Article: Bad Wiring? State of the Knowledge Workshop III: Systems Biology

Comments

Cort - Great article; thanks for making this digestible. It's heartening to read about an ace researcher with excellent, targeted ideas, who's got funding. An interesting (to me) aspect of working with systems is that you can intervene in a variety of places and end up with similar results. There isn't always one best "fix."
 
Cort,
Excellent review. This was definitely one of the workshop highlights with great potential to unravel the disease by understanding the different systems and their interactions.
Thank you for pulling this together
 
Cort - Great article; thanks for making this digestible. It's heartening to read about an ace researcher with excellent, targeted ideas, who's got funding. An interesting (to me) aspect of working with systems is that you can intervene in a variety of places and end up with similar results. There isn't always one best "fix."
I think its so hopeful in a number of ways; one the NIH is obviously really interested in Broderick's - that was a huge grant! Another is that a variety of researchers are interested in finding the kind of on-off switchs that turn temporary problems (flu-like illness) into a chronic one. I was glad to see Kelley there and I don't know why other researchers in his field haven't jumped in yet but the Lights are working on the same problem.

Broderick and Suzanne Vernon also proprosed a model of HPA axis functioning which they believe might be able to resolved by temporarily reducing cortisol levels in the blood to near zero - at which point they believe the system will reset itself. Its not the system is broken - its that its gotten stuck in a less than optimal way of functioning.

Of course if pathogens are 'it' in ME/CFS as they appear to be for some people - the system analyses should show evidence of that too - as they appear to be (the TH2/Th1 shift.)
 
Cort,
Excellent review. This was definitely one of the workshop highlights with great potential to unravel the disease by understanding the different systems and their interactions.
Thank you for pulling this together
It'll be so interesting to see how it will play out. My sense is that Broderick is doing cutting edge work not just in CFS but in the medical field as well. This kind of multi-systemic work is what the ORWH said they would be willing, 10 years ago, to fund - and they seem to willing to do that, at least with Broderick. When the NIH does fund a study they tend to fund pretty innovative studies.

They basically said some years ago that they weren't interested in pathogens and, until XMRV came along, they were funding nothing on pathogens. Now they're actually funding a couple of pathogen studies on CFS - the Lipkin Montoya study, quite a few studies on XMRV and the Huber endogenous retrovirus study...

but my sense is that they what they really want are these kind of multisystemic studies that cross boundaries..that is why, after all, we got kicked out of the NIAID - because we didn't fit really well into the immune Institute...although the immune aspect seems to be getting ever more focus.
 
From Dr. Broderick's presentation in Miami, I recall him saying that in GWS patients the methyl-napthalene pathway seems to be the problem, not phenylalanine like it is with CFS. I found this interesting as I have a horrible reaction to napthalene (moth balls) and I am not a Gulf War Vet.
 
Let me take a wild guess -- Gordon Broderick has a background in engineering. Engineers have been doing network analysis and analysis of multiple interacting systems for years. Medicine has been stuck in the dark ages in terms of data analysis and analysis of dynamic systems. And the human body is a dynamic system if there ever was one.

I always thought it was strange that so many doctors seem to think that they can take a single data point and know all they need to know about a dynamic system. I can well imagine that those doctors are grumbling about whether Broderick's system analyses mean anything -- their understanding of system interactions is 50 years behind the times (meaning nonexistent) and they can't begin to grasp the complexities of multiple interacting systems.
 
Brilliant Cort, many thanks for yet another understandable "overview" in current research. It is good to see this important part of the whole jigsaw coming together. Whoopee.
 
Thank you for an excellent summary Cort. This gives me hope.
 
Sickofcfs is spot on. I'm a mathematician who used to make a living out of optimising complex systems, and Broderick's approach is, IMHO, both brilliant and, with the technology available today, certain to discover stuff. The medical establishment is really going to struggle with it though, as they have zero training in quantitative methods and mathematical sciences, and are taught in the most reductionist fashion imaginable. It's impossible to explain to a doctor that A is connected to Z because they "know" it's not, and since they don't comprehend mathematics no mathematical proof will convince them either. Kudos to the funders for seeing the importance and potential of the research - may we one day see the triumph of Science over Medicine!
 
Interesting comments moblet - just to add UK wise the simplistic medical approach - too much confuses - eyes glazed over rapidly with more than two symptoms I found. And posted in a local family GP surgery "no more than two symptoms at a time". Hooray for the recognition of interacting systems.
 
Let me take a wild guess -- Gordon Broderick has a background in engineering. Engineers have been doing network analysis and analysis of multiple interacting systems for years. Medicine has been stuck in the dark ages in terms of data analysis and analysis of dynamic systems. And the human body is a dynamic system if there ever was one.

I always thought it was strange that so many doctors seem to think that they can take a single data point and know all they need to know about a dynamic system. I can well imagine that those doctors are grumbling about whether Broderick's system analyses mean anything -- their understanding of system interactions is 50 years behind the times (meaning nonexistent) and they can't begin to grasp the complexities of multiple interacting systems.
I agree 100%. It's also worth noting that Dr. Broderick seems to be an outstanding person. I spoke with him for 5 minutes after a recent presentation that he gave. He really seems interested in making a difference in this field.
 
Cort,

Excellent article, well-organized and clearly written!

It's reassuring that cutting-edge technology is being applied to ME/CFS and so rewarding that patient funding made it happen!

Yesterday's New York Times reported a major discovery in the area of Systems Biology that ME/CFS researchers may want to look at --gut bacteria divide people into three types:

http://www.nytimes.com/2011/04/21/science/21gut.html?_r=1&scp=1&sq=Human gut&st=cse
 
Hi, Cort.

I'm hopeful that Gordon Broderick's "top-down" systems analysis will mesh well with my "bottoms-up" biochemical analysis of the interaction of the various body systems in ME/CFS. I had a brief talk with him at the Workshop, and have sent him copies of my 2004, 2007, and 2009 IACFS/ME poster papers, which are posted on your site at

http://aboutmecfs.org.violet.arvixe.com/Trt/TrtGSHIntro.aspx

It would be very nice if all this will fit together!

Thanks for posting this report, and I enjoyed talking with you there, too.

Best regards,

Rich
 
Thanks once again Cort.

This seemed to be the most exciting presentation of the workshop for me, and it was referred to a few times later in the workshop by other speakers - it seemed to have made quite an impression.

There were one or two great slides showing the 2 or 3 different network patterns which characterise GWI, ME/CFS and healthy controls. Particularly interesting was that the GWI pattern was really quite different from the ME/CFS pattern - in the latter you could see, in a great visual representation, how all the connections between markers were somehow more chaotic and disordered. As with the spinal fluid study, it's really exciting to see such clear distinctions between what until now have seemed like overlapping syndromes.

I didn't see images of those particular slides in your piece - is there any way of getting hold of them? Should be possible to screengrab from the video.

A picture can paint a thousand words, and as I commented before, the Light study graphs showing the phenomenon of PEM visually look to me like "our hockey stick". I think that a simple page of information with these two sets of images, and a very brief and simple explanation as to what they mean, could work wonders educationally.
 
Let me take a wild guess -- Gordon Broderick has a background in engineering. Engineers have been doing network analysis and analysis of multiple interacting systems for years. Medicine has been stuck in the dark ages in terms of data analysis and analysis of dynamic systems. And the human body is a dynamic system if there ever was one.

I always thought it was strange that so many doctors seem to think that they can take a single data point and know all they need to know about a dynamic system. I can well imagine that those doctors are grumbling about whether Broderick's system analyses mean anything -- their understanding of system interactions is 50 years behind the times (meaning nonexistent) and they can't begin to grasp the complexities of multiple interacting systems.
Glad to hear from SickofCFS and Moblet that this stuff really works and yes, he does have an engineering background :rolleyes:. Pandora did a nice interview with him in that outlines his background and his work when they gave him his grant in 2009. Its below but for easier reading you might want to check it out on its own page on PR here

http://www.pandoranet.info/gordonbr...chgrantrecipientnewsletterionterview2009.html

Dr. Gordon Broderick: Recipient of P.A.N.D.O.R.A Grant

Interview by Marla Schwartz & published in our April 2009 newsletter


Dr. Gordon Broderick has been an Associate Professor since 2006 in the Division of Pulmonary Medicine, Department of Medicine, University of Alberta, in Edmonton. Dr. Broderick is one of those quiet geniuses who have joined the research community in searching for biomarkers to trace the disease progression of chronic fatigue syndrome (CFS).

The basis of Dr. Broderick's current research is to study the immune and endocrine response in adolescent patients who become ill with CFS after contracting infectious mononucleosis, which is caused by the Epstein-Barr virus. By studying patients from the time they get infectious mononucleosis to the development of CFS through the first 24 months of the illness, he hopes to identify disease progression biomarkers, including those essential for early diagnosis.

Researchers in the field have been aware for years that CFS develops after a viral infection, but the immune mechanisms for this are not yet well understood. Early diagnosis is essential in any disease because early implementation of treatment and lifestyle changes results in higher success rates in allowing people to live within the parameters of this disease.

Dr. Broderick holds a PhD in chemical engineering from the University of Montreal, and a Master's degree in chemical engineering and undergraduate degree in mechanical engineering from McGill University. He worked for 12 years in the private sector before joining the Institute for Bimolecular Design at the University of Alberta, leading the Cybercell computational team in creating a dynamic spatial model of a living cell. His breakthrough research in this specialty led to his current application in classical systems engineering and his work with discrete probabilistic models to study self-organization and the emergence of complex behaviour in distributed physiological systems. His particular interest has been narrowed down to the context-specific population dynamics of the immune system.

This all basically means that Dr. Broderick is one of few researchers who are attempting to show how the hypothalamic-pituitary-adrenal (HPA) axis, one of the body's major control systems that regulates functions ranging from digestion to immune responses to metabolism, that when not working properly, leads to a number of neuroimmune disorders. These disorders include CFS, Gulf War Illness, and posttraumatic stress disorder. The reason treatment and objective diagnosis for these disorders have proven difficult is because there has not been any type of identified lesion, for example, to "prove" they exist. However, because the body's various components do not work in isolation, it is important to figure out how their interactions might causes these disorders.

Dr. Broderick has agreed to answer someone questions about his research for P.A.N.D.O.R.A..

Q: Where did you grow up? When you were young, did you have any idea as to the direction your professional life would take?

A: I am French Canadian and was born in one of the older cities in North America located between Montreal and Quebec City. I have always been attracted to medicine and actually completed a double major in junior college (a 2-year pre-university program in the Quebec school system) before finally deciding on pursuing an engineering degree at McGill. It was only after my PhD, working as a postdoctoral fellow that I returned to medical research by applying my computational skills to the study of gene expression in various forms of leukemia. You might say I took the long way home.

Q: How did your journey to McGill University and then to the University of Montreal begin? What influenced your decision(s) toward attending these institutions on your path to what has become a remarkable career?

A: Thank you for the kind words. I have always been motivated to look at a problem from a variety of perspectives. This has essentially positioned me at the interface between disciplines right from the very start of my training and subsequent research career. Looking back, this is a fortunate occurrence because I firmly believe that the next chapter in research into complex illnesses will require interdisciplinary science on a grand scale. With regard to my selection of academic institutions I think McGill has a well-deserved international reputation as a highly regarded research university. After having completed a Masters degree from McGill, I was looking for an opportunity to continue my interdisciplinary training beyond the bounds of engineering. The University of Montreal offered me an opportunity to do that by facilitating interactions with the Department of Applied Mathematics. My timing was fortunate as the Dean of Graduate Studies and Research was actively looking for ways to promote cross-pollination between departments and schools within the University and saw my proposed PhD work as an opportunity to test and develop new avenues for facilitating such collaborations.

Q: Did you have a mentor(s) in your field of study?

A: I have been fortunate enough to have had several excellent mentors at different stages of my career. One of the most influential has been Dr. Svante Wold, Professor of computational biochemistry (chemometrics) at the University of Umea in Sweden. Professor Wold is the father of a branch of mathematics that is uniquely suited to study large complex problems such as gene expression. In addition to opening my eyes to this fascinating and powerful field, he has been a steadfast supporter of my career and research interests as well as a valued friend and colleague.

Another person who comes to mind is Dr. Suzanne Vernon. I can think of no better example of a visionary scientist who is redefining the field of CFS research. Dr. Vernon has a unique ability to identify synergies across scientific disciplines and molding these into highly creative and effective research initiatives. Known for her "out of the box" thinking, it is Suzanne who introduced me to the complex problem of diagnosing and treating CFS. She continues to be an inspiration for me. In my opinion Suzanne is a model of what a truly effective interdisciplinary scientist can be.

Q: What got you interested in chronic fatigue syndrome research?

A: I was first introduced to the CFS research community when Dr. Vernon, who at the time was with the CDC in Atlanta, invited me to lecture at the Cold Spring Harbor Laboratory in Long Island. Through discussions with Dr. Vernon and her colleagues I became intrigued by this illness that incapacitates several of the body's major systems simultaneously without leaving so much as a single lesion or other easily observable anatomical trait.
To be honest, I was also struck by the magnitude of the illness' impact and by how poorly understood it still is. I was also saddened by the stigma often associated with this illness and how poorly equipped physicians are to recognize this as a very real physiological disorder. My background and interest in understanding complex systems like the immune and endocrine systems were a natural fit with the clinical scientists active in this field, and we have been collaborating ever since.

Q: What are your research goals?

A: Ultimately, the generic goals of my research are three-fold: diagnosis, understanding the mechanisms the underlie CFS, and identifying treatment strategies. The most immediate objective for me is to develop a diagnostic test that clinicians can use to objectively and unequivocally diagnose CFS. Such a test will not only empower clinicians but will also legitimize CFS as an illness with a very real molecular and cellular fingerprint.

My perspective on this is that we are very close to mapping such a fingerprint. To achieve this, we are using the latest technologies for detecting the relative amounts of key immune proteins and hormones in the blood. These proteins are the biological equivalent of telephone conversations between the immune, endocrine, and nervous systems.

To listen
in and decipher these molecular conversations, my group is developing supercomputing algorithms and applying the mathematics of telecommunication networks. Eventually, we hope to be able to introduce our own molecular messages in the form of hormone and immune therapies to reset the body's response to infection and other stressors.

Q: You received a $3,000 grant from P.A.N.D.O.R.A. in memory of Dr. Steven Croft. How will this help you in your research?

A: First, let me just say that nothing means more to a researcher than the trust and support of the patient population he is trying to serve. I am very touched and appreciative of this vote of confidence in my group's research. Through my teaching at the School of Medicine, I have an opportunity to raise awareness of CFS and similar complex disorders in the next wave of clinicians. My teaching activities have allowed me to recruit bright young medical students into summer research positions in my laboratory and introduce them to CFS research and members of this research community.

I have found the students to be exceptionally receptive and interested in this problem. As a result I would like to use this donation from PANDORA to sponsor a summer research studentship involving my laboratory and that of a collaborating clinical investigator. This accomplishes two things: First, it furthers research into CFS and second, it trains and re-introduces into the health care system a clinician who is more in tune with these patients and the challenges they are facing.

Q: The CFIDS Association of America announced early in December 2008 its recipients of grants for the very first Accelerate CFS Research Initiative. It is my understanding that you also received a grant from this organization. How will the grant you received under the auspices of this association also help you with your progress toward identifying disease progression biomarkers in CFS?

A: Yes, my team was one of six that have been funded following an international competition. The project funded by the CFIDS Association will be directed at understanding the factors involved in the onset and progression of CFS in adolescents with infectious mononucleosis. This research builds on the hard work of Drs. Renee Taylor (University of Illinois in Chicago) and Ben Katz (Northwestern University) who initially recruited and assessed this patient population. In this next phase, my co-investigators and I will measure gene expression in immune cells that were collected in these patients over the course of 2 years.

By doing this, we hope to understand at a molecular level why the immune status of some individuals might predispose them to remain chronically fatigued 2 years after being diagnosed with this viral infection. We also hope to learn exactly how the virus might highjack the immune system in these individuals and chronically affect several other systems in the body.

Q: How long do you think it will take to obtain your research goal(s)? Once you have reached your current goal(s), what will be the next step in CFS research? Perhaps this is looking too far ahead into the future?
A: There is an increasing amount of evidence relating to the molecular underpinnings of CFS, and I am quite optimistic that we are well on our way to defining a first generation of diagnostic tests. As I mentioned this is the first and most important objective. In developing these tests we will also increase our understanding of how CFS is triggered and how it progresses. We are at the early stages of this already and have been using what we now know to create computer simulations of possible treatment strategies. I think the next big push will be to explore these ideas and begin testing their feasibility. The nice thing is that we can start exploring treatment strategies even as we continue to learn about the exact mechanisms that cause CFS. There are many examples in medicine of effective therapies being discovered and made available to patients before the illness became fully understood. We intend to conduct these activities in conjunction with the ultimate goal of safe and effective therapies as quickly as possible.

Q: Do you have an opinion as to the continual debate over whether the disease should be called chronic fatigue syndrome, chronic fatigue immune dysfunction syndrome, myalgic encephalopathy, or by any other name?

A: Fatigue is only one of many symptoms and I feel that this is probably the most negatively perceived by the general public. Our research is showing us that CFS and Gulf War Illness involve detectable and characteristic imbalances in the immune and endocrine systems. Although The exact name is a minor point, it is my opinion that a label specifically referring to neuroendocrineimmune dysfunction would improve the perception of this illness for many clinicians and lay people.

Q: Can you share personal information about your life? For example, are you married, if so, for how many years? Do you have any children? Pets? Hobbies? Time for anything outside of your research?
A: I have to smile at this question. Research is indeed a very demanding or should I say engaging mistress. Research is definitely not a pursuit that you can turn off at the end of the day. I have often gotten out of bed in the middle of the night to write down an idea in my lab book to make sure I would remember to pursue it the next day. I am passionate about what I do, and I cannot see myself doing anything else. I'm blessed with a very understanding wife who is also a very busy working through her medical residency in obstetrics. I am also blessed with a healthy and very bright little boy who is my daily ray of sunshine. He helps me to see the world for all of its marvels and teaches me more than I can say. All of us are very active. My wife and I are distance runners and have run several marathons. With Jason's arrival and Jenn's medical residency, we have had to scale back our training somewhat and now run half-marathons instead because they are easier to prepare for. We also enjoy our evenings with the Alberta ballet that we find very progressive.

Q: Is there anything you would like to add that you feel is important for people to know about CFS?
A: Only that there is hope. That we understand much more now than we ever did before. And that with the continued advocacy of patients, we can encourage government to support research in this area and find a cure. There is hope.

********************************************************************************************
Thanks to Dr. Broderick and so many other people who conduct their research in the name of treatment and a cure - there is hope! Three cheers for this amazing scientist from Canada!

A NOTE FROM PANDORA

Dr. Broderick CFS, Gulf War syndrome & Fibromyalgia research center at the Department of Medicine, University of Alberta, Canada is the recipient of a $3,000 special grant from P.A.N.D.O.R.A. in memory of Dr. Steven Croft.

The grant will fund 2 medical students, Andrea Kreitz and Landon Berger for a summer internship in 2009. Both are embarking on their 3rd year of medical school at the University of Alberta. (See picture below.)​

The grant for Andrea Kreitz will focus on the study of immune imbalance in Gulf War Illness and is funded by the U.S. Department of Defense. Landon Berger (middle of photo) will receive a travel stipend to work with a collaborator at Cornell University in the use of neuro-imaging for diagnosis of chronically fatigue syndrome patients and is funded by the CFIDS Association of America, Inc.​

Dr. Broderick seen in the photo below shares his comments with P.A.N.D.O.R.A. and our community: "This type of cofounding for medical student awards is crucial for the patient community as these individuals will be in the first line of health care delivery in the very near future. I commend P.A.N.D.O.R.A. for recognizing this need and helping us better serve the patient population. It is my hope that P.A.N.D.O.R.A. can continue this important work benefitting the patient community. "​

Photo of Dr. Gordon Broderick, Landon Berger & Andrea Kreitz
 
Thanks once again Cort.

This seemed to be the most exciting presentation of the workshop for me, and it was referred to a few times later in the workshop by other speakers - it seemed to have made quite an impression.

There were one or two great slides showing the 2 or 3 different network patterns which characterise GWI, ME/CFS and healthy controls. Particularly interesting was that the GWI pattern was really quite different from the ME/CFS pattern - in the latter you could see, in a great visual representation, how all the connections between markers were somehow more chaotic and disordered. As with the spinal fluid study, it's really exciting to see such clear distinctions between what until now have seemed like overlapping syndromes.

I didn't see images of those particular slides in your piece - is there any way of getting hold of them? Should be possible to screengrab from the video.

A picture can paint a thousand words, and as I commented before, the Light study graphs showing the phenomenon of PEM visually look to me like "our hockey stick". I think that a simple page of information with these two sets of images, and a very brief and simple explanation as to what they mean, could work wonders educationally.
Yes, those were great slides! I just do not know how to do that. I tried - I'm pretty sure it can be done...does anyone know how to do that?
 
This is very exciting, esp the fact that NIH have made a $4m grant a) because you can do a lot with this and b) because it's the NIH taking CFS seriously. My one caution is that with enough data and computing power you will find a pattern in any set of patients - the trick is to find the same pattern using the exact same methodology in repeated sets of different CFS patients.
 
This is very exciting, esp the fact that NIH have made a $4m grant a) because you can do a lot with this and b) because it's the NIH taking CFS seriously. My one caution is that with enough data and computing power you will find a pattern in any set of patients - the trick is to find the same pattern using the exact same methodology in repeated sets of different CFS patients.
Good point Oceanblue - we need validation; that's been the problem with gene expression results - except for Kerr's. It is good to see some similar abnormalities popping up - validation is key...just think if they can put all this data using 'supercomputer algorhythms - and then come up with the same findings again....in a way that would be astonishing - and very convincing.

As both Dr. Klimas and Dr. Broderick noted - we're not even adjusting for gender yet......

I am looking forward to seeing the $4 million grant...that's an astonishing figure - that's what I heard and it'll be amazing to see it. Its so much bigger than any other grant that I'm crossing my fingers...
 
Yes awesome, Im only worried that the concentional disciplines wont pick up on it/ wont be convinced (too weird). And those are the peeps that are going (or not going) to treat us.