a microbiology newsletter -april, 2021
A newsletter of, by, and for microbiologists. Copyright 2021, all rights reserved
The ACE2 Receptors

Could this explain why some are more susceptible to COVID-19?

The SARS-CoV-2 virus gains entry to the epithelial cells lining the respiratory tract by way of the ACE2 (angiotensin-converting enzyme 2) receptor. This is the protein to which the viral spike proteins attach in order to gain entry into the cell.

If we knew more about this important receptor, it could be the key to unlock future therapies and preventive measures. 

This ACE2 receptor is a transmembrane protein, in that it is embedded in the cell membrane. This protein is found on epithelial and endothelial cells of the upper and lower respiratory tract, heart and vasculature, kidneys, and portions of the gastrointestinal tract. It is an ectoenzyme, meaning its actions occur outside of cells. The ubiquitous nature of this receptor explains, in part, why so many different organs can be affected by SARS-CoV-2.
ACE2 is a vital element in a biochemical pathway that is critical to regulating processes such as blood pressure, wound healing and inflammation, called the renin-angiotensin-aldosterone system (RAAS) pathway.

 Why are children so rarely
affected by the disease?

ACE2 is present in all people but the quantity can vary among individuals and in different tissues and cells. Some evidence suggests that ACE2 may be higher in patients with hypertension, diabetes and coronary heart disease. This may explain why these patient groups are more prone to serious COVID-19 disease.
The ACE2 receptor concentration in the cell membranes may also explain why children are less susceptible to serious COVID-19 disease. It is known that children have less ACE2 receptors in their tissues. Also, their ACE2 receptors have less maturity and functionality while having less expression and affinity to invading viruses.

Researchers have also found that ACE2 lung airway expression is upregulated and intensified in smokers and those with COPD (chronic obstructive pulmonary disease.)
When the amount of ACE2 is reduced because the virus is occupying the receptor sites, individuals may be more susceptible to severe illness from COVID-19 thus increasing susceptibility to inflammation, cell death and organ failure, especially in the heart and the lung.
Currently, clinical trials are being conducted to determine if ACE inhibitors could be effective in treating COVID-19. Undoubtedly, the extensive research being conducted on this topic will eventually bring exciting news and relief to many.

By Jay Hardy, CLS, SM (NRCM)

Ref: 1, 2, 3, 4, 5, 6

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and the COVID-19 Vaccine
Nanotechnology refers to the manipulation of molecules for large-scale manufacturing purposes. It is a broad field of science, which combines chemistry, physics, energy storage, microfabrication, and molecular engineering.

Recently, it has been popularized by its role in nanomedicine for the COVID-19 vaccine. (1) Currently, with the introduction of mRNA vaccines by Pfizer and Moderna, the importance of nanotechnology and the use of liposomes has become even more apparent. Advances in nanotechnology allow for the transport of molecular information, increased protein expression, protection from nucleases, and the improvement of the overall safety of mRNA-based vaccines. (2) Note that the new Johnson & Johnson vaccine uses a modified adenovirus carrier to transport DNA rather than a liposome to transport mRNA.

The primary improvement for mRNA vaccines has to do with the lipid nanoparticle. Lipid nanoparticles (liposomes) are comprised of a phospholipid bilayer, which can be loaded with target drug or mRNA that codes for a target protein, such as those developed for the SARS-CoV-2 vaccine. Although a newer improvement for vaccines, this delivery method has existed for many years and originally gained popularity in 2018 by Onpattro. This was the first drug approved by the FDA to deliver siRNA to treat polyneuropathy. (3) Onpattro offers protection for RNA to avoid host RNAses and, consequently, improves the safe transport of the mRNA to target cells where it is readily absorbed. (2)
The liposomes deliver their mRNA payload into the cell, but the mRNA does not enter the nucleus, nor does it replicate.
Molecular transport is not the only hurdle for mRNA vaccine development. Due to their fragile nature, RNA strands must also go through a strand optimization process. RNA sequences are optimized by adjusting the 5’ and 3’ flanking UTR regions. (2) Alteration of the 5’ cap can be done by several methods and provides more efficient protein synthesis whereas changes to the 3’ poly (A) tail provide greater stability and enhanced translation. (2) In addition, scientists also look at the rarity of codons in the sequence as well and the G:C content for further strand optimization. (2)

With the FDA emergency use authorization (EUA) of the SARS-CoV-2 mRNA vaccines, safety is the main concern for patients. So far, these vaccines have shown to be both safe and effective via large scale clinical trials, after their data was reviewed by the US FDA. (4) The main reason these vaccines are considered safer than other types of vaccines is due to the nature of mRNA’s function within cells. Once mRNA enters the host, it remains in the cytosol until the strand is translated by the ribosomes into a protein product. Soon thereafter, the mRNA transcript is degraded by host enzymes, which reduces the chance of repeated protein production. Furthermore, when the liposome encapsulated mRNA enters the cell in this artificial manner, it lacks the necessary machinery needed to enter the cell nucleus. Thus, new mRNA molecules from the original vaccine source cannot be reproduced. (5)

In conclusion, the use of nanotechnology and liposomal mRNA based vaccines are a promising advancement for future vaccine development. Their current use during the COVID-19 pandemic is showing promising results, and they have the potential for swift modification over other types of vaccines should the need arise with SARS-CoV-2 variants. Their use on a global scale is still new, yet more research and developments in the coming years are being conducted with this technology.

by Miles Amby
R&D Microbiologist

Work Cited: 1, 2, 3, 4, 5
The diagram above shows how liposomes can be used to transport both mRNA or DNA into the cell. The liposomal carriers penetrate the cell membrane and release their nucleic acid cargo where it is then used for protein production.
Can COVID vaccine technology be used against cancer?

mRNA Vaccines in Cancer Care

Information on messenger RNA (mRNA) vaccines is frequently in the news due to the ongoing COVID-19 pandemic, since mRNA technology is used in the Moderna and Pfizer vaccines against SARS-CoV-2. Long before the start of the pandemic, however, researchers have been attempting to use this technology to treat cancer.

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. (1) It is also the third most common cancer worldwide. (2) The standard treatment for many colorectal cancer patients is surgery, but this can leave some cancer cells undetected in the body. Cancer cells left behind can shed DNA into the bloodstream, known as circulating tumor DNA, or ctDNA. If ctDNA is detected after surgery treatment it is associated with higher rates of cancer recurrence. (3) A clinical trial led by Van Morris, M.D. and Scott Kopetz, M.D., Ph.D. follows high risk patients with stage II or stage III colorectal cancer who test positive for ctDNA after surgery. (4)

During his procedure, tissue from the tumor removed during surgery is sent to a specialized lab and tested to find genetic mutations in the patient’s own DNA that lead to cancer growth. A targeted mRNA vaccine is then created based on a prioritized list of the mutations found. In this way, each patient receives a personalized mRNA vaccine based on their individual mutated DNA test results. Once administered, the mRNA encodes the instructions for the patient’s cells to produce protein fragments based off the identified mutations. Cells present these fragments as foreign to the body’s immune cells. The immune system can then search for other cells with mutated proteins and destroy any circulating tumor cells, thus eradicating the cancer for good. This clinical trial is currently in Phase II and is estimated to be completed in July 2027. (4)

These clinical trials are just one of many research studies involving the use of mRNA to treat cancer. In another study, researchers tested a way to stabilize mRNA and allow for slow release using hydrogels. One of the challenges in using mRNA technology to treat disease is that mRNA deteriorates quickly in the body due to exposure to degrading enzymes. With this newly developed method, mice with melanoma were given a treatment and experienced both reductions in tumor size, as well as obstruction of metastasis in lung tissue after treatment with the mRNA vaccine. (5) With these promising results, the future of this type of treatment would allow therapies to last over the course of 30 days.

Additionally, in a separate study, a clinical trial in humans found success in treating melanoma patients with personalized mRNA vaccines. (6)
To date, mRNA vaccines have been applied to treat aggressive, less accessible and metastatic solid tumors, including non-small cell lung cancers, colorectal carcinoma, melanoma, and others. (7)

There is an unending need for safe and effective cancer treatment, and mRNA technology allows for personalized treatment specifically designed for each patient. Now that the pandemic is almost behind us, great headway can be made in this field and the future looks hopeful for those that can benefit from this type of targeted therapy.

By Alani Vasquez
R&D Manager

References: 1, 2, 3, 4, 5, 6, 7, 8
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How do the four new COVID-19 vaccines work?

What are the stated effectivity rates?

What are the shelf life and storage requirements?

How many doses are needed?

How much do they cost?

Where are they made?

What are the risks and side effects?
The Four New COVID-19 Vaccines Compared

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I hate telling people I'm a taxidermist.

When they ask me what I do, I say "Y'know...Stuff"

Wisdom to Ponder...
I. M. Pei

1917 ~2019

A Chinese American that is noted for being one of the greatest architects of all time. He won numerous awards during his 102 year lifetime. A sample of his work is seen below..

"Stop worrying about missed opportunities and start looking for new ones."

"Great artists need great clients."

"Life is architecture and architecture is the mirror of life."

"Success is a collection of problems solved."

"Let's do it right. This is for the ages."

"Be the best, not necessarily the original."

"I haven't taken any new projects in the past years. I told myself, if I cannot live long enough to finish it, I don't want it."

* * *
"When you can do the common things of life in an uncommon way, you will command the attention of the world."
~ George Washington Carver
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Increasing your protection...

How Zinc Ionophores can effectively fight COVID-19

References for utilizing Vitamin D and Zinc supplementation for the adjunct therapy
and prevention of COVID-19.

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Jay Hardy, CLS, SM (NRCM)
CEO of Hardy Diagnostics