Cancer Initiation: February 2017

Friday, February 10, 2017

Extending our G6 Model for neuro-developmental abnormalaties

Introduction


  We previously discussed how toxic components such as mercury could be entered into our 6th Generation model of medical science. In that case, mercury is considered as an additional non-independent variable on the input to the model. Now, we want to extend the same model to neuro-development, a process that is known to be very dependent upon epigenetics, that is, gene regulation by DNA promoter methylation.
   If DNA methylation capacity is limited by reduced function of the single carbon metabolism cycle ( production of glutathione, SAM ) then consequently, neuro-development will be impacted.

 

Identification of methylation deficiency in impaired children


   It has previously been recognized that impairment at the single carbon metabolism level is a significant factor in autism [1]. A nutritional supplement targeting methylation deficiency was successful in returning the system to it's normal range of function.

 This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children.
                                              James (2004) [1]
This study was successful in returning glutathione and SAM to normal ranges, but what is not clear from this study,  or further studies by this group, is whether the neurological symptoms are reversible.

Cognitive Ability 


Education is the study of cognitive ability. Educators are really more interested in the bottom line than with blood levels of chemical intermediaries. For the final chapter of this post, we have to go to China, particularly the Harbin Medical University in Harbin China. A group led by Sun et. al. [2] tested related dietary supplements and their effect on in-class performance of afflicted students.
The results illustrated folic acid intervention improved autism symptoms towards sociability, cognitive verbal/preverbal, receptive language, and affective expression and communication. Furthermore, this treatment also improved the concentrations of folic acid, homocysteine, and normalized glutathione redox metabolism. Folic acid supplementation may have a certain role in the treatment of children with autism.
                                          Sun (2016) [2] 


Conclusion

 Many types of autism are due to failures at the level of glutathione and SAM production. These processes may be dependent upon multiple interacting ( non-independent ) factors that include nutrient availability and toxic load. It has been shown that nutrition supplements can:
  • Restore function of single carbon metabolism cycle
  • improve neurologic performance as measured in a structured teaching mode

References


[1] S Jill James, Paul Cutler, Stepan Melnyk, Stefanie Jernigan,  Laurette Janak, David W Gaylor, and James A Neubrander Metabolic biomarkers of increased oxidative stress and  impaired methylation capacity in children with autism1,2 [Full Text]


[2] Sun C, Zou M, Zhao D, Xia W, Wu L. Efficacy of Folic Acid Supplementation in Autistic Children Participating in Structured Teaching: An Open-Label Trial. Nutrients. 2016 Jun 7;8(6). pii: E337. [PubMed]

Thursday, February 9, 2017

Extending our 6th Generation Science model for Methyl Mercury Toxicology

Introduction


 In previous posts, we discussed how biotechnology was changing the nature of medical science and somewhat arbitrarily assigned generations to each mode of scientific research, as they were introduced . We noted that in our model, a 6th generation study was one that took into account many, possibly interacting variables, that is, non-independent variables as inputs, and processed their impact on core systems related to genetic, epigenetic and immunological outputs. We went on to note that this type of thinking was already happening. In one relatively recent paper that we discussed, the authors uses single nucleotide polymorphisms ( SNPs ) related to single carbon metabolism as an input, and related their impact to four disease conditions that included cancer, Parkinsons and others.

The mathematics of non-independent variables


   While most of our traditional statistical models assume "independent" variables as inputs, in our models, we are using "non-independent" variables as inputs. In fact, we do not want to ignore or filter out interactions between variables, we want to find them. For example, what is the interaction between two SNPs, between a SNP and a toxin like methyl mercury, or an interaction between a SNP and a nutrient deficiency, for example in folate or b12.  As we discussed, the model that we use for this is called Dimension Reduction Analysis, were we wish to find interacting non-independent variables and combine them, producing a "dimension reduction" in our resulting model. A package for this is now supported and is available on the web.

Glutathione Detoxification of Mercury


  In our previous discussions, we discussed the Single Carbon Metabolism pathway and its evaluation using glutathione as a biomarker. We once again find that glutathione is an appropriate marker with respect to mercury toxicity. Here is a quote from our reference for the day, Andreoli (2017)[1]. What what we note is that our glutathione biomarker is a primary driver in the subjects attempt to detoxify mercury. Excuse, the length of this quote, but they are saying about what I would like to say.

      
Reduced glutathione (GSH-γ-glutamyl-cysteinyl-glycine), an essential tripeptide present in large quantities in all mammal cells, is the main agent of the glutathione detoxification system (GSHs). This system, which neutralizes the free radicals producing reactive oxygen species (ROS), protects cells against damage resulting from exposure to many external agents and oxidative stress. GSH, therefore, fosters a positive body’s response to the negative Hg actions towards natural detoxification process, and it is essential to heal the damage within the cells.
Various epidemiological studies have suggested that the response to Hg may be influenced by molecular variants in several regulatory GSHs genes, involved in absorption, distribution, metabolism and excretion process, better known as the Hg toxicokinetics, as reflected in Table 2. Consequently, the genetic component of human Hg susceptibility has now become another aspect not to be underestimated in this context
                                 Andreoli and Sprovieri ( 2017) [1]

At the risk of providing too much from our reference, I am going to add a brief comment from their discussion, which makes part of this articles point:
With the advances in genetics and high-quality information on Hg pollution, current research has shown that the interplay between genes and environment is critical to better understand the Hg impact on human health [87]. Despite the great potential, there has, however, been little use of genetic information in Hg risk assessments for both occupational and environmental exposures.
                               Andreoli and Sprovieri ( 2017) [1]

The Neglected Aspects 


   Andreoli goes on to discuss more pathways that are impacted by Methyl and inorganic mercury, but I would like to take a different direction. We know from our model is the Popeye Diet context that epigenetic processes ( that is DNA methylation ) is linked to glutathione and Single Carbon Metabolism. As such, ALL other pathways are potentially impacted by mercury, by the indirect impact of epigenetic mis-regulation. Time and time again, it is the Single carbon Metabolism pathway that is the most sensitive to toxic insult, and othery pathways follow suit,  presumably as a result of epigenetic mis-regulation.

Discussion 


  We know that auto-immune response is a result of mercury toxicity. Since this is my blog, I am going to go ahead and conclude that this is of failure to suppress Wingspans antigens, and their resulting stimulation of the immune system in those locations where cell division and active immune cells overlap ( the digestive system ) .

References


[1 ] Virginia Andreoli and Francesca Sprovieri Genetic Aspects of Susceptibility to Mercury Toxicity: An Overview Int J Environ Res Public Healthv.14(1); 2017 Jan [PubMed Central]


Tuesday, February 7, 2017

Circumstancial evidence for an epigenetic checkpoint in the cell cycle

Introduction

   We have introduced the concept of a checkpoint in the cell cycle, which prevents premature progression of the cell cycle, that is, cell division or mitosis before a new copy of DNA has been completed. At the present time, checkpoints have only been considered with respect to DNA sequence completion, not duplication of the appropriate epigenetic marks, alternately referred to as methylation of the CpG islands. This duplication of methylation process is called "maintenance", and is mediated by the primary maintenance DNA methyl-transferase, DNMT1.

The case of vitamin b12 deficiency


   It is now known that the cell cycle can be blocked in prospective blood cells ( megaloblasts) by a deficiency in vitamin b12. The condition is known as megaloblastic anemia and is described below, or in the first reference . [1] 


From the wikipedia entry on megaloblastic anemia :
 Megaloblastic anemia (or megaloblastic anaemia) is an anemia (of macrocytic classification) that results from inhibition of DNA synthesis during red blood cell production.[1] When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis.
 

Why would b12 deficiency inhibit DNA synthesis?

 
  Vitamin b12 has two known functions, or pathways in the body. In relation to the citric acid cycle, ( also called the Krebs cycle ), vitamin b12 mediates the conversion malonal CoA to succinal CoA.  Succinal Coenzyme A is an intermediary in the Krebs cycle, and can go on to function in the production of ATP.
   The other function of b12 is in the Single Carbon Metabolism pathway. In relation to this pathway, b12 is necessary for the production of SAM and glutathione.  In turn, glutathione deficiency is known to impact DNA methylation. [2]

Bingo!

Even though we have never heard of b12 being a factor in the production of DNA, it is a factor in methylation of CpG islands, or promoters, associated with a cells differentiation. We now have a connection between a new prospective checkpoint type mechanism and a potential factor in cancer and other diseases, that is b12 deficiency.

Discussion


   If in fact there is some mechanism that could be called a checkpoint, then loss of this mechanism could be considered a new source of cancer causation. We know that single nucleotide polymorphsms associated with single carbon metabolism may be significant in increasing risk of caner.  Perhaps this epigenetic checkpoint is active in stem cells which are dividing in environments that are immunologically privileged. Such is the case in bone marrow.


Conclusion


   After consideration of some other types of cells, I am going to go out on a limb and say that the epegenetic checkpoint is not a universal feature of cells. In some cells, such as in the hematopoetic ( blood generation ) system, b12 blocks cell cycle progression because of epigenetic failure associated with the function of DNA methyl-transferase,    DNMT1.

References


[1] Emmanuel Andres, and Khalid Serraj  Optimal management of pernicious anemia J Blood Med. 2012; 3: 97–103.[PubMed Central]

[2]  Lertratanangkoon K, Wu CJ, Savaraj N, Thomas ML.    Alterations of DNA methylation by glutathione depletion. Cancer Lett. 1997 Dec 9;120(2):149-56. [Abstract]


Friday, February 3, 2017

Wingspans Antigens provide potential targets for CAR-T cell therapy

Introduction


The emergence of new advanced genetic engineering, even "editing" techniques has created new potential for engineered cancer therapies.  One approach that is receiving much attention is that of CAR T-cell therapy[1].  The acronym CAR stands for Chimeric Antigen Receptor, where Chimeric means combination of different genomes, and Antigen Receptor refers to that Receptor that Targets a particular antigen on a target cell. In short, we engineer T-cells, portions of the immune system, to attack specific targets.

This is an enhancement of a natural system that exists between the immune system and cancer cells.  In short, all cells "of the body" or somatic cells, have repressed antigens called (my terminology) Wingspans antigens.I  These markers all have the property is that their sole (apparent) purpose is to attract the attention of the immune system, and  they are always epigenetically suppressed in normal cells. As cancer stage progresses, the cell goes through what is called "hypomethylation", or failure to suppress those antigens which are supposed to be suppressed. As such, these antigens become uniquely expressed on cancer cells. If the immune system has not been previously destroyed, an immune response will build up against the cancer.

Identification of Wingspans Antigens


With the advent of modern methylation oriented DNA sequencing techniques, such as bi-sulfite sequencing, it is possible not only to enumerate antigens that fit the description of "Wingspans Antigens", but specific tumor biopsy samples could be analyzed to find the best potential treatments.
  The logic is simple. As a cancer progresses, see which genes get turned on which should not be there.   Many Wingspans antigens have already been identified so they are easy to fine. Unknown antigens which have no other known function are candidates.

The Point


 These are two ideas that could and should be combined. The sequencing equipment for customized medicine is available, and new gene editing technques such as CRISPR makes designer "chimerics" a relative snap.

Conclusion


   Each time I read about a new high speed biomedical technique I cringe and think about the difficulties I had in the gene cloning/ gene expression laboratory courses I had. It was like having to paint a Da Vinci of a beautiful sunset, when all you really wanted was a cell phone with a camera.

References


[1] Dach, Jeffrey Steven A Rosenberg and Cancer Immunotherapy [JeffreyDachMD]