Genome Advance of the Month

Researchers view DNA through 3D lens

By Andrea H. Ramirez, M.D., M.S.
Clinical Fellow, NHGRI

Shapes designed using tiles of DNA
DNA sequence is decoded into a string of the bases A, T, C and G in two dimensions on a computer screen, but three-dimensional thinking is required to understand the effects of changes in our DNA as well as use DNA molecules to solve problems. This month, we explore two studies — one uncovering a functional role of DNA in chronic pain and another manipulating DNA to form useful shapes — both advances in translating 2D data into 3D thinking that may improve our 4D lives.

In Nature Medicine, Robert Sorge, Ph.D., of McGill University and a multi-national group of collaborators1 identified a potential new drug therapy for chronic pain by understanding the effect of a change in the linear DNA sequence of a gene on the 3D protein made by the gene.

Chronic pain frustrates both patient and physician. While pain from an injury like a paper cut goes away as it heals, chronic pain extends beyond the initial 'ouch,' either due to ongoing inflammation (chronic inflammatory pain) or nerve damage (chronic neuropathic pain). Both types of chronic pain often include the puzzling state of allodynia, pain due to a normally non-painful event such as light touch. While both are difficult to treat, chronic inflammatory pain may respond better to available drugs like ibuprofen and morphine. Unfortunately there are few effective treatment options for chronic neuropathic pain, an increasingly common result of diseases including diabetic neuropathy, fibromyalgia and stroke and a side effect of therapies including amputation, radiation and chemotherapy.

To begin to address this unmet need for treatment, Dr. Sorge and colleagues used a simple, reproducible model of chronic pain in mice to identify genes that might also be important to chronic pain in humans. They performed a surgery on the mice called spared nerve injury to cause allodynia, then looked for differences in DNA sequences between mice with more and less pain. (For a visual demonstration, check out this video2 online). Researchers found that mice with one different base in the gene P2RX7 had less pain after the injury than mice with a different nucleotide. This single change of an A to G in the two-dimensional string of DNA bases made the mice produce fewer pores in the three-dimensional membrane of a cell. Like skin pores, these cell pores regulate the flow of substances in and out of the cell. Understanding this 3D effect, they developed a drug to reduce the number of pores in mice with more pores because of their DNA sequence, and found this medicine reduced their pain level after the nerve surgery.

Researchers went on to study the P2RX7 gene in humans. They found that if people had a similar DNA variation that made fewer pores, they had less chronic pain. This was true in people with chronic neuropathic pain whose nerves were injured after breast cancer surgery and in people with chronic inflammatory pain from arthritis. These findings suggest that people who make more pores because of their DNA sequence might benefit from a drug similar to that given to the mice.

Creating a drug based on a person's unique DNA sequence is known as pharmacogenomics, but many hurdles exist to developing such targeted therapy. One technique to make these personalized drugs is using DNA itself as a building block to carry a medicine in the body, known as DNA nanotechnology. This method requires manipulating two dimensional strings of DNA bases to form three-dimensional shapes. Researchers can predict how two-dimensional strings of DNA will assemble because DNA always binds in a predictable pattern of A to T and C to G, forming strong, rigid double helices of uniform size and shape. The concept of DNA nanotechnology has been around since the early 1980s, but has gained momentum recently as computer technology and robotics have caught up to implement these ideas.

In Nature this month, Bryan Wei, Ph.D., of the Wyss Institute for Biologically Inspired Engineering at Harvard University and colleagues3 assembled complex shapes from short pieces of DNA called tiles. Using these tiles, they made two-dimensional shapes varying from basic numbers and letters to more complex emoticons and a rubber ducky, as well as a three-dimensional tube (see images). More than just interesting art, this work advances scientists' ability to manipulate DNA in three dimensions, an important step towards developing targeted therapies for stubborn problems like chronic pain.

While personalized therapies based on individual DNA sequences using nanotechnology remain a distant goal, studies such as these exploring the 3D nature of DNA are essential to understanding why different DNA sequences change disease and how we might manipulate and use our knowledge of the amazing structure of DNA itself to improve human health. Even if you're not ready to make your own nanoscale DNA shapes, you can get into a 3D state of mind by making your own origami alpha helix4: yourgenome.gov.

Further reading

1. Sorge RE, Trang T, Dorfman R, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nature Medicine, 18(4):595-599. 2012. [PubMed]

2. Richner M, Bjerrum OJ, Nykjaer A, Vaegter CB. The Spared Nerve Injury (SNI) Model of Induced Mechanical Allodynia in Mice. Journal of Visualized Experiments, (54). 2011. http://www.jove.com/video/3092/the-spared-nerve-injury-sni-model-of-induced-mechanical-allodynia-in-mice.

3. Wei B, Dai M, Yin P. Complex shapes self-assembled from single-stranded DNA tiles. Nature, 485(7400):623-626. 2012. [PubMed]

4. Bateman A. Wellcome Trust Sanger Institute's yourgenome.org.

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Posted: July 9, 2012