In the microscopic world, cells are economies balancing a variety of chemical and physical inputs towards maximising growth and chances of producing progeny.
Our economies and societies are built over organisational principles that many of us non-experts are familiar with at an intuitive level. Many economies are organised by demand and supply: demand for a productive outcome, given supply of a certain level of raw materials. The objective is to maximise output for a given output – a problem of optimisation.
In the microscopic biological world, cells are economies balancing a variety of chemical and physical inputs towards maximising growth and chances of producing progeny. In the previous instalment of this series, we had seen how the most populous bacterium on the planet is a model for streamlining its assets and processes toward making the most of limiting nutrients. Other organisms are not so streamlined, and instead ‘regulate’ their processes such that only a subset of their genetic material is ‘expressed’ or ‘utilised’ to produce cellular molecules at any given time. This is achieved by a process of sensing a signal(s) in the environment, transducing the signal into a series of molecular processes, ultimately resulting in the deployment of specific molecular regulatory agents that decide which other protein or other biomolecule should be produced in response to the original signal(s).
The importance of regulation is often illustrated by the consequences of misregulation. If you search the scientific literature for the molecular basis of cancer, you will find that you regularly hit upon the cryptic term ‘p53’. P53 is the name of a protein, a tumour suppressor regulatory protein, which in normal cells is responsible for ensuring that various anti-cancer provisions that our cells normally possess are switched on when needed. Mutations which inactivate p53 can result in cancers. Similarly, defects in other regulatory proteins can result in deformities during body plan development in many organisms. For example, mutations in a set of regulatory proteins called the Hox proteins in the fruit fly can result in organs showing up at the wrong places, including gross things such as a limb showing up where the antenna should have been!
Regulation contributes to determining the habitat of an organism. A classic example for this is the colonisation of the light generating organ of a squid by the luminescent bacterium Vibrio fischeri. Here, it is the bacterial symbiont that allows its host, the squid, to glow, and thereby attract prey and/or confuse predators. Mandel and colleagues found that a regulatory protein called RscS in Vibrio fischeri controls its production of certain gooey substances that help the bacterium attach itself to the squid and thus colonise it.
A second variety of the same bacterium, which normally colonises certain fishes, is unable to colonise squids. A comparison of the genetic material of the two varieties of V. fischeri allowed these researchers to discover that the two bacteria differed from each other in the presence of the RscS protein. Then the researchers genetically engineered the fish-colonising bacteria by adding the gene for RscS into its genetic material. This addition of one gene – over and above the 4,000 genes that the bacterium normally contains – enabled the fish coloniser to become a squid-coloniser!
This is not to say that the mere presence of a regulatory protein would permit habitat switching by an organism: for example, had the fish colonising V. fischeri not contained the genes that produce the gooey colonising substance, the mere addition of RscS would not have helped. However, this illustrates the possibility that gain or loss of a regulatory system can potentiate or initiate the evolution of new characteristics in an organism! In this case, a regulatory decision to produce or not to produce a certain gooey substance has determined whether a bacterium colonises a fish or a squid.
In a previous episode of this series, we had seen how in the absence of a certain protein, the bacterium Salmonella, responsible for diseases such as typhoid, “throws down its weapons and calls for a truce.” It turns out that this critical protein is a regulator, which ensures that the bacterium’s weaponry is not produced when it is not needed. Just as human wars are expensive, inappropriate production of proteins that a bacterium would use to wage its own forms of warfare is expensive. Therefore, it becomes important for a bacterium to produce these weapons only when it really needs to.
Viruses that prey on bacteria use regulation to decide whether they want to go dormant, be benign and stealthily replicate as a part of the bacterium itself, or whether it wants to initiate explosive biosynthesis of new viral particles that can eventually lay their host bacteria to waste! In fact, the discovery of these regulatory mechanisms in a virus called lambda, which preys on the famous bacterium E. coli, is a landmark event in the history of molecular genetics.
The list of examples illustrating the importance of regulation to the lives of cells is endless. The question is are there any general principles. One attractive hypothesis is one that the biochemists Juan Ranea and Janet Thornton proposed about twelve years ago. They equated metabolic proteins of a bacterial cell to its productive output, and regulatory proteins to the logistic cost of achieving this output. Across the large diversity of bacteria known at that time, they calculated how the number of regulatory proteins encoded by a bacterium (its logistic cost) scaled with its metabolic gene content (productive output).
They found that as the genetic material – and thereby the metabolic gene content – increased in size, the logistic cost increased more than linearly. In other words, the logistic cost of adding a new metabolic output is much higher for an organism with a large variety of metabolic outputs than for an organism with a limited metabolic repertoire. Understanding the basis for this scaling is beyond the scope of this piece. The authors boldly suggested that rapidly increasing logistic costs would impose a ceiling on how broad the metabolic repertoire of an organism can be!
And it turns out that such superlinear scaling of regulators with outputs is true not only for cells, but also for academic institutions, where an increase in the number of the academic personnel is accompanied by a disproportionately high increase in the number of administrative officials.
Aswin Sai Narain Seshasayee runs a laboratory researching bacterial biology at the National Centre for Biological Sciences, Bengaluru. Beyond science, his interests are in classical art music and history.