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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #331
    It doesn't seem as if you are both on the same page to me....

    I thought we were headed in the right direction but, alas, we're as far apart as ever. The scar (or let's call it the lesion environment) is a potent barrier that needs strong measures to remove or over power it. It is absolutely not growing weaker and weaker just because Wise says so. Crabby person and Wise mention the Tuszynski paper as an example of axon regeneration past an established glial scar. Here's what they had to do to get a very small number of sensory axons past an established scar without physically removing it. (1) They fill the lesion with genetically altered neurotrophin expressing marrow stromal cells, then they (2) express the same powerful neurotrophin just beyond the scar using a virus and finally (3) they have to condition the sensory neurons with a prior crush lesion. At 6 weeks following injury using this approach they get several dozens of axons across the lesion and at 15 months post injury they get just a handful of sensory axons across a well established scar. Once past the scar the axons stop abruptly in the trophic oasis in the white matter on the other side of the lesion. No synapses, no functional recovery. I encourage you all to carefully read this paper ( it's downloadable from the Crabbyfish post above) and learn what it takes to get the smallest number of axons past an established scar. Does that sound weak to you? Just yesterday I saw a guardrail on the side of the road that had been smashed through by a fast moving vehicle. It was good example of the point I am trying to make. No barrier is absolute but would you suggest that steel guardrails are not potent barriers?

  2. #332
    Quote Originally Posted by jsilver View Post
    Here's what they had to do to get a very small number of sensory axons past an established scar without physically removing it.
    (1) They fill the lesion with genetically altered neurotrophin expressing marrow stromal cells, then they
    (2) express the same powerful neurotrophin just beyond the scar using a virus and finally
    (3) they have to condition the sensory neurons with a prior crush lesion.

    At 6 weeks following injury using this approach they get several dozens of axons across the lesion and at 15 months post injury they get just a handful of sensory axons across a well established scar.

    Once past the scar the axons stop abruptly in the trophic oasis in the white matter on the other side of the lesion. No synapses, no functional recovery.
    One would assume then that these wound preparations would continue to be studied and become more sophisticated and successful over time for the cellular therapies to work in this inhibitory environment?

  3. #333
    Quote Originally Posted by jsilver View Post
    It doesn't seem as if you are both on the same page to me....

    I thought we were headed in the right direction but, alas, we're as far apart as ever. The scar (or let's call it the lesion environment) is a potent barrier that needs strong measures to remove or over power it. It is absolutely not growing weaker and weaker just because Wise says so. Crabby person and Wise mention the Tuszynski paper as an example of axon regeneration past an established glial scar. Here's what they had to do to get a very small number of sensory axons past an established scar without physically removing it. (1) They fill the lesion with genetically altered neurotrophin expressing marrow stromal cells, then they (2) express the same powerful neurotrophin just beyond the scar using a virus and finally (3) they have to condition the sensory neurons with a prior crush lesion. At 6 weeks following injury using this approach they get several dozens of axons across the lesion and at 15 months post injury they get just a handful of sensory axons across a well established scar. Once past the scar the axons stop abruptly in the trophic oasis in the white matter on the other side of the lesion. No synapses, no functional recovery. I encourage you all to carefully read this paper ( it's downloadable from the Crabbyfish post above) and learn what it takes to get the smallest number of axons past an established scar. Does that sound weak to you? Just yesterday I saw a guardrail on the side of the road that had been smashed through by a fast moving vehicle. It was good example of the point I am trying to make. No barrier is absolute but would you suggest that steel guardrails are not potent barriers?
    Doesn't that imply that while the scar is a barrier there are other factors at work which are inhibiting axonal growth? I mean, a (albiet limited) number of axons are growing through the scar, but once on the other side they stop. It seems to me the logical conclusion is that there is a good possibility there are other inhibitory factors at play which have not yet been identified. Unless someone has a theory as to why it grows through the 'scar/lesion' and then stops at the other side. It doesn't sound to me though that the glial scar theory does an a particularly good job of explaining this phenomenon.

    Am I wrong?

  4. #334
    The likely explanation for the halting growth of axons once beyond the scar using this method is that they become "addicted" so to speak within the territory of trophic factor production. The Tuszynski lab has reported this unfortunate side effect of using neurotrophic strategies for luring axons across barriers for a long time. In another paper they borrowed a technique from our lab and made the dorsal column lesion much closer to the target nuclei of the sensory axons. This is called nucleus gracilis. Now the neurotrophin is expressed at relatively lower levels within the lesion via transplanted stromal cells as before but beyond the lesion the highest neurotrophn expression lands right within the target of the axons. In this case the axons now do cross the lesion and are lured a few millimeters rostrally into the nucleus where they do form synapses with their proper target neurons. However, again, no functional recovery. Another problem has reared it's ugly head in this paper and that is the lack of myelination of the regenerated axons. In our model we use peripheral nerve bridges who's Schwann cells can remyelinate the axons that re-grow within it. Also, in our model many of the descending systems of axons that control urination are normally unmyelinated.

  5. #335
    Quote Originally Posted by jsilver View Post
    The likely explanation for the halting growth of axons once beyond the scar using this method is that they become "addicted" so to speak within the territory of trophic factor production. The Tuszynski lab has reported this unfortunate side effect of using neurotrophic strategies for luring axons across barriers for a long time. In another paper they borrowed a technique from our lab and made the dorsal column lesion much closer to the target nuclei of the sensory axons. This is called nucleus gracilis. Now the neurotrophin is expressed at relatively lower levels within the lesion via transplanted stromal cells as before but beyond the lesion the highest neurotrophn expression lands right within the target of the axons. In this case the axons now do cross the lesion and are lured a few millimeters rostrally into the nucleus where they do form synapses with their proper target neurons. However, again, no functional recovery. Another problem has reared it's ugly head in this paper and that is the lack of myelination of the regenerated axons. In our model we use peripheral nerve bridges who's Schwann cells can remyelinate the axons that re-grow within it. Also, in our model many of the descending systems of axons that control urination are normally unmyelinated.
    Thank you for further clarification Jerry.

    This may be an obvious and stupid question, (esp since the axons are not reaching their targets and are sitting in the neurotrophin oasis) but have any of these animals been given 4-apa to remyelinate those axons?

    Also, for further clarification, in your model where voluntary mictrition has been reestablished, are you saying those axons which have made this possible are not myelinated?

    I also am starting to see where you are coming from in your criticism of Wise. However, I still fail to see how the criticism is necessarily relevant, or how it explains some of the examples of functional recovery Dr. Young has given. I say 'necessarily relevant' because I think if the phase III trials go ahead we will get useful evidence either one way or another. If the evidence is not positive for functional recovery there is a further data point in 'your favour.' However, if there is functional recovery attributed to the therapy, there is a further data point indicating further follow up is necessary. Either way, my understanding is that is how science works. It seems like it is still a relevant 'live' issue in 'regeneration.'

    I am with you in that I would like to see your model tested as quickly as possible in human beings but as I understand it your model is not that close to being ready for this type of testing. Especially with Dr. Young's opinion of cutting out scar tissue from the cord. However, it seems to me that the better your evidence that cutting our the scar and bridging it works, the more likely human testing will happen, whether Wise supports it or not.

  6. #336
    Quote Originally Posted by GRAMMY View Post
    I don't know anything about the relevance of clever titles, but here's the factual information about the research on restoration of diaphragm for breathing for those not familiar with the work being done at Case Western Reserve University by Dr. Silver's Lab. It was published in Nature and presented at W2W 2011. It's been discussed here already many times for those following SCI research.
    GRAMMY,

    I was able to find the full article from the 2011 abstract you shared. Thank you. In the article, there was nothing about a chronic contusive injury, animals breathing again after 1.5 years, or cutting into the spinal cord resulting in functional improvement. I'm looking for stuff released in peer reviewed journals about that (especially the bit about cutting into the spinal cord). If you have something, please send it my way. The videos are ok but if Jerry Silver has taught us anything, it's that we should be extremely skeptical of anything said in a video.

  7. #337
    Quote Originally Posted by jsilver View Post
    It is absolutely not growing weaker and weaker just because Wise says so.
    What if another researcher said it was so?
    Quote Originally Posted by jsilver View Post
    Would it not be possible that a 10 year post chronic spinal cord may have made changes over time to breakdown a portion of the gilia scar barrier that was originally developed?

    Yes, indeed, the scar does change over time. It becomes thinner and its associated inhibitory proteoglycan extracellular matrices become more restricted to the cell surfaces. In some very severe contusive injuries, Schwann cells eventually invade through the dorsal portion of the scar and enter the core of the lesion. It is unknown how they do this.
    Quote Originally Posted by jsilver View Post
    Crabby person and Wise mention the Tuszynski paper as an example of axon regeneration past an established glial scar. Here's what they had to do to get a very small number of sensory axons past an established scar without physically removing it. (1) They fill the lesion with genetically altered neurotrophin expressing marrow stromal cells, then they (2) express the same powerful neurotrophin just beyond the scar using a virus and finally (3) they have to condition the sensory neurons with a prior crush lesion. At 6 weeks following injury using this approach they get several dozens of axons across the lesion and at 15 months post injury they get just a handful of sensory axons across a well established scar. Once past the scar the axons stop abruptly in the trophic oasis in the white matter on the other side of the lesion.
    Notably, axons cross at several dorsoventral levels of the host/graft interface, not simply at the most dorsal or ventral aspects of grafts where spared axons might be mistaken for regenerating axons. (E) Several varicose axons continue to extend 500 mm beyond lesion site in host white matter. (F and G) 2 mm and 2.5 mm beyond the lesion, respectively, bridging axons remain visible in host white matter.
    Did they stop growing or was that simply where the growing axons were at when they took the pictures?

    Quote Originally Posted by jsilver View Post
    No synapses, no functional recovery.
    From another study I've attached:
    Combination of ChABC treatment with GFs and NPC transplant improves locomotor function without exacerbating neuropathic pain after chronic SCI.
    Quote Originally Posted by jsilver View Post
    I encourage you all to carefully read this paper ( it's downloadable from the Crabbyfish post above) and learn what it takes to get the smallest number of axons past an established scar. Does that sound weak to you? Just yesterday I saw a guardrail on the side of the road that had been smashed through by a fast moving vehicle. It was good example of the point I am trying to make. No barrier is absolute but would you suggest that steel guardrails are not potent barriers?
    Over time, steel undergoes oxidation and turns into rust.

    There are two papers now. Here is a third.

    Attached: "Synergistic Effects of Transplanted Adult Neural Stem/Progenitor Cells, Chondroitinase, and Growth Factors Promote Functional Repair and Plasticity of the Chronically Injured Spinal Cord"
    Last edited by crabbyshark; 02-01-2013 at 05:16 PM. Reason: grammar error

  8. #338
    Questions for Jerry or Wise:

    1) What is the risk of 1000s of regeneratied CST axons that are not making synapses and/or are unmyelinated?

    2) In humans or animal models, how can you tell what type of axons have regenerated without performing a histology?

    3) What mechanism guides long-distance regeneration in the right direction? ie why doesnt the axon say "hey, I dont fancy the lesion site much - Im going left instead"?

    4) If the CST is responsible for more advanced/finer motor control - why would you choose pattern generators as training modailities? Wouldnt you want brain engagement for training finer motor control?

    5) In the case of target neurons - what evidence do have that they are indeed ready? I overheard some researchers at W2W speculating that these target neurons may have created associations elsewhere. Also, do we not have perineuronal nets to contend with too?

    Cheers

  9. #339
    [quote=cripwalk;1650535]thank you for further clarification jerry.

    This may be an obvious and stupid question, (esp since the axons are not reaching their targets and are sitting in the neurotrophin oasis) but have any of these animals been given 4-apa to remyelinate those axons?


    ....If you are referring to 4-ap (acorda fampridine) this drug allows action potentials to cross small gaps in demyelinated axons. It is not known but an interesting question whether chronic 4-ap treatment might somehow stimulate oligodendrocyte progenitor cells indirectly to remyelinate axons that are now conducting due to the drug....


    Also, for further clarification, in your model where voluntary mictrition has been reestablished, are you saying those axons which have made this possible are not myelinated?


    ....We do not yet know for certain if the improvements in micturition that we see in our animals are due to voluntary control per se or enhancements in the mechanisms that regulate urination that are related to more reflexive mechanisms. Our evidence is that brainstem centers that are involved with both voluntary control and reflexive mechanisms are regenerating. Whatever the underlying mechanisms might be it is likely that the descending axons that regenerate in our model are not myelinated. However, we still have to examine the regenerating fibers in our model to see if they are or they are not re-myleinated. The sensory fibers that regenerate in the Tuszynski paper were not myelinated and i have a suspicion because of the Tuszynski observations that ours are not myelinated either......

    I also am starting to see where you are coming from in your criticism of wise. However, i still fail to see how the criticism is necessarily relevant, or how it explains some of the examples of functional recovery dr. Young has given. I say 'necessarily relevant' because i think if the phase iii trials go ahead we will get useful evidence either one way or another. If the evidence is not positive for functional recovery there is a further data point in 'your favour.' however, if there is functional recovery attributed to the therapy, there is a further data point indicating further follow up is necessary. Either way, my understanding is that is how science works. It seems like it is still a relevant 'live' issue in 'regeneration.'

    ...I remain skeptical that recovery in wise's patients, if it does occur, would be due to frank regeneration. Recovery could be due to a variety of factors that influence plasticity...

    I am with you in that i would like to see your model tested as quickly as possible in human beings but as i understand it your model is not that close to being ready for this type of testing. Especially with dr. Young's opinion of cutting out scar tissue from the cord.

    ...We don't cut it out we gently dissect it away...

    However, it seems to me that the better your evidence that cutting our the scar and bridging it works, the more likely human testing will happen, whether wise supports it or not

    see my inserts ..... within the quote
    Last edited by jsilver; 01-29-2013 at 09:28 PM.

  10. #340
    Questions for Jerry or Wise:

    1) What is the risk of 1000s of regeneratied CST axons that are not making synapses and/or are unmyelinated?

    SO FAR EVEN WITH PTEN/SOCS3 DELETED IN CST NEURONS AND HUNDREDS (NOT THOUSANDS) REGENERATING THERE IS NO FUNCTIONAL RECOVERY. IN OUR EXPERIENCE, AXONS THAT ARE INDUCED TO REGENERATE AND SOMEHOW FIND A SYNAPTIC PARTNER, SEEM TO PROMOTE USEFUL RATHER THAN ABERRANT FUNCTION


    2) In humans or animal models, how can you tell what type of axons have regenerated without performing a histology? YOU CAN'T

    3) What mechanism guides long-distance regeneration in the right direction? ie why doesnt the axon say "hey, I dont fancy the lesion site much - Im going left instead"? SOMEHOW THE SPINAL CORD AND BRAIN "FIGURE THINGS OUT" EVEN WHEN THE CONNECTIONS ARE NOT IN THERE PROPER PLACES

    4) If the CST is responsible for more advanced/finer motor control - why would you choose pattern generators as training modailities? Wouldnt you want brain engagement for training finer motor control? I WOULD THINK SO. WITHOUT THE BRAIN INVOLVED WITH CPG ONLY MEDIATED STEPPING, ANIMALS HAVE A DIFFICULT TIME FREEING THEMSELVES FROM THEIR HARNESSES TO SUPPORTIVE DEVICES. THEY HAVE NO BALANCE.

    5) In the case of target neurons - what evidence do have that they are indeed ready? WE ARE SEEING PRODUCTIVE RETURN OF URINARY FUNCTION AT LEAST WHEN REGENERATION IS STIMULATED CHRONICALLY. I overheard some researchers at W2W speculating that these target neurons may have created associations elsewhere. Also, do we not have perineuronal nets to contend with too? WE DO AND CH'ASE HELPS

    Cheers

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