Could bone marrow studies be useful?

Hutan said:
Sounds interesting, that could be a valuable resource. Is there anything we can do to help progress a study on the samples?
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I don't think so, I'll ask some questions about their availability and quality.

It would be nice to try clear up if the cell themselves are developing abnormally or if they're responding normally in the context of their environment. Though I'm not sure a bone marrow study would entirely answer the question.
 
A big problem with bone marrow is heterogeneity within the tissue. Different types of cells are competing for niches to develop in. We have no successful studies of marrow in other diseases like lupus or RA that answer this sort of question as far as I know.

Bone marrow sampling is also very painful in many cases.
 
Jonathan Edwards said:
A big problem with bone marrow is heterogeneity within the tissue. Different types of cells are competing for niches to develop in. We have no successful studies of marrow in other diseases like lupus or RA that answer this sort of question as far as I know.

Bone marrow sampling is also very painful in many cases.
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Yes, although so often an investigation of a person with ME/CFS is like that story of a drunk man looking for his keys at night- he looks under the lamp post, not because he thinks the keys are there, but because that is where the light allows him to see. Every single doctor I've seen would do a blood test, even though they only looked for the same things that had been looked at before and that had failed to show anything much.

I'm not sure that we know what the question is. So, an existing collection of ME/CFS bone marrow, collected, as you say, with a significant amount of sacrifice on the part of the donors, is a bit like turning on a light in a new part of the street to widen the search. If the samples are in any sort of condition that allows some investigations, it seems to me a shame not to look at them.

But yes, I see what you are saying about heterogeneity - a needle in a haystack problem. Perhaps, even if there is a problem in the bone marrow, we'd have to sample from the exact right spot. There was a theory that antigens were being harboured in skull bone marrow.
 
Hutan said:
I'm not sure that we know what the question is.
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I think we know what the question is and I think @MelbME would agree. It is whether any skewing to VH3-30 is occurring because of a shift in checkpoint-dependent selection in the bone marrow environment or once the cells have gone out into lymph nodes. If we could answer that it would be of huge value.

But it needs very careful usage of controls and normalisations of data. If bone marrow sampling was easy it would be a viable project - maybe a pilot study of 50 pro bands and 50 controls and then scale up and replicate with 200 of each. But that would be very tough.

It is not so much looking for a needle in a haystack as trying to establish whether heartsease is a commoner weed in Martlesham fields than Boromeswell fields using 20 samples of ground ten metres in diameter at each site when heartsease grows in scattered clumps depending on the amount of moisture, sunshine, slope, recent fertiliser dressing and what crops were grown last year. You might need 1000 samples, not because heartsease is hard to find but because it is patchy.

I suspect that to get a reliable estimate of a B cell repertoire shift you might need ten bone marrow samples from the same patient.
 
Jonathan Edwards said:
If bone marrow sampling was easy it would be a viable project - maybe a pilot study of 50 pro bands and 50 controls and then scale up and replicate with 200 of each.
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Does that mean 50 PwME and 50 control people? (I'm not sure if you're talking about people here or some bit of people's biology).

I suspect that to get a reliable estimate of a B cell repertoire shift you might need ten bone marrow samples from the same patient.
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What disease would a PwME have to have to have ten bone marrow samples as part of the investigation/treatment? Is there such a thing? If so, can we glom onto the relevant clinics and do the research?
 
Sasha said:
Does that mean 50 PwME and 50 control people?
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yes

Sasha said:
If so, can we glom onto the relevant clinics and do the research?
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The problem is that one bone marrow sample is very unpleasant. People with life-threatening leukaemia may get half a dozen bone marrows over a period of months or years but one at a time. To do this B cell sampling in ME/CFS you would need ten samples on the same day. A bit like being in the first row at Agincourt I suspect.

And of course it would be of no value to that person's treatment. There is no way I could ask a patient to undergo that.
 
Jonathan Edwards said:
The problem is that one bone marrow sample is very unpleasant. People with life-threatening leukaemia may get half a dozen bone marrows over a period of months or years but one at a time. To do this B cell sampling in ME/CFS you would need ten samples on the same day. A bit like being in the first row at Agincourt I suspect.

And of course it would be of no value to that person's treatment. There is no way I could ask a patient to undergo that.
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Could bone-marrow sampling be done as part of organ donation when a PwME has passed away? The MEA has an information leaflet about organ donation, though it says that only about 1 in 100 people die in circumstances that would allow organ donation.

Or could a single bone marrow sample taken from a PwME because of leukemia be grown in a lab to yield more samples? (Not sure if that addresses the patchiness problem.)
 
Sasha said:
Could bone-marrow sampling be done as part of organ donation when a PwME has passed away?
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If they were killed in a traffic accident maybe but the cost of organising that would be astronomical - many millions.

Sasha said:
Or could a single bone marrow sample taken from a PwME because of leukemia be grown in a lab to yield more samples?
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No because B cells only grow in bottles if you bock normal selection controls - so the population of antibodies produced would be entirely an artefact of the culture system.
 
Jonathan Edwards said:
The problem is that one bone marrow sample is very unpleasant.
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I'm going to have one last go. This says that that bone marrow is usually taken from the hip. What about PwME going under anaesthetic for hip surgery, such as hip replacement? Or indeed general anaesthetic for anything? Or would the pain or infection risk after taking samples be significant?
 
Jonathan Edwards said:
It is not so much looking for a needle in a haystack as trying to establish whether heartsease is a commoner weed in Martlesham fields than Boromeswell fields using 20 samples of ground ten metres in diameter at each site when heartsease grows in scattered clumps depending on the amount of moisture, sunshine, slope, recent fertiliser dressing and what crops were grown last year. You might need 1000 samples, not because heartsease is hard to find but because it is patchy.
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Ah, ok. So, with this existing collection of ME/CFS bone marrow samples that @MelbME mentioned, you might find the equivalent of heartsease in some of the samples, but because of the patchiness etc, and especially given the collection is probably small, you don't have enough data to know if that is abnormal or not.

Like I said, there has been conjecture that pathogens or at least antigens might be in bone marrow. If a pathogen was found in ME/CFS bone marrow that could be a clue. That might be a useful study for the samples MelbME mentioned.

I rather like @Sasha's hip replacement sampling idea for getting new samples. Could a chunk of the old hip, or a sample of bone marrow not be frozen and sent off to a researcher? I guess there would be the confounding of the cause of the hip replacement, but you would be collecting bone samples from people without ME/CFS who needed a hip replacement as well. Maybe the confounding would be too big a problem. Maybe there would be another disease community that might want a bone sampling project done as well, so that the admin effort had a greater pay-off.

And the idea of bone marrow samples from people with ME/CFS who die seems possible. There is discussion of getting stem cells from deceased donors - the cells might remain viable for a few days after death. Bone marrow cells from mice are reportedly ok for 4 days after death. If there was enough funds and a feeling that it was worth doing, I expect it could be done. Logistically, it would be difficult. I expect the biggest problem with this is ethics. You would not want to incentivise people with ME/CFS to give up on life.
 
https://www.hra.nhs.uk/planning-and...ation,and cartilage tissues in osteoarthritis.
Scottish study:

This study and ethics application is for tissue sampling whilst patients are undergoing total hip replacement surgery. Tissues to be sampled include (1) bone marrow, (2) waste tissues which are normally discarded following a total hip replacement (e.g. labrum, synovium, excised cartilage/bone, ligaments, capsule), and (3) peripheral blood (20ml).

A bone marrow aspirate is obtained via a needle inserted into the pelvis intra-operatively and drawing up a small volume of the marrow fluid. This is a standard procedure and technique used in the management of haematological disease (normally done under local anaesthetic) As our patients will be under a general/regional anaesthetic for their hip replacement, the bone marrow aspiration will not cause any additional discomfort.

Adult stem cells occur in many tissues and can differentiate into specialised cells in their tissue of origin or differentiate into cells characteristic of other tissues. Adult stem cells are already used to treat haematological malignancies and have huge applications in the field of tissue engineering and regenerative medicine, in particular the regeneration of bone and cartilage tissues in osteoarthritis. We aim to harvest stem cells from these tissues to better understand the resident cells, including mature and progenitor cells from mesenchymal/stromal and haematopoietic systems. Through this, we aim to increase a mechanistic understanding of the interaction of these heterogeneous cell mixtures.
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Collection of samples while people are undergoing hip replacements.
They aren't taking the bone marrow from the excised bone, they are collecting it separately via needle. So, that doesn't solve the problem of not getting a good enough representation.
 
Jonathan Edwards said:
I think we know what the question is and I think @MelbME would agree. It is whether any skewing to VH3-30 is occurring because of a shift in checkpoint-dependent selection in the bone marrow environment or once the cells have gone out into lymph nodes. If we could answer that it would be of huge value.

But it needs very careful usage of controls and normalisations of data. If bone marrow sampling was easy it would be a viable project - maybe a pilot study of 50 pro bands and 50 controls and then scale up and replicate with 200 of each. But that would be very tough.

It is not so much looking for a needle in a haystack as trying to establish whether heartsease is a commoner weed in Martlesham fields than Boromeswell fields using 20 samples of ground ten metres in diameter at each site when heartsease grows in scattered clumps depending on the amount of moisture, sunshine, slope, recent fertiliser dressing and what crops were grown last year. You might need 1000 samples, not because heartsease is hard to find but because it is patchy.

I suspect that to get a reliable estimate of a B cell repertoire shift you might need ten bone marrow samples from the same patient.
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Yeah this was my fear and I hadn't even thought 10 samples, that's just not something worth doing now. If the VH3-30 was to become accepted as a clear part of the disease mechanism then maybe someone does the bone marrow study but this is a project on the scale of DECODE in terms of cost and time.

Nevertheless, I'll still check to see what number of samples are available if any.
 
Sasha said:
I'm going to have one last go. This says that that bone marrow is usually taken from the hip. What about PwME going under anaesthetic for hip surgery, such as hip replacement? Or indeed general anaesthetic for anything? Or would the pain or infection risk after taking samples be significant?
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Hip replacement idea is clever, I wonder if that would be possible.
 
MelbME said:
Yeah this was my fear and I hadn't even thought 10 samples, that's just not something worth doing now. If the VH3-30 was to become accepted as a clear part of the disease mechanism then maybe someone does the bone marrow study but this is a project on the scale of DECODE in terms of cost and time.
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I think DecodeME only cost £3.2m, which is peanuts in the grand scheme of things. The UK government blew £5m on PACE, which was utterly without merit. RECOVER spend $US 1bn without finding anything. If this is an important study, I think the money should be spent, if a strong case can be made.
 
MelbME said:
Hip replacement idea is clever, I wonder if that would be possible.
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It is, but I wonder how many are done?

Several friends and close relatives of my age (mid-60s) have already had hip and knee replacements. Mine are in fantastic nick, though! Not because I've been lucky or careful; because for the last 25 years I've been unable to do most of the things that wear them out.
 
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