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X Marks the Spot for Jumbo DNA

Super-sized strands of the double helix molecule could act as a diagnostics marker-and may eventually open the way to tailor-made genetic systems.
January 14, 2004

The hot action in many areas of technology revolves around how to make things smaller and smaller. Bucking this trend, scientists at Stanford University have synthesized an artificial DNA strand with molecules about 15 percent larger than the natural variety. This so-called xDNA has properties lacking in the puny DNA that nature cooks up. It is more stable, for example. It also glows under ultraviolet light. These traits suggest that xDNA could be useful in genetic diagnostic procedures and, potentially, artificial forms of life. “Our biggest interest is whether we can design our own genetic system,” says chemistry professor Eric Kool, who led the Stanford research team. “I think we’re well on our way.”

What makes xDNA different from regular DNA is its structure. Normally, DNA is a string of nucleotides, each of which comprises a sugar, a phosphate, and a base: either adenine, thymine, guanine, or cytosine (represented in DNA descriptions as A, T, G, and C). When DNA strands bond with one another, the bases match up in a particular way: adenine always bonds with thymine, and guanine with cytosine.

About thirty years ago, Nelson Leonard, then a University of Illinois chemist and now at the California Institute of Technology, found a way to stretch adenine so that it would fluoresce when exposed to ultraviolet light. What Leonard couldn’t do was attach the sugar and phosphate to the base, making a complete nucleotide; scientists at the time didn’t know how to make DNA, though now the process of creating artificial strands is commonly used in genetic medical diagnostics.

What Kool sought was a way of making a DNA double helix. First he synthesized two expanded bases: adenine and thymine (xA and xT). He then made nucleotides out of the xA and xT bases with appropriate sugars and phosphates. By pairing an xA with a normal T and an xT with a normal A, Kool was able to assemble them into a double helix just wide enough to contain the stretched bases.

Building the nucleotides took four years of work. Kool started by designing the structure of the stretched bases, then moved to synthesis, which required finding appropriate forms of sugars and phosphates. “We did chemical reaction after chemical reaction after chemical reaction,” Kool says. Purification of the results can take days, or even weeks. And because such synthesis hadn’t been done before, there were many dead ends.

Once the researchers had synthesized stable, super-sized nucleotides, they used commercially available equipment to link them together into DNA sequences. Natural DNA needs approximately 10.5 paired nucleotide “steps” to make one full rotation in the double helix. The enlarged bases increase the diameter of the helix, which needs more such steps as a result. Being larger, the molecular structure offers increased stability; while natural DNA in Kool’s lab fell apart at 21C, xDNA remained intact up to 56C. Kool’s research “shows that the double helical structure of [natural] DNA does not have to be the only one,” says Danith Ly, an assistant chemistry professor at Carnegie Mellon University and an expert in developing chemical tools for studying genomics and proteomics.

Kool’s ultimate quest for a tailor-made genetic system is a tall order-and not one to be rushed, says Ly: “In order for a biological function to exist independent of anything, it needs proteins, lipids, enzymes-all sorts of things. For us to do it in the next hundred years might be possible, but it would be difficult.” And before that, Kool must create expanded versions of the G and C bases, which will likely be comparable in difficulty to his work on xA and xT.

Science fiction scenarios of designer genes aside, Kool believes xDNA has practical implication in diagnostics-particularly in improving the existing medical procedures that detect health conditions based on the structure of a person’s DNA. Clinicians looking for particular DNA or RNA in a person take a tissue sample and introduce an artificial DNA strand that will bond to that material. Techniques that wash away everything but bound pairs containing the artificial DNA allow labs to readily search what is left. “If it doesn’t bind properly, you know that it either a mutation or the [sought] DNA isn’t there,” says Paul Billings, vice president and national director of genetics and genomics at Laboratory Corporation of America, a diagnostics testing company in Burlington, NC.

Because xDNA bonds more strongly than regular DNA, it would be more resilient in this testing process. Moreover, its natural fluorescence could act as a beacon, making detection easier. Even after the technique was more than a lab curiosity, however, its diagnostic utility would have to be demonstrated in the field. “First of all, you have to prove that it gets into the cells and behaves in other ways as other DNA,” Billings says. “Second, you have to prove that it’s better than other methods.” There are well-established methods that work now, and no evidence yet that the binding and fluorescent properties of xDNA would be a clear improvement.

Furthermore, the fluorescent characteristics of xDNA would likely need adjusting, says Ly. According to the paper by Kool’s team, the molecule lit up when illuminated by ultraviolet light with a wavelength of about 390 nanometers. “Tissues do not absorb very well at these wavelengths,” Ly notes, suggesting that for diagnostics use, the base would have to be adjusted to respond to light that was closer to the red end of the spectrum. But, according to Kool, this would not necessarily pose a significant problem in examinations of sufficiently thin slices of tissue. In fact, xDNA nucleotides may even change their fluorescent color or intensity when bonding to natural DNA or RNA-a phenomenon that would add more possible tools to the diagnostics kit. Call it a big light for medical workers.

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