Cancer Initiation: January 2017

Saturday, January 28, 2017

Glyphosate (Roundup) is not approved as a food additive

Introduction


  Roundup is a common herbacide that is used in the production of many crops. Typically a genetically modified crop that is resistant to Roundup will be planted, and then application of Roundup will reduce the crop to a mono-culture of the desired product.
  Roundup (glyphosate) is a combination of the amino acid glycine with an extra phosphate group. It looks like a nutrient to the plant but cannot be metabolized. The proposed "beauty" of glyphosate is that after application, it decomposes to natural nutrients, phosphate and an amino acid. For that to be the case, Roundup has to be applied early in the plants life cycle. It has now become apparent that this is not always the case.
   It has been recently recognized that Roundup is also popular "off label". By that I mean that in the case of wheat, glyphosate is applied as a "harvest sweetener" to help dry out wheat before harvest. This novel application of glyphosate has the potential and affect of placing a large amount of un-degraded chemical in the food supply, as a component of flower. Even if the wheat itself is a "non-gmo", it may be harvested with the aid of glyphosate as a "sweetener".

 

Increasing Toxicological Evidence 


 Because  Roundup was never intended to be in the food supply, there is a dearth of toxicological data. The manufacturers maintain that toxicological data is unnecessary becasue it is not for human consumption. Now that it is on the food supply, more detailed toxicological studiesr are becoming available. [1] The results show that Roundup is liver and kidney toxic in environmentally relevant dosages. The following is a quote from Mesnage[1]

  In an effort to address this gap in commercial GBH toxicity evaluation, a 2-year study was conducted where rats were administered with a Roundup GBH via drinking water at a concentration of 0.1 ppb (0.05 μg/L glyphosate; daily intake 4 ng/kg bw/day), which is an admissible concentration within the European Union (0.1 μg/L) and USA (700 μg/L)18. The results showed that Roundup caused an increased incidence in signs of anatomical pathologies, as well as changes in urine and blood biochemical parameters suggestive of liver and kidney functional insufficiency18.
                                      Mesnage[1]

  Oxidative stress and single-carbon metabolism

   The study be Mesnage et. al. goes on to discuss the contribution of Roundup ( glyphosate  ) to single-carbon metabolism disruption ( oxidative stress) . We have previously noted that disruption of this pathway is the foundation for a number of diseases, currently in epidemic mode, As we mentioned, incidence of coronary artery disease, cancer, lupus and Parkinsons are shown to be connected to methylation capacity ( single carbon metabolism). Of course there are others, including intestinal autoimmune and autism. We should also note that these factors are not necessarily independent. Varibles that affect this  pathway are (non) independent, and may interact strongly with each other in otherwise unpredictable ways, partially as a function of a persons particular genetic makeup.

 Significance


  The significance of this 2017 study is the term "ultra-low dose".   Notice the abbreviation "ppb" is parts per billion. It really does not take much to get in the parts per billion range. Roundup use at harvest time is threatening for many reasons. Of course less time hurts the ability to decompose, but also cooler temperatures of harvest season could hurt biodegradability.
 

Conclusion


   Glyhphosate( Roundup )  was never intended to be part of the food supply. It was intended to be a biodegradabale portion of early crop development. With uncontrolled usage it has become a key contaminant in the world food supply.

References


[1]  Mesnage R1, Renney G2, Séralini GE3, Ward M2, Antoniou MN Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide  . Sci Rep. 2017 Jan 9;7:39328.[PubMed Central]

An example of a 6th generation medical science study


Intoduction

 In previous posts, I enumerated the history of medical science paradigms from my point of view. I went on to describe a forthcoming sixth generation.
The underlying sixth generation model consists of a single carbon metabolism cycle that produces glutathione, a convenient biomarker for these studies. Glutathione then is the primary support for DNA methylation by the DNA methyl-transferases, DNMTs.  Study of failure at this level is what is known as  epigenetics study.
 Many disease conditions are now known to be epigenetic in nature. A short list is cancer, lupus, Parkinson's and coronary artery disease.
  An example of what a study of various interacting factors relating to single carbon metabolism is given in Naushad [1].

Whats in that Title?


 The title of Naushad[1] will seem a little unusual so I will discuss just the title for a moment. First of all "multifactor dimensionality reduction" is a term that may be unfamiliar to us old timers. Of course, we are much more familiar with terms like multiple regression and principle component analysis. These "old fashioned" approaches assume that all of the incoming variables are "independent". But what of we don't have a problem that consists of independent variables? In biomedical applications, such as gene/gene interactions or gene/environment interactions, we are looking for a case where the incoming variables are NOT independent. When we find a combination of variables that provides some "zing", then we can start building our model. On other words, we are moving from the world of linear models, to the world of nonlinear models. Lets think of a slot machine. Most of the time, we get a combination that produces no outcome. When the same variables come up "three cherries", we get a big pay out, much bigger that just 3X one cherry, which it typically a zero payout.
   The next term we want to look at is "crosstalk between one-carbon and xeniobiotic metabolic pathways". What this means is that we are going to look at a number of genetic anomalies that may occur in genes that are related to the one-carbon pathway, such as the gene MTHFR, a primary component of the pathway cycling glutathione, 
  The final term is "multi-disease models". In this case, this study is not related to a single medical condition, but four medical conditions,  cancer, lupus, Parkinson's and coronary artery disease, all known to be related to the single-carbon metabolic pathway.

Results

This model that the authors made showed good predictability Parkinson's Disease (PD) and Lupus (SLE). and moderate predictability for breast cancer and Coronary Artery Disease (CAD).
These interaction models showed good predictability of risk for PD (The area under the receiver operating characteristic curve (C) = 0.83) and SLE (C = 0.73); and moderate predictability of risk for breast cancer (C = 0.64) and CAD (C = 0.63).
                                                   Naushad [1] 

Telling us what we know!


Health professionals tell us that we must get a good supply  of vitamins and exercise,   all  of which support good single carbon metabolism. Here we say that genetic components that affect single carbon metabolism are also significant. Good call!.

Direction and suggestion. This type of study and model could be easily extended. For example,  the (non) independent variables (model inputs) could be extended to include known toxins, such as mercury and known nutritional supports, such as folate and vitamin b12. Likewise, dependent variables, or model outputs could autism and Alzheimers.

The immune system (Missing)

 

 So, amid all the excitement about Naushad ( woohoo ), there is an aspect that is missing. All of the clinical conditions enumerated as dependent variables have immunological components. In the case of cancer, the immunological component is thought to be a natural defense. In the others, such as systemic lupus  erythematosus,  the immune response is part of the disease.
A true 6th generation study, as I have defined them, would also quantify the expression of wingspans antigens, as well as the degree of hypomethylation of the patients DNA.

Conclusion

 Biological systems are very different in nature than economic systems, or social science systems. Our system of statistics has grown up around problems where the "independent variables" are um, "independent". In biomedical systems, models have to built that can handle nonlinear interactions between variables. Presumably, a traditional "principle components" analysis would have been insufficient to model this data.
 

[1]  Shaik Mohammad Naushad Sana Venkata VijayalakshmiYedluri RupasreeNadella
 Kumudini Sampathkumar Sowganthika Janardhanan Venketlakshmi NaiduM. Janaki RamaiahDunna
 Nageswara raoVijay Kumar Kutala   Multifactor dimensionality reduction analysis to elucidate the cross-talk  between one-carbon and xenobiotic metabolic pathways in multi-disease models
Molecular Biology ReportsJuly 2015, Volume 42, Issue 7, pp 1211–1224  [Abstract]






Tuesday, January 24, 2017

Dear PLOS: Why "vaccines dont cause autism" is not a scientific statement

Introduction

  The following is a critique of  the article The “Why Vaccines Don’t Cause Autism” Papers
hosted on the Public Library of Science (PLOS) Blog page.

The term vaccine is not specific 


 First of all the term "vaccines" is not scientific. The debate has, in fact for many years, even decades, turned away from the antibody and protein contents of vaccines and turned to mercury, colloidal aluminum, and biological impurities that may include viruses or proteins that were not intended to be in the vaccine. As such, the debate in not vaccines, but vaccine safety. Intravenous delivery bypasses a host of defenses against potential toxins.

Autism is not a scientific term

 Autism essentially means "unusual". In includes  a "spectrum" of individuals ranging from those who are completely incapacitated to those who have Ph. D.s, particularly in technical fields.  In fact in previous years a controversy has arisen over the term  "Aspergers" which includes those on the high performing edge of the so called "spectrum". When these people are classified as autistic, it has the function of burying important variables. Autism is a social science term ( not science at all ). The education system (social science) likes people at the middle of the bell curve, and those at both ends are usually classified as problematic,  at least in the eyes of education system socialists.

 Medical Science has already progressed past nonspecific descriptions


 In what is now considered the base of the argument on vaccines and neurological impact, a vaccine associated "syndrome" is described which includes gastrointestinal autoimmunity and distress in single carbon metabolism. (Wakefield [1] ). This paper detailed elevated methyl-malonic acid, which is a marker for b12 deficiency, or other disruption of single carbon metabolism. Methylation disruption is known to be associated with autoimmunity and neurological defects. I dont believe this paper specifically discusses mercury, but mercury is associated with disruption of single carbon metabolism ( methylation pathways). Many factors affect single carbon metabolism, and as a result DNA methylation. An interaction of factors could obviously disrupt normal development.

Correlation and medical science

  In a previous post, expressly for the purpose of evaluation of the scientific validity of specific arguments in "medical science" terms, I enumerated epistemological generations in medical science. Correlation between raw variables, such as "vaccine" and "autism" is what I would classify as a "Generation 1" argument. That means, no longer part of medical science at all. In the case of Wakefield [1], were specific measurements of single carbon metabolism ( methylmalonic acid level) and histological gastrointestinal pathology ( autoimmune ) are described in medical terms, the appropriate follow up is a Generation 6 study, that means evaluation of more single carbon metabolism and the epigenetic basis of observed autoimmunity.

Statistical arguments are useless serious cases

 Arguments based on statistical outputs are not appropriate in medical cases that involve incapacitation for life. Other statement that are inappropriate are "Russian Roulette works out fine in most cases", and  "generally speaking, apples, peaches, pears, plums and hand grenades are not dangerous." I believe that appropriate term is "confounding" for lost variables in scientific arguments. We are now at about 2 decades of confounded science on the issue of vaccine safety.

Mercury has many sources, and impacts are cumulative


 Mercury may come from amalgam in dental fillings, mothers amalgam in dental fillings, fish, fish mother ate, livestock that was produced with fish meal ( chicken ) other environmental exposure including water and broken light bulbs.   Not to mention,  if several vaccinations are given, and all contained mercury, the impact of the "trace" amounts is cumulative. 


References


[1] Wakefield et. al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and
pervasive developmental disorder in children
, the Lancet, 1998 [pdf[


Sunday, January 22, 2017

The 6th Generation of Medical Science: One Carbon Metabolism and its connection to the Immune System

Introduction


   In an earlier post, for the sake of classifying medical knowledge by my self-defined generations, I defined a system of scientific epistemologies, or paradigms numbered 1 through 5. Unfortunately, the reason for doing this is because the current system is proving to be insufficient. In particular, there has been a large number of medical conditions that are classified as "auto-immune", or the result on attack by ones own immune system. There are many theories as to why these medical conditions come about, but conclusive evidence has proven to be elusive.
   Medical data that is Generation 1 and Generation 2, that is correlations and chemical analysis, has shown clearly that there is a strong relationship between stress in the single carbon metabolism system autoimmune disease. Unfortunately, further reasoning behind this relationship is "all over the place". For example, one theory promoted [1] is that maternal antibodies affect their male offspring disproportionately. There are potential physiological flaws with this argument. The brain is known to be isolated from the rest of the body to cross the blood brain barrier. Ok. Further discussions on the connection between autoimmune response and autism relate to alterations that allow permeability to intestinal barriers and the blood-brain barrier.[2] At this point, all proposed connections remain conjecture.

Innate cancer defenses and autoimmunity


 We have proposed other possible connections between oxidative stress ( failure in the single carbon cycle ) and the immune system. Specifically, we have identified a class of epigenetically suppressed antigens that we refer to as wingspans antigens, which are though ( by me ) to be a cancer defense. On the other hand, if epigenetic suppression fails for some reason other than cancer ( for example, failure in the single carbon cycle ) then these antigens would erroneously trigger the immune system. A short discussion of this is here.

A larger cancer defense framework


 We have proposed that wingspans antigens are part of a system that we have called the Rattlesnake Hypothesis. In very brief, higher organisms ( such as us ) have multiple levels of defense against cells that have lost control of the cell cycle ( cancer ) . The first is that the telomeres of the cells DNA strands ( chromosomes ) shorten with each cellular division. When the telomeres are gone, the cell is senescent, and can no longer divide. In cancer, in most all cases, the cell clone is immortalized through the expression of telomerase, or a group of enzymes that can perform the same action.  (extending the telomeres ) . Thus there needs to be another line of defense. If a cell line is undergoing global hypomethylation, suppressed antigens will be expressed erroneously. Their proposed function is to signal the immune system that cell cycle regulation has been lost. We call this conceptual system the rattlesnake hypothesis.

Clinical Status


To my knowledge, clinical auto-immune conditions have not been been tested for the presence of wingspans antigens. Thus, Generation 6 is hypothetical.

References


[1]  MOISES VELASQUEZ-MANOFF  An Immune Disorder at the Root of Autism Retreived from The New York Times, Aug. 25, 2012 [NYT]

[2] Fiorentino M, Sapone A, Senger S, Camhi SS, Kadzielski SM, Buie TM, Kelly DL, Cascella N, Fasano A. Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism. 2016 Nov 29;7:49. [PubMed]


Saturday, January 21, 2017

Paradigm change in Medical Science as a result of Biotechnology innovation

Introduction

  A paradigm in medical science is a "formalized way of knowing". In the field of science, this is also called an epistemology. In recent years the rapid advance in biotechnology has changed epistemological frameworks so quickly, that research discussed on particular issues is often of mixed generation.  For the sake of providing a framework to evaluate the level of reliability, we are going to take the time to formally enumerate generations and paradigms in medical science.

Generation 1 - Statistical Inference


   A statistical inference is a study where we make no internal assumptions about the details of causation. We are all familiar with these studies. For example a study of smokers and non smokers shows that smokers have a significantly increased risk of cancer. At this point, these studies are now considered "social science" because they do not necessarily tell us anything about cause and effect.

Generation 2 - Chemical modelling


  Chemical modelling studies extend statistical inference by identifying particular chemicals a causes. For example, if we believe that nicotine is of particular interest in smoking, we could leave the actual behavior, or environmental factor aside, and do laboratories that specifically focus in the chemical impact of nicotine. The hallmark of these studies is the "dose dependent" relationship. That is, we want to extend our "two group" studies to the level where we have a line that closely fits the data on a graph. These studies were the heavy lifters for a generation of researchers.

Generation 3 - Genomics


  Genomics has emerged as a result of better understanding of the central dogma of molecular biology.    The central dogma states that :
  1.  DNA stores information necessary to make proteins in the form of nucleotides.( represented as T,A,C,G )
  2. DNA is transcribed ( copied ) to messenger RNA in the nucleus of the cell, and transported to the ribosomes
  3. The ribosomes use messenger RNA to translate the message into a strings of amino acids, or proteins. Proteins do the metabolic work of the cell.
A good example of this line of thinking is the famous ( sort of ) case of the inheritable gene and disease called retinoblastoma. A retinoblast is a developmental cell in the retina of the eye. Retinoblastoma is a cancer of these cells.  Susceptibility to this type of cancer was known to have a genetic link.  The gene that was found to be linked is also called retinoblastoma, and its protein product, as described in the central dogma steps above is usually referred to as pRB,  The small letter p is commonly used for protein when naming proteins. The gene product was subsequently found to be a key component is the system that regulates cell division. Loss of pRB can lead to cells dividing uncontrollably.
   This level of data is useful. For example, in my note on the mystery of Low Dose Naltrexone in cancer treatment, I note that pRB must be active in order for inhibition if cyclin dependent kinase to be of value.
 

Generation 4- Epigenetics

 
   Genomic studies were not the endpoint ( that we thought they were going to be ) .  Continuing our example of retinoblastoma and pRB, it was initially predicted that mutations to the sequence of pRB were the cause of the cancer with the same name. With the availability of genomic data from specific patients, it was found that very of often, maybe more often than not, the sequence of the nucleotides was fine in the retinoblastoma gene, but the protein product was not expressed.
  Now we must extend our model from the central dogma to include expression.  Each gene has a regulatory region called a promoter. Promoters are typically rich in the nucleotides C and G, and particularly the sequence CG, which it typically referred to as CpG where p represents a phosphate.
  A protein known as a DNA methyl transferase ( DNMT ) can add a methyl group to the C in the CpG sequence. When a promoter is methylated in this way, in binds to methyl CpG binding protein 2 ( MeCP2 ) .

   The result is that when MeCP2 is bound to a genes promoter on DNA, expression of that gene is blocked.

 I put this line in bold because if there were such a thing as a central dogma of epigenetics, this would be it.
 
   Cancer is an epigenetic disease. Progression of cancer is often identified as global hypomethylaton. (the prefix hypo means under or less than normal ) That means with each generation, the cell is losing some of its differentiation. Differentiation is a biological word that approximates "grade" in the medical world. Less differentiation -> higher grade. More "hypomethylation" means higher grade cancer.

Generation 5 - Metabolic support for Methylation 


  As a result of epigenetic data becoming available for specific patients with a wide range of maladies,  attention has turned to the metabolic processes that support DNA methylation. Increasing attention has been placed on what has recently been termed the single carbon cycle or single carbon metabolism. The term "single carbon" refers to a methyl group in chemical terms being a group that contains 1 carbon. This is a complex system that serves many functions. I have provided a simplified diagram of one carbon metabolism in the post on nutrition support for this system.
 

Conclusion


In some ways, medical science has come full circle. On can argue that medical science began with the discovery of vitamins, and specific nutrients necessary for health. As we gain better understanding of single carbon metabolism, and its support for epigenetic mechanisms which in turn support cellular differentiation . In some ways, the progression to G5 has been reassuring. For example, giving folate to pregnant mothers, as may have been suggested by statistical data, is also supported by folate's integral role in the Single Carbon Cycle.
   In other ways, the progression of scientific paradigm has exposed misconceptions. For example, the Ames test, a test for carcinogenic potential of chemicals, is nearly worthless as a result of our current understanding of cancer as an epigenetic disease.


Thursday, January 19, 2017

Medical Science zeros in on the "Popeye Diet"


Introduction

For those of you who are not old enough to remember, Popeye was a "Sailor Man" who received exceptional power, even for a cartoon character, from eating spinach, in fact right from the can. No, there was never any mention of fried chicken. For those of you who are not familiar with the nature of the historic occupation of "sailor", one of the foundations was consumption of lots of fish. Fish and sailing go together. Fish is known to be a good source of vitamins b12, and omega 3 fatty acids. Spinach on the other hand is rich in folate and magnesium ( from chlorophyl, the green stuff ) .

 The One Carbon Cycle 

 These "Popeye Nutrients" have in common that they are all necessary to support what has become the One Carbon Cycle, or One Carbon Metabolism.  The relationship between the One Carbon Cycle nutrition is shown in this diagram that I retrieved from Khot ( 2014 ) [1] . It is online here .  What I really like about this article is that it clearly demonstrates what we already have known for ages. That is "prenatal vitamins are real good". Even better than that, they draw a diagram of the One Carbon Cycle that seems workable for what I want to say. I am not brave enough to try to draw my own One Carbon Cycle diagram.


The steps in Khots Diagram

 At the top of the Diagram are the nutrients that are necessary to support one carbon metabolism, as tested by Khot et. al. [1]. At the bottom of the first box, or one carbon box is the molecule glutathione. Glutathione is thought to do the "heavy lifting" of one carbon metabolism, but cycling of glutathione is dependent on dietary nutrients. The result of the top of this diagram is the generation of "methylation capacity". In this context, we are not taking about "anti-oxidant" capacity, but the ability to methylate DNA. DNA methylation is now known to be the essential currency of cellular development and differentiation. Methyl groups are the markers "on DNA", which is the common language translation of the term epigenetic. ( epi means "on top of", genetic means DNA )

Clinical Observation and Glutathione level

 So the question then is "Is Glutathione level a good biomarker for health". For that, we really need to leave the laboratory an the company of little mice and go to an actual medical practice. We could feel better about this whole article if we could show that clinical glutathione level is correlated with degenerative disease. For that, we can kindly reference the work of Dr. Jeffrey Dach on the subject.[2]. To quote Dach[2]:

One might argue that the root cause of most if not all disease and even aging itself ismitochondrial dysfunction. (7,8,9)  To name a few, glutathione deficiency has been implicated in neurodegenerative diseases (Parkinson’s), cataract formation, macular degeneration, coronary atherosclerosis, diabetes, renal insufficiency and hypertension.(7,8,9)

Conclusion

 As hoped, we have shown that we can show some logical biological/scientific background to the anecdotal evidence of Popeye the Sailor man, and his diet of spinach and ( presumably ) fish. Along the way, we have shown that the importance of "prenatal vitamins" extends all the way to degenerative disease conditions in older people, who may have never been at risk of pregnancy.

References

 [1] Vinita Khot, Anvita Kale, Asmita Joshi, Preeti Chavan-Gautam, and Sadhana Joshi Expression of Genes Encoding Enzymes Involved in the One Carbon Cycle in Rat Placenta is Determined by Maternal Micronutrients (Folic Acid, Vitamin B12) and Omega-3 Fatty Acids Biomed Res Int. 2014; 2014: 613078. [PubMed Central]


[2] Dach, Jeffrey, Nanotechnology meets Glutathione retrieved from [jeffreydachmd.]