Richard Feynman once wrote a poem which included a line “I... a universe of atoms, an atom in the universe.” It aptly captured the immensity of the universe and at the same time indicated the vastness within us. From the eye of a biologist, human is a tremendous assembly of 10 trillion cells working seamlessly to keep it alive.
AT LEVEL ONE: The importance of these huge number of cells to maintain co-ordination among themselves could be well understood from the fact that its failure could lead to disorders such as cancer. The rebel cells usually refuse to communicate with the healthy cells and their unstoppable division is deadly for the overall survival of the host. In normal circumstances, our cells communicate with distant cells through a battery of methods. Hormones, exosomes, cytokines etc are packets which assist in long distance communication in our body to work as a single unit. The ability of individual cells to adapt, respond and communicate through health and disease is essential for the survival of living organisms.
AT LEVEL TWO: Let us now consider bacteria for a moment. It is small organism, with 1/10th the size of human cell. They appeared to live a singular or lonely life until recently when they were caught communicating with each other by exchanging small molecules. This means of communication was named quorum sensing. It has been shown that these help these bacteria to act together in unison. As all the cells inside our body join together and collectively work for our survival similarly, bacteria act in concordance with each other for the survival of their species.
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| Group of phages attacking a bacteria. (Source: The Eye of Science) |
AT LEVEL THREE: Let's take bacteriophages (phages), which are viruses of bacteria and are 1/100th in its size compared to bacteria. Depending on the availability of their host bacteria, these phages determine whether to continue their division by reproducing to such a huge numbers that the bacteria explodes and in the process shedding all its progeny phages into the surroundings (lytic pathway). Or keep on its 'sleeper-cell' mode activated by integrating itself into the bacteria's DNA and divide slowly (lysogenic pathway). The mechanism by which virus undergoes this lytic/lysogeny pathway is known in detail here.
Now our understanding has been greatly enhanced by series of elegant experiments done by Zohar et al. at Weizmann Institute of Science in Israel. This new research shows that these phages communicate with each other to select lytic/lysogeny decision. Zohar et al. began by releasing a large number of phages in bacterial culture. This lead to lytic cycle whereby large number of phages are produced as the number of bacteria kept dying. In the next step they filtered the same media (all the phages and bacteria were cleared) and re-cultured new batch of bacteria later re-introduced phages. Surprisingly, this time the phages retreated their aggressive stance and stopped lysis. It appeared that somehow the phages sensed the previous 'bloodshed' of bacteria and have detected diminishing number of their host population leading to temporary pause in their lytic pathway. It makes evolutionary sense because less number of prey to infect would reduce the long-term survival of phages. Overall if we see, we will find that at one extreme, If only lytic cycle persists then at one time there would be no host to infect and at other, if there is only lysogeny then the phage is forever trapped in the genome of bacteria in-turn compromising the opportunities for its dispersal which is required for its spread and survival. Thus, a critical balance needs to be maintained and this is where a novel encrypted communication strategy comes in with the name of ‘arbitrium system’.
The mechanism by which these phages deicide to reproduce rapidly or slowly is a very interesting one and its mechanism has been understood in detail and is part of many textbooks. The phages undergoing a lytic cycle poses a problem because it kills the host bacteria. As the population expands more and more host bacteria die. These phages could prevent the incessant killing of bacteria by integrating into their DNA and wait for the number of bacteria to to increase. Only then it would be advantageous to undergo lysis for further dispersal. But how do phages know that it is time for ceasefire? How do they collectively communicate? The phages themselves do not have any surface receptors to sense the change in media nor can they bind to any protein to sense its level. They cannot process any signal per se. They are almost non-living. Then how do they communicate?
The answer lies in its ability to hijack the bacterial cell and use it as a communication system. It is really amazing how viruses manipulate's host's machinery not only for its survival and propagation but for signal processing also.
At molecular level, the mechanistic findings are equally interesting. In the beginning, when the lytic activity of these phages peaked, they found that small peptide named arbitrium accumulates in the media as infected bacteria die and spew away their cellular content into the medium. Arbitrium later gets transported inside the new bacteria through specialised transporters which are part of standard bacterial system. Once these peptides are shuttled inside the bacteria they bind to its receptor called AimR. Arbitrium binding to AimR triggers a change from its active dimer configuration to a monomeric one which renders its inactive. What is the big deal if AimR is inactivated? Its answer comes if the observation from newly infected cells are taken into account. In the absense of Arbitrium AimR normally binds to phage's genomic region inside the bacteria. AimR has high affinity for a specific region in phage's genome. There it assists in transcription of two peptide molecules AimX and AimP. First, Aim X is the critical molecule which blocks lysogeny pathway through unknown mechanism. So, the initial absence of arbitrium leads to stability of AimR which causes higher expression of AimX, which in turn inhibits lysogeny and promotes lytic cycle. It's second product is AimP , which in its mature form is called arbitrium which is anti-AimX as it inhibits lytic cycle. So, a single control event generates molecules of opposite effect, This is an elegant example of a natural check and balance system.Simply put, Accumulation of AimX leads to lysis and of AimP lysogeny.
This paper adds to our previous understanding of lac operon, trp operon and phage level control of gene expression. It is amazing how nature finds novel ways to fine-tune gene regulation. But it is not as straightforward as it seems and should not be oversimplified. Biology is not a binary science where one gets 0 or 1 as result in an experiment. AT ONE HAND we have events that are inherently based on threshold levels and examples of them can be seen throughout the field. Some biological reaction sat the cellular level are normally triggered only when a critical threshold is crossed. The intracellular calcium surge or conductance of nerve impulse are one of the many phenomena echoing this theme. On the other hand, we have events which follow a stochastic or random pattern.
Surely the data suggests that as the arbitrium level rises in the medium so is the probability of future lysogenic events but authors found it to be a stochastic event, with probably unknown factors in play. Here they found out that even after 1 hour of phages infection only 50% of the cells showed lysogeny. Similarly, in the absence of arbitrium, whereby rampant lysis was observed there was still a quantifiable number of lysogenic events. These systems are far from perfect and are continually being selected through ‘the axe of natural selection’. The biology is inherently complex with the increasing amount of factors and variable experimental conditions but this study is bound to have far-reaching consequences.
These observations provide a fresh line of thought for investigating the role of arbitrium like systems in the maintenance of natural ecological communities of viruses in the wild or it’s effect in human viral diseases.
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