The Niche

Cross-posted from The Great Beyond

Last week, the US Food and Drug Administration put the brakes on Geron Corp's clinical trial in spinal cord injury because of just-completed animal studies that raised red flags. The Menlo, California-based biotech company announced Thursday that the animals developed microscopic cysts in the injury site. These lumps, however, did not spread to other parts of the body and none of the animals developed tumours. A second concluded study showed no cysts in spinal cord injured rats, according to a Geron press release.

“I think it provides people with a reasonable explanation,” said Stephen Brozak, an analyst with WBB Securities LLC in Westfield, New Jersey. “Everybody was afraid of the T- word, teratomas, and it clearly wasn’t that.” (Bloomberg)

Analysts rejoiced at the news. Geron shares rose more than 3% yesterday, closing higher than any day since the clinical hold was announced.

Geron is now working with the FDA to relaunch the stalled trials, the company said. No date was set.

by Elie Dolgin

Posted by Monya Baker on August 28, 2009
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Differentiated human cells have been reprogrammed to an embryonic-like state with the addition of only one gene, rather than the standard four [1]. This should advance techniques for the efficient production of high-quality patient-specific stem cells.

The ability to make induced pluripotent stem (iPS) cells using cells from specific patients could enable unprecedented new ways to study disease and also ease the development of cell therapies. However, such applications have been stymied in part because making induced pluripotent stem cells efficiently requires the introduction of pluripotency genes, which are typically inserted at random sites throughout the genome. This unwanted source of variation stymies rigorous comparisons between cells, and could make them behave in unpredictable, dangerous ways if used for cell therapies. Several techniques to make cells without permanent insertion of the genes have been reported, including some that do not use genetic material at all.
See: Human iPS cells with no genetic integration
Virus free pluripotency for human cells
Integration-free iPS cells
Reprogramming to pluripotency without genetic engineering
Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins

However, researchers are eager for additional, ‘gentler’ ways to reprogram cells, and one possibility would be starting with cells that are more prone to reprogramming. Evidence in mice suggests that the tissue of origin affects how often and how well differentiated cells reprogram.
See: Cell origin and variation in induced pluripotent stem cell lines
Stomach and liver cells reprogrammed

Scholer and colleagues reasoned that neural cells would be a good candidate, since these cells already express high levels of three of the four standard pluripotency factors (Sox2, Klf4 and c-myc). The team had previously shown that this strategy worked in mice. The researchers used viruses to insert copies of the fourth pluripotency factor, Oct4, into the cells. This produced reprogrammed cells that passed all standard tests of pluripotency.

The current study reprogrammed neural stem cells from human fetal tissue. While adult tissues tend to be more difficult to reprogram, and brain biopsies are difficult to obtain, Scholer and colleagues say they are already working out practical solutions. More-accessble cells, such as those found in dental pulp, might also be good candidates.

1. Kim, J.B. Direct reprogramming of human neural stem cells by OCT4. Nature advance online publication, doi:10.1038/nature08436 (28 August 2009)

Posted by Monya Baker on August 28, 2009
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Alexey Bersenev, whom many of you know from his blog Hematopoiesis, had this additional info on the Russian stem cell IPO reported yesterday by Reuters and blogged by me in the previous post. (Thanks Alexey!)

I know Dr. Isaev in person very well. He is a businessmen, but not a scientist. That's why he has no PubMed record. He also has a medical degree (MD). He is a pioneer of private cord blood baking in Russia. For scientific part of Institute you can look at PubMed for "Kiselev SL" Dr. Kiselev is a scientific director.

The Institute is a publisher of russian scientific journal dedicated to stem cell research and regenerative medicine. The Institute organize conferences for professionals in cord blood banking and also have a research laboratory, dedicated to develop of "cord blood-based cell products" for clinical trials and gene therapy technologies.

I think IPO for his company (aka institute) is a huge leap in commercialization of stem cell and regenerative medicine technologies in Russia and Eastern Europe regions.

Posted by Monya Baker on August 26, 2009
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Moscow's Human Stem Cell Institute hopes to break the ice in Russia's frozen IPO market with a $5 million offering, according to an article in Reuter’s.

I’d never heard of this group, which according to Reuters was founded in 2003.

A bit of Googling brought me to this reference, which appears to be a review about cord blood. The last author of the review is A Isaev (Isayev) described as the general manager of the company by Reuters. When I searched PubMed for the authors, I found only four articles by AA Isaev, all written about colon diseases in Russian-language journals.

Its major competitor is a cord-blood banking company called Cryo-Cell. It’s an odd business model, but one that seems to be proliferating. See last year’s run down on cord-blood companies springing up in Asia, as well as a (critical) feature story. Stem cell banking: lifeline or subprime?

Posted by Monya Baker on August 26, 2009
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Six months after giving it the green light, the U.S. Food and Drug Administration has told Geron to put plans for a clinical trial in spinal cord injury on hold. The company has differentiated embryonic stem cells into precursors of cells known as oligodendrocytes, which help keep neurons alive. Geron hopes this cell product could promote healing in people who have recently severed their spinal cords.

In a press release, Geron said that the hold was placed after the company submitted data on animal studies done to support delivery of increased doses of its cell product and on animal studies applying the cell product to other neurodegenerative diseases. (See the story from the San Jose Mercury News; here’s the Nature story when trial won approval)

I asked Evan Snyder, who directs the stem cell program at the Burnham Institute and is not privy to the confidential information, to speculate what might have been in the preclinical data that prompted teh FDA's action. It’s possible that the FDA just wanted more time to review newly submitted data, he said. Or on the other end of the extreme perhaps some sort of tumour or adverse reaction had been observed in the animals. Most likely, he thought, given that the company is trying to make larger doses of the cells, is that undifferentiated or non-neural cells have been observed in the cell product.

Clinical holds are not unusual particularly for innovative therapies. The FDA issued a clinical hold for NeuralStem in February on a trial in Lou Gehrig’s disease (the company uses neural stem cells derived from fetal cells)

At a large FDA advisory committee meeting in April last year, experts discussed the risks and benefits of products derived from embryonic stem cells. They were particularly concerned about uncontrolled cell growth. Even if the cells are not cancerous, tumours in the contained spaces of the brain and spinal cord could be devastating. Committee members were particularly concerned for diseases that are debilitating but not immediately deadly, since adverse events caused by experimental procedures could mean that people with years to live die early or end up suffering more. Patient advocates protested that they should be allowed to decide whether to take that risk.

See previous posts: Overview of FDA meeting (includes links to transcripts)
Nitty-gritty questions for making safe products
Posted by Monya Baker on August 18, 2009
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Francis Collins, the new director of the US National Institutes of Health, says that he had no timetable for when the NIH will re-establish a registry listing human embryonic stem cell lines eligible for human research funding. He did, however, say that the registry would be a “very high priority.”

Last month the NIH announced guidelines for hESC research that outlined strict informed consent criteria for the donation and use of embryos. Existing, well-studied hES cell lines, many previously eligible for federal funding, do not meet these criteria exactly, and the NIH announced that it would soon establish a working group to ascertain whether these lines were derived with adequate informed consent. However, said Collins, the NIH will not seek out which lines to examine. Instead, researchers must submit applications to the working group that document and explain how the lines meet informed consent standards at the time of derivation. This process, said Collins, will ensure that the lines of the greatest scientific interest are examined first. Until then, some researchers worry that funding for their work is in limbo. (See uncertainty around NIH guidelines)

Continue reading "NIH chief's first day: stem cell registry “high priority” but no ETA" »

Posted by Monya Baker on August 18, 2009
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A recent Cell paper by Priyush Gupta, Rob Weinberg, Eric Lander and other researchers from the Broad and MIT reports a potential way to kill the cancer cells that really matter.

Here is A screen for cancer killers from NatureNews (quotes from University of Toronto’s John Dick, others)
Here is New screening for more potent cancer drugs in the New York Times. (quotes from Stanford’s Mike Clarke, others)

Cancer stem cells are cells capable of growing malignant tumours anew, and there is a surfeit of controversy about whether this is an elite subpopulation or the majority of cells in the tumour. (See Cancer stem cells, becoming common)
The researchers manipulated immortalized cancer stem cells and were able to sort out a subpopulation that resembles cancer stem cells, then they were able to identify drug that selectively kills the cancer stem cells. That’s a big deal, as a growing body of evidence indicates that the cells best able to cause a tumour to regrow are also particularly able to resist cancer drugs. (See Cancer stem cells resemble healthy ones, resist chemotherapy)
Two questions come to mind:
1) How well do these cells represent cancer stem cells? (See Careful assays for cancer stem cells )
2) Will compounds that kill cancer stem cells also kill healthy stem cells? (See How breast cancer resists treatment )

Here’s a nice summary from Jane Visvader, a breast cancer stem cell expert at the The Walter and Eliza Hall Institute of Medical Research.
This is an elegant demonstration of the power of using high throughput screening to target resistant cancer cell subsets. The authors have shown that they can specifically target mesenchymal-like cells in breast tumors, found to be resistant to a standard chemotherapeutic agent (Paclitaxel), using salinomycin.

Here’s this from Piyush Gupta, which addresses whether the cells act like bona fide cancer stem cells

The gist: Cancer stem cells have been difficult to study because they
cannot be maintained as pure populations in culture. Passage through
an EMT has been recently reported (by the Weinberg groups) to induce a
significant increase in the proportion of stem-like epithelial cells.
We show that passage through an EMT also confers increased drug
resistance to cells. Using genetic vectors to induce an EMT, it was
possible to induce a stable increase in the proportion of stem-like
cells. We then performed a chemical screen to find compounds that were
specifically toxic to cells that had passed through an EMT. Compounds
that were identified in this way were then tested the identified
compounds on cancer cell lines that we had not genetically
manipulated, to determine if they acted on bona fide cancer stem cells.

Why the study is of interest:
Cancer stem cells are resistant to many forms of death-inducing
insults. This has suggested that it may be difficult to find therapies
that specifically target CSCs. Our study shows that it is possible to
find agents that selectively kill cancer stem cells and provides a
general method for doing so.

Caveats and further experiments:
Further study will be needed to determine if the chemical we
identified, salinomycin, can be used in patients. In such studies, the
long-term effects on normal stem cell biology will also need to be
evaluated.

Posted by Monya Baker on August 14, 2009
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Coming this Thursday,
Five “immortality boosts reprogramming” papers are summarized (Nature: Yamanaka, Hochedlinger, Blasco,) See also Nature News,
a highlight probing molecular mechanisms behind breast cancer stem cells (PNAS from Baylor’s Jenny Chang and Cell from Stanford’s Mike Clarke)
An analysis of what human embryonic stem cell lines are being used (Nature Biotech from Stanford’s Chris Scott and University of Michigan’s Jason Own-Smith)
A comparison of bone nodules formed from cells derived from bone marrow, mesenchymal stem cells, and embryonic stem cells (Nature Materials from Imperial College’s Molly Stevens))

We will also have one coming next Thursday on a trio of paper on how cancer stem cells in both leukemia (Cell) and bladder cancer (PNAS) use a “don’t eat me signal” to evade the immune system,, mentioned in last week.

Continue reading "So many papers, so little time" »

Posted by Monya Baker on August 10, 2009
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Two papers out the first week in August probe the molecular machinery behind cells that fuel breast cancer.

Researchers led by Jenny Chang at Baylor College of Medicine in Houston found a characteristic signature in a group of tumour cells remaining in a patient after treatment for breast cancers.1 These resistant cells were enriched whether patients underwent chemotherapy or were given drugs that block the action of tumour-promoting sex hormones, suggesting that there is a particular population of cells that can resist treatment and cause the tumour to regrow. Chang found that the gene expression in this subpopulation overlapped with two other sorts of cells: those that readily perpetuate tumours and those that allow cells to self-renew over long periods in culture. What’s more, these resistant cells may also be responsible for the spread of cancer outside the breast. Cells with this gene expression are particularly dominant in a relatively uncommon cancer called “claudin-low,” which displays characteristics of undergoing a process called the epithelial–mesenchymal transition (EMT), implicated in the spread of a malignancy. Similarly, cells remaining in tumours that had been treated with an estrogen-blocking drug showed elevated expression of mesenchymal markers. Homing in on unique characteristics of these cells may, says Chang, allow researchers to identify drugs that could eliminate these cells.

Just a few days later, researchers led by Michael Clarke of Stanford University tried a different approach to identify regulatory pathways in breast cancer stem cells. This work showed that these stem cells are governed by the same regulatory pathways as their healthy counterparts, mammary stem cells. The researchers were able to isolate cancer stem cells from human samples and perform analysis on small quantities of cells.2 This identified some three dozen microRNAs differentially expressed between tumourigenic cells and other cells in the tumour. The researchers also compared tumourigenic cells with normal mouse and human mammary stem/progenitor cells as well as embryonal carcinoma cells. Three clusters of microRNA were downregulated in all these cell types, one of which was miRNA-200c, previously found to regulate the epithelial–mesenchymal transition. Elevating levels of this microRNA suppressed self-renewal and encouraged differentiation in both normal and cancerous breast stem cells. Further work showed that this microRNA controls levels of a well-known protein called BMI1, which also regulates stem cells of the blood and brain. Thus, it seems, stem cell functions such as self-renewal, proliferation and EMT all seem to be governed by similar mechanisms—not just in healthy and disease tissue, but across different types of tissues.

Continue reading "Breast cancer stem cells resemble healthy stem cells, resist chemotherapy" »

Posted by Monya Baker on August 10, 2009
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Under former US president George W. Bush, fewer than two dozen human embryonic stem cell lines could be studied with federal funding. That number could soon extend into the hundreds, pending ethical review by the US National Institutes of Health. However, research led by Christopher Scott of Stanford University in California shows that of the 20-odd lines available for funding, researchers have so far depended primarily on just 2 of the oldest human embryonic stem cell lines1.

Scott and colleagues collected data from two major repositories of human embryonic stem cells (hESCs). Of 1,217 requests made to the National Stem Cell Bank in Madison, Wisconsin, between March 1999 and December 2008, 1,052 were for just 3 of the approximately 17 lines available and eligible for funding; of those requests, 941, or 77%, were for just 2 lines (H1 and H9). The research didn’t examine informal lab-to-lab transfers, which might show up as acknowledgements or coauthorship, says study coauthor Jason Owen-Smith of the University of Michigan. “The work we have done, though, suggests that if a lot of folks are avoiding the banks, they are still using the lines that are most requested from the banks. The pattern of concentration we report for publication is even more striking than for cell-line requests.” An analysis of over 500 peer-reviewed articles on research using hESC lines and published between 1999 and 2008 found that roughly two-thirds used just the three most popular lines from the National Stem Cell Bank.

Continue reading "Human embryonic stem cell research stuck on two early lines" »

Posted by Monya Baker on August 10, 2009
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A thorough analysis finds tissue-specific stem cells make chemically and functionally different bone than embryonic ones

Many sorts of cells are able to form superficial bone-like nodules in culture, but how these nodules compare to native bone has been unclear. New work reveals that embryonic stem cells form a bone-like material quite different from that formed by adult-derived cells1. This finding has implications for osteogenic engineering, which could be used in the over two million bone-replacement procedures that take place every year.

Molly Stevens’s team at Imperial College London compared the nodules formed by neonatal osteoblasts from mice with those differentiated from both mouse mesenchymal stem cells (MSCs) and mouse embryonic stem (ES) cells. Although all of the nodules became calcified, this did not necessarily mean that they were forming similar bone-like material.

Continue reading "Building bones from stem cells" »

Posted by Monya Baker on August 10, 2009
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This piece, by Elie Dolgin, builds on the more-general article now up on Nature News.

The tumor suppressor gene p53 is usually thought of as a master regulator that helps stave off cancer, but it's also a major barrier to cellular reprogramming. Blocking the p53 pathway vastly improves the efficiency of transforming differentiated cells into induced pluripotent stem (iPS) cells and with fewer genes than the commonly used reprogramming recipes, new research shows. The findings, which should make it easier to derive patient-specific stem cells from any tissue, provide a bridge between tumour formation and cellular reprogramming that could force a rethink about cancer development.

Continue reading "p53, guardian of the genome, also blocks reprogramming" »

Posted by Monya Baker on August 10, 2009
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At a board meeting for the California Institute of Regenerative Medicine yesterday, President Alan Trounson said the organization needed to prepare to move laboratory research into clinical trials within four years. That, he said, means hiring a new vice president with corporate experience to work closely with industry and regulatory agencies and shepherd the work of the soon-to-be-funded disease teams.

The new vice president will replace the position of chief scientific officer, which is vacant since CSO Marie Csete resigned last month, saying that her opinions had been sidelined. (See the news story from Nature ) When Csete, who had previously worked on both embryonic stem cells and liver transplantation at Emory University, was hired, CIRM leadership emphasized her clinical and scientific expertise as important for translating basic research to human trials.

Continue reading "CIRM to look for Vice President of Research and Development to Replace Chief Scientific Officer" »

Posted by Monya Baker on August 07, 2009
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Here are descriptions of papers that caught my eye over the last couple weeks. Some of these will be covered in more depth over the next week or two as research highlights. I’ll make a list of those later in the week.

Stem cells need special cell-cycling protein; amino acid makes mESC grow speedily
Harvard’s Piotr Sicinski finds that fibroblasts can proliferate just fine without cyclin A (they compensate with another cyclin, cyclin E). However, both hematopoietic and embryonic stem cells get stuck in the cell cycle. Cyclins are the regulatory subunits of a class of kinases that regulate cell division.
(See the paper in Cell Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. )
Steven McKnight at the University of Texas Southwestern Medical Center found that cultured mouse embryonic stem cells were making lots and lots of threonine dehydrogenase an enzyme necessary for breaking down the amino acid threonine, essential for energy production in the mitochondria. The researchers tried growing ES cells in different culture media, each lacking one of the 20 amino acids. The mouse ES cells were just fine, except when threonine was missing. (After 36 hours, all of the other cultures had about 1000 colonies; the one lacking threonine had less than 50!) In contrast, human cells seem to lack a functioning gene for threonine dehydrogrenase. And as anyone who has worked on both mouse and human cells will tell you, human cells are SLOOOOW. Maybe, just maybe, the researchers speculate, activating the gene in human cells can make their doubling just a big more speedy.
(See the paper in Science Dependence of mouse embryonic stem cells on threonine catabolism .)

New and better bone-makers
Circulating blood cells seem able to home to injury and form new bone in both humans and animals, according to work published in Stem Cells by Robert Pignolo at the University of Pennsylvania, College of Medicine.
(See Circulating Osteogenic Precursor Cells in Heterotopic Bone Formation.)

Also, some sources of cells are better than others when it comes to growing bone for tissue replacement. In Nature Materials, Molly Stevens and colleagues at Imperial College London report that bone made by the normal bone-forming cells found in adults produce strong bone nodules, normal in terms of its mineral composition. In contrast, the bone made from cells differentiated from embryonic stem cells is more like bone that is weakened with age. (See Comparative materials differences revealed in engineered bone as a function of cell-specific differentiation)

Cancer spawns in a latent niche
Working in the worm C. elegans, researchers led by Jane Hubbard at the New York University School of Medicine, find that differentiated cells that normally have no contact with stem cells can, under the wrong circumstances, allow the wrong cells to self-renew and proliferate. This works through aberrant signaling of that ubiquitous protein Notch and need not require genetic changes to sustain itself. (See A "latent niche" mechanism for tumor initiation in PNAS.)

Leukemia cells say ‘don’t eat me’ to the immune system
Stanford’s Irv Weissman has two papers in Cell The show that the marker CD47 is transiently activated in hematopoietic stem cells constitutively on in mouse cell leukemias and also that CD47 is an adverse prognostic factor in human malignancies.

Bioengineered tooth really works
Takashi Tsuji of the Tokyo University of Science and colleagues had combined mesenchymal stem cells and epithelial cells into "tooth germ". Transplnated into a mouse, it developed into a tooth that really chews. The researchers, affiliated with the company Organ Technologies, says it is a harbinger for more functional bioengineered organs. (See Fully functional bioengineered tooth replacement as organ therapy in PNAS)

Posted by Monya Baker on August 03, 2009
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