by NCF Medical Committee
Written permission required for reprinting © 2010

From Fall 2010 Forum

In this column, we will discuss the latest information that links CFIDS/ME to radiation and more. We do suggest that you read our press release if you haven't done so for clarification.

The tale of two very important published papers: A critically important paper was published by Zhang et. al. in 1995. In this paper, a specific mitochondrial DNA deletion (mtDNA) was identified in a patient with CFS ^[1]. Mitochondria play a key role in energy metabolism in many tissues, including skeletal muscle and liver. Inherent disorders of mitochondria, such as DNA deletions, cause major disruptions in metabolism and can result in severe impairment or death ^[2]. In fact, it has been found that mtDNA deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues ^[3].

The mtDNA deletion that was identified, in the skeletal muscle, was unique in that it hadn't been identified nor classified previously. It was found to have the following characteristics: The mtDNA deletion was 4881 bp (base pair) in length and the deletion occurred between a pair of 7 bp direct repeats identified in "DNA speak" as CTCCAAA. In a nutshell, approximately one-third of the mtDNA was missing! The authors suggested that this type of deletion could be connected to dysfunctional mitochondrial energy production. Ultimately, they concluded that "It will be important for future work to establish whether involvement of mitochondrial dysfunction occurs regularly in the chronic fatigue syndrome, and also whether there is an identifiable subset of patients in whom analysis of mtDNA would be informative." Six years later, Chazotte extensively documented the mitochondrial dysfunction along with the lack of energy (ATP) production at the cellular level in CFIDS/ME patients ^[4]. Mitochondrial dysfunction was found to be a common trait among patients.

Little did Zhang et. al. know how informative this analysis of mtDNA would be! Fortunately, Murphy et.al. published a paper ten years later, in 2005, that would carry with it significant ramifications for CFIDS/ME patients ^[5]. Their results indicated that the induction of a novel deletion in the mitochondrial genome occurred after direct exposure to low-level radiation.

In the Murphy paper, the authors state that "It is becoming apparent that there may indeed be no such thing as a ‘safe’ level of radiation exposure. This would concur with the characterization of the ‘bystander’ effect. This is a mechanism whereby cells, never exposed to radiation, display radiation-like damage if in the vicinity of irradiated cells. More importantly, the extent of this effect remains the same no matter how low the radiation dose may be. Evidence suggests that at very low doses of radiation the damage induced is predominantly a result of the release of ‘bystander’ factor(s) and the direct radiation effects are indeed negligible." The authors further comment that "The mitochondrion is the only other location of genetic material outside of the nucleus. Although the mitochondrial genome encompasses a minute fraction of the total genetic material in a cell, any damage or alteration to it can still have serious implications for a cell’s viability and/or survival."

Murphy found that cells exposed to low-level radiation produced a novel mtDNA deletion that was 4881 bp in length flanked by a 7 bp repeat (CTCCAAA). This is identical to that first identified by Zhang in the muscle tissue of a patient! Furthermore, these authors state that "Should the accumulation of this deletion continue, the implications would be grave for the viability of the distal progeny of these cells. This is a relatively novel deletion and to our knowledge, there has been only one previous report of this deletion." At this point the authors reference Zhang's CFS paper! Thus, this formally and technically established a critically important link between CFIDS/ME and low-level radiation exposure!

The link to Stat-1:
The NCF has previously discussed the vital importance of Stat-1 in patients due to its own research that had been completed in 2004 ^[6]. Of course, you may recall, parainfluenza virus-5* (PIV-5) directly targets Stat-1. In fact, these NCF grant funded researchers had found evidence for this infection in patients. However, it wasn't until several months ago, when the concept of radiation involvement crossed our minds, that we had determined that radiation may actually play an important role in CFIDS/ME. One of the papers we found had determined that ionizing radiation had a negative impact on Stat-1 ^[7]. We felt that this was important because we knew that any appropriate disease model must take Stat-1 modulation into account since its role in CFIDS/ME had been confirmed by two other research groups. One of these groups had in fact confirmed Stat-1 depletion in NIH selected patient samples.

Even though Stat-1 is critical for proper immunity, it is important to note that lymphocytes are very sensitive to radiation ^[8]. In CFIDS/ME patients, it is well known that the ratio of CD4/CD8 cells can be unusually high (3:1 to 14:1 is what the NCF has seen) ^[9]. In other words, there is a drastic reduction in CD8 lymphocytes. In ionizing radiation, CD8 cells have greater sensitivity to apoptosis than CD4 cells ^[10]. The yield of radiation-induced apoptosis in the total lymphocyte fraction decreased with increasing ratios of CD4(+) to CD8(+) T-cells (CD4/CD8 ratio), a finding which is consistent with those seen in CFIDS/ME. The NCF has much more data regarding other important markers but will reserve those for another column.

The link to myelodysplasia and myeloid leukemia:
The NCF had previously discussed both myelodysplasia and myeloid leukemia since we funded research in this area that is currently on-going. These had been discussed within the context of their relationship to ciguatera poisoning. As such, we will not repeat that information here but refer you to our article archives. It is interesting to note that exposure to ionizing radiation is associated with myelodysplasia as well as myeloid leukemia ^[11]. However, an even larger revelation is that mtDNA deletions have been suggested as having a role in the development of myelodysplasa and myeloid leukemias ^[12]. In light of the findings above, this evidence should certainly not be ignored.

The link to ciguatera poisoning:
The NCF has developed a model for a radioactive toxin and we believe that this model fits the CFIDS/ME disease profile. The model is, of course, also reinforced by various scientific data. The NCF has chosen to not disclose the complete details for the model at this time. However, what we can comment on is that a relationship between radioactivity and ciguatera poisoning has previously been suggested. For example, there appears to be a long-standing relationship between ciguatera poisoning outbreaks and military activities ^[13]. In fact, nuclear testing and ciguatera poisoning have even been the topic for discussion on two different occasions by U.S. Congressman Eni Faleomavaega, from American Samoa, on the House floor ^[14-16]. Congressman Faleomavaega expressed his outrage over this very serious situation that has greatly impacted the inhabitants of the islands in the South Pacific. The NCF has linked these CSPAN videos to its own homepage to encourage readers to view these accordingly.

More hints:
If this data isn't enough to make you really give some serious thought to all of this, then we suggest you take some time to read about the relationship between the Chernobyl reactor disaster and the development of CFS ^[17-20]. This data suggests a direct relationship between low-level radiation exposure and the development of CFS.

In closing, as data accumulates, it is imperative that patients, physicians, researchers and scientists keep an open mind about these findings to date. There is tremendous patient suffering with CFIDS/ME and we are now fully aware of why this is. Our research, along with others, provides us with the following simplified view for this emerging scientific disease model: Marine Toxin + Radionuclide = Radioactive Toxin. This is the only existing disease model that: * accounts for many of the biomarkers that have been previously reported on; * fits the epidemiologic profile for the disease; * provides the first true glimse of the global magnitude of this problem. It is imperative that we continue our search for appropriate therapies to relieve the patient suffering. After all, these patients may have only been canaries in the coalmine.

[*Editor's note: Ionizing radiation creates an innate immunity 'hole' that is exploited by parainfluenza virus-5 infections. Stated differently, ionizing radiation predisposes to PIV-5 infections due to its direct effect on Stat-1.]

References:

1. Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome; Zhang C, Baumer A, Mackay IR, Linnane AW, Nagley P; Hum Mol Genet. 1995 Apr;4(4):751-4.
2. The role of mitochondria in health and disease; Johannsen DL, Ravussin E; Curr Opin Pharmacol. 2009 Dec;9(6):780-6.
3. What causes mitochondrial DNA deletions in human cells?; Krishnan KJ, Reeve AK, Samuels DC, Chinnery PF, Blackwood JK, Taylor RW, Wanrooij S, Spelbrink JN, Lightowlers RN, Turnbull DM; Nat Genet. 2008 Mar;40(3):275-9.
4. Mitochondrial Dysfunction in Chronic Fatigue Syndrome; Chazotte B; Mitochondria in Pathogenesis; Lemasters JJ, Nieminen AL editors; Plenum Press NY, 2001; Chapt 21, 393-410.
5. Mitochondrial DNA point mutations and a novel deletion induced by direct low-LET radiation and by medium from irradiated cells; Murphy JEJ, Nugent S, Seymour C, Mothersill C; Mutation Research 585 (2005) 127–136
6. Deficiency in the Expression of STAT1 Protein in a Subpopulation of Patients with Chronic Fatigue Syndrome; Knox KK, Cocchetto A, Jordan E, Leech D, Carrigan DR; American Association for Chronic Fatigue Syndrome (AACFS) Conference; Madison, Wisconsin; October 8-10, 2004
7. Gamma irradiation-reduced IFN-gamma expression, STAT1 signals, and cell-mediated immunity; Han SK, Song JY, Yun YS, Yi SY; J Biochem Mol Biol. 2002 Nov 30;35(6):583-9.
8. Clearance of radiation-induced apoptotic lymphocytes: ex vivo studies and an in vitro co-culture model; Benderitter M, Durand V, Caux C, Voisin P; Radiat Res. 2002 Oct;158(4):464-74.
9. National CFIDS Foundation Inc., Personal Communication
10. The effect of the ratio of CD4+ to CD8+ T-cells on radiation-induced apoptosis in human lymphocyte subpopulations; Wilkins RC, Kutzner BC, Truong M, McLean JR; Int J Radiat Biol. 2002 Aug;78(8):681-8.
11. Cytogenetics of myelodysplasia and acute myeloid leukaemia in aircrew and people treated with radiotherapy; Gundestrup M, Klarskov Andersen M, Sveinbjornsdottir E, Rafnsson V, Storm HH, Pedersen-Bjergaard J; Lancet. 2000 Dec 23-30;356(9248):2158.
12. A role for mitochondrial DNA in the pathogenesis of radiation-induced myelodysplasia and secondary leukemia; Hatfill SJ, La Cock CJ, Laubscher R, Downing TG, Kirby R; Leuk Res. 1993 Nov;17(11):907-13.
13. Ciguatera in the Pacific: a link with military activities; Ruff TA; Lancet. 1989 Jan 28;1(8631):201-5.
14. CSPAN video; Outrage over France's nuclear testing program in South Pacific; U.S. Congressman Eni Faleomavaega; Dec. 5, 1995; http://c-spanvideo.org/videoLibrary/clip.php?appid=597096245
15. CSPAN video; French nuclear nightmare in the South Pacific; U.S. Congressman Eni Faleomavaega; Jan. 26, 1996; www.c-spanarchives.org/videoLibrary/clip.php?appid=597071563
16. Congressional Record-House #H13933; Outrage over France's nuclear testing program in South Pacific; U.S. Congressman Eni Faleomavaega; Dec. 5, 1995; Available at www.ncf-net.org/pdf/CREC-1995-12-05ciguatera.pdf
17. Chronic Fatigue Syndrome as a characteristic aftermath of radioecological catastrophe; Loganovsky KN; International Journal of Psychophysiology, Abstracts; 35 (2000) 61-75.
18. Psychophysiological Features of Somatosensory Disorders in Victims of the Chernobyl Accident; Loganovsky KN; Human Physiology, Vol. 29, No. 1, 2003, 110–117.
19. Vegetative-Vascular Dystonia and Osteoalgetic Syndrome or Chronic Fatigue Syndrome as a Characteristic After-Effect of Radioecological Disaster: The Chernobyl Accident Experience; Loganovsky KN; Journal of Chronic Fatigue Syndrome; Vol 7, Issue 3 Sept 1999, 3-16.
20. Chronic Fatigue Syndrome a Possible Effect of Low and Very Low Doses of Ionizing Radiation; Loganovsky KN, Nyagu AI, Loganovskaja TK; Abstracts of the International Conference "The Effects of Low and Very Low Doses of Ionizing Radiation on Human Health," World Council of Nuclear Workers, Univ. of Versailles, France, 16–18 June, 1999, p. 14.