Wednesday, December 23, 2020

Holiday Message for the Coming Year - 2021

The year 2020 has been in many ways disturbing and unsettling.  What, of course, comes to mind almost immediately is the COVID 19 pandemic that has claimed so many lives and has been so economically devastating to many facets of the national economy, and especially for those who have lost their livelihoods and businesses.  Added to this national burden are the deep fractures that have been exposed in regard to a national sense of unity, shared-mission and purpose.

Along with this overwhelming sense of loss, however, is the untold bravery, courage and unwavering energy displayed by so many who have risked their own lives and safety to come to the aid of all of us for the unselfish commitment to the greater good.  These individuals have come from many diverse positions - as doctors, nurses, emergency response teams, members of the police and fire departments and first responders of all kinds.  To this list, we should include all those responsible for providing food; for delivering the mail; for the taxi and bus drivers, train operators and pilots; for the teachers; for all those who care for the elderly and for all those who provide the essential services that we all too often take for granted.

My wish for the New Year (2021) is that we grow wiser from the events that have befallen us and see the future as a time for healing and learning from our collective missteps.  My hope is that the new year will be a time of new beginnings.  My dream is that we will finally come to recognize that regardless of our national origin, religious affiliation, skin color or sexual orientation we are all members of the same species with the same physical bodies, the same architecture of the brain, the same genetic makeup, the same constellation of feelings, of hopes and of dreams.  Each of us is worthy of the same opportunities to grow and develop as sentient beings on this most remarkable planet that also needs our kindness, care, and attention.  Earth is, after all, our only home.

Best Wishes to All

CRISPR and Other Tools May Radically Change the Treatment of Intractable Genetic Disorders

Genetic diseases such as Sickle Cell Anemia and others have posed a serious and seemingly intractable problem for the science of medicine since any cure would require the repair of the damaged gene(s) involved.  However a number of significant technological breakthroughs in recent years have begun to change that bleak impasse.  In 2003, the complete mapping of the human genome was accomplished.  This technology and the information provided with its use have led to discoveries that have pinpointed the genetic origin of many diseases and continues to do so.  In 2012 a new tool was fashioned – the genomic editor referred to as CRISPR.  This remarkable tool can precisely edit particular sequences within the introns of targeted genes.  The designers of this capability, Jennifer Doudna and Emmanuelle Charpentier were awarded the Nobel Prize in Chemistry in 2020.  These two advances are changing the prospects for the treatment of genetic diseases.  CRISPR and an additional methodology (described below) have demonstrated great promise.

It has recently been reported in the prestigious scientific journal Science that, “Two strategies for directly fixing malfunctioning blood cells have dramatically improved the health of a handful of people with these genetic diseases.  One relies on CRISPR, marking the first inherited disease clearly helped by the powerful tool created just 8 years ago. And both treatments are among a wave of genetic strategies poised to expand who can get durable relief from the blood disorders. The only current cure, a bone marrow transplant, is risky, and matched donors are often scarce.”

The two genetic diseases referred to are so-called, “blood disorders.”  One is Sickle Cell Anemia, and the other is Beta Thalassemia.  Sickle Cell Anemia is a disease in which the red blood cells are mishappen and their ability to carry oxygen to the tissues is seriously compromised.  The origin of this disease is genetic -the alteration of both alleles that carry the blueprint for hemoglobin protein, the protein responsible for binding oxygen.  This disease particularly impacts the African-American population.  In Beta Thalassemia, the patient makes little or no functional hemoglobin.  The result, for the patient, is a dangerous and debilitating anemia since the body’s tissue cannot receive enough oxygen to effectively function.

The treatment devised that has been applied to both Sickle Cell Anemia and Beta Thalassemia involve modifying the genes that carry the information for the structure of hemoglobin in the following way.  The stem cells responsible for producing red blood cells resident in the bone marrow are harvested from the patient, and the BCL11A gene responsible for shutting off the fetal form of hemoglobin is disabled thereby allowing it to be produced.  The research tool utilized for this kind of genetic modification is CRISPR.  The patient then receives chemotherapy to destroy any resident diseased cells and the modified stem cells are then reintroduced into the patient.  If successful, the patient will then produce red blood cells with the completely functional fetal hemoglobin.

In addition, Dr. David Williams from Boston Children’s Hospital has achieved the same result using a novel technique - a specially genetically engineered virus is utilized to introduce a fragment of DNA encoded RNA into the harvested stem cells that effectively silences the BCL11A gene (referred to earlier).

It has been reported that, “Patients treated in both trials have begun to make sufficiently high levels of fetal hemoglobin and no longer have sickle cell crises or, except in one case, a need for transfusions.”  The Boston team described a particular case in of a teenager, “who can now swim without pain, and a young man who once needed transfusions but has gone without them for nearly 2.5 years.”

These are, indeed, exciting developments, but represent only the beginnings of what could be an amazing era in the approach to many other diseases of this kind. 

Wednesday, October 21, 2020

The Role of Microglia in Alzheimer's and Parkinson's Diseases

 

Alzheimer’s and Parkinson’s are diseases that directly impact and impair brain functions. They are degenerative and devastating illnesses that result in severe dementia in the case of Alzheimer’s and a serious degradation of motor control in the case of Parkinson’s disease. There is no cure in either case and no known biomarkers that could predict onset of these conditions. There is a type of cell resident in the brain referred to as microglia that function as amyloid phagocytes – they are cells capable of monitoring the local environment and can ingest and clear amyloid protein.

It seems that in addition to this known role, microglia may play an additional and essential role in maintaining neuronal function and homeostasis. In fact, the build up of amyloid protein in brain tissue may not be the primary cause of dementia that is the result of neuronal dysfunction and cognitive decline in neurodegenerative disease – some centenarians have been found to display good cognitive health and a build up of amyloid proteins in their brain tissue. It seems that accumulated patient data demonstrate that some aging individuals with accumulated amyloid protein show cognitive dysfunction while others do not. It is important from a therapeutic standpoint to understand the nature of this difference.

Several genetic studies indicate that microglia may provide the answer to this difference in health outcomes. According to Soyon Hong from the UK Dimentia Research Institute at University College, London, “Emerging data in developing, adult, and diseased brains collectively suggest that microglia are critical to neuronal homeostasis and health. These observations raise the question of whether, and which, microglia-neuron interactions may be impaired in Alzheimer’s disease (AD) and Parkinson’s disease (PD) to confer neurodegeneration. Insight into this question will enable the development of methods to assess and modulate microglia-neuron interactions in the aging brain and allow for a desperately needed expansion of focus from clearing amyloids alone to monitoring neuronal health in biomarker and target engagement efforts.”

It seems that in addition to their role in clearing pathogens and amyloid protein and responding to the presence of injury and dying neurons present in the environment of the brain, microglia are involved in monitoring changes in neuronal activity and the modulation of such distinct functions as memory and learning. In AD, for example, synaptic loss and dysfunction have been shown to be associated with the disruption of cognitive ability in patients. It is, therefore, of great importance to understand the underlying mechanisms that are responsible for this degenerative process and the role that microglia play in maintaining synaptic integrity.

Thursday, July 2, 2020

Evidence for the Role of Dramatically Increased Numbers of Megakaryocytes Associated with Blood Clots in COVID-19

Disturbing new evidence is emerging from the post-mortems of patients who have died from COVID-19 disease that demonstrates the presence of blood clots (thrombi). These thrombi have been shown in this extensive study to be present in major organs and systems including the lungs, heart, kidney, and brain. 

In addition, a particular cell type referred to as a megakaryocyte has also been found associated with these thrombi. Platelets (thrombocytes) are often associated with thrombi. Platelets, themselves, are generated from so-called progenitor, promegakaryocytes that reside and multiply within the bone marrow. Megakaryocytes are formed from promegakaryocytes and from these megakaryocytes are formed that ultimately break up to produce platelets (see diagram below) that are released into the blood and tissues. The fact that megakaryocytes are evidenced in higher than usual numbers in tissues such as lung, heart, kidney, and brain in patients with COVID-19 disease is a cause for concern.





According to an abstract published by Lancet – a prestigious medical publication – and authored by Amy V. Rapkiewicz, “In seven patients (four female), regardless of anticoagulation status, all autopsies demonstrated platelet-rich thrombi in the pulmonary, hepatic, renal, and cardiac microvasculature. Megakaryocytes were seen in higher than usual numbers in the lungs and heart. Two cases had thrombi in the large pulmonary arteries, where casts conformed to the anatomic location. Thrombi in the IVC were not found, but the deep leg veins were not dissected. Two cases had cardiac venous thrombosis with one case exhibiting septal myocardial infarction associated with intramyocardial venous thrombosis, without atherosclerosis.” In addition, The presence of circulating megakaryocytes on autopsy in various organs was also found and thoroughly studied.

The fact that thrombi have been found in the post-mortems of a significant number of patients who died of COVID-19 disease can account for systemic organ failure in vital organs such as lung, kidneys and heart and such a set of conditions could easily lead to subsequent death.

These data are exceedingly troubling and leaves researchers with a profound question – how does COVID-19 infection trigger such a disastrous response?

The Apparent Efficacy of the Steroid Drug Dexamethasone as Therapy for COVID-19 Patients

As medical professionals, epidemiologists, immunologists, and molecular biologists work in the midst of the COVID-19 pandemic, many aspects of the biology of this virus are being studied and as a result, new understandings are emerging.

It seems that patients with advanced disease that require intervention using a ventilator may be suffering from a hyper-active immune response. In such cases, the use of steroid-based anti-inflammatory drugs may prove efficacious.

An extremely encouraging report from the highly respected Science journal, Nature, has shown the results of a trial study using the proven steroid drug Dexamethasone.

According to the report, the results have indicated that, “An inexpensive and commonly used steroid can save the lives of people seriously ill with COVID-19, a randomized, controlled clinical trial in the United Kingdom has found. The drug, called dexamethasone, is the first shown to reduce deaths from the coronavirus that has killed more than 440,000 people globally. In the trial, it cut deaths by about one-third in patients who were on ventilators because of coronavirus infection.”

This study was expansive involving 2100 participants who received the drug at what is considered a low to moderate dose – 6 milligrams (mg.) per day for 10 consecutive days. The results from the patients were then compared to the results from 4300 patients who received standard care for COVID-19 infection.

Although the drug had no noticeable impact on patients showing no severe symptoms, the positive effect was most striking on patients on ventilators and even on those undergoing just oxygen therapy (not on ventilators) where the rate of death was reduced by 20%.

These are, indeed, encouraging results.

Tuesday, June 9, 2020

The Respiratory Syncytial Virus (RSV) and Pulmonary Disease

Respiratory Syncytial Virus Infection (RSV)According to the Center for Disease Control (CDC), “Respiratory syncytial virus, or RSV (see image below), is a common respiratory virus that usually causes mild, cold-like symptoms. RSV is an RNA virus and a member of the pneumoviridae family of viruses belonging to the genus orthopneumovirus. Most people recover in a week or two, but RSV can be serious, especially for infants and older adults.”

According the National Institutes of Health (NIH), “It is one of the most commons causes of infant viral death worldwide. In fact, RSV is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia (infection of the lungs) in children younger than 1 year of age in the United States. It is also a significant cause of respiratory illness in older adults.”
 


RSV infects cells of the mucosal lining of the respiratory tract resulting in the fusion of the infected cells to form a syncytium – a cytoplasmic mass containing a multiplicity of nuclei. It is a major cause of lower respiratory tract infections and hospital visits during infancy and childhood.

A further characterization of the virus is described by an article from the NIH, “The RNA of RSV contains 10 genes encoding 11 proteins. The envelope of the virus is formed by four proteins associated with the lipid bilayer: the matrix (M) protein, the small hydrophobic (SH) protein, and the two glycosylated surface proteins: the fusion (F) and the attachment glycoprotein (G). F and G proteins are crucial for virus infectivity and pathogenesis since the G protein is responsible for the attachment of the virus to respiratory epithelial cells, while the F protein determines the entry of the virus, by fusing viral and cellular membranes, as well as the subsequent insertion of the viral RNA into the host cell inducing the formation of the characteristic syncytia. Moreover, the F and G proteins stimulate the neutralizing antibody immune response by the host.

"The G protein is a type II glycoprotein synthesized as a polypeptide composed by 300 amino acids (depending on the viral strain) with a single C-terminal hydrophobic domain and a large number of glycan added [20]. Three types of epitopes have been identified in the G protein by murine monoclonal antibodies: (I) conserved epitopes, detectable in all viral strains; (II) group-specific epitopes, expressed only by to the same antigenic group and (III) strain-specific epitopes, that are present only in specific strains of the same antigenic group and expressed in the C-terminal hypervariable region of the G protein ectodomain [21].

"The F protein is a type I glycoprotein which has a structure comparable to the F proteins of other Pneumoviridae (e.g., metapneumovirus) and Paramyxoviridae (e.g., parainfluenza virus type 5) viruses. The F glycoprotein derives from an inactive precursor containing three hydrophobic peptides: (I) the N-terminal signal peptide, which mediates translocation of the nascent polypeptide into the lumen of the endoplasmic reticulum; (II) the transmembrane region near the C-terminus, which links F protein to the cell and viral membranes; and (III) the so-called fusion peptide, which inserts into the target cell membrane and determines the fusion process. The binding of prefusion F protein to the cell surface is followed by its activation and conformational changes, which leads to the fusion of the virion membrane with the host cell membrane.”

These details regarding the molecular biology of RSV is vitally important in establishing the mode of infection and suggests approaches to the development of suitable therapies and the creation of an effective vaccine. For example, a detailed understanding of the molecular structure of the attachment glycoprotein G as described above is of immense importance in regards to establishing methodologies to prevent attachment of the virus to host cells and thereby curtailing infection including the potential for the production of a vaccine for this purpose.

Monday, June 1, 2020

Promising News Regarding Cellular Immunity and COVID-19

As medical professionals, epidemiologists, immunologists, and molecular biologists work in the midst of the COVID-19 pandemic, many aspects of the biology of this virus are being studied and as a result, a new understanding is emerging.

As a result of these efforts some promising aspects of the immunological response have been revealed. Primary among the results of these accumulated data is the fact that individuals infected with this virus harbor T-cells – an important subset of circulating lymphocytes that play a critical role in the human immunological response – that actively target the virus and may assist in recovery. In addition, it seems that some individuals who have never been infected with COVID-19, have these cellular defenses – suggesting that this potential immunological defense arose; because they were previously infected with other coronaviruses that cause the common cold. 


Helper T Cells

These findings provide suggestive evidence that the potent T cell responses that were shown to exist may play an important role in long-term protective immunity. In addition, a more complete understanding of how the human body responds to this particular virus will undoubtedly enhance the search for an effective prophylactic vaccine.

There are more than 100 COVID-19 vaccines in various stages of development focusing on a wide rage of modalities. Within the arsenal of the so-called “adaptive” arm of the human immune system are circulating B and T lymphocytes. The B cells are responsible for the production of antibodies against particular targets. The mechanism that the immune system employs in this regard is that the B cell produced in response to exposure to the virus is to attach itself to the viral particle and prevent it from entering healthy tissue cells. This role can be exploited in the development of a vaccine. In addition, to this part of the natural arsenal against infection, there are circulating T cells that can activate and enhance B cell response. In addition to these players, there are killer T cells that actually target and destroy tissue cells that have been infected. Given the interrelationship of these defense mechanisms, there is a correlation between the severity of the disease and the strength of the T cell responses.

Shane Crotty and Alessandro Sette – immunologists from the La Jolla Institute of Immunology – determined what proteins from the surface of COVID-19 particles were most likely to stimulate immune response and subsequently exposed cells grown in culture (in-vitro) from 10 patients who had recovered from mild cases of COVID-19 to these virally-derived protein pieces. In all the samples studied, the patients carried helper T cells that were specific for the COVID-19 spike protein – the predominant protein of the viral surface that is involved in targeting tissue cells. In addition, 70% of the patients studied showed the presence of virus-specific killer T cells. Whether these patients also acquired long term immunity is not completely clear. These data, however, are very encouraging.

Although not unambiguous, these results are of great interest and suggest that an effective vaccine against COVID-19 infection needs to stimulate the production of helper T cells.