Heart rejuvenation is fundamentally a DNA programming problem. With enough knowledge about how to run the DNA software we can make stem cells become replacement cells in cardiac muscle and in the rest of the body.
SAN FRANCISCO, CA –March 5, 2008--Researchers at the Gladstone Institute of Cardiovascular Disease (GICD) and the University of California, San Francisco have identified for the first time how tiny genetic factors called microRNAs may influence the differentiation of pluripotent embryonic stem (ES) cells into cardiac muscle. As reported in the journal Cell Stem Cell, scientists in the lab of GICD Director, Deepak Srivastava, MD, demonstrated that two microRNAs, miR-1 and miR-133, which have been associated with muscle development, not only encourage heart muscle formation, but also actively suppress genes that could turn the ES cells into undesired cells like neurons or bone.
“Understanding how pluripotent stem cells can be used in therapy requires that we understand the myriad processes and factors that influence cell fate,” said Dr. Srivastava. “This work shows that microRNAs can function both in directing how ES cells change into specific cells—as well as preventing these cells from developing into unwanted cell types.”
These microRNAs trigger gene activity that turns the embryonic stem cells into cardiac muscle. With more knowledge about the activity of hundreds (or perhaps thousands) of microRNAs we will be able to make large numbers of tissue types from stem cells. It is a matter of discovering a large number of possible ways to instruct cells to do our bidding.
How long will it take to figure which microRNA can tell which cell type to become which other cell type? I'm thinking that microfluidics will speed up this process by automating the testing of large numbers of microRNAs with large numbers of cell types. The rate of advance in stem cell manipulation will accelerate every year as microfluidic devices and other tools for lab automation allow the solution space to be searched orders of magnitude more rapidly.
Yet another step toward clinically usable stem cells.
Donovan and Leslie Lock, assistant adjunct professor of biological chemistry and developmental and cell biology at UCI, previously identified proteins called growth factors that help keep cells alive. Growth factors are like switches that tell cells how to behave, for example to stay alive, divide or remain a stem cell. Without a signal to stay alive, the cells die.
The UCI scientists – Donovan, Lock and Kristi Hohenstein, a stem cell scientist in Donovan’s lab – used those growth factors in the current study to keep cells alive, then they used a technique called nucleofection to insert DNA into the cells. Nucleofection uses electrical pulses to punch tiny holes in the outer layer of a cell through which DNA can enter the cell.
With this technique, scientists can introduce into cells DNA that makes proteins that glow green under a special light. The green color allows them to track cell movement once the cells are transplanted into an animal model, making it easier for researchers to identify the cells during safety studies of potential stem cell therapies.
Scientists today primarily use chemicals to get DNA into cells, but that method inadvertently can kill the cells and is inefficient at transferring genetic information. For every one genetically altered cell generated using the chemical method, the new growth factor/nucleofection method produces between 10 and 100 successfully modified cells, UCI scientists estimate.
Gene therapy has been a great disappointment. Back in the mid 1990s gene therapy research seemed more promising. This gene therapy method is for cells that can be removed from the body. So it is useful for preparing stem cells (and probably non-embryonic stem cells) to accept DNA. But it is not a general solution for gene therapy.
This report is especially interesting because the improvement by orders of magnitude. To get from where we are to where we need to be with gene therapy and stem cell therapy we need many advances that bring orders of magnitude improvements in our ability to manipulate cells and genes
Confirming work reported a few months ago by other researchers, a group at UCLA have demonstrated that adult human skin cells can be reprogrammed to act like embryonic stem cells.
UCLA stem cell scientists have reprogrammed human skin cells into cells with the same unlimited properties as embryonic stem cells without using embryos or eggs.
Led by scientists Kathrin Plath and William Lowry, UCLA researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells.
The UCLA study confirms the work first reported in late November of researcher Shinya Yamanaka at Kyoto University and James Thompson at the University of Wisconsin. The UCLA research appears Feb. 11, 2008, in an early online edition of the journal Proceedings of the National Academy of the Sciences.
The implications for disease treatment could be significant. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient’s skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types – beta islet cells to treat diabetes, hematopoetic cells to create a new blood supply for a leukemia patient, motor neuron cells to treat Parkinson’s disease.
“Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells,” said Plath, an assistant professor of biological chemistry, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and lead author of the study. “Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications.”
This research helps to get around the opposition to embryonic stem cell research. But these results also demonstrate progress in understanding cellular differentiation. Scientists first had to discover genes that play a role keeping cells in the embryonic state before they could know how to turn very differentiated (specialized) cells into much more flexible wider purpose cells
Our biggest obstacle for turning stem cells into useful therapies probably is our limited understanding of how cells regulate their conversion into a large assortment of specialized cell types. If we knew much more about how cells regulate themselves we'd have a much better idea of how to intervene to control them for therapeutic purposes.
In a paper to be published Nov. 22 in the online edition of the journal Science, a team of University of Wisconsin-Madison researchers reports the genetic reprogramming of human skin cells to create cells indistinguishable from embryonic stem cells.
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The new study was conducted in the laboratory of UW-Madison biologist James Thomson, the scientist who first coaxed stem cells from human embryos in 1998. It was led by Junying Yu of the Genome Center of Wisconsin and the Wisconsin National Primate Research Center.
For several years I've been expecting clever scientists to figure out ways to basically program around the limitations on embryonic stem cell research. By finding ways to turn the knobs on genetic switches in the cell it was inevitable that scientists would figure out how to make cells change state into embryonic cells. They will next find more genetic knobs to turn in order to convert embryonic cells into precisely desired cell types and they will even find ways convert between various non-embryonic cell types while totally avoiding an intermediate state where the cells are like embryonic cells. Cells are just complex state machines. The next few decades of advance in biotechnology can be seen as a series of advances in techniques for causing desired and useful cell state transitions.
Shinya Yamanaka of Kyoto University led a separate team that also accomplished this same goal of reprogramming adult skin cells to turn them into pluripotent stem cells
The same feat is reported in the journal Cell by Prof Yamanaka with colleagues in Japan and America, the scientist who pioneered this approach of "nuclear reprogramming" in mice. He too reports that a simple recipe turns human skin cells into embryonic stem cell-like cells, he calls "iPS" cells.
From about 50,000 human cells treated with four factors introduced by a virus, his team obtained 10 distinct kinds of embryonic like cells.
"This efficiency may sound very low," said Prof Yamanaka but in practice it means a single experiment in a Petri dish will yield several lines of embryo like cells, while cloning would require dozens of human eggs to achieve the same feat.
Each team introduced 4 genes into the nucleus to create this effect.
Doug Melton, a stem-cell researcher at Harvard University, heralded the breakthrough.
Yamanaka, of Kyoto University in Japan, last year was the first to reveal the successful creation of reprogrammed cells in mice; he and two other research groups published improvements on that step this July. Many scientists thought it would take years to do the same with human cells.
"We appear to be closer than we ever thought we might be to a day when we could use this alternative method," Melton said in prepared remarks.
Though Thomson and Yamanaka both reprogrammed human skin cells using four genes, their methods differed slightly. They used different viruses to deliver the genes. Both used genes called Oct4 and Sox2, but Thomson used two others called Nanog and Lin28, while Yamanaka used c-Myc and Klf4.
These results aren't surprising. The most important difference between embryonic cells and adult cells is whch genes are activated. These scientists basically figured out how to apply a software patch to human cells that made them express genes that make them act like embryonic cells. Scientists have already identified these genes as active in early stage embryonic stem cells and have experimented with activating them in mouse cells.
These results might not yet provide perfect substitutes for embryonic stem cells.
"While this is exciting basic research, it could still take years to get this to work in humans in a way that could be used clinically," said Robert Lanza, chief scientific officer of Advanced Cell Technology in Worcester, Mass. "I cannot overstate that this is early-stage research and that we should not abandon other areas of stem cell research."
It seems unlikely that these cells have been pushed into a state that is exactly like the state of an embryonic stem cell. That state might have very subtle aspects that are important in ways we have not yet discovered. The cells created by these two new methods might suffer lingering effects from the introduced genes and a technique to silence those genes at some later step might be needed. But then cloning didn't produce perfect embryonic stem cells either.
Christian opponents of embryonic stem cell research are celebrating this discovery since the result reduces the advantage of working with embryo-derived cells.
Today, Family Research Council President Tony Perkins praised the research of Dr. James Thomson and Dr. Shinya Yamanaka. Thomson, the first to grow human embryonic stem cells, and Yamanaka from Japan, published results in the journals Science and Cell, respectively, showing that embryonic-type stem cells can be produced directly from ordinary human skin cells, without first creating or destroying human embryos
Here's yet another group opposed to embryonic stem cell research who are hailing this result
Wesley J. Smith, the Discovery Institute's Senior Fellow in Bioethics and author of Consumer's Guide to a Brave New World, hailed the breakthrough as demonstrating that ethical science is also good science: "Everyone should applaud this tremendous scientific achievement. We now have the very real potential of developing thriving and robust stem cell medicine and scientific research sectors that will bridge, rather than exacerbate, our moral differences over the importance and meaning of human life."
They are happy about this result because it probably will make the use of embryonic stem cells unnecessary. But the result also seems to show that the difference between embryonic stem cells and other cells is just different settings on a few genetic switches in the cell. So doesn't this result make embryonic stem cells seem less magical and less supernatural?
CAMBRIDGE, Mass. (October 10, 2007) – The protein Oct4 plays a major role in embryonic stem cells, acting as a master regulator of the genes that keep the cells in an undifferentiated state. Unsurprisingly, researchers studying adult stem cells have long suspected that Oct4 also is critical in allowing these cells to remain undifferentiated. Indeed, more than 50 studies have reported finding Oct4 activity in adult stem cells.
But those findings are misleading, according to research in the lab of Whitehead Member Rudolf Jaenisch.
In a paper published online in Cell Stem Cells on October 10, postdoctoral fellow Christopher Lengner has shown that Oct4 is not required to maintain adult stem cells in their undifferentiated state in mice, and that adult tissues function normally in the absence of Oct4. Furthermore, using three independent detection methods in several tissue types in which Oct4-positive adult stem cells had been reported, Lengner found either no trace of Oct4, or so little Oct4 as to be indistinguishable from background readings.
This means that pluripotency, the ability of stem cells to change into any kind of cell, is regulated differently in adult and embryonic stem cells.
“This is the definitive survey of Oct4,” says Jaenisch, who is also an MIT professor of biology. “It puts all those claims of pluripotent adult stem cells into perspective.”
Why does this matter one whole heck of a lot? If we could turn adult stem cells into pluripotent stem cells (i.e. into stem cells that can then become all other types of cells in the body) then we might not need embryonic stem cells for that purpose. If we could reduce the need for embryonic stem cells then research into pluripotent stem cells would probably progress more rapidly.
Cellular differentiation is the process by which stem cells become specialized cell types such as muscle cells, nerve cells, skin cells, and liver cells. Research into genes that control differentiation is also generally useful for efforts to develop replacement organs and other replacement body parts. We need to know how all the genes that regulate differentiation interact with each other in complex signaling networks. We also drugs, gene therapies, techniques that can control the process of cellular differentiation. The ability to control cellular differentiation will give us replacement parts as our bodies wear out.
Once we can coax stem cells to go into places in the body and repair decayed tissue we are well on the way toward achieving the ability to do full body rejuvenation. Granted, we'll need other capabilities as well. But the ability to coax and direct stem cells is going to be one of the key pieces of the rejuvenation puzzle. With that in mind, this report about a special class of adult stem cells which can repair muscles is intriguing. Adult myoendothelial stem cells isolated from blood vessel walls can form muscle strands.
In a study using human muscle tissue, scientists in Children's Stem Cell Research Center - led by Johnny Huard, PhD, and Bruno Péault, PhD - isolated and characterized stem cells taken from blood vessels (known as myoendothelial cells) that are easily isolated using cell-sorting techniques, proliferate rapidly and can be differentiated in the laboratory into muscle, bone and cartilage cells.
These characteristics may make them ideally suited as a potential therapy for muscle injuries and diseases, according to Drs. Huard and Péault. Results of the study are published in the September issue of the journal Nature Biotechnology.
"Finding this population of stem cells in a human source represents a major breakthrough for us because it brings us much closer to a clinical application of this therapy," said Dr. Huard, the Henry J. Mankin Professor and vice chair for Research in the Department of Orthopaedic Surgery at the University of Pittsburgh School of Medicine. "To make this available as a therapy, we would take a muscle biopsy from a patient with a muscle injury or disease, remove the myoendothelial cells and treat the cells in the lab. The stem cells would then be re-injected into the patient to repair the muscle damage. Because this is an autologous transplant, meaning from the patient to himself, there is not the risk of rejection you would have if you took the stem cells from another source."
Muscles shrivel with age. Can myoendothelial stem cells restore muscles to something approaching their youthful glory? One problem is going to be that the myoendothelial stem cells will also age and myoendothelial stem cells isolated from a 70 or 80 year old might grow slowly and form tired muscle fibers.
But combine isolation of myoendothelial stem cells from an old body with some gene therapies to repair those stem cells and youthful stem cells for body repair could become available. How to develop those cellular rejuvenating gene therapies will probably turn out to be the hardest problem to solve to make adult stem cells fully useful in rolling back the ravages of aging.
Other types of adult stem cells can also form muscle. But the other types of adult stem cells form muscle much less efficiently.
Working in dystrophic mice while searching for a cure for Duchenne muscular dystrophy (DMD), Dr. Huard's laboratory team first identified a unique population of muscle-derived stem cells with the ability to repair muscle 8 years ago.
Dr. Péault, a professor in the Department of Pediatrics, Cell Biology and Physiology at the University of Pittsburgh School of Medicine, recognized the importance of determining the origin of these muscle-derived stem cells. His team applied, among others, techniques of confocal microscopy and cell sorting by flow cytometry which led to the discovery in human muscle biopsies that these myoendothelial cells are located adjacent to the walls of blood vessels.
According to their study, myoendothelial cells taken from the blood vessels are much more efficient at forming muscle than other sources of stem cells known as satellite and endothelial cells.
A thousand myoendothelial cells transplanted into the injured skeletal muscle of immunodeficient mice produced, on average, 89 muscle fibers, compared with 9 and 5 muscle fibers for endothelial and satellite cells, respectively. Myoendothelial cells also showed no propensity to form tumors, a concern with other stem cell therapies.
These researchers are chasing after better treatments for Duchenne muscular dystrophy (DMD). The development of stem cell treatments for DMD will inevitably lead to stem cell treatments to treat aged muscles. That is the way many rejuvenation therapies will come about. Efforts to repair damage caused by trauma, infection, and genetic defects will produce therapies that work to repair the damage caused by aging.
Melbourne, Australia; 20 August 2007: Australia's adult stem cell company, Mesoblast Limited (ASX:MSB;USOTC:MBLTY), today announced that preclinical trials of its patented adult stem cells had shown that the therapy significantly protected knee cartilage against damage in osteoarthritis.
Millions of people have osteoarthritis of the knee.
More than 10 million people in the US currently suffer from osteoarthritis of the knee, making it the most common joint disease. Osteoarthritis results in loss of cartilage which cannot repair itself after injury and for which there is no effective therapy. Current treatments attempt to alleviate painful symptoms but are unable to preserve the cartilage lining the joint. Moreover, many of the currently used pharmaceutical therapies are associated with severe side-effects and can even cause death. Joint replacement is often the only option for restoring function.
You may have knee osteoarthritis some day even if you don't now. Or you'll have it in your back or hands or shoulders or hips or some combination thereof. Your parts are wearing out. You need replacement parts.
People and dogs really suffer from decaying joints. We need stem cell therapies for joint rejuvenation and repair.
With the support of the Australian Government's Commercial Ready Grant award, Mesoblast's cartilage trials evaluated the effectiveness and safety of the company's allogeneic (donor unrelated) adult stem cells to treat osteoarthritis of the knee in 48 sheep arthritic joints. The results showed that joint cartilage in osteoarthritic knees of animals receiving Mesoblast's stem cells had significantly greater thickness, reduced breakdown, and greater biomechanical strength three months after injection into the knee than did control joints receiving injections of hyaluronic acid.
The trial's principal investigator, Professor Rick Read at the Murdoch University in Western Australia, said: "We are delighted with the significant cartilage protective effects of Mesoblast's allogeneic cells in our large animal model of knee osteoarthritis, without any adverse events of the cells at all".
We need this technology to work in humans. The benefits will be enormous. We need it faster.
For several years here I've argued the ethical conflict over human embryonic stem cell research would get resolved by discovery of techniques to dedifferentiate adult cells (make cells less specialized and more flexible). Well, at least with mice a method has been discovered to do exactly that. The use of gene therapy to turn on 4 genes in adult mouse cells transforms those cells to make them as flexible as embryonic stem cells.
Now, in three papers published simultaneously this week, Yamanaka and two other groups report that by turning on expression of the same four chemicals in adult mouse cells, the cells run their differentiation process backwards, reverting to an ESC-like state (Nature, DOI:10.1038/nature05934 and DOI:10.1038/nature05944; Cell Stem Cell, DOI:10.1016/j.stem.2007.05.014). "We have shown that cells can be generated by these four factors, that are indistinguishable from embryonic stem cells," says Konrad Hochedlinger of the Harvard Stem Cell Institute, who wrote one of the papers (watch a video of Marius Wernig - first author on the same paper - describing the cells - 3.8 MB, .wmv).
These cells are pluripotent which means they are capable of turning into all the cell types in a body. Need new parts to replace old worn out organs, blood vessels, muscles, tendons, and joint tissue? Pluripotent cells will some day serve as starter cells for the growth of replacement parts. Replacement cells and organs will usher in the age of regenerative medicide and eventually full body rejuvenation.
What was the enabler that made these experiments possible? The discovery by Yamanaka's team that 4 genes could cause a cell to become pluripotent. As scientists discover more about which genes control cellular differentiation (how cells change to take on specialized jobs) more ways to manipulate cell type will come from use of this knowledge.
Engineered viruses were used to deliver genes into the mouse cells.
Using artificial viruses called vectors, the team activated the same four genes in a batch of mouse skin cells. These genes, Oct4, Sox2, c-Myc and Klf4, are called transcription factors, meaning that they regulate large networks of other genes. While Oct4 and Sox2 are normally active in the early stages of embryogenesis, they typically shut down once an embryo has developed beyond the blastocyst stage.
It says something about the immaturity of gene therapy techniques in the year 2007 that only 1 in 1000 cells exposed to viruses with the 4 genes got reprogrammed by the attempt to add genes to the cells.
“We were working with tens of thousands of cells, and we needed to devise a precise method for picking out those rare cells in which the reprogramming actually worked,” says Wernig. “On average, it only works in about one out of 1,000 cells.”
To test for reprogramming, the team decided to zero in on Oct4 and another transcription factor called Nanog. These two hallmarks for embryonic stem cell identity are only active in fully pluripotent cells. The trick would be to figure out a way to harvest Oct4- and Nanog-active cells from the rest of the population.
Nicholas Wade of the New York Times claims the technique, once replicated with human cells, will clost less and take less effort than cloning to create embryonic stem cells.
The technique, if adaptable to human cells, is much easier to apply than nuclear transfer, would not involve the expensive and controversial use of human eggs, and should avoid all or almost all of the ethical criticism directed at the use of embryonic stem cells.
“From the point of view of moving biomedicine and regenerative medicine faster, this is about as big a deal as you could imagine,” said Irving Weissman, a leading stem cell biologist at Stanford University, who was not involved in the new research.
Replicating this study with human cells poses some problems which scientists must solve. But some of the scientists are optimistic about solutions:
A third issue is that two of the genes in the recipe can cause cancer. Indeed 20 percent of Dr. Yamanaka’s mice died of the disease. Nonetheless, several biologists expressed confidence that all these difficulties would be sidestepped somehow.
“The technical problems seem approachable — I don’t see anyone running into a brick wall,” said Owen Witte, a stem cell biologist at U.C.L.A. Dr. Jaenisch, in a Webcast about the research, predicted that the problems of adapting the technique to human cells would be solvable but he did not know when.
The threat of cancer is a big problem with stem cells. We need better methods of doing gene therapy so that stem cells can get genetically altered to repair all genes that prevent cells from growing uncontrollably.
Thanks to Brock Cusick for the tip.
Adult stem cells reduced stress urinary incontinence.
ANAHEIM, Calif., May 21 -- Women with stress urinary incontinence (SUI) treated using muscle-derived stem cell injections to strengthen their sphincter muscles experience long-term improvements in their condition, according to a study led by researchers at the University of Pittsburgh School of Medicine and Sunnybrook Health Sciences Centre in Toronto. The study, which followed patients for more than one year, suggests that the approach is safe, improves patients’ quality of life and may be an effective treatment for SUI. The findings will be presented at the Tissue Engineering and Regenerative Medicine in Urology press briefing at the annual meeting of the American Urological Association (AUA) in San Diego, and will be published in Abstract 1331 in the AUA proceedings.
The results of this study illustrate a pattern: Stem cell therapies for maladies of aging bodies look like rejuvenation therapies. The development of stem cell therapies to treat various problems will produce treatments that do rejuvenation. As long as civilization isn't destroyed by a natural disaster such as an asteroid or massive volcanic eruption the development of rejuvenation therapies is inevitable.
Someone might object and argue that this treatment has a very narrow effect on one location in the body. But these researchers are developing a rather general capability where they can supply replacement muscle cells where lack of muscle cells is the problem. Well, as we grow old our muscle cells become hobbled by damage and die. This happens in all our muscles. The ability to grow stem cells and turn them into muscle cells is a key capability needed to rejuvenate our bodies.
In the study, Dr. Carr and colleagues took biopsies of skeletal muscle tissue from eight female patients and isolated and expanded the stem cells from the tissue in culture. In an outpatient setting, the patients then received injections of the muscle-derived stem cells into the area surrounding the urethra. Each patient received an equal dose of stem cell injections using three different injection techniques – a transurethral injection with either an 8-mm or 10-mm needle or a periurethral injection.
Five of the eight women who participated in the study reported improvement in bladder control and quality of life with no serious short- or long-term adverse effects one year after the initial treatment.
A future enhancement of this treatment will be to take the muscle stem cells, treat them with gene therapies to correct accumulated DNA damage, and then grow them up for injection. Eventually scientists will even discover genetic variations that enhance muscle performance and the stem cells will get genetically engineered to form better muscle cells than we were born with.
A pair of genes controls whether a type of stem cells turns into cartilage or bone cells.
Skeletal progenitor cells differentiate into cartilage cells when one master gene actually suppresses the action of another, said Baylor College of Medicine researchers in a report that appears online in the journal Proceedings of the National Academy of Sciences.
Skeletons are made of bone and cartilage cells that are differentiated from the same multipotent stem cell, said Dr. Brendan Lee, associate professor of molecular and human genetics at BCM, director of the Skeletal Dysplasia Clinic at Texas Children’s Hospital and a Howard Hughes Medical Institute investigator. This same stem cell gives rise to bone, cartilage, fat and fibroblasts.
“The big question is what are the master genes that make a stem cell go one way versus another,” said Lee.
Both SOX9 and RUNX2 are master transcription factors involved in the process of differentiating bone and cartilage.
SOX9 and RUNX2 are obvious candidates for drug development. A drug that could block SOX9 would probably cause skeletal progenitor cells to become bone cells. That'd be handy for bone repair and bone restoration for people suffering osteoporosis. A drug that could turn on SOX9 could produce cartilage to replace aged or damaged cartilage.
The master protein SOX9 directs skeletal progenitor cells to become cartilage and another master protein, RUNX2, directs such cells to become bone, However, he said, the primordial skeletal cell has both RUNX2 AND SOX9.
“We then asked a simple question: Could these master transcription factors (that direct the expression of other genes) directly affect one another’s function"” he said. After studies in the laboratory, with mice and with humans, the answer was yes.
“SOX9 appears to be the dominant player,” said Lee. “When it is present in a progenitor cell, it turns off RUNX2 and allows the cell to become cartilage.”
That does not answer the question of how such cells become bone.
“Clearly, something must turn off SOX9,” said Lee. “That’s the next question we have to answer.”
These two genes are part of a much larger set of genes that control cell differentiation (i.e. the process by which cells turn into all the specialized cell types on the body). Advances in biotechnology are accelerating the rate at which scientists working in labs can figure out how all these genes work. The more they learn the better able they will be to intervene and turn cells into any types needed for repair and rejuvenation.
Here's the paper: Dominance of SOX9 function over RUNX2 during skeletogenesis.
Using mouse embryonic stem cells Harvard researchers funded by the Howard Hughes Medical Institute have created a first draft map of how a set of proteins interact with each other to maintain embryonic stem cell state.
Howard Hughes Medical Institute (HHMI) researchers have created a map that charts the largely unexplored protein landscape that regulates a stem cell's ability to differentiate into multiple types of mature cells.
Understanding this protein network in greater detail could give stem cell biologists a new set of tools to coax mature cells to revert to an embryonic state, said the researchers. Reprogramming adult cells in this way could provide an alternative source of stem cells to use in regenerating tissues damaged by disease or trauma, rather than employing embryonic cells, they said.
HHMI investigator Stuart Orkin and his colleagues at Children's Hospital Boston and Harvard Medical School published their findings November 8, 2006, in an advanced online publication in the journal Nature.
They've also shown that depletion of concentration of a few of the proteins causes the cells to start showing signs that they are becoming more differentiated (specialized) to become cell types that carry out specific functions.
All these proteins will become targets for drug development to block or enhance their effects in order to shift cells into other states. Scientists will build on this work to create more detailed maps of how these proteins interact to control cell state. Likely still other proteins will be found to also interact with these proteins to control cell state. An increasingly more detailed map of relations between these proteins will provide a guide for where to intervene to control stem cell state. This report is a great foundation for further work along this line.
Orkin hopes the map will help guide the development of improvements in methods to better control reprogramming of cell state.
Orkin said that thus far experiments aiming at reprogramming mature cells into a stem cell-like state have yielded cells that imperfectly resemble embryonic stem cells. “However, with this new understanding of the network of regulatory factors, it might be possible to refine this approach to reprogramming,” he said.
He's being overly modest here. Of course this map will be useful for development of techniques to control cell state.
Note how these researchers think of the proteins in cells as forming complex circuits just as computer chips have complex circuits.
The regulatory network that maintains a stem cell's ability to become many different cell types - a characteristic called pluripotency - also prevents the cell from inappropriately differentiating into a mature cell, while keeping it poised to undergo maturation when required. This precise control relies on intricate circuits of interacting proteins that both regulate one another and govern the activity of genes.
While I sometimes write posts about promising individual stem cell treatments no one announcement of a promising treatment or even a dozen such announcements will amount to much of a breakthrough given our current deficient state of knowledge on how cells work. The real breakthroughs that will provide us with the most power to produce treatments are going to come from the development of knowledge on how cells control their differentiation (i.e. how cells specialize to become heart muscle cells or liver cells or other specialized types). So this announcement is much more important than the average report about stem cell advances.
Once scientists understand the complex circuitry governing cell differentiation the next set of real important breakthroughs (though mostly invisible to the general public) will come. Scientists will seek to intervene in those cellular circuits and to do so they will develop techniques to tweak those circuits in highly precise and controlled ways.
Cells in the embryonic state are several state changes away from any other state such as muscle cell or artery lining cell or liver cell. Once we have detailed knowledge of the circuits that control cell state the need for embryonic stem cells will go way down. It will become possible to start with a cell in any state and tweak it to shift into any other state.
Previous research has shown that the Nanog gene is a key regulator of whether a stem cell acts like an embryonic stem cell. Orkin's team used this previously discovered knowledge about Nanog to use it as a starting point to map the cell differentiation regulatory circuitry.
As the jumping-off point of their mapping effort, Orkin and his colleagues used a protein called Nanog, which other researchers' experiments had indicated was central to regulation of stem cell pluripotency. The researchers first tagged Nanog so that when they removed it from cells, they would simultaneously remove any proteins that were attached to it.
These experiments enabled them to identify numerous proteins that interact with Nanog, including some already known to regulate pluripotency. To confirm that the proteins they had found functioned to maintain stem cell pluripotency, they depleted the levels of several proteins in embryonic cells and observed that the cells then expressed markers of differentiation.
Drugs could emulate the depletion of a protein by blocking its activity. So each of these several proteins are obvious targets for drug development. To change stem cells into specialised cells or vice versa we need drugs that will bind to these regulatory proteins to turn them on or disable them. Scientists will gradually assemble large toolsets of molecules that can bind to regulatory proteins and by using them in different combinations and orders they will be able to change any cell type to any other cell type.
The researchers have created an initial map of how the proteins interact to maintain embryonic stem cell state.
Next, the researchers created a protein interaction map that showed the relationships among the various proteins. The map will provide stem cell biologists with an important guide for future studies, said Orkin. “Even though some of these factors were known to be important in pluripotency, exactly how they work and who they talk to and interact with was completely unknown,” he said.
This research is important for another reason: These scientists did not try to study one or two proteins at a time. If they did we'd have to wait another century before rejuvenation therapies become possible. The development of assay tools which allow measurement of many proteins or many genes at once has allowed scientists to study complex networks of interactions. Since cells contain many kinds of components functioning in complex networks this ability to collect more data about more target cell components at once is essential if we are to have a chance of benefitting from stem cell therapies.
Embryonic stem cells can serve as a renewable source of replacement tissue to rescue visual function in rats with degenerative eye disease similar to age-related macular degeneration, a leading cause of blindness in humans, according to a report to be published in the Fall 2006 (Volume 8, Number 3) issue of Cloning and Stem Cells, a peer-reviewed journal published by Mary Ann Liebert, Inc. The paper is available online ahead of print at www.liebertpub.com/clo
Robert Lanza, M.D. and Irina Klimanskaya, Ph.D. at Advanced Cell Technology (Worcester, MA), and Raymond Lund, Ph.D. and colleagues at the University of Utah Health Science Center (Salt Lake City) generated retinal pigment epithelium (RPE)--the cells that support photoreceptor function in the eye--from human embryonic stem cell lines grown in culture in the laboratory. They transplanted the engineered tissue into the eyes of rats that had a defect in their RPE. This defect results in the loss of photoreceptors and visual function.
The authors reported 100% improvement in visual performance (spatial acuity) in treated animals compared to an untreated control group, and the transplanted RPE cells did not cause any pathology. In the treated rats, spatial acuity, or the ability to see fine detail, was approximately 70% that of normal rats (that had no RPE defect).
"These observations are very exciting as they show that one day it will be possible to treat diseases of human eyes with cells," says Ian Wilmut, Ph.D., Editor-In-Chief of Cloning and Stem Cells and director of the Centre for Regenerative Medicine, in Edinburgh, Scotland. "They also emphasize the great potential benefit of research with human embryo stem cells, in this case for cell therapy."
Macular degeneration is the leading cause of blindness in persons over age 60 in the United States and affects more than 30 million people worldwide. Embryonic stem cells would offer a readily available, safe, and reproducible source of replacement tissue to restore photoreceptors damaged or destroyed by disease and to restore a range of visual functions.
All 18 hESC lines they worked with could produce retinal cells.
"One important advantage offered by hES-derived cells over other cells developed to mimic or replace lost retinal pigment epithelium is that they more closely resemble primary human RPEs," stated Raymond D. Lund, Ph.D., Professor at the Moran Eye Center, University of Utah Health Science Center, Salt Lake City and the study's lead author. "Another significant advantage of using these cells is that a range of lines can be derived allowing the opportunity to 'tissue match' donor cells with recipient, a real advantage given that RPE cells are highly immunogenic and susceptible to rejection without some form of immunosuppression."
"Embryonic stem cells promise to provide a well-characterized and reproducible source of replacement cells for clinical studies," stated Robert Lanza, M.D., Vice President of Research & Scientific Development at ACTC and senior author of the paper. "All 18 human embryonic stem cell lines we studied reliably produced retinal cells that could potentially be used to treat retinal degenerative diseases, such as macular degeneration. We showed that these cells have the capacity to rescue visual function in animals that otherwise would have gone blind. Importantly, the cells did not appear to cause any unwanted pathological responses in the animals following transplantation."
Once useful human therapies are available which have been created using hESC the people making ethical arguments against the use of hESC are going to face much more opposition than they do today. The hypothetical future promise of hESC doesn't today motivate people to support hESC research as much as the availability of real treatments will.
The opponents of the use of hESC really ought to push harder to increase funding to develop other methods to create flexible and youthful stem cells. If they fail to do that they will find they are fighitng for a losing cause.
In a move that might provide a away around ethical objections to other ways to create human embryonic stem cells scientists were able to extract human embryonic stem cells from embryos that had ceased to grow
The journal STEM CELLS(R) today announced that scientists were able, for the first time, to derive pluripotent human embryonic stem cells (hESCs) from non-viable early human embryos.
The team, led by Professor Miodrag Stojkovic, derived hESCs using surplus and donated embryos that had stopped their cleavage. The scientists demonstrated that these non-viable embryos could be used under suitable laboratory conditions for derivation of hESCs and for study of early human development.
This progress, published in STEM CELLS(R), encourages other scientists to perform hESC research using both viable and non-viable pre-implantation embryos in their attempt to understand and fight debilitating diseases.
'This should get round opposition to stem cell science because live embryos will no longer need to be used in all experiments,' said Professor Miodrag Stojkovic, the researcher who carried out the experiments at the Centre for Stem Cell Biology at Newcastle University last year.
The embryos used were from attempts at in vitro fertilization where the embryos stopped growing even before implantation.
Stojkovic's experiments were carried out while he was working at the Centre for Stem Cell Biology at Newcastle last year. In a paper, published last week online on the website of the journal Stem Cells, Stojkovic reveals he and his colleagues took 13 embryos, created by IVF. All 13 had stopped developing a few days after conception. 'They were in a very early stage of development,' said Stojkovic, now head of Sintocell, the Serbian medical research centre.
The team then waited 24 hours to check that the embryos were no longer dividing before beginning their experiments.
Some ethicists still see problems with this approach.
But other stem cell scientists and ethicists quickly raised a host of reasons that the advance may have little practical impact on the stormy research field. Among them are concerns that cells from dead embryos may be genetically abnormal, and the lack of a definitive test for proving that an embryo has no lingering potential for life.
How to get around the genetic abormality problem? In theory doctors could take embryos from pregnant women who die from trauma such as from car accidents. The removal of cells from embryos to use for therapy development would be analogous to using organs. But I'm guessing that the early stage pregnancies where the embryos still have pluripotent (highly flexible) stem cells aren't going to be recognized either by the mother or by emergency room workers.
It could turn out that some of the IVF embryos stop dividing for epigenetic (chemical state around the genes rather than the genes themselves) reasons. If that turns out to be the case then some stem cells extracted using this technique might turn out to be in good genetic shape.
The full paper is available with free access.Here's the abstract excerpted from the paper (PDF format).
Human embryonic stem cells (hESC) hold huge promise in modern regenerative medicine, drug discovery, and as a model for studying early human development. However, usage of embryos and derivation of hESC for research and potential medical application has resulted in polarised ethical debates since the process involves destruction of viable developing human embryos. Here we describe that not only developing embryos (morulae and blastocysts) of both good and poor quality but also arrested embryos could be used for the derivation of hESC. Analysis of arrested embryos demonstrated that these embryos express pluripotency marker genes such OCT4, NANOG and REX1. Derived hESC lines also expressed specific pluripotency markers (TRA-1-60, TRA-1-81, SSEA4, alkaline phosphatase, OCT4, NANOG, TERT and REX1) and differentiated under in vitro and in vivo conditions into derivates of all three germ layers. All the new lines including line derived from late arrested embryo have normal karyotype. These results demonstrate that arrested embryos are additional valuable resources to surplus and donated developing embryos and should be used to study early human development or derive pluripotent hESC.
Biotech company Advanced Cell Technology (ACT) has announced development of a technique that can extract pluripotent human embryonic stem cells from a human embryo without destroying the embryo. In theory this technique provides a way to get human embryonic stem cells without destroying what some religious people think is a human life.
Alameda, CA, August 23, 2006 – Advanced Cell Technology, Inc. (OTC Bulletin Board: ACTC.OB) today reported that company scientists have successfully generated human embryonic stem cells (hES cells) using an approach that does not harm embryos. The technique is reported in an article appearing online (ahead of print) in the journal Nature. The article describes a method for deriving stem cells from human blastomeres with a single-cell biopsy technique called Preimplantation Genetic Diagnosis (PGD). This technique is used in in vitro fertilization (IVF) clinics to assess the genetic health of preimplantation embryos. The cell lines produced using this technique appear to be identical to hES cell lines derived from later stage embryos using techniques that destroy the embryo’s developmental potential. ACT had previously reported the successful use of a similar technique in mice in Nature in October 2005.
“Until now, embryonic stem cell research has been synonymous with the destruction of human embryos,” stated Robert Lanza, M.D., Vice President of Research & Scientific Development at ACT, and the study’s senior author. “We have demonstrated, for the first time, that human embryonic stem cells can be generated without interfering with the embryo’s potential for life. Overnight culture of a single cell obtained through biopsy allows both PGD and the development of stem-cell lines without affecting the subsequent chances of having a child. To date, over 1,500 healthy children have been born following the use of PGD.” Current technology derives hES cells from the inner cell mass of later-stage embryos known as blastocysts, destroying their potential for further development. ACT’s approach generates human embryonic stem cells from a single cell obtained from an 8-cell-stage embryo. The researchers used left-over embryos from fertility clinics which use IVF to create embryos for implantation. To create hES cell lines, the researchers used single cells obtained from unused embryos produced by IVF for clinical purposes. Nineteen stem-cell outgrowths and two stable hES cell lines were obtained. These cell lines were genetically normal and retained their potential to form all of the cells in the human body, including nerve, liver, blood, vascular, and retinal cells that could potentially be used to treat a range of human diseases.
But some human embryonic stem cell research opponents remained unpersuaded.
But the new method, reported yesterday by researchers at Advanced Cell Technology on the Web site of the journal Nature, had little immediate effect on longstanding objections of the White House and some Congressional leaders yesterday. It also brought objections from critics who warned of possible risk to the embryo and the in vitro fertilization procedure itself, in which embryos are generated from a couple’s egg and sperm.
Regarding possible risks: Trying to get a pregnancy started the natural way poses large risks to the eggs that get fertilized using old fashioned sexual procreation. Perhaps half of all conceptions spontaneously abort with most never even recognized as pregnancies.
The incidence of spontaneous abortion is estimated to be 50% of all pregnancies, based on the assumption that many pregnancies abort spontaneously with no clinical recognition.
Estimates for the percentage of clinically recognizeable pregnancies that miscarry range from 10% to 15% to 15% to 20%.
I predict that advances in reproductive biotechnology will eventually lead to the ability to create embryos and start pregnancies that have a far higher chance of going to term than pregnancies started the natural way.
Many scientists would like to take human embryonic stem cells (hESC) and find ways to instruct the cells to become whatever cell type that is needed. But restrictions on funding hESC work has slowed that avenue of investigation. Well, scientists at the University of Florida may have found a way to avoid the need for hESC to create neurons or neural progenitor cells for therapeutic purposes.
GAINESVILLE, Fla. -- University of Florida researchers have shown ordinary human brain cells may share the prized qualities of self-renewal and adaptability normally associated with stem cells.
Writing online today (Aug. 16) in Development, scientists from UF's McKnight Brain Institute describe how they used mature human brain cells taken from epilepsy patients to generate new brain tissue in mice.
Furthermore, they can coax these pedestrian human cells to produce large amounts of new brain cells in culture, with one cell theoretically able to begin a cycle of cell division that does not stop until the cells number about 10 to the 16th power.
They can grow large numbers of neurons. But how hard will it be to instruct those neurons to go into the brain and take up positions that replace lost neurons? For example, people with Parkinson's Disease have lost a lot of dopaminergic neurons. But neurons grown in culture aren't helpful unless they can be made to take up residence in those regions of the brain that have lost neurons and then once there the neurons would need to form appropriate connections with other neurons. Still, this is a hopeful result.
"We can theoretically take a single brain cell out of a human being and - with just this one cell - generate enough brain cells to replace every cell of the donor's brain and conceivably those of 50 million other people," said Dennis Steindler, Ph.D., executive director of UF's McKnight Brain Institute. "This is a completely new source of human brain cells that can potentially be used to fight Parkinson's disease, Alzheimer's disease, stroke and a host of other brain disorders. It would probably only take months to get enough material for a human transplant operation."
The findings document for the first time the ability of common human brain cells to morph into different cell types, a previously unknown characteristic, and are the result of the research team's long-term investigations of adult human stem cells and rodent embryonic stem cells.
Some people think that human neurons should not mix with animal neurons. This position reminds me of the Monty Python Catholic family in Yorkshire England who believed every sperm is sacred.
Every sperm is sacred,
Every sperm is great,
If a sperm is wasted,
God gets quite irate.Let the heathen spill theirs,
On the dusty ground,
God shall make them pay for,
Each sperm that can't be found.Every sperm is wanted,
Every sperm is good,
Every sperm is needed,
In your neighbourhood.
Every neuron is sacred? Does every neuron contain part of a soul? If you torture a human neuron in lab culture are you torturing a human?
Well, whether or not human neurons are sacred they can grow in mouse brains. They also can grow in culture. Once sperm can be created from regular cells and grown in large numbers in culture dishes will those spem be sacred too?
Human neurons in the brain of a mouse or rat will not make that animal think human thoughts. Their skulls are far too small to provide enough space for enough human neurons to form links that make higher level thought possible.
With the introduction of just four factors, researchers have successfully induced differentiated cells taken from mouse embryos or adult mice to behave like embryonic stem cells. The researchers reported their findings in an immediate early publication of the journal Cell.
The cells--which the researchers designate "induced pluripotent stem cells" (iPS)--exhibit the physical, growth, and genetic characteristics typical of embryonic stem cells, they reported. "Pluripotent" refers to the ability to differentiate into most other cell types.
"Human embryonic stem cells might be used to treat a host of diseases, such as Parkinson's disease, spinal cord injury, and diabetes," said Shinya Yamanaka of Kyoto University in Japan. "However, there are ethical difficulties regarding the use of human embryos, as well as the problem of tissue rejection following transplantation into patients."
Those problems could be circumvented if pluripotent cells could be obtained directly from the patients' own cells.
"We have demonstrated that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors," Yamanaka said. Fibroblasts make up structural fibers found in connective tissue.
Pluripotent stem cells can become any type of cell in the body. Adult stem cells are not as flexible. But currently the only way to get pluripotent stem cells is from embryonic cells. That raises ethical opposition in some quarters. Pluripotent stem cells created from adult cells would avoid most of the political resistance and at the same time be more immunologically compatible.
If this approach works for humans as well then some day we'll be able to have pluripotent stem cells made from our own cells. Then those cells could be used to grow replacement parts such as internal organs or injected into joints to supply joint material to those suffering from arthritis.
The researchers chose factors to introduce into adult cells by looking at which genes are turned on in embryonic stem cells. Note that advances in biotechnology in recent years have made it a lot easier to measure the levels of activity of many genes at once.
The researchers selected 24 genes--all previously found to play a role in early embryos and embryonic stem cell identity--as candidate factors that might give body cells the ability to become other cell types.
The researchers found that four of those factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated fibroblast cells taken from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells.They further reported that transplantation of the iPS cells under the skin of mice resulted in tumors containing a variety of tissues representing the three primary types found in mammalian embryos. Those primary "germ layers" in embryos eventually give rise to all an animal's tissues and organs.
The researchers still need to repeat this experiment with human cells to find out if this method will work for human cells as well. If they succeed then this discovery could open the gates for much higher levels of research funding for pluripotent stem cells.
Embryonic stem cells converted into astrocyte cells repaired damaged rat spinal cords and allowed the rats to walk normally again.
Researchers believe they have identified a new way, using an advance in stem-cell technology, to promote recovery after spinal cord injury of rats, according to a study published in today's Journal of Biology.
Scientists from the New York State Center of Research Excellence in Spinal Cord Injury showed that rats receiving a transplant of a certain type of immature support cell from the central nervous system (generated from stem cells) had more than 60 percent of their sensory nerve fibers regenerate. Just as importantly, the study showed that more than two-thirds of the nerve fibers grew all the way through the injury sites eight days later, a result that is much more promising than previous research. The rats that received the cell transplants also walked normally in two weeks.
The University of Rochester Medical Center, Rochester, N.Y., and Baylor College of Medicine, Houston, collaborated on the work. Researchers believe they made an important advance in stem cell technology by focusing on a new cell type that appears to have the capability of repairing the adult nervous system.
"These studies provide a way to make cells do what we want them to do, instead of simply putting stem cells into the damaged area and hoping the injury will cause the stem cells to turn into the most useful cell types," explains Mark Noble, Ph.D., co-author of the paper, professor of Genetics at the University of Rochester, and a pioneer in the field of stem cell research. "It really changes the way we think about this problem."
The breakthrough is based on many years of stem cell biology research led by Margot Mayer-Proschel, Ph.D., associate professor of Genetics at the University of Rochester. In the laboratory, Mayer-Proschel and colleagues took embryonic glial stem cells and induced them to change into a specific type of support cell called an astrocyte, which is known to be highly supportive of nerve fiber growth. These astrocytes, called glial precursor-derived astrocytes or GDAs, were then transplanted into the injured spinal cords of adult rats. Healing and recovery of the GDA rats was compared to other injured rats that received either no treatment at all or treatment with undifferentiated stem cells.
The rats without the GDA cell transplant did not show any nerve fiber regeneration and still had difficulty walking four weeks after surgery.
Note the use of embryonic stem cells. As more therapies are developed in animal models using embryonic stem cells the pressure to allow more research on human embryonic stem cells is going to build. The political opponents of human embryonic stem cell (hESC) research who want to be able to resist this pressure ought to add a couple of billion dollars a year to the money available for adult stem cell treatment.
Mind you, I'm not taking sides in that fight. Rather, I'm always on the look-out for more arguments for why research funding ought to be increased. I figure if hESC opponents can be convinced that they need to fund far more rapid development of alternatives to hESC-based therapies then the total amount of money available to develop rejuvenation therapies will increase.
Researchers at the Medical College of Georgia have demonstrated the ability of a commercial human stem cell line to partially repair surgically induced stroke-like damage in rat brains.
A single dose of adult donor stem cells given to animals that have neurological damage similar to that experienced by adults with a stroke or newborns with cerebral palsy can significantly enhance recovery from these types of injuries, researchers say.
Using a commonly utilized animal model for stroke, researchers administered a dose of 200,000-400,000 human stem cells into the brain of animals that had experienced significant loss of mobility and other functions. The stem cells used in the study were a recently discovered stem cell type, referred to as multipotent adult progenitor cells, or MAPCs.
Treated animals experienced at least 25 percent greater improvement in motor and neurological performance than controls, said Dr. Cesario V. Borlongan, neuroscientist at the Medical College of Georgia and the Veterans Affairs Medical Center in Augusta.
Improvement in function continued for the length of the study. This suggests that even greater improvement would have been seen over additional months. Also, it opens up the possibility that additional treatment doses might yield even greater improvement.
Following the stroke, both control animals and those that received a single injection of stem cells were evaluated for a period of up to 2 months. Improvements in stem cell treated animals included enhanced performance across the range of tests, which examined strength, balance, agility and fine motor skills, and also included greater recovery of injured tissue.
“A single dose of the cells produce robust behavioral recovery at an early period post-transplantation and the recovery was durable, lasting up to two months, which was the entire length of this study,” Dr. Borlongan said. “Furthermore, animals continued to show improvement over time.” In the newborn model of ischemic injury, enhanced recovery was found within two weeks.
Even though less than 1 percent of the transplanted cells were present two months later, animals receiving treatment developed new neurons, apparently formed from endogenous stem cells. “The mechanism that we are putting forward is these donor cells are secreting nourishing trophic factors that are helping the host brain cells survive and stimulating stem cells from the host to multiply,” Dr. Borlongan said.
I can imagine such a treatment providing benefit even to those who do not suffer from stroke or cerebral palsy. Aged brains with slowly dividing stem cells could get partially rejuvenated if injected stem cells could stimulate existing cells to divide.
This method of treatment for stroke does not repair the core location of damage. However, repair on the periphery could prevent the core damage area from getting even larger and could make the difference between, for example, being wheelchair bound or walking with a cane. Or it could mean the difference between drooling out the side of one's mouth or being able to keep one's mouth closed.
In the adult stroke model, MCG researchers found giving stem cells increased the number of injured cells that survived in the area just outside the area of greatest damage, also referred to as the ischemic core, by 5-20 percent.
“Up to this point, all the treatment approaches, including transplantation and tPA, cannot get rid of that ischemic core,” Dr. Borlongan said. “But outside of that core there is a lining, what we call the penumbra, and that penumbra, if you do not treat it over time, becomes part of the core. We are showing, that even one week after a stroke, we are able to increase the number of cells surviving along that penumbra and that is how we feel it is producing significant recovery, by rescuing cells within the penumbra.”
What we most need are stem cell therapies, gene therapies, and still other therapies that will go into the vascular system and repair blood vessels that put us at risk of stroke. Any therapy aimed at restoring function after a stroke won't be able to put back neurons that held memories or that were trained to do complex physical movements such as, say, playing a musical instrument. Better not to lose the neurons in the first place.
The stem cells used in this experiment came from a Cleveland Ohio biotech company named Athersys.
Athersys, Inc., a Cleveland-based biopharmaceutical company pursuing cell therapy programs in cardiovascular disease, stroke, cancer and other diseases, funded the research in which previously frozen human or rodent multipotent adult progenitor cells, which the company calls MultiStem™, were thawed and injected directly into the brain.
Researchers believe that MultiStem™ cells are able to deliver a therapeutic benefit in multiple ways, for example by producing factors that limit tissue damage and stimulate repair, according to Dr. Gil Van Bokkelen, the company’s chairman and chief executive officer. In addition, MultiStem™ cells can safely mature into a broad range of cell types and can be produced on a large scale, something which should ease the move toward clinical studies and eventual clinical use. “Given the number of stroke victims each year, it would be a big step forward if a safe and effective stem cell therapy could be produced, conveniently stored, and efficiently delivered on a widespread basis. We believe that we can achieve that with MultiStem™,” commented Dr. Van Bokkelen.
As stem cell therapies become used to treat a wider range of diseases and disorders the revenue from sales will feed back toward the development of improvements and the development of stem cell therapies for yet more conditions and problems. We are on the threshold of a virtuous cycle of stem cell development funded by the enormous amounts of money in the medical industry. Sales of stem cell therapies will replace far less effective therapies and also shift money away from nursing homes and palliative treatments.
Update: Another study using stem cells to repair neuron damage found that a special gel can align the growth of neural stem cells to help bridge spinal cord injury gaps.
The second study addressed a significant problem in the use of stem cells for spinal cord repair, that of directing cells to align in the proper direction along the cord. Misdirected or undirected cell orientation limits the ability of injured nerves to reconnect with other nerve cells further down the spinal cord. “A regrowth-directing structured scaffold is required for spinal cord repair,” said lead study author Norbert Weidner, MD, of the University of Regensburg, Germany.
The research group tested anisotropic capillary hydrogels (ACH) made of a seaweed derivative, which have an internal structure that preferentially guides axons (nerve cell extensions) in one direction. In brain slice cultures, they showed that ACH promoted regrowth of existing axons and improved their ability to reconnect with their target nerve cells. They then tested this strategy in adult rats with damaged spinal cords, where ACH promoted directional regrowth across the scaffold. Ongoing studies demonstrate that ACH can be "seeded" with neural stem cells, which now align properly and may further enhance the regenerative capacity of ACH.
To give you some measure of the potential benefit of a treatment that could repair damaged spinal cords in the United States about a quarter million people have spinal cord injuries and the average age at the time of injury is about 28 years old. So a lot of people will gain decades of greater mobility and richer lives when their spinal cord injuries become repairable. The economic value of effective spinal cord repair techniques will be enormous.
The researchers, from the Georg August University in Gottingen, isolated sperm-producing cells from the testes of adult mice.
They were able to show that, under certain culture conditions, some of them grew into colonies much like embryonic stem cells.
They called these cells multipotent adult germline stem cells (maGSCs).
Like ES cells, maGSCs can spontaneously differentiate into the three basic tissue layers of the embryo - and contribute to the development of multiple organs when injected into embryos.
I wonder how old the mice were. Would such results be achievable from old mice?
Also, adult stem cell lines tend to grow more slowly (even orders of magnitude more slowly) Than embryonic stem cell lines. So how fast do these msGSC lines replicate? Can they grow fast enough to be used to grow replacement organs for example?
One observer says more work needs to be done to confirm the result.
Gerd Hasenfuss from the Georg-August-University of Göttingen and colleagues report the results in Nature1. Their work shows the extraction of the cells from male mice, but it should be possible to produce similar results with samples taken from human testicles through a biopsy, says Wolfgang Engel, a human geneticist also at the Georg-August-University of Göttingen and a co-author on the paper.
The cells have been shown to have some of the same characteristics as embryonic stem cells, but not all, notes Chris Higgins, director of the Medical Research Council's Clinical Sciences Centre at Imperial College London, UK. "There needs to be further research before we really get excited about it."
The researchers are currently trying to reproduce this result using humans.
The discovery that cells which behave like ESCs can now be obtained from adult mice may now open up the possibility of a similar “ethical� source from grown men.
“We’re in the process of doing this in humans, and we’re optimistic,� says Gerd Hasenfuss of the Georg-August University of Göttingen, Germany, and head of the team which pioneered the breakthrough.
Here is a report I really hope holds up. PrimeGen Biotech of Irvine California claims they've already produced pluripotent stem cells from human adult testes.
-- PrimeCell(TM) -- First Human Adult Stem Cell Showing Ability to Differentiate into Any Cell in the Body -- Paves Way for Cellular Replacement Therapies to Cure a Multitude of Diseases
-- Does Not Require Generation or Destruction of an Embryo
In a breakthrough for stem cell research and cellular replacement therapies, PrimeGen Biotech LLC (www.primegenbiotech.com) today announced that its researchers have successfully developed the first human adult therapeutic germ stem cell. Derived from adult stem cells but with the advantageous genetic characteristics of embryonic stem cells, PrimeCells have successfully been transformed into human heart, brain, bone and cartilage cells -- cardio, neuro, osteo and chondrocytes.
Therapeutically reprogrammed from germ line stem cells found in the testes of adult human males, PrimeCell(TM) is the first non-embryonic stem cell showing the potential to become any type of cell from any organ, something previously thought possible only for embryonic stem cells -- the definition of true pluripotency.
This week, the company's researchers are scheduled to present a summary of their complete data and manuscript in a poster presentation at the Serono Symposia International's Therapeutic Potential of Stem Cells In Reproductive Medicine conference in Valencia, Spain. PrimeGen first presented its preliminary human experimental data at the 1st International Symposium on Germ Cells, Epigenetics, Reprogramming and Embryonic Stem Cells, held in November 2005 in Kyoto, Japan.
Scientists will find ways around the use of embryonic stem cells and will develop other means to make highly flexible cells. The restrictions on human embryonic stem cell research are going to seem like a speed bump 5 or 10 years from now. I'm not saying that to attack or defend those restrictions. I just think the restrictions aren't going away but they can be worked around. People who fight for lifting those restrictions ought to fight for a lot more research funding to find ways around the restrictions.
"The medications and interventional therapies available so far are intended only to limit further damage to the heart," said Andreas Zeiher, professor at J.W. Goethe University in Frankfurt, Germany, and a senior author of the study.
"In contrast, progenitor cell therapy has the potential not only to limit further damage, but to regenerate heart function," he said.
The improvement was small.
But patients who received the bone marrow cell infusion saw an improvement in their left ventricular ejection fraction -- a measure of heart efficiency -- on average, of 5.5 percent. Those getting placebo saw a 3 percent improvement.
The hearts of treated patients also swelled less and had better blood supply.
More than 200 individuals who had had a heart attack were enrolled in the trial. Half of the participants received infusions of their own bone marrow progenitor cells into their hearts while the other half received placebo infusions.
Both groups had similar left ventricular function (LVEF), a surrogate predictor of a patient's prognosis after a heart attack, at the beginning of the trial: 47 percent in the placebo group and 48 percent in the bone marrow cell group.
What we really need: Therapies that can prevent heart attacks in the first place. In most cases such therapies will involve clearing arterial plaque, prevention of plaque formation, and growth of new blood vessels. You can do some of that now with better diet and statin drugs to lower cholesterol.
Heart specialist Sebastiano Marra at Turin University in Italy found that injection of cytokine hormones into the body after a heart attack marshals stem cells to repair the heart and leads to better outcomes.
In the new technique, hormones called cytochines are injected into the body during the 24 hours after emergency heart surgery and immediately spur the production of stem cells in spinal fluid.
The stem cells race to rescue the damaged heart, Marra said.
"The acute inflammation of the heart attracts the stem cells whose role in the body is to repair cardiac tissue," said Marra, who operated on the patients at Turin's Molinette Hospital.
Tests on eight patients who were operated on immediately after a heart attack have produced "amazing" results, he said.
"They were soon back on their bicycles or going to swimming pools." Compared to experimental methods used so far, the Turin technique is far less invasive, Marra continued.
Mind you, this is a news report on only 8 patients and not a journal article with a larger number of patients with controls and a detailed comparison of outcomes. Still, the approach is at least plausible. Stimulation of the production of stem cells is already used to make stem cells from donors to treat leukemia. But Marra is trying to stimulate stem cells within the same body that needs them for heart muscle repair.
The technique might work less well in the really old because stem cell reservoirs in older people are aged and do not divide as quickly. However, one study found that elements in the blood of the old mice caused their stem cells to grow less rapidly. So it isn't so much that the stem cells are old but that they are getting signals telling them not to grow. Perhaps cytokines or other compounds can override those suppressor signals. So Marra's approach might work even for old folks.
Thanks to Brock Cusick for the pointer.
Researchers at the UC Irvine Reeve-Irvine Research Center have used adult human neural stem cells to successfully regenerate damaged spinal cord tissue and improve mobility in mice.
The findings point to the promise of using this type of cells for possible therapies to help humans who have spinal cord injuries. Study results appear online in the Proceedings of the National Academy of Sciences Early Edition.
In their study, Brian Cummings, Aileen Anderson and colleagues injected adult human neural stem cells into mice with limited mobility due to spinal cord injuries. These transplanted stem cells differentiated into new oligodendrocyte cells that restored myelin around damaged mouse axons. Additionally, transplanted cells differentiated into new neurons that formed synaptic connections with mouse neurons.
The ability to grow new myelin sheath would also be very beneficial to patients suffering from multiple sclerosis.
Myelin is the biological insulation for nerve fibers that is critical for maintenance of electrical conduction in the central nervous system. When myelin is stripped away through disease or injury, sensory and motor deficiencies result and, in some cases, paralysis can occur. Previous Reeve-Irvine research has shown that transplantation of oligodendrocyte precursors derived from human embryonic stem cells restores mobility in rats.
“We set out to find whether these cells would be able to respond to the injury in an appropriate and beneficial way on their own,” Cummings said. “We were excited to find that the cells responded to the damage by making appropriate new cells that could assist in repair. This study supports the possibility that formation of new myelin and new neurons may contribute to recovery.”
Coordinated walking ability was restored.
Mice that received human neural stem cells nine days after spinal cord injury showed improvements in walking ability compared to mice that received either no cells or a control transplant of human fibroblast cells (which cannot differentiate into nervous system cells). Further experiments showed behavioral improvements after either moderate or more severe injuries, with the treated mice being able to step using the hind paws and coordinate stepping between paws whereas control mice were uncoordinated.
The cells survived and improved walking ability for at least four months after transplantation. Sixteen weeks after transplantation, the engrafted human cells were killed using diphtheria toxin (which is only toxic to the human cells, not the mouse). This procedure abolished the improvements in walking, suggesting that the human neural stem cells were the vital catalysts for the maintained mobility.
The lack of need to condition the stem cells to become specific types of cells makes this a simpler approach to apply than attempts which used less differentiated human embryonic stem cells.
This study differs from previous work using human embryonic stem cells in spinal cord injury because the human neural stem cells were not coaxed into becoming specific cell types before transplantation.
If human cells can improve movement in mice the likelihood that these same cells would deliver a similar benefit in humans with spinal cord injuries seems high.
The British newspaper The Guardian reports that the stem cells came from neural tissue of aborted fetuses.
Neuroscientist Aileen Anderson and her team at the Reeve-Irvine Research Centre at the University of California, Irvine, used stem cells taken from the neural tissue of aborted foetuses. When injected into the body, they can develop into any type of nervous tissue.
Can anyone confirm this? Neither the UC Irvine press release or the press release of the company that supplied the stem cells (see below) make any mention of this fact.
The company that supplied the stem cells to the UC Irvine researchers is Palo Alto California based StemCells Inc. The StemCells Inc. press release mentions that the Christopher Reeve Foundation was one of the sources of funds for this research (bringing to mind that South Park episode where Reeve's character ate fetal brains and became extremely vigorous as a result)
PALO ALTO, Calif., (September 19, 2005) – StemCells, Inc. (Nasdaq: STEM) today announced results of a published study that demonstrates that the Company’s proprietary human neural stem cells restore the lost motor function of mice with spinal cord injuries. This study is also the first to show the causal relationship between transplanted human neural stem cells and long-term recovery of motor function: The human neural cells were subsequently ablated in some of the mice, and their improved motor function was lost.
The study was conducted by Drs. Aileen Anderson, Brian Cummings and their colleagues from the Reeve Irvine Research Center at the University of California, Irvine. It will be published today online in the Early Edition of the Proceedings of the National Academy of Sciences of the United States of America (PNAS), and will appear in the September 27, 2005 print issue. The study was funded in part by a Small Business Innovative Research Grant from the National Institute of Health (NIH) to StemCells, Inc. Support was also provided by the Christopher Reeve Foundation through its International Research Consortium on Spinal Cord Injury.
The CEO of StemCells Inc. says these are still early days. But what obstacle exists for trying out these stem cells in paralyzed humans right now?
“While we are early in our quest to find a stem cell therapy for spinal cord injury, the design of this study raises the bar for evaluating experimental cell-based therapies in this extremely debilitating medical condition,” said Martin McGlynn, President and Chief Executive Officer of StemCells. “The study clearly demonstrates that our proprietary human neural stem cells make functional new neural cells, and are responsible for the restoration of hind limb function in this animal model of spinal cord injury.”
In the StemCells Inc. press release they refer to the cells as having been isolated from "normal brain tissue".
StemCells, Inc. is a development stage biotechnology company focused on the discovery, development and commercialization of stem cell-based therapies to treat diseases of the nervous system, liver and pancreas. The Company’s stem cell programs seek to repair or repopulate neural or other tissue that has been damaged or lost as a result of disease or injury. StemCells is the first company to directly identify and isolate human neural stem cells from normal brain tissue. These stem cells are expandable into cell banks for therapeutic use, which demonstrates the feasibility of using normal, non-genetically modified cells as cell-based therapies. StemCells is the only publicly traded company solely focused on stem cell research and development and has more than 40 U.S. and 100 non-U.S. patents, as well as 100 patent applications pending worldwide.
On one hand abortion is already legal in the United States and has been for decades. So use of neural stem cell tissue from aborted fetuses does not result in more fetuses getting killed. On the other hand, abortion opponents will surely get angry at the idea of remains of aborted fetuses getting used to develop medical treatments.
Put aside the ethical considerations. Think about the medical implications. The scientific lesson here is that types of neural stem cells already exist that can at least partially and substantially repair spinal cord injury. The delivery of those cells does not require creation of a futuristic high tech artificial biochemical environment in the spine (say complex chemical gradients varying through time) or an elaborate system for controlling the migration and differentiation of the cells. Given the development of the right sort of neural stem cells a substantial amount of spinal repair becomes possible pretty easily.
The technical point here, even for abortion opponents, is that if a way to make the right sorts of neural stem cells can be found then stem cells can fix damaged spines. Granted, some people would prefer a different way to make these stem cells. I expect other ways will be found. But once stem cells can get programmed to the right epigenetic state then the cells will repair spinal cords. That's good news.
The full article (PDF format) is open access and you can start with the abstract.
Update: Be sure to read the comments on this post. Garson Poole points to the use of premature births that die as a source of cells. This neatly sidesteps opposition to abortion. The use of organs from people who unexpectedly die is morally accepted across the political spectrum (with the exception of perhaps a couple of religious demoninations that do not oppose this choice by others). So why not the same with premature births?
An international team of researchers has discovered that human embryonic stem cell lines accumulate changes in their genetic material over time.
The findings do not limit the utility of the cells for some types of research or for some future clinical applications, the researchers say, but draw attention to the need to closely monitor stem cell lines for genetic changes and to study how these alterations affect the cells' behavior. The researchers' work is described in the Sept. 4 online edition of Nature Genetics.
"This is just the first step," says Aravinda Chakravarti, Ph.D., one of the research team's leaders and professor and director of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "While this is a snapshot of the genomic changes that can happen, it's certainly not everything going on. We still need comprehensive analyses of the changes and what they mean for the functions of embryonic stem cells."
"Embryonic stem cells are actually far more genetically stable