Cancer Initiation: 2016

Friday, January 29, 2016

The danger of "Dimension Reduction" in science and education

   Science education exists at the cusp of the epistemology known as science, and the cognitive ability recognized as "education". The historical foundation of science has built around finding the proper function, as determined by various types of statistical analysis, such as correlation. Beyond correlation, scientists use various logical methods to "prove" causation between two variables.
    This foundation has worked very well for physics and chemistry.  We can easily define an ion's concentration as a function of pH, or a particle's position as a function of time and force. As such, we are tempted by conditioning to apply the same principles to biomedical science, such as physiology.
  The focus of this note is to demonstrate that we are wrong when we try to force biological systems, systems of multiple dimensions, into the single dimension systems  that give us such great comfort in physical and chemical systems.
  Homeostasis is a fundamental concept in physiology. In simple terms, components of complex systems feed back into each other to keep vital variables at physiological levels. Each component of these systems has both positive and negative response elements.  An M.D. intuitively looks at vital variables not only to see if they are at best levels, but to see if the components of a system are responding properly to perturbations of the system of interest.
  All of this seems very rational, even obvious. The aforementioned discussion seems to be relatively intuitive for a century at least. So how can top scientists still reduce multidimensional functionality in a system down to a single largely non-relevant value? This seems to happen in the discussion of telomerase (hTERT), a gene system responsible for maintenance of the ends of chromosomal DNA. As I have discussed in a previous post detailing a system I call the Rattle Snake Hypothesis expression of telomerase is a double edge sword. On one hand, cells known as stem cells need to express telomerase as a component of the stem cells ability to continue producing a relatively infinite number of new cells. A good example is bone marrow where blood cells are produced. On the other hand, differentiated cells, or somatic cells ( of the body ) always seem to have telomerase repressed by being blocked epigenetically.
    It has long been observed these somatic cells can only divide a limited number of times and then become senescent. This observation has been attributed to Hayflick , and as a result is known as the Hayflick Limit.  The Hayflick limit is generally regarded as a cells first line of defense against cancer.
  In cancer cells, the Hayflick Limit has always been defeated either by expression of telomerase or acitvity of the ALT pathway which accomplishes the same purpose.
   The Hayflick limit is by no means the last line of defense against cancer. The immune system is an important next level of defense against cancer.  As a conceptual model, we have introduced this level of defense as the Rattlesnake  Hypothesis.
  So what then is the best expression level for telomerase? The answer depends upon the physiological function of the particular cell in question. None the less, the question continually seams to come up, not only for telomerase, but for all genes, each of which has an appropriate expression level depending upon the physiological function of the particular cell.
  The "it depends" answer never seems to be sufficient as an answer in science. In todays assignment, Tom Cech describes the best gene expression level for telomerase. Hey says at 1:01:46  :
It's on a knife edge, you don't want two times too much or two times to little, it has to be like Goldy Locks, it has to be just right. And so that could be, that is an issue with the people with too little.
So my point is that on a large discussion of a cutting edge issue on a critical topic related to cancer, regulation of telomerase, it always has to be reduced at some point to a single dimension. This seems to be a compulsory  requirement of people, not physical or biological systems.
   With  that point made, I would like to thank Tom Cech for placing this video online for the science education community, and for people interested in cancer research at the molecular level. Since Mr. Cech already has a Nobel Prize and a successful laboratory, I believe he will survive the accusation of "dimension reduction" by a blogger. Hopefully in the end, students will be encouraged to think in more dynamic terms about dynamic systems in equilibrium.

Thursday, January 28, 2016

Checkpoint Loss and Paul Nurse's "Wee Mutants"

In previous posts we have referred to "Checkpoint Loss" as a presumed underlying cause of loss of control of the cell cycle. Here, we discuss further the historical science behind the concept of checkpoints and their loss. The first "popular" discussion of checkpoints comes as part of Paul Nurse's Nobel Lecture of 2001.        In it, he refers to the "wee mutants" as those members of his fission yeast culture which divided before they reached full size. He reasoned that that there must be some cellular mechanism that kept cells from progressing through the cell cycle before their "Synthesis" or "S" phase was complete. As such, cells which had a defective mechanism, or checkpoint, would appear smaller under the microscope. These cells could be isolated and geno-typed to find the specific genetic, or DNA based mutation that was responsible.
  Based upon isolating the "Wee Mutants" and development of a genetic toolkit for working with fission yeast, Paul Nurse and his associates decoded the mechanism of cell cycle regulation in Eukaryots.
   Possibly Foremost in this system are the "Cyclins" or those protein products that accumulate as each stage of the cell cycle progresses. When the level of  a specific cyclin in the cell reaches a threshold level, it activates an enzyme known as a cyclin dependent kinase ( CDK ) .  A kinase is an enzyme which phosphorylates, or adds a phosphate group, and these CDKs act to phosphorylate a substrate known as E2F. When E2F has been phosphorylated, it can no longer bind to retinoblastoma (RB, pRB ), and as such it is free to translate to the nucleus where it is a transcription factor, and acts to move the cell through the cell cycle.
  We already have a great cancer research flag flown up here.  The gene retinoblastoma ( pRB ) has already been predicted and described as associated with cancer. The prefix "retinoblast" is a type of precurser cell in the retina of the eye.  A particular type  of cancer then has been characterized as " cancer arisen from the precursor cells of the retina" or "retinoblastoma". Susceptibility to retinoblastoma had been studied as a genetic condition, and lead to the formation of the "two hit" hypothesis of Alfred Knudson.
  The "two hit" hypothesis would have worked like this. When a patient suffers a mutation in the second allele of rb, it fails to function. As such, it can no longer bind to E2F and prevent progression through a checkpoint to the next stage of the cell cycle. This was the foundation for cancer causation for most of modern medical history.
  Nevertheless, with the development of more sophisticated medical technology, it was discovered that in fact, more often than not, the gene sequence of rb is in good shape. What has happened is that its expression has been suppressed by promoter methylation. This promoter methylation is a foundation of what is now called  epigenetics.
   A missing link in the logic here is that fission yeast are single cell biota. As such, they do not suffer cancer. Cancer is a disease of organisms which have some degree of differentiation. This differentiation is increasingly being as a function of DNA methylation. As such, we have proposed a methylation maintenance model to describe the molecular/genetic organization of higher animals.
  As such, our cancer model is currently more sophisticated than Nurses "wee mutant" mode. When a checkpoint is lost, dividing cells fail to complete the duplication of DNA methylation patterns upon division, or mitosis.  This leads to a clinically observable condition known as global hypomethylation which is observed on the molecular level as a particular cancer progresses. As such, not only does DNA sequence mutate as cancer progresses, regulation of expression disintegrates as well.
  On an cellular level, this happens quite often. There are multiple levels of defense. The first is epigenetic suppression of telomerase. A somatic cell can divide a certain number of times until its telomeres expire and all descendants become senescent. 
  The next level of defense involves triggering the immune system. We refer to this as the rattlesnake hypothesis.  In brief, this states that a cell contains a number of "danger flags" known as wingspans antigens. When these epigenetically suppressed genes become expressed, their sole purpose is to trigger the immune system to attack the cell. In the presence of a healthy immune system, this mechanism is sufficient to protect against cancer.
  In summary, although much of what has been known as cancer research has been swept to the side by the advance in molecular analytics, the original concept of the checkpoint, and associated "wee mutant" seems to be one that will stay as a foundation of future cancer models.

Tuesday, January 12, 2016

What is meaning of the word "epigenetics"

 The word epigenetics has become the term of the decade in cancer research, and in some degree, almost all degenerative diseases. Epigenetics appears as though it will fill in missing gaps in developmental diseases as well. It appears now that there is a diverging opinion of that this word actually means.
   At to core of the word, is the well understood base known as genetics. In general terms, genetics refers to the heritable information which is passed from one cell generation to the next cell generation. This heritable information was almost always presumed to be the DNA sequence.
  As the tools of molecular biology have been refined, automated and personalized, it has become apparent the DNA sequence does not account for all of the information passed from each cell generation. In particular, methyl groups can be added to specific sequences in the cells DNA known as CpG islands, where C and G represent nucleotides and p in the connecting phosphate.
   The regulatory region of a cells DNA known as a promoter is typically rich in CpG islands. When these become methylated, a protein known as Methyl CpG Binding protein 2 binds to the promoter, and "epigenetically" blocks expression of that gene.
   A key to the concept of epigenetics is that these methylation patterns are copied upon cell division, the same as DNA sequence. That is, modifications to promoter status are passed from one generation to the next. The prefix "epi" means "on top of" in medical and scientific terminology. Thus DNA methylation is a type of genetics which "piggy backs" on DNA sequence genetics.
  In a recent article in The scientist reviewing RNA methylation, the authors refer to this as "RNA epigenetics".   
   In fact I feel that "RNA modification" or "RNA decoration" would be a better term. There does not seem to be any evidence presented that these modified RNAs can be duplicated and perpetuated from generation to generation. As such, it is not quite in the same class as DNA modifications which are duplicated by a "DNA methyltransferase"


 By Dan Dominissini, Chuan He and Gidi RechaviRNA Epigenetics, The Scientist | January 1, 2016