22 December 2010—This situation occurs far too often: A person arrives at his doctor’s office complaining of some unknown ailment, only to find out that cancer has invaded his body and that it is too late for any of the standard treatments to work. But a group of scientists dream that cancer and other maladies could be diagnosed and treated without the person ever knowing anything had been amiss. The scientists, at the Hebrew University of Jerusalem, in Israel, the University of Liege, in Belgium, and the University of California, Los Angeles, say they have built a molecular machine out of DNA that could act as a logic device for chemical sensing and medicine delivery. Unlike earlier DNA machines, the new device has a degree of memory, making it potentially programmable.
The machine comprises three DNA "tweezers." These molecular mechanisms, which have been around for a decade, take advantage of the mechanical properties of and the chemical bonding relationships between DNA’s four bases—adenine, cytosine, guanine, and thymine. It is possible to connect strands of these bases to create two rigid arms with a flexible hinge between them. Scientists already know that when a strand is added that bridges the arms of a tweezer, the new strand pulls the arms together, closing the tweezer. An additional nucleic acid acts as an anti-linker, stripping away the DNA strand and reopening the tweezer.
In a report in Proceedings of the National Academy of Sciences, the researchers say they have identified two additional pairs of triggers for closing and opening the tweezers. Mercury ions cause the tweezers to snap shut; adding cysteine removes the mercury, causing the tweezers to reopen. Itamar Willner, a chemistry professor at the Hebrew University of Jerusalem who was a member of the team, says pH is also a trigger. Making a tweezer’s environment acidic, by adding H+, causes it to open; when the pH is made neutral with the addition of OH–, the tweezer closes. Each set of tweezers in a machine can have a different trigger. For example, tweezer A could be programmed to also respond to the addition of mercury and cysteine, while tweezer B could be made sensitive to changes in pH, and tweezer C could be sensitive to just the right strand of DNA.
The DNA machine they created consists of three tweezers whose open or closed positions altogether represent eight states (open-open-open, open-closed-open, open-closed-closed, etc.). The state is not only identified by the open or closed configuration of the tweezers but also by how the tweezers got into that position—their previous state. Because the state of the tweezers depends on their previous state, Willner says it is possible to deduce the tweezers’ state before the last set of chemical triggers is added.
This memory of the device’s previous state adds another eight "words" that can be useful for programming the DNA device. The team has identified all the states and has charted how to reach a given configuration from any of the others.
Asked how the device would treat cancer and other diseases, Willner explains that medical maladies have biochemical signatures. DNA machines implanted throughout the body would be programmed to respond to such biomarkers the same way they respond to acid in a laboratory setting. The biomarker would activate the DNA machine, causing it to spring open and release medicine to treat the problem.
Willner provides two examples. He reasons that because cancer cells have an acidic pH, while normal cells have a neutral pH, "if our DNA machine is implanted everywhere, and suddenly the pH at a certain place becomes acidic, the tweezers will open, releasing a chemical that can act as an inhibitor for an enzyme that causes the disease." The same sensing and reacting steps, he says, would also prevent the lasting damage that can result from a stroke. In the past, Willner and his colleagues have demonstrated that this machine, when opened, can release a nucleic acid that inhibits the uptake of a brain-cell-killing enzyme called thrombin, which is released in the body after a stroke. Just as important, says Willner, is the fact that the biomolecular logic device could be programmed to automatically return to its dormant state until another biomarker appears.
As great as these possibilities are, he says the DNA robots they’ve built are very primitive. "We feel it’s possible to think of much more complicated logic operations that will allow us to program a single DNA machine to respond to several biomarkers," says Willner. Such devices, which would act as sentries guarding against an array of ailments, could someday be the basis for a new kind of medicine.
They say an ounce of prevention is worth a pound of cure. DNA machines may change the balance of that equation.