Embryonic versus Adult Stem Cells and other spinal cord injury therapies [Archive]

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Wise Young

11-25-2006, 06:28 PM

Znop asked if I would start a discussion concerning embryonic and adult stem cells. I said that I would start with a summary and hope that others will contribute to the discussion. ]\

Before we begin the discussion, it is important that we define the terms because there is so much misunderstanding and misuse of the terms:

Stem cells. These are cells that can make many different kinds of cells, as well as themselves. There are many types of stem cells

Embryonic stem cells. These are cells that are derived from blastocysts, a very early stage of development that occurs during the first two weeks after fertilization. A blastocyst is a small ball that contains about 200-300 stem cells. The blastocyst is pre-embryonic. A developing fertilized egg becomes an "embyro" only after a midline appears. This usually occurs shortly after implantation of the egg into the uterus and a "primitive streak" develops. So, the term "embryonic stem cells" is a misnomer. They should be called "pre-embryonic stem cells".
Fetal stem cells. These are cells that are derived from fetuses. A fetus refers to the stage of development when body parts are evident, including a head, arms, and legs, usually starting 6 weeks after conception and continuing until birth. Many types of stem cells are present in fetuses, associated with the various organs of the body that are developing. These include:

Fetal neural stem cells. These are obtained from the developing brain.
Fetal bone marrow stem cells. These are obtained from developing bone.
Fetal stem cells isolated from various tissues, including skin, blood, bone, etc.

Neonatal stem cells. These are cells that are derived from cells collected from newborns. These include:

Umbilical cord blood stem cells. These are obtained from umbilical cord blood collected from the umbilical cord shortly after birth.
Umbilical cord and placental stem cells. These are obtained from the umbilical cord and placenta shortly after birth.

Adult stem cells. These are cells that are derived from cells collected from any person older than newborn, from several days to elderly. They include:

Bone marrow stem cells. These are cells obtained from bone marrow, usually autologous or from the same person that will receive the transplant. Although the markers for bone marrow stem cells are well defined in humans, many investigators use CD34+ which is a maker for hematopoietic stem cells (i.e. stem cells that make blood cells). Please note that we did not know that there were pluripotent stem cells in bone marrow until 1999.
Mesenchymal stem cells. These are cells collected from a variety of tissues, including peripheral blood. There are some markers, such as CD144+ but the markers are controversial. Tuli, et al. (2003) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14595128) for example reports that mesenchymal derived from human trabecular bone are CD73(+), STRO-1(+), CD105(+), CD34(-), CD45(-), CD144(-) while Mayer (2004) (while Mayer (2004) suggests that bone cells are CD13+, CD44+, CD90+, CD147+, CD14-, CD34-, CD45- and CD144- in elderly women, Mitchell, et al. (2006) (CD13, CD29, CD44, CD63, CD73, CD90, CD166) suggests that such cells obtained from adipose (fat) tissues are CD13, CD29, CD44, CD63, CD73, CD90, CD166 are initially low but increase progressively with passage. Kuwana, et al. (2006) report that human monocyte derived multipotential cells are expressed CD31, CD144, vascular endothelial growth factor (VEGF) type 1 and 2 receptors, Tie-2, von Willebrand factor (vWF), endothelial nitric oxide synthase, and CD146, but CD14/CD45 expression was markedly down-regulated.
Neural stem cells. We have only known since the mid-1990's that there are neural stem cells in adult brain that continue to make neurons throughout adult life.
Enteric glia. These are stem cells from the gut. Although known for a long time to be able to produce neurons, these cells are now believed to be a type of stem cell or a neuroprogenitor cell.

Progenitor cells. These are cells that make several different kinds of cells but are usually more limited than stem cells and may not be able to make themselves. The difference between progenitor and stem cells is not clear and may become moot as if becomes clear that it is possible to "dedifferentiate" cells to become stem cells.
Precursor cells. These are even more limited than progenitor cells and make only a few types of cells and cannot make themselves. These are further down the differentiation path from progenitor cells.

There are several possible goals for using stem cells for treating spinal cord injury.

Bridging the gap. The injury site is frequently a "bombed out" tissue that has lost many cells and is filled with macrophages and other inflammatory cells in the weeks that follow injury. In the months and years after injury, it may be taken over by reactive glial cells that may express substances that repel axonal growth. One of the goals of spinal cord injury repair is to fill this site with cells that are conducive to axonal growth.
Growth factors. Many stem cells and progenitor cells are believed to secrete growth factors that stimulate growth of cells. Many of these factors are also produced by other cells. These include neurotrophins (that stimulate neurons), proliferative factors such as fiberblast growth factor (FGF) and epidermal growth factor (EGF), survival and protective factors such as glial-derived neurotrophic factor, insulin-like growth factor (IGF), and others.
Remyelinating axons. Injury damages oligodendroglial cells (the cells that provide myelin for axons). Oligodendroglia come from oligodendroglial precursor cells called O2A. These cells may be in short supply or cannot migrate well into the injury to to remyelinate axons. Note that regenerated axons are "naked" and need to be remyelinated in order to conduct efficiently.
Replacing neurons. Neurons may be lost, particularly when the injury is close to the lumbar enlargement where the neurons from the legs are present or in the cervical enlargement where the neurons for the arms are located. The sacral tip of the spinal cord or conus contain neurons that innervate the bladder, anal sphincter, and other important functions.

Tissue niches for stem cells. As investigators gain more experience with stem cell transplants, it is becoming clear that many tissues don't have the factors that tell a stem cell what to do, what kind of cells to produce. In adult tissues, stem cells must interact with other cells, sometimes called a "niche" in order to produce other kinds of cells. This may be a very important regulator of stem cells so that they do not produce the wrong type or wrong number of cells. For example, it would not be good if bone marrow stem cells produced blood cells in the spinal cord. In general, many investigators attempt to differentiate stem cells in culture before transplantation so that they will produce the right type of cells. For example, one can differentiate embryonic stem cells by treating them with a factor called retinoic acid which pushes them to differentiate towards neural stem cells and then using factors such as sonic hedghog (SHH) to differentiate the cells further to become neurons. These approaches have worked to produce neurons in the brain and motoneurons in the spinal cord.

Neural stem cells. During development, the stem cells of the central nervous system are radial glial cells. These are very specialized looking cells that haveStem cells versus differentiated cell transplants. Most of cells transplanted into the spinal cord in animal studies and human clinical trials are not stem cells and, even if they are, it is not clear that they are performing as stem cells. For example, olfactory ensheathing glia are not stem cells. Likewise, while nasal mucosa may contain some stem cells, it is not clear transplanted nasal mucosa are producing neurons in the spinal cord after transplantation. The only exception has been embryonic stem cells. These cells appear to behave like stem ells when transplanted into the spinal cord, producing some neurons, astrocytes, and oligodendroglia. To date, neither adult bone marrow nor umbilical cord blood cells have been reported to produce neurons or glia in the spinal cord after transplantation. In fact, most umbilical cord blood and bone marrow cells simply remain undifferentiated when they are transplanted into the spinal cord. While they may proliferate (i.e. produce additional cells), it seems that they produce more of themselves and not necessarily neurons, astrocytes, or oligodendroglia. However, they may stimulate endogenous cells to remyelinate the spinal cord axons.

Drug stimulation of stem cells. Some drugs seem to stimulate certain cells to produce more growth factors. For example, lithium seems to do this and this may be one of the reasons for the beneficial effects of lithium when used to treat depression. Lithium has been reported to stimulate bone marrow cells to grow. Erythropoeitin is known to stimulate bone marrow stem cells. Several bone marrow stimulation factors are known to stimulate bone marrow cell prolieration and differentiation. This approach may enhance the neuroregenerative and remyelinative effects of bone marrow and umbilical cord blood cells. This is one of the reasons why we are interested in assessing the effects of lithium on spinal cords that have been transplanted with umbilical cord blood mononuclear cells. Mononuclear cells presumably include mesenchymal stem cells. There is also substantial interest in the effects of lithium on neural stem cells because this is one of the theories as to why lithium is beneficial as a treatment of manic depression. It would be of interest to see if lithium stimulates transplanted bone marrow cells as well.

Many therapies regenerate the spinal cord without stem cells. Marie Filbin and her colleague have reported that increased cAMP levels inside neurons will allow axons to grow despite the presence of growth inhibitors. Thus, there was a great deal of excitement when Mary Bunge and colleagues at the Miami Project showed that treatment with rolipram and dibutyryl cAMP and Schwann cells (a source of growth factors and a cell that supports axonal growth) allowed large numbers of axons to grow across the contusion site of injured spinal cords, associated with improved functional recovery. Schwann cells are not stem cells. Likewise, olfactory ensheathing glial cells are not stem cells.

Embryonic stem cells need to be combined with other therapies. Douglas Kerr and colleagues has shown that human embryonic stem cells transplanted to the spinal cord will not only survive and produce motoneurons but, when stimulated with rolipram and dibutyryl cAMP, send axons out of the spinal cord to re-innervate muscle. So far, only embryonic stem cells have been shown to do this. But, it is important to note that embryonic stem cells alone cannot do this. They must be pre-differentiated and combined with other therapies in order to achieve the objective of replacing neurons for these neurons to regenerate and reconnect with muscle.

Stem cells must be differentiated before they are transplanted. Much evidence suggest that it is important to differentiate the stem cells before they are transplanted. In the case of embryonic stem cells, it is necessary to differentiate them or else they may produce inappropriate types and numbers of cells in the spinal cord. Note that it is not necessary for embryonic stem cells to become cancers (i.e. cells that have lost their growth control). All they have to do is produce the wrong number and types of cells. For example, it would not be good if embryonic stem cells produced fibroblasts (skin cells) or hair cells in the spinal cord. To avoid this, most investigators pre-differentiate embryonic stem cells before they transplant them into the spinal cord. Thus, what is being transplanted are not stem cells but rather progenitor or even precursor cells that produce astrocytes, oligodendroglia, or neurons in the spinal cord. In fact, Steven Davies and his colleagues recently reported that it is helpful to differentiate fetal neural stem cells into a particular kind of astrocyte before transplanting them into the spinal cord, to encourage regeneration.

Embryonic stem cells are important. Embryonic stem cells are potentially a source of all the cells in the body. They provide the possibility of producing cells rather than having to harvest the specific cells from different organs for transplantation. While this is controversial, I personally believe that we (not our group but scientists in general) someday should be able make many kinds of cell of the body behave like stem cells. However, in order to reach this goal, it is critical that scientists be allowed to study human embryonic stem cells, find out what makes them pluripotent, identify factors that cause them to produce or differentiate into different kinds of cells, and how to regulate them. Why can't this be done in animal cells? There are important differences between animal and human cells. In fact, for reasons that we still don't understand, scientists have had very little success growing rat embryonic stem cells even though we can grow mouse, human, and primate embryonic stem cells. The fact that we cannot grow rat embryonic stem cells should give people an idea how little we understand of the factors that control and sustain embryonic stem cells and that there are species differences that we don't understand.

Embryonic stem cells alone are not a cure. It is important that people don't expect a cure from just by transplanting human embryonic stem cells into the spinal cord for several reasons. First, there is no reason why embryonic stem cells should or would know what to do when they are plugged into an injured spinal cord. Second, the studies with embryonic stem cell transplants in animal spinal cord injury models have been done shortly after injury and in chronically injured spinal cords. Third, there is the problem of immune rejection of transplanted cells. Although several laboratories have hypothesized that embryonic stem cells are not rejected when transplanted into the spinal cord, this is not the experience of most investigators. That is the reason why there is strong interest in cloning of embryonic stem cells. Fourth, the mechanisms of immune rejection in the central nervous system may be different from immune rejection in other parts of the body.

Adult stem cells alone are not a cure. Likewise, it is important that people don't expect a cure from just infusing umbilical cord blood cells into people. Many clinics are advertising umbilical cord blood treatments as if umbilical cord blood stem cells injected into the bloodstream will go directly to the spinal cord and start to produce the right types of cells and the right types of growth factors to repair the spinal cord. I am very skeptical of claims that are saying that umbilical cord blood cells are doing this. For the past two years, at the Rutgers Keck Center, we have been transplanting umbilical cord blood cells into the spinal cord and finding that the cells do not produce neurons, astrocytes, or oligodendroglial cells. Yes, when they are transplanted directly into the spinal cord, umbilical cord blood cells do produce growth factors that may be beneficial for the spinal cord. However, when we have injected human or rat neonatal blood cells intravenously into rats after spinal cord injury, we find that few or none of the cells go into the spinal cord, even when we suppress the immune system.

Stem cells are one of several tools that we should use to repair the spinal cord and stimulate regeneration. Scientists must be allowed to study a diversity of human embryonic stem cells to understand what and how they do what they do. By understanding stem cell biology, we should be able to make any cell behave like a stem cell. After all, a stem cell is just a cell that is expressing certain genes. Also, it is important to understand how the central nervous system recognize "foreign" cells and reject them. If we know the mechanisms, we may be able to trick the spinal cord to accept transplanted cells are "native" to the spinal cord. Finally, we need to know the factors needed to get the cells to do what we would like them to do, to stimulate regeneration, to provide a substrate that is conducive to axonal growth, to replace neurons, and to remyelinate the spinal cord.

No reason to be discouraged. After reading the above, many may conclude that it will take a long time before treatments become available to restore function to people with spinal cord injury. I don't think so for the following reasons. First, stem cells do provide an important substrate of regeneration in the spinal cord. For regeneration, it may not be necessary for the transplanted cells to stay there forever. For example, once the cells have created a bridge and the axons have grown across, it may not be necessary to keep the bridge. In fact, it might even be a good idea for the bridge to go away. In fact, this may be one reason why stem cell transplants have been relatively safe. Second, stem cells are a very efficient way of delivering growth factors to the spinal cord. I am quite excited by the discovery that umbilical cord blood cells secrete most of the growth factors that are known to stimulate regeneration and remyelination in the spinal cord. Third, although we may not understand the mechanisms, many studies have reported beneficial effects of stem cell transplants to the spinal cord.

Nogo receptor blockers. Many studies indicating that blockade of axonal growth inhibitors will allow regeneration to occur in the spinal cord. For example, there are phase 1 trials of the Nogo antibody by Novartis and Cethrin (the blocker of Nogo receptor intracellular messenger rho) by Bioaxone. Dozens of studies have shown the beneficial effects of chondroitinase in animal studies. Likewise, Biogen has identify other blockers of the Nogo receptor. These need to be taken to clinical trial. When these are combined with cell transplants and sustained growth factor support, I hope that we will see substantial regeneration in human spinal cords. It is not trivial to get such complicated combination therapy trials tested. We have to develop the clinical trial infrastructure now so that we are ready when the therapies are available to be tested in humans.

Wise.

Keith

11-25-2006, 11:17 PM

Wise Young

11-26-2006, 09:44 AM

Wow Dr. wise, I love your enthusiasm & your power in believing going to happen. Of course the multimillion dollar question is when? I know you don't have a crystal ball, everybody is just hoping for sooner than later. Keep up the good work.

Keith, don't thank me. I am just doing what I can to help. One doesn't need a crystal ball to be able to see the increasing exponential slope of research progress in the field. Techniques to grow human embryonic stem cells were discovered less than a decade ago (1997). In the past ten years, we have gone from just the theoretical possibility of creating neurons from embryonic stem cells to actually being able to do it in culture and using the resulting cells to repair and replace central nervous tissues in animals. As I predicted in 2001, we would make significant progress in stem cell research.

Unfortunately, progress in applying the human embryonic stem cells to human central nervous system injury has been held back for three reasons. First and foremost, we don't have diverse enough lines of human embryonic stem cell (hESC) to study and particularly to use for clinical tests. Second, funding for such research has been limited. Total NIH funding for all stem cell research has been in the range of $220 million with less than $30 million for human ESC research. Third, we still have not solved the problem of genetically compatible cell transplants. Efforts at cloning human embryonic stem cells have failed to date and was also held back to some extent by the fraudulent activities in South Korea that convinced many scientists to stop working on the cloning problem because they had solved the problem in Korea.

I am not convinced yet that cloning of human embryonic stem cells will be a feasible approach to creating immune-compatible stem cells that can be applied to large numbers of people. At the present, cloning of embryonic stem cells require successful implementation of two low probability events. The first is the cloning of blastocysts. It may take nuclear transfer of a dozen or more eggs to get one cloned blastocyst. At the present, even the best laboratories around the world have not been able to derive a viable and pluripotent embyronic stem cell line with an efficiency better than 1 cell line per four blastocysts. At the present, this is still quite a labor-intensive approach. Even if we were to assume that the efficiency improves by tenfold over the coming decade, it may take a very skilled technician with the help of good robotics a week or more of effort to create one stem cell line. It is difficult to conceive this process being carried out for millions of people. The cost will be staggering.

Fortunately, other techniques may become more efficient and economical. For example, i t is known that embryonic stem cells have propensity to fuse with somatic cells. The resultant cells have two nuclei and some of these cells behave like embryonic stem cells. If an efficient method becomes available for inactivating the original nucleus from the embryonic stem cell, allowing the somatic cell nucleus to take over, this will allow the creation of embryonic stem cell-like lines by fusing billions of somatic cells with standardized embryonic stem cells and selection of the appropriate fused cells where the somatic nucleus dominates. This is an exciting possibility that should allow large-scale production of individual embryonic cell lines from millions of individuals.

An alternative approach is to select embryonic stem cells that have common HLA antigens. HLA antigens are proteins expressed in the surface of the cells that stimulate the immune system to reject the cells. Because some HLA antigens are commonly expressed by many people, it is conceivable that one can make a library of several thousand embryonic stem cell lines that can match 90% of the population. Such a library of the cells can be used to treat millions of people. Of course, additional technology need to be developed to screen the cells for genetic abnormalities and to ensure the quality of the cells. This, however, is something that industry does well and it will allow production of cells for therapeutic purposes.

As we know, the speed of research depends in part of the amount that is invested into the research. If 100 laboratories worked on a problem, not only is the likelihood of success 100 times greater but the research should progress more rapidly. At the present, with NIh spending only $220 million per year on all stem cell research (adult and embryonic), we don't have enough of the best scientists in the United States working on the problem. When California starts investing >$300 million per year and New Jersey investing $30 million per year in the area, this will more than double the research in the field. Finally, if the Stem Cell Research Enhancement Act (SCREA) of 2006 were to pass, it would allow NIH to fund derivation of human embryonic stem cell lines.

We need more funding spinal cord injury research. At the present, NIH is spending less than $100 million per year on all spinal cord injury research, including rehabilitation. This is a pitifully small investment considering the importance and difficulty of the research. Achieving regenerative and remyelinative therapies for spinal cord and getting them successfully through clinical trials is much more difficult and challenging than flying to the moon. It is estimated that it take industry over $800 million to move one therapy from discovery to market. At this rate of investment, e.g. $100 million per year spread out over dozens of therapies, progress on any indivdiual treatment will necessarily be slow. Considering that spinal cord injury now costs the country over $10 billion per year, you would think that Congress would be willing to consider investing 10% of this amount or $1 billion per year to develop regenerative and remyeliative therapies. Note that such therapies will be useful not only for spinal cord injury but multiple sclerosis and peripheral nerve diseases.

Finally, we need a clinical trial infrastructure to test these therapies. I know that this sounds like an old saw to people on these forums but much of the delay in moving therapies from laboratories to clinical trial results from delays in organizing and funding clinical trials. Once set up, clinical trial networks significantly reduce the activation energy barrier for therapies to go into clinical trial. An efficient network can cut years off the average 11.4 years required for treatments to go from discovery to FDA approval. It may still take a number of years for the work to be done but I know that if we don't start now, it will still take the same amount of time 10 years from now.

Thus, we know what is needed for the cure. It is difficult for me to comprehend why our Congress has failed to understand the above. It is not as if the problem has not been articulated before and told to Congress over and over again. Even after the debate has been won and public opinion polls indicate that majority of American voters strongly support embryonic stem cell research and I know of almost nobody who opposes adult stem cell research, Congress has failed to act on this matter. Perhaps the urgency of the situation has not yet dawned on our political leaders. Many senators and representatives of course "get it" and are pushing hard for stem cell research. What we have to do is make sure that stem cell research doesn't become a political football.

Wise.

Cripply

11-26-2006, 04:02 PM

Wise Young

11-26-2006, 05:05 PM

Dr Young, what do you think of stem cells derived from peripheral blood, reportedly CD34 positive? In terms of their use for regenerative therapies. I know a recent Japanese paper, which I´ll try to find an dpost, reported that these cells can differentiate into nervous system cells.
I would also think that the number of stem cells in peripheral blood must be minimal. How good is the technology for replicating and storing the cells?
Also, is there a possibility that the Korean fraud might be partial? That there has indeed been a good amount of work that is valid in cloning? What is the inside view?

Cripply, you have crammed many questions into one short paragraph. Let me try to take each of the questions in turn.
• Peripheral blood does have circulating mesenchymal stem cells. Normally, the number of CD34+ cells is very low. However, these can be increased dramatically by having the blood donors take bone marrow stimulants. This is what they do in many countries when there are no HLA-matched bone marrow or umbilical cord blood available for transplantation. Infusion of peripheral blood from bone marrow stimulated donors can be used to replace bone marrow and many people believe that these cells are mesenchymal stem cells, even though CD34 is not a particularly good marker for such cells.
• There are no reliable marker(s) for mesenchymal stem cells in blood or bone marrow. Neither CD34 or other markers have been shown to be reliable indicators of stem cells. This is the main reason why we are planning to use mononuclear cells (rather than CD34+ or other markers) for our trial. If one selected cells with one marker and expanded them, one may not have pluripotent stem cells.
• Intravascularly administered cells may not engraft in the central nervous system. in the case of bone marrow replacement therapies, it is all right to infuse the umbilical cord blood or peripheral blood cells intravascularly and there is evidence that the cells will engraft in many cases. However, there is no convincing evidence that intravascularly infused cells will engraft in the brain or spinal cord. There has been some controversy about this because early studies suggest that peripheral stem cells will get into and occasionally engraft into the central nervous system.
• The importance of HLA-matching. Cells must be HLA-matched or else they are immune-rejected, particularly if they are injected into the peripheral blood. This is one other reason why I am skeptical about the Beike claims (Shenzhen) that they are getting good results on spinal cord injury from intravascularly or even intrathecally infused umbilical cord blood cells that have been expanded. They are not using HLA-matched cells and I believe that the cells will be rejected, particularly if they are injected into the peripheral blood. If the cells are injected into the spinal cord directly, immune rejection tends to be slower.
• Technology for expanding adult stem cells. It is possible to grow stem cell-like cells from peripheral blood, bone marrow, and umbilical cord blood. However, it is not a slam dunk. For example, we have now been trying for several years to expand umbilical cord blood cells. While it is possible to grow these cells occasionally from peripheral blood, bone marrow, and umbilical cord blood, it is by no means reliable. For example, even under optimal conditions, we were unable to grow stem cell-like cells from umbilical cord blood in 3 out of 4 units of umbilical cord blood or other sources of mesenchymal stem cells. Many companies are trying to do this now and we are workiing with several companies to test the cells that they are growing out.
• Cloning fraud in Korea. After extensive investigation by Seoul National University, there is no evidence that Woo-Suk Hwang had successfully cloned any human embryonic stem cell line. He had of course claimed to have cloned 11 stem cell lines. If he had successfully cloned even one line, I think that the authorities would not have treated him with such disdain. Before he submitted his paper to Science, he had claimed to have lost all the cell lines in an freezer "accident". After exhaustive checks of all the cells contained in all the laboratories and hospitals that his work involved, the investigators were unable to find a single example of a cloned human stem cell line. I think that I would be more optimistic about his approach if there were evidence that even one line was cloned. However, there were no lines at all. That is why I believe that the his whole claim was fraudulent and why I find it hard to believe that this was just a matter of his underlings deceiving him. I wish this weren't so and that he had succeeded.

Wise.

Cripply

11-26-2006, 06:00 PM

Wise, thank you very much for the time and expertise you are sharing here.
I hope other people post and this thread continues to expand.

tskushi26

11-26-2006, 08:23 PM

I just want to thank you for taking the time to give us such an in depth explanation. I have been continuously checking this site since my accident (6/5/05) and find it extremely helpful. I am absolutely baffled by our government's economics and lack of basic human compassion. The amount of misinformation and contradictory policies burns me up! :mad: I know it's not much but I started a myspace site dedicated solely to educating others about SCIs & current research(www.myspace.com/sci_cure (http://www.myspace.com/sci_cure)). It's my hope that through awareness people will care enough to vote wisely and support research. Knowing that there is a possibility for a cure to be found (before I'm old & grey) keeps me going forward every day <3

PS- I don't know if you've seen this, but I think it makes for a great introduction into the topic:
http://www.eurostemcell.org/Outreach/Film/film_eng.htm

john smith

11-26-2006, 09:15 PM

Hi tskushi2;

Thanks for posting. Your site is outstanding as is the smile in your profile pic. Welcome to CC.

John

Schmeky

11-26-2006, 09:57 PM

maryonwheels46

11-27-2006, 07:49 AM

Thank you DR Wise for this explanation. I didn't know there were so many different stem cell. I emailed it to my self so I can read it over again so I will be able to explain it to others that think that the cells just come from a fetus.
Mary

Leif

11-27-2006, 08:18 AM

It would make sense to have ESC "breakthroughs" in the lab be represented by the scientists involved. How feasible is it to have people like Douglas Kerr and Stephen Davies present their latest research findings to Congress? If you want to shoot down an elephant, you need to muster the best firepower you have available.
Good thinking, more of this should be done. Likewise I was puzzled when I watched the Senate discussions here earlier; Geron was not mentioned at all from what I heard although both Brownback and Coburn was babbling all the time about this nose stuff from Portugal? I agree with you, it would have been nice to present sound research like you suggest here. How to do it is more the question?

znop

11-27-2006, 11:24 AM

Wise Young

11-28-2006, 02:52 AM

Thus, we know what is needed for the cure. It is difficult for me to comprehend why our Congress has failed to understand the above. It is not as if the problem has not been articulated before and told to Congress over and over again. Even after the debate has been won and public opinion polls indicate that majority of American voters strongly support embryonic stem cell research and I know of almost nobody who opposes adult stem cell research, Congress has failed to act on this matter. Perhaps the urgency of the situation has not yet dawned on our political leaders. Many senators and representatives of course "get it" and are pushing hard for stem cell research. What we have to do is make sure that stem cell research doesn't become a political football.

Dr. Young,

It would make sense to have ESC "breakthroughs" in the lab be represented by the scientists involved. How feasible is it to have people like Douglas Kerr and Stephen Davies present their latest research findings to Congress? If you want to shoot down an elephant, you need to muster the best firepower you have available.

In my opinion, these 2 gentlemen have proven, in the lab at least, that hESC's hold promise. Our generation has to fight to ensure the next generation will not have to suffer this abominable condition.

Schmeky,

In general, while individuals can visit their representatives and senators, one doesn't invite oneself to speak to Congress. Congress has to hold hearings on the subject and they invite people to speak. Hearings on spinal cord injury is something that the spinal cord injury community can ask their representatives to do. Generally, the hearings have to be called by a committee chair (probably Health... or other). For example, the Chair of the Senate Health and Human Services Committee will probably be Tom Harkin. He can hold hearings. I am not sure who will be the Chair of the House Committee but I hope that Jim Langevin can try to do something about it. While the Republicans were in charge of Congress, I don't think that there was any interest in holding such hearings on spinal cord injury, in the same way that there was not much interest in holding hearings on stem cell research.

Wise.

cdurfee99

04-13-2009, 09:57 PM

wait a minute, as far as reality is concerned, there are no sci therapies, and I plan to start fundraising for end of care rights, not hocus pocus sci-fi!

znop

04-15-2009, 12:58 PM

any chance you could make this thread near the top of the list. I think this would alleviate you anwsering the same question over and over, just a thought

john
chicago

Wise Young

04-15-2009, 01:49 PM

OK. Wise.

poobear

07-02-2009, 08:59 AM

Leo

07-02-2009, 10:51 AM

dr. wise is there a list of clinics that give stem cell treatment? or where can i go to find the stem cell treatment clinics to check which ones would be best for my condition? thanks poobear7788@aol.com

Hi poobear,

in the opinion of most on here you would be wasting your money on any current treatment.

save up, stay in shape, advocate, and raise money and awareness

Wise Young

07-06-2009, 08:21 AM

dr. wise is there a list of clinics that give stem cell treatment? or where can i go to find the stem cell treatment clinics to check which ones would be best for my condition? thanks poobear7788@aol.com

Poobear,

It is premature for such a list. Since there is not yet any credible clinical trial evidence that any stem cell therapy is useful for spinal cord injury, most of the places that are charging money for stem cell therapies are making false claims of efficacy. Most of these clinics are overseas. At the present, I would not go to any of them.

There will be several places that are starting clinical trials of various stem cell therapies. Geron will be doing oligodendroglial precursors derived from human embryonic stem cells in California in patients with subacute spinal cord injury. The SCINetUSA will be starting trials in the coming year, to assess umbilical cord blood mononuclear cell transplants and lithium therapy of chronic spinal cord injury.

Wise.

cypresss

07-26-2009, 07:29 AM

Why is used the term embryonic stem cells, when is not the case? Maybe we(not me, the scientists) have to find a better word to define pre-embryonic state of cells, but something which will not contain the word embryonic in it.

topperf

07-26-2009, 08:00 AM

woops

topperf

07-26-2009, 08:01 AM

cypresss

07-26-2009, 08:36 AM

I think that might be Blastocyst. (not 100% sure though) :thinking:
You are 100% right, but subconsciously ppl associate blastocyst with embryonic. Even in natural conditions, not all the blastocysts are becoming embryons. Same thing happen when is about the invitro fertilization.

I cannot find now the right English word to explain it properly(sorry, my fault). I'll give you an example. Is not off-topic, the same idea is somewhere at the end of the video(from the minute 2.30, but pls watch it all). Idea is to put proper words to the things.

rk8Vr00EBHA

that dude

08-20-2009, 06:03 PM

hi, i'm wit spinal cord injury (t12 paraplegic). i was planning to get adul stem cell threapy in german, what kind of research i need to do before i proceed?

Wise Young

08-20-2009, 06:12 PM

hi, i'm wit spinal cord injury (t12 paraplegic). i was planning to get adul stem cell threapy in german, what kind of research i need to do before i proceed?

That dude,

I presume that you are going to X-cell in Cologne, Germany. There is no evidence that the taking your own bone marrow and then reinfusing it or placing it intrathecally will do anything to improve function in people with chronic spinal cord injury (>1 year).

I know several people who have gone and have had no functional recovery. By the way, this does not mean that bone marrow cells are not beneficial to the spinal cord. It may be that they have the wrong type of cells, the cells are not being put into the right places, or the cells were put in too late.

I know that Alok Sharma in Bombay has been implanting bone marrow cells in patients with both acute and chronic spinal cord injury and he believes that his patients are showing significant improvement. I am not sure how what he is doing differs from that in Germany.

There have few published studies on the subject of bone marrow autografts to the spinal cord. In Inchon, Korea, a group has transplanted bone marrow stem cells into subacute (within 2 weeks after) spinal cord injury and reported improved sensory recovery, although the study was not controlled.

In Czechoslovakia, Sykova, et al. has transplanted cells into subacute spinal cord injury and found some beneficial effect when transplanted early but not late after spinal cord injury.

In my opinion, available evidence does not warrant paying for this therapy.

Wise.

BaliMike

08-20-2009, 11:13 PM

Doctor:

Are you familiar with any work being done with stem cells and anal sphincter tone? I find studies in rats but nothing yet with humans.

I am a guy with Spina Bifida.

Thanks,

Mike

that dude

08-28-2009, 03:38 PM

Dr. Wise

Is there risk invovled in bone marrow stem cell implant or embryo stem cell implant? Can you also let me know what is the best spinal cord inury treatment there is out there?

lunasicc42

08-28-2009, 07:25 PM

that dude... I am sorry to report that no stemcell Treatments are available... At least no real ones... Only minimal return. I would wait for real clinical trials to start that show improvements

asoka

08-30-2009, 02:46 PM

Wise Young

08-30-2009, 02:50 PM

dr young can you please clarify... though the ESC are pluripotent each has highly unique HLA system, is it correct?

it looks like you recent work is focused on the radial glial transplants? are they autografts? are they the subject of your upcoming clinical trial? did the clinical trial infrastructure improved since 2006?

Asoka,

ESC are pluripotent. Like all cells, they have genes for HLA expression. Some stem cells do not express HLA-antigens. However, the progeny of these stem cells (i.e. cells made by the stem cells) should express HLA when they become more differenitated.

The work on radial glial cells are mostly done by my colleague Martin Grumet and his colleagues. I have been working on umbilical cord blood cells. Most of our work with the cells have not yet been published. Most of my effort of the last four years has been to build the infrastructure for clinial trials in China and the United States.

Wise.

asoka

08-30-2009, 03:13 PM

Wise Young

08-30-2009, 03:57 PM

thank you for the such a quick reply....what is your opinion on the geron's study that i understand is suspended at the moment? have you been a part of it? where and when do you plan to publish your latest work on the umbilical cord cells and is it possible to know more about it at least in general.... thank you,,

Our work has been focused on developing the GMP procedures that would allow the treatment to get into trial. Many laboratories have studied and reported on the beneficial effects of umbilical cord blood mononuclear cells transplanted to the spinal cord. Likewise, many laboratories have studied the effects of lithium on brain and spinal cord. We studied the effects of lithium on umblical cord blood cells and release of neurotrophins by the cells.

I have posted extensively about all the work here. If you just look for posts by me (Wise Young) on this forum, for example, about lithium or umbilical cord blood, you will find many dozens if not hundreds of posts that I have done.

Wise.

lepups3

09-04-2009, 06:58 PM

I guess this means I won't be going to the X-Cell Center anytime soon.

lunasicc42

09-04-2009, 08:16 PM

I guess this means I won't be going to the X-Cell Center anytime soon.

I hope you don't

that dude

09-28-2009, 01:14 AM

Wise Young

09-28-2009, 07:53 AM

Dr. Wise

I was thinking about going ahead and get the bone marrow stem cell transplantation. Which hopital you recomend from x-cell in German or Dr. Alok Sharma in India? And how do I check the accreditation for this hospitals?

dude,

X-cell provides the cells but I don't know who and how the cells will be transplanted. I know several people who have had the procedure without benefit.

Regarding Alok Sharma, I have visited him and talked to several of his patients. It seems to have helped some of his patients but didn't do much for others. It is not clear what patient will benefit from the therapy.

Dr. Sharma works at one of the major public hospitals in Bombay. I don't think that acreditation of hospitals mean all that much in India. While I think that he is a good doctor, I am not yet convinced that the treatment is restoring function in chronic spinal cord injury.

Wise.

cdurfee99

10-02-2009, 08:19 PM

well for one, there are no such thing as embryonic stem cell therapies, at least for humans. Rats enjoy these benefits, go back to running on their wheel, and have mind-blowing sex.

Wise Young

10-03-2009, 10:21 AM

well for one, there are no such thing as embryonic stem cell therapies, at least for humans. Rats enjoy these benefits, go back to running on their wheel, and have mind-blowing sex.

cdurfee,

The Geron trial tells us how difficult the task will be for getting the first embryonic stem cell therapy into clinical trial. The IND (Investigational New Drug/Device) application for the clinical trial costed $45 million and had 22,000 pages of safety and other data. It has also taken about ten years to gather all the data.

Despite all the expense and time, Geron has not yet solved the two major barriers to using the cells in people.
• The first is immune-compatibility of the cells. The cells of course come form one cell line. The company is assuming that embryonic stem cells or the cells derived from the cell line will not be rejected by the recipients. This was of course reason why Woo-Suk Hwang and so many others tried hard to clone and produce immune-compatible stem cells. The company will be using immunosuppression in the trial, hoping that the time and dose that they chose would be sufficient to keep the cells from being rejected.
• The second is that the cells will not form tumors or produce inappropriate cells in the spinal cord. To overcome this, Geron had chosen a cell line that has been differentiated to the oligodendroglia and showed no sign dedifferentiating in culture. But, the last animal test that they sent to the FDA suggest that the cells produced microcysts in the spinal cord. To solve this problem, the company found a marker for the cells that produces these cysts and will be selecting out cells that express these markers.

I am very appreciative of the herculean efforts that Geron has been making on behalf of the spinal cord injury community. Most other companies, faced with such obstacles, would have given up. Most companies would have given up. Geron stayed the course through thick and thin. We have learned a lot about the FDA and its likely approach towards embryonic stem cells. Their first concern is safety of the patients.

Wise.

GRAMMY

10-15-2009, 11:04 PM

Wise Young

10-16-2009, 07:15 AM

Dr Young, With the announcement from the Salk Institute concerning the ability to now get embryonic like cells from umbilical cord blood...how will this discovery affect stemcyte and possibly the future therapies devised for SCI using UCB cells?

It is a very important development http://www.salk.edu/news/pressrelease_details.php?press_id=380. Please understand, however, that they are not the first ones to do this. Two other groups have reported successful induction of umbilical cord blood into pluripotent stem cells. The Salk Institute is the third.

http://www.salk.edu/news/pressrelease_details.php?press_id=380
"Patient-specific iPS lines have been advocated as a theoretically ideal clinical option to regenerate tissue but from a practical and cost-benefit aspect, this approach may not be feasible," says Izpisúa Belmonte. He hopes that the "large scale production and banking of cord blood-derived iPS lines in a publically available network could be a viable alternative for future clinical applications."

With this in mind, Belmonte and his colleagues set out to transform hematopoietic stem cells isolated from cord blood into iPS cells. They not only successfully converted them using only two out of the four most commonly used factors—OCT4 and SOX2—but also in less time than any other previously published methodology require. No matter, whether the researchers started with freshly collected cord blood or previously frozen samples, the resulting iPS cells were indistinguishable from human embryonic stem cells.

"The population of cord blood cells used for reprogramming express reprogramming/stem cell factors at higher levels than those found in other adult somatic cells, which could explain why cord blood cells can be reprogrammed with less factors and in less time," says Izpisúa Belmonte. "It's almost like they are already half-way there."

In addition, the cord blood-derived iPS cells, CBiPS cells for short, passed all standard tests for pluripotency: The gave rise to stem cell tumors known as teratomas and differentiated into derivatives of the three embryonic tissue layers, including rhythmically beating cardiomyocytes and dopamine-producing neurons.

Izpisúa Belmonte's next goal is to convince cord blood cells to turn back time using methods that are considered safe for clinical applications in humans. The original protocols for producing iPS cells—including the one used by Belmonte and his team—rely on the integration of foreign "reprogramming" genes into the host-cell genome, a process associated with risks including mutation and the development of cancers after iPS-cell transplantation, limiting their therapeutic value.

But researchers are hard at work to develop alternative methods that allow them to reprogram cells without leaving any genetic traces, such as simply exposing differentiated cells to small molecules. "Several studies have already shown that this could be possible," says Izpisúa Belmonte. "If we can show they also work for cord blood cells, this certainly could be a step forward towards the clinical application of iPS cells. We should focus our efforts on this particular cell source, CBiPS cells, at least in the near future."

Let me review the history of IPS cells and discuss why this work is important. In 2006, Yamanaka, et al. at Kyoto University found that insertion of four genes into fibroblasts (skin cells) can convert the fibroblasts into pluripotent embryonic stem cell like cells. The cells not only behave like embryonic stem cells but several groups reported that mouse fibroblasts induced with these four genes can produce other mice. By 2007, both Yamanaka's group and Thomson's group in Wisconsin showed that the same could be done with human cells.

Everybody was very excited because this suggests that pluripotent stem cells can be cloned from skin cells of an individual, giving rise to the vision of individualized personal stem cell lines for everybody. But, a little bit of arithmetic tells you that this is not going to be feasible economically. Inducing IPS is still a fairly inefficient process. Even with the most efficient viral transduction methods, probably less than 10 out of a million tranfected cells turned out to be pluripotent. So, if one starts out with several million cells, one can isolate a small number of colonies of cells. If one puts in a fluorescent marker, these colonies can be readily identified, isolated and tested for pluripotency, genetic integrity, and other qualities. Such testing may take many weeks or months, because human cells grow relatively slowly.

At the present, even the most efficient laboratory take 3 months and probably over $100,000 to create a well-characterized IPS cell. Let us suppose that we were to create an industry that is capable to making 1000 IPS cell lines per day. This is an enormous number, by the way, but let us assume that such an industry exists and that it costs $100,000 to make and validate each cell line for treatment. This industry would be able to make at most 365,000 cell lines per year. In order to treat 1% of the U.S. population by 2020, this industry would require 10 years and $365 billion to create 3.65 millon IPS cell lines. To treat 1% of the world's population require over 100 years and over $4 trillion. So, IPS cells will not be a treatment for common people.

The only way around this is to create a library of IPS cells that can be HLA-matched to potential recipients. We know that a library of about 30,000 umbilical cord blood cells can be matched 4:6 HLA and engraft in 80% of the population of the United States. The same industry mentioned above should be able to create 30,000 IPS cell lines in a month for about $30 billion, well within the realms of possibility. By the way, while this approach would circumvent the need to use embryonic stem cells (ESC) for therapeutic purposes, it would not eliminate the need for access to embryonic stem cell lines to compare IPS and ESC cells.

I was attending the New York Stem Cell Foundation meeting and was impressed by Kevin Egan (a Harvard stem cell scientist who is the chief scientific officer for the NYSCF) saying that we continue to need to study embryonic stem cells because they are the real thing and IPS cells are just facsimiles of ESC. We know so little about ESC and will need to compare the two and figure out both similarities and differences. Regarding application to humans, several hurdles still must be overcome before IPS cells can be applied to humans. First, the tendency of the cells to become teratomas (pluripotent stem cell tumors) must be controlled. IPS cells are even more likely than ESC cells to become teratomas, because the genes may not be as well controlled. Second, efficient non-viral means of inducing the cells must be developed. At the present, most laboratories still use viruses.

The exciting thing about this discovery from the Salk Institute is that they need to use only two of the four genes to induce umbilical cord blood cells. This could have been predicted because many studies indicate that a particularly type of umbilical cord blood cells that are positive for CD133 also express SOX2 and OCT3/4, two of the pluripotency genes used by Yamanaka and Thomson http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell.

Several years from now, historians will all be looking back at this time, puzzling what the fuss was all about regarding embryonic stem cells. Even back in 2001, when Bush restricted the research, many scientists (including myself) had predicted that we would be able to create IPS cells. After all, a stem cell is only a cell that is expressing certain genes. Once those genes were found, IPS cells could be created from any cell. It turned out to be simpler than any of us could have imagined. At the same time, the simplicity is misleading and it is probably more complicated that any of use can imagine.

I predict that Yamanaka and Thomson will get the Nobel Prize for this work.

Wise.

keeping on

11-14-2009, 02:49 PM

Wise Young

11-20-2009, 11:36 AM

Dr Young, who are the supporters in Congress for stem cell research and therapy? We should investigate what they are proposing and we should push others to do the same. We should all encourage those with the willingness and understanding what this means to us and others. As I said the other day, I heard a frivilous comment from Joe Scarboro on stem cells. I e-mailed him with my thoughts, but got no reply. I would also suggest the funding needed for follow thru be substaiated with facts of current research and hopefully upcoming human trials.

You can find out who voted in Congress for SCREA (Stem Cell Research Enhancement Act), which was vetoed twice by President Bush. There is a lawyer with spinal cord injury by the name of Mark Neuhauser who is planning to write a letter to President Obama about repealing the Dickey Amendment.

The strongest supporter of both stem cells and spinal cord injury research in the Senate is Tom Harkin. He has a spinal-injured nephew and has supported the Christopher Reeve Paralysis Act and the Stem Cell Research Enhancement Act through thick and thin. He is also head of the Health and Human Services Budget/Appropriations Committee.

Some of our former strongest Democratic spinal cord injury supporters have now left the Senate. This includes Hilary Clinton and Ted Kennedy. Our best supporter in the House of Representatives is Jim Langvin, the only quadriplegic in Congress.

Wise.

keeping on

11-20-2009, 06:11 PM

Thank you Wise!

christo231

11-22-2009, 01:38 AM

Dr. Young, I am very thankful for you and your incredible knowledge of stem cells and spinal cord injury. Thanks for all that you do!

jasonsunero

11-22-2009, 05:13 AM

Thanks for that great information on the true supports Mr. Young.

Domosoyo

12-17-2009, 11:27 AM

So happy to find this sticky! The other day after talking expressing my excitement in all the new stem cell research opening up, an older nurse started to explain to another person in the room where stem cells come from. She explained they are taken from the spinal cord of aborted fetuses and went into detail. I stopped her and said there are many types of stem cells and that I hadn't heard of stem cell harvesting in the manner she was describing.

Two days later, after much research that has included reading posts at this site, I am SO READY to tackle this with anyone!

SharonD

01-22-2010, 09:19 AM

This thread has been very helpful in understanding the various types of stem cells, research developments, controversy and tips for advocacy. As I was reading the website of some politicians who support stem cell research I came across a site "On the Issues" and found that stem cell research was listed in the Abortion category. I also found this definition which states stem cells are taken from human fetuses...

Stem Cells’ are undifferentiated cells, which are useful in research for cloning and for treating many diseases. Stem cells are best taken from human fetuses; hence the pro-life opposition. Many pro-life advocates support fetal stem cell research because of the medical potential. In 2001, Pres. Bush announced that the federal policy would be to allow fetal stem cell research on existing stem cell lines but not on new ones.
‘Embryonic Stem Cells’ are stem cells derived from embryos, newborn's umbilical cords, etc. The 2008 election debate focuses entirely on embryonic stem cell research, because adult stem cell research (with source cells from non-embryonic sources) is no longer controversial.

keeping on

01-22-2010, 09:40 AM

Wise, I e-mailes Tom Harkin in an effort to see what is being accomplished. He is a strong supporter, as you have stated, for stem cell progression. I'm wondering if you think that an effort to get all of our voices to Harkin via e-mail to his site would be beneficial, or would a controversy start up that would stifle our cause. If you have any ideas where we can help, please let us know.

You are ther voice that we or amny of us have faith in. We will help in any manner that you propose.

SharonD

01-22-2010, 12:24 PM

Keeping on, I like your idea and will wait to hear Dr Youngs response

keeping on

02-12-2010, 11:26 AM

Dr young, the last couple of days has been a series of blubs on problems with some of the propsed treatments; except for yours. Can you give us your fix on these blubs?

Wise Young

02-12-2010, 02:29 PM

Dr young, the last couple of days has been a series of blubs on problems with some of the propsed treatments; except for yours. Can you give us your fix on these blubs?

Can you be more specific? I don't know which "blubs" you are referrring to. Wise.

dr.zapp

02-16-2010, 10:58 PM

Wise Young

03-09-2010, 07:54 PM

Hello, I just joined here and was reading through this thread, and thought I should bring into the discussion the risk of cancer from many of the stem cell treatments. I am a molecular biologist that has been researching different types of cancer for over 15 years, and just 2 years ago I hit a tree snowboarding and am now a t6 complete para, so I've become interested in SCI research, though I have little time to work it in w/ my currently funded cancer research... I am working on ways to target brain cancer stem cells (I should explain to the non-scientists here that these are not the same as the stem cells you hear about in the media, but the same idea) it seems that over a long term, introducing stem cells into the CNS may lead to cancer unless some way of differentiating the injected cells is developed. Also, what of the loss of telomere length in adult stem cells or induced cells? Won't this decrease longevity of these types of stem cells, and make their progeny inherently more prone to cancer?

Dr. Z,

In practice, very few (if any) transplants of stem cells into the brain and spinal cord (of both human and animals) have resulted in cancer. Maybe this is because almost all the transplants that have been done have been allografts (i.e. from one individual to another) or xenografts (i.e. from an individual of one species to an individual of another species) and therefore were rejected by the immune system.

Only one case of cancer has been reported from transplants of fetal cell transplants into human and this is in a child who received multiple fetal cell transplants for a condition called ataxia telangiectasia and developed a tumor that came from the transplanted cells http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000029.

Ataxia telangiectasia is a condition that has a propensity for brain tumor formation and may involve a defect in the brain's immune system. Over the past two decades, hundreds (or even thousands) of people have received fetal cell transplants for Parkinson's disease, spinal cord injury, and other conditions. This is the only case of tumor that has been reported.

Of course, there has not been a documented case of embryonic stem cell transplants in human. Note that I would not consider the cells that Geeta Shroff is transplanting in India to be embryonic stem cells until some independent group has examined and verified the cells. So, the concern that stem cell transplants cause brain tumors is still largely theoretical.

If you read the literature of telomere lengths in iPS, you will find that most iPS cells acquire the characteristic of indefinite self-renewal capacity through the induction of telomerase reverse transcriptase gene (TERT). The iPS cells have long telomere http://www.ncbi.nlm.nih.gov/pubmed/19200803. A recent study reported that telomere lengths are lengthened in IPS cells from dyskeratosis congenita patients, a condition where telomere maintenance is defective http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08792.html, suggesting that reproramming restores telomere elongation even in the presence of genetic lesions affecting telomerase.

Wise.

lonibaloney

03-10-2010, 08:17 AM

wondering if this type of treatment can be used for dead or underdeveloped nerves like in SB?

Wise Young

03-10-2010, 08:36 AM

wondering if this type of treatment can be used for dead or underdeveloped nerves like in SB?

As you know, spina bifida is a extremely diverse condition resulting from failure of the lower spinal canal to close to failure of the spinal cord to develop. In severe cases of spinal bifida, there may be failure of the lower spinal cord to develop. I am skeptical whether implantation of stem cells alone would recapitulate development and restore the spinal cord. On the other hand, if there is loss of some neurons, it is possible that neural stem cells can replace the neurons. Neural stem cells can be obtained from the subventricular zone of adults, fetal neural stem cells from the brains or spinal cord of fetuses, induced neural stem cells (recently there was a study indicating that neural progenitor cells can be induced from skin and other cells).

Wise.

keeping on

10-21-2010, 10:59 AM

eli

10-21-2010, 08:04 PM

Darryl

10-24-2010, 09:07 PM

http://www.gadaily.com/index.php/section-blog/37-column/2219-georgia-becoming-hotbed-for-stem-cell-research-debate; the furitless debate goes on; this is getting old and the burgermeisters are still hanging on. We need the testin g at Shepherfd to be successful and Wise's tirals to be successful. We need definitve success to point to and to put the Republicans to sleep once and for all.

Is there an organization for people living with SCI, their family and friends who are democrats, republicans or independents to write letters as a group?

From: A Service of the U.S. National Library of Medicine National Institutes of Health ". . . 12,000 new cases each year. Since there have not been any overall incidence studies of SCI in the U.S. since the 1970's it is not known if incidence has changed in recent years."
http://www.spinalcord.uab.edu/show.asp?durki=116979

Since the 1970s? Are there current statistics?

number1advocate

10-27-2010, 12:10 AM

Dr. Young many thanks to you and all of the brilliant minds out there engaged in Stem cell research. Too bad you and I are going to hell (eyes rolling) for believing in one of the great evils of Science.
Regarding the discussion about Dems and Reps and who believes what I suggest you good folks go take a short test on the Politics of Fear I devised (in the Politics forum) to find out where you "stand".
Seriously, keep up the great work Doctor.

Jim

10-27-2010, 10:48 AM

Hello dr young , I am new to the forum. My daughter has an 8 year old injury - c1/c2 on a vent. She's 10. You discuss the need to ensure the stem cells aren't immune rejected. Does it help to store the umbilical cord of a newborn sybling?thank you for all your work. We actually live in nj

Hi eli,

Dr. Young is traveling and prob didn't see this.
Sorry to hear about your daughter.
It is a good idea to store umbilical cord blood. I believe there is only a 1 in 4 chance that siblings will match.

If you donate your UCB to this company, they will provide you with a match in return for your cord blood. http://www.stemcyteinc.com/

We have an Open House next Friday 11/5 if you can make the trip- http://keck.rutgers.edu/contact/contact.html

eli

10-28-2010, 02:49 PM

Hi eli,

Dr. Young is traveling and prob didn't see this.
Sorry to hear about your daughter.
It is a good idea to store umbilical cord blood. I believe there is only a 1 in 4 chance that siblings will match.

If you donate your UCB to this company, they will provide you with a match in return for your cord blood. http://www.stemcyteinc.com/

We have an Open House next Friday 11/5 if you can make the trip- http://keck.rutgers.edu/contact/contact.html

Hi jim , thank you for the information. The timing of the open houses doesnt work for me this time of the year.

Wise Young

10-29-2010, 06:28 PM

Hi jim , thank you for the information. The timing of the open houses doesnt work for me this time of the year.

eli,

Sibling cord blood is more likely to match than any other source. Let me show you mathematically why the chances of a perfect match is 1 out of 4. People have 6 HLA genes, 3 HLA genes from the mother and 3 from the father.

So, if your husband has genes H1, H2, H3; H4, H5, H6 while you have H7, H8, H9; H10, H11, H12, the number of possible combinations that a child from the two of you will have are:

H1, H2, H3; H7, H8, H9
H1, H2, H3; H10, H11, H12
H4, H5, H6; H7, H8, H9
H4, H5, H6; H10, H11, H12

Therefore, each child of yours will have at least a 1 out of 4 chance to have a 6:6 HLA match with another child and a 3 of 4 chance to be at 3:6 match.

The above assumes that you and your husband have completely different HLA genes from each other. If you and your husband have one HLA gene that is the same, i.e. H1 = H7, then any children of the two of you may have the following combination:

H1, H2, H3; H1, H8, H9
H1, H2, H3; H10, H11, H12
H4, H5, H6; H1, H8, H9
H4, H5, H6; H10, H11, H12

In such a case, 1 of 4 chances to have a 6:6 match, 1 chance in 4 to have a 5:6 match, and 2 chances in 4 to have a 3:3 match, etc. Note that one of the HLA antigens, i.e. HLA-DR1, is more important than any of the others. The sibling child has 1 of 2 chances of getting that gene. So, the chances are really closer to 1:2 of having a match that could be used. Because of this, most genetic counselors recommend collecting the umbilical cord blood of a sibling if there is a possibility that the blood may be useful to a child.

Many people have asked me what the likelihood of a parent matching a child is. If we do the same analysis as the above, it is clear that because a parent has contributed 3 of the 6 genes to a child, either of the parents will have a 100% chance of getting at least a 3:6 match. However, if the mother has at least one HLA gene that is the same as the father, there is a 100% chance of getting at least a 4:6 match and 50% chance of the cord blood sharing the same HLA-DR1.

The American Academy of Pediatrics http://www.aap.org/advocacy/releases/jan07cordbloodfaq.htm recommends against private storing of umbilical cord blood for autologous use (i.e. use of the cord blood for the donor) because the chances that the child will need the blood to treat itself is less than 1%. Note that if the child has a genetic disease, the cord blood contains the same disease and therefore will not be useful. The cord blood would be useful if the child gets an acquired disease that cord blood could be used to treat the child, e.g. leukemia and other cancers.

I recently attended a cord blood banking symposium and listened to the number of units they have "released" to the parents who have stored cord blood with various companies. One company which has been collecting for 8 years and has 35,000 stored units released only 4 units for use by the families and all four were for sibling use. It is interesting that several cord blood banks indicated that they have released units for treatment of cerebral palsy. Joanne Kurtzberg at Duke has transfused autologous cord blood into over 150 kids with cerebral palsy and these include families that have banked their blood privately with various companies around the world. Several clinical trials are starting around the world, to confirm whether autologous cord blood is beneficial for cerebral palsy.

Wise.

eli

10-30-2010, 10:42 PM

Dr young, thank you for the in - depth explanation and for the time you give to answer the numerous posts on these forums.

keeping on

11-11-2010, 05:03 PM

http://www.christianpost.com/article/20101111/groups-form-coalition-to-advance-embryonic-stem-cell-research/ this article might be the future. The end doesn't justufy the means. With the Republican HOUSE AND THE BUDGET BEING THE MOST IMPORTANT TOPIC OF THE LAME DUCK CONGRESS, doesn't look good. Hope I'm wrong.

keeping on

chris arnold

11-12-2010, 07:15 AM

Thank you kind sir!!!

Most Christian and other religious groups condemn ESC as being unethical and destroys human life. Of course you and I know that is NOT true!
Maybe an explanation by you and others here can help me explain to many people that they are misinformed on this matter. There are so many educated and excellent writers here that I would greatly appreciate everyone's input.

"Either get busy living or get busy dying"

Shawshank Redemption

Znop

Hi znop, I know that the overall reaction of Christians is one of ethical concern.

The official view of the Roman Catholic Church is divided as to ESC v. ASC. A crucial part of their thinking hinges on "respect for life" - when does an embryo become a living soul. A bit academic, as it is impossible to prove or disprove.

Anglicans generally object to ECS research, while the Church of England "reserves concerns". I quote from The Church Times:

The ethical dilemmas that the group faced included “the status and ensoulment of the embryo, the respect for human life, and the possible abuse of the cloning technique should it be perfected for research purposes, which is not illegal in the UK.

The reaction of the Free Churches is similar, but not quite so rigid. The consensus, including the RCs, is that ASC therapies do not pose ethical issues and then idea of placental "cell banks" is acceptable. The cell bank raises questions that are logistical rather than ethical - eventually we are looking at tens of millions of samples!

There is one school of thought, that Republican opinion in USA muddies the distinction between types of cell used, quite deliberately to save money.

My own feelings are, and I accept membership of the Church, that hellfire does not ensue for such researches, and the appalling actions of Joseph Stalin (25,000,000 Soviet Citizens murdered), Hitler and other political tyrants are as deserving as any for such a destination, if such a place exists.

If anything, "convenience abortion" is far worse.

keeping on

11-12-2010, 10:58 AM

Wise Young

11-13-2010, 07:56 AM

Hi znop, I know that the overall reaction of Christians is one of ethical concern.

The official view of the Roman Catholic Church is divided as to ESC v. ASC. A crucial part of their thinking hinges on "respect for life" - when does an embryo become a living soul. A bit academic, as it is impossible to prove or disprove.

Anglicans generally object to ECS research, while the Church of England "reserves concerns". I quote from The Church Times:

The ethical dilemmas that the group faced included “the status and ensoulment of the embryo, the respect for human life, and the possible abuse of the cloning technique should it be perfected for research purposes, which is not illegal in the UK.

The reaction of the Free Churches is similar, but not quite so rigid. The consensus, including the RCs, is that ASC therapies do not pose ethical issues and then idea of placental "cell banks" is acceptable. The cell bank raises questions that are logistical rather than ethical - eventually we are looking at tens of millions of samples!

There is one school of thought, that Republican opinion in USA muddies the distinction between types of cell used, quite deliberately to save money.

My own feelings are, and I accept membership of the Church, that hellfire does not ensue for such researches, and the appalling actions of Joseph Stalin (25,000,000 Soviet Citizens murdered), Hitler and other political tyrants are as deserving as any for such a destination, if such a place exists.

If anything, "convenience abortion" is far worse.

Chris,

Thank you very much for your cogent comments. The views of ESC research by different religions vary from encouragement (Jewish) to damnation (Catholic). The answers also vary depending that how the question is phrased. Not all uses of embryonic stem cells would be considered ethical. For example, most Americans would not approve of somebody creating a clone of oneself and using organs from that clone for life extension or to treat his or her own spinal cord injury. On the other hand, most people would not object to scientists studying stem cells that have been derived from excess blastocysts that were created in the course of in vitro fertilization and would be discarded anyway.

The blanket prohibition of NIH funding of all embryonic stem cell research by Judge Royce C. Lamberth because he considered doing such research is equivalent to killing embryos has no support in accepted law or ethics. If the same logic were applied to a county coroner doing an autopsy of a murdered person, one would conclude that the coroner is guilty of murder and therefore there should be no government funding of autopsies of murdered people.

It is true that religious ethics tend towards damnation of not just acts but intentions. For example, it is a sin to covet your neighbor's wife even though you have and will never touch her. One you start down the slippery slope, you have sinned. Likewise, there is also the argument of complicity and economic encouragement, i.e. the fact that NIH funds research on cells that derived from discarded blastocysts may result in demonstration of therapeutic effects that would provide incentive for unethical derivation and trafficking in embryonic stem cells.

The discovery of induced pluripotent stem (iPS) cells, however, has removed the slippery slope argument. The future will be iPS cells that completely avoids the issue of embryos and are superior in many respects to use of unmatched embryonic stem cell lines. Therefore, research on embryonic stem cells will not lead to widespread harvesting of embryos for their cells. In fact, research should reduce such practices.

Is it truly more ethical to throw away the blastocysts (and they are indeed being thrown away by the hundreds of thousands every year) or to use them to derive cells that would save lives? Every year, hundreds of thousands of in vitro fertilization procedures are carried out in the United States. Each procedure results in multiple embryos that are not used or stored and must be discarded.

Some in the anti-ESC community have argued that all the unused IVF embryos should be kept and put up for adoption. Even if the parents were willing to put their embryos up for adoption (by the way, i don't think that there will be much support for a law saying that parent must put their excess embryos up for adoption by any family), many of the embryos that are being discarded cannot and should not implanted.

In any in vitro fertilization procedure, the fertilized embryos are graded by their appearance. Many do not develop normally in the dish. Only the healthiest, plumpest, and most viable-looking blastocysts are selected for implantation. The abnormal looking ones are the ones that are discarded. So, there may be a strong ethical argument against using abnormal blastocyts.

To be fair, the Catholic Church forsaw this ethical connundrum in the early 1980's and consistently opposed in vitro fertilization from the beginning. So, they have been consistent but many consequences of their stances on embryonic stem cell research, abortion, and birth control are simply unacceptable to the American people. In the end, the country is a democracy and should follow the rule of the majority.

The Catholic Church can get itself out of this dilemma by encouraging what they consider ethical research. For example, the Catholic Church can and should be funding umbilical cord blood, bone marrow, and induced pluripotent stem cell research. All of these would supplant and relieve the pressure for harvesting embryonic stem cells from blastocysts.

The worst thing is to freeze research progress. For example, if we froze polio research in 1960, we will have millions of people lying in iron lungs in hospitals today. For a decade now, we have frozen federal funding of embryonic stem cell research. That simply delayed the discovery of iPS cells that many scientists, including me, predicted at the beginning of the decade. We do have millions of people dying and suffering from conditions that could and should have been cured. That is a moral tragedy.

Wise.

chris arnold

11-15-2010, 06:51 AM

Chris, the Catholic popualtion is significantly in favor of stem cell reseqrch, including embryonic. The hierarchy is opposed. I'm Catholic and the population of the chruch is in favor of embryonic research. this is good, and those that believe in God know that God is in favor also. careful yes, but going forward.

keeping on

Thanks for these thoughts. Many RCs practice contraception. Not sure of any predilection for pork chops from the Jewish community. Enough said!

chris arnold

11-15-2010, 07:09 AM

Thanks to Wise. Yes, the points you raise are very interesting, and could keep theologians and philosophers going for generations.

I try to be (not very successfully) Christian. This reminds me of assertions that Christ was Mary Magdelene's lover, that he may have been homosexual, could have suffered from HIV and goodness knows what else. These views are purely subjective. What is reported, in the Bible is that he healed the sick. It is possible that some may have had some kind of STD. The idea of sins as precursors, lends something to this; but Christ was never judgmental. On the one hand you could say that such things are irrelevant, and the other, that they are inaccurate. HIV is a condition that was unknown until the late 1970s.

Any how those who hold the view that moral questions should asked, are right. I do not believe that the answer should be rubber stamped as "NO!!".
On this tack, I always remember some of the points raised in Koestler's Sleep Walkers where comments about for example about Galileo were somewhat biased. The Pope actually demanded a proof, for what at the time was a hypothesis, proof being available later. In this context it needs to be remembered that the position of Vatican Astronomer has been around for centuries.

keeping on

11-15-2010, 09:39 AM

Wise, your thought on coveting your neighbor's wife and then not touching her is aview not widely accepted. We are human you know. I can say that Catholics in general accept the evolution of science and in particular stem cell research; including embryonic. As the science is futher exposed and cures commence, the denial and protests will further diminsish and those who opeeose it now will have a need in their lives or those who are close to them in their lives. History repears itself.

keeping on

keeping on

Tetracyclone

11-17-2010, 08:07 PM

People- coveting your neighbor's wife is good- it makes her feel desirable and, if you both practice virtue in your behavior, you both also get to feel proudly virtuous. It is a win-win situation.

keeping on

12-24-2010, 02:23 PM

Looks like Congress will not take up stem cell research; especially embryonic stem cell. We'll fight another day; a succesful trial will lead the way for scientific advancement.

keeping on

keeping on

12-26-2010, 05:07 PM

http://rocnow.com/article/essays/201012260339'' more bullshit.

keeping on

kivi66

12-27-2010, 05:56 AM

http://rocnow.com/article/essays/201012260339

Wise Young

12-29-2010, 11:51 PM

I apologize for my clumsy attempts to voice the legal or ethical arguments against NIH funding of embryonic stem cell research. Let me try again. As I understand it, Judge Lambert is basing his decision on the Dickey-Wicker amendment. In 2009 and subsequent years, this amendment was appended to the appropriation for the Department of Health and Human Services. It stated

SEC. 509.

None of the funds made available in this Act may be used for--

the creation of a human embryo or embryos for research purposes; or
research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero under 45 CFR 46.208(a)(2) and Section 498(b) of the Public Health Service Act [1](42 U.S.C. 289g(b)) (Title 42, Section 289g(b), United States Code).

For purposes of this section, the term "human embryo or embryos" includes any organism, not protected as a human subject under 45 CFR 46 (the Human Subject Protection regulations) . . . that is derived by fertilization, parthenogenesis, cloning, or any other means from one or more human gametes (sperm or egg) or human diploid cells (cells that have two sets of chromosomes, such as somatic cells).

By prohibiting NIH funding to study embryonic stem cells that have already been derived and with non-federal funds, Judge Lambert has gone well beyond the statute. He stated that the research "clearly violates" the Dickey-Wicker amendment, listed above. Judge Lamberth believes that research on embryonic stem cells, even those derived before the ban by President George W. Bush and derived with non-Federal funding, is illegal.

The research itself clearly does not kill or harm embryos. Judge Lamberth is arguing that studies of the cells to the procedure of deriving the cells. This is simply not true. To illustrate how irrational this argument is, I gave the example of a county coroner that is doing an autopsy of the body of a murdered man. The coroner is not responsible the murder.

Judge Lamberth's argument is similar to one that is sometimes made by ethicists to suggest that it is unethical to use products of an unethical procedure. For example, some ethicists suggest that it is unethical to use information from medical experiments done by Nazis in concentration camps. But this argument is not implicit in the law.

The Dickey-Wicker amendment forbids "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death..." It does not forbid research on cells derived from those embryos. Those embryos are already dead. Studying them will not destroy, discard, or knowingly subject to risk of injury or death.

Ethicists often include intent and consequence in assessing culpability. In religious and legal ethics, intent is an important part of culpability. Likewise, consequences may be important. if research on embryonic stem cells resulted in killing of more embryos, even though the killing was not funded by federal dollars, one can argue that the research is killing the embryos.

There is no intent to fund research to kill or hurt embryos in any way. NIH is seeking to fund studies of embryonic stem cells that have been derived for reasons that are completely unrelated to research. For example, it forbids research on cells derived from embryos that are created for the purpose of providing cells. The cells must come from embryos created for procreation.

The research is will not intentionally result in the killing of more embryos. In fact, one can argue that by allowing NIH to fund studies of already derived embryonic stem cell lines, NIH would be discouraging the killing of more embryos to derive more cell lines. It can be fairly argued that the prohibition of embryonic stem cell research has not saved a single embryo to date.

If the true interest of opponents of stem cell research is to prevent or reduce killing of embryos, they should be focusing their attention on reducing the number of eggs being fertilized in IVF clinics. A similar argument can be made concerning opponents of animal research. If their true interest is to prevent or reduce killing of animals, they should be focusing their attention on reducing eating of meat.

Allowing studies of existing embryonic stem cell lines will not increase the use of embryos. Banning studies of embryonic stem cells has not and will not save any embryos. Such bans may actually encourage the use of fetal and embryonic cells because it cuts off an important future supply of stem cells. Judge Lamberth is saying that studying the cells is equivalent to harming the embryo. This is not true legally or ethically.

Wise.

krk

02-04-2011, 09:57 PM

My boyfriend is a C5 C6 quad who has been that way for 5 years. 3 years ago he had a stem cell surgery in Portugal with Dr. Lima involving his olfactory cells. He got no improvement. I live in Louisiana and heard a story on the news about an Iraq war veteran that was receiving a newly FDA approved therapy right where I live. My boyfriend and I have met with doctor and are seriously considering trying the procedure involving injection of MSC cells from bone marrow that have been seperated, purified and multiplied. Following is an article about it. Do you have any opinions on this????

http://www.myquadriplegia.com/2010/08/tca-cellular-therapy-to-begin-adult-stem-cell-trial-for-spinal-cord-injury/

chris arnold

02-05-2011, 08:47 AM

I wish you both the best of good fortune.

keeping on

02-05-2011, 09:17 AM

Wise, thank you for your explanation of the whole argument agaisnt fudning of stem cell reaearch, embryonic stem cell research, and the ruling by Judge Lambrythe. Hopefully, no matter what happens here in the US, the research will continue in the rest of the world. Hopefully your study and that of Geron's and others will be so successful that the cry for research with embryonic cells will shout out the supposed anti research.

keeping on

Wise Young

02-05-2011, 01:18 PM

0xSquidy

05-11-2011, 05:26 PM

give a fish to a man, he will eat for a day...............
teach a man to fish, he will eat for a life time............

saludos Ox, de un amigo Mexicano ay un amigo Espanol.

Saludos :)

fti

06-08-2011, 08:43 AM

</SPAN>Znop asked if I would start a discussion concerning embryonic and adult stem cells. I said that I would start with a summary and hope that others will contribute to the discussion. ]\

Before we begin the discussion, it is important that we define the terms because there is so much misunderstanding and misuse of the terms:
Stem cells. These are cells that can make many different kinds of cells, as well as themselves. There are many types of stem cells
Embryonic stem cells. These are cells that are derived from blastocysts, a very early stage of development that occurs during the first two weeks after fertilization. A blastocyst is a small ball that contains about 200-300 stem cells. The blastocyst is pre-embryonic. A developing fertilized egg becomes an "embyro" only after a midline appears. This usually occurs shortly after implantation of the egg into the uterus and a "primitive streak" develops. So, the term "embryonic stem cells" is a misnomer. They should be called "pre-embryonic stem cells".
Fetal stem cells. These are cells that are derived from fetuses. A fetus refers to the stage of development when body parts are evident, including a head, arms, and legs, usually starting 6 weeks after conception and continuing until birth. Many types of stem cells are present in fetuses, associated with the various organs of the body that are developing. These include:

Fetal neural stem cells. These are obtained from the developing brain.
Fetal bone marrow stem cells. These are obtained from developing bone.
Fetal stem cells isolated from various tissues, including skin, blood, bone, etc.

Neonatal stem cells. These are cells that are derived from cells collected from newborns. These include:

Umbilical cord blood stem cells. These are obtained from umbilical cord blood collected from the umbilical cord shortly after birth.
Umbilical cord and placental stem cells. These are obtained from the umbilical cord and placenta shortly after birth.

Adult stem cells. These are cells that are derived from cells collected from any person older than newborn, from several days to elderly. They include:

Bone marrow stem cells. These are cells obtained from bone marrow, usually autologous or from the same person that will receive the transplant. Although the markers for bone marrow stem cells are well defined in humans, many investigators use CD34+ which is a maker for hematopoietic stem cells (i.e. stem cells that make blood cells). Please note that we did not know that there were pluripotent stem cells in bone marrow until 1999.
Mesenchymal stem cells. These are cells collected from a variety of tissues, including peripheral blood. There are some markers, such as CD144+ but the markers are controversial. Tuli, et al. (2003) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14595128) for example reports that mesenchymal derived from human trabecular bone are CD73(+), STRO-1(+), CD105(+), CD34(-), CD45(-), CD144(-) while Mayer (2004) (http://while Mayer (2004) suggests that bone cells are CD13+, CD44+, CD90+, CD147+, CD14-, CD34-, CD45- and CD144- in elderly women, Mitchell, et al. (2006) (http://CD13, CD29, CD44, CD63, CD73, CD90, CD166) suggests that such cells obtained from adipose (fat) tissues are CD13, CD29, CD44, CD63, CD73, CD90, CD166 are initially low but increase progressively with passage. Kuwana, et al. (2006) report that human monocyte derived multipotential cells are expressed CD31, CD144, vascular endothelial growth factor (VEGF) type 1 and 2 receptors, Tie-2, von Willebrand factor (vWF), endothelial nitric oxide synthase, and CD146, but CD14/CD45 expression was markedly down-regulated.
Neural stem cells. We have only known since the mid-1990's that there are neural stem cells in adult brain that continue to make neurons throughout adult life.
Enteric glia. These are stem cells from the gut. Although known for a long time to be able to produce neurons, these cells are now believed to be a type of stem cell or a neuroprogenitor cell.

Progenitor cells. These are cells that make several different kinds of cells but are usually more limited than stem cells and may not be able to make themselves. The difference between progenitor and stem cells is not clear and may become moot as if becomes clear that it is possible to "dedifferentiate" cells to become stem cells.
Precursor cells. These are even more limited than progenitor cells and make only a few types of cells and cannot make themselves. These are further down the differentiation path from progenitor cells.

There are several possible goals for using stem cells for treating spinal cord injury.
Bridging the gap. The injury site is frequently a "bombed out" tissue that has lost many cells and is filled with macrophages and other inflammatory cells in the weeks that follow injury. In the months and years after injury, it may be taken over by reactive glial cells that may express substances that repel axonal growth. One of the goals of spinal cord injury repair is to fill this site with cells that are conducive to axonal growth.
Growth factors. Many stem cells and progenitor cells are believed to secrete growth factors that stimulate growth of cells. Many of these factors are also produced by other cells. These include neurotrophins (that stimulate neurons), proliferative factors such as fiberblast growth factor (FGF) and epidermal growth factor (EGF), survival and protective factors such as glial-derived neurotrophic factor, insulin-like growth factor (IGF), and others.
Remyelinating axons. Injury damages oligodendroglial cells (the cells that provide myelin for axons). Oligodendroglia come from oligodendroglial precursor cells called O2A. These cells may be in short supply or cannot migrate well into the injury to to remyelinate axons. Note that regenerated axons are "naked" and need to be remyelinated in order to conduct efficiently.
Replacing neurons. Neurons may be lost, particularly when the injury is close to the lumbar enlargement where the neurons from the legs are present or in the cervical enlargement where the neurons for the arms are located. The sacral tip of the spinal cord or conus contain neurons that innervate the bladder, anal sphincter, and other important functions.
Tissue niches for stem cells. As investigators gain more experience with stem cell transplants, it is becoming clear that many tissues don't have the factors that tell a stem cell what to do, what kind of cells to produce. In adult tissues, stem cells must interact with other cells, sometimes called a "niche" in order to produce other kinds of cells. This may be a very important regulator of stem cells so that they do not produce the wrong type or wrong number of cells. For example, it would not be good if bone marrow stem cells produced blood cells in the spinal cord. In general, many investigators attempt to differentiate stem cells in culture before transplantation so that they will produce the right type of cells. For example, one can differentiate embryonic stem cells by treating them with a factor called retinoic acid which pushes them to differentiate towards neural stem cells and then using factors such as sonic hedghog (SHH) to differentiate the cells further to become neurons. These approaches have worked to produce neurons in the brain and motoneurons in the spinal cord.

Neural stem cells. During development, the stem cells of the central nervous system are radial glial cells. These are very specialized looking cells that haveStem cells versus differentiated cell transplants. Most of cells transplanted into the spinal cord in animal studies and human clinical trials are not stem cells and, even if they are, it is not clear that they are performing as stem cells. For example, olfactory ensheathing glia are not stem cells. Likewise, while nasal mucosa may contain some stem cells, it is not clear transplanted nasal mucosa are producing neurons in the spinal cord after transplantation. The only exception has been embryonic stem cells. These cells appear to behave like stem ells when transplanted into the spinal cord, producing some neurons, astrocytes, and oligodendroglia. To date, neither adult bone marrow nor umbilical cord blood cells have been reported to produce neurons or glia in the spinal cord after transplantation. In fact, most umbilical cord blood and bone marrow cells simply remain undifferentiated when they are transplanted into the spinal cord. While they may proliferate (i.e. produce additional cells), it seems that they produce more of themselves and not necessarily neurons, astrocytes, or oligodendroglia. However, they may stimulate endogenous cells to remyelinate the spinal cord axons.

Drug stimulation of stem cells. Some drugs seem to stimulate certain cells to produce more growth factors. For example, lithium seems to do this and this may be one of the reasons for the beneficial effects of lithium when used to treat depression. Lithium has been reported to stimulate bone marrow cells to grow. Erythropoeitin is known to stimulate bone marrow stem cells. Several bone marrow stimulation factors are known to stimulate bone marrow cell prolieration and differentiation. This approach may enhance the neuroregenerative and remyelinative effects of bone marrow and umbilical cord blood cells. This is one of the reasons why we are interested in assessing the effects of lithium on spinal cords that have been transplanted with umbilical cord blood mononuclear cells. Mononuclear cells presumably include mesenchymal stem cells. There is also substantial interest in the effects of lithium on neural stem cells because this is one of the theories as to why lithium is beneficial as a treatment of manic depression. It would be of interest to see if lithium stimulates transplanted bone marrow cells as well.

Many therapies regenerate the spinal cord without stem cells. Marie Filbin and her colleague have reported that increased cAMP levels inside neurons will allow axons to grow despite the presence of growth inhibitors. Thus, there was a great deal of excitement when Mary Bunge and colleagues at the Miami Project showed that treatment with rolipram and dibutyryl cAMP and Schwann cells (a source of growth factors and a cell that supports axonal growth) allowed large numbers of axons to grow across the contusion site of injured spinal cords, associated with improved functional recovery. Schwann cells are not stem cells. Likewise, olfactory ensheathing glial cells are not stem cells.

Embryonic stem cells need to be combined with other therapies. Douglas Kerr and colleagues has shown that human embryonic stem cells transplanted to the spinal cord will not only survive and produce motoneurons but, when stimulated with rolipram and dibutyryl cAMP, send axons out of the spinal cord to re-innervate muscle. So far, only embryonic stem cells have been shown to do this. But, it is important to note that embryonic stem cells alone cannot do this. They must be pre-differentiated and combined with other therapies in order to achieve the objective of replacing neurons for these neurons to regenerate and reconnect with muscle.

Stem cells must be differentiated before they are transplanted. Much evidence suggest that it is important to differentiate the stem cells before they are transplanted. In the case of embryonic stem cells, it is necessary to differentiate them or else they may produce inappropriate types and numbers of cells in the spinal cord. Note that it is not necessary for embryonic stem cells to become cancers (i.e. cells that have lost their growth control). All they have to do is produce the wrong number and types of cells. For example, it would not be good if embryonic stem cells produced fibroblasts (skin cells) or hair cells in the spinal cord. To avoid this, most investigators pre-differentiate embryonic stem cells before they transplant them into the spinal cord. Thus, what is being transplanted are not stem cells but rather progenitor or even precursor cells that produce astrocytes, oligodendroglia, or neurons in the spinal cord. In fact, Steven Davies and his colleagues recently reported that it is helpful to differentiate fetal neural stem cells into a particular kind of astrocyte before transplanting them into the spinal cord, to encourage regeneration.

Embryonic stem cells are important. Embryonic stem cells are potentially a source of all the cells in the body. They provide the possibility of producing cells rather than having to harvest the specific cells from different organs for transplantation. While this is controversial, I personally believe that we (not our group but scientists in general) someday should be able make many kinds of cell of the body behave like stem cells. However, in order to reach this goal, it is critical that scientists be allowed to study human embryonic stem cells, find out what makes them pluripotent, identify factors that cause them to produce or differentiate into different kinds of cells, and how to regulate them. Why can't this be done in animal cells? There are important differences between animal and human cells. In fact, for reasons that we still don't understand, scientists have had very little success growing rat embryonic stem cells even though we can grow mouse, human, and primate embryonic stem cells. The fact that we cannot grow rat embryonic stem cells should give people an idea how little we understand of the factors that control and sustain embryonic stem cells and that there are species differences that we don't understand.

Embryonic stem cells alone are not a cure. It is important that people don't expect a cure from just by transplanting human embryonic stem cells into the spinal cord for several reasons. First, there is no reason why embryonic stem cells should or would know what to do when they are plugged into an injured spinal cord. Second, the studies with embryonic stem cell transplants in animal spinal cord injury models have been done shortly after injury and in chronically injured spinal cords. Third, there is the problem of immune rejection of transplanted cells. Although several laboratories have hypothesized that embryonic stem cells are not rejected when transplanted into the spinal cord, this is not the experience of most investigators. That is the reason why there is strong interest in cloning of embryonic stem cells. Fourth, the mechanisms of immune rejection in the central nervous system may be different from immune rejection in other parts of the body.

Adult stem cells alone are not a cure. Likewise, it is important that people don't expect a cure from just infusing umbilical cord blood cells into people. Many clinics are advertising umbilical cord blood treatments as if umbilical cord blood stem cells injected into the bloodstream will go directly to the spinal cord and start to produce the right types of cells and the right types of growth factors to repair the spinal cord. I am very skeptical of claims that are saying that umbilical cord blood cells are doing this. For the past two years, at the Rutgers Keck Center, we have been transplanting umbilical cord blood cells into the spinal cord and finding that the cells do not produce neurons, astrocytes, or oligodendroglial cells. Yes, when they are transplanted directly into the spinal cord, umbilical cord blood cells do produce growth factors that may be beneficial for the spinal cord. However, when we have injected human or rat neonatal blood cells intravenously into rats after spinal cord injury, we find that few or none of the cells go into the spinal cord, even when we suppress the immune system.

Stem cells are one of several tools that we should use to repair the spinal cord and stimulate regeneration. Scientists must be allowed to study a diversity of human embryonic stem cells to understand what and how they do what they do. By understanding stem cell biology, we should be able to make any cell behave like a stem cell. After all, a stem cell is just a cell that is expressing certain genes. Also, it is important to understand how the central nervous system recognize "foreign" cells and reject them. If we know the mechanisms, we may be able to trick the spinal cord to accept transplanted cells are "native" to the spinal cord. Finally, we need to know the factors needed to get the cells to do what we would like them to do, to stimulate regeneration, to provide a substrate that is conducive to axonal growth, to replace neurons, and to remyelinate the spinal cord.

No reason to be discouraged. After reading the above, many may conclude that it will take a long time before treatments become available to restore function to people with spinal cord injury. I don't think so for the following reasons. First, stem cells do provide an important substrate of regeneration in the spinal cord. For regeneration, it may not be necessary for the transplanted cells to stay there forever. For example, once the cells have created a bridge and the axons have grown across, it may not be necessary to keep the bridge. In fact, it might even be a good idea for the bridge to go away. In fact, this may be one reason why stem cell transplants have been relatively safe. Second, stem cells are a very efficient way of delivering growth factors to the spinal cord. I am quite excited by the discovery that umbilical cord blood cells secrete most of the growth factors that are known to stimulate regeneration and remyelination in the spinal cord. Third, although we may not understand the mechanisms, many studies have reported beneficial effects of stem cell transplants to the spinal cord.

Nogo receptor blockers. Many studies indicating that blockade of axonal growth inhibitors will allow regeneration to occur in the spinal cord. For example, there are phase 1 trials of the Nogo antibody by Novartis and Cethrin (the blocker of Nogo receptor intracellular messenger rho) by Bioaxone. Dozens of studies have shown the beneficial effects of chondroitinase in animal studies. Likewise, Biogen has identify other blockers of the Nogo receptor. These need to be taken to clinical trial. When these are combined with cell transplants and sustained growth factor support, I hope that we will see substantial regeneration in human spinal cords. It is not trivial to get such complicated combination therapy trials tested. We have to develop the clinical trial infrastructure now so that we are ready when the therapies are available to be tested in humans.

Wise.

pr young donc il y a des cellules mesenchymal dans le cordon ambilical http://www.ncbi.nlm.nih.gov/pubmed/21097398

mamadavid

06-08-2011, 12:20 PM

</S

pr young donc il y a des cellules mesenchymal dans le cordon ambilical http://www.ncbi.nlm.nih.gov/pubmed/21097398

So Professor Young, are there mesenchymal cells in the umbilical cord?

Wise Young

06-22-2011, 12:21 AM

So Professor Young, are there mesenchymal cells in the umbilical cord?

Yes, there are mesenchymal stem cells in umbilical cord, as well as umbilical cord blood. Many investigators have described mesenchymal stem cells that are present in cord blood. But, the umbilical cord itself is a rich source of mesenchymal stem cells. The central part of the umbilical cord is filled with a jelly-like substance called Wharton's jelly, containing many mesenchymal stem cells, that have been transplanted into the spinal cord and shown to improve recovery in animal spinal cord injury models. Finally, the lining of the umbilical cord has pluripotent stem cells.

Wise.

c473s

10-09-2011, 03:38 PM

Yes, there are mesenchymal stem cells in umbilical cord, as well as umbilical cord blood. Many investigators have described mesenchymal stem cells that are present in cord blood. But, the umbilical cord itself is a rich source of mesenchymal stem cells. The central part of the umbilical cord is filled with a jelly-like substance called Wharton's jelly, containing many mesenchymal stem cells, that have been transplanted into the spinal cord and shown to improve recovery in animal spinal cord injury models. Finally, the lining of the umbilical cord has pluripotent stem cells.

Wise.

Hope to see you in Atlanta this Wednesday at the ACRM meeting before your talk. It is sounding like Deb has you coming in/ talking and flying right back out.

fti

01-26-2012, 01:09 PM

Yes, there are mesenchymal stem cells in umbilical cord, as well as umbilical cord blood. Many investigators have described mesenchymal stem cells that are present in cord blood. But, the umbilical cord itself is a rich source of mesenchymal stem cells. The central part of the umbilical cord is filled with a jelly-like substance called Wharton's jelly, containing many mesenchymal stem cells, that have been transplanted into the spinal cord and shown to improve recovery in animal spinal cord injury models. Finally, the lining of the umbilical cord has pluripotent stem cells.

Wise.

dear professor

pr you in your clinical trials transplanting these cells also

thank you

keeping on

01-26-2012, 02:38 PM

Ira Weissman of Stem Cell Inc says that mesenchymal cells won't work in spinl therapy. Who knows? http://www.youtube.com/watch?v=Tj3mhgfLDGg&NR=1 just for information. Comments welcome.

Anthony

GRAMMY

01-26-2012, 03:50 PM

Ira Weissman of Stem Cell Inc says that mesenchymal cells won't work in spinl therapy. Who knows?

Irving L. Weissman, MD, is the Director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine.
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http://med.stanford.edu/profiles/Irving_Weissman (http://med.stanford.edu/profiles/Irving_Weissman)

Colin83

01-26-2012, 04:02 PM

That's cool. My brother goes to Stanford.

keeping on

01-26-2012, 04:56 PM

Although this video doesn't reflect what I'm describing; you can see the video I posted and get Dr Weissman's comments on different cells as per his view on treatment of spinal cord problems.

Anthony

GRAMMY

01-26-2012, 05:27 PM

Who knows? Comments welcome. Anthony

I think Irving L. Weissman, MD, the Director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine would be pretty well qualified to give an opinion on it. He stays up on the results coming out of the research labs and clinical trials around the globe.

(I notice you called him Ira)? It is "Irving" L. Weissman for people wanting to check his credentials, profile and research publications. http://med.stanford.edu/profiles/Irving_Weissman (http://med.stanford.edu/profiles/Irving_Weissman)

Perhaps Barb Turnbulls lecture series would help...It is interesting.

Charles H. Tator, CM, MD, MA, PhD, FRCSC, FACS http://www.cahs-acss.ca/charles-h-tator/ (http://www.cahs-acss.ca/charles-h-tator/)

This is Dr. Charles Tator's lecture from the 2011 Charles H. Tator - Barbara Turnbull Lectureship Series in Spinal Cord Injury.

Which Stem Cell Will Win The Race To Repair The Spinal Cord? They are indeed narrowing down the prospects.

cNTJmdyIDS8

Wise Young

04-18-2013, 09:13 AM

GRAMMY,

Irv Weissman was my professor at Stanford in the 1970's. He is a great man and good scientist but he is not always right. For example, throughout the late 1990's and up to 2007, he strongly denied the possibility of dedifferentiation and transdifferentiation, saying that cells don't go backwards after they have differentiated (unless they become cancer cells) and don't convert to become another type of cells. He represented the old guard (I was taught, for example, that differentiation is a one-way street when I was a graduate student) even when the data suggested strongly that some stem cells were switching from one type to another.

The discovery that embryonic stem cells can be cloned by transferring a nucleus from a somatic cell into an egg did not convince him that dedifferentiation was possible. The Yamanaka iPS story probably swayed him because he was not so vocal on the subject after 2007. It was not until Marius Wernig found that he could reprogram fibroblasts to become neurons in Weissman's own institute at Stanford around 2009 that Weissman relented on the issue of transdifferentiation. Transdifferentiation and dedifferentiation are now of course moot issues. While it may be difficult to get stem cells to change from one type to another by feeding them different nutrients and growth factors, the vast majority of scientists believe that it is a matter of changing the expression of several genes.

Several years ago, Weissman was the President of the International Society for Stem Cell Research. I remember attending a luncheon for sponsors and speakers in which Weissman gave a talk attacking mesenchymal stem cells. He pointed out that there are no reliable markers for mesenchymal stem cells and that a majority of studies making claims about mesenchymal stem cells having beneficial effects on animals really did not document what cells they transplanted. He was and is still pointing out that the scientific studies are not very good and that we must be more critical. He is right of course but this does not mean that mesenchymal stem cells do not exist and are not beneficial in certain conditions.

Science is not and should not be an authoritarian endeavor. Evidence matters. No scientist, no matter how important and great, is always right, particularly at the frontiers of knowledge where we don't have enough information and what I call the fog of discovery shrouds everything. Much of what we know depends on how good our tools are. At the present, most scientists rely on surface "markers" that cells express to classify them. These markers are often misleading. Nature is usually more complicated than we think. So, rather than by saying the Irv Weissman should be believed because he is a great scientist, we should be saying that scientists don't agree and that we don't know enough to come to a consensus.

Wise.

I think Irving L. Weissman, MD, the Director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine would be pretty well qualified to give an opinion on it. He stays up on the results coming out of the research labs and clinical trials around the globe.

(I notice you called him Ira)? It is "Irving" L. Weissman for people wanting to check his credentials, profile and research publications. http://med.stanford.edu/profiles/Irving_Weissman (http://med.stanford.edu/profiles/Irving_Weissman)

Perhaps Barb Turnbulls lecture series would help...It is interesting.

Charles H. Tator, CM, MD, MA, PhD, FRCSC, FACS http://www.cahs-acss.ca/charles-h-tator/ (http://www.cahs-acss.ca/charles-h-tator/)

This is Dr. Charles Tator's lecture from the 2011 Charles H. Tator - Barbara Turnbull Lectureship Series in Spinal Cord Injury.

Which Stem Cell Will Win The Race To Repair The Spinal Cord? They are indeed narrowing down the prospects.

cNTJmdyIDS8