Thursday, May 26, 2016

Origin of Life on Planet Earth

A question that has plagued scientists for a long time is centered around the question as to how life began on planet earth.  It is well known that life is found even under the most inhospitable conditions – a stunning example of this is that life exists within the deep sea hydrothermal vents that are found on the ocean floor.  In addition, microorganisms such as Hormoconis resinae contaminate jet fuel – using this hydrocarbon source as a vital nutrient – and are known to cause corrosion in the tanks that hold this fuel.

Therefore, it can be reasonably postulated that simple life forms could thrive in the harsh conditions of prebiotic earth when oxygen was not present within the atmosphere at that time.  But the question remains as to how did life begin – what was the process by which self-sustaining living organisms were formed from rudimentary compounds.

It has been shown that in an artificial environment created in the laboratory  in which an atmospheric environment was created to simulate the conditions believed to have existed in the prebiotic world, the addition of an energy source – such as lightening – produced rudimentary organic compounds found in living cells.  These experiments were conducted in the 1950's, by the biochemists Stanley Miller and Harold Urey.  These results are only suggestive evidence that organic compounds could have been created spontaneously in the early-earth environment.  It is, of course, far from the complete story.

Since DNA and RNA are fundamental ingredients to all of life as we know it and capable of self-replication, a key step in the evolution of life would be the conversion of simple organic compounds to purines that are some of the important building blocks for both DNA and RNA and for the synthesis of Adenosine Triphosphate (ATP) – the molecule that is responsible for trapping energy derived from metabolism for all of life.

Furthermore, the preponderance of evidence now suggests that RNA may have preceded DNA as the repository of genetic information capable of self-replication.  Certain forms of RNA also demonstrate catalytic properties (ribozymes) that are essential to sustain life.  Of course, contemporary advanced cell structure uses a host of enzymes to accomplish essential catalytic functions.
RNA is made of four different nucleobases  -two pyrimidines – cytosine and uracil – and two purines adenine and guanine.  Previous work done by John D. Sutherland from the School of Chemistry, University of Manchester, UK has shown a plausible synthetic route to pyrimidines in an abiotic environment.  But the route to purines has been more elusive.

Recent work by T. Carell from the Department of Chemistry, Ludwig-Maximilians University Munich, Germany and fellow investigators has recently demonstrated a mechanism that could account for spontaneous creation of purines from simpler compounds readily available within the natural environment of early earth.  The pathway involves the spontaneous synthesis of aminopyrimidines from hydrogen, cyanide and water – compounds readily available in the early earth environment.  Although aminopyrimidines can produce a wide range of synthetic products, in an environment of formic acid, the predominant product is formamidopyrimidine (FaPy) known to readily produce purines.  Furthermore, formic acid has been shown to be present in comets that collided frequently with earth during the early stages of its evolution.


Although this work is very significant, it does not explain how purines and pyrimidines would lead to the creation of more complex and sophisticated RNA molecules.  Nor does it shed any real light on the requisite formation of a cellular environment for biosynthetic reactions so necessary for the containment and sustenance of life processes.

Wednesday, May 4, 2016

Successful Treatment of B-Cell ALL Using Adoptive Cell Transfer

The standard treatment of cancer patients has consisted of an approach involving some combination of surgery, chemotherapy and radiation.  Admittedly, these methodologies have grown sophisticated over the years especially in the areas of surgery and radiation.  However, chemotherapy is a “shotgun approach” employing powerful drugs that target any dividing cells.  The nature of these drugs cause significant side-effects in the patients that they are administered to.

There are a new family of drugs that have been developed to combat certain types of cancers that are more highly targeted.  Among these are Imatinib Mesylate – Gleevic –(see illustration below).  Gleevic has been used in the treatment of acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumor.  This drug specifically targets the enzyme tyrosine kinase that has been implicated in certain cancers. 


Another drug that has shown promise in trastuzmab – Herceptin (see illustration below).  Herceptin has been used to treat patients with HER2+ breast cancer and adenocarcinoma of the stomach, for example.  Herceptin is a monoclonal antibody (mAb) that targets the HER2 protein found on certain types of cancer cells.


The new approach to fighting certain types of cancers involves a methodology referred to as adoptive cell transfer (ACT).  ACT actually employs the patient’s own immune system in fighting the cancer cells.  Impressive results using this methodology has been shown in clinical trials involving patients with advanced B-cell ALL.

The cancerous B-cells in ALL have a protein on their cell surface that is referred to as CD19.  This protein makes an appropriate target for immunotherapy.  The rationale behind ACT is to utilize the patient’s own T-cells to selectively kill ALL B-cells bearing this marker.  The following steps have been successfully employed in this treatment –

  • CD4 and CD8 lymphocytes are harvested from the patient’s blood.  CD4 T-cells are so-called helper cells and the CD8 T-cells are the cytotoxic cells.
  • These cells are genetically modified using an engineered retrovirus.  The genetic information that is introduced results in the production of a protein referred to as a chimeric antigen receptor (CAR) that binds to a specific cancer cell surface protein (see illustration below).  Structurally, CARS are modified mAbs.  In the case of ALL, the target protein is CD19.
  • Once the patient’s CD4 and CD8 lymphocytes have been successfully modified in the laboratory, they are grown out into billions of cells.  These are the cells that are reintroduced into the patient via infusion.  

CAR Signaling

There is one significant side effect from this approach; it is referred to as cytokine release syndrome that is a direct result of the modified T cells actively involved in killing their cancerous targets.  However, this is a manageable condition.

The results to date in clinical trials have been extraordinary.  This methodology shows great promise that eventually may have broader applications in the treatment of cancer.