How did life chemically originate?

Research undertaken in our lab has implications for discerning a very fundamental question in Biology: How did chemistry transition to biology on the early Earth. In particular, the processes by which monomers oligomerize to form biopolymers such as RNA and peptides, the replication and information transfer of RNA molecules in an RNA World etc. are aspects that we focus on. We also are discerning how self-assembly of amphiphiles and their crosstalk with the aforementioned oligomers would have resulted in cell-like structures. In all, the important question we hope to answer is: what plausible processes lead to the different aspects of protocell formation and their subsequent evolution.

Prebiotic informational molecules

One of the big focus areas is on delineating relevant processes that might have enabled the formation of complex mixtures of informational molecules (oligomers like nucleic acids and peptides) on the prebiotic Earth. One pertinent scenario involves amphiphiles and their potential catalytic role in nonenzymatic polymerization reactions. We are discerning the role of liquid crystalline matrices of amphiphiles on nonenzymatic polymerization of prebiotic relevant RNA nucleotides in fluctuating hydrothermal conditions. We have optimized various parameters that result in efficient polymerization of nucleotides to result in RNA-like oligomers. Interestingly, under these harsh conditions, sugar-phosphate oligomers form readily, resulting in oligomeric backbones. Such backbones are thought to have allowed for sampling of larger informational (base) space, prior to the emergence of the RNA World. Our current focus is to discern this base space to better understand the types of "informational" polymers that might have populated these pre-RNA World(s). 

Role of co-solutes on information transfer in an RNA World

We are also interested in understanding how functional informational sequences (capable of catalysis), when once formed, might have efficiently replicated their information on prebiotic Earth despite high intrinsic mutation rates, which is a hallmark of nonenzymatic replication mechanisms.  We started out by characterizing the role of prebiotically relevant co-solutes on the process of prebiotic replication. For an RNA molecule that evolved catalytic property, it is crucial that it replicated this information faithfully in an early RNA World. Previous studies that characterized nonenzymatic replication rates were carried out in solution phase, without the addition of any co-solutes. This is unrealistic as prebiotic soup would have been a solution containing a mixture of many different molecules, rather than being a concentrated solution of only certain kinds of molecules. Thus, it is critical to consider this while studying enzyme-free replication, as the addition of correct or incorrect monomers could get exaggerated by concentration effect, resulting from molecular crowding in such scenarios. This would increase the concentration of otherwise diluted molecules, which will potentially have important consequences for nonenzymatic replication fidelity in such scenarios. Therefore, in this project, we are delineating the role of molecular crowding on template-directed primer extension reactions.  Our research in this regard indicates a very intriguing effect playing out in these scenarios, which is increasing the overall error rate associated with such replication. Consequently, this research has important implications for understanding the role of replication fidelity, mutation rate and replication kinetics on the exploration of sequence space 

Evolution of the Lipid World and Protocell formation

The ubiquitous nature of bilayer in contemporary cellular life, and the importance of compartmentalization to separate the internal components from the outside environment, highlight the fundamental role of amphiphilic membranes in the emergence of life. The ability of simple amphiphiles to assemble into cell-like structures, and their presence on the early Earth, suggests their potential role in the origin of cellular life. The precise composition of primitive membranes is still speculative.  Nonetheless, primitive membranes are thought to have been composed of mixtures of single-chain amphiphiles, such as fatty acids and their derivatives. In order to have a better understanding of the physio-chemical properties of such model protocellular membrane systems, we aim to systematically study various mixed single-chain amphiphile membrane systems using different biophysical tools. The physicochemical properties of such membrane would have been largely affected by the environment they are such as pH, temperature, and concentration of ions etc. These constraints would have acted as important prebiotic selection pressures to shape the evolution of prebiological membranes. 

Co-evolution of membrane assembly and non-enzymatic oligomerization processes on early Earth

The ubiquitous nature of bilayer in contemporary cellular life, and the importance of compartmentalization to separate the internal components from the outside environment, highlight the fundamental role of amphiphilic membranes in the emergence of life. The ability of simple amphiphiles to assemble into cell-like structures, and their presence on the early Earth, suggests their potential role in the origin of cellular life. The precise composition of primitive membranes is still speculative.  Nonetheless, primitive membranes are thought to have been composed of mixtures of single-chain amphiphiles, such as fatty acids and their derivatives. In order to have a better understanding of the physio-chemical properties of such model protocellular membrane systems, we aim to systematically study various mixed single-chain amphiphile membrane systems using different biophysical tools. The physicochemical properties of such membrane would have been largely affected by the environment they are such as pH, temperature, and concentration of ions etc. These constraints would have acted as important prebiotic selection pressures to shape the evolution of prebiological membranes. 

Two processes are thought to have driven the early stages of protocell formation, namely, membrane assembly from prebiotically relevant amphiphiles, and the non-enzymatic oligomerization of amino acids and nucleotides. Given that the starting monomers of aforementioned processes would have coexisted in a prebiotic soup, it is important to discern a possible synergy (if any) between these processes, under the geochemical settings like hot springs, which are considered to be prevalent on early Earth. Our systematic efforts to delineate the possible interplay between membrane assembly and non-enzymatic oligomer synthesis follows a bipartite approach: 1. Studying aforesaid processes under simulated hot spring-like conditions in the laboratory and 2. Validating these results in actual hot spring water samples collected from early Earth analogue sites.