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Abstract:
ASU can now shout the classic exclamation of discovery - "Eureka!" - twice.

Fueled by a new initiative at the National Institutes of Health called the EUREKA program, two ASU teams have received million-dollar grants to pursue the next frontiers in biomedical research.

‘EUREKA’ program funds innovative ASU research projects

Tempe, AZ | Posted on September 8th, 2008

EUREKA, an acronym for Exceptional, Unconventional Research Enabling Knowledge Acceleration, is intended to boost exceptionally innovative research.

Biodesign Institute researcher John Chaput and Ira A. Fulton School of Engineering associate professor Rudy Diaz each have received $1.2 million research grants from the new, high-impact NIH program. The EUREKA program represents the NIH's increased emphasis on supporting unconventional, paradigm-shifting research.

"EUREKA projects promise remarkable outcomes that could revolutionize science," says Elias Zerhouni, NIH's director. "The program reflects NIH's commitment to supporting potentially transformative research, even if it carries a greater-than-usual degree of scientific risk."

Adds ASU President Michael Crow: "The National Institute of Health's decision to fund these key biomedical research projects not only speaks to the intellectual merits of ASU's outstanding proposals, but also confirms ASU's success in attracting federal investment in bold, high-risk, high-impact research central to our mission."

Chaput and Diaz's projects were two of 38 proposals deemed exceptional. This is an impressive showing for ASU, and it demonstrates the university's ability to compete with the best and brightest scientists from across the nation.

"The EUREKA competition provided a unique forum for our Biodesign team to develop a transformative platform that represents a convergence of chemistry, biology and informatics," says John Chaput, a Biodesign Institute researcher and ASU assistant professor in the Department of Chemistry and Biochemistry.

Discovering ‘hidden' proteins

During his four-year research project, Chaput will lead a Biodesign Institute team on a project that plans to search the human genome for regions of DNA that contain important, but as of yet unidentified genetic information.

If successful, Chaput's project may confirm the possible existence of novel protein-coding regions that remain hidden in the shadows of the classic proteome. Determining how and when such proteins are made could have a major impact in diseases, such as cancer, by helping us to understand how cellular function is deposited in our genomes.

Within the code of life, three polymers - DNA, RNA and proteins - provide nearly all of the information content. Each is made from a slightly different set of chemical building blocks, and the exact sequence of these blocks within each chain carries out the instructions of the genetic code. Fifty years ago, Francis Crick, co-discoverer of the DNA double helix, first postulated the "central dogma" of molecular biology, where DNA information is transcribed to make RNA, and RNA is translated to make proteins.

The bounty of the Human Genome Project has identified nearly 25,000 genes. It's estimated that the human body could make more than a million different proteins, the majority of which remain to be discovered. This entourage of proteins, the proteome, is ultimately responsible for everything good or bad that is related to human health and disease.

Chaput's team, which includes fellow Biodesign colleagues Sudhir Kumar and Bertram Jacobs, has produced tantalizing clues that suggest there may be many proteins hidden within the DNA sequences of our genome. Together, they will combine their expertise in molecular and cellular biology, bioinformatics and virology to uncover how and when such proteins are made.

"We have developed a combined experimental-bioinformatics approach that allows us to quickly search entire genomes for sequences that enhance the translation of a downstream gene," Chaput says. "By determining the identity and location of these motifs, it should be possible to determine when specific genes are being made and possibly discover new genes that contribute to our proteome. Since many of these genes will likely be made by non-traditional methods, this technology will also allow us to investigate new mechanisms of protein translation."

The motifs they hope to identify help recruit ribosomes, the protein translation machinery of the cell, to the correct translation start site on the RNA message. By identifying these landing sites, the team can use bioinformatics to learn where these motifs are located in the genome.

This information will enable Chaput's team to create an annotated map of the human genome showing all possible locations where protein translation could occur.

Neural nanomachines

Research to be led by Diaz will focus on assembling nanomachines designed to deliver electrical signals to neurons on command. Applications of the technology would include bio-sensing and delivery devices that could be used to detect and treat a variety of human neurological disorders.

Diaz, an associate professor in the Department of Electrical Engineering and the Center for Nanophotonics in ASU's Ira A. Fulton School of Engineering, will work professors Thomas Moore and Hao Yan in the Department of Chemistry and Biochemistry. Yan also works in the Center for Single Molecule Biophysics in the Biodesign Institute.

The team's goal is to gain new insights into the pathological obstruction of neural signals and the development of new and more precise neural-stimulation technology.

With existing technology, viewing the "microscopic dynamics" of what is occurring in the human body at a cellular level "is like observing human activity on Earth from an orbiting satellite," Diaz says.

Even with the development of laser tweezers and nanoelectrodes, "most of our cellular bio-chemistry knowledge is still extracted from circumstantial evidence," Diaz says.

The method Diaz's team proposes would permit "direct interaction with cells at the local level." That would be achieved with a nanoscale structure that could be injected into the body, targeted to attach itself to certain clusters of cells and then controlled by chemical reactions triggered by light delivered either through the skin or via microscopic optical fibers.

The team will molecularly assemble a nanodevice that is best described as a remotely powered and remotely controlled pacemaker.

It will be built on a DNA chassis that includes antennas for receiving power and commands from the outside world, and batteries to store and deliver that power.

The antennas are built of Noble metal nanospheres that take advantage of the plasmon resonance to amplify and focus light with nanometer precision.

Artificial electrocytes - electric organ cells that work like batteries, such as those that naturally occur in fish such as electric eels - will be constructed from liposomes (fat cells) that will have ion pumps and ion gate molecules incorporated into their lipid membranes.

The whole structure will have to be encapsulated in a DNA "cage" to prevent the components from being short-circuited by the body's fluids.

Under the correct wavelength of light, the power-receiving antennae would amplify the incident light to drive the electric charging of the artificial electrocyte.

The structure would include a set of plasmonic antennae. These are microscopic metal nanostructures that behave as antennae in the presence of photons (light) the way metal antennas behave in the presence of radio waves.

The antennas would be tuned to a different wavelength and coupled to the ion gates in the membranes to serve as light-activated switches to perform a "gate-opening" process that triggers the discharge of the artificial electrocyte chain, thus delivering an electrical impulse that can stimulate neurons.

The group hopes to prove the functionality of each component independently and to demonstrate that the entire assembly works as designed.

These nanostructures could lead to advanced neuro-imaging sensors operating at the cellular scale. Such nanosensors delivered to their targets by chemical tags, or during surgical intervention, could reveal new details about the transmission of neural signals and of their pathological interruption.

The light-powered artificial electrocyte could become a critical tool for improving microsurgery, and advancing the understanding of cellular biology.