Friday, March 13, 2020

An Appreciation of the Commons

We are now in the midst of what might be regarded as a raging pandemic in relation to the spreading impact of the corona virus on human populations throughout the world. To me, this new reality is a not so subtle reminder of the precarious nature of civilization and the inescapable reality that our species in general and our place in the so-called “developed” world in particular does not grant us any immunity to the nature of our individual and collective frailty as living beings on our planetary home. We are all subject to the physical and biological forces that constitute our everyday existence for better or worse.

From a biological perspective, viruses portray unusual properties in that outside of living cells they are quite incapable of independent existence. They are specifically engineered to “infect” living cells and have the capacity to commandeer the cellular machinery that ordinarily sustains the life of the cell and appropriate cellular processes to a singular role – the production of more viral particles. They are so successful at this that the infected cell usually succumbs, and the viral progenies go on to invade neighboring cells that in the case of the corona virus are the cells that constitute lung tissue. As entities, viruses have been among the living for billions of years. As a matter of fact, portions of human DNA contain the remnants of an array of viral DNA from many sources. In this regard, viruses have apparently played an important role in the evolution of life, including human life, on the planet. For this reason, viruses will always be with us.

Thanks to the multitude of scientific discoveries and the cumulative efforts embodied in scientific research, we are extremely knowledgeable regarding the biology of many viruses including the corona virus and its mode of infection. One possible outcome of the acceptance of this basic reality, may hopefully be a renewed appreciation of the Commons – those aspects of civilization that are fundamental to the sustainability and viability of communal life. Examples of the these would be public health, clean air, drinkable water, adequate shelter and nutrition, etc.

It has become a patent reality that in the United States the wholesale neglect of the Commons has made us particularly vulnerable to this pandemic and its ineluctable impact on societal institutions. It also has placed particular emphasis on the essential importance of smart government leadership that places appropriate reliance on the important role that science and professional expertise can play in dealing with a national crisis such as this one.

It is my hope that the lessons from this throughout the world will find direct application in preparing for future calamities including climate change to help ensure the future viability of the species.

Tuesday, February 4, 2020

The Biology of the Coronavirus

The global spread of viral pneumonia associated with the so-called “Wuhan coronavirus” appears to be reaching pandemic proportions. Given this distressing reality, it is important to more fully understand the biology of this virus.

Viruses represent a class of infectious agents that pose interesting challenges as witnessed by the HIV/AIDS virus that is the causative agent of the devastating acquired immunodeficiency syndrome (AIDS) that targets a particularly important cell type in the human adaptive immune system – the so-called, “T-helper cells (CD4).” Viruses possess the unusual property of being inert when outside a living cell. However, once they gain access to a living cell, the infective agent – either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) - commandeers the host cellular machinery to make copies of itself. This process can lead either to the ultimate death of the target cell or can result in a transformation of the host DNA that in some instances can lead to cancer – T-cell leukemia (HTLV-1 virus) and Cervical cancer (Human Papilloma virus – HPV) being some important examples.

Coronaviruses are a family of enveloped, single-stranded, positive-strand RNA viruses that are classified within the Nidovirales order. The name coronavirus was coined on account of the corona-like appearance of this virus as viewed under the electron microscope (See accompanying image). The existence of this type of virus was first reported in 1949 and the molecular mechanisms of both replication and disease formation was well-studied in the 1970s. The coronavirus family comprises pathogens that infect many animal species. Coronaviruses have been shown to be the causative agents for acute and chronic respiratory, enteric and central nervous system (CNS) diseases. This family of viruses have been associated with infectious disease in mouse (murine), a pig (porcine) transmissible gastroenteritis (TGEV), cow (bovine) and a bird (avian) bronchitis (BCoV). The first example of a potentially life-threatening human emerging coronavirus was the acute respiratory syndrome coronavirus (SARS-CoV).

Until 2003 the human coronavirus was only known to produce cold-like symptoms. This changed with the onset of severe acute respiratory syndrome (SARS) and now the Wuhan coronavirus that is apparently spread readily from human to human. These kinds of changes in infectivity are not unusual in the evolution of a virus; since, the infective material is prone to mutation. It is for this reason that it has proven exceedingly difficult to come up with an effective vaccine against HIV/AIDS.

Structurally, a virus particle consists of a protein outer coat that interacts and fuses with the cell membrane of the host cell. This is generally followed by the transfer of the infective agent – in this case the RNA of the coronavirus. Once this RNA enters the host cell, it directs the replication of its viral RNA and interferes with host cell processes. These tasks are accomplished through the transcription of viral RNA into proteins that exploit the cell’s protein synthesis “machinery.” It seems that coronavirus contains 7 genes – each gene having the blueprints for the production of a unique protein. One of the products of these genes is the so-called “spike” protein that plays a role in attaching to the host cell and has been shown to play a major part in the virus’ pathogenicity. The end result of this process is the formation of multiple copies of the virus followed by the death of the host cell and subsequent release of the new viruses into the extra-cellular environment.

The global nature of this threat can be circumvented by a number of different approaches - the first being isolating infected individuals and thereby thwarting the spread of the disease to others. It is likely that the virus is spread through aerosols as a result of coughing from infected individuals. This standard epidemiological approach is made particularly difficult given the reality of the constant movement of people to all areas of the globe.

However, it is also imperative that research efforts be directed towards developing a vaccine in order to assist the human immune system in its attempt to destroy the coronavirus once it has gained entry into the host. In regard to SARS, several studies were directed towards the development of active immunization strategies. These included Inactivated virions, recombinant antigen, DNA vaccines, and adenoviral vectors as well as other avenues of research. Undoubtedly, these kinds of studies will continue with added urgency.

Monday, January 20, 2020

Resistance to the anti-malarial drug Artemisinin in Malaria Parasites

Image showing human red blood cells infected with Plasmodium falciparum

Resistance of the anti-malarial drug Artemisinin in Malaria ParasitesMalaria continues to be a scourge in many parts of the world. The problem is particularly acute in Africa. Malaria is a pervasive illness characterized by high fevers, shaking chills, flu-like symptoms, and anemia. It is caused by a parasite referred to as Plasmodium falciparum. Plasmodium is carried by the Anopheles mosquito prevalent in the tropics.

The drug, Artemisinin (ART) has proven to be an effective drug against the malarial parasite – plasmodium falciparum. However, the parasite has apparently developed an immunity to this efficacious drug. It is, therefore, imperative that the mechanism of this resistance be more fully understood if an effective remedy is to be found. The collaborative efforts from research investigators at the Bernhard Nocht Institute of Tropical Medicine in Hamburg, Germany and the Department of Molecular Biology at Radbound University in the Netherlands have helped elucidate this mechanism.

The life-threatening aspect of infection by the Plasmodium falciparum parasite is the capacity of this parasite to continuously multiply within human red blood cells. Residing within human red blood cells, these parasites actively breakdown hemoglobin thereby obviating its capacity to deliver oxygen to the body’s tissues. Artemisinin has been long regarded as a first-line drug. However, ART resistance has manifested itself as a decreased susceptibility of young ring-stage parasites to a short pulse of this drug.

ART resistance has been shown to be associated with point mutations in the parasite’s so-called, Kelch propeller protein (Kelch13). However, the precise mechanism of this resistance to ART was essentially unknown. Although cellular stress, reduced protein translation and altered DNA replication had been implicated, the role of Kelch13 within the parasitic cell remained enigmatic. Here, the authors report an entire pathway in ART resistance and the Kelch13-dependent mechanism that effectively describes the reduced susceptibility to ART in resistant parasites.

The investigators in this extensive study, “show that Kelch13 defines an endocytosis pathway required for the uptake of host cell hemoglobin and its subsequent breakdown and that this pathway is critical for ART resistance. Their data indicate that Kelch13 and its compartment proteins mediate resistance upstream of both, drug activation and action. They have proposed a model where Kelch13 and its compartment proteins control endocytosis levels, thereby influencing the amount of hemoglobin available for degradation and hence the concentration of active drug.”

As a result of these findings that help elucidate the mechanism of ART resistance in malarial parasites, the authors conclude that, “We envisage that the mechanism of ART resistance indicated by this work will aid in finding ways to antagonize it. It may also inform the choice of ART partner drugs, particularly as hemoglobin digestive processes are the target of existing drugs.”