Fold Your Genes!: The Playful and Powerful Applications of DNA Origami

Everyone has heard of origami, I’m sure. The Japanese paper-folding art form has been greatly influential in pop culture, and is a fun and addictive skill to master.

As a child, I was an origami hobbyist. Poring over thick origami guidebooks became my favourite pastime and soon, any piece of paper I could get my hands on became a box, or a crane, or a leaping frog.

Now, researchers have found a new material to fold, and it is unarguably more abundant in our world than paper: DNA. Indeed, the genetic material found in the nuclei of our cells can be folded as well!

Just look at the creations of some scientists.

Little DNA smileys 🙂

https://cen.acs.org/articles/90/i28/Just-Smiley-Face.html

DNA Mona Lisa

https://www.kijkmagazine.nl/science/dna-origami/

3D DNA nanostructures

https://www.genengnews.com/news/dna-origami-adds-multilayered-curved-shapes-to-its-catalog/

Let’s dive into a brief history of DNA origami, how it works, and its potential applications (aside from being used to create mini sculptures).

In the early 1980s, nanotechnologist Nadrian Seeman, who would come to be known as the father of DNA nanotechnology, introduced the idea of using DNA as a construction model. Almost 26 years later, research professor Paul Rothemund developed the method of DNA origami. How did he do it? The method is simpler than you may think.

Secondary school Biology students might recall that each monomer of DNA contains one of four bases: adenine, thymine, cytosine or guanine. Adenine binds with thymine, while cytosine binds with guanine, forming the iconic double-helix  structure of DNA. This double-helix DNA is composed of two strands, so it is said to be double-stranded, as shown in the picture below.

https://www.shutterstock.com/image-vector/base-pairs-dna-molecule-chains-600nw-2060268152.jpg

When split apart into its two strands, DNA goes from looking like the double helix in the picture above, to resembling a shoelace. These pieces of single-stranded DNA are the starting point for DNA origami.

These strands are typically obtained from a virus. A bioengineer roughly hand-draws the desired 2D or 3D model, before running it through a computer programme to visualise the folding path of the DNA. Then, the bioengineer plans how to manipulate the four bases of DNA in such a way that when they bind together, the desired origami structure is achieved. Restriction enzymes are used to create “sticky ends” of DNA, which stick to adjacent ends.

Nanostructure formed using sticky ends

https://pmc.ncbi.nlm.nih.gov/articles/PMC3397516/

Short DNA strands called “staples” are also used, which bind to certain parts of the single-stranded DNA. These staples hold disconnected parts of the DNA strand together, causing them to fold into the desired three-dimensional shape, similar to the 3D creases that form when you tape two opposite corners of a piece of paper together.

Gigadalton-scale DNA origami nanostructures explained

A common question posed to DNA bioengineers is this: why not just use more common technology, such as 3D printing, to create the desired structures?

The first reason is quite simple — DNA, by nature, exists at the nanoscale, so it makes sense to use DNA in the creation of nanostructures. The next reason is that there are a few highly advantageous features of DNA that alternative materials cannot replicate.

For instance, the bases of DNA (A, T, G and C) bind together in a very specific way that is easily predicted and controlled. This means that, when planned correctly, the pieces of DNA come together all on their own to form desired nanostructures, with almost no “manual construction” required from biological engineers. Since DNA bases naturally bind to their complementary bases (A to T, G to C and vice-versa), the staple strands can easily locate and bind to the correct position on the single-stranded DNA and form a link. Extending the paper-tape metaphor, staple strands are kind of like magical pieces of tape that can move precisely to the desired points on the paper, and tape the structure together. Complex DNA structures assemble themselves, enabling researchers to manufacture billions of copies.

A preliminary diagram of the folding path. The dotted lines represent DNA, while the short segments of letters “A”, “T”, “G” and “C” represent the “staple” strands.

https://www.nature.com/articles/nature14860

Moreover, since DNA is a biological molecule, it is more well-suited to the biological environment than other materials (such as the plastics used in 3D printing), a trait that makes it suitable for use in the bodies of living organisms.

Speaking of its uses, this recently-developed method of manipulating biological material has various fascinating and powerful applications.

Firstly, DNA origami could aid in delivering drugs to specific cells in the body. In one study , researchers utilised this technology to create a DNA nanorobot shaped like a tube that can be clasped shut to treat lymphoma. They filled this tube with the necessary drug, then injected it into the body. The DNA structure was configured to seek and identify lymphoma-related protein in the body and break apart, releasing the drug. In this way, only the infected cells and those surrounding it are exposed to the drug, minimising the potentially harmful side effects of the drug on other parts of the body. Another study showed that a drug was more effective at reducing tumour sizes in mice when it was contained in DNA Origami Nanostructures (DONs) than when it was in free form.

Secondly, DNA origami can aid in immunotherapy (that is, the enabling of the body to identify and destroy malignant cancer cells). Antibodies that bind to certain tumour cells are added to one side of the DON, while antibodies that are recognised by the immune system’s T-cells are added to the other side. In the body, the DON binds to the tumour, and activates the body’s T-cells, which then destroy the tumour cells marked by the DON.

Thirdly, DNA origami can be used to simplify the process of vaccination. The method involves creating a DON that is shaped like a virus, and attaching viral antigens (particles that viruses have) to the virus-shaped DON, in order to mimic the virus to develop vaccines. This means that scientists would no longer have to obtain viruses in their pure form and modify them to create vaccines — instead, they can introduce these “impostor viruses” created using DNA origami into the body, familiarising the body’s immune system with the virus in question.

There have also been suggestions on how DNA origami can be applied in the field of nanotechnology, such as creating nano-boxes that open and close repeatedly in response to data, making them programmable.

Though the process of folding DNA is complicated and, like all other forms of design technology, requires tedious periods of trial and error, its potential to improve disease treatment more than makes up for the effort required. So the next time you’re fiddling with a piece of paper, think about the amazing work being done to create similar structures using the genetic material found within your cells, and the potential of those structures to better humanity.

References:

1. Rothemund, Paul W. K. (2006). "Folding DNA to create nanoscale shapes and patterns" (PDF). Nature. 440 (7082): 297–302.

2. Garde, Damian (May 15, 2012). "DNA origami could allow for 'autonomous' delivery". fiercedrugdelivery.com.

3. Ludwig Maximilian University of Munich. (2023, August 18). Artificial DNA structures fitted with antibodies may instruct the immune system to target cancerous cells. Phys.org. https://phys.org/news/2023-08-artificial-dna-antibodies-immune-cancerous.html

4. "Engineers use "DNA origami" to identify vaccine design rules". MIT News | Massachusetts Institute of Technology. 2020-06-29.