For his work in developing Record-seq, a breakthrough technology that records the activities of microbiota in the gut noninvasively and furthers the understanding of gastrointestinal health, Florian Schmidt is the grand prize winner of the 2022 Science & SciLifeLab Prize for Young Scientists.
Schmidt's essay describes engineering cells of Escherichia coli (E. coli ), a bacterium commonly found in the human gut, to act as sentinels that travel through the gastrointestinal tract and record in their DNA the transcriptional response to varied interactions between themselves and the host. Unlike RNA, which is relatively short-lived and fragile, the DNA produced by the E. coli sentinel cells records information from various time points that can be efficiently and noninvasively recovered by deep sequencing from host feces.
"Schmidt's work is highly creative and a technical landmark. Following a path from concept to realization, his research has led to the development of a unique method that allows bacterial sensor cells to detect changes in the gut of their host. Tracking the response to interactions between different microbiota and the host could greatly improve our understanding of the influence of the microbiome on health and disease," said Sacha Vignieri, deputy editor at Science.
Intrigued by the thought of repurposing the adaptive microbial immune system CRISPR, Schmidt and his colleagues leveraged the CRISPR spacer acquisition complex to develop Record-seq, adapting it to store and record transcriptional responses as DNA to report on conditions within the intestine.
Creating the Best Method
As a new technology, Record-seq was not originally intended as a noninvasive tool to interrogate the gut microbiome, Schmidt said. But once its full potential for recording the cellular histories of bacteria was discovered, he and his colleagues Tanmay Tanna and Jakob Zimmermann from the laboratories of Randall Platt at ETH Zürich and Andrew Macpherson at Bern University Hospital worked to start applying Record-seq to the gut microbiome.
Current methods to investigate intestinal tracts involve invasive surgeries to measure the activity of the intestine, or stool- and blood-based tests that do not report on specific conditions within the intestine. Record-seq-derived E. coli cells introduce a lens into proximal sections of the intestine and the adaptations and behavior of the microbiota so they can be investigated noninvasively.
"Other scientists have previously developed biosensors that can sense the presence of a specific small molecule … yet they are fine-tuned to sense the presence or absence of a small set of molecules, but blind to anything else," Schmidt explained. "With Record-seq, we remove this proverbial blindfold … anything that the bacteria interact with and that changes their behavior could be captured."
Hopefully, researchers can now use Record-seq as a tool to discover new biomarkers relevant to nutrition and disease, Schmidt mentioned. In the future, this may enable further translational efforts in diagnostics and therapeutics.
The Future of Gut Health
Schmidt and his colleagues fed mice these E. coli cells to test the recording of transcriptional information inside the gut. The group was able to recover this information by DNA-sequencing cells from the feces of the mice, prompting the researchers to alter the diets of the mice to test the intricacies of what was being recorded.
Record-seq was able to capture distinct adaptations of E. coli to different diets and to retain this information. Whereas both RNA-sequencing (RNA-seq) and Record-seq could distinguish between a standard chow or starch diet, only Record-seq retained information of an earlier diet after a switch. Record-seq also retains information over the length of the gastrointestinal tract, whereas much information is lost from fecal RNA-seq samples.
These insights into the hidden lives of microbiota inside the intestine are fascinatingly complex, and Record-seq opens a new window into understanding how nutrition, inflammation, and microbial interactions inside the gastrointestinal tract shape health and disease.
"Think of all the diseases and interactions that involve your gut and also consider that we could use it to investigate how humans interact with their diets. The diversity of ways different individuals respond to different diets is astonishing and also may contribute to pathological conditions like malnutrition or obesity. Record-seq could be deployed to investigate and inform treatment decisions in these diseases as well as food intolerances," Schmidt said.
The Science & SciLifeLab Prize for Young Scientists acknowledges that global economic health is dependent upon a vibrant research community that needs to incentivize the best and brightest to continue in their chosen fields of research as they begin their scientific careers. The grand prize winner receives a prize of $30,000.
"Over the years, what is striking about the winners of the Science & SciLifeLab Prize is their ability to clearly explain their exciting scientific discoveries and place them into the broader context of biology, medicine, and even urgent societal challenges. This is also the case this year, with three essays describing different types of research on microbes and one on the regulation of a protein involved in cell growth in health and disease," said SciLifeLab Director Olli Kallioniemi. "We at SciLifeLab are excited to take part in this award and hope that this recognition will promote the careers of these next-generation research leaders and make their research widely known. Congratulations to all the four winners of this year's prize."
Stefany Moreno-Gámez is a winner for her essay, "How bacteria navigate varying environments." Moreno-Gámez received an undergraduate degree from Universidad de los Andes and a Ph.D. from the University of Groningen and ETH Zürich. She is currently a postdoctoral fellow at the Massachusetts Institute of Technology. Her research focuses on how dietary and host-derived glycans shape ecological and evolutionary dynamics in the gut microbiome.
James L. Daly is a winner for his essay, "Endosomes, receptors, and viruses." Daly received undergraduate and Ph.D. degrees from the University of Bristol. After completing his studies, he received a Wellcome Early Career Award fellowship and moved to the department of infectious diseases, King's College London. His current research continues to explore the molecular interface between neuropilin receptors and viruses and the potential for antiviral inhibition of this process.
Daniele Simoneschi is a winner for his essay, "Uncovering the degrader of D-type cyclins." Simoneschi received an undergraduate degree from Manhattanville College and MPhil and Ph.D. degrees from the Vilcek Institute at New York University. He is a research assistant professor in the department of biochemistry and molecular pharmacology at NYU, where he explores molecular and cellular mechanisms by which cullin-RING ubiquitin ligases regulate cell cycle execution.