Remyelination: new research from Karolinska Institute

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Remyelination: new research from Karolinska Institute

Post by cheerleader » Thu Nov 20, 2014 6:11 pm

New research from the Karolinska Institute shows us, once again, that human and mouse brains are not the same. Past assumptions about remyelination have been incorrect. Attempting to understand remyelination in the human brain using a mouse model simply does not work.

But there are things humans can do to remyelinate their own brains---and it's all about using the brain, and plasticity.

Here's the new research, which is calling into question all MS specialists thought they knew about myelin.

http://www.cell.com/cell/abstract/S0092-8674(14%2901298-7


The brain's plasticity and its adaptability to new situations do not function the way researchers previously thought, according to a new study published in the journal Cell. Earlier theories are based on laboratory animals, but now researchers at Karolinska Institutet in Sweden have studied the human brain. The results show that a type of support cell, the oligodendrocyte, which plays an important role in the cell-cell communication in the nervous system, is more sophisticated in humans than in rats and mice - a fact that may contribute to the superior plasticity of the human brain.

The learning process takes place partly by nerve cells creating new connections in the brain. Our nerve cells are therefore crucial for how we store new knowledge. But it is also important that nerve impulses travel at high speed and a special material called myelin plays a vital role. Myelin acts as an insulating layer around nerve fibres, the axons, and large quantities of myelin speed up the nerve impulses and improve function. When we learn something new, myelin production increases in the part of the brain where learning occurs. This interplay, where the brain's development is shaped by the demands that are imposed on it, is what we know today as the brain's plasticity.

Myelin is made by cells known as oligodendrocytes. In the last few years, there has been significant interest in oligodendrocytes and numerous studies have been conducted on mice and rats. These studies have shown that when the nerve cells of laboratory animals need more myelin, the oligodendrocytes are replaced. This is why researchers have assumed that the same also applies in humans. Researchers at Karolinska Institutet and their international collaborators have shown that this is not the case. In humans, oligodendrocyte generation is very low but despite this, myelin production can be modulated and increased if necessary. In other words, the human brain appears to have a preparedness for it, while in mice and rats, increased myelin production relies on the generation of new oligodendrocytes.

In the study in question, researchers have studied the brains of 55 deceased people in the age range from under 1 to 92 years. They were able to establish that at birth most oligodendrocytes are immature. They subsequently mature at a rapid rate until the age of five, when most reach maturity. After this, the turnover rate is very low. Only one in 300 oligodendrocytes are replaced per year, which means that we keep most of these cells our whole lives. This was apparent when the researchers carbon-dated the deceased people's cells. The levels of carbon-14 isotopes rose sharply in the atmosphere after the nuclear weapons tests during the Cold War, and they provided a date mark in the cells. By studying carbon-14 levels in the oligodendrocytes, researchers have been able to determine their age.

"We were surprised by this discovery. In humans, the existing oligodendrocytes modulate their myelin production, instead of replacing the cells as in mice. It is probably what enables us to adapt and learn faster. Production of myelin is vital in several neurological diseases such as MS. We now have new basic knowledge to build upon," says Jonas Frisén, PhD, Professor of Stem Cell Research at the Department of Cell and Molecular Biology at Karolinska Institutet.
http://www.eurekalert.org/pub_releases/ ... 110414.php
read more:

http://ccsviinms.blogspot.com/2014/11/h ... n-new.html

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Re: Remyelination: new research from Karolinska Institute

Post by 1eye » Sat Nov 22, 2014 6:37 am

The mouse model is completely discredited, so why are we still using it to determine a drug's eligibility for human trials? I realize mice are cheap, but are we not cheapening the value of our own research?

What does this mean about stem cells? Are adult stem cells less capable of producing oligodendrocytes? Embryonic ones are better because they are pluripotent but are they more capable of producing oligodendrocytes? If we only replace one in 300 after age 5, isn't that a limitation based on the age of the stem cells? Do we get much more bang for the buck if the stem cells are embryonic? Isn't it time the world of science stopped following George Bush's insane logic, and started to use embryonic cells rather than trying to use adult ones? Those fundamentalist scientists need not involve themselves if they are ethically opposed to using embryos.
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Re: Remyelination: new research from Karolinska Institute

Post by cheerleader » Sat Nov 22, 2014 2:57 pm

What the Karolinska researchers are saying is that new oligodendrocytes are not an integral a part of remyelination as we had thought. Remyelination in the human brain is a result of usage and plasticity. We don't require stem cells to generate new oligodendrocytes to form new myelin--because the existing cells do this on their own when we use our brains to learn new processes.

Remyelination in the MS brain has been a mystery---we know it occurs, and it's not related to type of disease, years of progression, types of medication or age. Check out the links on the blog---the research is all on there.
http://ccsviinms.blogspot.com/2014/11/h ... n-new.html

This is very much in line with what researchers have been saying about stroke recovery. Dr. Norman Doidge has a wonderful book called, "The Brain that Changes Itself." Highly recommended. He talks about how forcing stroke patients in rehab to only use paralized limbs eventually allows the brain to rewire, so that once immovable limbs become usable again. Doidge addresses the problem of a mentality which believes only outside drugs can repair the brain--this fallacy keeps researchers from pursuing other therapeutic investigations.

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Re: Remyelination: new research from Karolinska Institute

Post by Youarethecure » Sat Nov 22, 2014 3:51 pm

This is very interesting.... And I have learned a lot from it so hopefully its true ! haha

Thanks for sharing.

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Re: Remyelination: new research from Karolinska Institute

Post by 1eye » Sat Nov 22, 2014 7:48 pm

I believe remyelination happens, as a result of learning, as part of the healing process, and probably for other reasons.

What the study showed was that we do not normally have to have oligos turn over much, because the adult ones continue to be useful after age 5. But oligos can and do undergo apoptosis and new ones come from the adult stem cell population... just not as often as we had thought. So oligos, both new and old, do remyelinate axons. Also, and in addition, if you learn something new, new and/or old axons are pressed into service, and where necessary new myelin is generated. But it doesn't just magically appear. Oligos produce it. In mice, this might have to be brand-new oligos, but in people, the old ones will do just fine.

It's the turnover that does not have to happen in humans.
•White matter oligodendrocytes show very limited turnover
•Nuclear bomb test-derived 14C reveals a high exchange rate of myelin
•Oligodendrocyte turnover has little influence on myelination in humans
•Myelin modulation may be carried out by mature oligodendrocytes in humans
However (and I expect this will be studied) inflammation and oxidants can damage myelin, and may be causing apoptosis of damaged oligos at a rate faster than normal, making remyelination more difficult or unlikely.

You can't teach an old dog new tricks. That's because brain resources keep getting used, to entrench stuff we know already, making it harder and harder to relearn as we age. Relearning stuff, when our know-how is damaged, involves using new resources and starting from scratch. Eric Clapton used to say he had to relearn the guitar every six months. I expect it's less often by now.

So damaged myelin may require an extraordinary turnover of oligos, because some of them may have died off too.

But we certainly don't do it the way mice do. I think I saw a clip about remyelinating a paralyzed mouse, using human stem cells. Of course it worked, but I bet the oligos were wondering how they got there.

((BTW I read The Brain That Changes Itself. I tried to get the NDP party interested in a device that used a 3-direction accelerometer, like they use in cameras and cell-phones and handheld computers. It controls a tongue array, like the woman in that book who fixed her vestibular balance with an earlier version of that device, worn built into a hat. This device worked for her. There was a study on the device that I read about here, I think. That would have been great if I could use it to fix my balance problems.

The device failed to get FDA approval. The same company makes one that is approved, that helps blind people to see. It works.

There is a lot going on in phone-based medical devices. There is a heart monitor that you put your finger over the camera lens, and it draws an electrocardiogram. There is an ultrasound probe you can use to see your unborn child. They are trying to build a glucose meter into a band-aid like gizmo so you don't have to poke yourself. Etc.))

But back to oligodendrocytes. Now that work sounds quite amazing. I had thought almost every cell in your body was replaced every 7 or so years. I thought that was the case with most life-forms. But carbon-dating has proved trees are thousands of years old. Now, courtesy of nuclear bomb tests in the 50s and 60s, they have calibrations down to a fine degree. They can prove that my oligodendrocyte cells are 55 years old!

So if 3 percent are replaced per year that means I have replaced 165 percent of my oligos. So either my oldest ones have all kicked the bucket, or some have been replaced more than once. I guess that is certainly possible. That means unless I have an embryonic stem cell replacement I will have to make do with oligos that matured only recently. Maybe that's one of the reasons we age, because some of our cells can only be replaced so many times, before we forget how. If I replace everything (except oligos) every 7 years that's 10 or more turnovers at the age of 70.

It seems important whether "MS" causes an extraordinarily high turnover of oligos or not!
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Re: Remyelination: new research from Karolinska Institute

Post by cheerleader » Sun Nov 23, 2014 7:52 am

Karolinska says we replace one in 300 oligos a year---or .33% turnover in a year.
Meaning, in a normal adult lifespan--at a rate of 1% turnover every three years-- we never come close to replacing all of these cells.

I didn't say myelin production was "magical"--Karolinska says that the human brain has a preparedness for dealing with lower oligo generation:
In humans, oligodendrocyte generation is very low but despite this, myelin production can be modulated and increased if necessary. In other words, the human brain appears to have a preparedness for it, while in mice and rats, increased myelin production relies on the generation of new oligodendrocytes.
There's no doubt that stem cells will be beneficial in the process of remyelination (someday)
http://www.buffalo.edu/news/releases/2014/06/038.html

but while we wait ---learning a musical instrument, to benefit the corpus callosum
http://ed.ted.com/lessons/how-playing-a ... ion-1--158
ballroom dancing, yoga, a new language, physical therapy
can not hurt.
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Re: Remyelination: new research from Karolinska Institute

Post by 1eye » Sun Nov 23, 2014 1:51 pm

cheerleader wrote:Karolinska says we replace one in 300 oligos a year---or .33% turnover in a year.
Meaning, in a normal adult lifespan--at a rate of 1% turnover every three years-- we never come close to replacing all of these cells.

I didn't say myelin production was "magical"--Karolinska says that the human brain has a preparedness for dealing with lower oligo generation:
In humans, oligodendrocyte generation is very low but despite this, myelin production can be modulated and increased if necessary. In other words, the human brain appears to have a preparedness for it, while in mice and rats, increased myelin production relies on the generation of new oligodendrocytes.
There's no doubt that stem cells will be beneficial in the process of remyelination (someday)
http://www.buffalo.edu/news/releases/2014/06/038.html

but while we wait ---learning a musical instrument, to benefit the corpus callosum
http://ed.ted.com/lessons/how-playing-a ... ion-1--158
ballroom dancing, yoga, a new language, physical therapy
can not hurt.
cheer
Right. I missed a decimal point. After 60 years I have only replaced about 1/5 of 4 or 5 billion oligos. But if there is a high turnover because of inflammation, the number of original ones I have might be some lower. In fact, anecdotally, I think I have actually experienced (felt even) remyelination, which is perhaps what happens when we have remission. One day a physio was amazed to see me raise my left knee up high in the air. I was amazed myself. But except for my CCSVI procedure, I have not had any remissions in some years now. I think I may be short on oligos.

I agree that we have smarter oligos than mice do. I just haven't heard from them lately...
I am getting better on the piano. All by ear though. Can't dance with my walker. I was at a wedding last nigh, and I would've felt silly.
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Re: Remyelination: new research from Karolinska Institute

Post by Leonard » Sun Nov 23, 2014 11:47 pm

I think the slow replacement of oligodendrocytes explains why it takes on average 15 years from diagnosis to go to a wheelchair.
For dogs (experiments Putnam), rats this may be much faster.

We need the oligodendrocytes for remyelination. But they are not replaced/refreshed. That is because the oligodendrocyte precursor cells and their progenitors are dying, because of attack of non-working immune (that are EBV infected themselves).

Underlying is of course the viral connection. See also http://www.thisisms.com/forum/general-d ... 15188.html

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Re: Remyelination: new research from Karolinska Institute

Post by 1eye » Mon Nov 24, 2014 1:54 pm

This doesn't get at why they are dying/apoptotic. It is still unknown but I think we have some clues. There is a drug being tested:

http://www.ucsf.edu/news/2014/07/115856 ... -sclerosis

This drug has been seen to differentiate oligodendrocye precursor cells into new oligodendrocytes in vitro. These oligos have been seen to myelinate in vitro.

The problem in chronic "MS" seems to be that the precursor cells stay dormant. This drug may help.
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Re: Remyelination: new research from Karolinska Institute

Post by NHE » Mon Nov 24, 2014 5:52 pm

1eye wrote:This doesn't get at why they are dying/apoptotic. It is still unknown but I think we have some clues. There is a drug being tested:

http://www.ucsf.edu/news/2014/07/115856 ... -sclerosis

This drug has been seen to differentiate oligodendrocye precursor cells into new oligodendrocytes in vitro. These oligos have been seen to myelinate in vitro.

The problem in chronic "MS" seems to be that the precursor cells stay dormant. This drug may help.
Here's the abstract...

Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.
Nat Med. 2014 Aug;20(8):954-60.
  • Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.

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Re: Remyelination: new research from Karolinska Institute

Post by 1eye » Mon Nov 24, 2014 10:29 pm

In phase II in San Francisco. Glad it isn't like the Canadian Government's Ebola juice. That one was still in safety trials last week. Bet that made the Ebola victims real happy. It's kind of like what George Carlin used to talk about: cleaning the injection site with an alcohol swab before administering a lethal injection. Only lawyers and politicians really understand. Hope it works, and I hope they didn't limit it to "RRMS", whatever that is.

Only thing is, mousie oligos might not be the same as ourn. Something about the OPCs being quiescent...
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Re: Remyelination: new research from Karolinska Institute

Post by NHE » Mon Nov 24, 2014 10:39 pm

The study is still in the recruitment phase.

http://clinicaltrials.gov/ct2/show/NCT0 ... ine&rank=1

It's interesting that they list B12 as a safety concern and untreated B12 deficiency as an exclusion criteria. The inference is that clemastine interferes with B12. Or it could simply be that B12 deficiency causes demyelination which would interfere with the interpretation of the data.

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Re: Remyelination: new research from Karolinska Institute

Post by Leonard » Tue Nov 25, 2014 2:13 am

1eye wrote:This doesn't get at why they are dying/apoptotic. It is still unknown but I think we have some clues.
The OPCs are attacked by the immune cells because they are transgenic. Gene transduction occured during immune deficiency periods. The incorporated viral genes (transgenes) are tolerant to the body or no immune memory against these transgenes has established.

This explains the "auto-immunity". We should get the virus under control. And think more about implementing a protocol like the one suggested on this page http://www.thisisms.com/forum/general-d ... 8-600.html

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Re: Remyelination: new research from Karolinska Institute

Post by 1eye » Tue Nov 25, 2014 8:09 am

Seems like there is quite a bit of excitement over clemastine. There are 7 trials listed. Several manufacturers licenced to make clemastine are involved. One of the trials included DM. It is used on an MS symptom for pseudobulbar affect. It is thought to be synergistic with clemastine. It has now been withdrawn. Perhaps because they haven't any safety data yet on that combination.

However I think this is a sure sign all the excitement is over the repurposing game. They figure to be able to charge varying amounts depending on the indication. Of course, as usual, "MS" is the blockbuster, since we have so much of that green stuff on our hands and can't think of any good ways to spend it.

Really, this re-purposing game is morally and ethically a very repugnant thing. My fellow Americans ought to be ashamed. Somebody should write to Mrs. Obama about this. I personally think, that although P.T. Barnum was right about suckers, Novartis should not be allowed to do this, and nor should anyone else. Especially if they are already making untold huge sums on other drugs for the same indication. Really the trials should not be that expensive. If they were not spending so many millions, paying doctors to participate, to do very little work, the trials would not be so expensive. I know what I'm talking about, having seen how that money is spent. It is a cash cow of significant proportions. That's what pays for all those BMWs and Rolls's you see these doctors driving around. "Hey it's not our fault they're sick!" The trial I was in took place in a hospital, probably benefited them, without costing very much. Then there are the cheapo MRIs, that also help pay the bills. The guy who injected gadolinium into me looked about 18. Everybody wins! Well, almost everybody...

Probably they just figure the potential is so huge, that they can afford to run a lot of trials on this drug. Even if they have to pay $5000 per subject. Isn't it so nice to have "MS" and contribute to such a big industry? And the accountants! They probably cry all the way to the bank.

BTW the trial is limited to "RRMS". Whatever that is. Even though it is thought it will help remyelination, which is what is really needed after the damage is done and the cause of the damage has been addressed. That means the ones with the most damage would be the ones to benefit the most from remyelination. Not people with remissions, which indicates they are still remyelinating on their own. That is why I think some doctors and big pharma are really just extensions of the insurance business, looking to actuarial numbers and not really concerned about human suffering. :evil:

Do they have any data that indicates people with SPMS or PPMS will not benefit? I notice they are not concerned if they happen to be already taking "DMD" drugs. I guess it doesn't matter, since they don't help people remyelinate anyway.
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Re: Remyelination: new research from Karolinska Institute

Post by cheerleader » Tue Nov 25, 2014 12:58 pm

Yup, 1eye, the repurposing game is alive and well....so much cheaper than looking at aetiology.
The laboratory of Dr. Jonah Chan, a professor of neurology at UCSF, used a high-throughput method to identify Tavist and seven other Food and Drug Administration-approved medicines as potentially efficacious for multiple sclerosis therapy
.
As described in the paper, the research team screened 1,000 bioactive molecules in a unique platform called “binary indicant for myelination using micropillars arrays.” Among the molecules, eight had a positive effect on oligodendrocyte precursor cell (the myelinating cells of the brain) differentiation and remyelination. All eight worked through muscarinic receptors on oligodendrocyte precursors, but of the molecules tested, clemastine was the most potent.
http://multiplesclerosisnewstoday.com/2 ... rial-ucsf/
Kinda like throwing spaghetti to the ceiling, to see what sticks...

Clemastine remyelinated mice.
But Karolinska says that mice and men are different.
Side effects of clemastine include depression-ranging from drowsiness to coma...because of its affect on muscarinic receptors, including slowed stroke volume of the heart, and other cholinergenic effects on parasympathetic neural impulses.
Yeah, don't think so....
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