Rho and degeneration

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Rho and degeneration

Postby TwistedHelix » Mon Mar 19, 2007 9:35 am

The Rho protein might be part of the pathway which, during 'overexcitement' and excess Calcium levels, triggers neuronal cell death:

tinyURL

Dom.
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Postby BioDocFL » Mon Mar 19, 2007 10:40 am

Dom,

Thanks for the link.

I have a meeting this afternoon to discuss a Rho project in cancer we have been working on. We are setting up to screen compounds to find potential drug candidates and we about have the assay ready for our robotics. Hopefully if we find something in our work, it could have some carry-over to neurodegenerative diseases. Once again, that's why I'm in cancer research, even though I'm interested in autoimmune diseases, the projects are further along in cancer research. If we find something, it will still need to go into cell-studies, mouse-studies, and clinical trials. Most drug candidates washout somewhere along the line but we'll just keep plugging away, hunting for more candidates.

Your posting was timely, at least it will keep a thought in the back of my mind.

Wesley
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Postby gwa » Mon Mar 19, 2007 11:54 am

BioDocFL,

Every now and then someone posts about how the drug companies don't want to find cures for diseases because they make more money by keeping patients on drugs for chronic conditions.

I am curious if anyone has ever told you to just come to work and look for continuing treatments rather than looking for a cure for cancer.

If you found a cure for cancer, would knowing that drug companies wanted to keep patients on forever therapies keep you from disclosing such a monumental find?

It has always seemed to me that whoever gets to the line with the cure product first, whether it is for cancer, MS, diabetes, etc., wins big. I cannot see an intelligent reason to not race for these cures before another company comes in first with a huge money making product.

Since you spend your life researching cancer, I am interested in what you think about this topic.

gwa
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Postby TwistedHelix » Mon Mar 19, 2007 1:33 pm

BioDocFL,

I'd be fascinated to learn what processes MS and cancer share--at a guess it's apoptosis or a problem during mitosis, which have been mentioned before in relation to MS, but I know Rho is being investigated in both diseases. It's great you have an interest in two areas: I sometimes fall into the trap of thinking researchers have a (necessarily) narrow field of view.

gwa: good question. I think the anonimity of scientists, the Hollywood view of evil corporations, added to our desperation and impatience, can sometimes lead to that impression. Being able to talk to BioDoc is very welcome,

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Postby BioDocFL » Mon Mar 19, 2007 4:42 pm

GWA,

Just finding something that inhibits the target enzyme is difficult. Often if it inhibits one enzyme, it might inhibit another that you did not intend. Therefore it might be toxic. If we screen 20,000 compounds, we might get maybe 30 that look promising. Then we need to test them in other enzymes to see if they are specific or not. Then we have to see if they can even get into cells to begin to work. Too often they don't get into the cell at a reasonably low dose. After that, we have to test them in multiple cell lines to see if perhaps kidney cells are particularly sensitive versus liver cells for example. Then it goes to mice. Then probably larger animals, then clinical trials. Just getting one compound to clinical trials is a major feat after screening 100,000s. We do rational design, which means if we have a possible candidate, we can figure out what modifications might make it better. We use computer modeling a lot for this when possible. We are all looking for the perfect cancer drug. The trouble is, if a drug kills tumor cells, it probably also kills a lot of intestinal tract cells as an example because these have a high rate of reproduction kind of like many cancer cells and so they are vulnerable. Thus you have to try to use the lowest amount of a drug so that it kills the tumor cells but doesn't destroy the GI tract. Of course nausea and dirrhea (sp.) are major problems with any treatment.

I think in another topic there was something about a CEO from a drug company wanting to make cancer chronic rather than terminal. I've got to believe that that is way out of context from what he/she intended. Cancer is usually terminal if not treated. Even if you treat it, you run the risk of killing the patient from the drugs. Even if you find a drug that will cure this bout of cancer (ie. kills this tumor), the patient is probably still going to be smoking two packs of cigarettes a day, even while towing an IV stand around during chemotherapy. So the patient's risky behavior is chronic, their intake of carcinogens is chronic by choice, so the risk of cancers will persist. If you find a drug that reduces the cancer to a manageable state (pain reduction, no spread, no loss of functions), even though the cancer or cancer-potential is still there, a drug that can manage it might be better than the patient dying untreated or the patient dying from too potent of a drug. It is very frustrating to work on cancer treatment but then have to walk through clouds of cigarette smoke just outside of the hospital where patients and visitors go to smoke. Even if they don't have lung or throat cancer, smoking exacerbates other types of cancers and reduces the effectiveness of therapies.

Anyway, I don't see any of that evil nature in researchers. There might be some people in sales at corporations who like to see sales figures go up for drugs they are marketing just because they are money oriented but I don't think any of them want to see patients suffer if the better drugs can be found. The research is expensive though so a successful drug in one field can fund the development of other drug candidates, bearing in mind that many will fail.

In another topic there was discussion of patents. I would like to see an improvement in the way scientists are motivated besides the patent process. Usually the patent is in the company's control even if you are one of the inventors. It varies from company to company as to what the inventors will ever recover. Often it is lawyers who are deciding the future of the invention early on and all we can do is watching from the sidelines as negotiations are occurring. Conflict of interest can prevent us from throwing in our two-cents worth even though it is our invention.

So, anyway, finding drug candidates is usually hit-or-miss (hit-or-a million misses actually). So to think we can focus on finding drugs that make big money and just maintain the patient as a chronically sick cash cow is completely unreasonable. I don't see anyone thinking like that in the research field. However, there are very big egos and it is extremely competitive to get funding and to get timely results. So some researchers are really pushing for their projects to progress in competition with others. That's where peer review is important among scientists to hopefully get the best projects funded, in academia and in industry. Sometimes pet theories and hypotheses can become entrenched, so it is not always efficient but eventually works out.

Hope you don't view all of us mad scientists as evil. I'll have to send my henchmen to persuade you.


Dom,

I think cancer and autoimmune diseases can have some common features. It is just that cancer cells are poised for replication when they get out of control and so they keep on dividing. In autoimmunity, the cells are already differentiated (matured) and poised for apoptosis when something goes wrong. So, if the same feature (say DNA repair) goes wrong, the cell poised for replication can become cancerous, the cell that is already matured and differentiated will simply go into apoptosis. One leads to a tumor of bad cells, the other leads to a loss of cells in some key site, like a lesion site in the brain.

It's late, I've been in meetings all day. Time for me to go home.

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Postby gwa » Tue Mar 20, 2007 11:37 am

Wesley,

Thank you for your well thought out reply to Dom and me. What you have indicated as far as why better treatments are not here yet confirms my own beliefs on the situation.

One of my neuros had told me many years ago that the technology simply was not here yet to find the cures that we all so desperately want. This sounds like your position too.

I have met a few scientific researchers and they were all very humble and encouraging people. I do not believe any of them would not go full force in finding cures for the diseases they are researching.

You need to post your response the next time that you see a drug company basher on the premises.

Good luck in your pursuits.

gwa
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Postby LisaBee » Tue Mar 20, 2007 5:10 pm

OK,

I posted the CEO remark that got me really spooked and I wish I had annotated it better. I didn't mean to imply that I personally think all research scientists are evil people wanting to have the entire world population limping along on multiple medications in order to keep whatever ailment they have at some "manageable" level that pumps up company profits. On the contrary, I think most basic researchers are highly motivated to find something that will benefit. It is the business model of the pharmaceutical industry that has got me concerned, and I believe it is a valid concern, not just for MS, but for other diseases. I am concerned that the bulk of basic research has become concentrated in these companies, and that tax-based public funding of research seems to have shrunk dramatically. If I'm wrong in that impression, someone please let me know.

A pharmaceutical company generates profits by selling drugs, and the more drugs they can sell at the highest possible profit margin, the better business is for them. It it wasn't we wouldn't hear the word "blockbuster" so much. That's the model. They advertise incessantly on the TV, spending billions on that alone. I see the term "chronic disease management" a lot, chronic disease managements meaning lifelong medications. There is so much focus on management, so much profit in management, that "management" vs. "cure" seems to be the over-arching goal. This is not unique to MS, which is what prompted me to put up the post about the cancer statement because that was the impression I got from CEO remark. Maybe I did take it out of context, but like I said earlier, my fear is that I didn't.

Conversely and sadly, the world is also full of people dying from completely treatable and curable diseases, but there is no profit in treating them because they and their governments don't have money to buy drugs. There is something very wrong in all this.

In the MS area of research, what has frustrated me most of all is that potential treatments based on existing drugs, vitamins, hormones, etc. that appear to have at least as good a response based on either animal model or intitial human data in small scale studies, do not receive any funding or attention for follow up. So I would argue with gwa that the technology is not there to explore these options. The reason is more fundamental: there is no money in it for a for-profit company to pursue research on them because they cannot be patented. There is no data that shows these treatments don't work, so we don't know that they don't work. There is insufficient evidence to show they do work. That is what has me angry. If we already had full scale clinical trials to show vitamin D doesn't work, uric acid levels don't matter, hormones don't matter, antibiotics don't help, etc. I wouldn't be so upset. Some of these are being investigated to the degree they can be, but they are starved of funding. And frankly, there was evidence to support their investigation decades ago, but once the autoimmune model for MS became dominant all other research areas were largely cast aside.

So they have languished. All has come out the end of the MS treatment pipeline as "FDA-approved" treatments are extremely expensive medications, difficult to administer, with numerous serious or quality-of- life-degrading side effects, and at best, only modest indication of efficacy. I concede the jury's still out on Tysabri on the efficacy point and I hope it will prove better, if its cost and side effects don't do it in.

The other big area of MS research that has been, IMO, underserved is the characterization of the differences of MS patients. We are all lumped together and treated like we have the same disease in spite of the huge differences in presentation and rate of progression. And then clinicians sit around and lament about how we respond differently, if at all, to the CRABs. I don't see any research coming out to support clinicians to make a better recommendation for an individual patient. I can tell you, there is more than one way to demyelinate a neuron. There are numerous different toxicants, different infectious agents, nutritional derangements, hypoxia, disturbances in myelin synthesis and repair, both congenital and acquired, on and on. Twisted Helix has been posting about various biochemical markers found in MS patients, and I've seen abstracts going back 20 or more years in which unusual metabolites would be found in a subset of MS patients, but not all of them. Why these findings seemingly got left in the dust, or don't get integrated into a medical survey of MS patients, I can't understand.

I also share BioDocFL's frustration regarding the known causes and contributors to developing diseases and how little there is on prevention. The biggest two source areas for chronic disease in the US and Europe, IMO, are diet and tobacco, in that order. I used to put tobacco first but I think diet is actually the #1 problem now, especially in relation to Type II diabetes. Yet the field of nutrition research is one of those unwanted stepchild areas. After all, it is only food. Agrobusiness certainly doesn't want us to eat less. And we get a steady diet of diabetes medications popping out the drug pipeline.

Personal observation: The more expensive the drug, the fancier the pamphlet put out to sell you on it. When I decided to give Copaxone a try, I got mailed a spiffy calendar and a Teva pen to write with. I'm surprised I didn't get a mug, a keychain, and a bumper sticker for my car, too. Put money into research. Don't FedX me a pen.

Frustrated? Absolutely.

Lisa
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Postby TwistedHelix » Wed Mar 21, 2007 12:18 pm

Hi Wesley,

Thank you very much for your informed and informative reply. Like LB, I never intended for you to think that I personally believe that scientists are wicked megalomaniacs, (I'm far too scared of your henchmen to do that), I was just trying to show how I think that opinion can arise amongst frustrated and desperate patients. A few weeks can seem like an eternity, and the years it takes to isolate, develop and test a drug can be too hard to contemplate.

LB: surprisingly perhaps, the last couple of paragraphs in Wesley's post are not a million miles away from what you are saying. You reminded me of something which I said recently: that public funding ought to be directed to some of the more promising areas of non-profitable drugs or supplements -- they might not be able to rake in the cash in the traditional sense, but governments would SAVE a small fortune if they could treat or eradicate certain diseases.

Also, my ears pricked up when I read the word,"hypoxia". I've got a bit of a thing about sleep apnoea being a potential cause of oxygen starvation, especially since recent research has shown it can cause "silent" plaques in the brain. I've always suspected that I might suffer from it, but so few people have been willing to wake up next to me that it's hard to prove :( !

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Postby BioDocFL » Wed Mar 21, 2007 12:37 pm

Dom,

Don't worry about my henchmen. A good thwack on the nose of one of them and they all run away crying. They're pretty good at groveling and excuse making but I had to send them back to remedial grave robbing for the third time recently!!! And don't get me started about their so-called 'kidnapping' attempts. It can really get embarassing!!!

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Postby TwistedHelix » Wed Mar 21, 2007 12:56 pm

Henchmen, eh? Just can't get the staff, can you?
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Re: Rho and degeneration

Postby TonyJegs » Mon Apr 23, 2007 1:50 pm

TwistedHelix wrote:The Rho protein might be part of the pathway which, during 'overexcitement' and excess Calcium levels, triggers neuronal cell death:


- Dom

It is not as simple as it seems.

First of all, Rho’s do not ‘kill neurons’, they regulate and limits their growth, esp. dendritic/axonal growth, under stimulation. They are only a part of very complex system of neuroplasticity.
Keep in mind that that Rho family activation regulates the initial morphogenesis of the myelin sheath; they work together with MLC phosphorylation, which increases dramatically but transiently at the onset of myelination.
A key role of Rho (through its effector ROCK) on OL lies in coordinating the movement of the glial membrane around the axon at the onset of myelination via regulation of myosin phosphorylation and actomyosin assembly.

In common language: without Rho – wild uncontrolled axonal growth without following proper myelination (defective could occur but it will not last long); with Rho – controlled, precise growth of the axon with following proper myelination. Take a guess, which variant is better.

- LisaBee

I try to believe that some scientists, when writing such kind of articles, were forced to do that for good reasons and not for funding purpose. Otherwise it could be another sample of false statement, when only part of the problem/action was shown without connection with others, which leads to formation of another misconception (please check my post on ‘pregnant mice’ article).
And you know, any new misconception will keep people busy since establishing, more studies and efforts will be required to disprove it.

Kind regards,
Tony
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First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer
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Postby TwistedHelix » Tue Apr 24, 2007 7:40 am

Tony,
The information you provided details some of the normal functioning of the Rho protein. The article which I provided the link to in my first post, however, describes the discovery of a brand new pathway involving Rho, which can lead to cell death,
Dom
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Postby TonyJegs » Sun Apr 29, 2007 3:41 pm

TwistedHelix wrote:... the discovery of a brand new pathway involving Rho, which can lead to cell death


Rho’s play a key role in regulating the actin cytoskeleton of the neuron that means – structural integrity and movements, mostly of dendrites/axons; presence of Rho is crucial for brain development. Rho’s are responsible not only for changes in axons configuration, they promote glial cells activation and their re-arrangement around the axon.
For any kind of movement the presence of calcium is mutual (like a gas for the car engine), no calcium - no movement. In mature cells Rho’s behave like a ‘gardener’ carefully pruning unused (or became unused) dendritic/axonal branches, maintain the current structure and promote carefully wrapping them up into myelin sheaths (activation in OL and other glia cells).
After Rho’s activation, which is partly mediated from myelin associated glycoproteins, there must be additional influx of calcium into the neuron (and glia cells) at once, to serve further Rho’s actions. The amount of calcium depends on amount of activated Rho, the regulation goes by demand. Under normal circumstances this amount will never go over the physiological limit, otherwise the structural development and constant repair of the brain tissue will be simply impossible. Rho’s never go ‘after’ the neuron’s body, they work on compartmental level only.

The extended time of survival in the neurons under extreme conditions, when Rho’s were inhibited, was depended on this ‘Rho assigned’ amount of calcium which was eliminated from total quantity of calcium influx/entry.
Keep in mind, when Rho’s are inhibited, the chain of further events associated with Rho is halted, and these events are calcium depended also. The intracellular calcium under this condition will be much lower than usual when the stress was applied.
In other words, in this study we have weak and delayed response of neurons to applied over-stress, and, of course, these neurons will last longer. But this has nothing to do with real life event – cell death.

That’s why Rho’s activation alone could not be considered as “brand new pathway of cell death”, it is technically incorrect. It is not even ‘new’, it is any.

Apoptosis is pretty complex, and I don’t think that it is correct to pick up the separate part of the whole process and claim its entire responsibility for neuronal death. It wouldn’t happen unless you have an idea to promote the compound which inhibits Rho.

In addition, it was shown that the Rho-kinase inhibitor only partially prevented axonal degeneration in brain; this confirms that other factors were participated (and actually caused the total axonal degeneration with following neuronal death).
Also, the attempts to detect activation of Rho in the injured axons following sciatic nerve transection have failed. There is a question: how it could be possible, that in this pretty complicated situation, when neuron’s body located within spinal cord (a part of CNS) and has the very long (leg’s long) axon and therefore is more vulnerable and dependent of the inner structure, this “brand new pathway of cell death” is not being deployed?
Take a guess.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer
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