Jerry Silver and Other Discussion from ChinaSCINet Update

[paolocipolla]

I have been studying this structure for most of my scientific career. I have had a long standing NIH grant entitled "Regeneration beyond the glial scar" for nearly 30 years. If one simply reads the literature , uses the proper techniques and does the right experiments there is no doubt that scar exists. Indeed, the scar is well known by neurosurgeons who attempt to aspirate away non-invasive brain tumors that are surrounded by scar. They, aspirate until they push up against a tough tissue border that is the surrounding scar. By the way, contrary to what Wise suggests, there is no need for fibroblasts to create the tough scar. If you'd like, read my 2004 Nature Reviews Neuroscience review. Regeneration beyond the glial scar : Article : Nature Reviews ...
www.nature.com/nrn/journal/v5/n2/full/nrn1326.html - Similar
Review. Nature Reviews Neuroscience 5, 146-156 (February 2004) | doi : 10.1038/nrn1326 ... the glial scar. Jerry Silver1 & Jared H. Miller1 About the authors ...

Here is another reference:


Glial scar
From Wikipedia, the free encyclopedia
Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the Central Nervous System. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system. In the context of neurodegeneration, formation of the glial scar has been shown to have both beneficial and detrimental effects. Particularly, many neuro-developmental inhibitor molecules are secreted by the cells within the scar that prevent complete physical and functional recovery of the central nervous system after injury or disease. On the other hand, absence of the glial scar has been associated with impairments in the repair of the blood brain barrier.[1]

Contents [hide]
1 Scar components
1.1 Reactive astrocytes
1.2 Microglia
1.3 Endothelial cells and fibroblasts
1.4 Basal membrane
2 Beneficial effects of the scar
3 Detrimental effects of the scar
4 Primary scar molecular inducers
4.1 Transforming growth factor β (TGF-β)
4.2 Interleukins
4.3 Cytokines
4.4 Ciliary neurotrophic factor (CNTF)
4.5 Upregulation of nestin intermediate filament protein
5 Suppression of glial scar formation
5.1 Olomoucine
5.2 Inhibition of Phosphodiesterase 4 (PDE4)
5.3 Ribavirin
5.4 Antisense GFAP retrovirus
5.5 Recombinant monoclonal antibody to transforming growth factor-β2
5.6 Recombinant monoclonal antibody to interleukin-6 Receptor
6 References

More very interesting things to learn for me.

Paolo

[Marcus]

Dr Silver seems to fear that the research of Dr Wise can overthrow his beliefs about spinal cord scar be a invencible barrier without removal surgery.

[paolocipolla]

Dr Silver seems to fear that the research of Dr Wise can overthrow his beliefs about spinal cord scar be a invencible barrier without removal surgery.

Marcus,

if you listen at minute 31 of the W2W presenattion of Dr, Silver you will learn that Dr. Silver saies that there might be other ways to deal with the scar.. so he is open to a less invasive solutions

http://vimeo.com/56641033

Paolo

[ay2012]

lol .. I think it would be much easier to 'espionage' in person than on an internet message board .. but what do I know. lol

They want to take lithium? Be my guest! It was used to treat schizophrenia - have fun!

If a course of lithium helps regenerate your spinal cord you wouldn't take it? Its toxicity level is well established: http://en.wikipedia.org/wiki/Lithium...y#Side_effects
Just because its used to treat manic depression doesn't mean you'll become a manic depressive if you take it...

[Marcus]

lol .. I think it would be much easier to 'espionage' in person than on an internet message board .. but what do I know. lol

They want to take lithium? Be my guest! It was used to treat schizophrenia - have fun!

Nobody is been asked to take any drug before the final results.

[Moe]

Just because its used to treat manic depression doesn't mean you'll become a manic depressive if you take it...

That is true.

[paolocipolla]

Oh, but you are wrong here. He does deny that in the absence of fibroblasts in the CNS there is scar. Thus, he denies that gliosis (astrocyte only behavior) can form a barrier. There are no fibroblasts in the brain or spinal cord normally, so in the absence of a penetrating injury that freely allows them into the CNS compartment from the meninges, it has been thought that few fibroblasts enter the CNS. So the astrocytes have taken over the job in the CNS of walling off inflammation. When fibroblasts do enter CNS in large numbers then the scar that is made by astrocytes becomes even more impenetrable because fibroblats produce a myriad of additional inhibitory molecules and the reactive astrocytes wall them off as well with a membranous structure called basal lamina. If you or Wise wish to call what the astrocytes do something other than "scar' that is no problem but you will not be able to communicate with the rest of the world where use of the word scar is more flexible. In the end, the important point is that reactive astrocytes contribute to regeneration failure in the CNS in a big way and they have to be overcome, removed or altered somehow to get regeneration to occur especially at chronic stages. Until data is presented, there is no evidence that UMBCs or lithium are capable of overcoming scar or the inhibitory molecules associated with it.

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

[paolocipolla]

This should be an average score. What MASCIS study are you referring to? Are you referring to the original BBB score paper? A 10.6 is not equivalent to an ASIA D. A lot of people can do weight-bearing and they are not ASIA D.

A 25 mm weight drop eliminates somatosensory evoked potentials in 90% of rats.

Wise.

Wise,
see the study that you uploaded for me here: http://sci.rutgers.edu/forum/showpos...3&postcount=85

As I know a rat with a BBB score of 10 or above can walk well enogh that can be examined with a catwalk and get usefull data while below 10 cawalk is not very usefull because the belly touches the flor and owerlap the foot prints of the rear paws: http://www.noldus.com/animal-behavio...oducts/catwalk

Paolo

[crabbyshark]

No I am not wrong.

Yes, you are. Axons are regrowing in your body right now, very slowly.

Understanding the answers to these questions require an understanding of the slow rate of axonal growth, the long distance of axonal growth, and the concept of neuron survival above and below the injury site. Let me first go through these three concepts and then answer your question.

1. Rate of axon growth. Axons grow slowly. In the peripheral nerve, regeneration occurs at 1 mm/day or less. So, if you crush your ulnar nerve at the elbow and lose sensation in the fourth and fifth fingers of your hand, the axons in the ulnar nerve will regenerate but the distance (at least for my arm) is 38-40 cm. At 1 mm/day, it may take more than a year before one regains sensation. Nobody really knows how fast spinal axons grow in human but I have suggested that the rate of growth spinal axons is no faster than peripheral nerve. It may well be slower than 1 mm/day, particularly if you are older. The other comparison is the rate of hair growth. Most of us grow hair at the rate of about a mm per day when we are young and slower when we are older.

2. Distance and barriers to axon growth. Axons usually die back to their first branch point before the injury site. This statement has multiple implications. First, most axons connect to many neurons. For example, a corticospinal neuron has branches that connects to the midbrain, the brainstem, the cervical spinal cord, and the lumbar spinal cord. So, an injury at the thoracic level will disconnect the axon from the lumbar spinal cord and the axon may die back to its first branch point in the cervical spinal cord. So, the regenerating axons must grow from the cervical spine down to the lumbar cord, in order to reconnect. On the other hand, in animal models, it is clear that most of the spinal axons will die back and then can and will grow from the first branch point to the edge of the injury site. This was one of the reasons by Jerry Silver (a very good scientist) once told me that this was why he did not believe in the Nogo theory of axon growth inhibition. After all, the axons that have died back and then regrow to the injury edge must have been growth amongst myelinated tracts and should have been inhibited. Jerry Silver showed and hypothesized that chondroitin-6-sulfate proteoglycans at the edge of the injury site stopped axonal growth. In experiments with treatments such as olfactory ensheathing glia, once axons cross the injury site, they seem to be able to keep growing, again suggesting that myelin inhibitors are not as important as originally thought. It is possible that axons grow slower in the presence of myelin growth inhibitors rather than stop altogether. Very recently, a former graduate student (Kai Liu) showed that if he shuts off a gene called PTEN in neurons, he could induce massive regeneration of the corticospinal tract in rats. This was the first time that anybody had demonstrated that the obstacles to axonal growth are not just axonal inhibitors but the presence of genes that hold back or prevent axonal growth. Finally, decades after spinal cord injury, one can see axons forming dystrophic terminals at the edge of the injury site. These terminals were once thought to be degenerating ends of terminals but is now thought of as "frustrated" growth comes. This indicates that axons are continuing to growing to the injury site and stopping at the edge, possibly due to chondroitin-6-sulfate-proteoglycans surrounding the injury site.

3. Neuronal survival above and below the injury site. Trauma damages not only axons but neurons in the spinal cord. When the neurons are damaged, this means that axonal regeneration may not restore function. Thankfully, most of us have more neurons that we need and we continue to be able to function even if we lose 20-50% of the neurons in a given segment. Until recently, although axonal regeneration is considered to be possible, neuronal replacement was considered to be in the neverneverland of scientific fantasy. However, the discovery of neural stem cells in the late 1990's and the demonstration that they can create neurons that incorporate into the neural circuity of the brain changed this pessimism. Today, most scientists believe that neuronal replacement is also possible, although there have not been many clear examples of neuronal replacements leading to functional recovery.

Given the above, you can perhaps understand why most neuroscientists are optimistic about the possibility of spinal cord regeneration and restoration of function. Please understand how new these are ideas are. In 1997, when I started Spinewire, we did not know the second two. In 2001, when we converted Spinewire to CareCure, we did not know the third point. IN fact, if you go back to my writings in the early days of CareCure, you will find that I was very pessimistic about neuronal replacement.

So, back to your question concerning what happens to the places where axons have degenerated. Do the degenerated pathways "collapse"? Do regenerating axons have to make new pathways for growth? I don't know the answers to these questions but can provide some educated guesses based on what I have seen. First, degenerated tracts often remain for months after injury. Called "Wallerian" degeneration, after Waller who noted that degenerating tracts can be identified with silver stains for months or even years after injury, these tracts are very likely to remain available to axons to regrow into them. This may or may not be true years after injury but I suspect that the problem may not be loss of physical space for growth but the loss signals to tell the axon that it is growing on the right path and to keep on going.

In the mid-1990's, I likened the journey of axons in the spinal cord to the journey of Odysseus back home. First, the Odyssesus is a long ways from home. Second, after he crosses the injury site where he had to combat a variety of monsters, including cyclops (macrophages), he has to sail past the syrens (neurons) along the way. Third, as he gets closer to home, he may stop at a place that is not his home (Circe's Island). Finally, when he gets home, he will find that many suitors have taken his place and he has to fight them off in order to get Penelope back.

I think that we have tools to start Odysseus on his journey. Getting him home is another matter. On the other hand, much evidence suggests that the nervous system is much more plastic than we had ever thought and that intensive exercise helps strengthen desirable connections and eliminates undesirable connections. Therefore, if we get a lot of sailors (axons) growing home and they connect, they can do the job but it will require a lot of learning and practice before things work again.

Wise.

If UCBMC injection is effective, recovery is likely to take a long time.

Neurons aren't known to regrow/regenerate like axons. That's one part of why the current UCBMC treatments being tested, if shown to work, are not the end-all-be-all silver bullet "cure" for SCI.

I'm not going to repeat myself on this. You can re-read my earlier posts. 20+ references of UCB studies and all on acute. None showing efficacy in chronic. That should tell you something on which is harder to fix.

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.

That is one scientist's opinion. I don't know if that is true or not. That seems like it is an easy thing to abuse.

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

Why not just do animal studies 2-3 months after injury to be sure it is a chronic model?

Because it's expensive to maintain chronic SCI animal and they often die before their part of the experiment starts.

c) I don't see them crossing all the way across the injury site, let alone going past it.

4.7A! They look like ants marching across the injury site (the black area). It's beautiful.

d)Is Wise's trial using USSC cells or Mesenchymal cells or both in his human trial?

The current trial is not using mesenchymal cells. USSC make up a portion of UCBMC.

Let me first define the cells that we are transplanting. We are using HLA-matched umbilical cord blood mononuclear cells (UCMBC). Umbilical cord blood contains four major categories of cells: red blood cells (RBC), platelets, neutrophils (polynuclear cells), and mononuclear cells. UCMBC are usually isolated by density centrifugation into what is called the "buffy-coat" layer, which excludes RBC, platelets, and neutrophils. Mononuclear cells include monocytes (40%), lymphocytes (30%), and other cells (macrophages, basophils, mast cells, etc.).

Mononuclear cells contain several populations of known stem cells and progenitor cells in cord blood.
• CD34+ cells. These are usually endothelial progenitor cells but some hematological and pluripotent stem cells may express CD34+. These are the cells that are most commonly counted in umbilical cord blood as a marker of the number of stem cells. They are usually about 0.5% of the UCBMC.
• CD133+ cells. These are pluripotent stem cells, many of which co-express CD34+. They are generally fewer in number than CD34+ cells.
• VSEL cells. These "very small embryonic-like" cells are believed to be pluripotent. They are usually less than CD133+ and, because of their size, often lost during the density centrifugation procedure.

b) I wouldn't consider the amounts of axons to be robust. Looking at figure 4.8 on pg. 67, I only see a few axons.

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.

In animal studies, we and many others have shown that less than 10% of the spinal cord is sufficient to restore unassisted walking in animals and probably in humans. I have been in the operating room with patients who have had tumors removed from their spinal cord and they walk out of the hospital even though they have no more than 10% of their spinal cords.

So, the goal of regenerating the spinal cord is to add enough axons that reconnect to the correct places to restore function. One does not have to regenerate more than 10% of the spinal cord to restore function. If there are already 8% of the spinal tracts present, perhaps it is sufficient to add 2% to the mix.

P.S. I'm not mad at you if that's the vibe you're getting. Rubber Soul is a great album.

[crabbyshark]

Oh, but you are wrong here. He does deny that in the absence of fibroblasts in the CNS there is scar. Thus, he denies that gliosis (astrocyte only behavior) can form a barrier. There are no fibroblasts in the brain or spinal cord normally, so in the absence of a penetrating injury that freely allows them into the CNS compartment from the meninges, it has been thought that few fibroblasts enter the CNS. So the astrocytes have taken over the job in the CNS of walling off inflammation. When fibroblasts do enter CNS in large numbers then the scar that is made by astrocytes becomes even more impenetrable because fibroblats produce a myriad of additional inhibitory molecules and the reactive astrocytes wall them off as well with a membranous structure called basal lamina. If you or Wise wish to call what the astrocytes do something other than "scar' that is no problem but you will not be able to communicate with the rest of the world where use of the word scar is more flexible. In the end, the important point is that reactive astrocytes contribute to regeneration failure in the CNS in a big way and they have to be overcome, removed or altered somehow to get regeneration to occur especially at chronic stages. Until data is presented, there is no evidence that UMBCs or lithium are capable of overcoming scar or the inhibitory molecules associated with it.

Our results suggest that transplanted cMSCs promote the formation of neuronal network through regulating the intracellular pathways of the actin cytoskeleton to overcome repulsive forces which result from scar formation and severance of axon.

SOURCE