Genetics + Environment = Multiple Sclerosis
Posted: Mon Nov 21, 2011 10:25 am
Apologies in advance for my verbosity. I just wanted to share an e-mail exchange I had this past week with someone in which I found this infrequently-discussed subject interesting. . . . . .
Subject: Question
Hi George:
I am planning on getting the same HSCT done at Heidelberg around spring or fall of next year (if they do not reject me for whatever reason ... I will seek advice from you when I see you in San Diego as far as ensuring my acceptance to hospital).
I have a question for you since you you have done a lot of research on MS as follows. Since most researchers theorize that MS develops because a person is born with a genetic predisposition to react to some environmental agent that, upon exposure, triggers an autoimmune response. Since the genetic factor is not going to be affected by HSCT procedure and we really do know what is the environmental factor(s) that triggered MS so we can try to avoid it, why do you think that MS would not come back after immune system get reset by the procedure?
Let me your thoughts on this, but regardless, I plan on getting HSCT procedure done.
rgds
[name redacted]
Subject: Question
Hi [name redacted],
I really like the way you think. It is very logical and rational and correctly takes into account the related scientific principles thought (but not yet proven) to be at work causing MS.
It is still not yet confirmed or validated what exactly causes / triggers MS. But the current data seems to point firmly in the direction that genetics + environment = Multiple Sclerosis.
I have previously given this specific subject you bring up a lot of thought. And the reasoning behind your concern would seem to me to be valid. If it's true that the cause of MS has both a genetic and an environmental component factor (the current research seems to indicate this to be true), utilizing an autologous stem cell transplantaton procedure to reset the antigen epitope would be curative for MS by offsetting only one part (environmental exposure) of the etiological cause of MS. As an extension of this rational it would also seem logical that if the foregoing is correct, if a post-transplantation patient were to be re-exposed to the same causative environmental antagonist following autologous stem cell transplantation then the MS could be expected to re-emerge or re-manifest.
However, it is also believed (mainly from immunological population migration studies such as the Orkneys and Faroe Islands research studies) that the environmental factor that causes MS likey occurs during childhood, early adolesence or early adulthood at the latest. So in effect an autologous stem cell tranplant is like "turning the clock back in time" to before the environmental exposure occurs when only the genetic factor remains, producing lymphocytes that are not programmed and reacting to / by the environmental factor and eliminating MS disease activity. Under such a circumstance I would almost expect that some HSCT-treated MS patients would relapse following transplantation because of the chance they might be re-exposed to the environmental factor. But as of so far the clinical studies don't bear this out. In fact, so far 100% of MS patients that have had their MS disease progression stopped via autologous HSCT are still stopped today at more than a decade following treatment. So far there has been no MS patient documented to "relapse" following HSCT treatment (even though not quite 100% of patients are able to have their disease stopped immediately following HSCT of which virtually all of this minority population being progressive cases, of which it is still a mystery as to why this occurs at all).
So bottom line it makes sense from a logical perspective to think that HSCT-treated MS patients might relapse. But based on the current clinical trial work the data does not show this happening. Not in any mathematically meaningful way anyway. The most probable theoretical reason for this is because at the time MS is diagnosed (average age 30 years of age), an individual is far passed adolescence and and far passed the likely environmental exposure event, living in a different world with different environmental factors present. So in effect, most people have a different environment as adults versus when they are younger and that they are less likely to be exposed to the same set of environmental factors they experienced earlier in their life when MS is likely initiated. Hence, the "trigger" of MS is less likely to be present later in life and the MS is less likely to be re-activated. But in actuality, at this point this is just conjecture because this is all part of the big mystery of MS. I would guess that someday when it is definitevely determined what causes MS, this will help to unravel the unexplained mysteries associated with the treatment, prevention and absolute cure of MS.
Just a side note about the whole subject of HSCT to treat MS. . . . . over the past couple decades there have been a few very small groups of patients that have been documented to have both MS and some form of cancerous condition that required an allogeneic (donor stem cells / bone marrow) transplantation to save their lives due to malignant dysfunction of their own bone marrow. The interesting fact is that when donor stem cells engraft and complete inter-osseus population within the patient, the new bone marrow & stem cells then have the genetic makeup of the donor, not the recipient. At this point the bone marrow is comprised of a genome of a completely different person. So in effect, an allogeneic HSCT will address both the combined "genetic + environment" factors. So in theory such a donor transplantation 'should' 100% eliminate both factors and result in an absolute halting of MS disease activity with no possibility of MS disease reactivation. Unfortunately allogeniec HSCT is a far riskier (25-35% mortality rate) medical procedure as opposed to an autologous HSCT procedure (1% mortality rate) currently used for MS. (Certainly I wouldn't take such a risk if I had a choice. Unfortunately some people with cancer don't have a choice, lest they would certainly die without the procedure.) So I wouldn't expect anyone to make any large-population studies or even take the wild risk of utilizing allogeneic HSCT soley for treatment of MS. At this point its just a medical curiousity.
Side note: The university of Louisville in Kentucky is doing a tiny study (only three patients) of allogeneic HSCT specifically for MS. I'm not sure how far this work will go. All three patients have already been treated and luckily all three patients are still alive:
http://www.clinicaltrials.gov/ct2/show/NCT00497952
Sorry for my long-winded response. It's just the science that keeps me going.
Regards,
George
Subject: Question
Hi George:
I am planning on getting the same HSCT done at Heidelberg around spring or fall of next year (if they do not reject me for whatever reason ... I will seek advice from you when I see you in San Diego as far as ensuring my acceptance to hospital).
I have a question for you since you you have done a lot of research on MS as follows. Since most researchers theorize that MS develops because a person is born with a genetic predisposition to react to some environmental agent that, upon exposure, triggers an autoimmune response. Since the genetic factor is not going to be affected by HSCT procedure and we really do know what is the environmental factor(s) that triggered MS so we can try to avoid it, why do you think that MS would not come back after immune system get reset by the procedure?
Let me your thoughts on this, but regardless, I plan on getting HSCT procedure done.
rgds
[name redacted]
Subject: Question
Hi [name redacted],
I really like the way you think. It is very logical and rational and correctly takes into account the related scientific principles thought (but not yet proven) to be at work causing MS.
It is still not yet confirmed or validated what exactly causes / triggers MS. But the current data seems to point firmly in the direction that genetics + environment = Multiple Sclerosis.
I have previously given this specific subject you bring up a lot of thought. And the reasoning behind your concern would seem to me to be valid. If it's true that the cause of MS has both a genetic and an environmental component factor (the current research seems to indicate this to be true), utilizing an autologous stem cell transplantaton procedure to reset the antigen epitope would be curative for MS by offsetting only one part (environmental exposure) of the etiological cause of MS. As an extension of this rational it would also seem logical that if the foregoing is correct, if a post-transplantation patient were to be re-exposed to the same causative environmental antagonist following autologous stem cell transplantation then the MS could be expected to re-emerge or re-manifest.
However, it is also believed (mainly from immunological population migration studies such as the Orkneys and Faroe Islands research studies) that the environmental factor that causes MS likey occurs during childhood, early adolesence or early adulthood at the latest. So in effect an autologous stem cell tranplant is like "turning the clock back in time" to before the environmental exposure occurs when only the genetic factor remains, producing lymphocytes that are not programmed and reacting to / by the environmental factor and eliminating MS disease activity. Under such a circumstance I would almost expect that some HSCT-treated MS patients would relapse following transplantation because of the chance they might be re-exposed to the environmental factor. But as of so far the clinical studies don't bear this out. In fact, so far 100% of MS patients that have had their MS disease progression stopped via autologous HSCT are still stopped today at more than a decade following treatment. So far there has been no MS patient documented to "relapse" following HSCT treatment (even though not quite 100% of patients are able to have their disease stopped immediately following HSCT of which virtually all of this minority population being progressive cases, of which it is still a mystery as to why this occurs at all).
So bottom line it makes sense from a logical perspective to think that HSCT-treated MS patients might relapse. But based on the current clinical trial work the data does not show this happening. Not in any mathematically meaningful way anyway. The most probable theoretical reason for this is because at the time MS is diagnosed (average age 30 years of age), an individual is far passed adolescence and and far passed the likely environmental exposure event, living in a different world with different environmental factors present. So in effect, most people have a different environment as adults versus when they are younger and that they are less likely to be exposed to the same set of environmental factors they experienced earlier in their life when MS is likely initiated. Hence, the "trigger" of MS is less likely to be present later in life and the MS is less likely to be re-activated. But in actuality, at this point this is just conjecture because this is all part of the big mystery of MS. I would guess that someday when it is definitevely determined what causes MS, this will help to unravel the unexplained mysteries associated with the treatment, prevention and absolute cure of MS.
Just a side note about the whole subject of HSCT to treat MS. . . . . over the past couple decades there have been a few very small groups of patients that have been documented to have both MS and some form of cancerous condition that required an allogeneic (donor stem cells / bone marrow) transplantation to save their lives due to malignant dysfunction of their own bone marrow. The interesting fact is that when donor stem cells engraft and complete inter-osseus population within the patient, the new bone marrow & stem cells then have the genetic makeup of the donor, not the recipient. At this point the bone marrow is comprised of a genome of a completely different person. So in effect, an allogeneic HSCT will address both the combined "genetic + environment" factors. So in theory such a donor transplantation 'should' 100% eliminate both factors and result in an absolute halting of MS disease activity with no possibility of MS disease reactivation. Unfortunately allogeniec HSCT is a far riskier (25-35% mortality rate) medical procedure as opposed to an autologous HSCT procedure (1% mortality rate) currently used for MS. (Certainly I wouldn't take such a risk if I had a choice. Unfortunately some people with cancer don't have a choice, lest they would certainly die without the procedure.) So I wouldn't expect anyone to make any large-population studies or even take the wild risk of utilizing allogeneic HSCT soley for treatment of MS. At this point its just a medical curiousity.
Side note: The university of Louisville in Kentucky is doing a tiny study (only three patients) of allogeneic HSCT specifically for MS. I'm not sure how far this work will go. All three patients have already been treated and luckily all three patients are still alive:
http://www.clinicaltrials.gov/ct2/show/NCT00497952
Sorry for my long-winded response. It's just the science that keeps me going.
Regards,
George