New technology supports discovery of new molecules from nature
Our latest research publication reveals how a cutting-edge technique is helping us to rapidly discover fascinating chemical structures.
We have a new research publication resulting from a collaboration between the Quave Lab at Emory University, Nelson Lab at California Institute of Technology, Kubanek Lab at Georgia Institute of Technology, and Tang Lab at the University of California, Los Angeles. The research findings were published in the American Chemical Society journal ACS Central Science. The full article is available through open access (free to the public!) at this link.
David A. Delgadillo, Jessica E. Burch, Lee Joon Kim, Lygia S. de Moraes, Kanji Niwa, Jason Williams, Melody J. Tang, Vincent G. Lavallo, Bhuwan Khatri Chhetri, Christopher G. Jones, Isabel Hernandez Rodriguez, Joshua A. Signore, Lewis Marquez, Riya Bhanushali, Sunmin Woo, Julia Kubanek*, Cassandra Quave*, Yi Tang*, and Hosea M. Nelson*. (2024) High-Throughput Identification of Crystalline Natural Products from Crude Extracts Enabled by Microarray Technology and microED. ACS Central Science DOI: 10.1021/acscentsci.3c01365
This project was made possible by Grant Number R01 AT011990 from the National Center for Complementary and Integrative Health (NCCIH) and the Office of Dietary Supplements (ODS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCIH, ODS, or the National Institutes of Health.
The Challenge of Natural Product Discovery
Discovering new natural products (NPs)—small molecules produced by living organisms—is a very challenging task. NPs are important because they often lead to the development of new medicines. Despite their importance, we've only explored a tiny part of the NPs that exist in the world!
The main challenges in finding and studying new NPs are:
Chemical Complexity of Extracts: NPs need to be extracted from organic matter like plants, fungi, marine organisms, or microorganisms. This organic matter contains hundreds or even thousands of different small molecules, making it tough to isolate just the one molecule we're interested in.
Structural Complexity: NPs often have very complex structures. Understanding these structures requires a lot of detailed analysis using various sophisticated techniques like NMR (Nuclear Magnetic Resonance), FTIR (Fourier-Transform Infrared Spectroscopy), MS (Mass Spectrometry), and X-ray crystallography (based on large, single crystals). These techniques help us determine the exact structure and composition of these molecules.
Need for High-Throughput Techniques: To overcome these challenges, there's a need for advanced, high-throughput methods. These are techniques that can quickly and accurately identify and analyze natural products. Developing such techniques would significantly speed up the process of discovering new natural products and could lead to the development of new drugs more efficiently.
What is MicroED?
MicroED, or Microcrystal Electron Diffraction, is a technique used to determine the structure of very small NP crystals (microcrystals, or a chemical powder). NPs can be challenging to study because they often come in mixed samples with many different molecules and are available only in tiny amounts. Understanding their structures is important drug discovery.
Here's how MicroED helps:
Dealing with Small Samples: Traditional analytical chemistry methods to determine the structure of molecules require relatively large quantities, which can be hard to obtain for NPs. MicroED, on the other hand, can work with nanogram quantities—that's incredibly tiny amounts!
Electron Diffraction Technique: It uses a process called electron diffraction, which involves shooting electrons at the tiny crystals of the natural product. The way these electrons scatter (diffuse) helps scientists like those on our research teams figure out the structure of the molecule.
Major Findings and Advances
Using MicroED for discovering new natural products isn't straightforward. It faces similar challenges as traditional methods, like needing high sample purity and the difficulty of handling many samples at once.
To address these issues, our collaborative research team across four universities have developed a new approach called ArrayED. This method combines MicroED with other technologies:
Transmission Electron Microscopy (TEM): This is a type of microscopy that uses electrons to create an image of the sample. It's used for analyzing the structure of the tiny crystals.
DNA Microarray Technology: This technology is generally used in genetic analysis but here it's used to miniaturize and organize the samples.
In ArrayED, NP samples are prepared in very small droplets and placed on special grids. These grids can then be analyzed all at once in the TEM, allowing for the rapid identification of many different molecules. This method has shown success in identifying the structures of several NPs, including some that couldn't previously be detected or analyzed by traditional methods!
In simple terms, MicroED is a powerful tool for figuring out the structure of very small amounts of complex NPs, and with innovations like ArrayED, it's becoming more efficient and effective in the field of drug discovery and natural product research.
If you would like to support more research like this, please consider a philanthropic donation to the Quave Lab at Emory University. Donations are tax-deductible and can be made on this dedicated Emory Giving page, which ensures all donations go directly to supporting research in my lab. In addition to cash donations, Emory can facilitate gifts of stocks, real estate, or planned giving in estate planning. More information is available at the main Emory Giving website.
The Takeaway
ArrayED is a new method that quickly identifies NPs in crude (highly complex) extracts of plants, fungi, and marine organisms, among other sources. It's highly efficient! In this study, we demonstrated the need for only a small amount of extract to determine the structures of 14 different NPs from 20 extracts! Looking ahead, ArrayED could significantly speed up drug discovery by rapidly linking the structures of natural products with their biological effects, making it a potentially vital tool in identifying new medicines from nature.
If you would like to learn more, please read the full paper, available to the public, here.
Yours in health, Dr. Quave
Cassandra L. Quave, Ph.D. is a scientist, author, speaker, podcast host, wife, mother, explorer, and professor at Emory University School of Medicine. She teaches college courses and leads a group of research scientists studying medicinal plants to find new life-saving drugs from nature. She hosts the Foodie Pharmacology podcast and writes the Nature’s Pharmacy newsletter to share the science behind natural medicines. To support her effort, consider a paid or founding subscription, with founding members receiving an autographed 1st edition hardcover copy of her book, The Plant Hunter.
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A very promising discovery!