Author: Xavier Larkin

Join the Duke Center for Quantitative Biodesign on Friday, April 18, 2025 as we welcome our last guest speaker for the Spring 2025 semester, Dr. Bowen Li, where he will be discussing  ” AI-Driven Design of Lipid Nanoparticles for mRNA Delivery.”

Bio: Bowen Li is an Assistant Professor at the Leslie Dan Faculty of Pharmacy, University of Toronto, and an Affiliate Scientist at the Princess Margaret Cancer Centre. He holds the Tier 2 Canada Research Chair in RNA Vaccines and Therapeutics and the GSK Chair in Pharmaceutics and Drug Delivery. Dr. Li earned his Ph.D. in Bioengineering from the University of Washington in Seattle and completed a postdoctoral fellowship under Profs. Bob Langer and Daniel Anderson at MIT. His lab employs interdisciplinary approaches—including biomolecular engineering, combinatorial chemistry, autonomous high-throughput platforms, and machine learning—to develop next-generation delivery systems for nucleic acid medicines. Dr. Li’s work has resulted in over 60 publications in leading journals such as Nature Biotechnology, Nature Materials, Nature Biomedical Engineering, Nature Medicine, Nature Communications, PNAS, and Science Advances, as well as ten patents. His research has been recognized with numerous prestigious awards, including the AAPS Emerging Leader Award, Biomaterials Science Emerging Investigator Award, CSPS Early Career Award, Cystic Fibrosis Canada – Marsha Morton Early Career Investigator Award, ACS Rising Star in Biological, Medicinal, and Pharmaceutical Chemistry, Gairdner Early Career Investigator Award, J.P. Bickell Medical Research Award, and Connaught New Researcher Award.

Abstract: Achieving effective functional delivery to specific cell types within targeted tissues is critical for unlocking the therapeutic potential of nucleic acid medicines. Despite significant advancements in mRNA vaccines, the optimal chemical and formulation composition of lipid nanoparticles (LNPs) for extrahepatic nucleic acid delivery remains poorly understood. Traditional approaches to lipid and formulation development are hindered by the complexity of biological systems and a lack of comprehensive historical data. In this talk, I will present an AI-driven self-driving laboratory (SDL) developed to overcome these challenges. At the core of this platform is a molecular foundation model utilizing few-shot learning to efficiently explore vast chemical spaces for designing ionizable lipids and predicting their suitability for assembling into LNPs for mRNA delivery. The SDL combines automated high-throughput synthesis and screening of thousands of chemically diverse lipid-like materials, enabling the discovery of structure-function relationships critical to improving mRNA delivery performance. This AI-driven approach identified potent LNPs with exceptional mRNA transfection efficiency, validated in vitro and in vivo, showcasing the platform’s potential to advance delivery systems and thus facilitate the development of nucleic acid therapeutics.

Join the CQB on Friday, March 21, 2025 from 3-4:00 pm in Wilkinson 021 as we hear from our next guest speaker, Dr. Ron Dror, Professor of Computer Science at Sanford University as he will be discussing, ” Discovering Safe, Effective Drugs via Machine Learning and Simulation of 3D Structure.”

Bio: Ron Dror is the Cheriton Family Professor of Computer Science in the Stanford Artificial Intelligence Lab and a professor, by courtesy, of Structural Biology and of Molecular and Cellular Physiology at the Stanford School of Medicine. He leads a research group that uses molecular simulation and machine learning to elucidate biomolecular structure, dynamics, and function, and to guide the development of more effective medicines. He collaborates extensively with experimentalists in both academia and industry. Before moving to Stanford, he served as second-in-command of D. E. Shaw Research, a hundred-person company, having joined as its first hire. Dr. Dror earned a PhD in Electrical Engineering and Computer Science at MIT and an MPhil in Biological Sciences as a Churchill Scholar at the University of Cambridge.

Abstract: Recent years have seen dramatic advances in both experimental determination and computational prediction of macromolecular structures. These structures hold great promise for the discovery of highly effective drugs with minimal side effects, but structure-based design of such drugs remains challenging. I will describe recent progress toward this goal, using both atomic-level molecular simulations and machine learning on three-dimensional structures.

Our third guest speaker for this semester is Dr. Rodrigo Reyes. Dr. Reyes obtained his BSc in Biology from the National Autonomous University of Mexico, followed by an MSc at Concordia University (Montreal) under the supervision of Prof. Elaine Newman, where he studied bacterial cell division. He earned his PhD in Biochemistry from the University of Oxford (UK), working with Prof. David Sherratt studying DNA replication and chromosome segregation in bacteria. He subsequently held a Todd-Bird Junior Research Fellowship (New College, Oxford), allowing him to continue as a postdoctoral researcher for three additional years.

In 2013, Rodrigo joined the Department of Biology at McGill University, where he is currently an Associate Professor. His laboratory focuses on leveraging recent advancements in microscopy to uncover the mechanistic links between DNA replication and genome integrity. Central to his work is the use of live-cell single-molecule microscopy to characterize the dynamic activities of proteins involved in DNA replication, DNA repair and chromosome segregation in bacteria, budding yeast, and human cells.

Abstract: This seminar will explore two themes in cellular regulation and genome integrity. First, I will present findings from single-molecule microscopy studies that reveal the mechanisms and functional advantages of subunit turnover within the bacterial replisome, highlighting its critical role in maintaining genome stability. Second, I will discuss how dynamic interactions between transcription factors and chromatin serve as a sensor for cell size, orchestrating the start of the cell cycle in yeast. Together, these studies shed light on fundamental processes that safeguard genetic information and regulate cell division across domains of life.

Join the CQB for our seminar series, featuring our second guest speaker of the semester: Dr. Shriya S. Srinivasan

Abstract:

The gut-brain axis is an exciting frontier in science. This complex communication network influences everything from mood and cognition to immune responses, emphasizing our gut’s key role in overall health. For many, diseases like gastroparesis and ileus disrupt the normal digestive process, leading to debilitating symptoms and impacting quality of life. These conditions hamper the natural rhythm of the gut, affecting the body’s energy balance and comfort.

Innovative neural interfaces are reshaping treatment by seamlessly interacting with the gut’s nervous system. These devices use precise electrical and mechanostimulation to engage with specific neural pathways, restoring digestive movements and optimizing organ function. By stimulating the nerves of the GI tract, they can restart peristalsis and even simulate sensations like fullness to modulate hunger and satiety.  Explore the design of ingestible neural interfaces to sense, monitor, and treat the gut.

Join the CQB & DMI for a special seminar with Dr. Yongshae Shin. Dr. Shin is an Associate Professor in the Department of Mechanical Engineering at Seoul National University, and an Adjunct Professor in the Interdisciplinary Program in Bioengineering and Department of Biological Sciences. The focus of Prof. Shin’s group research is to understand and engineer self-organization processes in living systems. Of particular interest are biomolecular condensation, especially its biophysical mechanisms and physiological functions. For this, he combines multiple approaches including single-molecule resolution quantitative imaging, reconstitution of biomolecular condensates both in test tube and in cellulo, and optogenetic manipulation of biological phase separation. He received his BS in Mechanical and Aerospace Engineering from Seoul National University, and MS/PhD degrees in Mechanical Engineering from Massachusetts Institute of Technology. He then went on to Princeton University as a Postdoctoral Research Associate in the Department of Chemical and Biological Engineering. He was selected as the World Economic Forum Young Scientist in 2019.

Abstract: Biomolecular condensates represent a condensed state of living matter, widely observed in various cellular processes. Condensates are composed of a set of distinct molecular components, organizing diverse biochemical reactions. How condensate function emerges from the collective interactions of its components remains elusive. In this talk, I will discuss our ongoing efforts to study the biophysical basis of condensate-driven cellular functions. I will first introduce density as a key parameter that can impact condensate function. Using refractive-index imaging, we uncovered that intracellular condensates exhibit a broad range of density, where RNA plays a key regulatory role in lowering condensate density. I will then switch to the second topic probing the effect of RNA condensation on translation activity. Using optogenetic cellular reconstitution, we found that condensation itself provides suppressive microenvironments for mRNA translation, and solidifying condensates further inhibits translation activities. Our works highlight an intimate link between the physical properties of condensates and associated biochemical functions.

Join the CQB for our last seminar series of the Fall 2024 semester on Friday, December 6, 2024 from 3-4:00 pm in Wilkinson 021.  We will be hearing from our guest speaker, Dr. Jim Pfaendtner.

Jim Pfaendtner is the Louis Martin-Vega Dean of Engineering at NC State University. Previously, Pfaendtner served as chair of the Department of Chemical Engineering at the University of Washington. His research focuses on using computer simulations to understand molecular behavior for applications in biotechnology and advanced materials. Pfaendtner earned his B.S. in chemical engineering from Georgia Tech and his Ph.D. from Northwestern University.

Abstract:

Peptoids, or n-substitued glycines, are complex and diverse oligomeric structures which have been explored for a number of biomimetic applications including drug delivery, surfactants, and catalysts. In contrast to their peptide counterparts, on peptoids the sidechain is bonded to the backbone nitrogen resulting in a flexible omega backbone dihedral that is able to isomerize into both stable cis- and trans- backbone conformations. This unique feature of peptoids allows for these structures to potentially span a significantly larger configurational space of chemical and structural functionality through the careful tuning of their side chains. This vast chemical and structural space has created significant challenges for rational design of new structures and functions as the underlying molecular scale driving forces that give rise to sequence/structure/function relationships have proven difficult to uncover.

This talk will highlight recent developments from our group in the use of statistical mechanical tools to accelerate molecular simulations of rare events like peptoid folding, aggregation and adsorption on inorganic surfaces. The first part of the talk focuses on studies of peptoid folding. Peptoids can freely explore a 12-dimensional helical configurational space with stabilization dictated largely by interactions between sidechains. I will discuss the thermodynamic basis of helix stabilization by chiral sidechains as well as fundamental aspects of the simulation science and the role of solvent in folding. Implications for rational design of higher order (tertiary structures) will be discussed. The remainder of the talk focuses on the use of peptoids in biomineralization. We discuss the rational design of peptoid mimics of the well-known R5/silaffin system, compare their nanoscale properties with peptides, and highlight experimental findings showing the efficacy of peptoids in biomineralization applications as well as similarities and differences between the peptoid and peptide systems. If available time remains, I will briefly discuss our group’s use of machine learning models to assist in high throughput screening towards inverse design of new sequences that precisely tune surface adsorption energies for biomolecules.

Join the Duke Center for Quantitative Biodesign on Friday, November 8, 2024 from 3-4:00 pm in Wilkinson 021 as we hear from our next guest speaker, Dr. Theresa M. Reineke.

Dr. Reineke is the Prager Endowed Chair in Macromolecular Science and a Distinguished McKnight University Professor in the Department of Chemistry at the University of Minnesota. She also holds graduate faculty appointments in the Departments of Chemical Engineering/Materials Science and Pharmaceutics. She received a B.S. Degree from the University of Wisconsin-Eau Claire, a M.S. Degree from Arizona State University, and a Ph.D. from the University of Michigan. She then received a National Institutes of Health Postdoctoral Research Fellowship for her work in gene therapy at the California Institute of Technology prior to beginning her independent faculty career.

Her research group is focused on enabling fundamental and applied technology advancements in the fields of macromolecules for nucleic acid delivery and gene editing, oral delivery of therapeutics, and sustainability. She has published over 200 peer-reviewed manuscripts and patents and manages a large group of researchers supported by several corporate, private and national funding agencies. Reineke is a Fellow of the American Chemical Society, Royal Society of Chemistry, along with the Kavli and Alfred P. Sloan Foundations. She has received numerous awards, including in the 2005 National Science Foundation CAREER and Beckman Foundation Young Investigator Awards, 2008 Camille and Henry Dreyfus Teacher-Scholar Award, 2009 National Institutes of Health Director’s New Innovator Award, 2012 Outstanding New Investigator Award from the American Society of Gene and Cell Therapy, 2017 Carl S. Marvel Creative Polymer Chemistry Award from the American Chemical Society Division of Polymer Chemistry, 2018 DuPont Nutrition and Health Sciences Excellence Medal, and 2022 Arthur C. Cope Scholar Award from the American Chemical Society. Reineke has also served for 11 years as an Associate Editor for the journals ACS MacroLetters and Chemical Science and in 2023 became Editor-in Chief of Bioconjugate Chemistry. Further, Reineke has cofounded three biotech companies in the field of nucleic acid delivery: Techulon, Inc., Nanite, Inc., and LiberateBio, Inc.

Join the Duke Center for Quantitative Biodesign on Friday, October 4, 2024 at 3:00 pm in Wilkinson 021. Our guest speaker, Dr. Alex Holehouse, is an Assistant Professor of Biochemistry and Molecular Biophysics at Washington University in St. Louis School of Medicine, where he will be discussing “Mapping from sequence to function in intrinsically disordered regions.”

The Holehouse Lab studies how biological function is encoded into intrinsically disordered proteins and how this goes wrong in disease. They use a combination of physics-based models, bioinformatics, deep learning, and quantitative cell biology.

Bio:  Alex received his Ph.D. Washington University in St. Louis, Computational Biophysics in 2017,  MsC. From Imperial College London, Computer Science in 2011, and his MBioch from University of Oxford, Molecular & Cellular Biochemistry in 2010.

Abstract:Intrinsically disordered protein regions (IDRs) are ubiquitous across all life kingdoms and play various essential cellular roles. Unlike folded domains, which are well-described by one or a small number of structurally similar states, IDRs exist in a collection of structurally distinct conformers known as an ensemble. While IDRs are ‘disordered’, they are not ‘unstructured’ – sequence-specific effects influence intra- and inter-molecular interactions that ultimately dictate biological function. Here, we will discuss recent advances that combine chemical physics, informatics, and deep learning to infer biologically important functions directly from sequence. These approaches offer opportunities for understanding IDR evolution, interpretation of disease-associated variants of unknown significance, and rationally designing functional IDRs with specific functional properties.