The Niche

There is some new research just out from StemCells Inc, which is running clinical trials for Batten's disease, a neuordegenerative disease. Here's a quick write up from my reading of the paper, a study of a mouse model. Motor coordination symptoms were delayed by a week or so based on a comparison between 14 mice that received transplants and 8 that did not. My initial thoughts are that the length of time of the experiment was too short, and I'm not sure if the magnitude of the observed effect would be clinically meaningful, but it does indicate movement toward ameliorating a serious disease.

Here's my post from the latest results from StemCells' Batten's disease trial indicating that cells survive in human patients for at least a year.

Here's the mouse research.

Some brains literally poison themselves. In the diseases known as infantile neuronoal ceroid lipofuscinosis or Batten’s disease, brain cells lack enzymes necessary to clear away their byproducts. Clinical symptoms of congenital forms of the disease include seizures, cognitive and motor decline, blindness, and early death. The Palo Alto company StemCells is conducting clinical trials to see whether cell therapy can ameliorate the disease. The rationale is that the functioning enzyme made by transplanted cells can help keep patients’ own cells alive. Work in Cell Stem Cell shows that the transplanted cells do indeed make and secrete the enzyme and that the transplantation delays the loss of motor coordination for a week in a mouse model of the disease.1
Previous, unrelated research had indicated that the transplantation strategy could delay onset of a similar malady called Sandhoff disease for a month and prolong lifespan by six weeks.2 However, this had not been demonstrated for lipofuscinosis nor for the human neural stem cell product the company has developed. A team of scientists led by Nobuko Uchida showed that these cells secreted a functioning lysosomal enzyme palmitoyl protein thioesterase, the enzyme that patients with Batten’s disease lack. Then they transplanted these cells into the brains of immunocompromised mice that were also unable to make this enzyme. When they examined these mice twenty to twenty-seven weeks later, they found that transplanted cells developed into neuronal-like cells in the olfactory bulb, and various types of support cells in other parts of the brain. They remained neural stem cells stem cells in the cortex.
Next, the researchers looked at the amount of lipofuscin, the toxin that builds up in Batten’s patients, in the brains of three mice that received transplants and four that di not. Overall, mice that received transplants had significantly less lipofuscin, 37% less in the cortex, and more than 50% less in the hippocampus.
Thus, the current work shows encouraging proof of principle that transplanted cells can support endogenous ones. According to the paper, evidence from 3,000 mice has not identified any instances of the transplanted cells causing a tumour. The next steps will be to see whether the cells survive long enough and secrete enzyme long enough to have a clinically meaningful effect.

1. Tamaki et al. Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis. Cell Stem Cell 5, 310–319 (2009) DOI 10.1016/j.stem.2009.05.022
2. Lee, J. P. et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nature Medicine 13, 439 - 447 (2007)

Posted by Monya Baker on September 03, 2009
Categories: Regenerative medicine | Permalink | Comments (0) | TrackBacks (0)

Two groups of researchers have at last completed a stringent test to show that induced pluripotent stem cells have the same developmental potential as embryonic stem cells: inserted into a special embryo, they can contribute to all the cells in a new mouse, litters of which have now been produced. (See the Nature news story)

GoogleNews was saturated this morning with stories of how to regenerate the heart:

Continue reading "Round-up of regenerative medicine stories and a big, squeaking accomplishment" »

Posted by Monya Baker on July 23, 2009
Categories: Clinical trials, Heart, Regenerative medicine, Reprogramming/Pluripotency | Permalink | Comments (0) | TrackBacks (0)

Headlines from a recent PNAS study showing that stem cells can reverse dementia in mice keep popping up in my inbox. Here's the press release. The cells don't actually become neurons but instead secrete a well-studied protein called brain-derived neurotrophic factor that stimulates neurons already in the brain to form new connections. The paper from UC Irvine scientists is supposedly out today, but I can't find it on the PNAS site. I'd like to know how much cognitive performance improved. Also, the researchers used mice genetically engineered to have Alzheimer's. That's often the only way to study this, but I'd like to know how well the model represents human disease and also whether te researchers started "treating" the disease pathology long before any clinical signs of the disease became obvious, which would mean the strategy may not work for patients that have had Alzheimer's for any significant time. Still, it's cool, and shows that the high, high bar of getting cells to integrate into highly complex tissue may not always be required. (Actually, human trials in the neurodegenerative horror called Batten's disease are underway with StemCells Inc. The injected fetal neural cells are not supposed to integrate into the brain tissue but to help it destroy a toxin that builds up in diseased patients' brains. It's too early to know efficacy yet, but the latest report was that the cells seemed safe.)

In less sanguine news, an autopsy of three Huntington's patients showed that transplanted neural cells did not survive, and that the transplanted cels degenerated faster than the patients' own neurons. (I'll paste the abstract below). Here is a link to this Open Access article as well as a news story from Nature.

Both studies emphasize that not only are techniques fo making specific cell types necessary, but researchers are also going to have to find ways to keep them alive. Compared to the most common animal models, patients are bigger, more complex, and have funcitoning immune systems. As someone recently said of the failure to cure cystic fibrosis in the two decades since the gene was discovered: "we haven't failed. It's only been twenty years."

Continue reading "Mouse study shows stem cells might help Alzheimer's" »

Posted by Monya Baker on July 21, 2009
Categories: Regenerative medicine | Permalink | Comments (0) | TrackBacks (0)

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" »

Posted by Monya Baker on June 01, 2009
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Two transcription factors and a chromatin remodeller help make mouse cardiomyocytes

{Here's a highlight of work recently published online in Nature}

Ever since researchers turned cultured cells into muscle, scientists have been searching for ways to do something similar to make heart cells.[1] That’s because, at least in the developed world, heart disease kills more people than anything else — in part because adult hearts are not able to replace damaged cells. Now, Jun Takeuchi and Benoit Bruneau at the Gladstone Institute of Cardiovascular Disease in San Francisco have found that adding cardiac-specific genes to developing mouse embryos can make even some extra-embryonic parts become beating cardiomyocytes[2].

Continue reading "A recipe for heart cells from amnion and more" »

Posted by Monya Baker on April 30, 2009
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A transplant of blood stem cells in early onset diabetes seems to stop the immune system’s errant attacks on patients’ insulin-producing cells and so allow 20 of 23 patients to forego daily injections.
Read about the new JAMA study in Bloomberg. The work moves forward previous research on diabetic children carried out in Brazil.
The authors have previously reported using this system to stop errant immune attacks in an early study for multiple sclerosis. The strategy of the treatment is not to replace the tissue lost to the disease, but to stop the body from destroying itself.

Posted by Monya Baker on April 14, 2009
Categories: Clinical trials, Regenerative medicine | Permalink | Comments (0) | TrackBacks (0)

The press resleases of two new studies are making the rounds, so I'll point to them here. One mouse study, published in Developmental Cell, shows that gene therapy can prompt liver cells toward beta cells. I'll cover the other press release tomorrow.

I'd actually looked into the mouse study a bit, so I'll put that up now. It will go on the site as a formal article next week.
A sort of beta-cell magic: transdetermination seems easier than transdifferentiation
A single added gene prompts liver progenitor cells to make insulin and reverse diabetes

With the introduction of a single gene, cells in the liver can take on the function of pancreatic cells and go on to reverse symptoms of diabetes in a mouse model of the disease. Researchers led by Lawrence Chan at Baylor College of Medicine in Houston, Texas had already shown that they could, in effect, cure diabetes in mice by infecting their livers with a virus containing the gene for neurogenin (Ngn3), a transcription factor that is expressed as cells begin differentiating into insulin-producing beta cells, the type of cells lost in juvenile diabetes. But while the researchers knew that it worked, they did not know why, so they began trying to figure out what cells in the liver began producing insulin.
Careful lineage tracing studies implicated two types of cells.1 The first were hepatocytes, mature cells that made insulin only for about six weeks after infection. The other, more-stable source of insulin-producing cells were liver progenitor cells. These actually switched lineages and went on to form clusters of islet cells that resembled those that the pancreas would make normally after an injury. Further analysis showed that the liver cells were expressing a wealth of genes made in pancreatic lineages in general and for the insulin-producing beta cells in particular.
“The phenomenon is certainly worth further investigation,” says Ken Zaret, a cell biologist at the Fox Chase Cancer Center in Philadelphia. He says that Chan’s work is similar to that of other researchers who showed that adding genes for transcription factors can change cell differentiation.2,3 “However, it differs in discovering that the more stable target in the target tissue is not the terminally differentiated cells, here the hepatocyte, but rather an apparent facultative progenitor cell.”
Chan believes that fully developed hepatocytes are not capable of transdifferentiating, or switching from one mature cell type to another. However, the progenitor cells are at a “weak point” in their differentiation pathway, in which their default lineage can be transdetermined to another lineage. Liver and pancreas are both endoderm organs, and some molecules expressed early in their development are the same. “I believe that the more closely the cells are related to the endocrine pancreas lineage, the more likely they will be ‘pushed’ into the beta-cell lineage,” Chan explains.
Several factors may be doing the pushing. “My sense is that the success of the experiments is due to the convergence of multiple stimuli,” says Zaret. In addition to the Ngn3 transcription factor, he says, other conditions, particularly the viral infection and the high blood glucose levels in diabetic mice could be necessary to stimulate the nascent beta-like cells to proliferate.
Chan believes that this approach of causing progenitor cells to switch lineages may have more general applications. “Induced transdetermination may be easier to accomplish than induced transdifferentiation, if one can identify the receptive cell lineage,” he says. Thus, “receptive” progenitor cells could be a viable target to regenerate organs in multiple diseases, including but not limited to diabetes.

Related articles

Smash the (cell) state

Thomas Graf: Cellular identity and transdifferentiation

1. Yechoor, V. et al. Neurogenin3 is sufficient for in vivo transdetermination of hepatic progenitor cells into islet-like cells but not transdifferentiation of hepatocytes. Developmental Cell (2009)

2. Lassar AB, Paterson BM, Weintraub H. Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 47, 649-56 (1986)

3. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627-32 (2008)

Posted by Monya Baker on March 17, 2009
Categories: Regenerative medicine | Permalink | Comments (0) | TrackBacks (0)

Here’s a trio of three early stage studies that look encouraging for using stem cells as therapies in the brain.

Continue reading "Neural clustering" »

Posted by Monya Baker on March 11, 2009
Categories: Neural stem cells, Regenerative medicine | Permalink | Comments (0) | TrackBacks (0)

One of the leading cell-therapy diabetes companies has just enlisted a rock star. The scientist who first described how to reprogram differentiated cells to pluripotency, Shinya Yamanaka of Kyoto University,has signed a deal with Novocell to use induced pluripotent stem (iPS) cells to replace the beta cells that are lost in diabetes.

Stem-cell approaches to diabetes continue to garner corporate interests. I described some stem cell diabetes deals involving NovoNordisk and Cellartis back in October.

Novocell and Geron are racing to develop protocols that can make beta cells from embryonic stem cells. The obvious experiment is to try these same protocols on iPS cells too. See our research highlight Perfect pancreatic cells, which links out to other stories.

Here’s the press release from NovoCell. Putting things mildly, it’s not big on details about financial or intellectual property agreements.

Yamanaka is famous for reprogramming cells to pluripotency, not nudging and coaxing and guiding pluripotent stem cells to glucose-responsive, insulin-secreting beta cells. No one is saying anything about what, exactly, Yamanaka might do to make iPS cells that are willing to be coaxed down this road. However, while I’ve yet to see anything in the peer-reviewed literature, more than one conference presentation has described that iPS cells created under different circumstances have different predilections for differentiation.

Also privately funded NovoCell itself is a bit of a new entity now. In November, CEO Alan Lewis announced that he’d be taking a job at the non-profit Juvenile Diabetes Research Foundation .

Posted by Monya Baker on December 10, 2008
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People who need a recent, accessible summary of what stem cells could do in medicine should check out this Newsweek piece, Will Stem Cells Finally Deliver? by Harvard professors David Scadden and Anthony L. Komaroff.

For those who want more-technical reading, Science has pulled together a special issue on organ development, that includes articles on regeneration of pancreas and liver cells (Marcus Grompe and Ken Zaret), stem cells’ origin in organogenesis (J.M.W. Slack), cardiogenesis (Ken Chien, Ibrahim Domian, Kit Parker), and more.

And, I’d be remiss not to mention the special issue that Nature put together several months ago on regenerative medicine. Here’s a web focus of reviews and relevant research articles, as well as accessible, informal interviews with experts including Robert Boyd, Ken Chien, Sheng Ding, Geoff Gurtner, Christine Mummery, and Len Zon.

Posted by Monya Baker on December 08, 2008
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A patient who had severe tuberculosis is breathing much better after receiving a transplant of a trachea seeded with her own stem cells. The work, published in the Lancet, has been reported by the New York Times. A team of researchers from four European universities took a trachea from a decesased donor, removed its cells, leaving behind the extracellular structure, and re-seeded it with mesenchymal stem cells, a cell type found in bone marrow and elsewhere that can make (among many other things) cartilage.

Tony Atala at Wake Forset University has also made organs, in this case bladders, from patients' own cells. These have been studied in a handful of human patients. here's a CBS story that covers this and a profile from Nature Biotechnology.

Techniques to seed scaffolds with cells are growing apace; so are collaborations among disparate types of scientists. (See Thinking in three dimensions) In the case of the trachea, the trick was not to create a new scaffold but to decellularize and existing one. Work along the same lines has been caried out by Doris Taylor of Minnesota. (See Ghost heart has a tiny beat.)

Posted by Monya Baker on November 19, 2008
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Stem cells for diabetes got a vote of confidence this week, with giant Novo Nordisk entering into a deal with Cellartis and Lund University to create insulin-producing cells for diabetes. Novo Nordisk has been selling insulin since 1923 and knows the diabetes market well. Additionally, Geron announced a publication on its progress coaxing embryonic stem cells into what it calls islet-like clusters. The cells secrete insulin, glucagon, and other factors, as well as responding to glucose levels. These technologies are still far from clinical trials, and the buzz is that southern California’s Novocell is in the lead for bringing ES-cell products to trial for diabetes.

Two stem cell stories this week come from Palo Alto. On Monday, Stanford University broke ground for their new stem cell building, reported to be the largest in the US. It is funded by private donors and funds from the California Institute of Regenerative Medicine.

On Thursday, company StemCells ( also known for its clinical trial in Batten’s disease ) reported that its purified preparation of neural stem cells preserved sight in a rat model of vision loss, and that grafted cells persisted for as long as 150 days. The results were presented in a seminar and have not yet been published in a peer-reviewed journal. CIRM leader Bob Klein is also enthused about using stem cells for sight. When he signed a memorandum of understanding with the UK last week, he constantly referred to work by Peter Coffee from the British Institute of Opthamology that he felt was close to clinical trials.

Finally, Harvard’s Konrad Hochedlinger was named one of MIT’s Technology Reviews top young innovators. Along with Rudolf Jaenisch and Shinya Yamanaka, he created iPS cells that could contribute to germline, a stringent test of pluripotency. He recently reported how to make iPS cells without permanently changing the genome (see Integration-free iPS cells). Technology Review has links to his work and will tell you exactly how young he is.

Posted by Monya Baker on October 31, 2008
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In Madison, Wisconsin, the former US secretary of health bellows: “Some inner hope!” Tommy Thompson yells at the crowd—a room full of stem cell research advocates—preaching to the converted that embryonic stem cells give disease sufferers a reason to believe in a better life.

This is an unusual conference: patients and patient representatives plus industry executives, politically active scientists, lobbyists, ethicists, policy experts and more are here.

Although the conference organizer stresses that the meeting is not partisan, the crowd and some speakers are vocally anti-Bush because of his refusal to fund human embryonic stem cell research. Thompson tells the crowd that the policies could easily have been more restrictive and describes how Bush called in pro-research Thompson to debate anti-research Karl Rove on the issue. (The president munched a peanut butter sandwich during the impromptu but lengthy discussion; a few days after that he announced his compromise position to fund lines created before August 2001.) After relating the story, Thompson warns them not to be too harsh on Sarah Palin; they might need to work with her.

Later that afternoon, Alta Charo, a professor of law and bioethics at the University of Wisconsin–Madison, says debates over the moral status of five-day-old embryos are simple compared to what will come when cell-based products enter full-fledged trials for spinal cord injury and the like. She delineates problems with cell therapies, going from the difficult animal studies (monitoring cell transplants for months in infection-prone rodents) to the “polarizing debate around class and access to health care” that will ensue if an expensive cell therapy hits the market.

In between there is the hurdle of conducting clinical trials. When that happens, she predicts, the number of patients hoping to participate in trials far exceeds the number that can be enrolled.

Indeed, one of the scientists here told me privately that the constant invocation of "the 'C word'" (cure) made him uncomfortable. Even if cell-based therapies help, most are a long way from being tested, and they are more likely to improve a patient’s condition than to reverse it.

The exuberant attitude worries scientists, but it’s part of US culture, says Charo. The American mindset is optimistic and forward thinking. That means US patients often assume that 'the new thing' must be better than the current standard. “Without controlled trials, we can be sorely misled. People can undergo terrible ordeals for something that might be worthless.”

This is something that Wise Young thinks about nearly every waking moment. The neuroscientist from Rutgers University, in New Jersey, has courted controversy by reaching out to help organize stem cell networks in China and elsewhere, urging commercial practitioners to disclose their procedures (some refuse). Patients would go anyway, he says, despite the high cost and risk. “No matter what we do and what we say, medical tourism will occur until we start providing something that will satisfy the demand.”

Young calls for greater willingness to do clinical trials in the United States and for scientists to talk with and monitor patients before and after they go abroad for poorly documented procedures. Anecdotes are very hard to assess, particularly for spinal cord injury. Over time, patients’ conditions do tend to improve somewhat, and performance can vary significantly from month to month.

A coordinated group of scientists who would assess patients at multiple time points before and after they undergo procedures could provide invaluable information, even in the absence of a clinical trial, suggests Graham Creasy, chief of Spinal Cord Injury Service at the VA Palo Alto Health Care System in California. Indeed, this has been done on a smaller scale already, one for a clinic in Portugal, another for a clinic in China. An evaluation showed no significant improvement in patients’ condition. But there are problems with the approach. Medical experts in the United States worry that even this kind of inquiry could legitimize and thus encourage potentially harmful approaches that disqualify patients from future trials in the United States. Besides, what incentive would the medical tourists have to participate in these inquiries?

BTW: The International Campaign for Cures of Spinal Cord Injury Paralysis provides information for the general public on participation in clinical trials. (This is different from paying money to a far-off clinic for undocumented procedures, but similar questions apply.)
The International Society for Stem Cell Research has proposed draft guidelines for the clinical translation of stem cells and is seeking comments until the beginning of October.

Related stories
Stem cell society condemns unproven treatments

Stem cell researchers face down stem cell tourism

Here are all three blogs from the conference

Companies have company

Stem cell trials balancing hope and harm

Stem cell therapies, ready for success?

Posted by Monya Baker on September 25, 2008
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Here's my summary of a couple v. cool papers just published on powerful cells within blood vessels, with potential for tissue engineering and regenerative medicine. (We'll have it as a formal article next week)

Extra rolls of fat certainly come from extra calories, but where new fat cells come from has been far less certain. New research in mice shows that blood vessels within fat tissue harbour cells that have already committed to becoming fat cells and that give rise to most new fat cells.

Jonathan Graff and colleagues at the University of Texas Southwestern Medical Center, in Dallas, used a slew of genetic tricks to figure out when fat cell progenitors are produced and to track the descendents of these cells1. They found, surprisingly, a set of fat stem cells within the walls of blood vessels. "These cells lead to the formation of fat and likely are activated in obesity, so if you can interrupt that, you could block cells from forming or keep them from functioning," says Graff.

In particular, blood vessels could well regulate the formation of new fat tissue. Studies have hinted that blood vessels within many tissues house powerful progenitor cells that seem similar to the mesenchymal stem cell populations known to exist in bone marrow. A 20-member international team led by Bruno Péault at the University of Pittsburgh Medical School, in Pennsylvania, recently reported2 that the vasculature of multiple human organs contains cells “indistinguishable from classic mesenchymal stem cells.” These cells, says Péault, “should constitute an ubiquitous stem cell reserve in the body.”

Péault says Graff’s work is important because knowing what pericytes, which are also called mural cells, can do in culture is not the same as knowing how they normally function within animals. “We demonstrated the existence of a potential, but we have no clue as to how this potential is used.” Graff’s work “nicely confirms, in an elegant dynamic model, our basic statement regarding the role of mural cells as a stem cell reservoir,” says Péault.

Péault, who is also working on cell-tracking models, says an important next step is studying the role of pericytes in other tissues besides fat. “This obviously opens a broad field of investigation,” he says.

References
1. Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science doi:10.1126/science.1156232 (published online 18 September 2008).
2. Crisan, M. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008). | Article |

Author affiliation
Monya Baker is editor of Nature Reports Stem Cells.

Posted by Monya Baker on September 18, 2008
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The National Institute for Arthritis and Musculoskeletal and Skin Diseases will be starting its own transplant center to investigate the potential of bone marrow stem cells for muscle and bone diseases, according to a recent article in Wired News.

The NIH is already investigating embryonic stem cells as well as mesenchymal stem cells (a type of stem cell found in the bone marrow) to see if they can make cartilage and ligaments in laboratory dishes. Wired News reports that damaged joints in race horses are currently being aided through injections of mesenchymal stem cells.

What the article doesn’t mention is that there’s already a company doing something similar in humans, and it just got a letter from the FDA stating that the company’s therapeutic claims violated regulations and asking for a written response of how the company, Regenerative Sciences, will address them. I could not find any other such letter to another stem cell company.

Continue reading "Stem cells for joints: NIH studies, FDA worries, horses run" »

Posted by Monya Baker on August 18, 2008
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There are a couple cool stem cell papers in this month’s Cell.

Using a screen of chromatin regulating proteins in embryonic stem cells, UCSF’s Barbara Panning discovers something surprising. (See below)

Also see another cool article by Amy Wagers at Harvard, where her team was able to identify skeletal stem cells from look-alike cells and then show that these stem cells could rescue the phenotype of a mouse model of muscular dystrophy. It was written up in the Washington Post. and ScienceNews.

Packaging DNA for pluripotency
An RNA interference screen reveals a surprising player

Continue reading "Cell papers: purified skeletal muscles help mice; packaging DNA for pluripotency" »

Posted by Monya Baker on July 10, 2008
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An article in TIME describes a San Diego company that is already offering a procedure using stem cells collected from fat to treat pets with bad hips. Fat is scooped from a dog's abdomen, and then the stem cells are isolated with centrifugation (spinning test tubes of cells so that the heaviest ones go to the bottom) and injected into the problematic area.

The techniques that I know of to isolate stem cells rely on identifying markers on cell surfaces; in fact, the company introduces a mixture of cells to the site of injury. Because these cells are minimally manipulated, they don’t require the FDA’s approval to be transplanted into the same patient they were collected from

But, it’s not so much the cells as it is their effects that matter, and the company has published an article on these effects in a journal indexed in PubMed. It examines results of treatment for 90 days and found improvement in the stem cell group. A follow-up would be interesting because these effects might be transient. Human transplants of mesenchymal stem cells for nonorthopedic indications sometimes show initial improvement that quickly fades away.

The TIME reporter writes that these cells then become cartilage and tendons, and it is true that mesenchymal stem cells, a sort that is found mainly in bone marrow but can also be derived from fat, can become cartilage-producing cells; however, there is quite a bit of debate about what the cells really differentiate into, and claims on this company’s website seem, to me, appropriately couched.

The company seems more keen to demonstrate efficacy than mechanism, which would make the most sense for the bottom line. It looks like there’s more to learn, though.

Posted by Monya Baker on June 25, 2008
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Here’s some news on the commercial front that shows stem cell therapy moving forward. The pharmaceutical giant Pfizer has made a teeny-tiny investment in stem cells, according to an article in Forbes.

Pfizer is financing a company called EyeCyte, which hopes to use cells from the blood and bone marrow to repair damaged blood vessels in the eyes of patients suffering from diabetes and macular degeneration. Pfizer spends over $8 billion in research and development and is investing $3 million in EyeCyte in exchange for having part ownership of the company and being its sole pharmaceutical partner. If the therapyworks, though, the payoff could be huge: biologics against macular degeneration have proved big business.

Posted by Monya Baker on June 25, 2008
Categories: Industry, Regenerative medicine | Permalink | Comments (1) | TrackBacks (0)

Once again, there are more great papers out there than I can write about. Below are two that will show up on the site in a few days. (Nature Reports web production schedule requires a week). Also check out Tom Zwaka's paper that finds another, powerful control over Nanog; Sheng Ding shows that small molecules can substitute for two of the four Yamanaka factors, inching closer to reprogramming without viruses; in a high-throughput screen, Lorenz Studer shows us how known drugs affect human embryonic stem cells, a technique that might reveal unwanted side effects. (Those are all in the most recent Cell Stem Cell; see our Q&A with Sheng Ding on the potential of small molecules.)

See below for these papers along with links to less specialized articles.
A metasignalling network makes muscles age (Irina Conboy on skeletal muscle)
Two networks of pluripotency (Chia-Lin Wei and Huck-Hui Ng map transcription factor binding sites to find 'stemness hotspots')

Continue reading "Old stem cells made young; more maps of pluripotency" »

Posted by Monya Baker on June 17, 2008
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On Thursday, an FDA advisory committee meeting met to figure out how to decide whether products derived from embryonic stem cells were ready to be tested in human participants. There was much talk, even more questions, and no firm decisions.

Even so, the attendees I spoke with told me they felt certain that the FDA was serious about moving stem cells to the clinic. One consultant said that previous to today’s meeting, investors had expressed worries that today’s meeting would serve to kill the field. Several years ago, patient deaths in gene therapy trials caused the FDA to halt all such trials under its jurisdiction, another consultant told me, and that field has never recovered.

Now, the consensus was, the agency seems cautious about moving forward, but not spooked. Three companies, Geron, Advanced Cell Technology, and Novocell described their work bringing embryonic-derived cells in (respectively) acute spinal cord injury, visual impairment, and diabetes. One expert who wasn’t on the committee said that the discussions had been impressively grounded in science, even getting into specifics about what assays might be considered. Attendees were surprised that no opponents of embryonic stem cell research showed up, but the FDA's announcement said explicitly that it was only the cells' safety that was under consideration.

The director of the FDA’s Office of Cellular, Tissue, and Gene Therapies Celia Witten called the meeting useful. “We got enormous information in three areas: preclinical, product characterization, patient monitoring.” She added that within each area there were lots of recommendations. She declined to speculate on when or if a guidance document would come out, but it didn't seem soon.

But the recommendations were really approaches to answering lots and lots of questions. How do we know what cells we have? How do we know what the cells will do in the body? Where do you put cells? Where do they go? What do they do? How many cells might be dangerous? How many can be useful? What can animals tell us? If the cells “go rogue” in a human participant, will we be able to stop them or even to track them? What’s the best way to balance risk and benefit?

“I don’t know that there’s a one-size fits all answer,” said committee member Steven Goldman, a professor of neurology at University of Rochester Medical Center. At the time, he was making the point that different stages of differentiation will be appropriate for different diseases. (Neurodegenerative diseases may need progenitor cells that proliferate and integrate; diabetes seems best off with fully differentiated islet cells.” Still, the notion “it depends” applies to disease, cell type, patient characteristics, delivery route, etc. etc. ( See our interview with Marie Csete, head of the California Institute of Regenerative Medicine, which is also wrestling with these issues.)

I thought attendees would be disappointed in this attitude. After all, aren’t researchers reaching for the clinic looking for the list of assays they need to do to put cells into human subjects? But I spoke with four people, including Witten, and everyone seemed quite satisfied; that every product was already assessed individually no matter what it was and that potential risks always had to be titrated to potential benefits.

In the open public session, Amy Rick head of the Coalition for the Advancement of Medical Research asked the committee to consider the risk of living with and dying from a horrible disease when assessing risks to clinical trial participants; that’s a tough request, since the earliest trials set out to show safety rather than efficacy.

Other issues will need to be wrestled with if ES-cell therapies move from potential experimental procedure in human participants to potential therapies: providing access to care and applying treatments to a heterogeneous population. Its roots can be seen in the attendees, mostly white, with a smattering of Asian. The mixture of men and women attending was slightly tilted to men, more so on the advisory panel. Most people seemed closer to 60 than to 30.

Posted by Monya Baker on April 11, 2008
Categories: Regenerative medicine | Permalink | Comments (1) | TrackBacks (0)

This Thursday and Friday, the FDA deliberates on how to decide that cells derived from embryonic stem cells are ready to be tested in humans. On Saturday and Sunday, patient advocates and stem-cell researchers meet in San Francisco to talk about how to accelerate discoveries and therapies.

Both indicate a growing momentum for moving stem cells into applications. I wrote a preview article on the FDA discussions. The FDA’s got a difficult job to do. It has to make sure that it doesn’t slow down therapies for horrible, debilitating diseases and that human subjects aren’t exposed to dangerous procedures. This meeting is regarded as a first step for moving embryonic stem cells into well-regulated clinical testing.

I’ve never attended an FDA Advisory Committee meeting before, and I called several people to get a sense of what to expect. One of them was Michele Keane-Moore, a former cell-product reviewer with FDA who is now with the Biologics Consulting Group. She told me that the public forum marks a good learning opportunity for the agency. FDA officials have discussion with many companies, she says, “but all of that work is confidential and can’t be discussed.” Now, she says, “A lot of the questions will be aired in a public forum, so all the stakeholders can say what their concerns are.” the transcripts will eventually be made available for this meeting. Keane-Moore believes the discussion will be similar to the one held in July 13 on stem cells in neurological diseases. You can get to it here.

You can read more in the Nature article, but the FDA is mainly worried that the animal tests used to assess safety problems aren’t good enough and that they won’t know until too late that the transplanted cells are causing harm rather than benefit. The FDA has to make these calls all the time, but there are a couple reasons why these cells are cause for concern. One is that the animal safety tests often require animals to be bred to lack immune responses or to be on immunosuppressive drugs (mouse bodies would attack human cells otherwise), so they want to figure out the limitations of these tests.

Also, stem cells are very different from drugs because cells can multiply and change. That makes them harder to predict. If you put the cells in an environment where they can grow quickly, a low dose of cells could become a high dose. That can’t happen with drugs. Of course, everyone also hopes that these cells can bring about cures for diseases that so far seem intractable to regular drugs.

If you have something you want me to have my eyes out for at either of these meetings, please send me an email or add a comment below.

Posted by Monya Baker on April 08, 2008
Categories: Community, Regenerative medicine | Permalink | Comments (1) | TrackBacks (0)

It’s worth noting that the exciting paper in Nature Medicine is grabbing headlines not so much for the advance in Parkinson’s disease but because it is the first time that cells derived from cloned embryonic stem cells have been used to ameliorate disease. In the Nature Medicine paper from Sloan-Kettering’s Viviane Tabar and Lorenz Studer and others, researchers report that cells survived much better and mice’s symptoms improved if they were transplanted with genetically matched neurons.

For those of you coming back from Easter weekend to see Monday’s headlines, Nature reported on this story on Friday, making it harder to find now. Here it is . Other reports come from Bloomberg and the Guardian. And just to keep things in perspective, here’s a report of a non-stem cell breakthrough in Parkinson’s in mice based on research published in Nature just over a year ago.

Continue reading "Therapeutic cloning helps mice with Parkinson's" »

Posted by Monya Baker on March 24, 2008
Categories: Regenerative medicine | Permalink | Comments (1) | TrackBacks (0)

By Natalie DeWitt and Monya Baker

Monkey embryonic stem cells have, for the first time, been created through somatic cell nuclear transfer (SCNT). All attempts to make human embryonic stem cells through nuclear transfer so far have failed, but Jamie Thomson got the recipe for human embryonic stem cells by first doing so in monkeys, so researchers will likely be going to Shoukhrat Mitalipov of Oregon National Primate Research Center for advice. Mitalipov made his announcement Monday at the International Society for Stem Cell Research in Cairns, Australia, in a special add-on presentation . This finding represents a proof of principle that therapeutic cloning to create patient-specific ES cell lines could work in primates.

Continue reading "Oregon scientist reports first ES cells from cloned primate embryos" »

Posted by Natalie DeWitt on June 18, 2007
Categories: Cloning, Regenerative medicine, Reprogramming/Pluripotency | Permalink | Comments (0) | TrackBacks (0)

Posted by Natalie DeWitt for Monya Baker

South Korean scientist Woo Suk Hwang actually did achieve an important first, just not the one he claimed. I was at the meeting where Hwang said, falsely, that he’d created the first human embryonic stem cell through cloning. It felt like a rock concert, except attendees held up recorders instead of lighters.

It turns out that Hwang might have gotten some rock-star status just by sticking to the truth. The human embryonic stem cells he made came from a parthenote, or an activated, unfertilized egg, and he really did do it first. George Daley, a stem cell scientist from Children’s Hospital, Boston, announced this fact to an absolutely packed crowd in an exhibit hall at the International Society for Stem Cell Research in Cairns, Australia. That Hwang's line came from a parthenote had been suspected, but this line of evidence hadn't been presented before.

(Last year, Tiziana Brevini and Fulvio Gandolfi of the University of Milan announced that they had derived two stem cell lines from 104 eggs that had been donated to fertility clinics. The news story is here: http://www.nature.com/nature/journal/v441/n7097/full/4411038a.html)

Over a year and a half ago, everyone assumed that cloning human embryonic stem cells had been reduced to practice. Now, Hwang is a symbol for the biggest scientific fraud so far this century.

Daley described how embryonic stem cells derived from parthenotes could generate transplant tissue less subject to immune rejection, and I think about how when I bump in from stem cell scientists from South Korea, they tend to bring up Hwang in the first few sentences. They have done nothing wrong, but they still seem embarrassed. Had Hwang simply stuck to his real achievement, they would be proud.

(In a subsequent post, I’ll describe Daley’s work comparing how embryonic stem cells made through cloning differ from their parthenote-derived equivalents.)

Posted by Natalie DeWitt on June 18, 2007
Categories: Cloning, Regenerative medicine, Reprogramming/Pluripotency | Permalink | Comments (0) | TrackBacks (1)

Posted by Natalie DeWitt for Attila Csordás

The sea squirt can regenerate its whole body from the vasculature. Here Attila Csordás interviews Ayelet Voskoboynik, postdoctoral fellow from the Weissman lab, Stanford University, to tell us how.

Their findings were published in a recent paper, entitled Striving for normality: whole body regeneration through a series of abnormal generations
(FASEB Journal, 2007 May;21(7):1335-44.)

Continue reading "Insights to regeneration from the sea squirt-- an interview" »

Posted by Natalie DeWitt on June 07, 2007
Categories: Regenerative medicine | Permalink | Comments (0) | TrackBacks (0)