Zurich, Switzerland, 13 April 2000—Scientists from IBM Research and the University of Basel have found a new approach for using tiny biochemical "machines" made of silicon to detect defects in DNA, which could eventually lead to new medical treatments.
As reported in the April 14 issue of the journal Science, the researchers discovered that DNA bends tiny silicon "fingers" that have a thickness of less than a 1/50 of a human hair. Using a process called "molecular recognition," in which molecules bind according to a key-lock mechanism, an array of fingers or cantilevers arranged like the teeth of a comb was made attractive to specific DNA codes and proteins. By observing the way different cantilevers bend as the DNA adhered to them, the researchers were able to detect the tiniest possible defect in a DNA sequence, a so-called single base mismatch. Advantages of the new technology are direct detection of the targeted substance, and it has good sensitivity even for small molecules.
"This biomechanical technique has the potential to enable fast and cheap biochemical analysis, and could be used for mobile applications," said Christoph Gerber of IBM Research. "For example, there is a need for rapid diagnosis of the condition that is a leading cause of sudden deathheart attack. If the technology can be developed as we hope, it could make it possible to determine on the spot whether chest pain is being caused by a heart attack or a more benign problem, saving time and potentially lowering treatment costs substantially."
The team's discovery that DNA and proteins will bend tiny silicon structures such as cantilevers has much wider implications, and could make it possible to extend the technology to the operation of micro- and nano-robotic machinery.
"Microbots and nanobots have been popularized in recent science-fiction stories and movies, but technological issues remain an obstacle to their realization," said James Gimzewski of IBM Research. "The ability to use biology to perform specific mechanical tasks on the nanometer scale with silicon provides a completely new approach to operate machinery autonomously, without external power or computer control. We have found a way to get DNA to do the work for us, so we don't need batteries, motors, or the like to operate tiny machines."
The ability of DNA and other biomolecules to operate machinery such as valves using the molecules' specific code or biochemistry could have applications in medicine. "For instance, we can envision a system to attack cancerous growth: the release of just the proper doses of chemicals in the appropriate location of the body could be achieved using tiny microcapsules equipped with nano-valves," said Gimzewski. "They could be programmed chemically to open only when they get biochemical signals from a targeted tumor type. This would enable the right therapy at the right place at the right time, with minimized side effects and no invasive surgery."
The technology underlying this new advance springs from development work on nanomechanical olfactory sensors, as pursued by the research teams at IBM in Zurich and at the University of Basel. To date, applications of this work are mainly in quality and process control, where the technology is used in sensing devices for gaseous analytes, such as process gases or solvent vapors. Such devices are not limited to gaseous environments, but also function in liquids. This led the way to the research now reported in Science on using the biomechanical sensors in biochemistry and medical diagnostics.
The method is based on directly transforming specific biochemical recognition into a nanomechanical motion. To do this, the researchers used hybridization, the base pairing between two single strands of DNA that results in the well-known double-helix structure. Hybridization is a prominent example of molecular recognition.
The core of the device is an array of silicon cantilevers, each 500 microns long, 100 microns wide and less than 1 micron thick. Each cantilever is coated on one side by specific biomolecules. When immersed in solution, molecules of an injected substance dock to a layer of receptor molecules that have been attached to one side of the cantilever. Sensitizing an array of cantilevers, each with a different receptor, allows docking of different substances in the same solution. The increase of the molecular "packing density" leads to surface stress and thus to bending of the cantilever.
The bending is of the order of 10-20 nanometers, which can be measured accurately by well-established methods, such as laser beam deflection. The hybridization was done with short strands of single-stranded DNA (12mer oligonucleotides) and proteins known to recognize antibodies of various mammals.
The scientific report on this work has been published in Science, Vol. 288, Number 5464, April 14, 2000. The authors of the report "Translating Biomolecular Recognition into Nanomechanics" are Jürgen Fritz, Marko Baller, Hans Peter Lang, Ernst Meyer and Hans-Joachim Güntherodt of the University of Basel, and Hugo Rothuizen, Peter Vettiger, Christoph Gerber, and James Gimzewski of IBM Research - Zurich.
The work was partially funded by research programs of the Swiss Government (MINASTMicro and Nanosystems Technologyand TOP NANO 21*) for micro- and nanosystems.
*TOP NANO 21 focuses on strengthening the Swiss economy through the development and application of new technologies based on the NANOMETER.