The road not taken: Part II

On 1 January, 2020

by Gayathri Sambamoorthy (and Karthik Raman)

One student questioned me, “Is your research about the evolution of microorganisms?” I smiled in happiness that she got something from what I spoke! “Great! Not really! I am coming to that! My research is about understanding how evolution alters reactions in an organism. When the microorganisms evolve, new reactions are added to the pathways. When I mean evolution, it doesn’t just have to be the addition of new reactions. There can also be the removal of reactions from the pathway if the organism thinks it is of no use anymore!”

Yamini, patiently listening to everything, commented, “Even such small organisms are clever!”

I laughed at the childish way she said that, although I was happy she was trying to comprehend all that I had said so far. The students were astonished at how such tiny organisms have robust mechanisms for survival.

Now, I threw some more questions for the students to ponder: “Organisms get new reactions as they evolve, but are there new synthetic lethals also? Are synthetic lethals unique to the environments in which the organisms grow? How similar or different are the reactions that form synthetic lethals?”

The students were seriously thinking over. I continued, “These are some of the questions I wanted to answer with my research! We do this on a computer, evolve microorganisms, mimicking what happens in nature.”

One student duly asked, “How do you do that using a computer?”

I sighed. “It’s a long process. To keep it simple, we add one reaction and remove one reaction at a time and further continue the process of evolving a metabolic network. We evolved 2000 metabolic networks and found which reactions form synthetic lethals (a computer-intensive procedure) in 10 different nutrient conditions. As I had mentioned before, synthetic lethals increase robustness in organisms. If that’s the case, do microbes that exist in nature have many such synthetic lethals for them to be robust? We compared the synthetic lethals in a natural organism, E. coli (to keep it simple, let me tell you, it’s a bacterium), with those of the metabolic networks we evolved. We found that nature does preserve a lot of these synthetic lethals, and they are higher in number than the evolved metabolic networks in all the nutrient conditions we studied.”

“Next, we looked if these synthetic lethals vary with different environments. We found that some synthetic lethals are common across different environments we studied. A larger portion of the synthetic lethals was uncommon, in the sense that they were unique to environments.”

“Now that we find a large number of synthetic lethals in these evolved metabolic networks, if we consider one reaction at a time, with how many other reactions do they form synthetic lethal pairs? Can you guess between what numbers these would lie?”

One student replied, “10 to 50”. Another said, “30 to 100”. I let them keep guessing so that they think for some time. “From our research, we could find that these numbers vary largely from 1 to 266!”

They were all surprised. “Fascinating, right? Do you know which reaction is the one that forms synthetic lethals with 266 other reactions? That is the reaction that forms the energy molecule of the cell called ATP! Interesting, right? Upon evolution, they not only add new reactions but also ensure that they add the right ones!”

“Then we went ahead to analyse how similar or different reactions form synthetic lethals. To our surprise, we found that the reactions were very different from each other and belonged to very divergent pathways.”

A student still thinking asked, “But what is the need to analyse and understand all this?” I explained, “Studying these synthetic lethals and their evolution in metabolic networks will give us an idea of the redundant mechanisms that organisms can acquire. We now understand the possible redundancies that can exist as organisms evolve. These would give us insights into the basic design approach that microbes have and also how they increase their robustness. We can thus target reactions that do not form synthetic lethal with another reaction for microbes that cause diseases, to develop a medicine!”

She was happy with my answer! I greeted the class and asked them to mail me any further questions. I saw the look on Yamini’s face. She was awestruck! I knew that she would have understood only a little of my studies that led to the roads not taken by the microbes. Nevertheless, I left with the contentment that I could make her ponder on my research.

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