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Beautifully constructed and with extensive laboratory facilities

Immaculately done and with extensive laboratory facilities, the Whittemore-Peterson-Institute is an amazing accomplishment given how little support ME/CFS research and treatment has traditionally received.

Last year as I visited the Whittemore Peterson Institute I was struck, more than anything, by what an immense accomplishment it was.  Built in the pre-XMRV era when chronic fatigue syndrome (ME/CFS) hardly registered on the national scene,  the idea that a $15.5 million dollar facility mostly dedicated to ME/CFS research and treatment could be built seemed fantastical, and even now, walking through the beautiful corridors,  rooms and labs there, I felt a bit like pinching myself. This is a project the ME/CFS community can only hope will succeed and succeed very well.

With the XMRV finding  failing, and the Institute, once the darling of the ME/CFS community, getting hammered by some after Dr. Mikovits dismissal, the WPI went through some rough times.  They’ve kept their heads down recently but their ability to land a Department of Defense grant, to get their original NIH grant renewed and publish a study on HERV’s and autoimmunity suggested things are on something of an upturn.

I was eager to get WPI President, Annette Whittemore’s take on the past, find out what she’d learned and what, if anything in hindsight, she’d have done differently and where the WPI was heading now.  I also wanted to get Dr. Lombardi’s take on some research issues in general and where he planned to be taking ME/CFS research at the WPI.

Annette Whittemore Talks

Annette Whittemore talks about lesson's learned from the XMRV experience

Annette Whittemore talks about lesson’s learned from the XMRV experience

I imagine you could not in your wildest dreams have imagined the ups and downs the WPI has gone through. Somehow you built that beautiful facility, the first of its kind, dedicated to ME/CFS. Then you, a first-time Research/Treatment Institute Director were immediately thrust into a high stakes environment with a passionate community and a strong-willed Research Director.  That must have tested you in so many ways. What did you learn from that experience?

It has been challenging at times, but it has also been incredibly rewarding to be able to be a part of this institute.  WPI was created to add to the medical and scientific knowledge around a group of very disabling diseases for the benefit of patients.  That has not changed.  As a result of past experiences, I’ve learned that there has to be a more cautious approach to all of this work.

It is easy to understand why individuals in this community are so passionate and involved.  Many have to be their own advocates in a situation where there are so few answers.   Advocating on behalf of particular diseases is an important part of the work that we can all do to increase awareness of the need for private and federal research funding.

Is there anything looking back you would have done differently?

Of course, we have always worked to make sure our research and data were pristinely accurate and we take that with the utmost seriousness. Despite assurances that every possible step had been taken to rule out contamination, I should have absolutely insisted on additional support to help ensure our findings were accurate and credible, rather than relying on a single researcher and her collaborators. I think, at some point, it became difficult for some of these folks to remain objective when they felt they had to defend these findings and their reputations.

In retrospect, should the WPI have brought in outside researchers or investigators or begun assessing contamination possibilities more when doubt began to arise regarding XMRV? 

Dr. Lombardi did seek outside advice after the Singh paper was published.  He was advised to try to deconstruct both studies to see if he could understand why there were discrepancies in the results.  The possibility of contamination was definitely in the back of everyone’s mind.  However, it turned out to be very difficult to identify the problems with the studies despite the best efforts of many experts.

XMRV turned out to be a tough nut to crack. That first paper was published in one of the premier scientific journals and the research world embraced the finding and I think most people, including yourselves, expected the finding to be immediately validated. In the end, though, you had to let go of what had appeared to be the biggest breakthrough for ME/CFS ever. The process of letting go of that huge possibility must have been very difficult. Can you talk about that? 

The demise of XMRV was a double-edged sword.  On the one hand, it was deeply disappointing to learn that XMRV was not involved in the disease because many were hoping that XMRV would validate this illnesses’ physical nature and lead to effective treatments.   On the other hand, I think that most were thrilled to know that the retrovirus, XMRV, wasn’t causing their illness.

Looking outside the WPI from the lobby area

Looking outside the WPI from the lobby area

You had such great support from the patient community and once XMRV took off the feeling was that the WPI could do no wrong. Dr. Mikovits was a dynamic, passionate leader and she became the face, for better or worse, of the Whittemore-Peterson-Institute and when she was let go there was an understandable backlash against you and the WPI.  After spending five years working on getting the WPI funded and built that must have hurt. How did you deal with the upset Dr. Mikovits removal resulted in?  

The institute is not about one person or one idea.  It took a tremendous amount of work by many individuals to create this institute and most are still here working hard every day to help us move our goals forward.   We never entertained the idea of giving up on our commitment to the patients.  When so many are still suffering, we have no other choice but to continue to move forward.  Although it is painful to be attacked by individuals who stand to gain by our work, we hope that they will soon realize that we are making every effort to help them and stop trying to sabotage our efforts.

Any final words on XMRV?   

We have taken what we could from those experiences and moved on.  XMRV gave us all a glimmer of hope as to what is possible; a cause and potential treatment.  It is my hope that this community can begin to heal from the negativity that was generated by a few individuals after the collapse of XMRV.

Dr. Mikovits

What is the status of the civil case regarding Dr. Mikovits? 

Two separate judges ruled in favor of the institute on all of the claims in the lawsuit.  Dr. Mikovits was found liable for the theft of WPI’s property and for causing the WPI other damage.

Have all the materials taken from the WPI at the time of Dr. Mikovits departure been returned?

No.

If not what is missing?  

We are still missing information that was erased from the institute’s computers and research notebooks.

Dr. Mikovits was a dynamic, passionate and sometimes controversial figure at the WPI.  What is the difference between the WPI in  the Mikovits era and the WPI in the Lombardi era?  

There is a stronger sense of camaraderie and certainty under Dr. Lombardi’s leadership.   He’s a team builder and a very positive influence.  His calm, methodical demeanor is a contrast to Dr. Mikovits’ mercurial personality.

Dr. Peterson

WPI-signDr. Peterson’s name is still on the building….Of all the things that happened during the turbulent XMRV era I wonder if his departure was the most significant.  If Dr. Peterson stays you probably have a full clinic, and you have outreach to numerous investigators and the WPI looks very different.

It works the same for Dr. Peterson.  While his  leaving meant he didn’t have to be associated with the XMRV letdown,  he had a superb lab and great facilities waiting for him and he doesn’t have access to that anymore.  It’s a shame for everyone concerned  that that partnership didn’t work out. What are your thoughts on this? 

Dr. Peterson recently reconfirmed that he made the decision not to move his medical practice to the institute for a number of personal, family, and work related reasons.  I’m sure that it was not an easy decision for him to make. Although we were very disappointed that things didn’t work out the way we had envisioned, we ended our relationship on a respectful note.  It is still our goal to have multiple physicians from various medical specialties practicing together at the institute for the benefit of these patients.

Renewal

I think everyone, honestly, was surprised when in the midst of the XMRV turmoil the WPI was the only CFS research group, I believe, to pick up a DOD grant. Then an NIH team came in, scoured the lab, and gave you a thumbs up to continue on the big NIH grant you’d scored earlier. These were good signs that the Lombardi lab has the kind of scientific integrity federal officials are looking for and suggests the WPI can be successful in bringing in grant money.  Has the WPI or is it in the process of applying for more grants?

We were all greatly encouraged by the comments we received after the site visit by the NIH.  Dr. Lombardi stepped into this important leadership role under very difficult circumstances and was able to add detailed studies and resources to the existing RO1, without adding costs to the government.  It is a testimony to his scientific abilities and to his work ethic that he is able to take the lead in this significant work.  His team will continue to apply for grants and to publish findings from various studies.  I’m hopeful that our soon-to-be-published research efforts will provide new avenues of possibilities both for research and patient treatment.

The Future

You’ve had some big dreams for the WPI; you saw it as a center for collaboration amongst researchers, as a hub of learning for physicians, there was the idea that the WPI might be the first of several regional centers.  After the XMRV letdown and Dr. Mikovits departure you’re kind of starting over in a way and I imagine that you have different priorities now.  What role do you see the WPI serving in the immediate future?

Annette-Whittemore-WPI's-Future

Annette Whittemore would like to see a one sentence disease definition for ME; one validated biomarker, clinical trials at the WPI and several significant publications over the next couple of years.

We haven’t given up on our dreams, but we know that it is going to take more time to get where we would ultimately like to be.   As we continue to build connections between ME, GWI, and other autoimmune and inflammatory diseases, we can build connections to additional resources.  I believe that greater success will come to this field as we build a stronger base of practical knowledge for doctors.

Hopefully, comprehensive translational research centers like the institute will be supported by the federal government in the near future.   Centers such as these can offer clinical trials based on the most current research, speeding up the length of time between discovery and effective therapies.  It’s been encouraging to see other groups of doctors combine their resources to create similar organizations.   The more people we have working to find the answers, the greater chance we have of being successful.

If you were to give three words that summed up the WPI right now, what would they be?   

“Moving steadily forward”.

What’s one thing most people don’t know about the WPI? 

Most people don’t know that we are in the process of hiring a new medical director for the institute.  We are also planning studies in Alzheimer’s disease, HIV, and autoimmunity.  They may not know that WPI’s vision is expanding, creating a deeper knowledge of neuro-immune diseases and hopefully additional sources of funding.

You’re well versed in the science. Even though XMRV didn’t turn out how do you feel about the state of the science of ME/CFS. Are you optimistic? Any areas in particular grab you?

Outside corridor at the WPI

Outside corridor at the WPI

The science of ME/CFS is beginning to include new discoveries that go beyond EBV, HHV-6 and NK cell dysfunction.   Many successful discoveries in human disease have come from uncovering similarities between various disease processes.  These similarities provide valuable clues to the illness and can aid our search for biological markers as well as effective treatments.  For instance, work which is being done in autism and the gut micro-biome may have important ramifications for those with ME who are known to have gut associated dysfunction.

Lesions have been found in the brains of some patients with ME, resembling those found in MS.  Symptoms of ME are similar to those with MS, including ataxia, muscle weakness, cognitive impairment and fatigue.  Therefore, knowledge gained in MS research could lead to cutting edge treatments for MS patients as well as those with ME.  Much of the work being done involving HIV and opportunistic pathogens can help us learn about the difficulties many ME patients experience with chronic and/or reactivated infectious pathogens.

Meanwhile, WPI researchers are doing tissue studies to take a deeper look into the immunological changes in ME that have been found in those with autoimmune disease.

One of the keys to speedier discovery and future treatment lies in having access to sophisticated research tools such as next generation genomic sequencing.  We believe that by combining WPI’s research tools and expertise with researchers, who study similar disease processes, we can speed discoveries made in the laboratories to effective treatments for those who are ill with ME.

What are you committed to have happen over the next couple of years at the WPI? What would you like to see happen?   

We have very ambitious goals for the institute and this field of medicine within the next couple of years.  We would like to see the creation of a one sentence disease definition for ME; the validation of at least one biological marker of disease; the start of clinical trials at the Center for Translational Medicine; and the completion of several significant publications surrounding ME and other complex diseases. (The Center for Translational Medicine is the clinical side of the WPI.)

If we could receive one gift, it would be enough funding to hold various clinical trials at the WPI for the next several years.   We know that patients with ME are waiting and willing to participate in such trials as critical financial support becomes available.

Dr. Lombardi Talks

The WPI and the University of Nevada, Reno (UNR) are reportedly pursuing a next-generation gene sequencer. whose capabilities UNR researcher Dr. Hunter stated were “mind-boggling”. What’s the status of that instrument? Do you have it and if you do what are you planning to use it for?             

WPI-Lab-3-University-Nevada

Laboratory area

The next generation sequencer (NGS) platforms have been delivered, and we are in the final stages of installation. Presently, we have several projects that will take advantage of this equipment.  Our NIH grant, New Strategies to Decipher the Pathophysiology of Chronic Fatigue Syndrome, was originally proposed to use data obtained with a viral micro-array. Unfortunately, the leads generated by this data have been unproductive; therefore, we will be utilizing NGS technology going forward. Our DOD grant, Pathogen and Biomarker Discovery in Gulf War Illness, will also utilize this new equipment.

The advantage of this technology is that it has the capacity to identify pathogens that are not represented in a specific viral micro-array. Moreover, it has the added ability to evaluate transcriptional differences of genes between study subjects.

Therefore, in addition to the pathogen discovery aim of these studies, we will also be unbiasedly assessing differences in immune and metabolic pathways. This aim was not proposed in the original grant applications, and therefore, represents a significant improvement of the original proposals.  Also, we are conducting a tissue-based ME/CFS study using NGS technology as well as two other studies that are not uniquely ME/CFS related, but may provide useful information to direct future work in ME/CFS and autoimmunity.

Annette Whittemore described the DOD grant as ‘wide-open’ ‘discovery’ grant you’re using to look for biomarkers both in ME/CFS and Gulf War Syndrome. Can you describe what kinds of biomarkers you’re looking for and where you are with that grant?

Although our primary interest is in the innate immune system and its dysregulation; particularly, the regulation of inflammatory cytokines, the NGS platform will give us the ability to look at virtually any difference between study subjects.

The WPI has a big Biobank and it was presumably used extensively for the XMRV studies. What is the status of the Biobank now?  Have any other researchers asked to use it?  Does the issue XMRV contamination was found (origin unknown) affect the Biobanks usability in any way? What are your plans for the Biobank?

We are writing a human subjects protocol to expand the Biobank and allow outside researchers to use stored specimens and information, but it will take some time in light of the number of projects we have ongoing. XMRV contamination isn’t an issue for the Biobank.

If I remember correctly Dr. Peterson  introduced you, as a graduate student, to Dr. Suhadolnik, the developer of the RNase L tests.  Drs. DeMeirler and Englebienne wrote  a book,”CFS A Biological Approach”, suggesting a unique dysfunction in interferon system played a major role in ME/CFS yet the last RNase L study was in 2008.  As research director for RedLabs and then Univex you routinely ran RNase L tests.  Where are we on this putative, past  breakthrough now? Does it figure in any WPI studies? Do you believe RNase L has relevance to ME/CFS?

Luminex

Luminex Flow Cytometry Analyser

I believe that the interferon system is dysregulated in ME/CFS, and this can indirectly affect the RNase L pathway as well as several others immune pathways. The entire 2-5A/PRK/RNase L pathway is upregulated by interferon so the dysregulation of interferon would certainly affect this entire pathway. Additionally, type I interferon is critical for the activation of NK cells, which are also known to be dysregulated in ME/CFS.

It’s also likely that one of the mechanisms of Ampligen is the upregulation of interferon. It is for these reasons, as well as a number of others, that the primary focus of my research continues to center on the dysregulation of interferon production. I do believe RNase L dysfunction is a downstream effect of a problem that occurs earlier in the immune response; however, I’m not specifically working on RNase L at this time.

Where do you think we are in the hunt for biomarkers? Are we close?  Do you think in the next five years we’ll have a biomarker for a group of ME/CFS patients?

Although biomarkers are important to give the disease credibility, it’s conceivable that we won’t identify just one unique biomarker. Even lupus and multiple sclerosis aren’t diagnosed by a single biomarker.  However, I do believe that it is conceivable that we will find biomarkers for discrete subgroups of ME/CFS patients.

For instance, recently, we had a manuscript accepted for publication that reports an observation that is found in more than half of ME subjects tested, but none of the healthy controls. However, it’s likely that this marker will be observed in subjects with lupus, MS, and other autoimmune diseases that have overlapping symptoms with ME.

The obvious limitation of this potential biomarker is that it is tissue-related and is not convenient for routine laboratory screening. Therefore, we are currently exploring its potential in more accessible biological samples. I won’t go into more detail about it now since the manuscript should be published within the next month or two, and the readers can make their own conclusions about the work.

The almost complete focus the WPI had on XMRV for several years had a surprising  silver lining; the technology progressed  enough to make their pre-XMRV NIH grant more effective.  A study that was supposed simply to detect viruses is now, using new ‘unbiased gene sequencing equipment’ that is able to detect all pathogens AND pick out unusual immune sequences. What is the status of this study now?

It’s true that a considerable amount of time was spent working on XMRV; however, I’m fortunate that I was personally able to dedicate a significant amount of my time working on the inflammatory component of ME/CFS, which is the primary reason we are as far along as we are.  Because all the original biological samples were manipulated in trying to culture virus and virtually no controls were collected, we found it necessary to recruit new study subjects, and that process is ongoing at this time. However, we anticipate the NGS analysis will commence sometime in the middle of this year.

You did graduate work at the University of Nevada, Reno where the WPI is based and you have ties there. Do those ties help your work at the WPI?

The Whittemore Peterson Institute fits snugly into other medical research areas on the Univ of Reno, Nevada campus

Fitting snugly into the Center for Molecular Medicine on the Univ of Reno, Nevada campus, the Whittemore Peterson Institute (on right), is well situated to collaborate.

Absolutely, in many positive ways! Having strong ties and a good working relationship with many of the excellent researchers at UNR has been instrumental in being able continue my research and being able make the advances we have made. In spite of the problems of the past, most of the research faculty at UNR have been very supportive and have made every effort to help me.

A second study will use transcriptome analysis to deeply scrutinize innate immune system functioning in Gulf War Syndrome (GWS) and ME/CFS patients. Do you see the early warning or innate immune system being key in ME/CFS and, if so, is that unusual? 

Yes. Everything we have seen in ME/CFS suggests a chronic innate immune activation. It’s likely that there is more to this story than just innate immune activation, but it’s clearly part of the puzzle. So to answer your question, its unusual in the context of what is found in a healthy individual, but it’s typical of what is observed in other diseases; particularly in inflammatory diseases like Crohn’s disease and autoimmune diseases like lupus.

What can we expect to see from the Lombardi lab from the next six months to a year?

In addition to the NIH and DOD projects, which will continue until 2014, we are currently working on a number of basic virology projects, including HHV-6 and EBV, as well as some basic immunology projects with a focus on cells of the innate immune system.  At this time, we have two manuscripts that have been accepted for publication, one of which is a ME/CFS project. We also have two others that are in the works and should be submitted for publication in the next few months. We also hope to present some of this data at some national meetings this year.

What do you want to see happen in your lab over the next couple of years?

At this time, we have more projects and ideas than can be realistically handled with the research staff we have; therefore, we are hoping to expand our research operation and personnel at least twofold over the next two years. If we can expand upon the work conducted over the last year, we will be in very good shape as a research group, and I believe we will have made progress into understanding the mechanism of this disease.

 




 

 

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