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Here's a quick note to say that I won't be posting for the few days before the big stem cell conference, as I'm taking a few insufficient days to see Spain. I've seen a glmipse of some of the announcements and journal articles set to come out as the conference opens, and it's going to be a very busy time in the beautiful city of Barcelona. Hope to meet a lot of you there.
Both the Washington Post and the New York Times are running articles today on the state's decision to pay women up to $10,000 for donating eggs for stem cell research. (The Post is the stronger article, but most of the nuances are on the second page). This was covered last week in the Niche and the Great Beyond.)
The articles do not mention the pressing scientific question these eggs might answer: how good are iPS cells? Everyone is excited about induced pluripotent stem cells, but no one understands their limitations. Right now, there is anecdotal evidence that iPS cells don't behave exactly like ES cells, but perhaps that's because the best techniques haven't been worked out yet. The best way to learn this is to compare genetically identical stem cells generated by both methods. For one set of stem cells, you'd take a skin biopsy from Patient A, reprogram the cells to pluripotency. That's iPS cells. For the other stem cells, you'd do somatic cell nuclear transfer: put a nucleus from one of Patient A's cells into an enucleated egg, grow that to a hollow-ball embryo, and use it to make embryonic stem cells. Now you've got both ES and iPS cells carrying patient A's genes.
(BTW: This is a tricky situation for career-minded scientists. Find no differences, no one will notice, AND you'll look foolish if someone else comes along later and sees something you overlooked. Find differences, and worry about looking foolish if you've published an artifact.)
Nonetheless, this is a situation in which people really do need more information for informed debate. Unlike for humans, embryonic stem cells have been cloned for monkeys and mice. iPS cells have also been made from these creatures. Those of you who have genetically identical iPS and ES cells for mice and monkeys, we need to see your results!
My guess is that the scientists hoping to use human eggs in stem cell research believe strongly that they will find something interesting (though of course that in itself does not justify research)
Objections to the research in the articles are 1) that paying women for eggs exploits them and 2) that scientists should avoid controversy. The Post article goes on to describe that women are already paid for eggs, but only if the eggs are intended for making babies, not stem cells.
The articles also did not mention the egg-sharing program which is widely accepted in the UK. Women seeking IVF treatment get a discount for donating unfertilized eggs collected. Also, bioethicist Insoo Hyun has argued that oocyte providers should be given the same consideration and compensation as other healthy research subjects. (See that Nature commentary)
It's unclear whether those objecting to egg payments for stem cells also object to egg payments for in vitro fertilization. But it is true that the most sought-after IVF egg donors are college-educated and so have more options to earn more money. If there is a worry that paying poor, oppressed women for eggs exploits them, why not only allow college-educated women to donate eggs for stem cell research? They can already choose to sell eggs to fertility clinics. (There is precedent for this kind of discrimination; I've been paid for participating in scientific research in which all subjects were required to have a biology degree; this was considered necessary for giving informed consent.)
Marie Csete will resign her post from the California Institute of Regenerative Medicine as of Aug 1st, according to the California Stem Cell Report, Consumer Watchdog and the Silicon Valley Business Journal. The resignation comes just before a huge round of grants aiming to push stem cells toward clinical trials is due to be awarded. No word on where Csete, who moved to San Francisco for the job, will go now.
Former CIRM President Zach Hall and his chief scientific officer Arlene Chiu previously resigned their posts after widely reported conflicts with Bob Klein, the businessman who spearheaded the legislation that gave birth to CIRM. Marie Csete is very widely respected for having both clinical science and basic research expertise. I interviewed her shortly after her arrival at CIRM, and was impressed with her very practical approach to the unglamorous parts of helping move stem cells into human testing (See Prepping stem cells for the clinic)
Just over a week ago, California Stem Cell Report had reported that CIRM had pulled at least one grant for apparent lack of progress. I recall that when I had spoken to Csete last year, she had said that she would ask grantees to set and meet goals. Such monitoring was not something basic scientists were used to, she'd said.
CIRM's governance and staffing is unusual and many would say a hindrance. (See CIRM's search for a president goes on which describes the time between Zach Hall's resignation and the hiring of eminent Australian scientist Alan Trounson)
According to the press release announcing her arrival at CIRM in March 2008: Prior to joining the CIRM, Dr. Csete was John E. Steinhaus Professor of Anesthesiology at Emory University, with adjunct appointment in Cell Biology, and program faculty appointments in Biochemistry, Cell and Developmental Biology, Neurosciences, and the Emory/Georgia Tech Biomedical Engineering Program. She was also the director of Liver Transplant Anesthesiology at the Emory University Hospital in Atlanta and director of the Emory/Georgia Tech Human Embryonic Stem Cell Core, and co-Director of the Emory MD/PhD Program.
Every time I’ve gone to an ISSCR meeting, I'm really busy trying to consolidate my note and get blogs up. All the sleep-deprived while, I'm feeling guilty about the stuff I don’t cover. This year, I’d like to ask you for your help. Are you willing to send me 50-200 words on the talks and posters you find most interesting?
If so, let me know before ISSCR starts (It starts July 8, but let me know by June 29). Describe your scientific or professional background in ten words or less. In four sentences or so, describe a paper or development that you think is exciting in stem cell biology or business. At the conference, you’ll write up what you like and send it to me for a quick edit. I’ll send it back to you so you can check for accuracy, and it will go up on the Niche with your name. I might be able to pay some grad students or postdocs (be forewarned: it won’t be much)
I’m not going to bar people from writing about whatever they think is the most interesting, but I may not put up every submission. Also, I encourage you to avoid perceived conflicts of interest. By agreeing to write for the Niche, you agree to disclose potential conflicts such as but not limited to the following: writing about researchers who have worked with or for you, writing about researchers you’ve slept with or reasonably plan to sleep with, writing about organizations or companies with which you have a financial relationship, etc. Also, if you hope to quote someone and you're not wearing a press badge, let the person know at the beginning of the conversation that you might be looking for information for quotation.
If this sounds fun, send an email to theniche[at]nature.com with the subject line “covering ISSCR” by June 29th. In any case, I'm looking forward to meeting many members of the stem cell community in Barcelona this year.
Cross-posted from the Great Beyond
The New York Empire State Stem Cell Board (ESSCB) has approved the use of state funds to compensate women who donate eggs for embryonic stem cell research.
The board, which implements New York’s $600 million stem cell research initiative, reached the decision on 11 June. Board members noted that taxpayer funds are already used to compensate some egg donors in state-subsidized in vitro fertilization programs. They also emphasized that researchers in other states that do not allow payment for eggs – including Massachusetts and California -- have largely failed to recruit donors.
Nevertheless, the decision sparked a predictable outcry from activists. The New York State Catholic Conference called it “a grossly unethical, dangerous and exploitative move that treats women’s body parts as commodities,” (Catholic Courier) and Thomas Berg, a Catholic priest and a member of the ESSCB’s ethics committee, criticized the board for not allowing public comment on the issue (Christian News Wire).
By Heidi LedfordSee also Nature news: Egg shortage hits race to clone human stem cells
Regulatory authorities in India have, for the first time, given the green light for clinical trials to test stem-cell products, according to an article in Nature Biotechnology. Sponsored by Stempeutics, those trials will test mesenchymal stem cells in patients who with critical limb ischemia or who have had heart attacks. Like a handful of other trials, these cells will be derived from the bone marrow of healthy donors, processed or expanded in vitro, and injected into diseased patients. (See Questioning the Self Cell)
Meanwhile, an unrelated article in the Times of India suggests that, because the US will soon be able to fund more human embryonic stem cell research, India could soon become a hotbed of clinical trials for products derived from these cells. The article includes a quote from the head of a prominent Indian eye clinic stating that most work in India is in non-embryonic stem cells.
Like him, I don’t believe that the Indian market will be flooded with embryonic stem-cell trials anytime soon. Geron is supposed to start trials this summer in spinal cord injury; it needs only a tiny number of patients, with very specific kinds of injuries. Neither Novocell or the London Project will be ready to test their products for, respectively, diabetes or blindness, for several years.
I remember that, at the ISSCR meeting last year, Alok Srivastava, head of the Centre for Stem Cell Research at Christian Medical College, Vellore, described the procedures unregulated clinics in India were performing on paying patients. His argument was that if these clinics could be persuaded to characterize their cells and monitor their patients, the scientific community could glean valuable information. Still, he admitted, such open reporting would usually be at cross-purposes with those trying to make the most money most quickly. (For an analysis of the multiple conflicting motivations in unregulated stem-cell therapies, see our commentary from last year.
Srivastava is on the ISSCR committee that drafted guidelines for conducting clinical research on stem cell products. See Stick to the guidelines and fewer get hurt
It's been a little slow around here with stem cells–related news, so I've compiled some things from the past few weeks to make this entry.
Researchers have long known that fat will move into the placesleft behind when blood-producing cells are destroyed by chemotherapy or irradiation. New work, however, suggests that there is more going on. “We were taught in med school that fat was a space filler in the marrow, inversely proportional to haematopoietic content,” says George Daley of Children’s Hospital Boston. “What we show is that the fat actively influences HSC [haematopoietic stem cell] activity.” More specifically, Daley’s team shows that discouraging fat production in the marrow actually helps HSCs engraft1. This has important implications for helping patients recover after bone marrow transplants.
Previous work on the bone-marrow niche had focused on the bone-forming osteoblasts and the pericytes found around capillaries, says Sean Morrison of the University of Michigan in Ann Arbor, who was not part of the study. “This paper presents some of the most convincing data we have so far implicating a specific cell type as a physiological regulator of stem cell function and haematopoiesis.”
The researchers began their work by comparing the relative amounts of fat- and bone-producing cells in different mouse vertebrae. Compared with vertebrae in the upper back, tail vertebrae had the highest percent of fat and also had 25% as many haematopoietic cells, as measured by the marker CD45. Next, they simulated the effects of radiation therapy and bone marrow transplantation in normal mice and genetically engineered fatless mice. Weeks after transplant, the fatless mice had more haemoglobin and white blood cells in their blood. Finally, they tested whether a compound known to keep fat from forming in the bone marrow could increase both haematopoiesis and bone marrow engraftment. More specifically, the treatment used a compound called BADGE (bisphenol A diglycidyl ether) that inhibits peroxisome proliferator–activated receptor-gamma (PPAR-gamma) and stalls adipocyte formation in the bone marrow, at least in mice rendered diabetic through doses of streptozotocin. The results might also reveal why experimental diabetes drugs designed to work by activating PPAR-gamma might reduce blood formation in the marrow.
Daley thinks there is likely an “orchestra” of several cell types interacting in the bone marrow niche to influence haematopoiesis. His lab is currently looking into several mediators released from fat cells that could have such effects. Additionally, PPAR-gamma antagonists are currently being studied to treat obesity, and Daley is testing whether these might also help blood systems recover in patients receiving bone marrow transplants. “I think the clinical implications are quite compelling.”
Related articles
Peeking through bone to blood formation
Making stem cell niches in vitro and in vivo
Clearing a patch for hematopoiesis
References
1. Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature advance online publication, doi:10.1038/nature08099 (10 June 2009).
The Interstate Alliance on Stem Cell Research has posted its comments on the NIH draft guidelines as a ppt presentation.
Here’s a twelve-word summary: The language in the draft guidelines could interfere with the guidelines’ intentions.
Transplants of a fetal neural stem cell product seem safe, according to a 12-month study on six children with a horrible neurodegenerative disease called neuronal ceroid lipofuscinosis or Batten disease. Furthermore, the company reported results from an autopsy of a treated patient who died from the disease. (See Girl dies in stem cell trial for Batten disease ). These indicate that the injected cells engraft and survive in the brain for close to a year.
Continue reading "StemCells clinical trial results: Cells survive, seem safe" »
Those of you who've met me know I'm constantly trying to figure out how to split my time between research highlights, summarizing news on the Niche, getting commentaries, Q&As, news features, etc. Now I've got a formal way to find out. Please take our brief survey. This link is only going to be live for a short while (I think it goes down on June 11th)
While covering a couple papers just out in Cell Stem Cell, reporter Simone Alves uncovered an interesting conversation about how the genetic constructs used to explore a protein's role can affect results: This will be on the main site next week, but I thought I'd post it here for now.
Besides illuminating basic biology, a better handle on how the blood supply is replenished could reveal ways to treat blood cancers and other diseases. Hedgehog signalling, vital in normal development, was thought to play an important role in haematopoiesis, but two papers published recently in Cell Stem Cell question whether this is really the case.
Iannis Aifantis and his team at New York University investigated a conditional knockout mouse in which the hedgehog (Hh) effector, a protein called Smoothened (Smo), is deleted in adult mice1. In this model, deletion was triggered by chemically inducing expression of interferon-alpha. To their surprise, they detected no difference between the knockouts and controls when they measured haematopoiesis, peripheral blood count and colony formation in blood samples in vitro. The cells could also compete with wild-type cells when transplanted into nude mice, and overexpressing the protein didn't expand the haematopoietic stem cell (HSC) numbers or abilities.
"This was a big surprise", says Aifantis, revealing that he had the whole set of experiments repeated just to be sure of the results. Gary Gilliland's team at Harvard University in Boston reported similar findings in the same mouse knockout model, confirming that Hh does indeed appear to be dispensable for haematopoiesis2.
Interestingly, these two studies contradict a lot of the published literature, which suggests a role for Hh signalling in HSC regulation. "Not only did we not prove this, we actually disproved it," Aifantis continues. "It took a long time, but we knew we had something interesting."
"This is surprising because previous work using both gain- and loss-of-function approaches has suggested a critical role for Hh in the development of haematopoietic cells,” says Tannishtha Reya of Duke University in Durham, North Carolina. “It's scientifically important to examine every aspect; we need to look at all the experiments in an integrated way." Earlier this year, Reya's lab showed, in a different mouse model in which Smo was deleted at an earlier stage, that blocking Hh signalling reduced the regenerative capacity of HSC. So why the difference?
In Reya's opinion, it comes down to three things: timing, context, and the method of deletion. Both Reya and Aifantis believe that because the vav-Cre model that Reya's lab used is active from embryonic stages, the timing of the deletion could be the key. Early deletion may prevent other pathways from compensating and thus may reveal defects more readily. In terms of context, the mouse model used by Gilliland and Aifantis requires interferon expression, which has been reported to activate HSCs, explains Reya. (Aifantis believes the effect of interferon is negligible.) Other differences could be due to whether the gene is deleted in germline, giving rise to animals that lack the gene entirely, or if the gene is deleted conditionally, using techniques that apply only in certain tissues or under certain circumstances.
Particularly interesting was that Aifantis's paper showed that the Smo knockout had no effect on T cell development, yet an earlier paper from his lab using a different mouse system had the opposite result. In addition, a recent germline deletion of Smo studied by yet another lab also caused a defect in T cell development3. "This was the biggest surprise", said Aifantis, because it further questions the importance of the backgrounds of the mice.
There are certainly clinical implications for these studies, agree Aifantis and Reya. Most studies, including these, demonstrate that loss of Hh signaling allows haematopoietic cells to retain at least some functional capacity. This suggests that the use of small molecule inhibitors of Smo may be valuable in the treatment of leukaemias, in which Hh plays a role, because they will be able to kill cancer cells without severely affecting normal stem cells.
These papers certainly leave a lot of questions unanswered. It will be important to look at early haematopoiesis and use alternative mouse models to gain a fuller picture of what is really going on, says Reya. Aifantis agrees, adding that "we may be looking for answers before we know if they even exist".
Related articles
Self-renewing blood and leukaemia cells need hedgehog
References
1. Gao, J. et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 4, 548–558 (2009).
2. Hofmann, I. et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 4, 559–567 (2009).
3. Dierks, C. et al. Expansion of Bcl-Abl leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell 14, 238–249 (2008).
Author affiliation
Simone Alves is a freelance writer based in London.
This letter, from Francisco Silva, President of DaVinci Biosciences, responds to a Nature Reports Stem Cells article on one of his research papers as well as subsequent correspondence.
In response to PrimeGen Biotech’s letter to NRSC, I would like to make it clear that my comments regarding PrimeGen Biotech’s position on publishing were in no way meant to imply that their strategy was wrong. Cell based therapeutics is a very challenging and competitive industry, developing a technology in the laboratory and translating it into human application is very difficult. During my tenure as Executive VP of Research and Development at PrimeGen Biotech, my primary responsibilities were to identify and develop new technology which is demonstrated by PrimeGen Biotech’s intellectual property portfolio with seven patent applications.
With PrimeGen Biotech’s revamping of their R&D management as per Dr. Izadyar, I look forward to seeing them in clinical application next year. After all, "Our goals are ambitious--we believe with this therapy, we can be in clinic in 2010," said PrimeGen president John Sundsmo in an interview. [Editor's note: Fari Izadyar emailed on June 6 to say that John Sundsmo left PrimeGen during the revamp.]
I would like to thank Dr Schwartz for his remarks. At the time of entering our clinical study for spinal cord injury (SCI), we understood that it would have been ideal to include a control group, but being that this was a safety and feasibility study, the safety of the patients came first.
Continue reading "Correspondence: Response to article on spinal cord study" »
The following letter, from University of Tokyo's Hisashi Moriguchi, responds to a recent news feature in Nature describing the scientific race for the assessment and production of induced pluripotent stem cells.
In your News Feature 'Fast and furious' (Nature 458, 962–965; 2009), the safety issues concerning induced pluripotent stem (iPS) cells are well summarized. However, reviewing some published manuscripts for iPS cells, I have found that the reports on the cells' safety are very different among nations.
The follow-up data needed to evaluate the cancerous transformations of iPS cells have been shown in most original manuscripts from Japan (Cell 131, 861–872; 2007. Nature Biotechnol. 26, 101–106; 2008. Science 321, 699–702; 2008). On the other hand, such follow-up data have not been provided in most manuscripts from other nations (Nature 458, 766–770; 2009. Science 324, 797–801; 2009).
Now, new technologies to lower the risk of cancerous transformations by iPS cells have been reported (Nature 458, 962–965; 2009). However, which of the technologies most consistently produces the iPS cells with the least chance of tumourigenicity? The evidence has not been shown.
Continue reading "Correspondence: iPS cell safety data needs tracking" »
The following letter, from Primegen's Fari Izadyar, responds to comments made about PrimeGen by former executive Francisco Silva in a recent article in Nature Reports Stem Cells.
We wish to comment on certain aspects of the interview with Francisco Silva published in Nature Reports Stem Cells (9 April 2009), which accompanied an analysis of his recent publication. First, we applaud Dr Phil Schwartz's rigorous discussions on the sham surgery effect of untethering the spinal cord and removing scar tissue, and the acknowledgement of both the placebo and the potentially therapeutic physical effect of the manipulation, which is separate and distinct from the cell therapy component. In other words, with so much noise, how does one see a signal in such a small uncontrolled study?
In the article, Francisco Silva described our company as having "...a corporate strategy regarding publishing their work, which differed from my belief that peer review is required and needed process providing validation and transparency. As a result, I left [the company] in 2007."
In the interview, PrimeGen Biotech was erroneously described by Silva as having a corporate strategy that did not believe in validation, transparency or the peer review publication process. Our company has a demanding corporate policy for a rigorous and careful validation process prior to publication of our results, and, contrary to Silva’s claim, our company has published research in respected peer-reviewed journals, such as Biochemical Biophysical Research Communication, Reproduction, Human Reproduction and Tissue Engineering and Regenerative Medicine (in press). Silva is one of the senior authors on two of these papers, which were submitted prior to his departure, and this clearly demonstrates that peer-review publication has always been an important part of our corporate policy and directly refutes Silva’s claims.
Continue reading "Correspondence: Primegen supports peer review, transparency" »
Posted for David Cyranoski; Cross-posted from The Great Beyond
Researchers in China have made pluripotent stem cells from a pig. The cells could be useful for making humanized pig organs for transplant to humans, pig models of human disease useful for testing drugs, and for improving pig farming productivity and nutritional value.
Lei Xiao, head of the research group at the Shanghai Institutes for Biological Sciences where the research was done, admits that none of these will happen for the next several years. But his creation in pigs of induced pluripotent stem (iPS)-cells which share with embryonic stem cells the ability to differentiate into any cell type in the body-is still a huge accomplishment. (Paper).
The isolation and culture of embryonic stem (ES) cells from mice in 1981 revolutionized the use of mice as a developmental and biomedical research model. But it is a difficult process. It took 17 years to culture human iPS
cells. Even now there are ES cells for only four mammals: mice, humans, monkeys, and rats. Pig ES cells, despite many attempts, still do not exist.
Stable iPS cell lines could be an easier alternative. iPS cell lines, which are made by using defined genes, proteins or small molecules to "reprogram" adult cells to an embryonic-like state, have been created in the same 4 species as those listed above for ES cells. Xiao's research make pigs the fifth.
Xiao's four iPS cell lines appear to match the key properties of ES cells, notably pluripotency. They express all the right markers, they form cancerous growths known as teratomas that show all the major cell types when injected into immune-deficient mice, and they have been able to maintain this pluripotency for more than 20 passages into new cell cultures.
The cells will still need to be compared with pig ES cells. Xiao says that his recipe for culturing the cells might work with ES cells. But he might already be scooped on that-the research group of once lionized now scandalized cloner Woo Suk Hwang in Korea has been promising in the Korean press a publication showing pig ES cells within a couple months. (Korean Times).
Pig iPS cells and ES cells will then have to prove their usefulness. Xiao will use the cells to either "knock in" genes (by introducing genetic material) or "knock out" genes (by interrupting some genes' functions).
For example, immunity-related genes can be knocked out to make the pig's organs compatible with humans. But transgenic manipulation of pigs has been going on now-albeit with a more time-consuming, less efficient, more difficult method using cloning procedures-for years now. Still there are no pig-based transplants ready. And some argue that using transgenics to solve problems in agriculture, like the creation of transgenic pigs with healthy meat rich in Omega-3 fatty acid, is a completely over- the-top, using a hammer to squash a flea, solution.
(Nature Biotechnology - 24, 1472 - 1473 (2006) doi:10.1038/nbt1206-1472)
Image: by johnmuk from Flickr under Creative Commons
Cells containing mutations for Fanconi’s anemia can be repaired and reprogrammed
Human cells carrying mutations for a complex genetic disease can be repaired and reprogrammed so that they appear indistinguishable from cells taken from healthy individuals. Juan Carlos Izpisúa Belmonte at the Center for Regenerative Medicine in Barcelona and colleagues have generated 19 lines of so-called induced pluripotent stem (iPS) cells from patients carrying a variety of mutations that give rise to Fanconi’s anemia, a rare and often fatal disease. “We show that genetic correction, combined with iPS cell technology, can be used to produce disease-free cells with potential value for cell therapy applications,” explains Belmonte.
Though the cells have not yet been tested in patients or even animal models, it is an important proof of principle for both cell and gene therapy, says John Wagner, clinical director of the Stem Cell Institute at the University of Minnesota. “The problem with gene therapy wasn’t with the gene but the fact that [the gene] wasn’t getting to the right cell. This is a new strategy that says now we can get many cells,” he says. “It’s very much boosted my enthusiasm for gene therapy, at least for this horrendous disease.”
Both Belmonte and Wagner cite several factors that must be overcome before the procedure is ready to move into patients. First come better procedures for making the necessary cells. Cells from Fanconi’s patients typically do not proliferate well, and Belmonte found that the cells’ genetic defects had to be repaired before they could be reprogrammed and differentiate.
Continue reading "Gene therapy combined with reprogramming makes disease-free cells" »
