Bob the Biotechquer

Archaea are a mysterious bunch. Distinct from bacteria and eukaryotes it wasn't until the 1970s that they were recognized as a third domain of life. These microbes are found everywhere and can play a big role in how carbon and nitrogen is cycled.

Recently a novel phylum of archaea was found by De Anda and her team, Brockarchaeota, named after Thomas Brock, a microbiologist who was the first to grow archaea in the laboratory.

Let's see how they were found. So, 15 archaeal metagenome-assembled genomes (in this the genetic material is directly obtained from environment and studied instead of using laboratory clones) were reconstructed from the terrestrial hot spring sediments in China and at the Guaymas Basin in the Gulf of California. This genetic information was compared with that of thousands of previously identified genomes of microbes and was revealed to be completely different. Not only that but based on the MAG sequence information some Brockarchaeota were found to be uniquely capable of mediating non-methanogenic anaerobic methylotroph* (i.e. didn't produce methane even in the absence of oxygen).

This indicated that not only did these microbes belonged to a new phylum they also had a new metabolism through which they recycled carbon without producing methane.

*Methylotroph don't produce methane in the presence of oxygen but do in it's absence.

The Central Nervous System is protected from physical trauma and invading pathogens by the surrounding meninges. Meninges contain a variety of innate and adaptive immune cells, such as the T cells, dendritic cells, mast cells, and meningeal macrophages as a defence against pathogens. However, not many studies have focused on B cells. Increased levels of IgG and IgA antibodies have been observed in various diseases states of the CNS. Previously believed to be a result of systemic production and transport through the blood to the brain, newer evidence establishes the existence of localized populations of IgA producing plasma cells in the meninges.

IgA in the gut maintains barrier integrity by preventing their entry through the epithelium and trapping them in the mucus layer. The slow blood flow and low shear forces in the dural venous sinuses make it susceptible to invasion by bloodborne pathogens. Thus the localisation of IgA producing plasma cells in the dural sinuses is a protective measure against the invading pathogens.

Further research suggests that these plasma cells train in the intestines and then migrate to the meninges. What is even more interesting is that the population of IgA producing cells is dependent on the microbiome present in the gut. A depletion in the gut microbiome resulted in a significant reduction in the meningeal B cells. It was also observed that different microbiomes of varying bacterial diversity resulted in a variation of the meningeal plasma cell population. A breach in the intestinal barrier resulted in an increase in meningeal IgA producing plasma cells.

Thus maintaining a healthy gut flora aids the body in more than just digestion.

Previously a study identified a list of domestication-associated genes in modern humans by comparing their genome with extinct human species. These genes overlapped with domesticated animals but not with their wild equals. This finding sheds light on the possibility of human domestication.

The self-domestication hypothesis suggests that during evolution, modern humans underwent a self-induced domestication process that anatomically resulted in a lighter built skeleton, a more juvenile look (smaller brow ridges, nasal projections, teeth, and cranial capacity), and a larger brain when compared to their earlier counterparts. In other words, this process encourages selection against aggression and preserves the “cuter” attributes.

One way of explaining the domestication process is the neural crest hypothesis of domestication, which proposes that domestication is attributable to alteration in migration and the mild deficiency of neural crest cells during embryonic development. Neural crest cells (NCC) are responsible for inducing and developing neuroendocrine cells, pigment cells, neurons and glial cells of the sensory, sympathetic and parasympathetic nervous systems, and many skeletal and connective tissue components of the head.

“Neurodevelopmental disease modeling for the study of human evolution” was the unique approach adopted by a recent study that dissects the role of BAZ1B in domestication as well as affirms the neural crest hypothesis.

The study considered a cognitive disorder, namely Williams syndrome (WS). WS shares many similarities with domestication-related modifications. The parallels between the two include decreased aggression, hypersociability, reduced head size, elfin face, pointy ears, small jaw and teeth, short stature, accelerated sexual maturity, etc. Hence, WS is synonymous with hyper-domesticated human phenotype. The syndrome is caused by hemideletion of 28 genes at the 7q11.23 region. BAZ1B (a chromatin regulator) gene plays a crucial role in NCC maintenance and movement; intriguingly, one copy of this gene is missing in individuals with WS.

To evaluate the contribution of BAZ1B in making us “cuter,” i.e., domestication/WS-related facial modifications, neural crest stem cell lines were cultured, and the gene activity was altered in each cell line. The paper concluded impairment in NCC migration and outgrowth upon a decrease in BAZ1B, proving the involvement of BAZ1B in NCC development in humans. Additionally, it was found that the reduced expression of the BAZ1B gene led to distinct facial features (similar to WS), establishing the gene as an essential driver of facial appearance. Thus this paper provided the first experimental evidence for the neural crest hypothesis as an explanation to domestication where BAZ1B is one of the genes driving this process. Furthermore, the knockdown of BAZ1B also affected EDN3, MAGOH, and ZEB2 expressions. These genes are associated with behavioral changes as a result of domestication.

Studies indicate that these genes are also involved in the development of cognitive processes like language or theory of mind. Thus further introspection can bring about a clear picture of the anatomical, behavioral, and physiological alterations resulting from self-domestication in humans.

Reference:

Gene drive can be explained as a phenomenon whereby a particular gene via genetic engineering methods biases inheritance in its favour (more than the Mendelian 50:50 inheritance chance) resulting in the gene becoming more prevalent in the population over successive generations. The speed of this process is inversely correlated to the generation time of the organism, eg: it is faster in mosquitoes with a generation time of 2-4 weeks than in whales with generation time of 50 years or more.

This idea is mostly being explored as a potentially durable and cost effective strategy for controlling the transmission of deadly vector-borne diseases that effect millions of people worldwide such as malaria, dengue, Zika virus, or to eliminate herbicide or pesticide resistance. Eg: The Cas9 mediated gene drive led by Gantz et. al. in the mosquito population by introgression of parasite-resistance genes, thereby modifying the ability of the vector to transmit the pathogen.

Though the dangers of this technology cannot be overlooked. One of the ideas was a suggestion to use CRISPR gene editing technology to avert extinction of endangered wildlife by spreading a fertility reducing gene in the other animals competing against them for resources. This with time turned from an innovative idea to a perilious one, as demonstrated in a CRISPR-Cas9 gene drive targetted at genes that control the differentiation of the two sexes of the Anopheles gambiae mosquitoes. Leaving the males unaffected it decreased the fertility of the female mosquitoes. The gene rapidly spread reaching 100% prevalence within 7-11 generation to the point of total population collapse despite various Cas9-resistant genes arising in each generation.

With just a few of these engineered organisms our ecosystem could be altered, irrevocably.

References: 1) Gantz, V. M., Jasinskiene, N., Tatarenkova, O., Fazekas, A., Macias, V. M., Bier, E., & James, A. A. (2015). Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. Proceedings of the National Academy of Sciences, 112(49), E6736. https://doi.org/10.1073/pnas.1521077112

2) Kyrou, K., Hammond, A., Galizi, R. et al. A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. Nat Biotechnol 36, 1062–1066 (2018). https://doi.org/10.1038/nbt.4245

3) Emerson, C., James, S., Littler, K., & Randazzo, F. (Fil). (2017). Principles for gene drive research. Science, 358(6367), 1135. https://doi.org/10.1126/science.aap9026

One of the distinct characteristics of Adaptive Immunity is Immunological Memory. Immunological memory aids the immune system to mount a faster and more efficient response to reinfection. However, this exclusivity has been challenged in the last two decades with evidence coming forth of immunological memory exhibited in innate immunity. The memory characteristic of innate immunity is termed as 'Trained Immunity' and it results in an elevated response to secondary infection.

It is important to note that despite being the same concept, the functioning of the memory characteristic of both types of immunity varies greatly. Unlike adaptive immunity which utilizes genetic recombination, trained immunity is mediated by epigenetic reprogramming of the transcriptional pathways within cells.

Trained immunity is said to last from 3 months to 1 year and in cases of live vaccines up to 5 years as opposed to adaptive immunological memory that lasts for an individual's lifetime.

Another interesting feature of trained immunity is its non-specificity. After an infection, the innate immune system is 'primed' for a stronger response to reinfection not only to the primary pathogen but also to several other unrelated ones.

An example of the non-specific nature of trained immunity is the protection provided by the BCG vaccine. Apart from priming the immune system against Mycobacterium tuberculosis, it also provides protection against Candida albicans and Schistosoma mansoni. The response to these unrelated pathogens has been confirmed to be produced by the innate immune system.

The BCG vaccine can also be applicable in cases of cancer treatments since studies have shown successful tumour remission as a result of trained immunity. The BCG vaccine is currently being employed as an FDA approved immunotherapeutic strategy to treat bladder cancer in the USA and is also used in some cases of lymphomas and melanomas.

Trained Immunity is a new discovery that drastically changes our view of innate immunity and the immune system as a whole. These new findings might lend us hand in understanding the several unexplained and unanswered questions that we still have about the system that has evolved with the sole aim to protect us. Trained immunity could also explain the evolutionary success of 97% of earth's lifeforms that depend upon innate immunity for protection against pathogens since adaptive immunity is an exclusive feature of vertebrates. Some studies suggest a link between trained immunity and autoimmune diseases. More knowledge about trained immunity could also usher in a new era of vaccines that target the innate immune system. Trained Immunity is a new and exciting avenue for future research in Immunology.

Checkpoint blockade immunotherapy employs the usage of immune checkpoint inhibitors. These inhibitors block the immune system cells made proteins called checkpoints. Since checkpoints obstruct the immune responses from being too robust and prevent T cells from killing cancer cells, blocking the checkpoints facilitates T cells to kill cancer cells better. However, for > 80% of cases, this therapy has been ineffective. Hypoxia and its lead modifications in tumor cells are responsible for this therapy resistance.

Hypoxia enables cancer cells to evade the immune system resulting in therapy resistance. It was recently found that hypoxia induces increased expression of the BIRC2 gene in breast cancer and melanoma cells. BIRC2 inhibits cell "suicide," or apoptosis of cancer cells, and blocks the recruitment of T-cells and natural killer cells, thus allowing cancer cell survival.

The study revealed that the knockdown of BIRC2 lead to:

1. Enhanced expression of CXCL9, which is responsible for drawing T-cells and natural killer cells to the tumors.

2. More immunogenic tumors.

3. Sensitized melanoma and breast cancer to checkpoint blockade immunotherapy.

Thus, BIRC2 is one of the culprits in making breast cancer and melanoma cells resistant to immunotherapy, and using drugs that inactivate BIRC2 or other apoptosis inhibitors can improve the response to immunotherapy drugs.

It is a long standing dogma that genes which code for essential functions tend to be conserved over the course of evolution. In a recent study, this was contradicted with the fact that some new genes had swiftly become crucial because they regulated heterochromatin (which is one of the fastest evolving part of the DNA, therefore, the genes that regulate it have to adapt quickly to keep up).

The researchers focused on the Nicknack ZAD-ZNF gene, which is an evolutionarily young gene in Drosophila species. Nicknack encodes a heterochromatin-localizing protein.

To see how quickly Nicknack might have taken over an essential function, the researchers replaced the Nicknack gene in D. melanogaster with the Nicknack gene in its closest evolutionary relative, D. simulans. They expected that the swap of an essential gene would have no effect as it would be conserved and hence similar in both species. But they found that the divergent D. simulans Nicknack protein could only localize to D. melanogaster heterochromatin and rescue viability of female but not the male fruit fly.

Reason: The swap adversely affected the males, with their abundance of heterochromatin in the Y chromosome. Rendering the D. simulans Nicknack gene incapable of handling the load of large quantity of evolutionary diverse heterochromatin.

Conclusion: D. melanogaster had rapidly evolved it's own version of Nicknack gene (despite being an essential gene) to prevent it from becoming obsolete.

The ADAR (Adenosine Deaminase Acting on RNA) enzyme family is responsible for the most common form of RNA editing in metazoans. It catalyzes the deamination of Adenosine into Inosine and Inosine is read as Guanosine during translation thus resulting in nonsynonymous recoding of the protein sequence. However, RNA editing rarely takes place in the coding region. The vast majority of the editing sites lie in untranslated regions and only 3% of mRNAs are edited. This distribution suggests the presence of an active mechanism that exclude editing sites from coding regions.

Contrastingly, the coleoid cephalopods exhibit unusually high levels of RNA editing. The common market squid edits two-thirds of its neural messages and the octopus and cuttlefish are said to recode a similar amount.

What is even more astonishing about this process is that editing of coding RNA at such a massive scale slows down the rate of DNA-level evolution. For editing a specific adenosine, ADAR requires the support of surrounding RNA structures. Even a single substitution in these regions would put a stop to the editing. Therefore thousands of stretches of sequences that span a significant portion of the genomic coding sequence are highly conserved. Consequently, the accumulation of mutations is reduced, which has a detrimental effect on genetic variation which in turn slows down conventional DNA-level evolution.

For cephalopods to recode their mRNAs at a massive scale by forfeiting DNA-level evolution suggests that RNA editing provides them with a colossal advantage. What that advantage is a question that is still unanswered.

How does the 2 m DNA fit into a nucleus of 10-15 μm diameter? The answer lies in DNA packaging.

To better understand the chromatin compaction levels, read our new infodump!

Click on the link below!!

https://sites.google.com/view/bobthebiotechquer/molecular-biology/dna-packaging

Link : https://sites.google.com/view/bobthebiotechquer/microbiology/types-of-microorganisms

There are millions of microbes inhabiting Earth and according to recent estimates  there are billions more yet to be discovered. These millions are categorised into various types based on their morphology, genetic material, cellular composition, means of locomotion and reproduction. To learn more about this click on the link in the bio and go to 'Microbiology' and read our latest infodump!!

Link: https://sites.google.com/view/bobthebiotechquer/immunology/cells-of-the-immune-system-pt-2

The CD4/CD8 T cell ratio is a good indicator of the proper functioning of the immune system. T cells are a category of cells that are part of the lymphoid lineage. To learn more about the various cells of the lymphoid lineage, read our new infodump! Click on the link above

Reference:

https://sites.google.com/view/bobthebiotechquer/molecular-biology/dna-topology

DNA topology is an essential property of the cell and is regulated by Topoisomerases for its proper functioning.

To learn more about Topology and the enzymes, read our new infodump!

Click the link in our bio and go to 'Molecular Biology'.

Reference:

Ahmad, M., Xue, Y.,et.al. (2016). RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals. Nucleic acids research, 44(13), 6335–6349. https://doi.org/10.1093/nar/gkw508

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#Infodumps of the following week -

1. Molecular Biology: Bob, let's talk TOPOLOGY (31st August)

2. Immunology: A lesson on the soldiers of the immune system for Bob pt. 2 (2nd September)

3. Microbiology: Let's classify the microbes in Bob's life (4th September)

Link: https://sites.google.com/view/bobthebiotechquer/microbiology/history-of-microbiology-part-2

Miasma theory is one of the many interesting theories made by curious minds to understand the enigmas surrounding the connection between diseases and microbes, which was later discarded with the introduction of new and advanced scientific discoveries like the 'Germ Theory of Disease'.

To learn more about these discoveries click on the link above!

Link: https://sites.google.com/view/bobthebiotechquer/immunology/cells-of-the-immune-system

To learn more about Hematopoietic Stem Cells and the cells types that arise from it, read our new Infodump!

Link: https://sites.google.com/view/bobthebiotechquer/molecular-biology/structure-of-dna-and-rna

To get an insight into the structure of DNA, its conformations as well as the structure of RNA, read our new infodump!