This is an extended version of an article originally published on ProHealth as “An Interview With Julia Newton, Founding Member of Newly Launched CFS/ME Research Collaborative.”
By Clark Ellis
Dr. Julia Newton is one of the founding members of the recently launched UK CFS/ME Research Collaborative (UK CMRC), a new initiative aimed at expanding medical studies into ME/CFS by bringing together experts in the field and several of the ME/CFS charities in the UK.
Dr. Newton is Dean for Clinical Medicine at Newcastle University in the United Kingdom. She is also Clinical Professor of Ageing and Medicine at Newcastle University and a Consultant at the Royal Victoria Infirmary within the Newcastle Hospitals NHS Foundation Trust. She is highly respected in her field, possesses a wide range of skills and has won awards for her communication skills, scientific presenting, teaching and innovation.
Dr. Newton kindly took the time to answer some questions about the new collaborative and her research activities.
What got you interested in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in the first place?
“I first started to be interested in fatigue as a symptom around the year 2000. At that time I was working with the autoimmune liver disease, primary biliary cirrhosis (PBC). It was recognized in this condition that fatigue occurred in 50% of people affected, making studying fatigue comparatively easy in a disease where half the population suffered from fatigue symptoms. Over the subsequent 13 or so years we have developed a tool to measure fatigue in PBC, showing that it is related to biological factors like sleep disturbance and blood pressure regulation, to the degree that this is now in the European guidelines and management strategies have begun to be suggested. We are currently performing the first randomized, controlled trial of a treatment that targets fatigue in PBC.”
ME/CFS is a horrid disease. Many patients feel that a lot of people, including doctors, don’t really take it seriously. But it’s clear from your work that you do. What do you see when you see a patient with ME/CFS?
“As well as being a researcher I am a clinician, and I do a clinic one day a week and research and management for the remainder of the week. So when I see a patient with ME/CFS my first question is: Do they really have ME/CFS or could they have fatigue related to something else? Once we’ve ruled out whether they may have secondary fatigue then we will focus on whether there are any biological associates for their ME/CFS, such as sleep disturbance or blood pressure abnormalities that we may be able to modify and improve their symptoms.
“In terms of taking the symptoms seriously, when you see lots of patients with this horrible symptom [of fatigue] it is quite clear that it has a significant impact upon people’s ability to function and to live their life. Some of the most distressing stories come from young people doing their GCSEs (General Certificate of Secondary Education) or A-Levels (GCE Advanced Level) just wanting to fulfill their ambitions, and this symptom limits their ability to do that. These are the patients that I find the most upsetting and who I really want to get to a level of function that allows them to do their exams because it has such an impact upon the rest of their lives.”
Many ME/CFS patients have suffered because of the negative perceptions that some people have had – and which some still have – about the illness. How have things changed since you began working with the disease and do you think there has been much progress?
“When meeting patients it is always very distressing to hear the experiences that some have had with clinical colleagues. I think things are changing, and I hope that the work that we are doing has, in some respect, changed our understanding of this disease. I hope that clinicians will take it seriously and believe patients when they describe their symptoms during a clinical encounter. However, I have to say there is still much work to be done.”
Leveraging experience from other diseases
ME/CFS is a big part of your job, but you also still work with other diseases, such as primary biliary cirrhosis (as you mentioned already). I note that the patients in one of your recent papers on PBS (Fatigue in primary billiary cirrhosis), had problems in getting clinicians to take their illness seriously too. That’s not a problem that this patient (the one described in your paper) had with you though; you recognize the severity of these two diseases. How different, if at all, are the symptoms of fatigue and other bodily impacts in these two diseases?
“The development of the article which was published in the British Medical Journal (BMJ) written by Matilda Hale is quite an interesting journey. It came about from our experiences pulling together the trial of Rituximab in PBC which is currently ongoing. We submitted the original application to a funding body called the National Institute for Health Research (NIHR), Efficacy and Mechanism Evaluation (EME) Programme where it was reviewed by their funding panel. As part of the normal grant review process we were given the opportunity to respond to the comments made by people who had reviewed our grant, and one of the comments was that the reviewer did not believe that patients with a symptom as mild as fatigue would be willing to undergo such an invasive treatment as Rituximab.
“Having calmed down from being annoyed, we then realized that this was an opportunity rather than a threat and our immediate response was to contact the patient group (Liver North, who we have very close working relationships with) and ask them to contact their membership for their response to this statement. This resulted in over 15 pages of comments from patients which made it quite clear that they would go to any lengths to have a treatment that might in any way improve the symptoms of fatigue. As you might imagine we got the grant as a result!
“I firmly believe that studies like this have a direct implication for patients with other fatigue associated diseases. We have previously shown, using data from questionnaires, that the experience of fatigue in one fatigue-associated disease is the same as that in another, i.e., the fatigue experienced by patients with ME/CFS is similar to that in character to PBC, which is similar to that in Sjogren’s syndrome, etc. The severity may change and the relative contribution of various biological factors but overall the perception and the symptom itself is the same. This means that if the experience of fatigue is the same in different diseases then the underlying mechanisms may well be the same, which highlights the fact that by performing studies in one fatigue associated disease we could potentially understand more about fatigue overall, which can then be applied to other diseases.”
So your study will be trialing Rituximab with fatigue as the primary endpoint in patients with the fatigue-associated disease PBC. Given the overlap between this illness and ME/CFS, particularly in the area of fatigue, does that suggest to you that there could be a common cause, at least of that symptom, biologically?
“Absolutely, people’s experience of the symptom of fatigue is similar across different fatigue associated diseases so we firmly believe that there will be lessons learned from other fatigue associated diseases. If Rituximab is shown to be of benefit in primary biliary cirrhosis (which, if we didn’t think it would be, we wouldn’t be doing the trial!!) then has benefits to patients with fatigue in other contexts such as ME/CFS.”
“We have previously shown, using data from questionnaires, that the experience of fatigue in one fatigue-associated disease is the same as that in another, i.e., the fatigue experienced by patients with ME/CFS is similar to that in character to PBC, which is similar to that in Sjogren’s syndrome, etc. The severity may change and the relative contribution of various biological factors but overall the perception and the symptom itself is the same. This means that if the experience of fatigue is the same in different diseases then the underlying mechanisms may well be the same, which highlights the fact that by performing studies in one fatigue associated disease we could potentially understand more about fatigue overall, which can then be applied to other diseases.”
With PBC being a recognized autoimmune disease there is a clear logic in administering Rituximab to patients, but with CFS/ME not being recognized at all in some quarters, but certainly not yet recognized to be an autoimmune disease, will that make it harder to carry out a trial of Rituximab on ME/CFS in the future, or do you think this study on PBC could lead you there?
“Absolutely, I think it depends a little bit on the extent of the benefit that we might see and whether or not we can convince a funding body to support the cost of the trial. The Rituximab in PBC trial is what’s called an EME trial and that stands for Efficacy Mechanisms Evaluation, so as well as giving the drug and it being a randomized controlled trial comparing fatigue severity against placebo, all participants are also having muscle magnetic resonance image scan (MRI) and a range of other metabolic and blood tests before, and after, they have received treatment.
“If we do see any changes in fatigue we may well gain information that will help us understand the mechanism by which that improvement occurs. It is important to point out at this stage that the muscle and cardiac abnormalities that we have seen in patients with ME/CFS are exactly the same as those that we have seen in patients with PBC and we have published these studies too which is one of the reasons I am optimistic that the results of the PBC study might apply to the ME/CFS too.”
Last year you looked at HIV patients with fatigue and remarked on the possible future potential for a shared therapeutic approach. This is where your diverse experience really could pay dividends. How similar is the fatigue of ME/CFS patients to those with HIV and do you think any existing HIV treatments might be repurposed for ME/CFS?
“I think what this illustrates is how keen young researchers working in an environment where it is acceptable to consider the symptoms that your patients are experiencing can potentially yield dividends not only for that patient group but for other groups. The first author on that publication, Brendan Payne, is a really enthusiastic, bright young researcher who heard me do a talk. We then started asking questions about the tools we were using, which he went out of his way to apply in his patients that he was seeing in the clinic. So to me, it illustrates the culture here in Newcastle and how making people consider the symptoms that are experienced by patients that they see is really important.”
Collaboration is a buzz-word across many industries, but it is especially important at the cutting edge. You already have a reputation for being a keen collaborator, already working with groups in the US, Europe and South Africa. How important do you think collaboration is in your field?
“I think collaboration is vital. What is really important in complex diseases is bringing expertise to a disease. I have my area of interest in which I am considered an expert but it’s really important to acknowledge that you can’t be the expert in everything and that other people have expertise and experience that is valuable. So by working with other groups you can extend the reach of the research that you are doing and in some instances also validate it by delivering the same tools to different patient cohorts.”
How did the new UK CFS/ME Research Collaborative come about?
“A number of years ago the Medical Research Council (MRC) pulled together a working group to try and improve the science that was being proposed in the area of ME/CFS. I attended a number of these workshops, which were very interesting and informative. The UK ME/CFS collaborative grew out of these initial meetings. I think also, having funded a number of projects, the Medical Research Council felt that it wanted to maintain the momentum that had been established by pulling together the researchers. So Stephen Holdgate has created a great opportunity for scientists and clinicians working in this field and I believe has to be congratulated for his vision and for his ability to see the bigger picture. Unfortunately I can’t get to many of the meetings as they are frequently held in the south.”
Some people are a bit wary of the new collaborative. Though your participation within the group is reassuring, some patients perhaps feel that progress toward uncovering the true nature of the disease has been hindered by some other groups taking part in the collaborative. How do you see it?
“It is not really clear to me why people would be wary of the new collaborative, it is probably a bit early to decide whether or not it will achieve its goals. So I would be disappointed if people were to damn it before it has been given a chance. I think Professor Stephen Holdgate is a great champion for this cause and is unlikely to see all his considerable work come to naught.”
From the press release, it seems that the aims of the collaborative are to improve understanding and treatment of ME/CFS. Is that accurate?
“I think this is everybody’s aim – it is certainly mine. I think one of the problems with the field in the past has been scientists carrying out single studies in one or two areas that didn’t ultimately lead anywhere. What to me is important is not only understanding the disease in its entirety, which I am sure will be very complex, but then ultimately making sure that that leads to a treatment and a diagnostic test. So this is a journey, as it has been with primary biliary cirrhosis, whereby we need to be able to measure not only the symptom but any associated abnormalities that we find. Once we are able to measure it, that then makes understanding it easier. Then once you have an understanding, and are able to study a symptom, you are then in a better position to modify it with a treatment.”
How does the collaborative work to achieve those aims?
“It is early days for the collaborative, so it is difficult to know at this point how it will achieve its aims, but I would remain optimistic that with high quality science, that is adequately resourced, it will meet its goals.”
Another group taking part in the Research Collaborative is Dr. Esther Crawley and her team at the University of Bristol. They are also using MRI to investigate cognitive symptoms. Does being in this collaborative together make it easier for your two teams to collaborate?
“By being part of a collaborative at the launch I became aware that Esther and her team were performing MRI studies to investigate cognitive symptoms. So it has made us aware at an early stage, though the studies that Esther’s team is performing are different from those that we are performing in Newcastle.”
One of the things you said in the Newcastle University press release was “…develops a generation of researchers skilled in this area, and attracts researchers to CFS/ME who have not previously worked in this area.” This is something we desperately need. In New York, Dr Enlander now has a fellowship programme at Mt. Sinai MEC, and when he spoke recently at a meeting in the House of Lords, he suggested that the UK needed the same. Is that something you can see happening?
“I firmly believe that encouraging young researchers to work in this area is really important. One of the roles that I think I have is protecting young researchers and encouraging them that this is a really interesting, exciting and innovative field to work in. Even at my stage in my career I still get sarcastic comments on occasions from eminent people about my research area. Being bold enough and brassy enough to not take that personally and respond appropriately is easier to do at my stage than it is when you’re a junior in the lab. But knowing you have a boss who will defend you to the hilt is very important.
“A number of the charities have recognized the need for career development in this area and we have one PhD student and hopefully a second one soon who will help us achieve the goal of developing a generation of researchers skilled in this area.”
Last year you secured £900,000 [$1,395,360 USD] of funding from the Medical Research Council. Funding of biomedical research into ME/CFS was well overdue in the minds of patients; we were all very impressed when we heard. It’s not easy to get funding for this disease, so how did you do it?
“’How did I do it’ seems quite a funny question. As a University employee it is my job to write grants so the opportunity of a specific ME/CFS call came as a real bonus. I spend my life writing grants, many of which don’t get funded and papers that are rejected, so as a clinical academic you get used to rejection. But being able to write for a specific call in an area of science that really excites you was a real opportunity. We strategically made the decision to submit three grants of which two were funded and we now have to make a decision about what we do with this third grant and whether or not we re-visit it after the pain of rejection has settled down!
“So when writing a grant the first thing to do is to decide what your research question is and what you need to do to formulate that. That usually involves gathering around you a team of people who will be considered experts in their area, and then from there writing the science of what you want to do in terms of the experiments is very exciting.”
Some of your funding comes from the Medical Research Council. Where does the rest of your funding come from?
“At the moment I have the two MRC grants which include funding for staff and consumables, I am also part of the team for the National Institute for Health Research (NIHR), Efficacy and Mechanism Evaluation (EME) Programme Rituximab trial in PBC. We also have some pump-priming funding from ME Research UK and part funding for a PhD studentship from Action for ME.
“I also receive funding from our NIHR Biomedical Research Centre in Ageing and Chronic Disease which funds the other half of the PhD studentship. At the moment I also supervise a number of clinical fellows, the first, Dr Claire MacDonald, is funded by Age UK to look at neurocardiovascular risk factors in cognitive decline, I have an NIHR clinical fellow, Katie Hester, who is looking at developing educational materials for patients with bronchiectasis and Kate Hackett who is an occupational therapist looking at a similar area in patients with Sjogren’s syndrome. So I hope this illustrates how funding can come from a whole range of different resources and the breadth of the research that goes on.
“Essentially your research interests are governed by where you get funding, so delivering projects is entirely dependent upon where your grants are successful.”
Current studies and new findings
You have several studies ongoing which have a bearing on ME/CFS. People may not realize how much is involved in carrying out even a single study: once the concept of a study has been thought up, you have to design your study, promote it and apply for funding (no small task), you have to get approvals and permissions for the study, recruit participants, schedule and organize everything, manage the budget, acquire and setup all the equipment, deal with contracts and HR, and that’s before you even begin carrying out tests and collecting data. Then, once that’s complete, you have to carry out the important analysis, write up the results and go through the process of publication. In this context then, if we take a look at the very long list of publications to your name, it’s evident that you are highly competent and have a wide range of skills. It’s clearly a monumental effort; how do you do it?”
“You are absolutely right, it is a minefield trying to get a project off the ground and once you actually start doing the science it is always an enormous relief because a lot of the background things that you have to do to get a project up and running is what takes the time. The thing that I really enjoy is analysing the results, that’s what really excites me is looking at the data at the end. So the steps that lead up to acquiring that data are less satisfying to me than actually analysing the data and it’s the data that ultimately shapes the publications. I enjoy writing and publishing things as a means of disseminating information which ultimately I hope will change clinical practice.
“We recently set up the ME/CFS Research Newcastle Facebook page to try and illustrate to those who are not directly involved in research some of the steps that it takes to get a project off the ground. In doing that we hope that it will, as you stated here, show people the complexity. I hope it will illustrate why it’s not always straightforward to have a question and then answer it, there are lots of steps between having the question and ultimately getting to the answer. One of the problems in the past has been that people have got an answer and published a paper but have not then taken it that final step which is towards a diagnostic test or a treatment that is so vital when we are looking to try to improve patient care and ultimately lead to patient benefit.”
You’re investigating blood pressure control (autonomic nervous system) and memory and concentration (cognitive function) in ME/CFS patients. This work involves newly-developed MRI techniques to examine the muscle, brain and hearts of patients and also includes more muscle cell biopsies. This sounds exciting, what can you tell us about this study?
“We have a whole range of different studies going on at the moment. The muscle, brain and heart MRI studies have mostly been published now in a range of different journals and to get a really good review of these studies I would suggest people have a look at the ME Research UK website. ME Research UK have been very generous to us in Newcastle and funded the initial pilot studies. It is having this pilot data which ultimately led to us being successful with the MRC grant applications.
“So the muscle MRI studies in a nutshell showed that people with ME/CFS accumulate large amounts of acid within their muscles and have difficulty getting rid of acid after exercise. The heart MRI scans showed that a third of people with ME/CFS have impaired bioenergetic function in their hearts which has a knock on effect upon the function of their hearts. In terms of the brain we have been able to show that people perform badly on memory tests, the degree of this associates with changes in cerebral blood flow during stress of the autonomic nervous system. Interestingly, when we look at the muscle, brain and hearts of those who have had all three of these investigations there is a relationship between the abnormalities that we have found suggesting that any problem is not just related to one organ but is generalised across a number of organs. Our muscle studies have now extended into taking muscle biopsies from people and growing the muscle cells and we have also recently been looking at mitochondria.”
Another study at Newcastle, led by Dr Fai Ng, explores the role that inflammation might play in the symptoms of fatigue, where there is already some evidence of inflammation playing a part in ME/CFS. What’s your involvement in this study?
“I am a co-applicant on Fai’s project which means that I contribute a number of hours a week to this study. There is some crossover between Fai’s MRC funded project and my MRC funded project so we believe that by having the two projects in one centre there is added value and both Fai and I have, in addition to the MRC funding, funded a technician to work across the two projects to allow us to gain the very maximum from having both projects. I am providing the fully characterized patient samples so that Fai, who is a rheumatologist, can be confident that the patients are fulfilling the appropriate criteria for CFS.”
One of the things that you talked about at the launch of the Research Collaborative, and that was picked up recently by the Times, was high levels of lactic acid in exercised muscle tissue grown from cultures taken from CFS patients. You talked a little bit about this study back at the Action for ME conference last autumn and I seem to remember that they funded part of it, but it sounds like you have finished, or are close to finishing your investigations?
“Goodness me, it is amazing how things you say come back to haunt you!
“There are a number of strands to the muscle biopsy work. We have been able to show that we can exercise muscle cells in the laboratory and get similar findings in the laboratory as we have seen in the MRI scans. So we have been exercising muscles and looking at what happens to these and whether or not any acid that we accumulate is potentially reversible. We are confident that the acid accumulation is reversible but the Action for ME funding is now directed at a 50% PhD student who is going to start looking at other drugs in this muscle system so that we can begin to tease out where the abnormality might lie and whether it is amenable to currently available drugs. So the initial development of the model and showing that it replicates the MRI is almost finished and we are in the process of writing this up at the moment and the next stage is to really begin to drill down in this model where interventions could best be directed.”
Your research is primarily focused on the integrity of the autonomic nervous system (ANS) in diseases, including ME/CFS, where you have reported several serious anomalies including general dysfunction, heart problems, decreased blood flow to the brain, etc. How does this fit with the finding of lactic acid in muscle cells?
“That’s a good question. Interestingly acid accumulation in the muscle is controlled by receptors or transporters on the muscle cell wall and some of these transporters are regulated by the autonomic nervous system so that would be one way that it works. Another way could simply be that the acid that is released from muscle cells is washed away and therefore is dependent upon the vascular system to ensure run-off of acid as the muscles exercise. The autonomic nervous system regulates the caliber of the blood vessels around muscles and this could therefore influence the muscles’ ability to get rid of acid.
“One of the studies that we would really love to do is to look at developing muscle MRI techniques that can measure blood flow in the muscles as they exercise so that we could directly measure blood flow and how it relates to muscle function. In terms of blood flow, interestingly, acid in the blood – or the pH of your blood – plays some part in determining cerebral blood flow, so that pH is very important and has effects upon blood flow because it regulates blood vessel dimensions.”
You recently published an interesting paper, following an investigation you made into whether CFS in older patients (50+) was a different disease from that which affects younger patients (16-29 years). I don’t think anyone has ever thought to look at that before. Can you give us a summary of what you discovered and what the implications are?
“Thank you. This paper just illustrates what you can do when you have pairs of hands. Ieuan Lewis is a medical student who decided to take a year out to do a masters with me, he is a bright medical student who spent a lot of time helping us collect and check for accuracy the data from an ME Research UK funded project.
“The thing that is very novel about this cohort is that, rather than just comparing old to young, in which case you might have difficulty with the older people having had the disease for longer, Ieuan very cleverly matched each older CFS patient to a younger patient who had had the disease for the same length of time. So what this takes away is the possible conflict of length of disease which is often something I get challenged about (deconditioning). So what Ieuan was able to do was to show that actually the disease may be slightly different in older patients and that they had a slightly different pattern of autonomic nervous system abnormalities. So we have emphasised that CFS can present for the first time in older people and that clinicians shouldn’t forget that, and that the pattern of the disease may also be different.“
You’ve also identified disease phenotypes in other ways, such as this study earlier this year looking at postural orthostatic tachycardia syndrome (POTS). Many patients in the community have been crying out for people to do this kind of work, literally for years, so it’s a real pleasure to see that this appears to be a focus for you.
“Thank you, you are very kind, what I would say is that science excites me; I love having questions and data that help to answer those questions. Often one of the greatest problems is having enough time or enough pairs of hands to answer all the questions that you want to! And I am lucky that over recent years more and more young researchers, masters students and medical students have been keen to come and work with me in order to help me do that.“
What the future holds
We’re all excited about your work. What do we have to look forward to from you and your team?
“It is great to hear that people are excited about the work that we are doing in Newcastle but it also puts us under a considerable amount of pressure! We are just a bunch of scientists who have recognised important research questions that we are keen and excited to answer with high quality research. We are lucky enough that the team in Newcastle is deep, has some really first class scientists who recognise the importance of fatigue as a problem and have an enthusiasm to apply high quality science to study it. What we are trying to do is understand this symptom with the ultimate aim of developing diagnostic tests that are fit for purpose, and treatments that improve quality of life.”
Thank you Dr. Newton, for taking the time to tell us about the work of you and your team. Any final comments?
“I can’t emphasise enough to anyone reading this to understand how important it is that we solve the problem of this terrible disease. But we can’t do it unless patients, scientists and clinicians work together.”
Clark Ellis writes about ME/CFS/Fibro research and aspires to be a novelist. You can follow him on twitter to hear about his work and what he thinks of ME/CFS research.
Follow @IamClarkEllis on twitter
Phoenix Rising is a registered 501 c.(3) non profit. We support ME/CFS and NEID patients through rigorous reporting, reliable information, effective advocacy and the provision of online services which empower patients and help them to cope with their isolation.
There are many ways you can help Phoenix Rising to continue its work. You can even donate significant sums, at no cost to yourself, as you shop online! To find out more, visit Phoenix Rising’s Donate page by clicking the button below.