The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Dr Hanson Solve CFS webinar transcript, Sept 2016

Discussion in 'Latest ME/CFS Research' started by AndyPR, Sep 4, 2016.

  1. AndyPR

    AndyPR Cookies for Tired Sam

    OK, first draft done. As there are four parts to Dr Hansons presentation, I'll split it between four posts directly underneath this one, ETA and a fifth for the Q&A section. To save clogging the thread up, if you spot any typos or potential transcription errors, probably best to PM me the details.

    Obviously I have taken some editorial decisions with the text. I have removed some natural speech repetition which I didn't feel added anything, although as my concentration fluctuated I have also left some in, but most of all I've tried to preserve the technical aspects as much as I possibly could.

    Please also note, this is the first time I've done something like this and , so it's very likely there are errors in there, always refer back to the webinar if anything technical needs clarifying.

    And anything, [like this], in square brackets and in bold is completely my own text and not from the webinar.

    And here's the video again

    Hope this is of use to people :)
    Last edited: Sep 4, 2016
  2. AndyPR

    AndyPR Cookies for Tired Sam

    [Introduction by Dr. Zaher Nahle]

    Greetings, this is Zaher Nahle from the Solve ME/CFS initiative, welcome to our webinar series.
    We have a special treat today, we have Dr. Maureen Hansen from Cornell University who will be educating us on the many developments in ME/CFS research.

    We do not have enough time to list all the qualifications of Dr. Hansen but briefly Maureen Hansen is the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell. She received a bachelor's degree from Duke University and a PhD in Cell and Developmental Biology from Harvard University. After completing an NIH postdoctoral fellowship at Harvard, she joined the faculty of the Biology Department at the University of Virginia.

    She then moved to Cornell as Associate Professor and became a full Professor in 1991, she's presently a member of the graduate Fields of Genetics and Development, Plant Biology, and Biochemistry, Molecular, and Cellular Biology. She has previously served as an Associate Director of the Cornell Biotechnology Program and Director of the Cornell Plant Science Center.

    Dr Hansen's work on ME/CFS is truly exciting and you'll see and and hear that right now. So we are thrilled to have you Dr. Hansen I took a peek at the slides, thank you so much for doing this, the floor is yours.

    [Dr Hanson]

    Ok well thank you for inviting me. So I'll be describing some current as well as previous research on ME/CFS that's been done at Cornell University. My lab website has some more information that you may want to consult, it's going to be updated further very soon.

    So I'm going to address four major questions and my top(?) talk is really divided into four sections. Each of these sections is somewhat independent so that if you get bored in one of the sections you can listen to the subsequent ones without having to know what I said in the previous ones.

    So there's really four independent parts to my talk and first I'm going to talk about mitochondrial
    genetic variation, then I want to talk about white blood Cells and their possible differences between patients and healthy individuals. I will also discuss how metabolism might be affected in ME/CFS and then discuss gastrointestinal function in ME/CFS.

    [Mitochondrial genetic variation]

    So, to start, I want to put out a genetic hypothesis regarding ME/CFS. That hypothesis is that it's possible that the diversity of symptoms that we see in ME/CFS patients may be due to genetic differences in the victims of the disease, who have been exposed to a single or to perhaps different inciting factors.

    ME/CFS is often referred to as a diverse disease. I'd like to say that doesn't mean, that there's really no evidence that it's many diseases, it's still possible there's a single disease, single fundamental disruption and it's also possible still, despite reports of getting sick after many different possible illnesses, it's also possible that there's a single factor that is causing the disease that we don't really understand yet, especially since diversity and symptoms could potentially be caused by genetic differences. So that's something that we wanted to investigate.

    Now we have published this year, we published a paper about mitochondrial DNA variation and
    it's that paper that I'm going to start with, to discuss. This work was funded largely by the Hutchins Family Foundation, the Chronic Fatigue Initiative, it also received some support from Cornell University internal funds, and one of our participants, one of the students, the lead author actually had some support from NSF for a graduate fellowship. This work was done not only in my lab, but also in the labs of Alon Keinan in Computational Biology Cornell and Zhenglong Gu who's in Nutritional Sciences at Cornell.

    So the first question we asked is whether some patients with ME/CFS who are identified by expert MDs might actually have a genetic mitochondrial disease. Is it possible some of these people didn't really have ME/CFS but they had a problem with their mitochondrial genomes, some mutant mitochondrial genes that were causing the disease. We analyzed 193 cases and 196 controls from samples that we received from the Chronic Fatigue Initiative, these were age and gender matched and the patients were identified by all of these expert physicians that many of you know, the list is there for you to see.

    They collected the blood and provided the blood to the central repository at Columbia and then this was been archived at Duke in a bio bank. So that is the blood that we use and we analyzed the blood to see if we could find in the mitochondrial genomes any abnormal mutant genes and we actually did not find in any of the patients any mutations that would lead to a known genetic mitochondrial disease, so the answer to this is no, these doctors have identified 193 ME/CFS cases that are not mistaken for mitochondrial disease.

    So one further thing that we needed to analyze was other variation that might occur in individuals with ME/CFS. So mitochondrial genomes often differ between normal people, of course most ME/CFS patients were healthy at one time, and normal people do have variation in their mitochondrial genome. They have what are called snips or single nucleotide polymorphism [abbreviates to SNP, pronounced snip], this is a single change in the DNA code.

    So you see there this purple person has got a nucleotide A at a particular part of their DNA while the blue person has a G and the orange person has a T, those are single nucleotide polymorphisms. They can sometimes be harmful but in many cases there's no known association of some snips that exist in mitochondrial genomes with any sort of disease or condition.

    So we asked the question whether this mitochondrial genome variation, that's not known to be harmful, could be correlated with whether you get ME/CFS or not, is it correlated with your chances of becoming ill, and we could find no correlation of this mitochondrial genome variation with susceptibility. We then went on to ask is mitochondrial genome variation correlated with particular symptoms or their severity in the patients and there we got some more interesting information and that is that there seems to be some correlation, the answer is yes.

    So as I mentioned snips on human mitochondrial genomes are sometimes known to be harmful, causing true mitochondrial disease, but we didn't see any of those in the patient population but we did see some other snips. This is a diagram of the mitochondrial genome and their little numbers that you see there are lists of these snips that exists in various populations around the world, some of these are harmful, are known to be harmful, but others are not. And the snips that we looked at 7, 19, 3010 and then the ones up here, in those regions, those three there and two there, those turned out to be somewhat interesting with regard to ME/CFS.

    We looked at 270 different symptom scores that were collected from patient questionnaires and it was an important aspect of the work done by the physicians in this, for the Chronic Fatigue Initiative, they collected a lot of information from the patients, it was also a lot of work for the patients to do with those questionnaires so we are very grateful that they were willing to fill out those forms because that allowed us to identify 8 mitochondrial DNA snips out of 70 total that were associated with 16 symptom categories.

    Now I'm not going to go through all of those 16 categories but I'm going to give you just 2 examples from 2 of the snips. So that's the 719 allele, with 17 719 A, in other words an A present at position 719 in the nucleotides of the mitochondrial genome is shown on the left, there's two graphs on the left, let's look at those. If you have an a nucleotide A at 719 you're more likely to have neuroinflammatory distress, according to this analysis, while if you have a G you have less. Now those little boxes are so-called boxplots, the line across shows the median value, and the boxplot gives you an idea of the range of the reported symptoms and, at the bottom, you can see chemical sensitivity was also reported to be higher in the people who had A versus the people who had a G at that particular location. And likewise for snip 16519, the people who had, that have a C at that position, reported more gastrointestinal distress than the people who had a T and they also reported more severe bloating, they had a C versus a T.

    So to conclude this first section about mitochondrial genetic variation, we can say that, in this particular cohort, we found certain mitochondrial DNA snips that were correlated with symptom type and severity. This then is consistent with this hypothesis that some of the symptoms variation could be due to genetic background rather than being due to a difference in the fundamental disruption that's present in the patients or a diversity in the causes of CFS.

    So we also have several caveats though on the study, one is that we really need to analyze mitochondrial DNA in a larger cohort to verify this and also further probe the mitochondrial

    DNA variation connection, it's possible that other variants are present that could be correlated. Most population genetic study don't use merely hundreds of patients and controls, they use thousands, so at some future date I would hope that a large, much larger, cohort of patients could be, and controls, can be analyzed with respect to population genetics. Now I would also like to mention that mitochondrial function is also controlled by nuclear genes, we only examined the mitochondrial genes, much smaller set, it would be important to look at genetic variation in nuclear genes that encode mitochondrial proteins, this could also be informative.

    [End of part 1]
    Last edited: Sep 4, 2016
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  3. AndyPR

    AndyPR Cookies for Tired Sam

    [White blood Cells - Starts at 12m 14s in the webinar.]

    So next I'd like to turn to my next topic, which is the question of abnormalities in white blood Cells in ME/CFS. There have been many studies over many years indicating that there's something going on in White Blood Cells in this disease that is is abnormal. One of the first findings was that Natural Killer Cells don't have the normal activity there, they have less activity than controls, that it that finding has been repeated in several groups, it's one of the most reproducible findings, one of these papers is actually from 1994 so this has been known for a very long time.

    Recently you probably remember there is a important paper showing differences in cytokines in patients and that there was a difference between people with short versus long duration of illness. There are a number of studies showing different subsets of white blood Cells, different abundances, and this evidence really is extremely strong, there's something wrong in white blood Cells, and one indirect evidence is the very important Rituximab studies which indicate that if you deplete B Cells that a subset of patients improve and that is also indicating there's something going on with white blood Cells that would like to learn more about.

    So I'd like to just review briefly the types of white blood Cells. What this diagram here shows the variety of types of white blood Cells, the ones that most studies have dealt with are B-Cells, the antibody producing Cells, T-Cells and these Natural Killer Cells, and those are the ones that I'm going to concentrate my talk on. There have been some other interesting studies on some of these other cell types but I'll stick with B, T and NK Cells through this talk.

    So I'd like to introduce a project that's still in progress and I'm not going to present any results but I thought it would be interesting for people to know about this project.

    This project has been funded by NIH and has been going on for several years, there's a lot of sample collection that had to be done, our collaborating physician on this project is Susan Levine in Manhattan, and as some of you know Weill Cornell Medical College is also in Manhattan, so she collected samples from patients, blood samples, and those samples were then sent to Weill Cornell Medical College, actually they were hand-carried to Weill Cornell Medical College, and given to Rita Shaknovich, who then separated the white blood Cells on an automated cell sorter, and there's a diagram there of, a picture of, an automated cell sorter like the one that she used to separate the cells into B-Cells, T-Cells and Natural Killer Cells.

    Now this project is being led by Fabien Campagne, a bioinformaticist(?), who is located at Weill Cornell Medical College, he is the P.I. and I'm one of his collaborators. So these B-Cells, T-Cells and Natural Killer Cells were then extracted for their RNA, and then the RNA converted into DNA for sequencing on this automated sequencer at the Cornell Sequencing Facility.

    So we're at the point right now of doing analyses to find out if there are differences in gene expression between ME/CFS patients and healthy individuals, and this kind of information may reveal why there are these differences in function in B, T and NK Cells that are implicated by those other studies.

    We also are carrying out another study using B, T and NK Cells. This is a study of mitochondrial function in B, T and NK Cells, this project is also in progress. This is funded by, also by, NIH. It's a two-year smaller grant, essentially a pilot project to investigate new ideas, for problems that might be existing in this disease, and I'm the P.I. on this, my collaborators are David Ruppert, the expert statistician, and Avery August, who is an expert in T-Cells and their function. Susan Levine again provided the samples for this study, so we are, again, taking B-Cells, T-Cells and NK Cells, we are separating those in Ithica in my lab and then analyzing them with this device, shown bottom left, which is a device that can analyze cell metabolism. It's sold by Agilent(?) Company and it allows you to measure the glycolysis and oxidative phosphorylation which are two energy transducing pathways in cells, you can get quantitative assays(?) of the function of these two systems.

    What we would like to find out is whether the B-Cells, T-Cells and NK Cells are having some difficulties with these energy transducing pathways or perhaps they're utilizing more of one than the other than normal people cells do, so we're looking at both ratios and and how active these pathways are in these patient's isolated white blood Cells so this project again is in progress.

    So that completes that section of my talk.

    [End of part 2]
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  4. AndyPR

    AndyPR Cookies for Tired Sam

    [Metabolism study – Starts at 18m 16s in the webinar]

    And I'd now like to turn to the question of metabolism, and how metabolism differs in ME/CFS cases versus controls. Of course the prior work that I just described, the project, also is studying metabolism but in this section of my talk I wanted to talk about metabolomics, looking at the molecules that are present in humans, instead of looking at mitochondrial function directly, we're looking at it indirectly by looking at metabolites that may be affected in ME/CFS.

    So I think many of you have probably heard or read this paper that just came out a few days ago, from a group at UC San Diego published in PNAS, in which they looked at 612 metabolites present in plasma of ME/CFS patients, they had 40 males and 44 females with or without ME/CFS and at a significance of Q less than .10 they found 28 metabolites that were different in the males and 25 in the females and what was interesting is that 86% of the metabolites that we're different we're actually decreased in amount in the males and eighty-four percent decrease in the females.

    They also detected some differences between males and females as to what metabolites were different, the differences in the males are shown in the lower left, the differences on the females in the lower right but there were some pathways that were common between males and females. Now it's not important for me to go through the details of what these metabolites do because my real point is to compare this work with some work that we've been doing here at Cornell.

    So we have been doing a pilot study on plasma metabolites as well and we actually have submitted a paper, this is under review at a journal right now, the title of our paper indicates that we also found some interesting differences between ME/CFS patients and controls, we saw disturbances in fatty acid and lipid metabolism.

    Now I led this project, Susan Levine again provided the samples, David Rupert provided the statistical analysis, and the work in my lab was done by a postdoc named Arnaud Germain. We also had the chance to do mass spectrometry in the lab of Jason Locasale. This is an illustration of the equipment this used, this is a mass spectrometer.

    Because we have actually no funding from any external research agency or foundation for this study this is totally funded by some small donations to to our research program from individual patients as well as Cornell University, this is a very small, necessarily a very small study, we were only able to look at seventeen patients and 15 controls and because we can only look at a small number we selected all female patients for this study. We also only saw 361 metabolites rather than the somewhat larger number of the UC San Diego study but what's interesting is some similarities between our results and their findings.

    So we also found that most of the significantly different metabolites were lower in the ME/CFS patient than in the controls, so on the y-axis is the amount of the various metabolites that we were detecting, the controls are shown in red and the patients in green, or blue, and again we have those rectangular shapes that indicate the range of the amounts of metabolites that we saw in those of those particular metabolites. So this shows 33 different metabolites all which had statistically significant differences between patients and controls, that horizontal bar in the middle shows the median amount of the metabolites detected in the patients or in the controls, as you can see if you look on the left, from left to right almost all the metabolites except the last four, the patients were lower than the controls. There were four metabolites that the patients actually had more of than the controls but most of them had less.

    So let's compare our results to that those reported in the PNAS paper. So first of all we had fewer metabolites because we used very different method for handling the blood, for analyzing the blood, both groups use mass spectrometry but there are different ways to to do mass spectrometry and our way we had in this pilot study we have 361 metabolites instead of 612. We also only did females and our cohort size of females are smaller than theirs, they had more samples. Interestingly enough we had about the same number of metabolites that we found to be significantly different.

    They had 37 that were different at the q value of .15 and we had 33. What's most fascinating is that they found 84% that were decreased while we found 88% decreased and this also means that we, like the UC San Diego group, found that the patients appear to have a hypo metabolic state. Not only that, another interesting aspect of our study is that we also found some of the same affected pathways so in common, for example, we found phospholipids and purines and some amino acids, fatty acid oxidation, bile acids, amino sugars to be affected in our study and these are affected in the PNAS study.

    On the left though there are some things they detected that we did not that had some significant differences, and on the right we also saw some differences that they did not see, and this could certainly be a result of our using different methods for doing the mass spectrometry, for handling the blood, we have a completely different cohort of patients than they do and so, but nevertheless the similarities are very promising for metabolomics to really be giving some extremely useful information about ME/CFS. So we hope to pursue this further, we currently do not have additional funding to pursue this, we have submitted a proposal to NIH to continue to do metabolomic analysis but it'll be some time before we know whether or not that funding will be available.

    [End of part 3]
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  5. AndyPR

    AndyPR Cookies for Tired Sam

    [Gut Microbiome – starts at 25m 52s in the webinar]

    So I'd now like to turn to my last topic and that is the topic that many of you already know about, it's our work in on the gut microbiome in ME/CFS. This was published in June in the journal Microbiome(?). This work was a collaboration between Ruth Ley's lab and in in my department and the two people in her lab that worked with us were Julia Goodrich and Tony Walters, again Susan Levine provided the samples from her patients and some controls and Ludovic Giloteaux was the lead author, he is a postdoctoral associate in in my lab.

    This work was funded again by a two-year NIH grant that is now expired, again it was a grant, a so-called R21 grant, that's used to explore new ideas in research relevant to NIH. So our study
    population were established patients of Susan Levine, she was able to persuade 39 controls, 30 female 9 male, 38 female patients and 11 male patients to provide us with samples, we received both blood samples and faecal samples from these individuals. Of these patients 25 of them reported a sudden onset of ME/CFS, in age the median age was fairly close between the controls and the patient's although there was quite a variation as far as the age between the two, and the body mass index was quite normal though again there was quite a variation from underweight to overweight. Of the controls, 8 of the 39 controls reported some sort of intestinal discomfort such as constipation or diarrhea or stomach ache occasionally, of the patients however 32 of the 47 actually reported that they had some sort of intestinal discomfort.

    So let's review the human microbiota briefly, in and on humans there are as many microbial cells as human cells so it's been, that's sparked, that knowledge sparked the interest in the microbiome that has existed in the last few years, along with some new technology that allows this type of microbial cells really to be analyzed quite thoroughly. The majority of these microbial cells are in the large intestine and it is known that they provide enhanced nutrition and protection against pathogens. So many ME/CFS patients complain of gastrointestinal symptoms, so that leads to the question is abnormal gastrointestinal function causing some inflammation that that could be causing some of the sickness symptoms that any CFS patients feel, also does the bacterial gut microbial of ME/CFS patients differ from that in healthy controls? Those are the questions that we asked.

    So to explain what we did I need to point out that some bacteria have lipopolysaccharides, abbreviated as LPS, on their surfaces. On the left you will see a diagram of a bacterium, a so-called gram-negative bacterium, and on its outer surface it has these so-called lipopolysaccharides that extend out and can be examined by various assays. So on the right is a diagram of a dysfunctional gut, so if you have some problems with your gut the cells, for example, might allow passage of bacteria from inside the digestive tract to the outside, and this can get into your bloodstream then and if the bacteria get into your bloodstream then the LPS is in there and you then have LPS in your in your blood which then can set off sort of alarm signals to the body that bacteria have invaded and the body will take measures to deal with that.

    So we look to see whether LPS and also LPS related proteins are elevated in ME/CFS cases versus controls, so on the left you see the amount of LPS present in controls vs ME/CFS patients. Each of those dots, on the left a red dot, on the right a blue dot for the ME patients and that's the actual measurement that we got to LPS so that you can see there's quite a range there are some patients who have the same amount of LPS in their system as the controls, but if you look at the median and you'll see the line there shows the median, the median indicates that in general the LPS is higher in ME/CFS patients than in the controls.

    We also looked, if you look at the far right graph, we looked at a protein called LBP, for LPS Binding Protein, this is a protein in the blood that binds to LPS and that is also raised in ME/CFS and it's significantly different, there again you can see the median line of the level of LBP in the patients and controls and that in the middle there is a receptor in our bodies that detects this LPS bound to LBP that lets the body know that that there are potentially bacteria around, and again it's increased in ME/CFS versus the controls so that's showing something different between patients and controls.

    This implies, this data implies, the fact that there's extra LPS and significantly higher levels of these other two, of these two proteins indicates that there is ongoing damage to the gut and this is likely than causing this increased microbial translocation in ME/CFS patients. This observation has been seen in other diseases, so other diseases also have elevated LPS, there's Fatty Liver Disease, it happens in HIV infection and two types of inflammatory bowel disease, Crohn's Disease and Ulcerative Colitis.

    So how did we analyze the gut bacterial microbiomes?

    Well the patient's themselves actually collected faecal samples, they put them in a preservative and then shipped the samples to Cornell where they were processed. They were processed for DNA extraction and then some of the DNA was then further processed for sequencing on so-called MiSeq sequencer, an automated sequencer that can give you as many as 140000 sequences per sample, so this sequencing data was obtained and then analyzed. So this DNA sequencing, by looking at the actual sequence of the ribosomal DNA, of a portion of the ribosomal DNA, in the bacteria you can identify the family and sometimes the genus and species of the bacteria that is present.

    So this happens to be the Fox family and you know that foxes are animals, they are belong to the class mammal, they are a carnivore, they are a member of the Dog family, and then as far as the genus, as far as the genus goes, here's an example of two different species within the genus of Fox, there's an Australian fox and the British Fox. These two species are different but they're in this genus and then of course each one of these, the British fox for example, is an example of the species.

    The reason I'm showing this is to indicate that while we can identify the family and sometimes the genus and sometimes the species, if we've only identified the genus of of bacteria we could have two bacterial types in the gut that are is different from one another as that Australian fox and the British Fox. So it so that we can have very different bacteria even though we think they're, we know that they're in the same genus, they can still be quite different in their function. One might be, for example, in the same genus the bacteria, you can have a pathogenic bacteria and you can have normal healthy type bacteria.

    So the other issues I should mention is a different species can't always be identified by sequencing. We have to group, if two bacteria have 97% identical sequences we say that they are the same species but we don't actually know, the same group, we don't actually know that they're, the same species.

    So what we found is, as we kept, as you look at more and more sequences per sample, we could find that the ME/CFS patients had fewer species in their gut microbiome than the controls so, as you get out to 30,000 sequences on the right, the controls had more, different types of species and gene genera and family members then the ME/CFS patients. This means we have a loss of species richness in ME/CFS microbiomes.

    We also found that 24 families and genera differentially abundant between ME/CFS and healthy individuals and this is statistically significant. So I'm going to put a red triangle here, these are all the species that have a lower amounts in patients than in the controls so this is again an indication of the reduced diversity in the patients versus the controls. Among those species that are reduced we see that the members of the Ruminococcaceae are significantly higher in healthy individuals then in the patients and, the reason this could be important is that this is a beneficial type of bacteria, it produces an anti inflammatory protein and butyrate which is an anti-inflammatory fatty acid so this abnormality is also seen in Crohn's disease and Ulcerative Colitis.

    So we attempted to use this information to see whether we could identify and distinguish between patients and controls and we, actually we're able to see that we could just identify patients pretty well if, in this particular cohort 55% of the cohort were patients and we were able to identify 53% of the cohort as patients. So that's actually quite high, it's over 90%, unfortunately however though we also identified a number of normal, 12% of the normal people, where classified as ME/CFS. Nevertheless we were able to identify 30% as being normal so this gives a total value of 83% correct classification by microbiome in combination with the levels of those three molecules in the blood.

    So I'd like to mention that there are limitations of bacterial microbiome analysis, we can't really tell whether strain is differentially present, for example you need to use other methods to determine whether you have a bad E.coli or an ordinary E.coli, now these bacterial studies don't reveal what eukaryotic pathogens might be present and also it doesn't indicate whether viruses are present in one and not in the other, other types of analyses are needed for that. So to conclude we have less bacterial diversity, we have association of the abundance of specific groups with patient or healthy status, we can classify 83% of the samples correctly and we see that anti-inflammatory species are reduced in patients.

    I now like to briefly describe a case report that was led by Betsy Keller who is a exercise physiologist at Ithica College. Now she had a pair of identical twins come to her, one of them had ME/CFS and one of them did not. These were male twins aged 34 and the ill twin had been sick for four years with ME/CFS. She performed two successive cardiopulmonary exercise tests on these individuals, she found that the ill twin on the first day had a lower maximum vo2 than the well twin, and I'm not going to go into what that means except to say that that does mean that the ill twin is less physically fit as you might expect for someone who's been sick for a few years, but what was more interesting is that on the second exercise the ill twin reached anaerobic, the necessity to use anaerobic, metabolism at 13% lower than he did in the first exercise.

    So that abnormality, that that reduction in the anaerobic threshold, indicates exertion intolerance in the ill twin and this is a significant result because ill people can usually repeat these results, for example someone with multiple sclerosis who took these two tests would be highly likely to be able to repeat their results from the first to the second, they would not have had this decrease in anaerobic threshold.

    So we decided to look at the gut microbiome in these individuals, and again just like the whole cohort that we looked at the ill twin had reduced gut microbiome diversity and also exhibited changes like the larger study in the relative amounts of different types of bacteria, so each color there shows a particular bacterial family and the ill twin clearly has a different composition than the well twin. So this is interesting because in this case the genetics of the two individuals being tested are identical but yet, because one of them has ME/CFS and the other is well, there are differences seen in the gut microbiome.

    So what attempts are being made to alter microbiomes in various diseases? In various diseases people are trying to use diet, pre- and probiotics, and antibiotics, and faecal transplants and a number of people have written to me asking whether one of these interventions might work in ME/CFS and the fact is that I don't know because we need more studies to find out whether these interventions could be useful.

    One, I would like to mention however that they're not necessarily completely innocuous to try these interventions and on this slide I'm putting up just one example of a review article which examined the effect on inflammatory bowel disease, in this case Crohn's disease, a table about Crohn's disease which as I mentioned earlier has some similarities in its gut disruption to what is seen ME/CFS. A number of different interventions and number of different pre- or probiotics were used and in some cases these are beneficial but note that in some cases they actually did harm to the patients, so we can't just automatically assume that prebiotics or probiotics are always going to be beneficial, and that's why we definitely need more studies to find out what might be beneficial to alter the gut microbiome in ME/CFS.

    We now have abundant evidence for biological disruption in ME/CFS. We have aberrant functioning of white blood cells, abnormal physiological responses to exercise, abnormal gut microbiota, altered metabolism and, something I haven't talked about, that there are anomalous images from brain scans. That is actually some work going on at Cornell Medical School as well as a number of other locations, that reveal abnormalities when you use MRI or patch(?) and other types of scan.

    So that's why it's unfortunate that inappropriate images of ME/CFS have given the distorted perception to the public of this disease not being as serious as it is. I'm just showing you six of the images is accompanied the many dozens of articles about our microbiome study across the country and the world. These are actual illustrations that is unfortunately often the type of illustrations often used because of the idea that we have a chronic fatigue rather than an actual disease, and I would like to suggest that it be very important for the patient organizations to be able to provide appropriate images to editors who need illustrations of what Chronic Fatigue Syndrome or Myalgic Encephalomyelitis is in one of their articles.

    Finally I'd like to say that you can get additional information about our microbiome study because I gave a longer talk about that at this Invest in ME meeting and there's a DVD that you can order. I also will be doing another webinar next week on September 8 at a virtual conference on microbiology and immunology. This conference is aimed at researchers and MDs, in fact MDs can get CME credit for attending this conference, so it's going to be in much more depth and detailed than what I was able to describe either here or at the Invest in ME meeting.

    I'd also like to mention that we will be, people from my lab and myself, will also be talking at the IACFS meeting in Fort Lauderdale. And finally I'd like to announce for the first time that our Vice Provost for Research has authorized the formation of a center for ME/CFS, we're going to call this symptom center, the Center for Enervating Neuro Immune Disease. [Enervating – causing you to feel weak and lacking in energy]

    This name was actually suggested by a patient given that it's very confusing, but to refer to use as a name for such a center given we've got ME/CFS and SEID as well as other names that various people have suggested, so we're going to call our center the Center for Enervating Neuro Immune Disease.

    This center will include people from both Ithica and Weill Cornell Medical College, and at the moment we have actually three researchers, three laboratories, that at Weill Cornell that are studying ME/CFS, we have eight researchers, eight labs, at Cornell and Ithica who either have or have applied for grants for ME/CFS research, and we have one at Ithica College, and we have five collaborating physicians who are working with these groups so we would like to actually increase the number of people at Cornell who are working on ME/CFS and we think that by having this Center we should be able to attract even more interest and increase the researchers who are working on this very important disease.

    OK, so that's my last, that's my last slide.

    [End of part 4]
    Last edited: Sep 4, 2016
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  6. AndyPR

    AndyPR Cookies for Tired Sam

    Q&A Section

    [Dr. Nahle]

    Thank you, thank you, thank you Maureen, this is, this is fascinating. I do not know where to start, you took us on a tour from genetics to mitochondria biology to immunity and inflammation, to metabolomics, as well as exercise physiology and I, we thank you for mentioning, I think for the first time here, a scoop on this Center for Enervating Neuro Immune Disease and all the best of luck with that, we are certainly very supportive. Let me go to some questions, we received so many and I appreciate you working with us outside to answer them as well.

    Many of the questions Maureen where on what type of bacterial strains one can use to improve the gut flora. You actually mentioned in a slide and showed data and qualified very much the danger, and perhaps the utility sometimes, but the danger of just probiotics without a better understanding, Would you care to comment on this further, we have maybe ten questions on this but that's the gist of them.

    [Dr. Hanson]

    OK, I will comment briefly, just also with the caveat I am not an MD, I'm a PhD, but I will say that among the bacteria that were lower in the ME/CFS patients is one that is used in probiotics, it's called bifidobacterium, so that one is lower, whether or not that would help taking that with help or not is not clear because, after all, these changes in the gut microbiome that we're seeing could actually be the result of some other problem, they may not be the cause themselves, but i know that a lot of people would like to treat the symptom, and if you can treat a symptom in a disease and you can't treat the entire disease it can sometimes be beneficial, so I don't know if taking that is going to help, there haven't been adequate studies to find out if it would help, but that is one that is available.

    I would also like to say that many of the number of people who have asked about this, I've got, I have to say, I've got a lot of emails and I haven't been able to keep up with them, I've been able to answer a few, so I apologize to those people who I've not been able to respond to, but many of those missing bacteria cannot be taken as probiotics because they can't be cultured, we don't know how to grow them, and that's one reason that people have faecal transplants for certain diseases, is because you can't replace by merely taking an oral probiotic, you can't replace those, and that's why people have to have faecal transplant but, although there's been some anecdotal evidence in case reports about faecal transplants and ME/CFS, again there's not enough information to know how helpful that will be to most people or not.

    [Dr. Nahle]

    Great, thank you and it's of note that maybe one trillion microbes are existing in our guts actually, this is a humongous number, so just to put things in perspective, and now let me give you this one on genetics question, can snips issues be treated? I think that's a very hard one to me. Can Single Nucleotide Polymorphisms issues be treated?

    [Dr. Hanson]

    Well, there is a very large effort in the mitochondrial disease community to find ways to ameliorate these mitochondrial, genetic you know, mitochondrial diseases and there are actually some drugs, and some molecules, and that one can take that that help these people who have the actual genetic mitochondrial diseases. Those are often very devastating diseases with a very poor prognosis, but there have actually been some treatments, whether one would be able to do anything about the variation we found, its it's really quite premature because as I mentioned we really need to do a larger population, and, even though again we found a correlation with symptom severity or types of symptoms, there are plenty of people in our cohort who who don't have those snips and that they still have those symptoms, so so I doubt that treating those polymorphisms is going to have much effect.

    [Dr. Zahle]

    Yes, and Maureen, do you think this CRISPR technology, the new gene editing technology, can can come in to play here with with these type of correction, genetic corrections for snips?

    [Dr. Hanson]

    Well, CRISPR technology would not probably be appropriate for this, for that particular type of problem, actually if we learn more about the disease and we understand its fundamental cause there could, I imagine, in the future be some application of CRISPR technology which, what one would do, would be to modify some cells and then put them back into the body presuming, of course, those are cells that one can do that with but, again, we don't know enough about the disease to know whether the CRISPR technology would actually be a way to provide a treatment.

    [Dr. Zahle]

    Great, thank you, and Dr. Hansen here on, related to to the microbiome, a question comes in here, as can this shed light on the optimal diet? So diet modification, not probiotics proper, but can we modify the diet, is your work telling us more about dietary and nutritional aspects of this disease?

    [Dr. Hanson]

    I actually think the gut microbiome is probably not as relevant to that as the metabolomics studies that are, that have been done, I think that with more work on metabolomics we may be learning the, you know, optimum types of fuel that people with ME/CFS might need to have in order to deal with their metabolic deficiencies.

    [Dr. Zahle]

    Yes, thank you, and a follow-up on that, how can one delineate better the results of these metabolomics in the context of different backgrounds of patients, the different comorbidities,
    cholesterol, hyperlipidemia, all these metabolic diseases that alter our analytes(?) in general.

    [Dr. Hanson]

    Well again, like with everything else, what's needed is all large studies. ME/CFS research has suffered from the fact of lack of funding and small studies, if we had a lot more patients and controls in our metabolomics studies and we had also very good information on their symptoms and all their cholesterol and all those other issues, I think we would be able to look for correlations and find what is correlated, what is not correlated, so again it's a question of if we can do a lot more patients, and have a lot more information about those patients, then we are more likely be able to figure out what's going on.

    [Dr. Zahle]

    Yes, thank you, and Dr. Hanson, this is also a question related to statistics and we, our audience is diverse, we have scientists and we have non-scientists, would you be able to calibrate the listeners to what is a good sample size for these types of studies? In fact this is a really good question that just came in, will there be a sufficient patient number that for us to consider a study valid?

    [Dr. Hanson]

    I don't consider either our study or the other study not valid. I think actually a thorough statistical analysis was done on both that allows us to make conclusions but every study needs to be repeated, we have to some extent validated some of the results in an independent study, of the working in the PNS paper but, clearly, just like the Natural Killer Cell differences have now been seen in several different laboratories, it's always important to see these differences and findings in multiple laboratories and really the more the subjects the better, to really get down to the fine details of what's happening in patients.

    [Dr. Zahle]

    Thank you, thank you, Dr. Hansen, this has been a fascinating overview of current and future research of ME/CFS, not only in your lab but in the field in general so thank you for doing
    this, this is truly fascinating. We promised our folks that we will stop at the top of the hour so we will conclude now but thank you for working with us on answering the questions that remains and I appreciate you giving this webinar today and good luck in there with the center and all the best to you, thank you so much.
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  7. Sean

    Sean Senior Member

    Much work there. Thanks.
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  8. AndyPR

    AndyPR Cookies for Tired Sam

    No problem, you're welcome. Fortunately, not as much work as there might have been. YouTubes automatic subtitles are pretty accurate, the majority of the more technical terms it got straight off, the vast majority of my time was spent formatting and cleaning up (or butchering, depends on your point of view ;)) the grammar of the subtitle download.
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  9. Denise

    Denise Senior Member

    Your time and energy on this are much appreciated!
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  10. daisybell

    daisybell Senior Member

    New Zealand
    Thank you @AndyPR - love your work!
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  11. bel canto

    bel canto Senior Member

    Yes, thank you, AndyPR. This was a lot of work and so many of us benefit from it!!!
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  12. Bob


    England (south coast)
    Thanks from me too, Andy. That's an enormous amount of work! :thumbsup::thumbsup::thumbsup:
    actup and AndyPR like this.
  13. geraldt52

    geraldt52 Senior Member

    Wow, thank you so much, AndyPR. My frazzled brain couldn't possibly take on such a task, so it is much appreciated that you were able and willing. Interesting read.
    Bob and AndyPR like this.
  14. hixxy

    hixxy Senior Member

    Has Hanson's research highlighting SNPs involved in chemical sensitivity been published yet?
  15. znahle


    Hi AndyPR, thank you for producing this transcript, friend. I should visit this great forum more often but I am just seeing this right now and wanted to say thank you. This is helpful to many to read and see in this format.
    ahimsa, RL_sparky, Comet and 10 others like this.
  16. unto

    unto Senior Member

    thanks for opening a discussion on the work of dr. Hanson, very interesting, could pave the way for understanding many other diseases beyond ME ..... Dr. Hanson speaks in simple language, direct and clear.
    I share his thoughts on the ME, that despite the considerable differences between the patients (symptoms and onset) could be only one manager (viruses, bacteria ...) to cause the disease .....
    I have to read everything even though
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  17. eastcoast12

    eastcoast12 Senior Member

    Long Island ny
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