Is the Food and Drug Administration taking inconsistent approaches to Duchenne muscular dystrophy drugs? How will a new batch of drug executives shake up their companies? And why is Adam talking to a recruiter?

We discuss all that and more on this week’s episode of “The Readout LOUD,” STAT’s biotech podcast.

Read the rest…

​Read More

The vast majority of proteins in our bodies contain regions that are in a constant state of wiggling, shape-shifting every few nanoseconds to completely change how they look. Information on how these proteins work is critical to understanding health and disease and to developing drugs for cancer, neurodegeneration, and myriad other conditions. However, it has been challenging for scientists to pin down precisely how these regions function, and how they go awry in disease.

Researchers at Washington University School of Medicine in St. Louis and at Syracuse University have now built a tool that can design such “disordered” proteins (intrinsically disordered protein regions; IDRs) and untangle their functionality. The team suggests the innovation has the potential to accelerate scientific exploration of a vast and underexplored area of biology.

Alex Holehouse, PhD, an associate professor in the WashU Medicine Department of Biochemistry and Molecular Physics, is research co-lead and co-corresponding author of the team’s published paper in Nature, titled “Rational design of disordered proteins for sequence–function investigation,” in which they explained, “Our work uses rational sequence design as a powerful method for exploring function in IDRs and provides a versatile tool for designing functional disordered proteins.”

An important way scientists study proteins is to design synthetic equivalents of the molecules that they can then test in various ways. Until now, advances in such protein design have applied almost entirely to “folded” proteins—or their folded parts—that have a defined three-dimensional shape.

Yet 70% of human proteins also contain what’s known as intrinsically disordered protein regions (IDRs) that don’t have a stable 3D structure. “IDRs exist as a dynamic collection of rapidly interconverting and structurally distinct conformations,” the team explained. These regions can play critical roles in a variety of different cellular processes and human diseases. Researchers’ ability to predict how they will behave, or to design synthetic versions to study their function, has been limited. “Despite their importance, systematically testing the relationship between IDR sequence and molecular function remains challenging,” the authors further wrote. “While rational design of folded proteins has seen substantial recent progress, our ability to design IDRs remains more limited.”

Holehouse said, “The way people would typically try to study and design stable, folded proteins doesn’t really work very well for disordered proteins.” He and colleague Ryan Emenecker, PhD, a faculty instructor in the same department and lead developer and co-corresponding author on the study, have been working on an alternative way to tackle this challenge for almost five years.

Holehouse, Emenecker and their collaborators, including co-corresponding author Shahar Sukenik, PhD, a faculty member in the Department of Chemistry at Syracuse University, have now reported on development of the protein-design system, which they called GOOSE (an acronym derived in an appropriately disordered way from Generate disOrdered prOtiens Specifying propErties).

Loaded with a large library of the sequences for protein building blocks that are associated with specific cell functions, GOOSE produces blueprints for custom-built disordered proteins that are then created in genetically engineered cells. Scientists can remove or add building blocks as desired and test what effect they have on the activities of a cell. “GOOSE enables rapid design of de novo synthetic IDRs and variants of provided sequences, facilitating broad exploration of sequence space,” they commented. “GOOSE can design IDRs by sequence properties (such as amino acid composition, charge, hydrophobicity and charge patterning), conformational properties, chemically specific intermolecular interactions or any arbitrary design constraint (such as specific three-dimensional conformational ensembles).”

Emenecker stated, “The ability to design disordered proteins at a large scale with our platform now allows us to learn how their component sequences affect the cell, and it gives us a lens through which we can learn how naturally occurring changes in these proteins might drive diseases like cancer.”

The technique has potential for driving medical advancements. Holehouse, who is a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, is seeking to optimize therapeutics that rely upon disordered proteins. Holehouse and Emenecker have received a grant to improve CAR T cells, an anti-cancer therapy in which immune cells are genetically modified to attack tumor cells.

A key protein on the surface of CAR T cells contains a disordered region that guides the cell’s attack response. Until now, scientific efforts to improve its performance in destroying cancer cells have been conducted largely by trial and error.

“With our technique, we can design better versions of these disordered regions to do the signaling in different ways,” said Holehouse. “The hope is we won’t be limited by the types of constraints that are currently hurting the efficacy of CAR T therapies. That’s a very concrete place where these tools can move medicine forward.”

Among various applications, one of GOOSE’s first tests was to generate synthetic proteins that could help cells respond to changes in external stressors—in this case, drought. “We were able to very quickly design 2,300 different proteins that would respond to drought conditions in yeast,” said Emenecker, who commented that many of these synthetic proteins proved GOOSE’s utility by working as intended, helping the cells’ recovery after drying out. Even more promising, many of them performed much better than the yeast’s natural proteins.

This work directly contributes to Holehouse, Emenecker and Sukenik’s ongoing work as part of a larger National Science Foundation initiative to engineer more environmentally resilient crops.

“More broadly, this opens the possibility of being able to make new sensors that are sensitive to things outside what natural sequences would be attuned to, like toxins or cell damage,” Emenecker said. “It has the potential to be very valuable.” In their paper the team concluded, “Taken together, our work highlights how GOOSE can be used to gain insights into IDR sequence–function relationships.”

The post A Computational Framework for Designing Disordered Proteins at Large Scale appeared first on GEN – Genetic Engineering and Biotechnology News.

Regulators say the telehealth company illegally shared patients’ health data with advertisers and misled its customers. Hims & Hers hit back, calling the claims “baseless.”

​Read More