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Dr. Lindsay, Center director, has pioneered scanning probe techniques for biological applications, including the first direct imaging of the DNA double helix in solution, the development of magnetically-excited force microscopy for imaging in fluids, observation of ion-induced kinks in DNA, antibody-based recognition imaging, and measurement of electron transfer in single molecules. Through collaboration with Molecular Imaging, an ASU spin-out company he co-founded in 1993, his lab helps to develop leading—edge technologies in Scanning Probe Microscopy (SPM).

The Atomic Force Microscope (AFM) is a scanning probe microscope. It uses a sharp probe, positioned with atomic precision, to both image (by scanning at constant force) and to manipulate individual molecules. In collaboration with a team from the University of Linz (Austria), and a team from Molecular Imaging, the Center’s researchers have developed new techniques that could have significant implications for drug development by allowing scientists to monitor the effects of potential drugs on the nanoscale.

Although the AFM has a resolution down to an atomic level, it has been blind to identifying specific chemical compositions. The new technique of ‘recognition imaging’ allows an AFM to "see" the chemical composition of molecules-identifing specific components in an image. It gives the AFM chemical sensitivity to nanometer-sized molecules similar to the way colored dyes gave optical microscopes optical sensitivity for much larger objects (micron sized).

The technique uses antibodies to individual proteins. These are attached to the tip of an AFM’s sensing probe. When an antibody reacts with the protein for which it is specifically targeted, a variation in the response of the probe, thus showing the presence of a protein or other specific material in the region being scanned. This allows researchers to see how specific molecular components of a cell react during biological processes triggered, for example, as a  response to a specific chemical.

Researchers at the Center are trying to understand the molecular basis of cancer. In collaboration with the Hager Lab at the National Cancer Institute, and funded by the NIH, we are studying the structure, physical properties and remodeling of promoter chromatin from the long terminal repeat of the Mouse Mammary Tumor Virus. This promoter chromatin controls a cancer causing gene. The goal of this work, funded by the NIH, is to understand the sequence of events whereby the glutocorticoid receptor (a steroid receptor) triggers transcription of this gene. The researchers are making AFM ‘movies’ of the structural changes in the chromatin as the factors that turn the gene on interact with the promoter chromatin.

The Center’s researchers are building molecular electronic devices based on paradigms taken from the electronic processes that occur in living systems during photosynthesis. This work is supported as an NSF funded Nanoscale Interdisciplinary Research Team (NIRT) and is being conducted in collaboration with Biodesign Institute researchers within the Center for BioOptical Nanotechnology and with Larry Nagahara at Motorola.

First the team had to develop a method for making reliable electronic measurements on single molecules. Then the method was extended to molecules of interest to the electronics industry.

In addition to extending measurements on single molecules to new structures, the Center’s researchers are working with Nongjain Tao and the Center for Solid State Electronics Research (CSSER) to make manufacturable nanostructures that incorporated molecules as active devices. This work is aimed at building the basis of new electronics based on molecular, as opposed to silicon devices, and is an essential step of the electronics industry is to continue its growth.

A second approach of the research is to incorporate molecular sensing capabilities into otherwise conventional semiconductor devices. Working with Trevor Thornton of CSSER, methods have been developed for attaching single-strained DNA to the gate of a Field Effect Transistor (FET). The device can detect the presence of a small amount of DNA with a sequence that is complementary to the sequence bound to the FET. If this technology becomes viable, it will replace the cumbersome, indirect optical readout of ‘gene chips’ with a direct electronic readout, greatly enhancing genetic analysis for both medical and biological research and diagnosis.

Current sequencing techniques of the human genome are extremely slow and costly. The initial sequencing, completed in 2002, took 11 years and cost $1 billion. Lindsay’s team of researchers have been working on a revolutionary new technology, that if successful, could sequence the genome in a few hours for less than $1000. To help bring the new technology to fruition, Lindsay was recently awarded a three-year $550,000 grant from the National Human Genome Research Institute (NHGRI) of the National Institutes of Health.

The new sequencing technology involves using Atomic Force Microscopy (AFM) in combination with naturally occurring ring-shaped sugar molecules called cyclodextrins. The hope is that the ring molecules, when coupled to the AFM probe, can effectively be used as sensors to read the sequence of the DNA bases. The cyclodextrins are just big enough to slide a strand of DNA through. Researchers propose to attach the reactive groups on the ring to the sensitivity of an AFM tip, which would thread an anchored DNA molecule into the ring and pull it through, recording the subtle differences in the ‘bumps’ resulting from the friction of the different DNA bases with the ring.  The resulting data might thus be translated into the precise sequence of the DNA molecule.

There are a number of significant technical hurdles to overcome, but if researchers are successful, the time it takes for sequencing the whole human genome could be reduced to a few hours. Another advantage of the new method is that it can be used for a single molecule. For example, one could take a piece of DNA out of a cancer cell and get its sequence; then take the DNA out of an adjacent normal cell and ask what its sequence is for comparison.  This can be done without modifying the DNA. Current sequencing techniques require the DNA to be copied through the polymerase chain reaction, which could result in errors and make it hard to see single base differences that may have to do with the particular disease. 

In August 2004, a grant from the National Science Foundation enabled the Biodesign Institute to purchase a Focused Ion Beam System (FIB)which enables researchers to construct nanoscale prototypes of objects that could be used in a wide range of biotech applications. Awarded to the Center for Single Molecule Biophysics in conjunction with the Center for Solid State Science within ASU's College of Liberal Arts and Sciences, the grant allowed purchase of the $1.3 million FIB System. The system is ultra fast and will allow unlimited possibilities for developing structures for use in many areas of science.

A three dimensional shape is programmed into the system’s computer which then guides highly focused ion beams to strike the surface of a material and sculpt it into the desired shape. The Center will use it to design probes for mapping electrical and chemical activity on surface cells. The Biodesign Institute's Center for Applied NanoBioscience will use the FIB to design small devices for separating biological molecules from blood. A condition of the grant is that ASU must make the equipment available at an hourly rate to other organizations, including start-up technology companies as well as other researchers.

Center Researcher, Hao Yan leads an effort to build nanoscale assemblies and nanostructures made out of DNA molecules. By choosing the sequence of the DNA molecules appropriately, three-dimensional nanoscale structures can be made to "self-assemble", driven by the Watson-Crick base pairing of the DNA molecules. This technology is expected to lead to better diagnostic tools and better materials for energy conservation.

ASU Professor, Michael Thorpe has developed new computational tools with which to understand large scale motions of proteins. These are the motions that enzymes use to carry out their function. In addition to shedding light on the fundamental mechanisms of enzyme action, these methods have proved valuable in drug design, and Thorpe’s codes are currently being used in the pharmaceutical industry.

Assistant Professor, Marcia Levitus uses optical tools to follow the motions of individual biological molecules. Molecules are labeled with dyes that fluoresce when excited by a laser. By exciting one dye molecule with a laser, and observing how a second dye molecule is influenced by the first dye molecule, motions of the molecule to which they are attached are detected.

Associate Research Professor, Peiming Zhang heads up a facility for synthetic chemistry, modifying surfaces and biological molecules as part of an effort to build better sensors, diagnostic arrays and improved DNA sequencing technologies.