On April 13, 2005, the National Academies Keck Futures Initiative announced the 14 recipients of its Futures Grants, each in the amount of $50,000 or $75,000, to support interdisciplinary research on nanoscience and nanotechnology. The research projects that were awarded the funding represent a wide range of approaches to the field, which was the subject of the second Futures Conference Designing Nanostructures at the Interface between Biomedical and Physical Systems, held in November 2004 in Irvine, Calif. These competitive seed grants aim to fill a critical missing link between research on bold new ideas and major federal funding programs, which do not currently provide grants in areas that are considered risky or unusual. The grants allow researchers to start developing a line of inquiry by recruiting students and postdoctoral fellows, purchasing equipment, and acquiring preliminary data all of which can position the researchers to compete for larger awards from other public and private sources.
The award recipients and their grant research topics are (names and affiliations at the time the grants were awarded):
ROBERT AUSTIN, ERIC WIESCHAUS, and DAVID TANK Princeton University, Princeton, N.J.
Up-Conversion Nanocrystals for Nano-Imaging in Tissue - $75,000
Up-conversion phosphors are an unusual class of ceramic rare-earth materials that can do "up-conversion'' of infrared photons to visible emission with high efficiency. They offer powerful advantages for high-resolution biological imaging: 1) they do not bleach; 2) they provide two or three photon excitation intensity dependence providing high spatial resolution; 3) they can be made at the nanometer scale for tissue and cell penetration; 4) the emission spectrum is spectrally rich and can be made from red to blue; 5) they can be excited by electron beams for optically detected scanning; and 6) they are background-free because the excitation is in the IR and the emission is delayed in time. Austin, Wieschaus and Tank will use these novel nanocrystals to image morphogen gradients in embyronic development, and to detect tumors in human tissue.
NATHAN BAKER Washington University, St. Louis
ENRICO DI CERA Washington University School of Medicine, St. Louis
Molecular Engineering of Thrombin-Based Nanocatalysts - $75,000
While biology offers countless "machines" as potential nanoscale surrogates of macroscale chemical, electrical, and mechanical engineering components, these machines often require adaptation to address specific problems of relevance to biotechnology and medicine. Evolution provides some insight into the basic principles for designing diverse regulatory and catalytic functionality into similar protein structural scaffolds. However, despite the numerous biological examples, the physical principles required to engineer such functional adaptation remain elusive. Baker and Di Cera propose to exploit the serine protease family to develop engineered biomolecules with flexible regulatory capabilities and a wide range of catalytic functionality. Efforts will be made to identify the minimum set of structural determinants that ensure catalytic function and allosteric regulation, thereby identifying a "scaffold" for rational engineering. The researchers will build upon existing knowledge of Na+-regulated substrate specificity in thrombin to accomplish the following aims: 1) identify the physical determinants of Na+ specificity and allosteric activation; 2) engineer alternative metal ion specificity into thrombin; and 3) engineer metal ion activation into other members of the serine protease family. In addition to contributing to the knowledge regulation in biocatalytic system, the proposed research will provide methodology to "mix and match" specific metal regulation with the natural range of substrate diversity provided by the serine protease family. The proposed work is highly interdisciplinary in nature, combining the biochemical methods of the Di Cera lab with the computational biophysics and theoretical methods of the Baker group.
PETER BURKE University of California, Irvine
Initial Steps towards a Carbon Nanotube Synthase - $75,000
The long-term goal of this project is to design or evolve an enzyme to synthesize a carbon nanotube. In the short term, Burke will use the funds to hire a graduate student and purchase equipment to set up a directed evolution protocol and system in a lab to generate some preliminary results that could be used to justify larger-scale funding for the long-term goal of making a nanotube synthase. Burke will also use a portion of the funds to attend a workshop in molecular biology and cloning techniques, giving him the training to set up a basic molecular biology lab for studies of genetic expression and enzyme engineering.
MARY JANE CUNNINGHAM Houston Advanced Research Center, The Woodlands, Texas
MARK BANASZAK HOLL University of Michigan, Ann Arbor
Safety Assessment of Dendrimers by Toxicogenomics - $75,000
Dendrimers are engineered nanomaterials being developed for a variety of uses as agents in biomedical and electronic applications, and in coatings. Funds from this grant will be used to observe dendrimers by using the cutting-edge "OMICs" technology (genomics) of gene expression microarrays, which contain tens of thousands of genes and make possible the evaluation of the activity of all these genes simultaneously. Cells will be exposed to dendrimers and evaluated not only by atomic force microscopy but also for changes in their gene expression profiles. By comparing gene expression profiles of known toxic compounds to the profiles obtained with the dendrimers, the actions of specific genes and proteins associated with toxicity can be observed. The combination of physical and genetic information will provide a more comprehensive view of the dendrimer-cell interaction.
ANDREW ELLINGTON University of Texas, Austin
DAVID LAVAN Yale University, New Haven, Conn.
Nano-Biocomposites for Conversion of Sunlight to Electricity - $75,000
The need for economical power generation is great. In the case of solar energy, unfortunately, the conversion into electrical energy is typically around 25% efficient, resulting in final electricity output of approximately 2%. Current plans for using biological photon capture for humanity's energy needs focus on using a relatively inefficient paradigm: captured sunlight transformed into organic mass, which is then transformed into a more tractable fuel such as ethanol, which is in turn transformed back into heat or electricity. Ellington and Lavan propose a more novel paradigm in which photons are transformed immediately into high-energy electrons, without going through the intermediate conversion to a reduced carbon compound. They will meld bio- and nanotechnologies to create a technology for solar capture that can be mass-produced and scaled to a variety of energy needs. Ultimately they would like to engineer organisms that can transfer energy directly from sunlight to electrodes. Much like tissue engineering for organ replacement, synthetic materials will be designed and synthesized to optimize cell attachment and growth, while also providing the necessary electrical connectivity, mechanical support, and providing for gas exchange.
DONALD INGBER Harvard Medical School and Children's Hospital, Boston
JEFFREY BYERS Naval Research Lab, Washington, D.C.
MICHAEL SIMPSON University of Tennessee and Oak Ridge National Laboratory, Oak Ridge, Tenn.
Multiplexed Dynamic Molecular Force Spectroscopy Array - $75,000
The project is designed to facilitate collaboration between three participants of the 2004 Keck Futures Initiative conference on nanotechnology to create a novel "multiplexed dynamic molecular force spectroscopy array" with combined sensing and response capabilities, as well as feedback behaviors that mimic properties exhibited by biological networks of living cells. Through a series of complex experimental studies in the changing of mechanical properties of the target molecule, Ingber, Byers, and Simpson will begin to self-assemble biological regulatory networks that will allow them to analyze how mechanical and chemical signals may be integrated at the nanometer scale.
SHANA KELLEY Boston College, Boston
EDWARD SARGENT University of Toronto, Toronto
Designer Biomolecular Templates for Inorganic Nanoparticle Growth: Bottom-Up Control Over Infrared Emitting Quantum Dot Synthesis and Properties - $75,000
The worlds of biology and semiconductor chips have traditionally been quite distinct. The spontaneous assembly of biological materials presents a stark contrast to the rational fabrication required for high-performance semiconductor chips. The merger of these diverse materials represents a tremendous opportunity for the next generation of materials in computing, communications, and energy. Kelley and Sargent will explore the properties of PbS semiconductor quantum dots built using DNA molecules, a novel class of hybrid inorganic bionanostructures. The Sargent group recently made the remarkable discovery that compared with established synthesis methods, synthesis using DNA as templating material produces radically more efficient light-emitting PbS quantum dots. The light-emitters are stable inside blood plasma at body temperature over weeks. This discovery opens doors to applications of these materials, for example in cellular imaging and fundamental studies in tissue engineering. Kelley and Sargent will investigate how DNA-templated PbS growth works and, with this new understanding, discover how to manipulate and control quantum dot growth using designer' biomolecules.
PHILIP LEDUC Carnegie Mellon University, Pittsburgh
JOHN CHRISTOPHER LOVE Harvard Medical School, Cambridge, Mass.
Biological Nanofactories - $75,000
Leduc and Love propose to develop a "biological nanofactory," an artificial nanostructure that will produce biologically relevant molecules from a source of raw materials; such a system could provide a new method for treatment or prevention of certain metabolic diseases. The researcher hope the significant preliminary results of this research will lead to additional funding from other agencies.
LUKE LEE University of California, Berkeley
Quantum Nanoplasmonic Probes for In Vivo Molecular Imaging - $75,000
A quantum nanoplasmonic probe is created to maximize the enhancement of a local electromagnetic field at the sharp edge area of a nanocrescent structure for label-free proteomics and in vivo molecular-level cellular nanoscopy. The asymmetric, hollow nanoscale composite metal nanocrescent features a large surface area for better molecular adsorptions and a long edge for the maximized total integration of multiple tips for surface-enhanced Raman scattering spectrum. Because of its hollowness, the inner and outer surfaces can be modified with different biomolecules for a wide variety of optical characteristics. Moreover, the sharp cusp of the nanocrescent structure results in an even higher degree of field enhancement ideal for single molecule detection. Lee proposes that successful use of unconventional nanostructures will be key for the development of ultrasensitive label-free biomolecular diagnostics, functional proteomics, and systems biology.
DAN LUO Cornell University, Ithaca, N.Y.
TODD THORSEN Massachusetts Institute of Technology, Cambridge
Mesoscale Patterning and Delivery of DNA-Based Nanoscale Buckyballs using Microfluidic Devices - $75,000
The long-term goal of Luo and Thorsen's collaboration is to combine two approaches top-down and bottom-up, to develop materials and devices that extend the nanoscale to the mesoscale and to interface nanomaterials with macro applications including drug delivery. The first purpose of their research is to use microfluidic emulsification devices -- a top-down approach -- to pattern DNA-based, nanoscale buckyballs that are created from the bottom-up approach. Because these buckyballs are hollow, in the size of 300 nm in diameter, and biodegradable and biocompatible, they are great for drug encapsulations, ideal for cell endocytosis, and suitable for intracellular release of drugs. Thus the second purpose is to develop addressable and scalable polyurethane microfluidic devices to deliver these drug-loaded -- and especially gene-loaded -- buckyballs to cultured cells. The research will focus on solving the interfacing problems between high throughput format (macro scale) and cells, between cells and microfluidic devices, between microfluidic devices and nano buckyballs, and between nano buckyballs and DNA/gene drugs.
NANCY MONTEIRO-RIVIERE North Carolina State University, Raleigh
ANDREW BARRON Rice University, Houston
Nature of Fullerene Nanomaterial Interactions with Biological Systems - $75,000
One of the critical questions in the biology of nanomaterials is how such particles cross membranes to allow for their interaction with cells. Monteiro-Riviere and Barron propose collaborative research to explore the transport nature of specific fullerenes with different substituted amino acids and their interactions with skin cells. The proposed studies are a direct extension of work conducted by the researchers defining the interaction of multi walled carbon nanotubes with human epidermal keratinocytes, and the synthesis on new nano-biohybrid materials by Barron. The researchers aim concerns the nature of a range of different fullerene amino acid sequences that would allow uptake into keratinocytes without producing an adverse effect. Physiochemical properties such as solubility and hydrophobicity, that are used to predict uptake and activity of traditional hydrocarbons, have not been extended to fullerenes. What properties correlate to cell uptake and what properties correlate to cellular activity? Standard cytotoxicity and ultrastructural techniques, extensively employed by the researchers to assess hydrocarbon effects on keratinocyte function, and recently to carbon nanotubes uptake by keratinocytes, will be applied to these experiments. Collaboration between groups will be encouraged by specifically scheduling inter group meetings between the two experimental phases of this project.
THOMAS PERKINS and ROBERT BATEY University of Colorado, Boulder
A Widely Applicable, Highly Sensitive RNA-Based Biosensor - $75,000
When applying biosensors in uses ranging from sequencing a single protein to homeland defense, one wants to rapidly distinguish chemicals and detect even trace quantities reliably. The central issues, therefore, are specificity and sensitivity while eliminating false-positive signals, or background. Perkins and Batey propose a system based on engineered allosteric ribozymes coupled with a nano fluidic flow system and spectrally distinct, fluorescent nano particles that further improves sensitivity. The ribozyme detection module will be designed using features of RNA-based bacterial genetic regulatory elements called riboswitches to overcome the poor performance of previous allosteric ribozymes, which have low sensitivities and poor signal-to-background ratio. This ribozyme's enhanced characteristics will be demonstrated both biochemically and at the single molecule level using fluorescence microscopy. By using in vitro selection, this RNA biosensor will be rapidly adapted to different chemical compounds. In its full implementation, the system is also scalable, allowing for real-time screening of many target compounds in parallel. These funds will help develop a novel allosteric ribozyme detection module, integrate it into a fluorescence microscope flow system, and acquire proof-of-principle data demonstrating an improved signal-to-background ratio acquired.
VINCENT ROTELLO and MARK TUOMINEN University of Massachusetts, Amherst
Integrated Nanoparticle-Protein Nanocomposite Systems - $50,000
Controlled assemblies of nanoparticles provide useful building blocks for pragmatic devices such as biosensors, switches, and high-density magnetic storage arrays. Rotello and Tuominen will integrate the knowledge and tools available from chemistry, biology, and physics to generate functional protein-nanoparticle nanocomposites. In their research, they will use the inherent properties of a well-characterized, stable redox protein, Cytochrome C, to dictate the collective electronic and magnetic behavior of nanoparticle-based ensembles. This will allow for the combination of biomolecular structure and function with tunable nanoparticle properties, and will provide a road map for the creation of new materials featuring novel functional properties.
HOLGER SCHMIDT University of California, Santa Cruz
XING SU Santa Clara, Calif.
Development of Integrated Biophotonic Raman Sensors using Composite Nanoparticles - $50,000
The past few years have seen a continuing development toward integrated systems -- such as "Total analysis systems" and "lab-on-a-chip" -- for medical and biological analysis. Two major trends along this path include miniaturization and increased sensitivity. Nanoparticles have been shown to enable the optical detection of molecule-specific signals with single molecule sensitivity via the surface-enhanced Raman scattering (SERS). At the same time, the optical detection apparatus remained bulky in the form of confocal microscopes or similar setups due to the lack of a way to guide light through picoliter volumes of liquid solution. Schmidt and Su propose to explore the combination of a new type of nanoparticles with integrated liquid-core optical waveguides to form the basis of a new type of ultrasensitive biophotonic detection instrument with unique properties. Both components were developed by the participating PIs. The scope of this proposal encompasses the design of integrated optical waveguides optimized for use with nanoparticle Raman scatterers, the demonstration of Raman spectrum detection from biologically functionalized nanoparticles, and the demonstration of simultaneous detection from parallel waveguide channels filled with different analyte solution on the same chip. The successful completion of these goals will pave the way for a paradigm shift in optical studies of single biomolecules from 3D microscopy to fully planar integrated semiconductor devices that afford highest sensitivity in a low-cost, robust, and highly parallel platform that can be naturally interfaced with other elements in a microfluidic analysis system.