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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #291
    Crabby - a few questions you need to ask yourself:

    - Why have the numerous human examples (both legitimate trials as well as pseudo experimental) of intraspinal transplants of various types of stem cells (containing MSCs and/or BMSCs) shown little or no benefit in the chronic setting?

    - Why has Dr Wise Young continued to postulate that he would like to consider adding Chondroitinase and/or Nogo to the UCBC+Lithium combination? For fun? Or is it that he believes (or believed) that the glial scar would still be a hurdle to overcome?

    - Why are the likes of Os Stewart/Zhigang He (working with PTEN/mTor) looking to collaborate with Dr Silver in order to regenerate these "proliferating" CST axons through the glial scar in a chronic setting? Why approach such an average scientist? Why don't they just skip the collaboration and stick some UCBCs into the rodents and witness that bridge in action? Actually, why bother creating a viral vector to knock out PTEN/SOCS3 when they can just grab some lithium off the shelf to activate mTOR? Maybe they are poor scientists too?

    The fact is (whether it matters to you or not), to a scientist, there is an element of speculation. Dont get me wrong, I'm looking forward to seeing the data. If it works, then great for us but don't blame scientists for doing what scientists do - be objective. If you do, we as advocates will have less of them working in our field, and less of them being so patient with us as layman.
    Last edited by Fly_Pelican_Fly; 01-25-2013 at 10:28 AM.

  2. #292
    Thanks for the explanation Wise. So I read this paper you cited below (or tried to), and to me it read as they took rats who had a transected spinal cord (which I think means it has been completely cut), put some stuff made of "fibrin matrices" that had a bunch of drugs and stem cells embedded in it, stuck that between the two halves of the severed spinal cord and nerves not only grew across it but quite a long way past it.

    So assuming I read it correctly (I may not have), intuitively you would want the ends of the spinal cord you are joining to the fibrin matrices to be free of scar tissue because that would make it easier to join to the bridging material (much like dead tissue is debrided from pressure sores to help them heal). If I interpret what you are saying correctly is that is not correct that having the scar tissue doesn't prevent the growth and in fact removing it for whatever reason is actually detrimental.

    Quote Originally Posted by Wise Young View Post
    T8burst,
    [*] Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M and Tuszynski MH (2012). Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150: 1264-73. Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Neural stem cells (NSCs) expressing GFP were embedded into fibrin matrices containing growth factor cocktails and grafted to sites of severe spinal cord injury. Grafted cells differentiated into multiple cellular phenotypes, including neurons, which extended large numbers of axons over remarkable distances. Extending axons formed abundant synapses with host cells. Axonal growth was partially dependent on mammalian target of rapamycin (mTOR), but not Nogo signaling. Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection, resulting in functional recovery. Two human stem cell lines (566RSC and HUES7) embedded in growth-factor-containing fibrin exhibited similar growth, and 566RSC cells supported functional recovery. Thus, properties intrinsic to early-stage neurons can overcome the inhibitory milieu of the injured adult spinal cord to mount remarkable axonal growth, resulting in formation of new relay circuits that significantly improve function. These therapeutic properties extend across stem cell sources and species.
    [/list]

  3. #293
    Senior Member mcferguson's Avatar
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    Quote Originally Posted by Wise Young View Post
    T8burst,

    Does this help?

    Wise.
    T5/6, ASIA A, injured 30 Nov 08
    Future SCI Alumnus.
    I don't want to dance in the rain, I want to soar above the storm.

  4. #294
    Quote Originally Posted by t8burst View Post
    Thanks for the explanation Wise. So I read this paper you cited below (or tried to), and to me it read as they took rats who had a transected spinal cord (which I think means it has been completely cut), put some stuff made of "fibrin matrices" that had a bunch of drugs and stem cells embedded in it, stuck that between the two halves of the severed spinal cord and nerves not only grew across it but quite a long way past it.

    So assuming I read it correctly (I may not have), intuitively you would want the ends of the spinal cord you are joining to the fibrin matrices to be free of scar tissue because that would make it easier to join to the bridging material (much like dead tissue is debrided from pressure sores to help them heal). If I interpret what you are saying correctly is that is not correct that having the scar tissue doesn't prevent the growth and in fact removing it for whatever reason is actually detrimental.
    T8burst,

    I am glad that you read the paper. By the way, I apologize to Paolo for my professorial glare when I post papers and he then asks questions that suggest that he has not read the paper. I forget sometimes that he is not my student and has had no training in reading scientific papers.

    So, let me go through the Lu, et al. paper, as I would go review the paper with my students.

    1. You should first note the journal. Cell is one of the most highly cited and rigorously reviewed journals in the the field. So, this is a prestigious journal that only publishes what most scientists would consider superb papers. I agree with their choice to publish this study.

    2. The introduction of the paper starts by mentioning the growth inhibition theories, i.e. the myelin-associated protein and inhibitory extracellular matrix (i.e. the chondroitin-6-sulfate proteoglycans or CSPG) theories. It also talks about the lack of "positive environmental stimuli such as growth factors", which they were too modest to announce as a theory, but what I brazenly call the neurotrophic theory of regeneration (for them). They mention the neuron-intrinsic mechanisms that contribute to axon growth failure (e.g. the cAMP and the PTEN/mTOR theories).

    3. To assess which of these theories are correct or wrong, they developed this experiment where they transected the spinal cord and then bridged the transection site with neural stem cells placed in a fibrin matrix to hold the cells and to release neurotrophins. The transplanted cells were neural stem cells that were genetically modified to express green fluorescent protein (GFP), so that they and their axons can be readily seen without staining or labelling.

    4. The transplanted neural stem cells formed neurons that sent axons that grew straight through the glial scar (which forms in the two spinal cord stumps that interface with the fibin matrix), grew long distances in the proximal and distal spinal cords, reconnected with neurons, and improved functional recovery.

    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.

    6. The regeneration was blocked by rapamycin, a drug that blocks mTOR. In fact, mTOR stands for mammalian target of rapamycin. PTEN deletion stimulated Akt and Akt stimulates mTOR. This is the mechanism by which PTEN works to stimulate axonal growth although figure 4 suggests that blocking mTOR only reduces (i.e. does not stop) all the axon growth. So, this experiments suggests strongly that mTOR plays a partial role in the axonal growth. Of course, they placed neurotrophins in the fibrin matrix.

    7. The treated rats significantly improved their locomotor function, as measured by BBB scores. In figure 5, note that the BBB scores are not particularly impressive, i.e. only went to 6-7 (which are non-walking scores) but nevertheless are significantly different from controls non-treated transected rats (scores of 1-2). They did neurophysiology (i.e. stimulate the spinal cord at one side of the transition and recorded responses in the other side) and showed that the transplanted rats had responses that crossed over to the other side while the controls did not. This strongly argues that axons not only crossed over but made synaptic contacts, accounting for the neurophysiological responses and the BBB scores.

    8. Finally, they re-transected the injury site and showed that all these neurophysiological and behavioral effects of the transplantation went away, indicating that the regenerated fibers were responsible for the recovery. Figure 6 shows the impressive number of axons that grew from the GFP (green fluorescent protein) expressing cells transplanted into the injury site. They stained the transplantation site with NeuN and found many mature neurons produced by the transplanted neural stem cells. Incidentally, they tried two neural stem cell lines, including one line that was neurally induced form a human embryonic stem cell line.

    9. Please remember that they are not looking at the host rat's axons but the GFP axons of the transplanted neural stem cells. In fact, this is a real problem for the authors to explain... why are the rats walking? Host axons from the rat must be going into the injury site and making synapses with the transplanted neurons and thereby activate them to produce movement.

    10. Lu, et al. concluded that properties intrinsic to early stage neurons are sufficient to overcome barriers to growth in the adult CNS. They also pointed out that transplants were effective even when delayed for a week after injury and still restored significant function. Finally, they pointed out that the human embryonic stem cell line that they employed is being tested in a human clinical trial of amyotrophic lateral sclerosis.

    Does this help?

    Wise.

  5. #295
    Quote Originally Posted by mcferguson View Post
    Thanks. Sorry, I accidentally moved my post to T8burst and therefore your post seems as if it occurred before the one that you were referring to. Wise.

  6. #296
    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.

  7. #297
    Dr. Tuszynski discusses the findings reported in the journal "Cell" that showed extensive growth of axons in spinal cord injury using grafts of early stage neural stem cells at the Working 2 Walk 2012 Science and Advocacy Symposium.



    Video of the Question & Answer Session following presentations by Drs. Hans Keirstead and Mark Tuszynski with Keirstead and Dr. Lu.


  8. #298
    Quote Originally Posted by Wise Young View Post
    T8burst,


    So, let me go through the Lu, et al. paper, as I would go review the paper with my students.

    4. The transplanted neural stem cells formed neurons that sent axons that grew straight through the glial scar (which forms in the two spinal cord stumps that interface with the fibin matrix), grew long distances in the proximal and distal spinal cords, reconnected with neurons, and improved functional recovery.

    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.


    Does this help?

    Wise.
    Dr. Young,

    According to this study (not sure how reputable it is), glial scar is not really formed until around 4 weeks post injury in both rats and dogs. So while the Lu/Tuszynsky paper showing new neuronal relays when given after 2 weeks post injury is getting closer towards a chronic time point, it is not. I would love to see the treatment given 8 weeks after injury to mitigate all doubt. So I'm not so sure that the Paul Lu paper can be used to show that glial scar is not inhibitory to axon growth.

    The publication in the link was contusion model, while Lu/Tuszynsky paper was on transection, so I'm not sure how that affects anything on timing of scar formation.

    http://thejns.org/doi/full/10.3171/2010.3.SPINE09190





  9. #299
    I am deeply disappointed with the progress and the science that has been done in spinal cord regeneration. Even in rats and larger mammals, the debate over mechanisms and strategies are all over the place. There seems to be a ton of work to do that will take longer than I hoped. Yes things grow but protocols for organized regeneration are nowhere near answered. Money is not there and the investment has no immediate upside, so private and public corps steer away. Geron got close but in the end , it was a publicity stunt just to be first to attract money. Money used for other projects that return investments faster. Human Clinical trials with a real treatment success are not even close. All studies show one or two things of a 10,000 piece puzzle. Where are we really? Grafting strategies at Jerry Silvers lab? With zero motor/sensory?
    I just hope there are more scientist that stand alone with new ideas. Like the one that believed the world was round and everyone else thinking it was flat. Until you prove with complete recovery, you are not asking the right questions or possessing correct answers.
    Han: "We are all ready to win, just as we are born knowing only life. It is defeat that you must learn to prepare for"

  10. #300
    Quote Originally Posted by Fly_Pelican_Fly View Post
    - Why have the numerous human examples (both legitimate trials as well as pseudo experimental) of intraspinal transplants of various types of stem cells (containing MSCs and/or BMSCs) shown little or no benefit in the chronic setting?
    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.

    Quote Originally Posted by Fly_Pelican_Fly View Post
    - Why has Dr Wise Young continued to postulate that he would like to consider adding Chondroitinase and/or Nogo to the UCBC+Lithium combination? For fun? Or is it that he believes (or believed) that the glial scar would still be a hurdle to overcome?
    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.

    Quote Originally Posted by Fly_Pelican_Fly View Post
    - Why are the likes of Os Stewart/Zhigang He (working with PTEN/mTor) looking to collaborate with Dr Silver in order to regenerate these "proliferating" CST axons through the glial scar in a chronic setting? Why approach such an average scientist? Why don't they just skip the collaboration and stick some UCBCs into the rodents and witness that bridge in action? Actually, why bother creating a viral vector to knock out PTEN/SOCS3 when they can just grab some lithium off the shelf to activate mTOR? Maybe they are poor scientists too?
    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.
    Quote Originally Posted by jsilver View Post
    It is absolutely clear that at acute stages following spinal cord injury, a variety of different types of stem cells can potently and therapeutically affect the inflammatory cascade that leads to secondary damage.
    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.

    Quote Originally Posted by Fly_Pelican_Fly View Post
    The fact is (whether it matters to you or not), to a scientist, there is an element of speculation. Dont get me wrong, I'm looking forward to seeing the data. If it works, then great for us but don't blame scientists for doing what scientists do - be objective. If you do, we as advocates will have less of them working in our field, and less of them being so patient with us as layman.
    I agree with you.
    Last edited by crabbyshark; 01-25-2013 at 05:22 PM.

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