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Tools & Techniques Genetics, Analytical science, Diagnostics & prognostics

Catching the Thermodynamic Express

The current standard for analyzing thermodynamic behavior of DNA or RNA – melting curve analysis – can take months. A new method developed by US researchers promises to slash the time needed to hours – and boost accuracy to boot (1). We spoke with David Zhang, Head of the Nucleic Acid Bioengineering laboratory at Rice University’s BioScience Research Collaborative, to find out more.

Why did you focus on finding a faster way to do thermal analyses?

We needed better parameters to design primers and probes for pathogenic DNA and RNA sequences. The current methods give a standard error of around 3 kcal/mol, which requires further empirical optimization, taking up significant time and money.

At first, we thought that maybe someone in industry had already done the work, but after extended discussions with partners at Integrated DNA Technologies and at Cepheid, we realized this is not the case. It’s been around 15 years since someone last did DNA characterizations, so we figured that unless we did the work, no one else would.

What has been the reaction?

The attitude of academic researchers we’ve spoken to is “cautious optimism.” In this work, we laid out a new method and used the method to obtain some new parameters, but to really improve DNA primer design, RNA folding, and so on, we’ll need a lot more parameters. It’s like a leaky ship... There are many holes that you need to patch to get it watertight – and patching up just one hole doesn’t bring much obvious improvement. Right now, we patched up one hole (DNA dangles) and we are working on a few others (DNA bulges and mismatches), but it’ll be a while until we’re comprehensive enough that there are major benefits to the research and biotechnology communities.

Tell us about your proposed “thermodynamic database”.

John Fang, one of the graduate students in the lab, is leading our efforts in this area, developing a software package we call “NABTools”. So far, we have built and launched several tools for DNA probe design and formulation, and we are working on a nucleic acid hybridization evaluator that allows users to visualize the structure and binding of primers to genomic DNA or RNA, with a graphical user interaction that allows dynamic changes in the primer sequence or structure.  NABTools Evaluator is close to completion, and we are excited to enable researchers and students to better design DNA reagents for the study of nucleic acids.

Why did you choose not to seek a patent?

As a lab, we seek to maximize our impact on the research community and on society in general. In some cases, such as our more applied technologies on rare allele PCR, seeking a patent increases the motivation for industry partners to build from our work. In other cases, such as the current work on nucleic acid thermodynamics, keeping the methods in the public domain will have a greater impact.

What’s next?

My lab is committed to the basic biophysical study of nucleic acids, because it really is the foundation of any applied work on DNA analytic and diagnostic assays. Just as shaky foundations will limit the height of a skyscraper, robust DNA biophysics knowledge is absolutely necessary as our society pursues precision medicine in which DNA molecular information is used to guide clinical treatment.

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  1. C Wang et al., “Native characterization of nucleic acid motif thermodynamics via non-covalent catalysis”, Nat Commun, 7 (2016).
About the Author
David Zhang

Head of the Nucleic Acid Bioengineering Laboratory at Rice University’s BioScience Research Collaborative.

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