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By Alan Cocchetto, NCF Medical Director Copyright 2016 – Written permission required for reposting

From Summer 2016 Forum

Any scientist who works in medicine certainly knows that radiation exposure results in direct DNA damage. Now using this as a reference point, let me introduce some simple terms and explanations to go along with this idea!

DNA is a molecule that carries most of the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms [1]. Most DNA molecules consist of two biopolymer strands coiled around each other to form a double helix. The two DNA strands are known as polynucleotides since they are composed of simpler units called nucleotides. The DNA acts as a repository to store biological information. The DNA backbone is resistant to cleavage, and both strands of the double-stranded structure store the same information. Biological information is replicated as the two strands are separated. Within cells, DNA is organized into long structures called chromosomes. During cell division these chromosomes are duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes.

As you may recall, Dr. Henry Heng identified high levels of chromosome damage and genomic instability in the NCF's patient cohort. This cohort had previously been identified as ciguatera-monoclonal antibody positive as well as testing positive for urinary alpha-radiation exposure, also known as internal high-LET exposure [2]. Remember, the NCF's patient cohort had higher chromosomal damage than cancer and Gulf War syndrome patients. In fact, Dr. Heng had identified new types of chromosomal damage in the NCF cohort that had never been seen before in medicine.

DNA damage can occur as the result of environmental exposures or as a result of other metabolic processes within the cell. As such, DNA lesions can form and if unrepaired, these lesions can affect the cell's ability to function properly. Lesions can also increase the risk of tumor formation.

There are several sources for such damage. DNA damage can be considered to be either endogenous or exogenous or a combination of both. An example of endogenous damage is damage that can result from the production of excessive reactive oxygen species (ROS) products, often referred to as oxidative stress. On the other hand, an example of exogenous damage is radiation. This may be ultraviolet radiation (UV) or X-rays. In the case of CFIDS/ME, alpha-radiation is highly damaging to the DNA as evidenced by genomic instability and chromosomal damage.

It is important to distinguish between DNA damage and mutation, the two major types of error in DNA [3]. DNA damage and mutation are fundamentally different. Damage is a physical abnormality in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. For CFIDS/ME, patients have previously been shown to have increased 8-hydroxydeoxyguanosine, an oxidative DNA damage marker [4].

DNA damage can be recognized by enzymes and thus can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked or the cell may die.

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands and therefore a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damage and mutations are related because DNA damage often cause errors of DNA synthesis during replication or repair; these errors are a major source of mutation.

Given these properties of DNA damage and mutation, it can be seen that DNA damage is a special problem in non-dividing or slowly dividing cells, where unrepaired damage will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damage that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism because such mutant cells can give rise to cancer. Thus, DNA damage in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damage in infrequently dividing cells are likely a prominent cause of aging.

Now, let's look at more CFIDS/ME related information. A couple of years back, Dr. Suzanne Vernon, who was the former Scientific Director for the CFIDS Association of America, published a paper related to DNA modifications in CFIDS/ME pathology [5]. In this paper, Vernon and colleagues looked at genome-wide epigenetic modifications in the peripheral blood mononuclear cells isolated from patients. What they found overall was an increased abundance of differentially methylated genes that were related to the immune response, cellular metabolism and kinase pathways. Now here is the best part. The genes associated with immune cell regulation, that represented the largest co-ordinated enrichment of differentially mediated pathways, showed hypomethylation within the gene regulatory elements in CFIDS/ME.

So why is this important? This takes us to a paper, published by scientists from the National Cancer Institute (NCI), that potentially explains this methodology [6]. The paper discusses radiation bystander effects and its influence on DNA methylation. Radiation-induced bystander effect, in which irradiated cells can induce genomic instability in unirradiated neighboring cells, has important implications for cancer radiotherapy and diagnostic radiology as well as for human health. What these researchers confirmed is that alpha-radiation induced bystander effects in human tissue models. This means that DNA damage occurred and was confirmed in cells that weren't directly irradiated! Furthermore, these increases in bystander DNA damage were followed by increased levels of apoptosis and micronucleus formation (a test for DNA damage) and by the loss of DNA methylation (hypomethylation). This is what Vernon and colleagues had identified in CFIDS/ME patient blood. Vernon concluded that modifications were being made to the DNA. In the case of the NCI scientists, the additional importance of their finding is that the bystander cells exhibited postirradiation signs of genomic instability that may be more prone than unaffected cells to become cancerous. Thus, these NCI scientists concluded that their study points to the importance of considering the indirect biological effects of radiation in cancer risk assessment.

Let's now take a brief look at another CFIDS/ME paper that was published by scientists in Italy [7]. In this paper, scientists examined four vastus lateralis muscle biopsies from both male and female patients. Though the group identified a number of genes that were altered, one in particular caught our eye. All four patient muscle biopsy samples showed an increase, or up-regulation, of DNA polymerase-beta, also known as polB. This finding is particularly intriguing due to the fact that polB is an error-prone enzyme that has been found to be overexpressed in several human tumors [8]. French scientists have reported that cells that overexpress polB are much more sensitive to ionizing radiation which results in increased apoptosis (cell killing). These scientists concluded that alterations to polB expression in irradiated cells strengthens both cell death as well as genetic changes associated with a malignant phenotype thus providing new insights into the cellular response to radiation and its carcinogenic consequences.

It would certainly be great if the CFIDS/ME world would consider the role of environmentally based alpha-radiation exposure in the development of this disease. After all, much has been published globally in this regard linking the two and we have the research scientists at Chernobyl to thank for their observations and data since the meltdown occurred. Now, the CFIDS/ME experts must get on-board to consider what other global scientists already know. To see the latest publications relating the development of CFIDS/ME to radiation exposure, visit the NCF's website at


  2. National CFIDS Foundation's Research Finds Chromosome Damage in Patients Diagnosed with Chronic Fatigue Syndrome and Myalgic Encephalomyelitis; Press Release — February 25th 2014;
  4. Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome; Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E; Neuro Endocrinol Lett. 2009;30(6):715-22
  5. DNA methylation modifications associated with chronic fatigue syndrome; de Vega WC, Vernon SD, McGowan PO; PLoS One. 2014 Aug 11;9(8):e104757. doi: 10.1371/journal.pone.0104757. eCollection 2014.
  6. DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models; Sedelnikova OA, Nakamura A, Kovalchuk O, Koturbash I, Mitchell SA, Marino SA, Brenner DJ, Bonner WM; Cancer Res. 2007 May 1;67(9):4295-302.
  7. Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome; Pietrangelo T, Mancinelli R, Toniolo L, Montanari G, Vecchiet J, Fanň G, Fulle S; Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):795-807.
  8. Deregulated DNA polymerase beta strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities; Fréchet M, Canitrot Y, Bieth A, Dogliotti E, Cazaux C, Hoffmann JS; Oncogene. 2002 Apr 4;21(15):2320-7.

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