Announcement

Collapse
No announcement yet.

Jerry Silver and Other Discussion from ChinaSCINet Update

Collapse
X
 
  • Filter
  • Time
  • Show
Clear All
new posts

    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!

    Comment


      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.

      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; 25 Jan 2013, 7:35 PM.

      Comment


        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

        Comment


          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!

          Comment


            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; 25 Jan 2013, 9:16 PM.

            Comment


              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.

              Comment


                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?
                http://spinalcordresearchandadvocacy.wordpress.com/

                Comment


                  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.

                  Comment


                    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

                    Don't ask what clinical trials can do for you, ask what you can do for clinical trials. (Ox)
                    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.

                    Comment


                      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...
                      "That's not smog! It's SMUG!! " - randy marsh, southpark

                      "what???? , you don't 'all' wear a poop sac?.... DAMNIT BONNIE, YOU LIED TO ME ABOUT THE POOP SAC!!!! "


                      2010 SCINet Clinical Trial Support Squad Member
                      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

                      Comment


                        Originally posted by jsilver View Post
                        Wise,
                        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.
                        There in lies the problem. Wise cannot because his subjects are humans. He cannot put humans to death and/or cut out sections of their spinal cords to view under a microscope. Nor can he insert green florescent dye into their spinal cords to see where the axons and neurons hit the glial scar wall or veiw where and how far they pass through. So, it seems that Wise, as promised, will have to wait 12 months or so for all the patient followup data before he can begin to have a cursory amount of convincing evidence. His objective was to test UCBSC cells and lithium (both proven safe in humans over the last 10+ years) in chronic SCIs and wait to see first if it was safe and produced NO HARM. If an Asia A patient happened to also show some improvement in sensory or motor, then that would be a BONUS if also first determined safe.

                        Thank you both for your herculean efforts to try to solve the SCI challenge. It is quite apparent that SCIs are still mostly paralyzed, even 50 years post injury. Something is obviously in place that prevents spinal cord self repair/regeneration.

                        I firmly believe that it will take a few more years and more collaborative efforts in both rodent spinal cord research and human trials to find the best cure available. I see it like the letter "V" where Jerry is on the right side of the top of the V and Wise on the top of the left side. Both approaches are slowly coming together towards the bottom of the V and the SCIs persons will be the eventual winner.

                        Comment


                          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
                          Tom,

                          Let me re-iterate two things that you seem to have missed in the paper and in my comments.

                          First, the axons that regenerated in the Lu study were not the rats' own axons. They were the axons of neurons produced by or differentiated from the transplanted neural stem cells! We don't know whether any of the rats' own axons are crossing the injury site. If not, the rats' brains must send axons to connect with the transplanted cells and those cells must then talk to neurons below the injury site in order to walk. On the other side, it is not clear whether any of the rats ascending sensory axons are crossing the injury site. If the rats' own sensory axons are not crossing the injury site and growing all the way to the brain, the rats have no sensation. By the way, rats with transected spinal cords can recover up to a BBB score of 4 but a score of 6 or 7 would be very rare.

                          Second, while they showed an improvement of BBB scores from 2 to 6-7, this is from a minor twitches of the legs to non-functional movements of the legs. It is possible that some of the rats' axons grew into the injury site and connected with the transplanted neurons. Lu, et al. showed activation of neurophysiological responses in the lower spinal cord in response to electrical stimulation of the spinal cord. This could happen if some transplanted sent axons both rostrally (towards the head) and caudally (towards the tail), some of the rats' axons grew into the injury site and connected with the transplanted neurons. They also showed responses in the upper spinal cord C7 when they stimulated the lower spinal cord at T6 (figure 5). The lesion site was at T3. These responses declined when they applied kynurenic acid to block excitatory synapses. This suggests that ascending axons from the rat have entered the injury site and connected with neurons that have sent ascending axons to the C7.

                          The study proved that transplanted neurons can send axons that grew across glial scars and reconnected with the rats neurons above and below the injury site. It suggests that some axons from the rat entered into the injury site and connected with the transplanted neurons that have sent axons into the rostral and caudal spinal cord. I don't think that this particular injury and treatment paradigm should be done in humans. On the other hand, we are trying to do something that this to replace neurons in the lumbosacral spinal cord. We want to transplant neural stem cells into the contused lumbosacral spinal cords, get the neural stem cells to produce neurons that replace damaged motoneurons, encourage these motoneurons to send axons out the ventral roots to reinnervate muscle. Then we want grow axons from the CPG and various descending tracts to connect with these new neurons.

                          Wise.

                          Comment


                            Cripwalk

                            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.

                            I like you er thinking and straight Talking . I say enough about scar tissue Why not put the lot in the one syringe then both will be right
                            AS I SIT HERE IN MY CHAIR . I LOOK OUT UPON THE GROUND .I WONDER WILL I EVER GET UP AND WALK A ROUND ??


                            http://justadollarplease.org

                            Comment


                              Originally posted by Wise Young View Post
                              1. Deng XY, Zhou RP, Lu KW and Jin DD (2010). [Lithium chloride combined with human umbilical cord blood mesenchymal stem cell transplantation for treatment of spinal cord injury in rats]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 30: 2436-9. Department of Spinal Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China. dengxuyong@tom.com. OBJECTIVE: To observe the effects of lithium chloride combined with human umbilical cord blood mesenchymal stem cell (hUCB-SCs) transplantation in the treatment of spinal cord injury in rats. METHODS: Eighty female SD rats with complete T9 spinal cord transaction were randomized into 4 groups (n=20), namely the control group (group A), lithium chloride group (group B), hUCB-SCs group (group C) and hUCB-SCs(+) lithium chloride group (group D). On days 1 and 3 and the last days of the following weeks postoperatively, the motor function of the hindlimb of the rats were evaluated according to the BBB scores. At 8 weeks, all the rats were sacrificed and the spinal cords were taken for morphological observation. The spinal cord tissues at the injury site were observed with Brdu nuclear labeling to identify the survival and migration of the transplanted SCs. The regeneration and distribution of the spinal nerve fibers were observed with fluorescent-gold (FG) spinal cord retrograde tracing. RESULTS: Brdu labeling showed that the transplanted hUCB-SCs survived and migrated in the spinal cord 8 weeks postoperatively in groups C and D. FG retrograde tracing identified a small amount of pyramidal cells that migrated across the injury site in groups C and D. The BBB scores of the hindlimb motor function 8 weeks postoperatively were 4.11-/+0.14, 4.50-/+0.15, 8.31-/+0.11 and 11.15-/+0.18 in groups A, B, C and D, respectively. CONCLUSION: Lithium chloride can promote the survival and differentiation of hUCB-SCs into neural cells at the injury site. Lithium chloride combined with hUCB-SCs transplantation may accelerate functional recovery of the hindlimbs in rats with complete transection of the spinal cord.
                              Full-text: http://www.j-smu.com/pdf2/201011/2010112436.pdf
                              ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

                              Comment


                                Originally posted by ay2012 View Post
                                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!
                                ay2012,

                                Please see my answer to T8burst. In my opinion, there is no reason why the lesion site should be removed. There are many ways to modify the lesion site so that it is more hospitable to axons and to produce neurotrophins at the lesion site. In fact, umbilical cord blood and lithium seem to do this and we are testing this in clinical trial.

                                Retarding the difference between transection and contusion, I personally think that contusion model is much more difficult to regenerate than a transection. The Liu and Lu studies were done respectively with hemisections and transection models. Liu is trying to get regeneration of contused rat spinal cords in the PTEN deleted mouse but it is difficult.

                                Wise.

                                Comment

                                Working...
                                X