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Jacob Witten

Publications and source records attributed to Jacob Witten.

2 recordsLinked to original sources

The Use of Deep Learning in RNA Therapeutic Development.

Ribonucleic acid (RNA)-based therapeutics have emerged as promising methods of disease treatment due to their ability to target the human genome and influence protein production, their versatility, and their relative lack of toxicity compared to other gene therapies. However, the RNA therapeutic design space is extremely large, encompassing multiple variables, including codon identities, secondary structure, and design of specific regions. RNA therapeutic optimization is difficult due to the impracticality of exploring such a vast design space experimentally. To address this limitation, deep learning methods have been employed to optimize RNA therapeutic development. In this review, we examine the application of deep learning models across three key aspects of RNA therapeutic development (RNA structure prediction, CRISPR activity, and RNA delivery), highlighting major contributions in these fields and analyzing how deep learning model architectures could affect model performance. We then discuss challenges associated with using deep learning for RNA therapeutics, such as computational and data limitations. Finally, we offer perspectives on areas for future exploration, such as emerging model architectures and methods of integration with more advanced high-throughput screening techniques. Ultimately, this review provides an overview of how deep learning is used in RNA therapeutic development and how it can evolve in the future.

Deep Learning

NumSimEX: A method using EXX hydrogen exchange mass spectrometry to map the energetics of protein folding landscapes.

Hydrogen exchange mass spectrometry (HXMS) is a powerful tool to understand protein folding pathways and energetics. However, HXMS experiments to date have used exchange conditions termed EX1 or EX2 which limit the information that can be gained compared to the more general EXX exchange regime. If EXX behavior could be understood and analyzed, a single HXMS timecourse on an intact protein could fully map its folding landscape without requiring denaturation. To address this challenge, we developed a numerical simulation method called NumSimEX that models EXX exchange for arbitrarily complex folding pathways. NumSimEx fits protein folding dynamics to experimental HXMS data by iteratively comparing the simulated and experimental timecourses, allowing for determination of both kinetic and thermodynamic protein folding parameters. After analytically verifying NumSimEX's accuracy, we demonstrated its power on HXMS data from beta-2 microglobulin (β2M), a protein involved in dialysis-related amyloidosis. In particular, using NumSimEX, we identified three-state kinetics that near-perfectly matched experimental observation. This proof-of-principle application of NumSimEX sets the stage for harnessing HXMS to expand our understanding of proteins currently excluded from traditional protein folding methods. NumSimEX is freely available at https://github.com/JaswalLab/NumSimEX_Public.

Protein Folding