It’s a question researchers have chased for decades, within different laboratories and across different fields: How did life begin?
For researcher Saurja DasGupta, assistant professor in the Department of Chemistry & Biochemistry at the University of Notre Dame, the quest for discovery is nearly as exciting as the possible results. The aim of his lab isn’t to make new drugs or cure diseases, but it’s to recreate the first flickers of life from non-living matter, to simulate the moment when the laws of physics and chemistry gave rise to biology.
“I’ve always been fascinated by origins; I think we all agree that origins questions are the most interesting questions, but often the hardest to answer,” DasGupta said. “Once something has emerged, you can study it. But how something emerged is such a big mystery.”
While a graduate student at the University of Chicago, DasGupta studied a class of ribonucleic acids (RNA) that can function as enzymes. RNA is a single-stranded molecule that stores genetic information, and carries the genetic messages from deoxyribonucleic acid (DNA) to make proteins. But the RNAs DasGupta studied function as enzymes, carrying out biological transformations. There are not many RNA enzymes in biology today.
DasGupta tried to solve their structures to determine their function.
“Because if you know what the structure of something is—like if you know the difference between a hammer and a screwdriver—you would be able to intuit what it does just by looking at it,” he said, adding that the philosophy works the same with RNAs.
Four billion years ago, life was much simpler than today. Even bacterial cells, which most consider to be simple forms of life, are complex systems, and likely were not the “beginnings” of life because the true genesis of life had to be simpler, DasGupta said. Even the enzymes in our cells that are made of proteins are complex, and made by much more complex machines called ribosomes.
Therefore, it is unlikely that there were proteins when life first emerged. But life needs enzymes to catalyze biochemical transformations, so the earliest enzymes were likely made of something else.
“So what was the molecule that did that?” DasGupta asked. “Perhaps RNA, which is a much simpler molecule.”
At his laboratory at Notre Dame, where he became a faculty member in 2024, DasGupta cannot go back in time to see ancient RNA in action. However, he can recreate the scene. His laboratory has developed a synthetic, model cell-like system, and has generated a collection of RNA enzymes, or ribozymes, that possibly would have catalyzed important steps during the origins of life. He and members of his laboratory, including postdoctoral scholar Annyesha Biswas, aim to inject the ribozymes inside the model cell systems to make them grow and divide like living cells do. But before they can do that, they “grow” these ribozymes in the lab using a technique known as test-tube evolution.
“So ultimately, if you are an RNA-based life form, you would want to make more RNA, obviously,” DasGupta said. “And the way to make more RNA is to take short pieces and stitch them together.”
The laboratory has successfully evolved a menagerie of ribozymes that do just that—make longer RNAs from shorter pieces. The results were even more surprising, Biswas described: Though the ribozymes were doing the same ligation reaction—where the RNA enzyme joins two RNA fragments together—they were using different biochemical reaction pathways to do this.
These reactions have not been reported before, DasGupta said. Although they evolved under artificially constrained conditions in a laboratory, the process shows how fluid the reactions can become.
“Imagine things happening outside in nature, where there are no scientists who are controlling the conditions,” DasGupta said. “Everything is leaky and more forgiving, right? So then you can imagine how diverse RNA enzymes could have been made by nature.”
Though the research is fundamental, and demonstrates how the essential components of life such as RNA could have emerged from simple building blocks, and how that could have ultimately led to the origin of life, learning about all aspects of RNA may lead to new medicines and other therapeutics, Biswas said.
Like all basic science, researchers might not be able to predict where or how their work will be applied. Consider a typical timeline: Messenger RNA (mRNA) was discovered in 1961, ribozymes were identified in 1982, a technique to make RNA in the lab using enzymes was invented in 1987, the first mRNA vaccine was approved for use in humans in 2013 (for prostate cancer), and the technology became widespread after the Covid-19 pandemic swept the world in 2020.
Why study the origins of life? It’s something that DasGupta said he is asked frequently. Notre Dame’s willingness to explore this area brought him to the University, he said, and he was pleased the College of Science was willing to explore “big questions.” People want to know what his research will do to move society forward.
“Including my parents!” he said, and laughed. “And I say, like, why is a Picasso important? It’s not going to feed anyone or cure cancer, but it’s important because art is part of the human condition. Discovering the origins of life is important for the human condition, because we all want to figure out where we came from.
“I think it’s really the ultimate triumph of science.”
Deanna Csomo Ferrell is Sr. Assistant Director of Marketing Communications in the College of Science, and editor of Catalyst.