Multiple sclerosis is a devastating condition that affects the nervous system of young adults and results in significant disability.
Research in my group aims to understand the reasons for damage to neurons in the brain in MS and how we can develop drugs to stop it.
To do this we use a combination of neurons grown in cell cultures, animal models of MS (primarily rats) and human brain tissues.
Research involving animals forms an important element of our work, but is not undertaken lightly. In recent years, we have worked at improving the animal models of MS to make them better reflect what we know about how MS affects the human brain.
This has also led us to carry out more of our research using human brain tissues donated after death, which has resulted in a substantial reduction in our use of animals.
This is also a reflection of my role as Chair of the 3Rs Advisory Group and my effort to improve and disseminate the 3Rs (Replacement, Reduction, Refinement) principles among Imperial researchers (http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/regulation/).
Multiple sclerosis research by me and my team:
Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space (2015) http://onlinelibrary.wiley.com/doi/10.1111/nan.12199/abstract;jsessionid=A067D6A5EA8B2B97DB524DF6BCBFCC8C.f02t02
Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats (2013) https://academic.oup.com/brain/article/136/12/3596/445144
An ex-vivo multiple sclerosis model of inflammatory demyelination using hyperbranched polymer (2013) https://www.sciencedirect.com/science/article/pii/S0142961213004547?via%3Dihub
Animal research at Imperial College London: http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/
About the Multiple Sclerosis and Parkinson’s Tissue Bank: http://www.imperial.ac.uk/medicine/multiple-sclerosis-and-parkinsons-tissue-bank/
Animal research report 2016/17: http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/annual-report/
I'll be back at 11:00 EST / 16:00 GMT to answer your questions!
11:00 EST: And we're live! Now answering your questions.
UPDATE: Thanks very much everyone for your great questions. I've really enjoyed answering them. I'll be checking back in from time to time, so please do submit any more questions you may have.
And a big thanks to /r/science for hosting this AMA!
Have you found any link between the promotion of issue/disease due to consuming animal products? Thank you for your time.
Hi. To my knowledge there is absolutely no evidence of a link to developing multiple sclerosis.
Hi Richard, and thank you for doing this AMA.
A couple of questions for you on B-cell targeting therapies in MS:
What is the turnover rate of autoreactive B-cells within the CNS of patients with MS? Are these cells moving in and out of the brain or have they largely taken up residence there? Are these kinetics different between RRMS vs. PPMS?
On tertiary lymphoid organs in MS: do you think these are required for disease progression/activity? Or can the autotreactive B-cells and T-cells sustain a pathologic response in the absence of TLOs?
For fun: in your mind, is there any substantial difference between rituximab and ocrelizumab.
Hi there. Thanks for your questions.
Sorry, I don’t know the turnover rate of autoreactive B cells in the brain of people with MS. There is evidence for the movement of B-cells from the circulation into the brain space at all stages of MS. However, there is also evidence that there is a build up of these cells in the fluid filled spaces around the brain that becomes self sustaining and may play an important role in the long term accumulation of pathology. We don’t know how this differs between the early stages of RRMS (Relapsing Remitting MS) and the progressive stages in SPMS (Secondary Progressive) and PPMS (Primary Progressive).
I think that the tertiary lymphoid organs we have described in the meninges of the MS brain are instrumental in causing neurodegeneration in the underlying brain and the more of these structures that build up then the more neurons are lost. So I do think that they can drive disease in the progressive stage.
I understand that ocrelizumab is a fully humanised antibody whereas rituximab is not, which means that the body does not make neutralising antibodies against it so readily. They also have different affinities.
Thank you very much for doing this AMA we appreciate it. I do have a few questions though:
Have you stumbled across any possible causes to MS that perhaps hadn't been, or have yet to be, fully considered?
How is it that you research animals with MS? Do you induce it in the rat or must you hunt around for rats already predisposed to the disease?
Again, thank you for your time, we all appreciate it.
Hi, you're very welcome.
No we have not uncovered any new possible causes. The great difficulty of studies on the causes of MS is that the initial trigger may well occur many years before the disease manifests itself. Therefore, it is extremely difficult to track backwards to work out what the trigger was.
Rats do not spontaneously get MS like disease. However, we use rats that are genetically susceptible to autoimmune disease and then induce an MS-like disease.
Hi Doc, I have a relative with MS and I'm also an insatiably curious, aspiring science fiction writer. I can't help but ask; what do you think of helminthic therapy (that is; introducing a parasitic infection such as a hookworm infestation as treatment) for MS or related diseases? Furthermore, if you dismiss it summarily, why do you do so easily?
Hi wandermike. It is possible that parasitic infections can change the way that the immune system interacts with the brain, in the same way that gut bacteria can. Therefore, I would not dismiss it completely. However, as a scientist I would not advocate a therapy that has not yet been shown to be effective following testing in a randomised placebo controlled clinical trial.
Can we replace the use of animals in such tests? And how much of the data obtained from the use of animals does not match the reality when the you go to human trial and testing?
Thanks for your question!
We can replace the use of some tests but not yet all. It is not yet possible to model the complex interactions that occur between the brain and the immune and endocrine systems in multiple sclerosis.
Once you have identified a molecule that may be causing damage in the brain, it is possible to test this using cells in culture, but the ultimate test needs a system in which all the complex interactions of the systems of the body occurs.
Difficult to say how many studies using animal models do not match what is happening in the human. The reasons most clinical trials fail is not to do with this.
What's your opinion on Using Fecal Matter Transplants for auto immune conditions like MS.
Hi John. This is a very new area of research and there is good evidence that the types of bacteria in our gut can have a big influence over how immune mediated conditions affect an individual.
Because MS is an autoimmune condition of the brain it is very likely that the gut bacteria may influence how the immune system is causing disease.
However, it is too early to know exactly how this occurs. The early studies are using fecal matter transplants, but ultimately it would be better to know which specific bacteria are involved.
Why are rats the most effective models for MS? How do you implement the 3Rs into your research?
Thanks for your question, hansyhobs.
MS is an immune mediated condition and the rat has an immune system that is much more similar to the human than the mouse is. Models of MS in the rat seem to mimic the characteristics of the human condition much better.
My research has concentrated first on a very detailed study of the human MS brain to work out what is causing the damage to the brain tissue. We only then use an animal model to test the idea obtained from the human tissue studies. At this stage we refined the animal model being used for MS studies by inducing MS-like damage in the brain but without any of the unpleasant symptoms often associated with these models.
So in this instance we have replaced the use of animals for these early studies with the use of human tissues and then refined the animal model. Once we have tested the idea in the animal model and found it to be correct, then we turn to cells in culture to identify a possible drug target. So the 3Rs (Replacement, Reduction, Refinement) are being implemented at every stage of the research. It is my opinion that good animal welfare is essential for good science.
If it’s of interest, you can read more about our animal research and welfare processes here: http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/
I'm curious about any research you may have done with cannibinoids (eg: THC/CBD/CBN and other sub chemicals within the group) research and MS? Being in Colorado and a patient advocate in a previous life I've seen first hand how a natural 'drug' like cannabis has very positive results for some MS patients. some specific cannabis strains also seem to be more effective. We have all seen numerous bad side effects from various formulated drugs, but we do not see the same with cannabis. can you address patient health with a natural substance versus a man made drug that may cause additional health problems?
Thanks for your question EC_CO. I have not personally conducted any research on cannabinoids in MS. As you probably know, THC is now licensed for use in MS for controlling spasticity and pain. It is possible that the natural substance is more effective but could also produce more side effects because it contains many different chemicals.
Natural substances also suffer from the problem that they might have a lot of batch to batch variation. As a scientist I would say that a mixture of chemicals/proteins in a natural substance should give rise to more side effects than a single purified molecule.
The current mouse model that I know of for MS is mice with experimental autoimmune encephalomyelitis (EAE). Are you working with a different model? How are you improving on the current model/s?
Thanks for your question. I have worked with this model in mice in the past. It has been very useful for understanding how immune cells get into the brain and then cause damage. It has also been instrumental for the development of some of the drugs that now are effective at blocking MS attacks.
On the negative side it does not reproduce all of the types of damage (pathology) that are seen in MS, in particular the changes that lead to the long term build up of disability.
We have been developing a new model that reproduces these long term changes in the brain via a mechanism that we think is causing the long term disability in MS. We have managed to create a model mimicking the long term damage in the brain without the accompanying disability.
MS is a nasty disease in humans. What steps do you take to minimise any potential suffering in the rats?
How is responsibility for animal welfare shared across personnel in the lab?
Thanks for your question, Tom.
We have created a new model in which we initiate MS-like damage in the brain in a very localised way. Because it is very localised it does not give rise to the type of physical suffering that is experienced by many people with MS, in whom the damage is much more widespread. The animals do undergo surgery under general anaesthesia to create the brain ‘lesion’ and post-surgery we give the rats access to analgesia in the form of edible jelly.
All personnel working with animals in my laboratory are trained to the same high level and work as a team with the technicians in our animal facility to provide the optimal welfare for the animals. My team members assist one another to provide the necessary animal care.
What are the most significant hurdles that hinder MS research?
Hi. In my 30 years involvement in MS research, the biggest hurdle has been lack of sufficient funding to carry out research on some of our ideas. The next biggest hurdle has been the lack of human tissue samples to study how MS affects the brain at a very detailed level.
This is one of the reasons we set up a human tissue bank for MS research (see above for link). This has helped a lot but we still need more people to agree to donate their brain to research when they die. I have actually been advising the National MS Society in the USA about how to set up a similar brain tissue bank.
Are different treatments more effective for those of different ages? For example, a drug that works on children with MS and developing brains but doesn't work on adults?
As a non-clinical scientist I do not have an in depth knowledge of drug effectiveness, but my understanding is that the disease in children has the same characteristics as that in young adults and therefore would be expected to respond to drugs in the same way.
How far are we from completely understanding how the brain works?
We have made amazing advances in our understanding of how the brain works but we are still a long way off complete understanding.
I read a study a while back (https://www.sciencedirect.com/science/article/pii/S0092867415011915?via%3Dihub) where they reconstructed a small piece of rat brain, a cubic millimetre, in terms of the types of cells and all their intimate connections. It took them 5 years to complete!
With all the next generation of techniques coming along, I would hope that things will speed up, but the human brain is the most complex thing on Earth.
Hi Dr. Reynolds: the University of Sheffield, UK and Northwestern in the USA are doing a lot of research on stem cell treatment (HSCT) to combat MS. Do you see this being the way forward? Perhaps a cure? Thank you for taking the time to do this.
Hi there. The use of HSCT in patients who have a more rapidly developing form of MS has shown some excellent benefits and in some cases has stopped all further disease activity for many years.
However, it is not without its risks, because before you can transplant the stem cells you have to first knock out the person’s immune system. It also does not show benefits in all patients that undergo the treatment. I think that it is a very viable way forward for some patients who are rapidly developing disability that does not respond to other drug treatments.
did you found the virus accusable causing the disease?
There is still a lot of debate about whether a virus causes MS and there is no one virus that is known to be involved at the moment. It seems possible that a viral infection at a particular stage of life in an individual with a particular genetic make up could give rise to MS, but this is still just a theory at the moment.
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