The Niche

George Daley, author of a paper published online today in Nature says that a simple skin biopsy can yield stem cells specific to an individual patient, and may mean that a bank of genetically matched stem cell lines is possible. Further, any group that knows how to keep human or mouse embryonic stem cells alive will probably be able to make and maintain induced pluripotent stem (iPS) cells.

Here's an advance peak of an article that will appear on our site in January 2008.

In January 2007, George Daley of Harvard University published proof of principle that pluripotent stem cells could be created so that they would not cause an immune response when differentiated for cell transplantation1. His forthcoming publication in January 2008 shows much the same thing, but through an entirely different technique. The first paper used unfertilized mouse eggs; the more recent one uses a skin biopsy from a human volunteer2. It is the first to demonstrate such complete reprogramming without starting from embryos or cell cultures available from commercial vendors.

These bookends highlight the major stem cell advance of this year: multiple laboratories have now shown that adult human skin cells can be reprogrammed to an embryonic stem-cell-like state.

Daley’s lab began work shortly after Kyoto University’s Shinya Yamanaka announced the four genes that could transform cultured mouse skins cells, or fibroblasts, into an embryonic-like state3. This summer, Yamanaka and two other groups proved that the mouse fibroblasts could be made truly pluripotent by showing that the cells could become sperm and eggs4-6. (See Skin cell to stem cell)

Meanwhile, labs across the world were racing to reprogram human cells. This November, Yamanaka and James Thomson of the University of Wisconsin-Madison became the first labs to announce that they had done so7,8. “Our paper was already submitted when the others were published,” Daley says. “It was frustrating, but the point is that this is a robust technology that lots of people can reduce to practice.” Indeed, he says, any group that knows how to keep human or mouse embryonic stem cells alive will probably be able to make and maintain induced pluripotent stem (iPS) cells.

Continue reading "Personalizing pluripotency" »

Posted by Monya Baker on December 23, 2007
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Since the recent announcement of successful reprogramming, editorials carrying statements such as “[r]arely has a president - so vilified for a moral stance - been so thoroughly vindicated” have been springing up across the United States. Now the fightback seems to be gearing up.

Key to their argument is the fact that ‘reprogrammed’ cells – where instead of obtaining stem cells from an embryo ‘induced pluripotent stem cells’ are created from adult human skin – are not yet safe for clinical use.

“For doing basic research on human cells, IPS as a method has won - it's huge. But for the ultimate goal of getting cells into a patient, it's a lot less clear. These cells may never be useful for direct therapy,” says George Q. Daley, a stem cell researcher at Children’s Hospital Boston, in the Boston Globe.

Douglas A. Melton, codirector of the Harvard Stem Cell Institute, is even firmer, saying: “It will never be approved [by the FDA] to put these cells in a patient.”

See also our Q&A on the topic with the head of the NIH Stem Cell Task Force and what scientists had to say

Posted by Monya Baker on December 21, 2007
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Posted on behalf of Brendan Maher, locum Nature biology features editor

Last night I went to the Philadelphia public television station WHYY, to see an independent film on stem cell researcher Jack Kessler of Northwestern University and the sharp turn his research took when his daughter lost the use of her legs after a skiing accident. The movie is called “Mapping stem cell research: Terra Incognita”.

Shot in stark video, the piece paints an intimate portrait of Kessler, his family and his “other” family -- the postdoc and student working on a spinal regeneration project under his direction. The movie is positioned to put a human face on the ethics of embryonic stem cell research. Kessler is an outspoken activist for this kind of work – moreso even than his college-aged daughter, who just wants to get on with her life.

I was more compelled by the personal look at his postdoc and student, as they test the effects of injecting a self-assembling gel matrix into severed mouse spinal cords and see if axonal growth is able to cross a crucial barrier. It’s a live animal follow-up to the experiments presented in this Science paper.

In the movie you see tense lab meetings with negative results, time-consuming troubleshooting, and that odd mistrust that junior researchers feel about their results that is overshadowed by the enthusiasm of a PI. Ultimately, their paper is rejected from Science without review. Not your happiest of endings, but certainly appropriate.

The screening was followed by panel discussion including science journalist Marie McCullogh from the Philadelphia Inquirer; Jonathan Epstein, a University of Pennsylvania stem-cell biologist; and two bioethicists, Paul Root Wolpe from Penn and Catholic priest and biologist, Father Tadeusz Pacholczyk, who appears in the movie comparing embryonic stem-cell research to slavery. Needless to say, it was a heated discussion about the nature of the embryo and the equivocation between potentiality and identity. The roundtable more or less proved that the recent discovery of reprogrammed, or induced pluripotent stem cells, in no way changes the nature of the debate.

The question was raised, but never adequately answered by the main stem-cell opponent in the room (that would be Fr. Tad) whether it would be acceptable to use treatments, if ever developed from these induced cells, based on the fact that they were made possible by research he finds otherwise abhorrent.

The film starts running on US public television stations on 15 January. A listing of screenings around the country is available here.

Posted by Monya Baker on December 21, 2007
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One of our recent commentaries brought this response from Doug Sipp, of Japan's RIKEN Kobe Institute:
Charis Thompson raises an interesting question in her article, "Can opposition to research spur innovation?" [1] and one that is particularly timely in light of the recent breakthroughs in the induction of pluripotency in differentiated mouse and human cells. It seems undeniable that resistance to a given field of research from some quarters can prompt support from others; this has certainly been the case for human embryonic stem cell research in the US. However, the furor surrounding human ES cells is not a global phenomenon, and is indeed restricted to a fairly limited number of countries (at least of those capable of conducting significant research efforts). Japan, where the first discovery of the four "Yamanaka factors" was made, provides a reasonably permissive regulatory framework for human ES cell research, and there has never been public opposition to the field of the sort seen in the States. This is not to say that there are not obstacles. As Norio Nakatsuji pointed out in his article, "Irrational Japanese regulations hinder human embryonic stem cell research," there are regrettable bureaucratic hurdles confronting would-be human ES cell researchers [2], but I don't feel that this can accurately be characterized as "opposition" in the sense used in Thompson's article. So it seems a bit inappropriate to use the discovery of induced pluripotency as an example of how opposition can lend impetus to a field of science, and thereby lead to new discoveries. This nonetheless appears to be the thrust of recent mendacious self-serving statements from the Bush administration claiming that the discoveries of Yamanaka and others somehow vindicate the restrictive policies in force in that country [3]. It should be remembered that the original discovery of induced pluripotency was not made by an American lab, and that the uproar, quibbling and qualms voiced in the US have for the most part been only a distant spectacle, not fuel for the engines of scientific discovery. So, while I agree that conflict may spur innovation, I do not think that induced pluripotency was the fruit of such a troubled union.

Doug Sipp
RIKEN Center for Developmental Biology

1 http://www.nature.com/stemcells/2007/0712/071213/full/stemcells.2007.128.html
2 http://www.nature.com/stemcells/2007/0708/070809/full/stemcells.2007.66.html
3 http://blog.wired.com/wiredscience/2007/11/bush-to-greet-g.html

Posted by Monya Baker on December 18, 2007
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This will appear as a regular, archived article on Nature Reports Stem Cells eventually. However, our production cycle will be even slower over the holidays, and I wanted to put this up as soon as possible. --Monya

Nature Reports: Did the induced pluripotent stem (iPS) cell breakthrough happen faster than you thought?

Landis: Yes.

Nature Reports: What do you think of the public response to this breakthrough?

Landis: It’s kind of very sad. Instead of focusing on the scientific potential—what you can learn in terms of reprogramming and the epigenetics of the cells—people seem to have focused on “We don’t need embryonic stem cells” or “Oh yes we do need embryonic stem cells”. It’s as if the science has been consumed by the political argument.

Nature Reports: What still needs to be assessed with induced pluripotent stem cells?

Landis: There are a zillion questions. The assumption on the part of a large part of the public that this does away with the need for embryonic stem cells is premature.

I find it hard to believe that you’d get back to the same starting point that a pristine embryonic stem cell would represent. You don’t know what the undifferentiated state actually is and you don’t know how they [the cells] are going to respond to differentiation.

If you’re taking a fibroblast that’s obviously gone through several developmental stages to get to its differentiated state and then you’re getting it to go back to its undifferentiated state, I would be surprised if it took the same pathway backwards.

[Regarding pluripotent stem cells as disease models] An interesting catch could be that the mutations that give rise to the disease could interfere with the ability to reprogram. Everyone has just assumed that they won’t, but I don’t think we have any data on that.

Nature Reports: How can researchers compare human iPS cells to embryonic stem cells?

Landis: Given that they’ve had the mouse embryonic stem cells and mouse iPS cells for some time and have not yet completed the epigenetic comparison, I think it will take a lot to do the human.

Nature Reports: But comparisons can’t be funded for the newer human embryonic stem cell lines.

Landis: You would be constrained to the identified lines that are available for funding. Obviously it would be better to have more lines. Jamie Thomson[who led one of the groups making the reprogramming breakthrough and was the first to generate human embryonic stem cells] has pointed out that one of the major disadvantages of the limited number of lines is that they come from a pretty narrow genetic repertoire.

Nature Reports: Scientists have called for comparisons between iPS and hES cells, but there is some ambiguity about what kinds of these studies the NIH could fund. For example, can people use data or RNA or techniques from newer embryonic stem cell lines that aren’t eligible for NIH funding?

Landis: That’s kind of outside my paygrade, that kind of regulation. Apparently Harvard has a very good policy that’s written up that outlines what Harvard feels are the appropriate safeguards to make sure that you don’t violate the NIH policy.

Nature Reports: What’s going to happen now in terms of what science is being done and who’s doing it?

Landis: [The buzz makes it sound] like it’s really easy and that anyone who’s cultured cells should be able to make their own pluripotent stem cells. In talking to people on the phone, it sounds like it’s much more complicated than that. Jamie Thompson said that it took him four years.

There will be new grant applications to take advantage of this scientific advance, whether or not they will be outstanding grant applications is unclear. Also, with the advance of SCNT [somatic cell nuclear transfer] in primates, I expect we’ll get more grant applications based on that.

Since this is a new area, and not many investigators have the expertise to make pluripotent stem cell lines, the issue won’t be that there are too many [grant applications] that are outstanding but that there won’t be enough that are outstanding.

Nature Reports: How will grants be chosen?

Landis: One of the most contentious issues at NIH is how much money is assigned by what the review says is the scientific merit of the grant versus how much money is assigned based on programmatic considerations.

If 50 grants come in and none of them are deemed outstanding, the institutes can then say ‘none of them make the payline, but this [research] is absolutely critical.’

Nature Reports: How do you feel about NIH’s leadership role in global science?

Landis: Do we want therapeutic advances using human embryonic research to come out of Singapore, China, Britain? That’s a piece of the tension that exists.

I don’t think that the NIH can do anything except talk about the fact that the science does not support the President’s policy and at the same time to implement the President’s policy.

Posted by Monya Baker on December 17, 2007
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I recently received the letter below objecting to my my use of the term oocyte-assisted reprogramming. I first heard the term myself when interviewing Shoukhrat Mitalipov about cloning monkey embryos. It seemed like a nice way to distinguish between two known ways of reprogramming a nucleus: putting it in an egg versus introducing pluripotency genes. However, oocyte-assisted reprogramming has also been used to refer to a method also known as altered nuclear transfer, which involved putting a nucleus into an egg such that no viable embryo results. I hope that it was clear from my article that Mitalipov et al did, in fact, clone monkey embryos by tranferring nuclei into enucleated oocytes. I did not mean to imply that Mitalipov was using altered-nuclear transfer.

To whom it may concern:

In a commentary entitled "Monkey embryonic stem cells cloned" (Nat.Rep. Stem Cells http://www.nature.com/stemcells/2007/0711/071121/full/stemcells.2007.119.html#top),
Ms. Monya Baker uses the term "oocyte assisted reprogramming" (or OAR) as a synonym for "therapeutic cloning".

The phrase “OAR” was introduced into the scientific literature as a consequence of a 2005 Westchester Institute Scholars Forum focused on the proposal by Dr. William Hurlbut to generate pluripotent stem cells using a process known as Altered Nuclear Transfer (ANT). In this Forum, a modification of ANT was proposed that incorporated “oocyte assisted reprogramming” (i.e. ANT-OAR). Cf. Arkes H, et al. “Production of pluripotent stem cells by oocyte-assisted reprogramming: joint statement with signatories.” Natl Cathol Bioeth Q. 2005 Autumn;5(3):579-83.

To our knowledge, OAR has never been equated with so-called 'therapeutic cloning' or used synonymously with somatic cell nuclear transfer. Indeed, the expressed purpose of the ANT proposal is to generate pluripotent stem cells without cloning of an embryo (therapeutic or otherwise).

Since the appearance of the term in 2005, no one has (to my knowledge, based on the PubMed database) used "oocyte assisted reprogramming" as synonymous with SCNT, except for Ms. Baker. Inaccurate identification of cloning with "oocyte assisted reprogramming" only serves to confuse your readers and the scientific literature.

Sincerely,



Fr. Thomas Berg, L.C., Ph.D.
Executive Director
The Westchester Institute for Ethics and the Human Person


________________________________
Fr. Thomas Berg, L.C., Ph.D.
Executive Director
The Westchester Institute for Ethics
& the Human Person
P.O. Box 78
582 Columbus Ave.
Thornwood, NY 10594
tberg at westchesterinstitute.net
www.westchesterinstitute.net

Posted by Monya Baker on December 17, 2007
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Last month, we posted an article that asked how one could declare human cells pluripotent, when the most robust tests are neither ethical nor feasible. Here are some of our favorite responses. If you've got more to say, please add your own comments.

Peter Andrews, Sheffield University

I rather think the discussion is becoming like the Middle Ages' discussions about how many angels can stand on the head of a pin. Does it matter? Sometimes in science it helps to have terms that are not so precisely defined - indeed the term 'gene' is an example. In fact it can mean a variety of subtly different things - which in fact makes it generally useful. When people wanted more precise terms, new ones were invented, like the 'cistron' based upon a very specific assay.

The same may be true of pluripotency. To me it means what it says - the ability of a cell to be capable of generating many cell types by differentiation. When we come to ES (and related EC) cells, we can actually find a very broad range of capacities - ranging from cells that have completely lost their ability to differentiatiate (nullipotent) to those with a very broad range – ultimately all somatic cell types. But we know very little about the molecular basis of pluripotency and what controls the range of cells into which a stem cell can differentiate. On the face of it at the moment I think we have little or no way of identifying which ES cells can generate a whole mouse in the tetraploid assay and which cannot even form the germ line in chimeras. In the face of this type of uncertainty, I would advocate retaining 'pluripotency' as a somewhat vague, term meaning ability to differentiate into a lot of cell types, and then as the need arises invent new terms with precise definitions based on specific assays - very much as the concept of the gene and its associated terminologies evolved.

Shinya Yamanaka, Kyoto University

This is an important, but difficult question. First of all, we don't know whether human ES cells are really ES cells or not. Because the lack of chimera experiments, we will not be able to answer this question. This means we lack a positive control. I have been telling my students that one of the worst experiments you can do is one without positive and negative controls.

In human ES cell field, all the scientists are forced to perform bad experiments without positive control. The best we can do is to describe how the cells are similar to human ES cells. This includes not only teratoma formation, but also surface marker, gene expression, DNA methylation, telomerase activity. You are right that some iPS cells can make teratomas, but do not give rise to germline transmission. However, these cells have different gene expression and DNA methylation.

I don't think it is governments to make definition of pluripotency. It should be scientific community.

Paul Tesar, Laboratory of Molecular Biology, National Institutes of Health, NINDS

Since I’m associated with NIH, I won’t comment on the recent nomenclature alteration.

I do, however, think that the definition of pluripotency sits at the heart of modern biology. Currently it is more of a semantic argument but I think further study will clarify the issue. Existing methodologies such as blastocyst injection and teratoma formation are inclusive but not exclusive when defining pluripotency. Additionally, they require secondary characteristics that are not necessarily involved in pluripotency. For example, cells that do not incorporate into the ICM, maybe because of cell adhesion or cell cycle differences, can not be examined by blastocyst injection. This does not mean that they are not pluripotent. Likewise, cells that do not rapidly proliferate when transplanted to an ectopic site will not form a teratoma. Can quiescent cells be pluripotent? Does growth or cell adhesion have to be linked to pluripotency? I think, thus far, pluripotent cells have satisfied one or the other of these basic assays but it is becoming harder to pinpoint the defining characteristic of pluripotency.
It sounds a bit outlandish but one could imagine something like a ‘pluripotency score’ which could be computed from a variety of cellular characteristics. It is difficult to define what exactly would need to be input, but in a current sense one could imagine looking across the genome at a large number of histone and DNA modifications. The ‘pluripotency score’ would basically be the probability that the chromatin is immediately capable of changing to form a panoply of differentiated tissues. SCNT and iPS cells have shown us that most, if not all, cells are capable of being pluripotent, but only after reprogramming. A much deeper understanding of multiple aspects of cell biology are necessary for something like a ‘pluripotency score’ to be a reliable and predictive measure, but at least it provides a framework to move forward instead of walking away or simply arguing semantics.

William Gunn, Tulane University
I would like to share what the consensus view is trending towards in my field, multipotent stromal cells(aka mesenchymal stem cells, MSCs).

I think the subtlety that is most often missed when talking about differentiation capacity is that differentiation is a cell-intrinsic process, but it's only assayed at the level of a whole culture. In other words, you're assaying a heterogeneous population of cells for phenotypes that different subpopulations possess to various degrees.

Further, these populations interact through cell-cell contacts and paracrine signaling, forming microenvironments which change constituency over time. Outside of ESCs and HSCs, it's an open question whether there's really one cell in a stem cell culture that could make all the various tissues, or if the pluripotency we see is a result of a mixture of progenitors of the various types that we just haven't learned how to distinguish yet. When exactly these progenitors may have become committed to a lineage isn't known.

The heterogeneity and dynamic nature of pluripotent cells is what has been confounding the studies which try to pin down markers of pluripotency or "stemness", and I'm not sure we'll get a satisfying answer until we develop the tools to study these cells on the single-cell level.

Evidence supporting this can be found in the work of Kuznetsov et al,
back in 1997: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9286749&ordinalpos=41&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Posted by Monya Baker on December 13, 2007
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Ten grant applications have been eliminated from consideration for new faculty awards from the California Institute of Medicine because the faculty were endorsed by CIRM board members. But while board members might learn something from the public flap and withholding of potential research funds, the scientists themselves are victims of members’ poor judgment.

CIRM’s board consists of several heads of prominent California research organizations, and the now-rejected grants required letters from applicant’s institutions stating that the institution would support new faculty members with resources like laboratory space, supplies, and mentorship. But in ten cases, these support letters were signed by institution heads who are also members of CIRM’s Independent Citizen’s Oversight Committee. Though the ICOC relies on scientific review panels to help decide on individual grants, it does oversee how funds are distributed. Board members must excuse themselves when discussing and voting on issues that represent conflicts of interest, but it’s unclear whether signing these letters about eligibility constituted a conflict. (A previous, more prominent flap was also about eligibility. CIRM board member and Burnham Institute president John Reed wrote a letter stating that a grant applicant affiliated with his institution was eligible to receive funds after CIRM staff decided that he was not. That prohibited communication is being investigated formally.

The San Diego Tribune has covered the story .

CIRM officials say they welcome investigations. They are making much of the fact that CIRM is breaking new ground and say they are still learning how to deal with public scrutiny and with juggling their dual roles to avoid conflict of interest. They’ve got a point: CIRM is the first state entity to fund scientific research through public bonds, as far as I know. And the board members are in a crazy situation. ( Read more about the unusual organizational structure here.) The legislation that enacted CIRM requires that 5 board members are executives from a University of California with a medical school and that 4 are executives from California research institutes. Those people achieved their positions by demonstrating that they could look after the interest of their research organizations. But because they oversee the biggest funder of stem-cell research, they are supposed to divorce themselves from any benefit their institutes could derive from the funds. Even the most savvy officials could slip up in such a situation, and CIRM officials like to proclaim that they are treading new, boggy ground. Incoming CIRM head Alan Trounson has been criticized in Australia for poorly considered public comments as well.

Let’s hope that experience is a good teacher. CIRM officials are being punished for their missteps, since their institutions are losing funds. The move to reject the applications has been praised by a press release from the Foundation for Taxpayer and Consumer Rights, “It’s simple: stem cell board members cannot take part in any way in grants to their institutions,” said John M. Simpson, FTCR’s Stem Cell Project Director. “The board is not some old-boys’ club for the benefit of the state’s universities. They are public officials and stewards of the public interest. Perhaps a few of these deans need to enroll in Ethics 101 at their universities and get the basics down.” The blog California Stem Cell Report has written about it extensively. CIRM has not issued a press release on the topic yet. When deciding not to fund the grant originally won by the Burnham Institute, CIRM decided not to announce the decision to avoid embarrassing the Institute. But such disclosures will be part of what it takes to keep the public’s trust.

Posted by Monya Baker on December 11, 2007
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Over the past few days, I’ve seen a series of press releases from stem cell companies. They’ve taken the excitement generated by recent breakthroughs to draw people’s attention to their existence. And why not latch on to the general sense of euphoria? Two big advances happened within a week of each other, and both were ones that the stem-cell community had been waiting for.

First, came the announcement that embryonic stem cells could be made from cloned monkey embryos, a feat that many had deemed impossible. Nature Reports Stem Cells had a feature describing what made the advance possible as well as exclusive information on what the anonymous peer reviewers had to say about the advance. Well before the accomplishment was printed, the Niche had posted expert opinion on whether cloning papers needed additional layers of scrutiny, and Nature had decided on independent verification for cloning papers.

Next, came the announcement that human skin cells could be reprogrammed to pluripotency. Back when the breakthrough was published for mice this summer, Nature Reports Stem Cells covered what would need to happen to generate useful cells through direct reprogramming. A month earlier, we’d explored how pluripotency could be defined for human cells since the most rigorous tests are neither feasible nor ethical for humans. We also ran a profile of Shinya Yamanaka, who found the suite of genes and slogged through the screens showing that differentiated cells could be reset to a state similar to that found in the embryo. A highlight of the papers showing how human cells can be reprogrammed with only three genes.

More Nature articles are listed here.

Posted by Monya Baker on December 04, 2007
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Shanghai crab is a delicacy available for only a short time each year, and the 20-million-strong href="http://query.nytimes.com/gst/fullpage.html?res=9A0DE2D91F3BF937A2575AC0A960948260&sec=travel&spon=&pagewanted=1" > residents of Shanghai devote themselves to its consumption. It was auspicious that the tasty crabs were still available during the first Shanghai International Symposium on Stem Cell Research, attended by around 500 scientists, hundreds of Chinese researchers and close to 100 foreigners. (NOTE: I wrote this on November 10th, but wasn't able to post until today.)

To put that in perspective, the last meeting of International Society for Stem Cell Research, the biggest annual stem cell conference, drew just over 1,900 attendees in June this past year.

China’s government and academies are pouring resources into stem cell research, and Chinese-born researchers trained in the United States are proving a huge asset. Some are returning to China to head up labs in that country; others are remaining in the US but forming collaborations with researchers in China.

Continue reading "Shanghai stem cell conference promises more to come" »

Posted by Monya Baker on December 04, 2007
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