Cancer Initiation: Paradigm change in Medical Science as a result of Biotechnology innovation

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.


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