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Life and Non Life inching closer: The story of phages

Illustration of a bacteriophage

Phages are one of the most abundant organisms on earth. There are around 10^31 phage particles on the planet. One more striking trait of the prokaryotic virosphere is its remarkable diversity. Phage virions vary widely in size, shape and complexity, and the genomes they contain are more diverse, ie; they are highly mosaic. Their size ranges from 3.4 kb to almost 500 kb, and unlike bacteria, there isn’t a single gene (e.g. 16S rRNA) present in all phage genomes.

Recently scientists at the University of California discovered large bacteria-killing viruses with capabilities normally associated with living organisms, blurring the line between living microbes and viral machines. They are called phages short for bacteriophages because they “eat” bacteria, and are of such a huge size that would be associated with living organism. They carry genes which are normally found in bacteria and use it against their bacterial host.

They found about these phages after scouring through DNA databases, generated from 30 different earth environments, premature infants, pregnant women, Tibetan hot springs, bioreactors, ooceans, lakes and deep underground. Through this they were able to identify 351 phages whose genomes were 4 or more times larger than the average genomes of viruses that prey on these single-celled bacteria. There is a new challenge to understand the ‘unseen majority’ or ‘microbial dark matter’ by sequencing SAGs- Single cell Amplified Genomes. Now, sequencing helps the researchers as they are interested in what metabolism is associated with the sequence data. SAG analysis revealed a complete genome of ssDNA virus associated with a cell of one clade, but not with two other marine picobiliphytes.

Now, bacteriophages are known to have two types of life cycles – lytic and lysogenic. Lytic phages infect cells and use host machinery for replicating their nucleic acids After self-assembly of capsid proteins with their DNA/RNA genomes, host cells are lysed to release 10–100s of progeny into the extracellular environment which then seek to infect other cells. In comparison to this, temperate phages infect a cell and then either continue with a lytic infection or they enter lysogeny whereby the phage chromosome is maintained either integrated in the host’s chromosome or extrachromosomally. Now sometimes under certain conditions for example: UV radiation, chemicals, nutrients, temperate phages are induced into the lytic cycle to produce progeny phages and lyse the cells.

Amongst these led to the discovery of the largest bacteriophage to date with 735,000 bps, its 15 times larger than the average phage. “These huge phages bridge the gap between non-living bacteriophages, on the one hand, and bacteria and Archaea. There definitely seem to be successful strategies of existence that are hybrids between what we think of as traditional viruses and traditional living organisms.” said Jan Banfield, of the UC Berkley . It might be possible that once these phages inject their DNA into bacteria, the viral CRISPR system augments the CRISPR system of the host bacteria, probably mostly to target other viruses Cas Proteins.

New Cas protein

The so called CRISPR-associated (Cas) genes encodes Cas proteins, is an important part of the CRISPR locus. The cas genes locate adjacent to the CRIPSR array and encode all proteins that are necessary for mediating the adaptive immune response.

It was found that one of the huge phage can make the protein analogous to the cas9 protein which is a part of the revolutionary tool CRISPR-Cas9 , they dubbed this teeny tiny protein CasΦ as Φ/phi is traditionally used to denote bacteriophage. This discovery could be of a great help because there are a lot genes whose function is known and finding them could be useful to the healthcare industries, agricultural sector or industries.

Viruses, usually, carry genes between cells, including genes that confer resistance to antibiotics and since phages occur wherever bacteria and Archaea live, including the human gut microbiome, they can carry damaging genes into the bacteria that colonize humans. Banfield also said “Some diseases are caused indirectly by phages, because phages move around genes involved in pathogenesis and antibiotic resistance and the larger the genome, the larger the capacity you have to move around those sorts of genes, and the higher the probability that you will be able to deliver undesirable genes to bacteria in human microbiomes.”

Sequencing Earth’s biomes

Banfield found out that there are many new microbes which are so small that impossible for them to survive on their own, they appear to depend on other bacteria and archae to support their life. She also reported an year about Lak pages, which preys on gut and saliva microbiomes.

While most of the genes in these huge phages code for unknown proteins, they were able to identify genes that code for proteins critical to the machinery, called the ribosome which translates mRNA into protein. These genes aren’t found in viruses but only in bacteria or archaea.

Typically, what separates life from non-life is to have ribosomes and the ability to do translation; that is one of the major defining features that separate viruses and bacteria, non-life and life, but because these large phages have translational machinery the line is getting blurred a bit. These monstrous phages use these genes to redirect the ribosomes to make more copies of their own proteins at the expense of bacterial proteins and they have alternative genetic codes, the nucleic acid triplets that code for a specific amino acid, which sometimes confuses the bacterial ribosome which decodes the RNA. These phages carry genes for variants of the Cas proteins found in a variety of bacterial CRISPR systems, such as the Cas9, Cas12, CasX and CasY families. CasΦ is a variant of the Cas12 family. They also have CRISPR arrays, which are areas of the bacterial genome where snippets of viral DNA are stored for future reference, allowing bacteria to recognize returning phages and to mobilize their Cas proteins to target and cut them up.

“The high-level conclusion is that phages with large genomes are quite prominent across Earth’s ecosystems, they are not a peculiarity of one ecosystem,” Banfield said. “And phages which have large genomes are related, which means that these are established lineages with a long history of large genome size. Having large genomes is one successful strategy for existence, and a strategy we know very little about.”

The researchers divided the 351 megaphages into 10 new groups, or clades:

  • Mahaphage(Sanskrit),

  • Kabirphage, Dakhmphage and Jabbarphage(Arabic),

  • Kyodaiphage(Japanese),

  • Biggiephage (Australian),

  • Whopperphage (American);

  • Judaphage (Chinese)

  • Enormephage (French); and

  • Kaempephage (Danish)

- written by Divya Ahuja

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