Scientists have long pondered the beginnings of life on Earth. One theory is that RNA, which is ubiquitous across all domains of life, played a central role in early life. Similar to DNA, RNA possesses the ability to store genetic information. However, to initiate life's processes, early RNA must have also possessed the capability to self-replicate and catalyze biochemical reactions independently, without the assistance of specialized enzymes.

Previously, it was unclear how a molecule this complex could arise without any precursors. However, in a new study published in eLife, Alexei Tkachenko, a physicist at Brookhaven National Laboratory, and Sergei Maslov (CAIM co-leader/CABBI), a professor of bioengineering and physics at the University of Illinois Urbana-Champaign, describe their model that demonstrates how such a molecule could gain functionality.

“RNA is very preserved across all organisms. So, it’s like a smoking gun that RNA has a central point in life,” explained Tkachenko. “The problem is that modern RNA is very finely tuned and complex, so we wanted to see how life might emerge from something much simpler.”

While modern RNA relies on enzymes for replication and catalytic activity, the origins of these enzymes themselves remain a puzzle. However, the discovery of ribozymes, RNA molecules exhibiting enzymatic properties, suggests a plausible pathway for the emergence of early functional polymers.

The challenge lies in understanding how these ancient RNA molecules could have possessed the ability to "cut" other molecules, a crucial step in the replication process of DNA and RNA.

“Experiments have shown that a cleavage ribozyme, which relies on only a handful of conserved bases to do its job, can emerge spontaneously with no prior information, if the experimenter artificially selects for things that cut other things,” said Tkachenko. “The problem is that it's not clear how evolution would select for something that cuts things, essentially selecting for a destructive enzyme.”

To tackle this question, the researchers devised a model simulating basic RNA molecules devoid of enzymatic activity. Within this model, random bond breakage was allowed to occur, mimicking real-world chemical processes. The researchers observed that breakage led to more copies of the polymer that was broken, meaning that molecules capable of self-cleavage would have been favored by evolution due to their ability to replicate.

Maslov illustrated this concept with an analogy, likening the process to cutting an earthworm in half, where both halves regenerate into whole organisms.

“In principle, if you wanted to make many earthworms from one earthworm, you would just start cutting them one by one,” explained Maslov. “The same idea is why cutting would be selected for in RNA, because when it’s cut it regrows itself from individual building blocks. And that was the connection, to explain why the first ribozyme was selected to cut things — because cutting is how RNA exponentially grows.”

But how does catalytic activity arise from such simple beginnings? In a second model, the researchers demonstrated how RNA molecules could evolve into complex ecosystems with functional properties, where different polymers in these ecosystems cleave and replicate each other.

Their model simulated a pool of polymer chains competing for nucleotide "building blocks", and cutting other polymers they encountered. Polymer chains pair in specific ways (such as the A-T nucleotide pairing in modern DNA), and as such, the chains in the simulation formed template and complimentary strands, essentially working together.

“Pairing rules are the basis for how information is preserved and propagated in the future,” said Maslov. “And it’s also important for function, because it gives way to hairpins in the strands that lead to a three-dimensional shape, and these are the ones which are capable of enzymatic activity.”

Polymer replication in the model occurred based on temperature being cycled between hot and cold phases (typical in day-night cycles), suggesting that ancient polymers may have relied on such cycles to grow. Nonorganic surfaces such as rocks may have also facilitated this process.

These findings offer compelling insights into the natural emergence and selection of ribozymes with enzymatic activity, shedding light on a crucial aspect of early life evolution. The researchers advocate for experimental validation of their models to confirm their predictions.

Additionally, they acknowledge the discrepancy between bidirectional growth in their model and the unidirectional growth observed in DNA and RNA replication in real life. Alexei says they plan to continue adjusting the model to see if they can find variations which would result in unidirectional growth.

“It is not a coincidence that Carl Woese, who our genomic institute is named after, used pieces of ribosomal RNA to make his trees of life,” said Maslov. “RNA inside ribosomes is universal to every single organism from bacteria to archaea to eukaryotes like you and me. This paper definitely doesn't solve the problem of origin of life, but it fills a tiny gap in our understanding of how early RNA may have functioned to bring about life.”
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This study was partially funded by U.S. Department of Energy Office of Science and can be found at https://doi.org/10.7554/eLife.91397.3

Living organisms produce a diverse suite of natural products which can be harnessed for medicinal and therapeutic purposes. Among these products, ribosomally synthesized and post-translationally modified peptides, or RiPPs, have garnered increasing attention.

Recently in a new study published in Nature Chemistry, a team of researchers at the University of Illinois Urbana-Champaign uncovered a novel class of hybrid gene clusters, that combines elements of RiPP biosynthesis with enzymes responsible for fatty acid synthesis. They named this newly discovered RiPP hybrid ‘lipoavitide’.

While hybrid gene clusters containing machinery from multiple natural product families are not uncommon in nature, only a few RiPPs have been found to be synthesized by such hybrid machinery. According to Huimin Zhao (BSD theme leader/CABBI/CGD/MMG), Steven L. Miller Chair of Chemical and Biomolecular Engineering at Illinois and anchoring author on the study, hybrid molecules theoretically possess increased versatility and functionality due to their mixed origins from different natural product classes, making them highly sought after.

“We're always interested in looking for novel RiPPs, and by definition, hybrids are novel because they give way to new structures,” said Zhao. “However, even though they occur naturally, they have been rarely studied. There are only three examples in the past that have shown that RiPPs can actually be fused with another class of natural products’ biosynthetic machinery to make hybrid compounds.”

Using advanced bioinformatics tools, the researchers first identified RiPP gene clusters of interest within Streptomyces bacteria. They then looked within these clusters for additional genes associated with other classes of natural products. Ultimately, they identified a cluster that included a gene linked to fatty acid biosynthesis.

The researchers then employed a method called ‘Cas12a assisted precise targeted cloning using in vivo Cre-lox recombination’, or CAPTURE for short, to extract the target DNA fragment containing the gene cluster that encodes the lipoavitide from its native host. The fragment is then cloned and expressed in a more manageable host organism, like Escherichia coli.

Lipoavitides are uniquely amphiphilic, consisting of both a hydrophobic fatty acid and a hydrophilic peptide. This allows them to interact with the membranes of cells, which also have both hydrophobic and hydrophilic components, something that peptide-based RiPPs alone cannot do.

While testing the lipoavitides for bioactivity, Zhao’s team discovered that the fatty acid component of the molecule also allowed for hemolytic activity, the ability to break down the cell walls of blood cells, which could have potential applications in medicine.

Zhao envisions lipoavitides as prototypes for the creation and discovery of other RiPP/fatty acid hybrids. Structural similarities between lipoavitides and other ribosomally synthesized peptides, such as thioamitides (which are used to treat thyroid hyperactivity), indicate further avenues for exploration into their biological functions.

The team hopes that new assays will allow for continued investigation of the bioactivity of these hybrid molecules.
“The challenge in natural product discovery is that we’re limited by the assays we can perform, which can make it hard to find the true application for the natural product,” explained Zhao. “We found that the fatty acid component allows for hemolytic activity, but we don’t know what the exact target of this is. But publishing this work is the first step, and it allows for others to approach us with new tests or assays that might uncover its true bioactivity.”

The discovery and characterization of lipoavitides represent a significant advancement in understanding the biosynthesis of ribosomally derived lipopeptides. Moreover, it opens up promising pathways for leveraging hybrid biosynthetic pathways in drug development, potentially leading to the creation of innovative therapeutics.
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The study was funded by the National Institutes of Health, and can be found at DOI: 10.1038/s41557-024-01491-3

Some animals possess the remarkable ability to regenerate lost structures, exemplified by a lizard regrowing its tail. However, this regenerative process must be tightly regulated by the body to ensure proper tissue organization and to prevent abnormal growths, such as cancer. Yet, the precise mechanisms underlying this regulation are not well known. In a recent study published in PLOS Genetics, researchers at the University of Illinois Urbana-Champaign have identified an RNA-regulator called Brat as a key player in restraining tissue regeneration through its modulation of downstream growth factors.

“There are constraints and protective factors that are important for making sure that regenerating tissue minimizes mistakes, but these haven’t been well studied,” said Rachel Smith-Bolton (GNDP/RBTE), an associate professor and associate head of cell and developmental biology. “When tissue regenerates, such as from a wound, even without any mutations, it sometimes makes mistakes, which I find really interesting. We want to explore what are the mistakes that can happen, and how can you protect against those mistakes.”

The team, led by Smith-Bolton, along with Syeda Nayab Fatima Abidi, a former graduate student in Smith-Bolton’s lab and first author on the study, and Felicity Ting-Yu Hsu, a current graduate student in the lab, investigated the genetic factors influencing regeneration of wing imaginal discs in Drosophila melanogaster, the common fruit fly. Drosophila larvae harbor imaginal discs, which serve as precursors for various appendages like wings, legs, and antennae. The intricate expression of genes within these discs dictates cell fate, or what appendage the cells will become, and the patterning.

Smith-Bolton says the process can be thought of in terms of growing a hand — the cells may be instructed to become fingers, but the patterning is what ensures you don’t end up with 5 thumbs rather than the usual fingers.  

To determine the genes involved in this process, the researchers induced cell death in the wing imaginal discs of fly larvae, resulting in damaged wing discs that subsequently regenerated during development. By comparing wings of adult flies with various mutations to those of control flies, they pinpointed Brat, an mRNA regulator, as a crucial component in regenerative growth. Flies with a mutation that reduced Brat were better able to regenerate their developing wings compared to controls, indicating that Brat specifically works to restrain and control regenerative growth.

“The way fly genes are named is based on the mutant phenotype,” explained Abidi. “Brat gets its full name, Brain Tumor, because in mutants it causes tumors in the brain. This is because it controls whether stem cells are able to differentiate or not. However, there are no stem cells in wing imaginal discs, so it’s interesting that in our results Brat is still essentially performing the same kind of function, controlling whether and how much cells differentiate.”
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While flies with reduced Brat demonstrated improved wing regeneration, this enhancement came with a trade-off: they exhibited a deficiency in bristles and veins within specific wing patches where damage had occurred. According to the researchers, this suggests a misstep in cell-fate specification at the wing margin, attributable to the unrestrained growth facilitated by reduced Brat expression.

Further investigation revealed that Myc, a downstream target of Brat and a growth factor, also plays a pivotal role in this process. Flies with Myc overexpression mirrored the phenotypes observed in Brat-reduced flies, underscoring the delicate balance required for proper regeneration.

“Brat reduces expression of its targets, and because Myc is a target of Brat, overexpressing Myc seems to result in the same phenotype as reducing Brat,” explained Smith-Bolton. “What was really interesting is no matter what we tried, we weren’t able to do the opposite and reduce Myc expression using our normal tools and tricks. This tells us that Myc is probably very tightly regulated in regenerating tissue.”

Hsu's ongoing research focuses on elucidating Myc's role in regeneration and its regulatory mechanisms. In her recent work, she was able to find an existing allele that causes underexpression of Myc in the flies. Surprisingly, this underexpression resulted in similar phenotypes to overexpression of Myc, suggesting a delicate balance in Myc’s expression is needed for proper regeneration.

“This just underscores the fact that you need the right amount of Myc during regeneration or you’re going to get mistakes,” said Smith-Bolton. “And we’re exploring now exactly what that amount is and how it’s regulated.”

Overall, the researchers concluded that Brat appears to act as a protective growth factor, constraining downstream growth factors such as Myc, and preventing errors in cell patterning and cell fate in regenerating tissue.

Given the presence of Brat orthologs — genes with similar function — in various species, including humans, these findings open the door for understanding and potentially manipulating regeneration in human contexts, particularly in curbing uncontrolled growth as seen in cancer.

“Though we didn’t look specifically at cancer, that is definitely the concern when you have a regenerative process that is unchecked, because the potential is that it could develop into a tumor,” said Abidi. “There have to be mechanisms in place that stop the process at the right time so that you are not just getting like a blob of growth, you're getting something that's functional. Uncovering the mutations that lead to unconstrained growth like this is a step towards understanding how those kinds of cancers develop.”
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The study was funded by the National Institutes of Health and the Roy J. Carver Charitable Trust, can be found at https://doi.org/10.1371/journal.pgen.1011103

Recently, the Carl R. Woese Institute for Genomic Biology hosted the third installment of its Genomics for Faith workshop series — a part of the broader Genomics forTM program designed to disseminate scientific knowledge and foster interdisciplinary discussions on emerging scientific technologies with various professional sectors of society.

The Genomics for Faith workshop series, supported by the Wayfarer Foundation, aims to bridge the gap between scientific knowledge and faith-based perspectives. By fostering dialogue and mutual understanding, these workshops serve as a platform for discussing complex scientific topics in the context of different faith perspectives.

Building upon previous discussions on the definition of life and gene-editing technology, the latest workshop, held at the I Hotel, delved into the realm of stem cell research. Stem cells, known for their remarkable capacity to differentiate into various cell types, hold much potential for medical applications. Stem cells can be used to regenerate and repair diseased or damaged tissues, and to create drugs to treat degenerative conditions.

Prior to the workshop, several faith leaders who volunteered to co-lead workshop discussions had the opportunity to tour university labs, and gain firsthand knowledge of stem cell research methodologies and facilities, facilitating informed discussions during the workshop.

Throughout the workshop, participants, including both scientists and faith leaders, engaged in group discussions while enjoying lunch. Expert researchers Sara Pedron-Haba (RBTE) and Haiting Ma, who had met with faith leader discussants prior to the workshop, also joined in the discussions to offer their insights. Pedron-Haba, a research assistant professor of chemical and biomolecular engineering, specializes in the design and implementation of biomaterial platforms to investigate the mechanisms of brain cancer progression and evaluate potential therapies. Ma, an assistant professor of cell and developmental biology, investigates how cells interact with their environments inside the body, including how a cell’s surroundings determine what kind of characteristics it will develop.

To further facilitate discussions, participants were given comprehensive packets containing fundamental scientific information on stem cells, such as the different types, how they are sampled, and their uses in medicine and research.
Throughout the discussions, a consensus emerged that the controversy surrounding stem cell research primarily stems from the sourcing of embryonic stem cells. It became evident that a prevailing misconception in society equates the term "stem cell" with "embryonic stem cell," when in fact stem cells are sourced from numerous adult organs, tissues, and blood as well.

While embryonic stem cells have garnered significantly more attention due to their versatility in medicine compared to other stem cell types, stem cells from alternative sources, such as bone marrow or organs, still offer promising avenues for therapeutic development without ethical dilemmas. Furthermore, stem cells from adult bone marrow and organs are already commonplace in medical treatments today.

Discussions also featured praise for ongoing efforts to bioengineer stem cells by reprogramming adult cells to act like embryonic stem cells, potentially alleviating ethical concerns associated with embryonic stem cell research while advancing medical innovation.

Faith leaders emphasized the crucial role of effective communication in fostering broader acceptance and understanding of stem cell research. Scientists and faith leaders alike agreed that by informing the public on the tangible benefits to society and emphasizing the ethical frameworks guiding their work, scientists can better inform public discourse on and perception of the use of stem cells in research.
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The Genomics for Faith workshop continues to exemplify the power of interdisciplinary dialogue in navigating complex scientific and ethical terrain. By fostering mutual respect and understanding between scientific and faith-based communities, such initiatives pave the way for transformative advancements that benefit humanity as a whole.