The Niche

Both the International Society of Stem Cell Research and the California Institute of Regenerative Medicine have issued statements about stem cell research in the state of the union address, which praised work in reprogramming adult cells to an embryonic-like state and called for expanded funding for “ethical” research. CIRM called it “misleading.” The ISSCR said “a great deal of work remains before these methods can be used to generate stem cells suitable for safe and effective therapies.”

The ISSCR also stated that the FDA has informed fertility clinics of its policy to prevent reproductive cloning. The agency instructed institutional review boards (the committees that must approve research on human subjects) that such investigations are under its jurisdiction and will not be allowed to proceed.

Generally though, the President’s speech held nothing new. The few queries I put out to ask what was meant by “expanded funds” or “legislation that bans unethical practices” were met by the phone and equivalents of shrugs: “who knows?”

I thought a blog in Wired did a nice job of summing it up. “Both sides will applaud the expansion of reprogrammed cell research, then regroup on their side of the debate.”

Here are links to my previous posts on potential ramifications in funding and legislahtion.

Posted by Monya Baker on January 31, 2008
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In his state of the union address, President Bush promised to expand funds for some stem cell research and to ban patenting of human life. (That has interesting implications, as discussed in my previous blog.)

There doesn’t seem to be additional money flowing to the NIH, but the NIH has already been directed to fund “ethically responsible” sources of pluripotent cells, a program announcement for this was described months ago, and there is a supplement program. These additional funds could not be used to directly compare reprogrammed cells with human embryonic stem cells derived from the most advanced techniques. (In one of our commentaries , Markus Grompe, head of the Oregon Stem Cell Center describes what questions these cells could answer and that he has made the decision, on ethical grounds, not to ask questions that would require newly derived human embryonic stem cell lines. In another commentary, the presidents of the California Institute of Regenerative Medicine lay out what some of those questions are and why they are important.)

(Also see my interview with Story Landis, head of the NIH Stem Cell Task Force)

Here’s the transcript of the relevant bit of the State of the Union speech. I have some calls out for clarification, and if anything interesting comes back, I’ll post it later:

On matters of life and science, we must trust in the innovative spirit of medical researchers and empower them to discover new treatments while respecting moral boundaries.

In November, we witnessed a landmark achievement when scientists discovered a way to reprogram adult skin cells to act like embryonic stem cells.

This breakthrough has the potential to move us beyond the divisive debates of the past by extending the frontiers of medicine without the destruction of human life.

(APPLAUSE)

So we're expanding funding for this type of ethical medical research. And, as we explore promising avenues of research, we must also ensure that all life treated with the dignity it deserves.

And so I call on Congress to pass legislation that bans unethical practices such as the buying, selling, patenting or cloning of human life.

Posted by Monya Baker on January 29, 2008
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Last night, President Bush announced expanded funds (see next blog) for research to reprogram adult cells to act like skin cells, but his proposed policy on patents would have more of an impact.

Bush called on Congress “to pass legislation that bans unethical practices such as the buying, selling, patenting or cloning of human life.” While current policy forbids federal funding to be applied to newer human embryonic stem cell lines, this is an actual ban. It could make certain kinds of work illegal, such as making new human embryonic stem (ES) cell lines by cloning human embryos, an advance reported recently by a US company. (Interesting that Bush didn’t include harming or destroying human life.)

However, that part of the legislation is unlikely to get anywhere. The US is actually unusual in that it does not forbid reproductive cloning of new human beings. Nobody is for this, but legislation to ban it always stalls because some legislators insist that bills also ban therapeutic cloning (to make ES cells), so those that back ES research withdraw their support.

What’s more interesting is the patenting part. Patents already exist on deriving human embryonic stem cells. These patents have been widely criticized for being too broad and its holder WARF for being too stingy. If Bush pushed for it, those patents could, perhaps, get invalidated because of this policy. Interestingly, that could bring the US much closer to the European patent position, and could mean a whole new playing ground for the WARF patents covering the derivation of human embryonic stem cells.

At first blush, this may seem like a boon to institutions who could have more freedom to operate. But it may not be as advantageous as one might think.

The University of Sheffield’s Aurora Plomer, Berkeley’s Ken Taymor, and Stanford’s Chris Scott wrote comprehensively on this issue recently in Cell Stem Cell. EU policy “prohibits the patenting of the human body at the various stages of its formation and development,” Human cloning is not patentable, nor is the use of human embryos for commercial purposes permitted. (Aside: But fertility clinics are legal. Why?) Their conclusion is that conflicting interpretations of this policy have stymied research and even allowed companies to play off each other. They even describe how Geron is trying to invalidate a German patent on stem cell derivatives on a morality clause.

Finally, Plomer et al point out that much of the damage may already be done. With other companies and institutions out of the race, Geron (the main holder of commercial rights for the WARF patents) and others that continued research have built up strong intellectual portfolios, much of which will still stand if original patents are invalidated. (Interestingly, they also argue that current US challenges to WARF patents could actually strengthen them, something the challengers don’t believe. (See our commentary by Jeanne Loring.)

Posted by Monya Baker on January 29, 2008
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My post on Inconsistent Christianity prompted this reply from Jessica Kolman, our office manager and art researcher:

In reading your entry about inconsistent Christian views on reprogramming, I can’t help thinking that one reason for the inconsistencies is that so few people actually know what the facts are. Your entry cites the garbling of facts, but it may be that the facts are more garbled in the mind of the average American than this small example indicates. I’m not saying I’m any better—I don’t have a scientific background or claim to understand an iota of technical detail. I only recently learned that an embryo is a bundle of cells that haven’t become tissues of the body yet, and until then, I thought “embryo” was a little dude with a big head and spots where the eyes will go. I’m increasingly convinced that a large segment of the public thinks that, too. Even Richard Dawkins, in his book “The God Delusion,” constantly refers to “embryos” in the context of abortions. I suspect the renowned biologist does know the difference between an embryo and a fetus, but he is pro-choice, so he disingenuously uses “embryo” to make abortion seem less distressing. Similarly, there may be ES cell research opponents who subtly conflate the two, in order to make embryonic research seem more distressing.

Continue reading "Blurring embryo-fetus distinctions disingenuous" »

Posted by Monya Baker on January 28, 2008
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Work in creating human embryonic stem cells from cloned embryos continues apace, and some of the most interesting stuff regulatory-wise is going on in Europe. (Apologies, many of these links will require a subscription)

First, the scientist to publish a reliable paper on human therapeutic cloning, Miodrag Stojkovic, has gotten a license to try to make stem cells from cloned human embryos in Spain. In the UK, efforts are already underway by Stojkovic’s former colleague and rival, Alison Murdoch. She is collaborating with Oregon scientist Shoukhrat Mitalipov, who was the first to create primate embryonic stem cells using cloned monkey embryos.

Meanwhile, the German Research Foundation has formally announced its skepticism of this technique and is advocating more efforts toward reprogramming human cells.

To help keep things sorted, the European Human Embryonic Stem Cell Registry (sponsored by the European Commission) will supply researchers with information about human embryonic stem-cell lines developed in Europe, including information about use and derivation. The goal is to help researchers make better use of lines already developed.

Posted by Monya Baker on January 25, 2008
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In the wake of UK’s green light to create human-animal embryos, scientists are protesting a bulletin from a Catholics Bishops Conference. The accusations hurled include “blatant inaccuracy” and “a radical violation of the truth.”

The technique that the Catholic Church highlights in its objections--combining human sperm and animal eggs—has nothing to do with using animal eggs to make human embryonic stem cells. (For that you swap out the nucleus in an animal egg with a human nucleus so that the elixir in the egg can elicit reprogramming.)

What both sides failed to say is that making sperm-egg chimeric embryos has actually been around and legal for decades as a means of assessing sperm’s viability, though it’s not done much now. Any fertilized eggs must be destroyed by the two-cell stage. (Try googling “hamster egg test”) The use of this test has been used to argue that making other sorts of human-animal embryos is ethical.

When the accusations are flying, everyone should still set out the facts.

Kudos to the Anglicans, who seem to me to have done a pretty good job of both explaining the science and their objections to the research. On the Lutheran side, a theological argument for chimeras also does an accurate job with the science.

Posted by Monya Baker on January 25, 2008
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I’ve been reading the coverage on making embryonic-like stem cells without embryos in the religious press, and two quotes going through my mind, both sarcastic. One is “Shocked! Shocked!” (from Casablanca) and the other is “Oh, Lord! Make me pure, but not just yet.” (from St. Augustine).

Continue reading "Inconsistent Christian views on reprogramming" »

Posted by Monya Baker on January 22, 2008
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A girl enrolled in a stem-cell trial for a fatal disease has died. In January, the nine-year-old received a brain transplant of neural stem cells derived from fetal tissue. She was one of six children in the trial for Batten disease, in which children rarely live into their teens. An independent group monitoring the trial decided that the death was due to the disease not the experimental treatment and said the trial could continue.

This starkly contrasts with the hope expressed by the father of one little boy enrolled in the trial just over a year ago: “He was a little boy who was basically waiting to die, now he's waiting to get better,” Marcus Kerner told the Associated Press in an article entitled
Child who received stem cells from aborted fetus on way home

"Coming into the study they have no prospect of survival," said StemCells Chief Executive Officer, Martin McGlynn quoted in the San Jose Mercury News. "These patients are in the very late stage of the disease and that is one of the criteria of enrollment" in the study, which is designed to determine if the treatment has any unsafe side effects.

A press release from the company expressed sympathy for the family and said the trial of the other children, who have all already received transplants of cells, would continue.

The clinical investigators involved in the trial who were quoted in this and other articles refused to hype the technique and even downplayed it, but should remind those involved in clinical trials of the danger of the therapeutic misconception, something that Nature Reports Stem Cells has covered in a commentary by Mildred Cho and David Magnus.

In Batten disease, the brain essentially poisons itself because it cannot clear away fats and proteins. The result is a slow, painful death accompanied by crippling debilities, including blindness. Since the disease is by mutations in the gene coding for an enzyme necessary to remove accumulating compounds, one hope is that injecting cells with a working version of the enzyme will ameliorate the disease. Such suffering will make parents and loved ones desperate.

Posted by Monya Baker on January 20, 2008
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The regulatory body that approves all research on human eggs has just been given the green light for the production of chimeras.
Here is the article from the AP. The idea is that, with human eggs in short supply, researchers should be allowed to practice techniques on more readily available animal eggs. Also, several researchers believe the process can answer questions about how and to what extent an egg resets a nucleus from an adult cell into an embryonic state.

Ian Wilmut (who cloned Dolly the Sheep) put for the scientific rationale for chimeras last year. It’s called Man or beast? Man and beast!

Nature Reports has several related articles.

A summary of the UK Academy of Medical Science’s position paper on human-animal chimeras

In a research highlight, the scientist who cloned frogs has studied how nuclei in cloned embryos remember the differentiated cells they came from.

Following the finding that, at least in mice, fertilized eggs could be used for cloning, we looked at the implications for humans and at the power of the egg to reprogram.

Also, an article on successful monkey cloning showed the necessity of good technique.

And recent news coverage describes advances in cloning human embryos from adult cells.

Posted by Monya Baker on January 18, 2008
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I asked veteran Nature reporter David Cyranoski what he had to leave out of his recent article that might interest Nature Reports Stem Cells Readers. Here's what he had to say:

They didnt use the OOsight imaging system that the Oregonians thought so crucial. (See Nature and NRSC stories on cloning monkey stem cells) They DID use
Hoechst, but they tried to minimize the UV exposure by using a very narrow
beam focused on just where they expected teh spindle to be. They did not
expose the whole cell. So, they did try to limit damage that Mitalipov was
worried about. Also, they didnt take too much cytopolasm or time.

If the first polar body wasn't in the near vicinity fo the spindle, they left
it in there. He [interview at Stemagen] said that there is no concern of the first polar body
creating a parthenote unless it is injected (ie, it cant merely fuse). He
focused on getting the whole thing over with very quickly. There seems to be
a trade-off between trying to treat the cell nicely (by not using Hoechst,
eg) and trying to do it quickly (use Hoechst, but get in and out).

Posted by Monya Baker on January 17, 2008
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An article at News at Nature today describes an advance in making human embryonic stem cells through nuclear transfer, or therapeutic cloning. Also, this month, a separate article describes making human embryonic stem cells by taking cells from embryos without destroying them.

The cloning group at California company Stemagen credits their success not with the technique reported for the successful derivation of cloned monkey stem cells but with a supply of oocytes freshly collected from women donors.

The group did not make a cell line but rather generated the early stage “hollow ball” embryos from which stem cell lines are normally produced. The group said they did not try to make a cell line because they didn’t have as many blastocysts as are normally needed to successfully make a cell line. Instead, they sent the blastocysts off for analysis to show that the cloning process worked. Robert Lanza, an unaffiliated researcher at Advanced Cell Technology (ACT) says that the blastocysts didn’t look very healthy.

The Stemagen accopmplishment is similar to what has been done before with two improvements: first that the cloned blastocysts were made using cells derived from adult cells. An earlier group had also gotten cloned human embryos to this stage, but without using adult cells. Another group at ACT that cloned human embryos could not make them grow past the six-cell stage.

Earlier this month, researchers at Advanced Cell Technology published results they had made several stem cell lines from embryos without destroying them. ( This follows on an announcement that Nature Reports first reported in June. ) The peer-reviewed article in Cell Stem Cell describes the production of five lines from individual cells taken from very early embryos without destroying them.
Conventional techniques pulls cells from the inside of the “hollow ball” stage of the embryo and destroy it in the process. This plucks one cell from the earlier “solid ball” stage when the embryo has around eight cells. The process is similar to that used in preimplantation genetic diagnosis. The team used frozen one-cell embryos that they cultured to the 8-cell stage. After the biopsy, the cells remaining in the embryo were allowed to continue growing.

In one set of experiments, one of the 26 embryos yielded a cell line, and 22 of 26 biopsied embryos continued development. A second set of experiments yielded a much higher efficiency, but a similar number of embryos that made it to the blastocyst stage after biopsy. A third set tweaks culture conditions and shows that biopsy-desrived embryonic stem cells don’t need to be cocultured with human embryonic stem cells. I saw no mention of how many frozen embryos would be expected to make it to the blastocyst stage without biopsy.

Posted by Monya Baker on January 17, 2008
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Our recent article, Thinking in three dimensions: some stem cell researchers think conventional culture falls flat, brought this response from Xiao-Dong Chen of the University of Texas Health Science Center:

There is no doubt that the use of 3-dimensional (3D) matrix for culturing mesenchymal stem cells (MSCs) is more closely relevant to physiological situation as compared to 2D culture systems. However, more important it is time to think in “tissue-specific 3D matrix” rather than 3D matrix that is simply prepared from a single component of synthetic products or purified matrix proteins such as type I collagen or fibronectin.

MSCs can differentiate into many distinct cell lineages. The direction of MSC differentiation is controlled by tissue-specific microenvironment or niche that is mainly constituted by extracellular matrix (ECM) proteins associated with growth factors. Indeed, it is very doubtful that the intricate and highly ordered nature of the ECM could be reproduced with synthetic or purified components. To attempt to reconstitute the MSC niche in vitro, we prepared an ECM made by bone marrow stromal cells. This marrow stromal cell-derived ECM dramatically promotes the replication of MSCs and facilitates the retention of their multipotentiality (Journal of Bone and Mineral Research 2007, 22:1943-1956). One potential mechanism for the retention of MSC properties may be associated with the ability of the ECM to sequester most endogenously produced growth factors that control MSC replication and differentiation. It is worth investigating whether the stromal cell-derived ECM is unique in its ability to preserve MSC properties by comparing to ECM made by fibroblasts from different tissues such as skin, fat and muscle. Establishment of a unique scaffold built by 3D synthetic materials coated with tissue-specific ECM proteins and deposited with an appropriated combination of growth factors will facilitate control of the fate of MSCs for the therapeutic applications.

Xiao-Dong Chen, MD, PhD
Associate Professor
Department of Restorative Dentistry
University of Texas Health Science Center
7703 Floyd Curl Dr. MC-7890
San Antonio, TX 78229-3900
chenx4 [ at ] uthscsa.edu

Posted by Monya Baker on January 08, 2008
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