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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #301
    Quote Originally Posted by crabbyshark View Post
    I'm not discounting what you say here. I'd have to see these examples of legitimate trials to better comment on this. How long ago were the trials done? Were the procedures similar to what they are doing now in China?

    UCBMC alone probably would not very well help chronic SCI walk again. Lithium alone is not going to help chronic SCI walk again. Rehab alone is not going to help chronic SCI walk again. The combination of the three could help chronic SCI walk again. I think this therapy, if shown to work, is in its infancy and is going to evolve and become more effective as scientists figure out what is going on.


    Chicken noodle soup and Vitamin C might effectively remedy a cold. Chicken noodle soup, Vitamin C and zinc might better effectively remedy a cold.

    I don't know what all is inhibiting axonal regeneration across the injury site. I suspect it's a combination of things. Perhaps chondroitinase effectively deals with one of these inhibitors. Perhaps a combination of UCBMC+Li+ch'ase would be more effective than UCBMC+Li alone. This is something I would think would be worth researching.


    Careful now. I did not say that Jerry Silver is a poor scientist. Part of science is remaining open-minded. I think too often scientists get married to a particular worldview. A five-star chef might not be making the best bread he could be making if he wasn't using the best ingredients available to him. The outcomes of Dr. Silver's current therapeutic interventions involving cutting into the spinal cord have been poor.

    Seems like a pretty damn good ingredient. What else could they potently and therapeutically affect? At what stages? Why not explore this further? Why not try stem cells and peptides? I don't get it. I think Jerry Silver is a great scientist. I would like for his outcomes to be great, too.


    I agree with you.
    Medical science is not the same as cooking!

  2. #302
    Jerry,

    It is hard to disprove a theory when it is constantly shifting. The original glial scar theory is that reactive glial cells form a "tight" barrier that walls off the injury site and prevents axon growth across the wall. I disagreed with this theory because we don't see walls of glial cells in contused spinal cords and many axons grow into the contusion site.

    Sometime in the late 1990's, the "glial scar" theory transformed to emphasize inhibitory extracellular proteins, particularly chondroitin-6-sulfate-proteoglycans in 2002 when Bradbury, et al. showed that chondroitinase allowed axons to grow across the injury site and restore function. The "scar" became a chemical barrier, rather than a mechanical barrier.

    The chemical barrier idea was attractive because it provided a therapeutic target. The original mechanical barrier concept led to no practical therapy and still has not. The chemical barrier, particularly CSPG, not only led to chondroitinase but also the search for the CSPG receptor, which you took leadership of. The inhibitory environment story was very popular in the early 2000's.

    However, the chemical barrier theory ran into trouble by the mid-2000's when three findings came out. First, Filbin, et al. found that increasing cAMP allowed axons to grow through inhibitory environments. Second, the Bunge lab showed that combination cAMP and Schwann cells allowed regeneration and functional recovery in rats after contusions. Third, serotonergic axons appeared to grow well in the inhibitory environment.

    These findings weakened the theory because they indicated that certain axons and under some circumstances can grow into and through the glial scar. While the glial scar is not impenetrable to axons, many scientists still believed that the regeneration seen in these studies was not robust and nobody has yet seen regeneration of the most difficult to grow corticospinal tract across glial scars.

    But in 2011, Liu, et al. from the He laboratory showed that many thousands of corticospinal axons will grow across a hemisection of mouse spinal cords when PTEN expression was suppressed in the cortex. This was very robust growth of the most difficult to grow tract in the spinal cord, the growth occurred across a hemisection, which even I admit will produce a "glial scar".

    Finally, Lu, et al. recently showed that axons from new neurons formed by neural stem cells send axons that not only crossed the glial scar in transected spinal cords interfaced with fibrin but the axons grew long distances both rostrally and caudally to make synaptic contact with neurons. While the behavioral recovery was not weight-supported walking, it is still significant.

    So, you ask why the Lu study disproved the glial scar theory. The reason is of course because the study showed that axons grew in large numbers across "glial scars". Why does it matter what the axons are? So what if they are neurons made by neural stem cells and they were implanted in a cocktail of neurotrophins? The glial "scar" simply did not stop their growth.

    In fact, I am hard put to say that the glial scar posed any barrier to the growing axons in the Cell paper. Nor am I impressed by your argument that these are "immature" neurons and that Lu, et al. had placed a cocktail of neurotrophins in the fibrin. In fact, the growth of axons in this situation strongly supports what I call the neurotrophic theory of regeneration, i.e. axons growth occurs when there is neurotrophic support whether or not glial scars are present.

    You mentioned that Lu showed in the recent Neuroscience meeting that there is less axonal growth in chronic spinal cord lesions. Actually, I find it remarkable that axons still regenerated across chronic "established" scar. Yes, of course I am aware of your work transplanting adult DRG neurons into the white matter and showing that the axons stop at lesion sites. I don't deny that CSPG and fibrotic scars can stop axonal growth but it seems that they do not form a "very potent" barrier to axonal growth even in the worse case scenario of a chronically transected rat spinal cord with a fibrin scaffold inserted between stumps.

    It is not just the Lu study. All these studies, one after another, showed that axons can grow into contusion, hemisection, and transection sites. They show that the axons that grow came from not just dorsal root sensory cells, serotonergic cells, noradrenergic cells, but rubospinal and corticospinal tracts. It occurred in both acute and chronic lesions.

    A theory is only as good as its predictions. The glial scar theory predicts that a glial scar stops axonal growth but I have just given examples of where the glial scar clearly did not stop all types of axon growth in all types of models. The glial scar theory predicts that if the scar is removed, we should see regeneration and better function but no study has shown this. In fact, the Sofroniew laboratory showed clearly that selective prevention or removal of glial scars actually made the lesions worse and reduced recovery. Finally, the theory predicts that if the scar is not removed, we should not see regeneration and the above examples show clearly that this is not true.

    Wise.

    Quote Originally Posted by jsilver View Post
    5. This was not just a few axons. Thousands of GFP axons poured across the glial scar (I have no problems calling this a glial scar because I know that there are both fibroblasts and glial cells that have formed a barrier in the two stumps), disproving the glial scar theory. The axons also had no difficulties growing long distances in white matter (myelinated tissues) and thereby disproved the Nogo and myelin-based axonal inhibitor theory.

    How does this disprove the glial scar theory? Again, I reiterate, the glial scar is not an impenetrable barrier but a very potent one. You argue that it is an almost non-existant one. In this paper the authors take extreme measures to overpower the still forming scar with the use of immature neurons which have a robust intrinsic growth potential. In addition you fail to mention in your review of the paper that they also use a cocktail of about a dozen neurotrophins and other growth factors to encourage growth of the axons. At the recent Society for Neuroscience meetings Paul Lu showed some new experiments from the Tuszynski lab using the same strategy in clearly chronically lesioned animals with more established scar. Some fibers can still get across however, the numbers of regenerating fibers is now markedly reduced. If one carefully transplants fully adult sensory neurons rostral to a scar the axons grow beautifully until they reach the scar and then stop abruptly. They cannot get through. I'm sure you know that work from our lab quite well. The questions still remain, have you demonstrated in work from your own lab or can you show from the work of others that at least in vitro that LI or UMBC can overcome inhibitory molecules known to be present in the scar that curtail axonal growth? If there is not even evidence in vitro that this combination is sufficiently potent then maybe we should be more tempered in our hope for robust regeneration over long distances in vivo.
    Last edited by Wise Young; 01-25-2013 at 07:35 PM.

  3. #303
    Quote Originally Posted by Wise Young View Post
    T8burst,

    Does this help?

    Wise.
    It does, thanks. One last question. From your earlier (or later) comments it is clear that this study shows growth through scar tissue. I am interested in the Lu study which transects the cord and places a medium with growth inducers. Do you see this as something that would become a therapy for someone like me, who doesn't have a transected cord? In other words to regrow connections will we need to cut the cord and put this bridge between the section or will simply surrounding the damaged area of the cord with the same cocktail be sufficient to produce grow across a damaged but not transected cord?

    Thanks,
    Tom

  4. #304
    Quote Originally Posted by t8burst View Post
    It does, thanks. One last question. From your earlier (or later) comments it is clear that this study shows growth through scar tissue. I am interested in the Lu study which transects the cord and places a medium with growth inducers. Do you see this as something that would become a therapy for someone like me, who doesn't have a transected cord? In other words to regrow connections will we need to cut the cord and put this bridge between the section or will simply surrounding the damaged area of the cord with the same cocktail be sufficient to produce grow across a damaged but not transected cord?

    Thanks,
    Tom
    I would have a similar question: much of this talk has surrounded the differences between a severely contused cord and a full transection. Is the latter a "harder" model to generate regeneration in? Would it then follow that the neural stem cells with the fibrin gel could perhaps result in even more robust regeneration and return of function in a severe contusion? Or are they simply not comparable models? Thanks!

  5. #305
    Wise,

    pTEN is one of the most powerful oncogenes on the planet and when it is deleted months before a cord lesion in mice, some but far short of all, cortico spinal axons can clearly cross a newly created lesion. This is exciting but to accomplish this was not a minor perturbation, it is rocket fuel for axon elongation. And yet, if the lesion in the mouse is made slightly larger or not in the right strain or not at just the right age or in the rat then even rocket fuel is insufficient to get robust numbers of axons to cross the lesion environment. The lesion environment is a potent barrier to regeneration. Also, filling a developing lesion cavity with a bucket of robustly growing immature neurons and their accompanying immature glial cells plus an entire kitchen full of trophic factors, growth factors and angiogenic factors is also powerful medicine that can help to overcome the constraints imposed by the lesion environment. Again, the lesion environment (which we can call scar, although it is far more complicated than that) has evolved to wall off the entire area of inflammation from healthy brain tissue. It is potent enough to constrain an ocean of angry macrophages and unfortunately in doing so it constrains axonal growth. Show me actual convincing evidence (not speculation or assumptions drawn from other papers) that your Li +UMBC strategy is sufficiently potent to stimulate regeneration clearly through ( not into) a well established glial scar and I will sing your praises.
    Last edited by jsilver; 01-25-2013 at 09:16 PM.

  6. #306
    Quote Originally Posted by jsilver View Post
    Wise,

    pTEN is one of the most powerful oncogenes on the planet and when it is deleted months before a cord lesion in mice, some but far short of all, cortico spinal axons can clearly cross a newly created lesion. This is exciting but to accomplish this was not a minor perturbation, it is rocket fuel for axon elongation. And yet, if the lesion in the mouse is made slightly larger or not in the right strain or not at just the right age or in the rat then even rocket fuel is insufficient to get robust numbers of axons to cross the lesion environment. The lesion environment is a potent barrier to regeneration. Also, filling a developing lesion cavity with a bucket of robustly growing immature neurons and their accompanying immature glial cells plus an entire kitchen full of trophic factors, growth factors and angiogenic factors is also powerful medicine that can help to overcome the constraints imposed by the lesion environment. Again, the lesion environment (which we can call scar, although it is far more complicated than that) has evolved to wall off the entire area of inflammation from healthy brain tissue. It is potent enough to constrain an ocean of angry macrophages and unfortunately in doing so it constrains axonal growth. Show me actual convincing evidence (not speculation or assumptions drawn from other papers) that your Li +UMBC strategy is sufficiently potent to stimulate regeneration clearly through ( not into) a well established glial scar and I will sing your praises.
    Me with Paolo sing backup.

  7. #307
    Quote Originally Posted by jsilver View Post
    At the recent Society for Neuroscience meetings Paul Lu showed some new experiments from the Tuszynski lab using the same strategy in clearly chronically lesioned animals with more established scar. Some fibers can still get across however, the numbers of regenerating fibers is now markedly reduced. If one carefully transplants fully adult sensory neurons rostral to a scar the axons grow beautifully until they reach the scar and then stop abruptly. They cannot get through. The questions still remain, have you demonstrated in work from your own lab or can you show from the work of others that at least in vitro that LI or UMBC can overcome inhibitory molecules known to be present in the scar that curtail axonal growth? If there is not even evidence in vitro that this combination is sufficiently potent then maybe we should be more tempered in our hope for robust regeneration over long distances in vivo.
    Do you think there is any chance we will see a Lu publication about the chronically lesioned animals with more established scar anytime soon?

  8. #308
    Quote Originally Posted by jsilver View Post
    Wise,

    pTEN is one of the most powerful oncogenes on the planet and when it is deleted months before a cord lesion in mice, some but far short of all, cortico spinal axons can clearly cross a newly created lesion. This is exciting but to accomplish this was not a minor perturbation, it is rocket fuel for axon elongation. And yet, if the lesion in the mouse is made slightly larger or not in the right strain or not at just the right age or in the rat then even rocket fuel is insufficient to get robust numbers of axons to cross the lesion environment. The lesion environment is a potent barrier to regeneration. Also, filling a developing lesion cavity with a bucket of robustly growing immature neurons and their accompanying immature glial cells plus an entire kitchen full of trophic factors, growth factors and angiogenic factors is also powerful medicine that can help to overcome the constraints imposed by the lesion environment. Again, the lesion environment (which we can call scar, although it is far more complicated than that) has evolved to wall off the entire area of inflammation from healthy brain tissue. It is potent enough to constrain an ocean of angry macrophages and unfortunately in doing so it constrains axonal growth. Show me actual convincing evidence (not speculation or assumptions drawn from other papers) that your Li +UMBC strategy is sufficiently potent to stimulate regeneration clearly through ( not into) a well established glial scar and I will sing your praises.
    Is it just me, or are you guys still arguing over semantics. If I understand correctly, wise agrees glial scars form a barrier, however, he claims that it is not, and you *seem* to agree, an impenetrable barrier.

    To him, that disproves the glial scar theory. To you, it does not. All that is really separating your view on glial scar theory is perspective.

    IMO it seems like Wise is saying that IF 'rocket fuel' neutrophons (sp?) can help axons grow through the lesion, then all we need is the correct rocket fuel.

    It seems to me Jerry that you are saying, regardless of which rocket fuel you use, the scar needs some sort of bridge for axons to cross.

    It is impossible for you both to be right, but it seems hard to believe either of you have enough evidence to have proven yourselves right. This might be the hill to die on for regenerating the cord, but you are both working towards the same goal. Can we get some fucking collaboration here?

    Obviously UBCMN cells + lithium are not going to cure spinal cord injuries. But the trial is into phase III. Whether the data is positive or negative, WHO CARES? It just helps us ALL figure out what might work, and what won't. The network to test human alone is a massive step forward, and hopefully the therapies in the future will build on each other. I will be the first one to cheer if and when there is a bridge built to overcome the scar which can be tested in humans. But until that happens, I find the discourse which although enlightening is not very open minded.

    Die on the hill of truth. The evidence will bare out the truth.

    I want to thank both Wise and Jerry for all their hard work and especially their passion for the truth. But this is far more personal than is necessary.

  9. #309

    Just repeating this:

    "I want to thank both Wise and Jerry for all their hard work and especially their passion for the truth. But this is far more personal than is necessary."

    "It's not the despair, I can handle the despair! It's the hope!" - John Cleese

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  10. #310
    Senior Member lunasicc42's Avatar
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    Quote Originally Posted by topperf View Post
    "I want to thank both Wise and Jerry for all their hard work and especially their passion for the truth. But this is far more personal than is necessary."

    Like...
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