Sunday, November 15, 2015

Somatic Mutation and Cancer

Cancer is a disease that can involve any tissue in the human body.  Some cancers, of course, are more common than others such as lung cancer, colon cancer, breast cancer in women and prostate cancer in men.  What all cancers share in common is that the tissue cell involved undergoes a transformation that imparts a selective advantage to that cell allowing it divide outside the normal controls imposed upon that particular cell type.  This process is known as clonal expansion.

It is now clearly understood that this selective advantage is a direct result of somatic mutation of the affected cell’s genetic material – DNA.  This causal relationship was first suspected in 1914 when it was observed that chromosomal abnormalities were present in cancer cells.  Note that this discovery was made even before DNA was known to be substance responsible for carrying hereditary information.    Considerably later, it was found that introducing DNA fragments from a malignant cell into a healthy one led to transformation of the recipient cell into a cancerous one.  Soon after this finding, oncogenes were discovered.  Oncogenes are the result of mutations in a class of genes responsible for cell growth or its modulation as is the case with tumor suppressor genes.

In nature, somatic mutations are common and are harmless for the most part – they do not generally impact genes that are involved in cellular process that would impart a selective advantage to the cell type affected.  These innocuous changes are referred to as “passenger mutations.”  Those rare mutations that do provide a selective advantage to the affected cell are referred to as “driver mutations.”  Ii is this type of mutation chat can lead to cancer – the production of a clone of cells that has the capacity to function autonomously and thereby no longer constrained by the controls normally imposed upon cells of a particular tissue.

Although this evolution of a cell from a normal state to one that is cancerous has been understood in general terms, the underlying process has not been amenable to discovery until the advent of high-throughput DNA sequencing. 

Utilizing this technology, the cancer-associated genes from over 10,000 human subjects have been sequenced along with over 2500 complete genomes from cancerous tissue samples.  Dr. Inigo Marincorena and associate from the Wellcome Trust Sanger Institute in Cambridge, UK have reviewed some of the result obtained from this data.

From this extensive study, new cancer genes have been discovered as well as new kinds of mutational events.    Mutations occur as a result of a number of possible factors.  These include:
  • DNA replication errors
  • DNA damage that is subsequently incorrectly repaired by the normal DNA repair machinery or damage that is left unrepaired
  • DNA damage that is a result of exogenous factors such as mutagens, ultraviolet light and ionizing radiation
  • DNA damage that is a result of endogenous factors such as reactive oxygen species (free radicals), aldehydes or mitotic errors
  • Viruses and endogenous retrotransposons that lead to insertions into the genome.

It seems that the frequency of mutations found in various cancerous cell types vary depending upon the tissue involved.  For example, pediatric brain tumors and various types of leukemia have the lowest numbers of mutations whereas lung and skin cancers show the highest rates.  Furthermore these mutation rates can be greatly enhance if there is definitive loss of DNA repair pathways.

One of the conclusions drawn from the extensive genomic data derived from these studies is that more than one driver mutation is required in order for a clone originating from a transformed cell to successfully evolve into the fully cancerous state with the capability of metastasis.

This report represents a brief and limited overview of the extensive of this work and its significance.  It is fair to say, that future studies of this magnitude will shed greater light on the complex processes that are involved in cellular transformation and oncogenesis.

Thursday, November 5, 2015

Climate Change – An Urgent Call to Action

Humanity does not seem to grasp the dim future that awaits the entire species if the dire warnings issued by climate scientists worldwide are not heeded regarding the absolute necessity to significantly diminish the burning of fossil fuels and thereby slow down the inexorable increase of the concentration of greenhouse gases in the atmosphere.

Ironically, human families work diligently towards fashioning a better life for their children, grandchildren and future descendants, yet their focus has been tilted towards material success and enhanced prosperity.  These are important goals.  However, if this onward rush towards greater and greater prosperity is not tempered by reality, the insidious consequences of climate change will make a significant portion of the planet essentially uninhabitable and rising seas will inundate the habitats of hundreds of millions of human populations wreaking havoc upon centers of economic power where great stores of human wealth reside.  Under such circumstances, such wealth would immediately be rendered quite meaningless.

It is quite absurd at this juncture to argue the merits of the science or allow short-term economic interests to resist the necessity for immediate and significant action.  If we do not act quickly as a world community, our descendants will find themselves marooned on what would increasingly become a hostile planet.  Is this the kind of future we are working so assiduously towards?

Obfuscation and resistance serves no useful purpose – the longer we procrastinate the more impossible it will be to make meaningful corrections on this our spaceship earth.