The accelerated evolution engine known as T7-ORACLE has revolutionized the field of medicine and biotechnology by allowing researchers to evolve proteins with new or improved functions at an unprecedented rate. This breakthrough was achieved by Scripps Research scientists who have developed a synthetic biology platform that enables continuous evolution inside cells without damaging the cell’s genome.

Directed evolution is a laboratory process where mutations are introduced, and variants with improved function are selected over multiple cycles. Traditional methods require labor-intensive steps and can take weeks or more to complete. In contrast, T7-ORACLE accelerates this process by enabling simultaneous mutation and selection with each round of cell division, making it possible to evolve proteins continuously and precisely inside cells.

T7-ORACLE circumvents the bottlenecks associated with traditional approaches by engineering E. coli bacteria to host a second, artificial DNA replication system derived from bacteriophage T7. This allows for continuous hypermutation and accelerated evolution of biomacromolecules, making it possible to evolve proteins in days instead of months.

To demonstrate the power of T7-ORACLE, researchers inserted a common antibiotic resistance gene into the system and exposed E. coli cells to escalating doses of various antibiotics. In less than a week, the system evolved versions of the enzyme that could resist antibiotic levels up to 5,000 times higher than the original.

The broader potential of T7-ORACLE lies in its adaptability as a platform for protein engineering. Scientists can insert genes from humans, viruses, or other sources into plasmids and introduce them into E. coli cells, which are then mutated by T7-ORACLE to generate variant proteins that can be screened or selected for improved function.

This could help scientists more rapidly evolve antibodies to target specific cancers, evolve more effective therapeutic enzymes, and design proteases that target proteins involved in cancer and neurodegenerative disease. The system’s ease of implementation, combined with its scalability, makes it a valuable tool for advancing synthetic biology.

The research team is currently focused on evolving human-derived enzymes for therapeutic use and tailoring proteases to recognize specific cancer-related protein sequences. In the future, they aim to explore the possibility of evolving polymerases that can replicate entirely unnatural nucleic acids, opening up possibilities in synthetic genomics.

Scientists at the University at Buffalo have made a groundbreaking discovery that could revolutionize our understanding of brain cell clumps associated with neurodegenerative diseases like Huntington’s and ALS.

For decades, researchers have struggled to understand how these solid-like clusters of RNA form in brain cells, making it challenging to develop effective treatments. The mystery was finally cracked when the University at Buffalo team uncovered that tiny droplets of protein and nucleic acids in cells contribute to the formation of RNA clusters.

But what’s even more remarkable is that the researchers not only figured out how these clusters form but also demonstrated a way to prevent and disassemble them using an engineered strand of RNA known as an antisense oligonucleotide (ASO).

“This is a major breakthrough,” said Priya Banerjee, PhD, associate professor in the Department of Physics at the UB College of Arts and Sciences. “We’re not only able to understand how these clusters form but also find a way to break them apart.”

The team’s study published in Nature Chemistry reveals that RNA-binding protein G3BP1 can prevent cluster formation by binding to sticky RNA molecules, while an ASO can disassemble the existing clusters. The researchers found that ASO’s disassembly abilities are highly tied to its specific sequence, suggesting it can be tailored to target specific repeat RNAs.

“This has significant implications for potential therapeutic applications,” Banerjee said. “We’re excited about the possibilities of using ASOs to develop new treatments for neurodegenerative diseases.”

Banerjee is also exploring RNA’s role in the origin of life, studying whether biomolecular condensates may have protected RNA’s functions as biomolecular catalysts in the harsh prebiotic world.

“It really just shows how RNAs may have evolved to take these different forms of matter, some of which are extremely useful for biological functions and perhaps even life itself – and others that can bring about disease,” Banerjee said.

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A groundbreaking study led by the Universities of Copenhagen and Bristol has made a significant breakthrough in predicting childhood obesity using genetic analysis. The research team, comprising an international collaboration of scientists, has developed a polygenic risk score (PGS) that can accurately identify children at higher genetic risk of developing obesity later in life.

By analyzing data from over five million people, the researchers have created a reliable measure that is associated with adulthood obesity and shows consistent patterns in early childhood. This breakthrough could help identify young children who may benefit from targeted preventative strategies, such as lifestyle interventions, to prevent obesity later in life.

The World Obesity Federation expects more than half of the global population to become overweight or obese by 2035. However, current treatment strategies are not universally available or effective. The new PGS has shown remarkable consistency between genetic risk and body mass index (BMI) before the age of five and through to adulthood.

“What makes this score so powerful is the consistency of associations between the genetic score and BMI before the age of five and through to adulthood,” said Assistant Professor Roelof Smit at the University of Copenhagen, lead author of the research published in Nature Medicine. “Intervening at this point could theoretically make a huge impact.”

The researchers drew on genetic data from over five million people, including consumer DNA testing firm 23andMe, and tested their new PGS against datasets of more than 500,000 people. The results showed that the new PGS was twice as effective as the previous best method at predicting a person’s risk of developing obesity.

Dr Kaitlin Wade, Associate Professor in Epidemiology at the University of Bristol, second author on this paper, said: “Obesity is a major public health issue, with many factors contributing to its development. These findings could help us detect individuals at high risk of developing obesity at an earlier age.”

The research team also investigated the relationship between a person’s genetic risk of obesity and the impact of lifestyle weight loss interventions. They discovered that people with a higher genetic risk of obesity were more responsive to interventions but also regained weight more quickly when the interventions ended.

Despite drawing on a diverse population, the new PGS has limitations, particularly in predicting obesity in people with African ancestry. This highlights the need for further research in more representative groups.

This breakthrough study offers hope for preventing childhood obesity and improving public health outcomes. By identifying young children at higher genetic risk of obesity, healthcare professionals can provide targeted preventative strategies to mitigate this risk. The new PGS represents a significant step forward in our understanding of the complex interplay between genetics and lifestyle factors that contribute to obesity.