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Outside the Box:  Inside Perspective

By Alan Cocchetto, NCF Medical Director 2006
As you can imagine, the NCF receives all types of communications from patients worldwide. Be it by phone, fax or email, we hear from you! We listen, support, assist, console and try to help each of you in your own way.
With that said, my own correspondence has continued to grow and at times, often seems out of control as it appears to have a life of its own. As one of many point guards here at the NCF, there's always work to be done. Recently, a patient faxed me an article on CFIDS/ME that was published by a well-known physician. After reading this, I feel that I must comment, especially in light of the NCF's recent research. In one of my e-mails, another patient sent me information on Dr. John Gow's gene research into CFS/ME. I will comment on this as well.
The article that was faxed to my office was titled "Wake-up call." This was published in MS Magazine this summer and was written by Dr. Nancy Klimas. Dr. Klimas primarily discussed the CDC's "hopeful new research" that showed that Chronic Fatigue Syndrome may have a genetic basis. Also, Dr. Klimas states that "this is a huge step forward in terms of diagnosing and hopefully treating CFS." In her article, I found one of Dr. Klimas' comments to be rather interesting. She stated "How I view the disease today, however, is not the way I once perceived it." As the NCF's Medical Director, you'll see why I have chosen to comment on that particular statement. Dr. Klimas also went on to discuss research money by stating that "It's difficult to raise research funding for an illness that is so misunderstood, yet lack of adequate funding has limited the kinds of studies that might yield definitive answers."
I must admit, perhaps I was looking for more from Dr. Klimas. After all, she holds the position as the current AACFS (IACFS) president. Why do I feel so strongly about this? Well, in 1990, Dr. Klimas published an article in the Journal of Clinical Microbiology on her examination of the immunity in CFS patients. Dr. Klimas' conclusion was that "CFS is a form of acquired immunodeficiency." Simply stated, most of us reading those very words would interpret them as CFS is a form of AIDS! Now, don't get me wrong, I'm not trying to put words in Dr. Klimas' mouth. After all, she is the one who wrote those words initially and published them in a peer-reviewed medical journal. What I now find most unfortunate is that Dr. Klimas never refers to "those words" anymore. As such, I really wonder what the readership of MS Magazine would have thought if Dr. Klimas had openly stated, based on her own published medical research, that "CFS is a form of acquired immunodeficiency." My guess is that the readers would truly be astounded and that they would come to view CFS as a very severe disease. Perhaps the readers would truly begin to finally understand what their family members, friends, colleagues, or acquaintances who suffered with this disease were going through. Readers would realize that this disease is not depression nor malingering nor a hodgepodge of symptoms but a very serious immune disease whose victims lose physical functionality. Wouldn't this description really be closer to the actual truth regarding this disease? Ask anyone who has had this disease for ten years or more and I'd bet you would reach a common consensus when it comes to physical dysfunction. What I don't understand is Dr. Klimas' initial research view to publish that "CFS is a form of acquired immunodeficiency" and to now comment that "How I view the disease today, however, is not the way I once perceived it" appear to be polar opposite thoughts. Certainly, as more is learned medically in this field, our scientific models undergo greater refinement. However, I wonder what Dr. Klimas now thinks of her 1990 publication? What of the immune abnormalities? Did they go away? Do they no longer exist? Does she no longer make these statements, as she had done in 1990, because that would somehow jeopardize her NIH funding for research, upset the CDC, or make her views oppose those of her peers? Hasn't a line really been drawn in the sand? I've always been taught that you can't take something that is black and white and try to make it grey. It's akin to backtracking to retract words you've said or somehow trying to smooth out the hard edges of the truth. In farm country we often say that it's like closing the barn door after the horses have gotten out. In my mind, I find it difficult to reconcile these views, especially given prior statements...statements made in a medical journal article.
Dr. Klimas does state that "it is difficult to raise research funding for an illness that is so misunderstood." If I were able to ask Dr. Klimas one basic question, it would be this: "Did you ever think that, perhaps, one of the very reasons that the disease is so misunderstood is simply because you failed to use the very words that you openly used sixteen years ago....that "CFS is a form of acquired immunodeficiency?" Aren't these the very words that can help to erase such misunderstandings about this disease? Aren't these the very words that help to imply severity? Should the disease then be viewed as "severe" among the medical community, then wouldn't this
honest description perhaps assist those who are trying to obtain appropriate research funding from either the private or public sector?
Let me now comment and provide additional inside perspective regarding the NCF's
current ongoing research.
The NCF has found the primary etiologic infectious agent that is operative in this disease - Parainfluenza Virus-5 or PIV-5. It was the SER strain that was isolated and that strain came from swine with PRRS disease. It appears that this strain has moved from swine to humans. The immunodeficiency that comes with CFIDS/ME is a result of PIV-5 damaging the immune system. It does so by directly infecting bone marrow B-cells, which act as the viral reservoir, and by directly antagonizing the effects of interferon thus altering innate host immunity. PIV-5 is a master of viral evasion. It acts as a slow viral infection that plays hide and seek with the host's antiviral response via alterations involving key interferon-based pathways. In the months ahead, the NCF will focus on some of the consequences of PIV-5 infection. You will also learn of new efforts by the Foundation that are directly aimed at finding therapies for this infection. We have been a very busy bunch here working for you, the patient community.
Let me provide you with some hints from our current efforts to review the recent advances in CFIDS research. The NCF firmly believes that all roads will ultimately coincide and therefore complement our scientific findings. Thus, with time, we would expect that additional research, performed by other scientists around the globe, should serve to illuminate the work that has already been completed by the NCF.
Here is perhaps the newest example of this. As readers may be aware, Dr. John Gow, from Glasgow University in Scotland, has announced the gene signature his research group has identified from patients with CFIDS/ME. Those who have an interest can refer to his World Patent that was just issued on August 10 (WO2006082390). This was sent to me via email from a fellow CFIDS patient. The patent discloses a number of genes that are identified which are expressed at abnormal levels in patients affected by CFS/ME as compared to normal healthy individuals. According to Dr. Gow, "The genes identified provide objective disease markers that may be used in diagnostic tests to support the diagnosis of CFS/ME."
Let's take a look at one of the gene markers that Dr. Gow is very interested in. After the NCF explains its connection to PIV-5, we're certain that the readers will begin to appreciate this specific connection to the Foundation's research.
In his patent, Dr. Gow expressed his interest in the ATPase system. According to his patent, "At the cellular level, fatigue has been linked with alterations in the cell membrane ion-channel traffic and ATPase system. ATPases are also linked with neurotransmitter release (e.g . dopamine) and cellular energy metabolism via creatine phosphatase. Increased ATPase activity has been reported in muscle biopsies from patients with CFS. Previous work has raised the possibility that patients with CFS may have an ion channel dysfunction. This dysfunction might be induced by changes in the ion channel function, neurotransmitters involved in "gating" the channel or by a shift in the balance of the cellular "energy charge", i.e - the ratio between ATP and ADP that is normally a function of the ATPase activity."
Dr. Gow continued, "A group at the University of UIm, Germany, has recently suggested that a pentapeptide (QYNAD) with Na+ channel-blocking function could be a biological marker of certain inflammatory and immunological disorders of the nervous system. The inventors asked whether or not the pentapeptide identified by the German group might play a role in CFS. Samples of serum were sent to the University of UIm for analysis. The 15 samples included 5 normal controls, 5 patients with CFS and 5 disease controls including two patients with MS. Samples were numbered 1-15 and the German group were not informed what the samples were, or which samples were which, until the experiment was concluded. When the code was broken, the results showed that the disease control group had levels of the pentapeptide which were 2.3X those of the normal controls (similar to the published data) and the CFS samples had levels which were 3X higher than the healthy controls....The German group was unable to identify an endogenous gene which encodes the pentapeptide. The inventors carried out NCBI BLAST and EMBL-Heidelberg Bioccelerator amino acid alignments for the pentapeptide QYNAD....A number of cloned nucleotide sequences were found and when these were run through the nucleotide databases, only one clone showed full-length homology to any human gene. This gene was a human ion-channel gene - the vacuolar proton pump H+ ATPase (v-ATPase)." Dr. Gow then stated "The inventors next asked whether the v-ATPase represents a candidate gene for a diagnostic test for CFS....the patient samples have a significantly higher level of v-ATPase mRNA than the healthy controls. Thus the v-ATPase gene appears to represent a genuine biomarker for CFS/ME."

Two items are of interest. First is that Dr. Gow looked at sodium channel function. This
is of importance because of Dr. Hokama's research on the ciguatera-epitope has also been shown to alter sodium channel function. Next, however, is another big find. Dr. Gow considers the dramatic up-regulation of vacuolar ATPase to represent a genuine biomarker for CFS/ME. That sounds great to us here at the NCF! Why is this important. Let me now explain. Dr. Richard Compans, who has the NIH grant for the SER strain of PIV-5, published a paper on the viral fusion process associated with this parainfluenza virus ("Activation of fusion by the SER virus F protein: a low-pH-dependent paramyxovirus entry process", Seth S, Vincent A, Compans RW; J Virol. 2003 Jun;77(11):6520-7). In this paper, Dr. Compans states that the "SER virus is a recently identified virus that was isolated from aborted pigs with porcine respiratory and reproductive syndrome. This virus belongs to the family Paramyxoviridae, genus Rubulavirus, and is very closely related to SV5 but replicates without causing syncytium formation.... Virus replication was found to be completely inhibited in cells infected with SER virus in the presence of BFLA1 (bafilomycin A1) at concentrations as low as 0.1 microM." Dr. Compans further stated that there is "high specificity of bafilomycin A1, BFLA1, in the inhibition of vaculolar ATPase."
This sounds like a match made in heaven to me! Here we have Dr. Gow who found a biomarker for high levels of vacuolar ATPase, v-ATPase, in CFS/ME and then we have Dr. Compans who found that SER viral replication was inhibited by a compound (bafilomycin A1) that inhibited vacuolar ATPase. This implies that SER replication is directly tied to v-ATPase and that its inhibition alters viral replication. As such, Dr. Gow has found a biomarker that further supports our NCF research findings for SER viral involvement in CFIDS. For those readers who may be wondering, Dr. Compans only found this replication effect for v-ATPase for the SER strain and not for other strains of PIV-5.
Furthermore, Dr. Gow states in his patent that "The v-ATPase is known to be involved in regulation of a number of metabolic functions which are deranged in CFS/ME. v-ATPase upregulation could therefore provide an explanation for a number of the symptoms observed. For example, increased v-ATPase activity could explain the intracellular acidosis in exercising muscles, chest pain (syndrome X), altered neurotransmitter (dopamine) function and abnormal regulation of hypothalamic hormones. In addition, it could explain the increased energy expenditure and fatigue associated with the condition."
Given the surging interests into gene studies, done by the CDC and other research groups, the NCF feels that Dr. Gow's finding for this specific biomarker is in agreement with our research finding for PIV-5 involvement in CFIDS. Hopefully in the next Forum, we will be discussing other biomarkers and their possible therapeutic implications. The NCF has contacted several new research scientists who have expressed interest in working for the Foundation. This is particularly exciting because all of our new research activity will be aimed at therapeutic intervention by increasing our understanding of several unique pathways that are involved in the disease. Our "out of the box" scientific approach has allowed us to make great progress to date. Please help us to help you! By donating to the NCF's Research Grant Program, you become a partner with us to continue our research momentum towards a therapeutic solution for CFIDS/ME. Together, we can reach this goal!

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