Thread: ChinaSCINet Update

  1. #1421
    Quote Originally Posted by ay2012 View Post
    Definitely agree with the above and would like to point out that I'm not suggesting that Wise is reporting or not reporting for funds; he's explicitly stated that he is not doing this and feels uneasy at the prospect. I was just pointing out that, regardless of how he feels, people in the community are likely to react by supporting a "front-runner". Although this isn't how science truly works, in the absence of understanding everything in these trials and in the subsequent papers people will likely feel that those with the "best" results are doing the "best" work. It's the publication bias and it's present in all fields....
    Agreed.
    "Wheelie Wanna Walk!"

  2. #1422
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    Quote Originally Posted by Geoman View Post
    I think the issue here is that Wise is trying to help us out by keeping us informed of the trial's progress, not for the purpose of soliciting funding as some suggest, but because he understands the position we're in, how it helps us get by each day knowing that we're a step (or push) closer. But some on this site, who are not from the medical profession (and obviously don't understand the protocols and procedures of scientific reporting), feel that it's their role to peer reveiw his work and question his integrity for the sake of self gratification, rather than ask geniune questions to improve our understanding, and this does nothing but waste his time (and our's as we have to plough through all of the rubbish lately to find the real info). I totaly understand where Wise is coming from regarding this. As a sceintist I would do the same if I was in a similar position with my work.

    Clayton
    I totally agree with the above. Had a feeling that these wanabees and so called BS meters were going to ruin things for us.
    "Talk without the support of action means nothing..."
    ― DaShanne Stokes

    ***Unite(D) to Fight Paralyses***

  3. #1423
    Two important quotes from Wise are reproduced below.

    “Last month, I was giving a talk to other scientists in the New Bedford workshop about the obstacles and lessons we have learned from clinical trials. I pointed out two interesting findings in our trial, i.e. that we are seeing white matter regrowth in some patients and that improved locomotor function can occur without significant changes in motor and sensory scores. This led to a spirited discussion that I hope helped the community understand some of the mechanisms of recovery from regeneration”.

    “What I believe we are seeing in our trial now is regeneration. Long fiber tracts are regrowing long distances in the spinal cords and they appear to be making some synaptic connections with distal motor structures at 6-18 months after umbilical cord blood transplants. At least in initial stages, subjects are showing improved walking without much change in motor and sensory scores.”

    These purported findings, especially the report of long distance regeneration (and now with evidence of synaptic connections) in a chronically injured human, could be extremely important to the spinal cord injury field. It is also important to point out that when one makes extremely bold statements about ones research or clinical trial findings at a conference (ie., the New Bedford Workshop) that is being widely disseminated via the web, that the information is now in the public domain and is deserving, indeed, crying out for answers to critical questions. I’ve watched the New Bedford video twice and I have lots of questions that I wish had been asked by those in your audience. I also believe that public disclosure of scientific findings here at Care Cure should be subject to the same level of scrutiny. I think both Paolo and I share this viewpoint, not because we wish to assault anybody, but because we are passionate about getting to the truth about what may or may not be a viable strategy to improve the lives of people with chronic SCI.

    Because of the unprecedented nature of Wise’s claims, I’d really like him to present what he believes to be the solid and convincing evidence that functional regeneration has occurred in his patients.

    Here are just a few of the myriad of questions:

    What is your evidence in vitro that umbilical cord cells are preferred surfaces for axonal regeneration? I have not seen this presented. If they are not good surfaces for growth in vitro how can they form a growth bridge in vivo?

    When axons truly regenerate in animal models they always take meandering trajectories. Indeed, this characteristic is a hallmark of acceptable evidence for regeneration. Yet, in your presentation you suggest that axon regeneration in humans occurs in tight, rectilinear bundles. Why would the human be different than all other animal species?

    You state that you see “white matter regrowth”. I have never heard of regeneration being described this way before. As stated above, axons always wander around as they regenerate and they completely lack myelin. Indeed, lack of myelin is another hallmark of true regeneration. Are you also suggesting that regenerating axons in your patients become re-myelinated? What is your evidence for this?

    You mention in your presentation that you saw no correlation between patients with purported regeneration and functional recovery. Yet you now suggest that you see evidence for synaptic reformation and imply that such recovery is correlated with regeneration. Could you explain the change in interpretation? Could you present your evidence that new synapses have formed? It seems impossible to conclude this solely from DTI data.

    You describe a patient in whom you saw a long “regenerated” bundle of axons that totally degenerated and then remarkably regenerated again. What is your convincing evidence for this spectacularly amazing finding?

    You mention repeatedly here at Care Cure that regenerating axons in your chronic patients is occurring at 1MM per day and, therefore, is going to take a long time for the axons to reach their targets. What is your evidence that in your patients the axons are continuing to elongate and at a given rate? Also, related to this, why do you suggest that axons have to grow all the way to their motor neuron targets before you might get functional recovery? All of us in the regeneration/SCI field appreciate that in animal models, axons can link up with distant targets via interneuronal connections. Why couldn’t that happen in humans?

    What is your evidence that the long strands of whatever they might be that pass through and beyond the lesion in your DTI images (those that were not especially visible in your presentation) are truly axonal and not something else? Might it be possible that such strands of tissue were at one time spared bundles of axons that may have degenerated (and had become DTI invisible) but then became intensely gliotic (DTI visible)? I think Dr. Tansey was getting at this with his question. In other words what is your evidence that there are, in fact, viable axons in these newly formed structures if, indeed, they are really newly formed? With only simple snapshots of these bundles at one timepoint and a claim that they were not there at an earlier stage, I suggest that one is hard pressed to conclude the remarkable conclusion that white matter “regrowth” is occurring. I am not an expert on all of the caveats that revolve around DTI imaging but I know they exist and it might be a good thing to discuss this.

    I think that showing that the distal tip of the bundle continues to elongate weekly would be your most compelling evidence, using DTI only, for ongoing regeneration. It would also surely be nice if you could show convincing long distance regeneration using these same strategies in an animal model of long chronic cord injury. Given that this has never before been shown in an animal model you can surely understand why one might be legitimately skeptical and why your claims are so profound.

  4. #1424
    jsilver and paolo should really change the focus of their questions. On want side you claim what you seek is knowledge, yet when I read your questions all I see is cynicism, meaning you care more about proving that there is not gonna be a cure within our life time than actually leaving anything positive to us.

    I don't see anything wrong with what Wise have said so far. All the data needed to make an accurate statement is not yet ready. Wise IMO express what seems to be happening and what that could lead to. If it not, understanding why not is gonna help future researches.

    It had been said before, but all this labeled "doubts" are starting to become annoying for some of us. You may or may not know more than us, but I swear I don't see anything positive with the way some of you rise questions. Actually feels like a POS attitude towards our situation and people on the research field who tries to help

  5. #1425
    To be fair, none of us know enough about the science to determine how fair or unfair Dr. Silver's questions are. Let Dr. Young respond...and it would likely be helpful for a "third-party" scientist to post some comments on these issues, so as to deescalate the emotions, help the community understand, and allow everyone to find some common ground. Good questions should be encouraged.... Unless we're all content to just sit on the sidelines while these things are discussed...

  6. #1426
    Quote Originally Posted by Lyerly
    I know that if I was raising money for something that has a good chance that will benefit me or even a proven or documented chance that it would be easier. It gives the donor something to see that there investment lead towards and would make them more comfortable and generous knowing the chances of improvement are high as opposed to just giving in general.
    You are of course correct that showing positive clinical trial results will encourage more donations. On the other hand, we are not talking about "giving in general". It is giving specifically for the purpose of supporting chronic spinal cord injury clinical trials. It should not depend on whether the trials are showing positive or negative results. Both are important. I know that I am being idealistic but think about the cancer field. There has yet to be a cure for glioblastoma or pancreatic cancer but people continue to give for clinical trials, knowing that it is the only path to a cure.

    Quote Originally Posted by ay2012
    While people should support clinical trials in general, good results or bad, this is probably an idealistic viewpoint relative to how people react. Then, the question becomes, where will the majority of the funding come from moving forward? If from outside institutions, agencies, corporations (as I would assume) then, as some above have suggested, if telling us anything jeopardizes the chances of publishing, forget about us. If the risk is not too much, and a lot of the funding will end up coming from Justadollarplease then perhaps it's beneficial to keep the community engaged with updated information. Sorry, but I'm an economist by trade and we always look at incentives!
    Yes, positive results will help raise money. Success is the most powerful of incentives. Everybody loves winners. Once we have had our first success, funding for more clinical trials will be easier to get. Not only private donors but also many companies will flock to ChinaSCINet, SCINetUSA, SCINetIndia, and SCINetNorway to offer therapies and money.

    I am under constant pressure to show "positive" results not only to potential donors, supporters, and spectators but also to doctors, nurses, and subjects who are working their hearts out in these trials. In Kunming, for example, the nurses have given up their weekends to examine subjects in their homes, often after many hours of travel. The subjects are walking every day. They all need incentives.

    We must be careful not to raise expectations too high. We cannot count on being lucky and getting a homerun on the first pitch. There will be failures, disappointments, and errors. The trials may not go the way we hope. We must weather the disappointments and continue to play. We are here to win the game and not just the first inning.

  7. #1427
    Keep up the great work and effort Wise!

  8. #1428
    Jerry,

    Thank you very much for your questions.

    Let me first put the talk that I gave into context. It was at a workshop on obstacles to clinical trials. So, I chose to talk about two surprising findings that we have found in our clinical trials to date. The first is that MRI/DTI show spinal fiber bundles that cross the injury site at 6-12 months after transplanting HLA-matched umbilical cord blood mononuclear cells. The second is improved locomotor scores that do not correspond to improvements in motor or sensory scores.

    I did not disclose these findings on CareCure. My colleagues at the Chinese University of Hong Kong had presented these results at two recent professional meetings. I was presenting these two findings for colleagues to discuss in the workshop. People had seen the video of the workshop and were asking me questions about the findings. I answered the questions as best as I could. From that discussion, I realized that people are having difficulty understanding how regenerating spinal tracts restore function and the concept of indirect motor activation. I did my best to explain.

    You point out one issue with my language that I agree should be corrected. I had used the words "white matter regrowth" to describe the phenomenon that we observed. Since white matter implies myelinated tracts and I have no idea whether these fibers are myelinated or not, the proper term probably should be simply "fiber bundles". Diffusion tensor tractography traces bundles of fibers that have similar anisotropy. They may or may not be myelinated.

    Before treatment, all patients had a clear gap at the injury site. In one patient who did not receive a transplant, there was no growth over a 2 year period. At 6-12 months after treatment, two subjects showed fiber bundles that grew across the injury site and extended many cm into the rostral and caudal spinal cord. We observed this phenomenon in two of five subjects. In my opinion, this finding is worth presenting for discussion at the workshop.

    We had used a 3T clinical MRI to do DTI so that we could see the border of the injury site for injection purposes. The fiber tracts that we saw were typically >1 mm thick. I agree that it would be of interest to do weekly or monthly tractography to see the fiber bundles elongating. It may allow us to calculate the rate of growth. In the upcoming Phase III trial, we are planning to do repeated tractography in subjects that show fibers growing across the injury site, as well electrophysiology.

    I am not sure that you and I disagree on the subject of indirect activation of motor activity. We observed improved locomotor scores without changes in motor scores. This is actually quite common. Many people who can walk after spinal cord injury cannot activate individual muscles as well as one would expect. This is consistent with descending axons activating the central pattern generator rather than direct activation of motoneurons.

    Wise.

    Quote Originally Posted by jsilver View Post
    Two important quotes from Wise are reproduced below.

    “Last month, I was giving a talk to other scientists in the New Bedford workshop about the obstacles and lessons we have learned from clinical trials. I pointed out two interesting findings in our trial, i.e. that we are seeing white matter regrowth in some patients and that improved locomotor function can occur without significant changes in motor and sensory scores. This led to a spirited discussion that I hope helped the community understand some of the mechanisms of recovery from regeneration”.

    “What I believe we are seeing in our trial now is regeneration. Long fiber tracts are regrowing long distances in the spinal cords and they appear to be making some synaptic connections with distal motor structures at 6-18 months after umbilical cord blood transplants. At least in initial stages, subjects are showing improved walking without much change in motor and sensory scores.”

    These purported findings, especially the report of long distance regeneration (and now with evidence of synaptic connections) in a chronically injured human, could be extremely important to the spinal cord injury field. It is also important to point out that when one makes extremely bold statements about ones research or clinical trial findings at a conference (ie., the New Bedford Workshop) that is being widely disseminated via the web, that the information is now in the public domain and is deserving, indeed, crying out for answers to critical questions. I’ve watched the New Bedford video twice and I have lots of questions that I wish had been asked by those in your audience. I also believe that public disclosure of scientific findings here at Care Cure should be subject to the same level of scrutiny. I think both Paolo and I share this viewpoint, not because we wish to assault anybody, but because we are passionate about getting to the truth about what may or may not be a viable strategy to improve the lives of people with chronic SCI.

    Because of the unprecedented nature of Wise’s claims, I’d really like him to present what he believes to be the solid and convincing evidence that functional regeneration has occurred in his patients.

    Here are just a few of the myriad of questions:

    What is your evidence in vitro that umbilical cord cells are preferred surfaces for axonal regeneration? I have not seen this presented. If they are not good surfaces for growth in vitro how can they form a growth bridge in vivo?

    When axons truly regenerate in animal models they always take meandering trajectories. Indeed, this characteristic is a hallmark of acceptable evidence for regeneration. Yet, in your presentation you suggest that axon regeneration in humans occurs in tight, rectilinear bundles. Why would the human be different than all other animal species?

    You state that you see “white matter regrowth”. I have never heard of regeneration being described this way before. As stated above, axons always wander around as they regenerate and they completely lack myelin. Indeed, lack of myelin is another hallmark of true regeneration. Are you also suggesting that regenerating axons in your patients become re-myelinated? What is your evidence for this?

    You mention in your presentation that you saw no correlation between patients with purported regeneration and functional recovery. Yet you now suggest that you see evidence for synaptic reformation and imply that such recovery is correlated with regeneration. Could you explain the change in interpretation? Could you present your evidence that new synapses have formed? It seems impossible to conclude this solely from DTI data.

    You describe a patient in whom you saw a long “regenerated” bundle of axons that totally degenerated and then remarkably regenerated again. What is your convincing evidence for this spectacularly amazing finding?

    You mention repeatedly here at Care Cure that regenerating axons in your chronic patients is occurring at 1MM per day and, therefore, is going to take a long time for the axons to reach their targets. What is your evidence that in your patients the axons are continuing to elongate and at a given rate? Also, related to this, why do you suggest that axons have to grow all the way to their motor neuron targets before you might get functional recovery? All of us in the regeneration/SCI field appreciate that in animal models, axons can link up with distant targets via interneuronal connections. Why couldn’t that happen in humans?

    What is your evidence that the long strands of whatever they might be that pass through and beyond the lesion in your DTI images (those that were not especially visible in your presentation) are truly axonal and not something else? Might it be possible that such strands of tissue were at one time spared bundles of axons that may have degenerated (and had become DTI invisible) but then became intensely gliotic (DTI visible)? I think Dr. Tansey was getting at this with his question. In other words what is your evidence that there are, in fact, viable axons in these newly formed structures if, indeed, they are really newly formed? With only simple snapshots of these bundles at one timepoint and a claim that they were not there at an earlier stage, I suggest that one is hard pressed to conclude the remarkable conclusion that white matter “regrowth” is occurring. I am not an expert on all of the caveats that revolve around DTI imaging but I know they exist and it might be a good thing to discuss this.

    I think that showing that the distal tip of the bundle continues to elongate weekly would be your most compelling evidence, using DTI only, for ongoing regeneration. It would also surely be nice if you could show convincing long distance regeneration using these same strategies in an animal model of long chronic cord injury. Given that this has never before been shown in an animal model you can surely understand why one might be legitimately skeptical and why your claims are so profound.
    Last edited by Wise Young; 12-21-2012 at 06:51 PM.

  9. #1429
    Quote Originally Posted by ay2012 View Post
    To be fair, none of us know enough about the science to determine how fair or unfair Dr. Silver's questions are. Let Dr. Young respond...and it would likely be helpful for a "third-party" scientist to post some comments on these issues, so as to deescalate the emotions, help the community understand, and allow everyone to find some common ground. Good questions should be encouraged.... Unless we're all content to just sit on the sidelines while these things are discussed...
    I agree. If you don't ask, you cannot know the answers.
    Stop waiting for things to happen, Go out and make them happen.

    http://curegirls.wordpress.com/

  10. #1430
    Quote Originally Posted by ResidentBio View Post
    jsilver and paolo should really change the focus of their questions. On want side you claim what you seek is knowledge, yet when I read your questions all I see is cynicism, meaning you care more about proving that there is not gonna be a cure within our life time than actually leaving anything positive to us.

    I don't see anything wrong with what Wise have said so far. All the data needed to make an accurate statement is not yet ready. Wise IMO express what seems to be happening and what that could lead to. If it not, understanding why not is gonna help future researches.

    It had been said before, but all this labeled "doubts" are starting to become annoying for some of us. You may or may not know more than us, but I swear I don't see anything positive with the way some of you rise questions. Actually feels like a POS attitude towards our situation and people on the research field who tries to help
    ResidentBio,

    I want a cure in my life time, I don't know if that will happen, but I am doing what I can to make it happen, including questioning things that don't seem right and and that might drive in the wrong direction money and advocacy effort.

    Then I just express my opinions supported by arguments that you and others may consider not valid, if so you can provide your opinions with your arguments.

    In this way the discussion can be usefull and educative also for people that just read. That in the end will affect positively SCI research, I believe.

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

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