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Thread: ChinaSCINet Update

  1. #901
    If I understand your clinical trial strategy correctly you are bolus injecting stem cells into both stumps of the cord on either side of the lesion in ASIA A patients at least one year following injury. Then patients will get intense rehab and some will or won’t get lithium. Given that the trials have already started, I am sure we all can agree that there is hope that at least some (and hopefully more) will get significant functional improvements. But what I cannot agree with is that regeneration across the lesion can be shown to be the underlying mechanism for improvement and especially using only DTI as a tool. I am purposefully and carefully separating the terms “regeneration” and “sprouting”. I define regenerating axons as those fibers induced to re-grow from previously severed fibers. I am defining “sprouting” as those axons that arise as collaterals from remaining fibers anywhere above or below the lesion. This is because you continue to discuss in a number of your public presentations and at CARE CURE the possibility of long distance regeneration at long chronic time points after cord injury directly across stem cell tissue bridges, that fibers can exit such bridges and that once beyond the lesion the regenerating axons would continue growing albeit very slowly so that recovery would take a long time. I think statements like this are at best highly speculative and lacking in corroborating experimental data. As you state in your rebuttal and I agree, DTI can be used to visualize linear bundles of axons especially if the bundles can be traced directly from white matter tracts where bundled axons live. However, it is well known that truly regenerating axons cannot grow linearly unless they are given a linearly aligned substrate to guide them. Given, that your stem cell grafts are not aligned it is highly unlikely and, indeed, improbable for axons to grow in aligned bundles. Indeed, it has been well accepted by all in the regeneration community that a major identifier of bonafide regenerating axons is that they take a meandering coarse, unlike the morphology of normal axon tracts. DTI will not be able to see them. Even if given an aligned scaffold, once regenerating axons exit the bridge (and this exodus can only occur under certain circumstances which are not being provided in your clinical trial) they instantly defasciculate and begin again a meandering course, even if this occurs in distal white matter. Again DTI will not be able to follow them. Even at acute stages after injury and under the most optimal circumstances such fibers would only be in small numbers likely well below the resolution of DTI. These observations of how regenerating axons behave have been documented in the best labs using well tested, anterograde tracing techniques, confocal microscopy and serial reconstructions to help substantiate the conclusion that such fibers are truly regenerating. While there are many who have professed that regeneration has occurred, without rigorous methods it has been difficult to rule out that sprouting from remaining fibers has occurred to account for the increased presence of fibers distally. Given that you are suggesting that far more substantial regeneration can occur, that entire aligned bundles of axons rather than scattered meandering fibers will emerge and, in addition, that they will continue to elongate well beyond the lesion even at long chronic time points after injury, one should base such hope building statements on experimental data rather than fantasy. There is not one shred of experimental evidence from any lab ever for the exuberant regeneration that you are predicting. It would be wonderful if chronically injured axons could regenerate long distances but this has yet to be demonstrated. That is precisely why we need increased resources from SCI funding agencies and increased interest in chronic injury models from SCI scientists in order to tackle this critical problem. By the way, if one reads the pTEN literature carefully, it is clear that these truly regenerating axons navigate across the lesion upon the surfaces of strands of astrocytes that form continuous bridges across the lesion. Whether such axon growth promoting bridges can be formed at long chronic time points by the stem cells that you are employing in a species that develops a more cavitated lesion (like those which occurs in humans) is unknown because the appropriate pre-clinical experiments have not been done. In the end, of course, if many of your patients really do get better then who gives a damn what the mechanism of recovery is.
    Last edited by jsilver; 06-23-2012 at 09:40 AM.

  2. #902
    I like how Dr. Silver portrays Dr. Young as a Forrest Gump-type character, just breezing along in life and lucking his way into assorted remarkable situations. He's gonna flip the day that Wise gets invited to the White House to be crowned man of the century for his work in curing sci - then drinks 15 Dr. Peppers and shows the president his butt.

    Speaking of 1994 films, I can't shake the vision of Dr. Silver as "the gimp" in Pulp Fiction, watching life pass him by through woebegone eyes from his cage in Zed's (Acorda's) basement.

  3. #903
    Senior Member
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    From Dr. Silver:

    "If I understand your clinical trial strategy correctly you are bolus injecting stem cells into both stumps of the cord" & "Given, that your stem cell grafts are not aligned"

    I don't think it's stem cell grafts at all - I think it's umbilical cord blood which contains stem cells.

  4. #904
    @wise: I specifically stated MRI as opposed to DTI. Not all hospitals doing MRI have the DTI capability that you describe, certainly not some smaller ones that struggle financially like the ones I go to.

    I have no idea why you'd think a neurosurgeon would ever re-lesion a person to prove regeneration. That's a bit far fetched.

    The number of neuroscientists doing pTEN nerve research has greatly expanded. As a result, papers will be published and collaborations are already forming. In May 2009, just three years ago, Zhigang He's lab was the only lab in the world doing PTEN nerve research. According to PubMed, today there are more than 17 labs conducting this research. This list does not include several labs in Europe also participating in this area of research. A growing number of researchers feel this research has the potential to provide answers to regeneration and as a result, grant requests are being reviewed and approved for funding.

    • Zhigang He – Harvard University
    • Oswald Steward - UCIrvine + 3 additional researchers (USCD)
    • Hans Kierstead – UC Irvine
    • Binhai Zheng – UC San Diego
    • Mark Tusznski – UC San Diego
    • Kai Liu – Hong Kong University
    • Mary Bunge – Miami Project, University of Miami
    • Wolfram Tetzaloff – University of British Columbia
    • Jerry Silver – Case Western Reserve University
    • Itzhak Fisher – Drexel University
    • Larry Recht and Jim Wiemann - Stanford
    • Doug Zochodne – University of Calgary
    • Kevin Park – Miami Project, University of Miami
    • Gary Westbrook – Vollum Institute

    Recently, Unite 2 Fight Paralysis organized a meeting to discuss a collaboration of labs interested in PTEN research and therapies which could be used in combination with it. The details of that collaboration are being finalized and the information of that collaboration will be provided on the U2FP website in the coming months.

    There is no need for me to defend my collaboration and questions to numerous other researchers in seeking information. In fact, anyone interested in finding a cure should be asking lots of questions and encouraged to do so. I am fortunate to have a large group of SCI researchers throughout the USA who are willing to take the time to answer all of my questions.
    Last edited by GRAMMY; 06-23-2012 at 02:12 PM.

  5. #905
    Grammy,

    Thank you for your response. I apologize that I assumed wrongly that you were referring to DTI. You posted in response to Paolo's comment that DTI cannot show regenerating axons and then point out that MRI cannot distinguish axons from other oriented tissues, that Schwann cells are present in the injury site and have oriented processes, that MRI cannot distinguish between sensory and motor axons, that there would be no way of knowing where the axons come from, and that there is no way of following the axons through the complex environment of the injury site. I thought you were referring to DTI. I agree that plain MRI images cannot show axons but I want to clarify that DTI can detect bundles of axons and can trace the origins of bundles as coming from above or below the injury site.

    I was quite surprised by your statements that there is no evidence that stem cells can form bridges and that the spinal cord should be re-lesioned in order to prove that regeneration is responsible for the recovery of function. Much evidence has been published showing that several cell types can form "bridges" across in the injury site. I disagree that the re-lesioning would be appropriate or necessary to take a therapy to clinical trial or to claim that spinal cord regeneration has occurred in animal studies or clinical trials. Re-lesioning is an old and, in my opinion, not very good method for showing that regenerated axons are responsible for recovery of function. There are far better methods today of showing the regenerated axons are responsible for recovery of function than re-lesioning the spinal cord.

    Finally, please understand that I was not criticizing your support of PTEN research. Many scientists are excited by the work, as am I. My former graduate student Kai Liu is the first author on the original paper reporting the effects of PTEN deletion on corticospinal tract regeneration [1]. However, in the context of your comments concerning regeneration, I pointed out that no functional improvement has yet been seen in PTEN knockout mice despite very impressive regeneration of the corticospinal tract. I simply brought it up to agree with you that it is important to correlate regeneration with functional recovery.

    Wise.

    1. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B and He Z (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 13: 1075-81. F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.






    Quote Originally Posted by GRAMMY View Post
    @wise: I specifically stated MRI as opposed to DTI. Not all hospitals doing MRI have the DTI capability that you describe, certainly not some smaller ones that struggle financially like the ones I go to.

    I have no idea why you'd think a neurosurgeon would ever re-lesion a person to prove regeneration. That's a bit far fetched.

    The number of neuroscientists doing pTEN nerve research has greatly expanded. As a result, papers will be published and collaborations are already forming. In May 2009, just three years ago, Zhigang He's lab was the only lab in the world doing PTEN nerve research. According to PubMed, today there are more than 17 labs conducting this research. This list does not include several labs in Europe also participating in this area of research. A growing number of researchers feel this research has the potential to provide answers to regeneration and as a result, grant requests are being reviewed and approved for funding.

    • Zhigang He – Harvard University
    • Oswald Steward - UCIrvine + 3 additional researchers (USCD)
    • Hans Kierstead – UC Irvine
    • Binhai Zheng – UC San Diego
    • Mark Tusznski – UC San Diego
    • Kai Liu – Hong Kong University
    • Mary Bunge – Miami Project, University of Miami
    • Wolfram Tetzaloff – University of British Columbia
    • Jerry Silver – Case Western Reserve University
    • Itzhak Fisher – Drexel University
    • Larry Recht and Jim Wiemann - Stanford
    • Doug Zochodne – University of Calgary
    • Kevin Park – Miami Project, University of Miami
    • Gary Westbrook – Vollum Institute

    Recently, Unite 2 Fight Paralysis organized a meeting to discuss a collaboration of labs interested in PTEN research and therapies which could be used in combination with it. The details of that collaboration are being finalized and the information of that collaboration will be provided on the U2FP website in the coming months.

    There is no need for me to defend my collaboration and questions to numerous other researchers in seeking information. In fact, anyone interested in finding a cure should be asking lots of questions and encouraged to do so. I am fortunate to have a large group of SCI researchers throughout the USA who are willing to take the time to answer all of my questions.
    Last edited by Wise Young; 06-23-2012 at 04:54 PM.

  6. #906
    Jerry, thank you very much for commenting.

    Let me first provide the context of the discussion that we are having. I mentioned verbally in an Open House several weeks ago that I believe that our data suggests that many axons are growing across the injury. Paolo Cipolla challenged my statement by saying that DTI cannot show regenerating axons. I responded to him saying that DTI can detect bundles of axons and that the appearance of bundles of axons crossing the injury site where there were none before treatment would be a strong argument for axons growing across the injury site. Paolo then said that it may show remyelination. I responded by saying that DTI would detect bundles of non-myelinated axons as well. Grammy commented that she was interested in DTI and then cited a number of reasons why MRI cannot detect axons growing across the injury site, the origins of the fibers, and inability of DTI to track growing axons. I responded that DTI imaging can detect whether bundles of axons are crossing the injury site and whether they come from above or below the injury site.

    Several groups have now used DTI to image injured spinal cords. DTI does not just show the presence of oriented structures. What one does is to select white matter above or below the injury site. The software then reconstructs contiguous areas of tissue that have similar fractional anisotropy (FA). Essentially what this does is to identify anisotropic fiber bundles that start in relatively normal white matter above and below the injury site and continues towards the injury site. Where there is a gap in anisotropy, the software stops tracing the oriented structure. If applied to normal spinal cords, this clearly shows the white matter of the spinal cord as a single continuous anisotropic structure that runs all the way up and down the spinal cord. When applied to patients with severe “complete” spinal cord injury, it shows a gap at the injury site. In patients with incomplete spinal cord injury, bundles of white matter can be seen to cross the injury site.

    We injected HLA-matched umbilical cord blood mononuclear cells (4 or 8 ┬Áliters of 100,000 cells/┬Áliter) into the left and right dorsal root entry zones above and below the injury site). By the way, as you know, there are no “stumps” in contused spinal cords. From the surface, the spinal cord usually looks continuous and intact at the injury site, even though the patients had little or no function below the injury site. In the 8 subjects with chronic ASIA A spinal cord injury, before treatment, we saw a 2-5 cm gap with little or no anisotropy between two wavefronts of white matter before transplanting cells. We obtained DTI images at 6 months, 12 months, and in one case 1.5 years after treatment. These subjects in Hong Kong did not receive lithium, just transplants. Our goal in the trial was to see what changes of DTI occurred after cell transplantation. To tell you the truth, we were not expecting very much of any change but thought that it would be of interest to use DTI to image the cord.

    DTI can reliably detect bundles of axons in the spinal cord. These bundles of axons are contiguous with white matter that we select in the proximal and distal cord. In ASIA A complete spinal cord injury patients before treatment, all bundles of axons stopped at the injury site and a clear cut gap was present with no anisotropic bundles crossing the injury site. Let me point out that MR-DTI is difficult to obtain from patients who have metallic devices (screws, rods, etc.) around the spine. We were very careful to use standard parameters and maintained the same parameters in the repeated images of the subjects. The groups did studies of 8 normal subjects to ascertain the reliability and consistency of the anisotropic measurements of the white matter. We also did DTI images of a patient with chronic incomplete injury (ASIA C) and found fiber bundles crossing the injury site.

    We are submitting a manuscript reporting our study of 8 spinal-injured subjects before and after umbilical cord blood mononuclear cell transplants, 8 normal subjects, and several untreated complete and incomplete spinal cord injury, correlating the DTI findings with neurological examinations. The best time for this discussion would be after we have submitted the work for publication although I would be very happy to share the data with you privately. Based on the data, I believe that MR DTI will be very useful for detecting white matter regrowth chronic spinal cord injury. I obviously cannot talk about this data in a public forum until it has been accepted in a peer-review journal.

    Wise.

    Quote Originally Posted by jsilver
    If I understand your clinical trial strategy correctly you are bolus injecting stem cells into both stumps of the cord on either side of the lesion in ASIA A patients at least one year following injury. Then patients will get intense rehab and some will or won’t get lithium. Given that the trials have already started, I am sure we all can agree that there is hope that at least some (and hopefully more) will get significant functional improvements. But what I cannot agree with is that regeneration across the lesion can be shown to be the underlying mechanism for improvement and especially using only DTI as a tool. I am purposefully and carefully separating the terms “regeneration” and “sprouting”. I define regenerating axons as those fibers induced to re-grow from previously severed fibers. I am defining “sprouting” as those axons that arise as collaterals from remaining fibers anywhere above or below the lesion. This is because you continue to discuss in a number of your public presentations and at CARE CURE the possibility of long distance regeneration at long chronic time points after cord injury directly across stem cell tissue bridges, that fibers can exit such bridges and that once beyond the lesion the regenerating axons would continue growing albeit very slowly so that recovery would take a long time. I think statements like this are at best highly speculative and lacking in corroborating experimental data. As you state in your rebuttal and I agree, DTI can be used to visualize linear bundles of axons especially if the bundles can be traced directly from white matter tracts where bundled axons live. However, it is well known that truly regenerating axons cannot grow linearly unless they are given a linearly aligned substrate to guide them. Given, that your stem cell grafts are not aligned it is highly unlikely and, indeed, improbable for axons to grow in aligned bundles. Indeed, it has been well accepted by all in the regeneration community that a major identifier of bonafide regenerating axons is that they take a meandering coarse, unlike the morphology of normal axon tracts. DTI will not be able to see them. Even if given an aligned scaffold, once regenerating axons exit the bridge (and this exodus can only occur under certain circumstances which are not being provided in your clinical trial) they instantly defasciculate and begin again a meandering course, even if this occurs in distal white matter. Again DTI will not be able to follow them. Even at acute stages after injury and under the most optimal circumstances such fibers would only be in small numbers likely well below the resolution of DTI. These observations of how regenerating axons behave have been documented in the best labs using well tested, anterograde tracing techniques, confocal microscopy and serial reconstructions to help substantiate the conclusion that such fibers are truly regenerating. While there are many who have professed that regeneration has occurred, without rigorous methods it has been difficult to rule out that sprouting from remaining fibers has occurred to account for the increased presence of fibers distally. Given that you are suggesting that far more substantial regeneration can occur, that entire aligned bundles of axons rather than scattered meandering fibers will emerge and, in addition, that they will continue to elongate well beyond the lesion even at long chronic time points after injury, one should base such hope building statements on experimental data rather than fantasy. There is not one shred of experimental evidence from any lab ever for the exuberant regeneration that you are predicting. It would be wonderful if chronically injured axons could regenerate long distances but this has yet to be demonstrated. That is precisely why we need increased resources from SCI funding agencies and increased interest in chronic injury models from SCI scientists in order to tackle this critical problem. By the way, if one reads the pTEN literature carefully, it is clear that these truly regenerating axons navigate across the lesion upon the surfaces of strands of astrocytes that form continuous bridges across the lesion. Whether such axon growth promoting bridges can be formed at long chronic time points by the stem cells that you are employing in a species that develops a more cavitated lesion (like those which occurs in humans) is unknown because the appropriate pre-clinical experiments have not been done. In the end, of course, if many of your patients really do get better then who gives a damn what the mechanism of recovery is.

  7. #907
    Teach them ! professor Wise
    keep (rolling) Walking

    Please join me and donate a dollar a day at http://justadollarplease.org and copy and paste this message to the bottom of your signature

  8. #908
    Quote Originally Posted by rjg View Post
    I like how Dr. Silver portrays Dr. Young as a Forrest Gump-type character, just breezing along in life and lucking his way into assorted remarkable situations. He's gonna flip the day that Wise gets invited to the White House to be crowned man of the century for his work in curing sci - then drinks 15 Dr. Peppers and shows the president his butt.

    Speaking of 1994 films, I can't shake the vision of Dr. Silver as "the gimp" in Pulp Fiction, watching life pass him by through woebegone eyes from his cage in Zed's (Acorda's) basement.
    I disagree with your charaterisations and I'm certain Jerry Silver's scientific peers don't regard him as a gimp.

    Let's hope Wise does cure sci, noone wants that more than me, however Alastair Sim, to name just one scientist, is in a video somewhere explaining that stem cells are highly unlikely to be a cure for sci. Stem cells are like popular media buzz words and we all buy into the fact that they will cure us with their magic powers.

    Perhaps it's more important to study what prevents the axons from crossing the injury site and make the environment less toxic or unfriendly.

  9. #909
    Quote Originally Posted by Christopher Paddon View Post
    I disagree with your charaterisations and I'm certain Jerry Silver's scientific peers don't regard him as a gimp.

    Let's hope Wise does cure sci, noone wants that more than me, however Alastair Sim, to name just one scientist, is in a video somewhere explaining that stem cells are highly unlikely to be a cure for sci. Stem cells are like popular media buzz words and we all buy into the fact that they will cure us with their magic powers.

    Perhaps it's more important to study what prevents the axons from crossing the injury site and make the environment less toxic or unfriendly.
    Who are you and why should I care about your opinion?

  10. #910
    You people who are on the Jerry Silver bandwagon amaze me. He's done nothing of note for the sci community. And he's in his 60s, so it's not like he's got a bright future ahead of him. Wise has formed a trial network, created this website, invented methylprednisolone, and palled around with Chris Reeve. And in a year or so, he will have told us whether or not cord blood cells and lithium help treat chronic sci - no one has done anything like that. Jerry Silver will still be awaiting Acorda's permission to test ch'ase in a year(spoiler alert: they'll say no). Is favoring Silver a cripple hipster thing? Is it so cool to doubt a cure that you'll tout the merits of a guy who's done nothing over those of a guy who's doing something? Is it self loathing? Please, help me understand.
    Last edited by rjg; 06-23-2012 at 09:39 PM.

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