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Recreating the lost RNA World of primordial life
Illuminating the hidden RNA World of modern life
RESEARCH GOALS
RESEARCH GOALS
We want to understand RNA at its most fundamental - its past in ushering the Origin of life by converting chemistry to biology, its present roles in biology, and its future applications as tools to understand biology.
RNA plays crucial roles in biology and its significance continues to grow as new discoveries are made. The DasGupta Lab focuses on a holistic exploration of RNA. We investigate RNA structure, function, and evolution. We are deeply interested in a special class of RNA molecules that show catalytic activity, called ribozymes. We will use biochemistry, high-throughput sequencing, and structural biology approaches to understand how ribozymes catalyze chemical reactions when most RNAs do not. We are also interested in the evolutionary processes that allow RNA molecules to adapt to new functions like enzyme catalysis or ligand binding (in aptamers). We routinely use combinatorial techniques like in vitro selection and directed evolution to discover RNAs de novo that perform functions not found in biology.
In addition to its many biological roles, RNA bears a profound weight of biological history. It is widely accepted that the earliest forms of life on Earth (~3.8 bya) used RNA to constitute their genomes and as enzymes. Understanding the biochemical capabilities of RNA is, therefore, crucial for unraveling the mysteries surrounding life's origins and advancing our knowledge of early evolutionary processes. We aim to create synthetic models of the earliest cells that show life-like behaviors such as growth, division, competition, and ultimately Darwinian evolution to understand how life emerged from nonliving matter. These studies will reveal fundamental physical and chemical principles underlying biology. We are also using evolutionary approaches to develop RNA-based technologies to probe largely unexplored areas of RNA biology and analytical chemistry. This includes generating reagents to interrogate the biologies of RNA cleavage and non-canonical RNA capping, and creating aptamer-based biosensors. In the future, we hope to expand our research into studying non-natural nucleic acids.
The origin of life is one of the hardest problems in science. How did a chaotic collection of chemicals assemble into the organized life we see all around us? We think RNA holds the clue to this mysterious transmutation of Chemistry to Biology. RNA has a unique ability to carry genetic information and catalyze chemical reactions, which led to the formulation of the RNA World hypothesis, which posits that primordial life used RNA to constitute its genomes and as enzymes (ribozymes). We are expanding the catalytic repertoire of ribozymes using test-tube evolution and aim to use these ribozymes to power models of RNA-based primordial cellular life that exhibit life-like properties such as replication, growth, division, competition, and evolution. Let there be Life!
The Hidden RNA World
The Hidden RNA World
RNA plays key roles in nearly all cellular processes. RNA biology has been revolutionized by next-generation sequencing (NGS), allowing us to look at thousands of RNAs at once. During library preparation for NGS, target RNAs are ligated to sequencing adapters, reverse transcribed, and PCR amplified. Adapter ligation requires the target RNAs to contain 5' monophosphate groups and 3' hydroxyl groups making RNAs with terminal modifications incompatible with NGS. Consequently, cellular RNAs containing modified termini remain hidden, and the related metabolic pathways remain undiscovered. We are developing a suite of catalytic RNA reagents to capture and sequence RNAs containing specific 5′ and 3′ modifications, with unprecedented specificity. These new technologies will illuminate hidden portions of cellular transcriptomes, generating new knowledge about their architectures, biogenesis, and functions.
RNA Biosensors
RNA Biosensors
RNA can fold into complex 3-dimensional structures that allow it to bind small molecules like dyes. We are leveraging structural changes in RNA to create fluorogenic RNA aptamers that bind dyes that are non-fluorescent by themselves, but emit strong fluorescence when bound to the RNA. We are currently focusing on developing RNA biosensors for environmental monitoring. We have built highly sensitive and selective fluorescence-baaed sensing platforms for lead and mercury detection. We aim to expand this to other toxic heavy metals like copper and cadmium. We are also working to integrate our RNA biosensors with paper microfluidic devices for rapid point-of-care environmental monitoring.
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