This section of the review describes current limits on the biological aspects of nanotechnology. It outlines selected broad areas of research opportunity, and it sets forth challenges for the intermediate and long-term future.

Enabling Technologies

We owe much of the recent progress in the biological aspects of nanotechnology and nanoparticles to important enabling technologies. Many of these enabling technologies are described in other parts of this report. Those that have had a significant impact on biological measurements include techniques and instrumentation such as optical traps, laser tweezers, and "nano-pokers" to measure femtoNewton forces (Svoboda and Block 1994), and AFM and STM (Wildoer et al. 1998).

There is also a need to move detection away from the ensemble, to the single molecule scale. This includes driving instrumentation toward single-molecule spectroscopy; single-spin detection (Rugar et al. 1994); chemical analysis of nanoliter volumes (Hietpas et al. 1996, 139-158); nuclear magnetic resonance microcoils; nanoscale electrode arrays and chemical sensing and detecting technology (McConnell 1996, 97-102); separations technology; chemical analysis of single cells (Hietpas et al. 1996); new biological transformations; and chemical probes of nanostructures.

Enhanced computational infrastructure, both hardware and algorithm development, will also be required to investigate supramolecular assemblies and to understand interactions that occur over a wide variety of time and length scales. At present, we are fairly well equipped to handle quantum mechanical calculations. At the next level of computational complexity, the molecular dynamics force fields and atomic charges can presently handle up to about a million particles and still retain their accuracy. The next scale of complexity, mesoscale modeling, currently requires the use of pseudo atoms. Much more research is required to improve the accuracy of finite element calculations and the modeling of materials applications (Goddard 1998).

Surface Interactions and the Interface Between Biomolecules and Substrates

Much of the progress in the biological aspects of nanotechnology has come from research on surface interactions. It will be important to continue to develop a better understanding of the interface between biomolecules and surfaces. Of particular interest are questions about whether surfaces cause biomolecules to denature, the optimum length of linker groups, and ways to communicate from the biomolecule, through the linker, to the substrate. Another challenge is to produce nanometer ultrathin films that have stable order (Jaworek et al. 1998).

Robustness of Biomolecules and Their Interactions in Aqueous Solution

Although much progress has been made on ways to confer additional robustness on biomolecules, it will be necessary to continue to improve the stability and reliability of biomolecular assemblies. Such research may be along the lines of understanding the thermal stability of biomolecules, perhaps by examining extremophiles and molecules produced by directed evolution. It will also be necessary to produce molecules that can work in the absence of water, or to devise ways in which aqueous solutions can be used reliably.

Assemblers or Templating

The hierarchical self-assembly of biomolecules is often touted as one of their key attributes for nanotechnology applications. However, there remains much to be learned about how to make periodic arrays of biomolecular assemblies, how to use biological templating in an efficient manner, how to mimic biological self-assembly with nonbiological molecules, and how to exploit differences between biological and nonbiological self-assembly.

Combinatorial Approaches to Nanotechnology

Combinatorial chemistry has had an enormous impact on drug discovery and development in the past several years. Ability to develop molecularly sensitive screening techniques is one of the limiting factors of combinatorial chemistry. It would be intriguing to discover screening methods that are particularly sensitive for picking up new phenomena exhibited by biological nanoparticles.

Biomimetics and Polymer-Biopolymer Chimeras

The largest impact of biological sciences on nanotechnology may prove to be through the lessons one can learn from biology, rather than from directly employing the biological molecules themselves. To this end, it is important to support research on various aspects of biomimetics, including activities in which synthetic and biologically-based molecules are combined in chimeric fashion.

Published: September 1999; WTEC Hyper-Librarian