the Times of intentionally employing a “scare tactic” in this case, but I agree that it can have that effect on uninformed readers such as myself. Perhaps it’s just sloppy reporting and lack of scientific expertise on the editorial staff. Still, there’s an important difference between the report and the facts – and what’s in the article qualifies as misinformation. (Surely the necessary expertise was available? Why, I believe we have some right here!)

    C-Fish: I have some friends who have diabetes. Two of them ages 16 and 11. The mother of the 16 year old believes it will be cured in her daughter’s lifetime. I hope she’s right. Onward and upward!

  13. #13 Kseniya... (OM)
    November 21, 2007

    Be proud of your orderism!

    Thanks, zer0 – and I am. The sad and silly truth is, I feel self-conscious about adding it because I feel unworthy.

  14. #14 Valhar2000
    November 21, 2007

    #4:

    You got the second one wrong. As PZ said, the Japanese were able to do this because they have been doing research on embryonic stem cells. American researches, whose ability to research with embryonic cells is much reduced, have not been able to do this.

  15. #15 JFlav
    November 21, 2007

    This discovery is probably going to become a political football in short order, with the far right politicians who have restricted American research into embryonic stem cells claiming vindication.

    They’re already ahead of you. From the NYT article:

    The White House said that Mr. Bush was “very pleased” about the new findings, adding that “By avoiding techniques that destroy life, while vigorously supporting alternative approaches, President Bush is encouraging scientific advancement within ethical boundaries.”

    Also, you say,

    Americans did not make this discovery; Japanese researchers did.

    However, from ScienceNOW:

    Two groups report today that they have reprogrammed human skin cells into so-called induced pluripotent cells (iPCs). In a paper published online in Cell, Yamanaka and his colleagues show that their mouse technique works with human cells as well. And in a paper published online in Science, James Thomson of the University of Wisconsin, Madison, and his colleagues report success in reprogramming human cells, again by inserting just four genes, two of which are different from those Yamanaka uses.

    So America isn’t that far behind.

  16. #16 colin
    November 21, 2007

    Thank you so much PZ for explaining this fully and in plan terms. I’ve been searching for any articles that discuss the details and pluses and minuses; and all I’ve found is hyperbole and blather about how the “culture wars about stem cells are over.” I knew in my gut that this wasn’t the case and that we still need embryonic stem cells but I couldn’t find any info on it.

  17. #17 cbone
    November 21, 2007

    #14:

    Actually you are wrong too. It wasn’t just the Japanese. Dr. James A. Thompson, from the University of Wisconsin simultaneously published similar results as the Japanese researchers. He also has a slightly different take on the impact:

    “The induced cells do all the things embryonic stem cells do,” said James Thompson, the leader of one of the teams and the University of Wisconsin researcher who first coaxed stem cells from human embryos. “It’s going to completely change the field. These cells are more clinically relevant than embryonic stem cells.”

  18. #18 Nathaniel
    November 21, 2007

    Thanks for the synopsis-for-non-biologigsts, PZ.

    One thing struck me here, though:
    “A similar procedure in mice has been used to create whole mouse embryos that then go on to develop into adults, demonstrating totipotency.”

    You go on to say this technique is no good for cloning; I’m confused because I would have thought these to be the same thing.

    In any case: this technique or it’s eventual non-ball-peen successor will be able to take some of my skin cells and turn them totipotent. Doesn’t this mean that, by Crazy Christian standards, we now have a new life? This new cell could conceivably be implanted in a uterus and grown into an adult? (Perhaps not; being pluripotent doesn’t mean it’s an egg, I guess.)

    But again, if so.. then the CCs basically would be forced to outlaw ANY stem cell research.. because as soon as you made it, it was potential life!

    Of course, this assumes logic.

    Never mind.

  19. #19 cbone
    November 21, 2007

    One other comment. Thompson’s group did not use the c-Myc gene that the Japanese did. What does it mean? Only that you can achieve pluripotent cells without that particular gene, it doesn’t mean that you won’t have problems with the ones you are using.

  20. #20 Norman Doering
    November 21, 2007

    Valhar2000 wrote:

    You got the second one wrong. As PZ said, the Japanese were able to do this because they have been doing research on embryonic stem cells. American researches, whose ability to research with embryonic cells is much reduced, have not been able to do this.

    Huh? Are you saying that American researchers could have done this without knowing “the reset button for mammalian cells,” the button that consists of four genes: Oct3/4, Sox2, Klf4, and c-Myc, together with maintenance of a specific extracellular environment?

    Are you saying that American researchers did not need to know these transcription factors that regulate the expression of other genes? Are you saying American researchers could know this if people hadn’t been doing research on embryonic stem cells?

    Are you one of the creationist liars I should be warning people about?

    Or, are you saying that American researchers haven’t done something?

    Please explain.

  21. #21 cbone
    November 21, 2007

    Re: 17

    I think you will still have some nutters who will never accept anything with the words ‘stem cell’ attached. The Vatican, one of the most vocal opponents of ESC research, has indicated that they have no objections to the new procedure. To me that signals optimism that the opposition to the research will diminish.

    My political advice, to those who support ESC, would be to lay low and let the research with the new stem cells continue. Let them make some advances and publish some results and get people equating ‘stem cell research’ with this new procedure. Then, quietly bring back the ESC research that still merits further study. let the issue die politically and then continue on with the research.

  22. #22 Galbinus_Caeli
    November 21, 2007

    Am I mixing things up here? Does this technique reset the ENTIRE cell to pluripotency? Or simply the nucleus, which must then be inserted into a viable egg cell from the same species (human in this case)? If the latter, then this is not going to do a lot of good, as human egg cells are not available in great supply.

  23. #23 SabrinaW
    November 21, 2007

    Thank you for the clarification, PZ. I have been avoiding weighing in on this because my Skeptic-Sense was going off in response to claims that this will end the ESC debate, and you’ve confirmed it. While we humans are brilliant at strongarming Nature into doing what we want, we’re not so great at coaxing Nature in ways that don’t end up backfiring (in this case, by overriding cancer-prevention mechanisms).

    I think that Biologists and Bioethicists have a duty to actively engage the public and the media on this story to help dispel misunderstandings and to provide more accurate context for this discovery. I’m also taking bets now from anyone who thinks this will actually end the jibberings from the Religious Radicals.

  24. #24 PZ Myers
    November 21, 2007

    It resets the nucleus. If you want to do reproductive cloning, you’d still need a stock of enucleated human egg cells for SCNT. For therapeutic cloning, you don’t need to start with an ovum.

  25. #25 FrumiousBandersnark
    November 21, 2007

    Thank you for the information, PZ. This provided a lot more information than has been reported in the mainstream news. The points I’m taking away are as follows:

    1. The cells produced by this technique cannot as yet be used for any therapies or treatments for diseases.

    2. The discovery of how to create stem cells from skin cells came about directly as a result of embryonic stem cell research.

    3. The discovery came from Japan, where embryonic stem cell research is not hampered by religious ideology.

  26. #26 Norman Doering
    November 21, 2007

    Valhar2000, try reading my “we” in #4 as the worldwide scientific community, not just American researchers.

    Again, did Dr. James A. Thompson not do something that the Japanese did?

  27. #27 PZ Myers
    November 21, 2007

    Thomson is right — these cells have the potential for greater therapeutic impact than embryonic stem cells. I don’t have any embryonic stem cells with my genotype on hand anymore, but I do have all these spare somatic cells…it sure would be nice to be able to transform them into useful pluripotent stem cells. Maybe someday someone will be able to take a few flakes of skin from me, grow them in a vat into a heart, and I’ll finally be able to get this black, shriveled thing lying in my chest replaced.

    My point still stands, though: this particular technique won’t do it. We need the development of new methods of activating pluripotency.

    I didn’t mention Thomson here because I haven’t seen his latest paper yet.

  28. #28 apalazzo
    November 21, 2007

    PZ,

    A couple of things I would like to clarify from your post and the comments. 1) The work that led Yamanaka’s group to the 4 gene protocol had been tried by many labs around the world (I know this first hand). Yamanaka just got the answer first. 2) the Thomson (note no “p” in Thomson) group used a similar gene selection strategy and came up with a 4 gene recipe: 2 similar genes (oct3/4 sox2) and two different genes (Nanog and lin28). Interestingly the proto-oncogenes myc and klf4 are not essential. 3) what is banned is NIH money towards human embyonic stem cell research. This is bad. But most of our knowledge comes from mouse stem cells. And as anyone who understands evolution should know, what applies to mouse, applies to humans.

    4) What the religious right doesn’t realize, is that IPS cells in fact explode a myth that they hold on to dearly: conception is required to make a “soul”. Because of this research we know that activating 4 genes can basically transform any old cell into an IPS cell that can go on to regenerate an entire organism. All this argumentation about “destroying life (i.e. a soul) is purely bunk!

  29. #29 kellbelle1020
    November 21, 2007

    “But again, if so.. then the CCs basically would be forced to outlaw ANY stem cell research.. because as soon as you made it, it was potential life!”

    Next thing you know, they’ll be introducing laws to give full human rights to any shed skin cells. It’s a slippery slope, I tell ya! ๐Ÿ˜‰

  30. #30 MarkH
    November 21, 2007

    I addressed Thomson’s technique over at denialism, but it was largely the same. He repeated the screening process and found Nanog and Lin28 worked with Sox and Oct, that is all. We also discussed some possible improvements to the technology, but my writing sadly lacks such wonderful tidbits like ball peen hammers. I must endeavor to improve this in the future.

    I’m more disturbed that the anti-ESC people (so long dedicated to crapping all over ESC research) are now rejoicing that we have an ESC-like cell. It’s like admitting they’ve been lying all this time, yet now they yell victory. And the precedent, that the religious dogma of ensoulment, could be used to federally restrict research is absolutely terrible.

    I’m still happy that we’ve found these cells though and I look forward to studying them in the future. This process, if it can be refined, will be far more ideal than SCNT ever would be. But it’s a mistake to think that these came about because of ESC restrictions. This has been a hot field of study ever since SCNT was discovered. Like you say, it’s been a hunt for the mystical reset button, which was interesting with or without ESCR.

    I have a lot of hope for treatment of hematologic problems, if it’s possible to make hematpoietic stem cells from these things then goodbye bone-marrow transplantation problems. Diabetes could go down in short order too.

  31. #31 Colugo
    November 21, 2007

    The sin of Onan, updated for the 21st Century: spilling his somatic cells on the ground.

    Every somatic cell is sacred, every somatic cell is great, if a cell is wasted, God gets quite irate.

  32. #32 arcturus
    November 21, 2007

    Go figure, your Mr. Bush is claiming victory on this. He says that his moral high ground has pushed towards this development.

    The irony … Judeo-Christian science in action.

    http://www.nytimes.com/2007/11/20/science/20tier.html

  33. #33 Scott Hatfield, OM
    November 21, 2007

    I think it worth noting that Dr. Thompson is one of the pioneers in the use of embryonic stem cells (ESC), and he has suffered a bit from this. His name has been one of those dragged through the mud by Catholic bishops and Congressmen alike during photo ops and other dog-and-pony shows by those who object (or at least wish to appear opposed to) ESC. Thompson, perhaps, has greater cause than many to be relieved that, for example, an early polling of bishops and politicians greet this particularly breakthrough as morally defensible.

    Having said that, I think Norm Doering’s summation is on-target: we wouldn’t have this breakthrough if it wasn’t for work on ESC, and additional work on ESC is going to be required in order for this breakthrough to lead to therapeutic applications. Relying upon viral infection to establish pluripotency won’t do.

    (Also, if we are honest we have to admit that ESC work is likely to continue as long as it remains a potential avenue to human reproductive cloning. The scientific community as a whole is formally opposed to same, but we all know that horse has already left the barn. Once it becomes feasible, there will be people who will have the means and the will to make it happen, and ESC work will almost certainly be involved. So we definitely haven’t heard the last word on ESC as a moral dilemma.)

  34. #34 Norman Doering
    November 21, 2007

    Valhar2000 wrote:

    American researches, whose ability to research with embryonic cells is much reduced, ….

    Let’s not go too far in saying American research has been “reduced.” Several states have funded embryonic stem cell research to take up the slack created by Bush. You don’t want the Bush supporters taking credit for American research that will come out of California’s end run around Bush’s restrictions.

    Here’s the DI view:
    http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/11-20-2007/0004708997&EDATE=

  35. #35 Kevin
    November 21, 2007

    Are there other differences in these cells when compared to embryonic stem cells that might make them better or worse candidates for therapy? I recall a SciAM Frontiers episode that discussed the need for longer telemeres for youth, is that a factor?

  36. #36 Jesse
    November 21, 2007

    Apalazzo, very well put. I’ll also add that, as with most novel therapeutics- including RNA interference- delivery and methodology remain problematic.

    Using 4 different viruses is just asking, BEGGING, for insertion into an oncogene. I also wonder about how these genes are subsequently shut off. I would imagine that epigenetics and imprinting are the best way to permanently shut them off. Reactivating c-Myc later on could be very, very problematic. Just imagine new pancreatic Beta cells subsequently becoming neoplastic. Not good.

  37. #37 Umilik
    November 21, 2007

    How fast we forget. Or didn’t anyone pay attention back in July ?

    Nature. 2007 Jul 19;448(7151):318-24. Epub 2007 Jun 6. Links

    In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.

    Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch

  38. #38 Kris Verburgh
    November 21, 2007

    Great article, mister Myers. Thanks!

  39. #39 Jesse
    November 21, 2007

    Dammit, People!!!

    The man’s name is Thomson! NOT Thompsen or Thompson.

    Umilik: Jaenisch’s work (your citation) was in mouse cells. Yamanaka also had a paper in Cell reprogramming mouse tail fibroblasts with the same quartet of genes as he used for human cells.

  40. #40 apalazzo
    November 21, 2007

    @37

    Yes we know … some of us have been blogging about this for a while, and these two papers are the latest in a long series that started back in 2006 with the first paper by the Yamanaka group. See my recent post at The Daily Transcript.

  41. #41 Umilik
    November 21, 2007

    # 39, I am aware of this. But I would argue that these older papers were more important because they proved the principle that cells could become reprogrammed. And since c-myc, Klf4, Oct-3/4 and c-myc are expressed in murine and human stem cells, it seemed a fairly reasonable expectation that this would work in human cells as well. So to me the mouse papers really are what stood out…

  42. #42 Olorin
    November 21, 2007

    After reading this morning’s Minneapolis Star-Tribune articles on how this development will kill the need for embryonic stem cells, I wrote the following letter to the editor:

    ============
    “The recent stem-cell breakthrough must not lessen efforts to allow research on embryonic stem cells. Embryonic cells are like the front door of a house. You can still get into the house without using the door, but you have to put up a ladder, try to find a second-story window you can pry open, then lug the groceries downstairs. The recent success means we have found a window we think we can jimmy. But it will take a long time to carry the groceries to the kitchen, even if they will fit through the window.

    “In the first place, today’s breakthrough would not even have been possible without previous research on embryonic cells. Second, to make the new technique succeed, we still need embryonic cells for comparison and guidance. Third, embryonic cells promise practical applications sooner than any other technique. Fourth, embryonic cells may well point the way to other breakthroughs such as this one.

    “Embryonic stem cells are still the front door to stem-cell research. We should not let this door remain locked.”

    MIKE ANGLIN, Apple Valley
    ================

    It was a shot from the hip in order to get it in soon. After the last letter I wrote (castigating ID), I got a threatening letter with a return address of “Jesus.” We’ll see.

  43. #43 Ritchie Annand
    November 21, 2007

    I think these are just the cells themselves. The nuclear transfer was just one attempted technique to ‘reset’ the nucleus.

    Apart from that, I don’t know whether enucleated eggs actually have to be from the same species. I believe the chemical gradients are the same, and mitochondria are pretty standard across vertebrates.

    Though it would be pretty odd to one day redo the National Geographic Deep Ancestry project and have someone’s mitochondria come up “rabbit” ๐Ÿ™‚

    Here’s an article on making human embryonic stem cells with rabbit eggs. It’s not by nuclear transfer alone, but with cell fusion. A pertinent quote:

    Another objection from some experts is that the rabbit mitochondria left in the enucleated oocyte would not support the growth and development of ‘human’ derived embryonic cells. However, since whole human fibroblasts (including their mitochondria) were fused with the rabbit oocyte cytoplasm, it is reasonable to assume that there would not be any problem due to the interspecies mix of mitochondria. Both types of energy producing organelles might grow in the initial stages, but be overtaken by the human derived later during development.

    The cells had been dividing for 26 generations at the time of publication, too, from the sounds of it. Are the human mitochondria necessary? Who knows?

    Rabbit eggs are certainly more plentiful than human eggs, though, so this kind of research helps.

  44. #44 Fatboy
    November 21, 2007

    Due to my ignorance on this topic, I’m a little confused – could someone clarify this for me, please? In the post, PZ stated:

    A similar procedure in mice has been used to create whole mouse embryos that then go on to develop into adults, demonstrating totipotency.

    But later, in the comments, he stated:

    If you want to do reproductive cloning, you’d still need a stock of enucleated human egg cells for SCNT.

    Am I missing something? The first quote would seem to indicate that these stem cells could go on to develop into adult organisms, without having to do a SCNT, as have several of the comments. Can someone please clarify for me if these cells can indeed develop into adults?

    I understand about how the current technique would produce organisms with a higher risk of cancer, but if these cells truly can go on to develop into adults, I’d have to agree with comments #18 & #28, and wonder how people could support this over ES cell recearch.

  45. #45 apalazzo
    November 21, 2007

    @41

    since c-myc, Klf4, Oct-3/4 and c-myc are expressed in murine and human stem cells, it seemed a fairly reasonable expectation that this would work in human cells as well. So to me the mouse papers really are what stood out

    I agree 100% Yamanaka’s first paper was the breakthrough and the second Yamanaka paper (+ the Jaenisch paper) were the validation. This paper just shows that you can extend these results to human cells.

    @44

    This technique does not use enucleated oocytes. All you need is a skin cell – that’s it.

  46. #46 PZ Myers
    November 21, 2007

    SCNT is Somatic Cell Nuclear Transfer — you take a skin cell nucleus, for instance, and put it in an enucleated egg. This was done with the mouse experiments. You could use this procedure to improve the likelihood of success with human SCNT, but you’d need an egg cell, and the resulting child, like the mouse embryos, would be highly prone to cancers. No one wants to clone themselves to have their new clone die a horrible death from cancer.

    Right now, you should NOT support this over ES cell research. This is an alternative avenue with tremendous amounts of promise. Maybe 10 or 20 years from now, it will make ES cell research superfluous, but by the time it does that it will also have capabilities that make the ethical concerns over ES cell work look trivial.

    Right now we have teenagers confessing to their parents that their boyfriend knocked them up. Will we be upset or proud when our teenagers confess that they made a mutant clone of themselves out in the lab in the garage?

  47. #47 apalazzo
    November 21, 2007

    @44

    Just to clarify. Right now the skin cells can turn into stem cells without the use of any oocyte. However if you wanted to use the cells for reproductive cloning (i.e. you want to implant them into a uterus and generate an entire organism) you need to inject the cells into a blastocyst. This is where the current technique stands at the moment.

  48. #48 Fatboy
    November 21, 2007

    PZ & apalazzo,

    Thanks for the clarification.

  49. #49 Rey Fox
    November 21, 2007

    “Rabbit eggs are certainly more plentiful than human eggs, though, so this kind of research helps.”

    Yeah, but only around Easter.

  50. #50 Mr. Gunn
    November 21, 2007

    If you look around the web, you’ll see that they want to use this to justify complete cessation of ESC research.

    I think it’s fantastic research, but I have to wonder where we would be if they had been able to apply their prodigious intelligence to solving a real problem, as opposed to one created by Christians.

  51. #51 windy
    November 21, 2007

    “Lanza noted that gene expression in the new stem cells wasn’t equivalent to that in embryonic cells. Even ESCs, he said, “all have personalities.

    If they have personalities, why not souls!!! ๐Ÿ˜‰

  52. #52 Coin
    November 21, 2007

    PZ, thanks for writing this, this is the most (only?) clear writeup of what exactly this research is that I have found anywhere.

    One question I have is, now that this method has been published how quickly can it be adapted for widespread use in research in the United States?

  53. #53 David Marjanovi?, OM
    November 21, 2007

    The sad and silly truth is, I feel self-conscious about adding it because I feel unworthy.

    Silly indeed.

    Yeah, but only around Easter.

    ๐Ÿ˜€

  54. #54 David Marjanovi?, OM
    November 21, 2007

    The sad and silly truth is, I feel self-conscious about adding it because I feel unworthy.

    Silly indeed.

    Yeah, but only around Easter.

    ๐Ÿ˜€

  55. #55 Calladus
    November 21, 2007

    The radical right to lifers have been saying that each human zygote requires full protection of human rights, under the law, merely because it might potentially become a human one day.

    I wonder how they will feel about the potential humans that can be made out of scrapings of skin cells?

    Okay, (somewhat) seriously – I do have a couple of questions.

    If PZ does clone a new heart to replace his old heart, how long will he have to wait until the new heart is viable for replacement? If he has to wait 10-20 years for the heart to reach the right size, well, that might be too late. (I’m assuming he’d use an interim artificial heart based upon steampunk technology driven by the power of shriven children’s daemons.)

    Also, how do you tell the cells to just grow a heart? The heart has to connect to something, and those cells at the border of heart / not-heart wouldn’t just split in one direction and not the other – would they? The old Sci-Fi standby would be to grow a clone in a vat, and then harvest him for parts.

    Lastly, what about genetic defects? Growing a new pancreas to replace your old diabetic pancreas would seem to me that it would just produce a brand-new diabetic pancreas. Do I just assume that if we understand how to create organs out of stem cells, that we’ll also understand how to ‘fix’ genetic problems with those organs?

  56. #56 Dave D.
    November 21, 2007

    PZ wrote:

    However, let’s point out some realities here. Americans did not make this discovery; Japanese researchers did.

    Someone else then wrote:

    James Thomson of the University of Wisconsin, Madison, and his colleagues report success in reprogramming human cells, again by inserting just four genes, two of which are different from those Yamanaka uses.

    Then PZ wrote:

    I didn’t mention Thomson here because I haven’t seen his latest paper yet.

    PZ, if you don’t want this issue to turn into a political football, would you care to retract the original conclusion? Else, you’re not being very scientific, imho.

  57. #57 tacitus
    November 21, 2007

    I wonder how they will feel about the potential humans that can be made out of scrapings of skin cells?

    They will say that it is immoral to use skin cells to create a new human life, but then if someone does do it anyway, they will say that the resulting zygote deserves full protection and should not be discarded or experimented upon.

    Theological issues over ensoulment will almost certainly come down on the side that despite human beings interfering with “His plan”, God would not deprive a new human life of a soul. Thus it would be considered in the same boat at those frozen IVF reject embryos.

    I don’t actually think this issue will be a particularly difficult one. The lines are fairly easy to draw (for the right-to-lifers, anyway).

  58. #58 tacitus
    November 21, 2007

    If PZ does clone a new heart to replace his old heart, how long will he have to wait until the new heart is viable for replacement? If he has to wait 10-20 years for the heart to reach the right size, well, that might be too late. (I’m assuming he’d use an interim artificial heart based upon steampunk technology driven by the power of shriven children’s daemons.)

    Replacing one heart with a newly grown one is still the stuff of science fiction. Who knows if it’s ever going to be possible?

    What will probably be possible nearer term are smaller spare parts — tissue grown and molded over some sort of framework into replacement flaps of heart tissue or valves to repair parts of the heart without fear of rejection.

    The other line of research, I believe, is growing the spare parts inside pigs after infusing your DNA into the pig’s (somehow) so rejection is less of an issue. I dunno if this will ever be feasible, the heart will only take as long as it takes for a pig to grow, I guess.

  59. #59 natural cynic
    November 21, 2007

    Calladus: Lastly, what about genetic defects? Growing a new pancreas to replace your old diabetic pancreas would seem to me that it would just produce a brand-new diabetic pancreas.

    My thoughts exactly. Type I diabetes is an autoimmune disease – the immune system destroys the beta-cells because they have certain antigens that the body mistakenly recognizes as foreign. The body will probaly produce the antibodies and T-cells responsible as long as it is immunocompetant, so any introduced beta-cells would probably have the same fate as the original ones. One way around this problem might be to suppress the TRPV1+ neurons that mediate the immune response – capsaicin may do the trick Cell 127:6 1097-9 [Dec ’06]. But I won’t be the first to mailine Tabasco sauce even though I have needed this kind of therapy for 30-odd years.

  60. #60 matty
    November 22, 2007

    Good work PZ! I really enjoy your site.

  61. #61 Epistaxis
    November 22, 2007

    Or we can just sit back and let the Japanese and Europeans and Koreans do it for us

    You forgot Californians.

  62. #62 Russell Blackford
    November 22, 2007

    Thanks for posting on this so quickly, PZ. I’m still trying to make sure I have a correct understanding before I kinda “go public” on the issue.

    The main points that I get out of it all at this stage are about the same as Norman Doering’s:

    1. It took a lot of research to get us to this point, and that research involved destroying human embryos.

    2. This technique will help in future research, but it will not remove the necessity for more research that involves destroying human embyros.

  63. #63 Peter Ashby
    November 22, 2007

    I think the confusion over the mouse work and this not being useful for SCNTF cloning is that the mice ‘made’ from these cells are not completely made from them, they are chimeras. What happens is some of these cells are injected into mouse blastocysts. Think a hollow soccer ball with a puddle of cells in the bottom. You use a drawn glass pipette to poke through the wall of the ball and add some of these cells to the puddle. They mix in and the added to puddle will go on to make all of the animal (the walls make the membranes and placenta). You mark the modded skin cells so you tell which cells in the chimera are yours and which the original mouse ones.

    Even if we could do this in humans it would not cure most diseases and might cause disease itself. it is certainly not a clone to make a chimera.

  64. #64 Hugo
    November 22, 2007

    When I saw the news I immediately came to Pharyngula.
    And you did not let me down PZ, THANKS!

  65. #65 Alex
    November 22, 2007

    There’s a gene in this called NANOG? As in NANOG?

    That’s so cool.

  66. #66 Amenhotep
    November 22, 2007

    I know others have said this, but I’m re-saying it because it’s important. Opponents of embryonic stem cell research (ESCR) have frequently cited the fact that there are very very significant difficulties in getting therapies for human diseases from “real” embryos; there aren’t enough, they’re not immunologically matched to the patient, etc.

    However, the objective (as I see it) of ESCR is not for simple immediate utility, but part of a process of understanding the switches and processes that control cellular differentiation. When we understand all that, kaboom, we will find ourselves in a position to use other cell types for doing the actual “technology” side of the enterprise (and learn a lot about cancers and birth defects along the way). So ESCR remains vital.

    If anything, this new technique is a stunning *vindication* of ESCR, because if we were not doing ESCR, we would have no clue about this. So, well done to our colleagues, and here’s hoping that this does indeed accelerate the pace of research. If this is being hailed as some sort of “victory” for the anti-ESCR lobby, that is just falsehood. If it is portrayed as indicating that ESCR researchers are somehow acknowledging the bogus “ethical” arguments of the anti brigade, that is also false.

    These are exciting times.

  67. #67 David Marjanovi?, OM
    November 22, 2007

    These are exciting times.

    These are interesting times! =8-)

  68. #68 David Marjanovi?, OM
    November 22, 2007

    These are exciting times.

    These are interesting times! =8-)

  69. #69 Norman Doering
    November 22, 2007

    The thing that puzzles me about these kind of developments, where we can seemingly reprogram any cell with a few genetic codes or chemicals – perhaps even turning them into embryos, is it makes me ask why in the world did the female egg cell become one of the largest and most complex cells in the body when that size and complexity aren’t necessary?

    Does that question make sense to anyone? Do I need to reword it?

  70. #70 SabrinaW
    November 22, 2007

    Norman, I remember reading somewhere that the egg and sperm co-evolved because that combination of big+immobile and tiny+supermobile led to increased fertilization rates over more equitably designed gametes (based on protists that were the forerunners of gametes). So in order for a sperm to becomes so tiny and mobile, the egg had to carry more and more of the “wetware” required to sustain the new life after fertilization.

  71. #71 Norman Doering
    November 22, 2007

    SabrinaW wrote:

    the egg had to carry more and more of the “wetware” required to sustain the new life after fertilization.

    What “wetware” sustains the new life? If any cell in your body can be (and we don’t know this for sure yet) reprogrammed back to an embryonic stage then you apparently don’t need any more wetware than you have in a normal skin cell.

  72. #72 David Marjanovi?, OM
    November 22, 2007

    why in the world did the female egg cell become one of the largest and most complex cells in the body when that size and complexity aren’t necessary?

    Much of it is sorta kinda yolk. It takes a long while from fertilization to implantation.

  73. #73 David Marjanovi?, OM
    November 22, 2007

    why in the world did the female egg cell become one of the largest and most complex cells in the body when that size and complexity aren’t necessary?

    Much of it is sorta kinda yolk. It takes a long while from fertilization to implantation.

  74. #74 liveparadox
    November 22, 2007

    Many thanks, Dr. Myers, for this extremely clear summary, since I don’t have time right now to read the relevant paper(s). Seems that this ties into some parts of my senior thesis topic (cell senescence)–I’ll have to look it up after finals.

    Also, thank you for pointing out:
    1) this technique is far from perfect and extremely experimental still, something that the MSM, even NPR, seem blissfully uninterested in mentioning;
    2) this research stands on the shoulders of ESC research.

    To be perfectly consistent with the current administration’s stupid, interfering, damaging, hypocritical policies, federal funds should not even be awarded to research that USES previous research on ESCs, and then where would their stupid “victory” be? Argh. I don’t have time to get angry right now, so I’ll stop there…

  75. #75 Dave Eaton
    November 22, 2007

    Will we be upset or proud when our teenagers confess that they made a mutant clone of themselves out in the lab in the garage?

    Horrified. I want my kid to grow up to be a chemist. I want him to confess that he has 2 kg of RDX and 500 milligrams of LSD in the garage. Disposing of these might present difficulties, but I’d still be proud.

    I’m excited by the prospect of these cells being useful for therapies someday. We still have to push for ESC research. There’s still so much to learn. I imagine that this important discovery will just cloud the politics, so I think it is really valuable when PZ points out that this research doesn’t mean experiments with ESCs are unnecessary. I intend to point chemist colleagues here.

    I’m pretty ignorant of biology, so I’ll ask a dumb question: would a skin-cell-derived stem cell produce an organ that would have no problems with the immune system? Is there any part of immune self-identification that is dependent on development in utero?

  76. #76 Peter Ashby
    November 23, 2007

    Dave Eaton said:
    “I’m pretty ignorant of biology, so I’ll ask a dumb question: would a skin-cell-derived stem cell produce an organ that would have no problems with the immune system? Is there any part of immune self-identification that is dependent on development in utero?”

    They will be treated as self since they will still have the same MHC genes and hence proteins. Chimeras get through because what is self and not self does get learned during development so both cell populations get tagged as self.

    Oh and no question about which you are truly ignorant is dumb. If people feel that way they will never ask questions so their ignorance will remain. Well done you for seeking to banish your ignorance ๐Ÿ˜‰

  77. #77 Keith Douglas
    November 23, 2007

    arcturus: As if we needed further evidence that Bush is delusional.

  78. #78 SabrinaW
    November 24, 2007

    Norman, stuff like organelles in cells (centrioles, mitochondria, etc) – things that couldn’t fit anymore in the now streamlined sperm, which basically are DNA delivery mechanisms with propulsion, fuel, and enzyme-laden tip. At the risk of overstepping my knowledge of devo, I also think that the zygote is able to keep dividing into more cells through blastocyst stage without needing to take a break to grow more (the cells just keep getting smaller while the whole mass of cells stays the same size as the original oocyte) – that could be another benefit of starting with a large oocyte.

    PZ – apologies for opening the door for… unsavory characters showing up in later posts. I can’t help but applaud you, and they can’t help but be annoying.

  79. #79 torcant
    November 25, 2007

    Don’t expect religious people be happy with this.

    In my opinion what religious people oppose (consciously or not) is the scientific advance itself. They fear that all this will eventually lead to totally artificial life, even humans – and they are right!

    And they also know that when this happens, all their beliefs will crumble.

  80. #80 Duka
    November 25, 2007

    I hate the very fact that we even had to invent some technology for the sole purpose of making morons happy. Yes, there are valid questions about ethics of stem cell research, like what if some company creates something that they know is harmful in the long run (something that, say increases strength but also gives cancer) and then get even richer by latter selling “debugger”. If we give up stem cell research entirely to free market there might be trouble. Think of global warming or claims that smoking doesn’t cause cancer.

    However, it is just utterly retarded to claim that using stem cells delivered from skin cells is any more ethical than using them from egg cells. This whole “debate” seems to be just a smoke screen to obscure real potential problems.

  81. #81 PZ Myers
    November 25, 2007

    No, no — this is not a discovery that was made to palliate morons, or to resolve ethical issues (although Thomson clearly held that as a consideration). There are definite benefits to inducing pluripotency in adult cells that would not be present in embryonic stem cells. #1: we adults don’t have embryonic stem cells anymore.

  82. #82 Chuck Goecke
    November 25, 2007

    I’m ready for the full body stem cell makeover. You know, they take a cell of mine, pluripotentiate it, grow it into stem cells for all my major tissue types, heart, GI tract, nerve, etc. and inject them, in the right proportion. They float around, find their correct tissues, and six months later, I start reverse aging, and I’m back to 20 years old in 3 years. No problem, when do I sign up. Will my insurance cover this?
    Chuck Goecke UMM Geology ’79
    PZ, Say hi to Ellen Ordway and Jim Van Alstine from me.

  83. #83 khan
    November 25, 2007

    I’m ready for the full body stem cell makeover. You know, they take a cell of mine, pluripotentiate it, grow it into stem cells for all my major tissue types, heart, GI tract, nerve, etc. and inject them, in the right proportion. They float around, find their correct tissues, and six months later, I start reverse aging, and I’m back to 20 years old in 3 years. No problem, when do I sign up.

    I’d go for age 28, that was my physical peak; can I keep the 55 year old ideas and insights?

    “We are too soon old and too late smart.”
    -old German saying

  84. #84 Chuck Goecke
    November 25, 2007

    “I’d go for age 28, that was my physical peak”
    As I’m am now 50, one thing that highly motivates me, did peak at age 20 as I recall. (Aw, summer of ’77(or was it ’76), Morris, Minnesota, sophomore working on campus, the girls, the Disco…. Biology Department, The Prairie Project, the insect collections, the herbarium specimens….Dr Ordway! Buzz Kill! Dang, that Bee didn’t die in his killing jar – musta been a Halictid. Sorry ya’ll, I guess you had to be there) I had to crack open my Borror, Delong, and Tripplehorn for that.

  85. #85 Chuck Goecke
    November 25, 2007

    natural cynic: “But I won’t be the first to mailine Tabasco sauce even though I have needed this kind of therapy for 30-odd years.”

    As someone who’s been mainlining Tabasco for about 25 years(or nearly so), I’ll attest to its ability to protect my insulin producing cells. Problem is that my fat belly cells seem to be convincing my muscle cells to ignore this fact. I think I need to move completely over to the Hard stuff – Habernaro!

  86. #86 Dr. Rivka Rachel
    November 26, 2007

    #1: we adults don’t have embryonic stem cells anymore.

    Posted by: PZ Myers | November 25, 2007 10:24 AM

    After birth we no longer have ES cells, but we certainly have adult stem cells. For therapeutic purposes, it may not even be necessary to go from differentiated cells like skin fibroblasts back to ES cells; we can learn how to stimulate adult stem cell circulation, which is already being done.

  87. #87 tim Rowledge
    November 26, 2007

    “They will say that it is immoral to use skin cells to create a new human life, but then if someone does do it anyway, they will say that the resulting zygote deserves full protection and should not be discarded or experimented upon.”

    Doubt it. One reaction would be that any such people are the Spawn of Satan and must be slaughtered immediately. The more pragmatic cheap-labour conservatives would demand that they be declared golems and not subject to labour protection laws, OSHS etc.

  88. #88 Kim G
    November 27, 2007

    Please forgive my ignorance, but how is this different then epigenetics? My wife and I saw the NOVA scienceNOW special on Epigenetics (http://www.pbs.org/wgbh/nova/sciencenow/3411/02.html) and are trying to make sense of it all.

    (Before I get flamed, I support embryonic stem cell research).

    We were also wondering why embryonic research was necessary for this discovery. Was there no other possible way to make a discovery like this without embryonic stem cell research.

    Thanks.

  89. #89 John Jamie Yen
    December 7, 2007

    Dear Jamie,

    This is online reference article of stem cells

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