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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #211
    Quote Originally Posted by paolocipolla View Post
    Wise,

    it is possible that you are not very well informed, as it could be the case that someone is not telling you the truth not to hurt you, but I am afraid that no UCB cells trial will happen in Norway as you keep saying.
    Time will tell who is right here.

    I hope this post will not be removed. I'll save the screen.. just in case.

    Paolo
    Isn't the purpose of Dr. Young's trial network to test the best of what is available now? Does Dr. Silver have something better to test now; if so, I would like to think Dr. Young has an open invitation to present it. If the invitation does not exist then that would be a misrepresentation of the purpose of the trial network. I don't think Dr. Young has misrepresented the combination therapy he is testing. He has stated why it was chosen, why it could not be fully vetted in animal studies, and while it appears he is showing some optimism for the outcome he is already looking for what is next. The amount of money financing the network would probably be lost in the black hole of perpetual research never to be heard from again. I'm all for continuous research but if there are some intermediate steps where people can get off respirators, get some triceps or wrist function, or unexpectedly discover something for neuropathic pain then I have to say test what you know and give us what you've got.
    With that being said, I personally enjoy the respectful exchanges between Dr. Young and Dr. Silver. Paco there, whatever your name is, nobody appreciates your demeanor. I'm not sure why Dr. Young bothers to respond to you, it seems to do nothing to satisfy you but extends your existence here on this forum. I can't see anyone missing you if you'd go away.
    please . . .test what you already know; and give us what you have. we may not be dying, but we certainly are not living either

  2. #212
    Quote Originally Posted by crabbyshark View Post

    Yes, you are. Axons are regrowing in your body right now, very slowly.
    No, my axons are not growing in my body. The spinal cord does not regenerate. That is why there are scientists trying to figure out a treatment that will get it to regenerate. Your post quoting Wise was him discussing hypothetical axon growth, not what occurs naturally in the spinal cord. This is not open to debate, it is fact.


    Quote Originally Posted by crabbyshark View Post

    It might tell me something about which one is harder to study. It tells me nothing about which one is harder to fix.

    For instance:
    According to this study, the scar resulting from a SCI is fully formed in a dog at 4 weeks.
    This study (click HTML, go to the discussion at the end), researchers divided dogs into four groups of three. One group was control, one group injected with cMSC (canine UCBC) 12 hours after injury, one group injected 1 week after injury (when scar was forming), and one group injected 2 weeks after injury.
    They determined injection at 1 week after injury was most effective, 2 weeks after injury was second most, and 12 hours after was the worst.
    If this is true, isn't it at least possible that an injection at 4 weeks (or 5 weeks or 10 weeks or 100 weeks) might be more effective than an injection given at 12 hours?
    Not saying you think it's likely, but you must allow for the possibility.

    The first study, in dogs showed that chronic stages in dogs STARTS at 4 weeks. Yet at only 2 weeks (still acute), the UCB treatment had already decreased in effectiveness from 1 week. There was no mention of benefits after 2 weeks. Not to mention the scores at 2 weeks were only very slightly better than the control that received no cells.

    Perhaps the better time to receive a treatment such as UCB cells would be a week after injury as opposed to 12 hours. Or something to that effect. However, that is still in the acute injury phase. So you can argue about what time is best to administer treatment in the acute phase but that doesn’t involve chronic time-points at all.


    Quote Originally Posted by crabbyshark View Post

    Do people normally live to be 80? Do golden retrievers usually live to be 12?

    This doesn't prove anything. Humans live 26X longer than rats, yet a rat's injury progresses only 4X faster according to Dr. Wise. I easily believe that a rat's injury will heal faster than a human but not to the extent where it is chronic in 7 days. No study looking at rats 7 days post injury called them chronically injured.

    Quote Originally Posted by crabbyshark View Post

    Because it's expensive to maintain chronic SCI animal and they often die before their part of the experiment starts.
    I understand that it is more expensive to test on a chronic injured animal. "More expensive" is a subjective term. I don’t consider extra $ to be the reason there has been NO chronic injury model publication in the 10 years since “efficacy” has been shown in an acute model. Paying out the extra tens of thousands (if it even costs that much) is the next logical step in the process of bringing it to human chronic population in a trial(s) that will cost millions.


    Why did labs waste the tens of thousands to test UCB on acute injury again when there are already 20+ other studies on the very same topic?


    Quote Originally Posted by crabbyshark View Post

    4.7A! They look like ants marching across the injury site (the black area). It's beautiful.
    I really can’t tell exactly what I’m looking at in 4.7A. I think it's a bird eyes view of the injury site. It’s confusing to a layman like me. I look at the image in the pten study, I can tell exactly what I’m looking at. I see where the cut is made and where the axons are growing across.


    Quote Originally Posted by crabbyshark View Post

    The current trial is not using mesenchymal cells. USSC make up a portion of UCBMC.
    I'm not so sure. But I'm going to concede on that because it is irrelevant to the main point I'm trying to make.


    Quote Originally Posted by crabbyshark View Post

    That picture was taken three weeks after injection. Compared to the control, axon proliferation in injury site is robust. The DTIs Dr. Wise saw were taken a year after injection. Either way, we may not need to regenerate very many axons to get better.


    The images in the publications we discussed are not DTI. That is why I don't know anything about DTI. From what I've heard, exactly what the DTI's are depicting is debatable.

    Looking at Figure 4.9, it compares amount of axons in the injury site between control and USSC treatment group. The treatment roughly doubled the number. That is not robust when the control group is supposed to have almost 0 axons in the site.




    None of that really matters because there is no study of a chronic injured animal that has shown benefit, let alone axon regeneration. There is no study in a complete injury to show axon regeneration. All have been acute AND incomplete. That is a whole different ballgame than chronic AND complete, such as in the human trials. You can’t go back ex post facto and say, “Well that study used treatment at a week post injury, rats heal 4X faster, therefore that was a chronic model. ” (paraphrase). Especially when those publications don’t consider their model to be chronic; and discuss tissue sparing and reduced gliosis (scar), which is not possible at a chronic time point.

    So to sum it up, all that has been shown is that if administered acutely (or subacutely) rats walk a little better than control animals who receive nothing. Even control animals walk. That does not impress me nor does it give me any reason to think it will work on humans with complete injury. However, I hope it does. Perhaps it can remylinate any surviving axons to restore something.

    Quote Originally Posted by crabbyshark View Post
    P.S. I'm not mad at you if that's the vibe you're getting.
    Quote Originally Posted by crabbyshark View Post
    Rubber Soul is a great album.
    I'm not getting that vibe at all...All the Beatles albums are great once they started taking drugs.

  3. #213
    Quote Originally Posted by paolocipolla View Post
    I think the above is very informative and open mind at the same time.
    All researchers and neurosurgeons I have had the opportunity to talk with about the scar so far are on the same line of thinking based on the scientific evidence so far available.
    If Wise can prove that the scar is no problem I'll be super happy as we'll have an easier way out of chair. Still waiting after many years hearing Wise's theory.

    Paolo
    Paolo,

    It seems to me that you have it upside down. The supporter of a theory should bear the burden of proof rather than demand that a critic of the theory show that a claimed phenomenon does not exist or does not do what is purported by the theory. By the way, I did not say that glial scars and gliosis do not exist. Glial cells do proliferate in contused spinal cords and “glial scars” do form when fibroblasts invade into the spinal cord. I just don’t believe that the evidence supports the claim that gliosis and “glial scars” block axonal growth to the extent claimed for the following reasons.

    1. Many axons grow into spinal cord contusion sites over time, including corticospinal and reticulospinal axons. If “glial scars” pose a tight mechanical or chemical barrier to axon growth, how can axons be growing into the contusion site? You seem to be arguing that a 25-mm contusion injury is a mild injury but this is not true. In rats, a 25-mm weight drop contusion destroys >90% of axons at the injury site and >90% of rats do not recover weight-supported stepping. Are you suggesting that “glial scars” form only when there is "complete" spinal cord injury?

    2. Axons can grow through even cuts of the spinal cord under certain circumstances. For example, Kai Liu and colleagues have shown if they delete PTEN from the motor cortex without doing anything about the "glial scar" in rat spinal cord, many corticospinal axons will grow across the cut site in hemisected spinal cords. You seem to be arguing that axons are sneaking across the injury site before the "glial scar" can form but this is not true. Liu, et al. observed axons continuing to grow across the injury site many weeks and even months after injury, long after the “glial scar” has formed. How are they doing that?

    3. Drugs such as chondroitinase that break down chondroitin-6-sulfate-proteoglycans (CSPG) allow fibers to regenerate through injury sites and improve recovery, suggesting that the glial barrier is primarily a chemical barrier rather than a mechanical scar. But some axons, such as serotonergic axons, not only grow but seem to grow better in gliotic areas where CSPG is present. Furthermore, chondroitinase increases sprouting of surviving axons and some of the recovery due to chondroitinase therapy may be from such sprouting rather than long distance regeneration.

    4. Treatments that prevent “glial scars” from forming or that ablate reactive glial cells from injured spinal cords prevent recovery in animals rather than improve recovery. For example, the Sofroniew laboratory used sophisticated molecular therapies to prevent gliosis and found that these therapies increase tissue damage, reduce recovery, and do not increase long distance regeneration. Yes, I understand and agree that gliosis play an essential role in limiting inflammation and repairing the blood brain barrier but, if gliosis does prevent axonal growth, shouldn’t such therapies increase regeneration? They do not.

    A theory is only as good as its predictions. If time and time again the predictions of a theory fail to be supported by evidence and the theory must be modified to accomodate conflicting evidence, the theory is weak. The first prediction of the “glial scar” theory is that if nothing is done to eliminate the “glial scar”, regeneration cannot occur. This is not true. Many axons grow into contusion sites and even across cut spinal cord sites after PTEN deletion. The second prediction is that prevention or removal of glial scars should increase regeneration and recovery. It does not.

    A theory is bad when it leads to unacceptable clinical practices that can harm people. The “glial scar” theory is now being used by some clinicians and companies to justify cutting out spinal cord to remove glial scar. Some people think that “glial scar” should be cut from the injury site and replaced by tissues or even biomaterials. I strongly supported chondroitinase research for many years and continue to support research and clinical trials on chondroitinase at Acorda. However, I spoke out against the term “glial scar” when I realized that clinicians are using the term to justify cutting out spinal cord at the injury site.

    Theories are just ideas. Weak theories are all right as long as they remain in the realm of ideas. However, when they lead to practices that can harm people, we must speak out. I just returned from China and heard yet another researcher proposing to cut out 10 mm of “glial scar” from the spinal cord of people and replacing it with biomaterials. Carlos Lima and his colleagues cut out a piece of the spinal cord at the injury site to put in nasal mucosa, saying that it is only “glial scar”. A clinical trial is going on in New Zealand still doing this. As you know, there are companies that are proposing to cut out the “glial scar” from the spinal cord. It is not theory any more. It is being practiced.

    Seriously, Paolo, what is the evidence that “glial scars” are preventing regeneration in people with spinal cord contusion injuries? Don’t you think that proposers and supporters of the theory should bear the burden of proof that glial scars exist and block regeneration, rather than demand that I provide such proof? We are not dealing with just theory any more. Clinical practice is being based on the “glial scar” theory. People bear a responsibility for the benefits and harm from theories and therapies that they support. Are you willing to do this? This is not a matter of being “super happy” for yourself. This is a matter of helping or harming others.

    Wise.
    Last edited by Wise Young; 01-15-2013 at 07:28 AM.

  4. #214
    Paolo,

    Please do take a look at this paper from Lu, et al. (2007). I reproduce the abstract of the paper here and append the reprint for you. This is not me speaking. Mark Tuszynski is saying this.

    Wise.

    Abstract
    Cellular and extracellular inhibitors are thought to restrict axon growth after chronic spinal cord injury (SCI), confronting the axon with a combination of chronic astrocytosis and extracellular matrix-associated inhibitors that collectively constitute the chronic “scar.” To examine whether the chronically injured environment is strongly inhibitory to axonal regeneration, we grafted permissive autologous bone marrow stromal cells (MSCs) into mid-cervical SCI sites of adult rats, 6 weeks post-injury without resection of the “chronic scar.” Additional subjects received MSCs genetically modified to express neurotrophin-3 (NT-3), providing a further local stimulus to axon growth. Anatomical analysis 3 months post-injury revealed extensive astrocytosis surrounding the lesion site, together with dense deposition of the inhibitory extracellular matrix molecule NG2. Despite this inhibitory environment, axons penetrated the lesion site through the chronic scar. Robust axonal regeneration occurred into chronic lesion cavities expressing NT-3. Notably, chronically regenerating axons preferentially associated with Schwann cell surfaces expressing both inhibitory NG2 substrates and the permissive substrates L1 and NCAM in the lesion site. Collectively, these findings indicate that inhibitory factors deposited at sites of chronic SCI do not create impenetrable boundaries and that inhibition can be balanced by local and diffusible signals to generate robust axonal growth even without resecting chronic scar tissue.
    © 2006 Elsevier Inc. All rights reserved.
    Keywords: Regeneration; Spinal cord injury; Chronic injury; Inhibition; Scar tissue
    Last edited by Wise Young; 01-15-2013 at 10:42 AM.

  5. #215

    scar tissue

    Hello Dr. Young,

    What about the ones that do have scar tissue? What approach do you think would be useful to overcome the problem. I was told I had a lot of it in my wound and it was removed to some extent before the cells were injected.

    Thanks,
    Bill

  6. #216
    Quote Originally Posted by bilby2 View Post
    Hello Dr. Young,

    What about the ones that do have scar tissue? What approach do you think would be useful to overcome the problem. I was told I had a lot of it in my wound and it was removed to some extent before the cells were injected.

    Thanks,
    Bill
    Bilby,

    The "scar tissue" that you were told about very likely were not in your spinal cord but between your spinal cord and the surrounding tissues. Removing these adhesions is called untethering. This is what we do when we inject umbilical cord blood mononuclear cells into the spinal cord.

    Several therapies have been reported to be beneficial in hemisection and transection models of spinal cord injury. These include chondroitinase (Bradbury, et al.), CSPG receptor blockers (Silver, et al.), peripheral nerve bridges (Cheng, et al.), and olfactory ensheathing glial cell transplants (Raisman, et al.).

    Wise.

  7. #217
    Quote Originally Posted by Wise Young View Post
    Paolo,

    It seems to me that you have it upside down. The supporter of a theory should bear the burden of proof rather than demand that a critic of the theory show that a claimed phenomenon does not exist or does not do what is purported by the theory. By the way, I did not say that glial scars and gliosis do not exist. Glial cells do proliferate in contused spinal cords and “glial scars” do form when fibroblasts invade into the spinal cord. I just don’t believe that the evidence supports the claim that gliosis and “glial scars” block axonal growth to the extent claimed for the following reasons.

    1. Many axons grow into spinal cord contusion sites over time, including corticospinal and reticulospinal axons. If “glial scars” pose a tight mechanical or chemical barrier to axon growth, how can axons be growing into the contusion site? You seem to be arguing that a 25-mm contusion injury is a mild injury but this is not true. In rats, a 25-mm weight drop contusion destroys >90% of axons at the injury site and >90% of rats do not recover weight-supported stepping. Are you suggesting that “glial scars” form only when there is "complete" spinal cord injury?

    2. Axons can grow through even cuts of the spinal cord under certain circumstances. For example, Kai Liu and colleagues have shown if they delete PTEN from the motor cortex without doing anything about the "glial scar" in rat spinal cord, many corticospinal axons will grow across the cut site in hemisected spinal cords. You seem to be arguing that axons are sneaking across the injury site before the "glial scar" can form but this is not true. Liu, et al. observed axons continuing to grow across the injury site many weeks and even months after injury, long after the “glial scar” has formed. How are they doing that?

    3. Drugs such as chondroitinase that break down chondroitin-6-sulfate-proteoglycans (CSPG) allow fibers to regenerate through injury sites and improve recovery, suggesting that the glial barrier is primarily a chemical barrier rather than a mechanical scar. But some axons, such as serotonergic axons, not only grow but seem to grow better in gliotic areas where CSPG is present. Furthermore, chondroitinase increases sprouting of surviving axons and some of the recovery due to chondroitinase therapy may be from such sprouting rather than long distance regeneration.

    4. Treatments that prevent “glial scars” from forming or that ablate reactive glial cells from injured spinal cords prevent recovery in animals rather than improve recovery. For example, the Sofroniew laboratory used sophisticated molecular therapies to prevent gliosis and found that these therapies increase tissue damage, reduce recovery, and do not increase long distance regeneration. Yes, I understand and agree that gliosis play an essential role in limiting inflammation and repairing the blood brain barrier but, if gliosis does prevent axonal growth, shouldn’t such therapies increase regeneration? They do not.

    A theory is only as good as its predictions. If time and time again the predictions of a theory fail to be supported by evidence and the theory must be modified to accomodate conflicting evidence, the theory is weak. The first prediction of the “glial scar” theory is that if nothing is done to eliminate the “glial scar”, regeneration cannot occur. This is not true. Many axons grow into contusion sites and even across cut spinal cord sites after PTEN deletion. The second prediction is that prevention or removal of glial scars should increase regeneration and recovery. It does not.

    A theory is bad when it leads to unacceptable clinical practices that can harm people. The “glial scar” theory is now being used by some clinicians and companies to justify cutting out spinal cord to remove glial scar. Some people think that “glial scar” should be cut from the injury site and replaced by tissues or even biomaterials. I strongly supported chondroitinase research for many years and continue to support research and clinical trials on chondroitinase at Acorda. However, I spoke out against the term “glial scar” when I realized that clinicians are using the term to justify cutting out spinal cord at the injury site.

    Theories are just ideas. Weak theories are all right as long as they remain in the realm of ideas. However, when they lead to practices that can harm people, we must speak out. I just returned from China and heard yet another researcher proposing to cut out 10 mm of “glial scar” from the spinal cord of people and replacing it with biomaterials. Carlos Lima and his colleagues cut out a piece of the spinal cord at the injury site to put in nasal mucosa, saying that it is only “glial scar”. A clinical trial is going on in New Zealand still doing this. As you know, there are companies that are proposing to cut out the “glial scar” from the spinal cord. It is not theory any more. It is being practiced.

    Seriously, Paolo, what is the evidence that “glial scars” are preventing regeneration in people with spinal cord contusion injuries? Don’t you think that proposers and supporters of the theory should bear the burden of proof that glial scars exist and block regeneration, rather than demand that I provide such proof? We are not dealing with just theory any more. Clinical practice is being based on the “glial scar” theory. People bear a responsibility for the benefits and harm from theories and therapies that they support. Are you willing to do this? This is not a matter of being “super happy” for yourself. This is a matter of helping or harming others.

    Wise.
    Wise,

    what would you do should you find fibrotic scar in the lesion site, would you remove it or not?

    About the glial scar I am happy that there are clinical trials coming that are based on the glial scar theory so that we'll see if it works better than UCBC + Li.
    At least there are many studies that support such trials, while you have not a single study that is the same as what you are doing. I think you have runned the risk to harm people much more than others are palnning to do.

    Sure I hope there will be a way to cure SCI that does not require an invasive surgery, but I think for that to happen it is necessary to study more the glial scar and the fibrotic scar, so that perhaps someone will find a way to make our body get rid of whatever stops axons from regenerating.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  8. #218

    thank you Dr. Young

    Did you ever consider Albany Medical Center for part of the SCI Network in the US. They already conducted one experiment, plus they opened the dura to inject the cells, something you said most American surgeons hesitate to do.

  9. #219
    Quote Originally Posted by Wise Young View Post
    Paolo,

    Please do take a look at this paper from Lu, et al. (2007). I reproduce the abstract of the paper here and append the reprint for you. This is not me speaking. Mark Tuszynski is saying this.

    Wise.
    Thank you Wise,

    I will read this carefully as soon as I have time.

    I believe that you can have some recovery without removing/dealing with the scar somehow especially in mild injury, but results has been minimal so far. I am thinking at the ongoing Stem Cell Inc trial for example. We need to have much better results than that even if that seems a positive step forward.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  10. #220
    Scar or no scar Dr. Silver will not be taking his work into humans unless he changes heart from what he said at a recent conference. He said he didn't need any more money for research since he was not interested in being involved in translating his rat work to a larger animal or primate model or work to see the research reach human studies. He said that was for someone else to pick up and run with.

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