Tag Archives: J. Alexander Liddle

Beginner’s guide to folding DNA origami

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I think this Aug. 6, 2010 post, Folding, origami, and shapeshifting and an article with over 50,000 authors is the first time I wrote about DNA (deoxyribonucleic acid) and origami (the Japanese art of paper folding).

Since then, the technique has become even more popular with the result that the US National Institute of Standards and Technology (NIST) has produced a beginner’s guide, according to a Jan. 8, 2021 news item on Nanowerk,

In a technique known as DNA origami, researchers fold long strands of DNA over and over again to construct a variety of tiny 3D structures, including miniature biosensors and drug-delivery containers. Pioneered at the California Institute of Technology in 2006, DNA origami has attracted hundreds of new researchers over the past decade, eager to build receptacles and sensors that could detect and treat disease in the human body, assess the environmental impact of pollutants, and assist in a host of other biological applications.

Although the principles of DNA origami are straightforward, the technique’s tools and methods for designing new structures are not always easy to grasp and have not been well documented. In addition, scientists new to the method have had no single reference they could turn to for the most efficient way of building DNA structures and how to avoid pitfalls that could waste months or even years of research.

That’s why Jacob Majikes and Alex Liddle, researchers at the National Institute of Standards and Technology (NIST) who have studied DNA origami for years, have compiled the first detailed tutorial on the technique. Their comprehensive report provides a step-by-step guide to designing DNA origami nanostructures, using state-of-the-art tools.

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Here’s an image illustrating some of the techniques for DNA origami,

Caption: Collage shows some of the techniques and designs employed in DNA origami. Credit: K. Dill/NIST

A Jan. 8, 2021 US NIST news release (also on EurekAlert), which originated the news item, provide more detail as to the authors’ motivations, objectives, and future plans for their beginner’s guide,

“We wanted to take all the tools that people have developed and put them all in one place, and to explain things that you can’t say in a traditional journal article,” said Majikes. “Review papers might tell you everything that everyone’s done, but they don’t tell you how the people did it. “

DNA origami relies on the ability of complementary base pairs of the DNA molecule to bind to each other. Among DNA’s four bases — adenine (A), cytosine (C), guanine (G) and thymine (T) — A binds with T and G with C. This means that a specific sequence of As, Ts, Cs and Gs will find and bind to its complement.

The binding enables short strands of DNA to act as “staples,” keeping sections of long strands folded or joining separate strands. A typical origami design may require 250 staples. In this way, the DNA can self-assemble into a variety of shapes, forming a nanoscale framework to which an assortment of nanoparticles — many useful in medical treatment, biological research and environmental monitoring — can attach.

The challenges in using DNA origami are twofold, said Majikes. First, researchers are fabricating 3D structures using a foreign language — the base pairs A, G, T and C. In addition, they’re using those base-pair staples to twist and untwist the familiar double helix of DNA molecules so that the strands bend into specific shapes. That can be difficult to design and visualize. Majikes and Liddle urge researchers to strengthen their design intuition by building 3D mock-ups, such as sculptures made with bar magnets, before they start fabrication. These models, which can reveal which aspects of the folding process are critical and which ones are less important, should then be “flattened” into 2D to be compatible with computer-aided design tools for DNA origami, which typically use two-dimensional representations.

DNA folding can be accomplished in a variety of ways, some less efficient than others, noted Majikes. Some strategies, in fact, may be doomed to failure.

“Pointing out things like ‘You could do this, but it’s not a good idea’ — that type of perspective isn’t in a traditional journal article, but because NIST is focused on driving the state of technology in the nation, we’re able to publish this work in the NIST journal,” Majikes said. “I don’t think there’s anywhere else that would have given us the leeway and the time and the person hours to put all this together.”

Liddle and Majikes plan to follow up their work with several additional manuscripts detailing how to successfully fabricate nanoscale devices with DNA.

Here’s a link to and a citation for the beginner’s guide,

DNA Origami Design: A How-To Tutorial by Majikes, Jacob M. and Liddle, J. Alexander. Journal of Research of the National Institute of Standards and Technology Volume 126, Article No. 126001 (2021) Published online Jan. 8, 2021. DOI: 10.6028/jres.126.001

This is open access and it include such gems as this,

1.2 Education or Skill Level

Readers of this tutorial should be familiar with the physical properties of B-DNA, single-stranded DNA (ssDNA), and crossover junctions. In addition, once ready to create a structure for a specific application, the designer should determine the full list of functional requirements. This list includes answers to the following questions: What should the structure do? What specific properties are critical to the system’s performance?

1.3 Prerequisites

The designer should have either sufficient paper for manual design (not recommended) or a design program such as cadnano [1] (all versions sufficient), nanoengineer®, ParaboninSēquio®, or equivalent.1 A registered account with three-dimensional (3D) structure prediction servers such as CanDo [2, 3] is also recommended.

1.4Tools or Equipment

Equipment includes desktop or laptop computer equipment, craft supplies for macroscale models, and DNA nanotechnology computer-aided design (CAD) software.

Feel free to go forth and fold!

Researchers, manufacturers, and administrators need to consider shared quality control challenges to advance the nanoparticle manufacturing industry ‘

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Manufacturing remains a bit of an issue where nanotechnology is concerned due to the difficulties of producing nanoparticles of a consistent size and type,


Electron micrograph showing gallium arsenide nanoparticles of varying shapes and sizes. Such heterogeneity [variation]  can increase costs and limit profits when making nanoparticles into products. A new NIST study recommends that researchers, manufacturers and administrators work together to solve this, and other common problems, in nanoparticle manufacturing. Credit: A. Demotiere, E. Shevchenko/Argonne National Laboratory

The US National Institute of Standards and Technology (NIST) has produced a paper focusing on how nanoparticle manufacturing might become more effective, from an August 22, 2018 news item on ScienceDaily,

Nanoparticle manufacturing, the production of material units less than 100 nanometers in size (100,000 times smaller than a marble), is proving the adage that “good things come in small packages.” Today’s engineered nanoparticles are integral components of everything from the quantum dot nanocrystals coloring the brilliant displays of state-of-the-art televisions to the miniscule bits of silver helping bandages protect against infection. However, commercial ventures seeking to profit from these tiny building blocks face quality control issues that, if unaddressed, can reduce efficiency, increase production costs and limit commercial impact of the products that incorporate them.

To help overcome these obstacles, the National Institute of Standards and Technology (NIST) and the nonprofit World Technology Evaluation Center (WTEC) advocate that nanoparticle researchers, manufacturers and administrators “connect the dots” by considering their shared challenges broadly and tackling them collectively rather than individually. This includes transferring knowledge across disciplines, coordinating actions between organizations and sharing resources to facilitate solutions.

The recommendations are presented in a new paper in the journal ACS Applied Nano Materials.

An August 22, 2018 NIST news release, which originated the news item, describes how the authors of the ACS [American Chemical Society) Applied Nano Materials paper developed their recommendations,

“We looked at the big picture of nanoparticle manufacturing to identify problems that are common for different materials, processes and applications,” said NIST physical scientist Samuel Stavis, lead author of the paper. “Solving these problems could advance the entire enterprise.”

The new paper provides a framework to better understand these issues. It is the culmination of a study initiated by a workshop organized by NIST that focused on the fundamental challenge of reducing or mitigating heterogeneity, the inadvertent variations in nanoparticle size, shape and other characteristics that occur during their manufacture.

“Heterogeneity can have significant consequences in nanoparticle manufacturing,” said NIST chemical engineer and co-author Jeffrey Fagan.

In their paper, the authors noted that the most profitable innovations in nanoparticle manufacturing minimize heterogeneity during the early stages of the operation, reducing the need for subsequent processing. This decreases waste, simplifies characterization and improves the integration of nanoparticles into products, all of which save money.

The authors illustrated the point by comparing the production of gold nanoparticles and carbon nanotubes. For gold, they stated, the initial synthesis costs can be high, but the similarity of the nanoparticles produced requires less purification and characterization. Therefore, they can be made into a variety of products, such as sensors, at relatively low costs.

In contrast, the more heterogeneous carbon nanotubes are less expensive to synthesize but require more processing to yield those with desired properties. The added costs during manufacturing currently make nanotubes only practical for high-value applications such as digital logic devices.

“Although these nanoparticles and their end products are very different, the stakeholders in their manufacture can learn much from each other’s best practices,” said NIST materials scientist and co-author J. Alexander Liddle. “By sharing knowledge, they might be able to improve both seemingly disparate operations.”

Finding ways like this to connect the dots, the authors said, is critically important for new ventures seeking to transfer nanoparticle technologies from laboratory to market.

“Nanoparticle manufacturing can become so costly that funding expires before the end product can be commercialized,” said WTEC nanotechnology consultant and co-author Michael Stopa. “In our paper, we outlined several opportunities for improving the odds that new ventures will survive their journeys through this technology transfer ‘valley of death.’”

Finally, the authors considered how manufacturing challenges and innovations are affecting the ever-growing number of applications for nanoparticles, including those in the areas of electronics, energy, health care and materials.

Here’s a link to and a citation for the paper,

Nanoparticle Manufacturing – Heterogeneity through Processes to Products by Samuel M. Stavis, Jeffrey A. Fagan, Michael Stopa, and J. Alexander Liddle. ACS Appl. Nano Mater., Article ASAP DOI: 10.1021/acsanm.8b01239 Publication Date (Web): August 16, 2018

Copyright © 2018 American Chemical Society

This paper is behind a paywall.

I looked at this paper briefly and found it to give a good overview. The focus is on manufacturing and making money. I imagine any discussion about the life cycle of the materials and possible environmental and health risks would have been considered ‘scope creep’.

I have two postings that provide additional information about manufacturing concerns, my February 10, 2014 posting:  ‘Valley of Death’, ‘Manufacturing Middle’, and other concerns in new government report about the future of nanomanufacturing in the US and my September 5, 2016 posting: An examination of nanomanufacturing and nanofabrication.

An examination of nanomanufacturing and nanofabrication

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Michael Berger has written an Aug. 11, 2016 Nanowerk Spotlight review of a paper about nanomanufacturing (Note: A link has been removed),

… the path to greater benefits – whether economic, social, or environmental – from nanomanufactured goods and services is not yet clear. A recent review article in ACS Nano (“Nanomanufacturing: A Perspective”) by J. Alexander Liddle and Gregg M. Gallatin, takes silicon integrated circuit manufacturing as a baseline in order to consider the factors involved in matching processes with products, examining the characteristics and potential of top-down and bottom-up processes, and their combination.

The authors also discuss how a careful assessment of the way in which function can be made to follow form can enable high-volume manufacturing of nanoscale structures with the desired useful, and exciting, properties.

Although often used interchangeably, it makes sense to distinguish between nanofabrication and nanomanufacturing using the criterion of economic viability, suggested by the connotations of industrial scale and profitability associated with the word ‘manufacturing’.

Here’s a link to and a citation for the paper Berger is reviewing,

Nanomanufacturing: A Perspective by J. Alexander Liddle and Gregg M. Gallatin. ACS Nano, 2016, 10 (3), pp 2995–3014 DOI: 10.1021/acsnano.5b03299 Publication Date (Web): February 10, 2016

Copyright This article not subject to U.S. Copyright. Published 2016 by the American Chemical Society

This paper is behind a paywall.

Luckily for those who’d like a little more information before purchase, Berger’s review provides some insight into the study additional to what you’ll find in the abstract,

Nanomanufacturing, as the authors define it in their article, therefore, has the salient characteristic of being a source of money, while nanofabrication is often a sink.

To supply some background and indicate the scale of the nanomanufacturing challenge, the figure below shows the selling price ($·m-2) versus the annual production (m2) for a variety of nanoenabled or potentially nanoenabled products. The overall global market sizes are also indicated. It is interesting to note that the selling price spans 5 orders of magnitude, the production six, and the market size three. Although there is no strong correlation between the variables,
market price and size nanoenabled product
Log-log plot of the approximate product selling price ($·m-2) versus global annual production (m2) for a variety of nanoenabled, or potentially nanoenabled products. Approximate market sizes (2014) are shown next to each point. (Reprinted with permission by American Chemical Society)

market price and size nanoenabled product
Log-log plot of the approximate product selling price ($·m-2) versus global annual production (m2) for a variety of nanoenabled, or potentially nanoenabled products. Approximate market sizes (2014) are shown next to each point. (Reprinted with permission by American Chemical Society)

I encourage anyone interested in nanomanufacturing to read Berger’s article in its entirety as there is more detail and there are more figures to illustrate the points being made. He ends his review with this,

“Perhaps the most exciting prospect is that of creating dynamical nanoscale systems that are capable of exhibiting much richer structures and functionality. Whether this is achieved by learning how to control and engineer biological systems directly, or by building systems based on the same principles, remains to be seen, but will undoubtedly be disruptive and quite probably revolutionary.”

I find the reference to biological systems quite interesting especially in light of the recent launch of DARPA’s (US Defense Advanced Research Projects Agency) Engineered Living Materials (ELM) program (see my Aug. 9, 2016 posting).