Nanomedicine is medical treatment at the level of single molecules or molecular assemblies that provide structure, control, signaling, homeostasis, and motility in cells, ie, at the "nano" scale of about 100 nm or less. There have been many scientific and technological advances in both the physical and biological sciences over the past several years that make nanomedicine research particularly attractive at this time. For example, new tools are being developed that permit imaging of structure at this scale, high speed measurement of the dynamic behavior of these molecular assemblies, and the forces produced by molecular machines as well as the forces needed to disrupt them. These advances are complemented, on the biological side, by the dramatically expanded knowledge of the human genome, a greater understanding of the pathophysiology of specific diseases at the molecular scale, the need to develop more specific treatments of disease, and the desire to understand the dynamic behavior of dysfunctional cellular machinery in the context of the total cell machinery.

The need for more precise measurements of the behavior of the nanomachinery within cells combined with the expanding array of tools capable of making these measurements led to the identification of Nanomedicine as one of five initiatives included under the major NIH Roadmap theme of "New Pathways to Discovery" (http://nihroadmap.nih.gov/). To begin this initiative, the Nanomedicine Roadmap implementation group has devised a novel process for developing Nanomedicine Centers where scientists, engineers, and mathematicians can work together to define and characterize the physical properties of selected cellular machines or assemblies leading to the ability to predict their function in both the normal and diseased states. The process for establishing these centers is unique and will involve a high level of interaction between the biomedical scientific community and the NIH (see below, "Implementation").

This Nanomedicine initiative represents part of a larger nanotechnology research effort of the NIH sponsored by individual institutes. Similar to other Roadmap initiatives, Nanomedicine is multidisciplinary. Unlike individual institute programs, this Nanomedicine Roadmap initiative will be widely applicable to the biomedical sciences of interest to medical and scientific communities served by most of the NIH institutes.

The NIH Nanomedicine Vision

The long-term goal of the Nanomedicine roadmap initiative is to characterize quantitatively the molecular scale components or nanomachinery of the cell and to control and manipulate these molecules and supramolecular assemblies in living cells to improve human health. There are currently many efforts underway across the NIH to understand the role of specific proteins and complexes in many diseases as well as efforts to develop treatments for these diseases. What distinguishes this effort is a long-term focus on characterizing all cellular processes and machinery and their interactions at a level of precision that has not been achieved to date. The Nanomedicine Roadmap Initiative will exploit and build upon the concepts, information, materials, and tools developed by research in nanotechnology, and apply them to studies of molecular systems in living cells. Inside cells, there exist many nanoscale processes and structures, such as the self-assembly of protein-DNA complexes, as well as nanomachines, such as molecular motors. Well controlled manipulation of these and other known intracellular molecules and processes has not yet been achieved. As the first step, this initiative will define what is needed to precisely control cellular events at the molecular level, collect precise data, and develop the concepts, models, and physical tools required for manipulating these processes and components in living cells. We anticipate that these tools and knowledge eventually will provide a scientific basis to repair or replace damaged or diseased cellular systems.

Precise control of molecular processes requires extensive knowledge about the physical properties of molecules and assemblies. A major goal of this initiative is to use engineering principles to manipulate cellular components. To this end, the approach will be informed by the design principles gleaned from knowledge of molecular processes and structures in living cells. In other words, biological tissues have evolved elegant, intricate pathways, molecular structures, and "devices" at the nanoscale. Ultimately, the goal is to develop design principles for assembly and function of nanoscale devices for biomedical use, based on information that we will learn from nature's nanosystems.

The NIH Roadmap Nanomedicine Initiative complements other governmental initiatives in nanotechnology. This Nanomedicine Initiative is distinguished by its focus on fundamental processes and design principles from biology that will be widely applicable for improving health and curing disease. Consequently, this initiative takes a longer-term view, attempting to address fundamental problems whose solutions would be important for researchers in all the biomedical sciences.

Achieving the Vision

The long-term goal of this initiative is to manipulate biology's nanosystems within living cells in order to improve health by engineering tools, devices, and molecules to interface with these nanostructures. To do so, we must identify and understand the physical and chemical characteristics and interactions of molecular machines and assemblies for biological model systems. At present, there are significant gaps in our knowledge about most of the physical characteristics of cellular components such as their exact quantities and variations, location, time scales, interactions, affinities, force generation, flexibility and internal motion. Progress, using analytical models of molecular interactions already in hand, is stymied by this lack of information. More comprehensive models describing cellular structures and associations will be developed using the knowledge gained from such precise quantitative physical measurements. To do so, new physical methods, instruments, and tools must be developed. In addition, computational tools for data collection, storage, analysis and dissemination must be refined. Ultimately, the goal is to generate a complete physical and biochemical description of cellular molecules, molecular assemblies, and machines.

In examining the long-term horizon, we expect that the next level of investigation would attempt to identify and define the design principles and operational parameters of naturally occurring nanostructures and complexes in cells. This knowledge will lead us to develop strategies and fabrication methods that can be used to build synthetic and/or hybrid nanostructures, assemblies and systems ultimately leading to specific control of individual cellular components, possibly as small as a single molecule or as large as an organelle, in order to treat disease or repair damage.

If we are to achieve improved health by employing new nanoscale materials, then the launch of this initiative also provides the opportunity, indeed bears the responsibility, to determine any deleterious interactions between the physical materials and devices that we develop and biological tissues. Most of the materials that have developed from nanotechnology so far (e.g., carbon nanotubes, quantum dots) were not designed to be compatible with tissues or to be biodegradable. One of our goals is to do just that - to design particles, devices or materials that are based on natural systems and can therefore be used in vivo without causing damage.

A First Step

What do we need to learn in order to engineer molecular-sized components? What types of measurements are lacking but, if made, could propel this effort forward? The following specific examples are presented only to illustrate what we mean by physical, quantitative measurements that may be required to fill gaps in our knowledge. We are not suggesting these as topics of particular interest to this initiative or areas that are any more or less in need than others, but simply as examples to convey the ideas presented above.

Protein-Protein Interactions. Knowledge of protein interactions is crucial for understanding the pathways and networks operating within and between cells. Collection of protein-protein interaction information on a genome-wide basis is now possible. However, most of the approaches available today fall short of gathering the information we really need. Yeast two-hybrid measurements, for example, remove the protein-coding DNA sequences from the cells of origin and place them in an artificial environment. In doing so, subtleties of the influence intracellular milieu are lost. The results are also not quantitative, for instance, with respect to binding constants. The next generation of tools will need to enable both qualitative and quantitative studies on the precise protein interactions in situ.

Intracellular Transport. The transport systems present in eukaryotic cells organize the cytoplasm, move organelles within the cytoplasm, orchestrate and implement the distribution of replicated chromosomes to daughter cells, and are the basic machinery of cellular migration. Years of innovative research have generated detailed knowledge of the cellular organization and control of these dynamic systems. Mathematical models of their operation have been developed, but many key parameters, such as, rates of polymerization, nucleation, capping, or dissociation, must be estimated because they cannot be measured directly. Indeed, measurements central to the functions of these transport systems, such as stresses on the fibers, forces generated by assembly of the fibers or by interactions of fibers with the motors or other cellular structures, and force and dynamics of adhesion to substrates cannot be measured in vivo.

Probing Biomolecular Events. Often, measurements of molecular processes on a biologically relevant time scale are inadequate. For example, studies of second messenger signaling require harvesting tens of thousands of cells to measure significant changes of intracellular concentrations of relevant molecules. The methods require substantial time, at least on the order of seconds, before the first data point is measured. Is 10 seconds a rapid enough measurement? 5 seconds? Are studies with techniques that require such large quantities of material feasible or necessary for precision studies of nanoscale events? Is the information from these types of studies adequate to lead to the precision required for more refined, quantitative models? Clearly, a very different set of tools is needed, with which to probe molecular events inside of cells on biologically-relevant time scales which may be on the order of milliseconds or even microseconds.

These are just a few examples that typify the shortcomings in available technology. A primary goal of the Nanomedicine Initiative is to stimulate development of radically new technologies that might provide novel strategies and new insights for cell biological studies of intracellular molecular interactions. That knowledge of both the biological mechanisms and the physical tools would become the jumping-off point for tools to improve health.

Implementation

To begin to address this emerging vision of Nanomedicine, the NIH will support the formation of Nanomedicine Development Centers in 2005. Initially, work at the Centers will define the measurements and analytical and computational tools needed to understand biological system design at the molecular level. Next, the Centers will also develop those tools and apply them to biological systems, refining the tools as we learn of their power and shortcomings. This, in turn, will lead to using the knowledge to engineer molecular structures, assemblies, and organelles for treating diseased or damaged cells and tissues.

Clearly, these studies will require collaboration by scientists from disciplines that may not typically interact. For example, centers might be populated with cell biologists, mathematicians, biochemists, engineers, molecular biologists, statisticians, etc. A key to progress in nanomedicine is the development of multi- and interdisciplinary teams of scientists who together will define the properties, knowledge, and concepts required by this initiative.

An Exciting New Opportunity: Defining the Nanomedicine Development Centers

This Centers program will be developed and implemented in a different fashion from standard NIH procedures. The structure and components required for the Nanomedicine Development Centers are currently undefined and are likely to be unique to each Center. The NIH Nanomedicine Roadmap Implementation team has devised a novel plan to work with the scientific community in developing the scientific and organizational ideas that will eventually lead to a solicitation for applications to generate these centers. Our plan will be distinguished by a high level of interaction between NIH staff and potential applicants with ample opportunities provided for meetings of the applicants with NIH staff and with other applicants prior to announcing the final solicitation. We expect that this high degree of interaction will lead to development centers that operate as a network with each center working on a unique set of problems.

The development and implementation of the Nanomedicine Roadmap Initiative will remain flexible and continue to evolve, and will be driven by the scientific needs of the program, involving extensive input from the research community. In addition, we expect that this program will provide a more rapid, flexible means for review and funding of the applications than is routinely used by the NIH.

A three-step process for applicants has been developed which is broadly outlined here. The anticipated steps include a late April or early May, 2004 solicitation with the specific information published in the NIH Guide. It is proposed that applicants must participate in each step of the process to be eligible to apply for the Center grant. The first step includes the submission of a concept that broadly outlines the applicant's vision for the content and structure for their nanomedicine center, as well as how planning funds would be used to further develop this vision. After an expedited review, successful applicants will receive an award for developing a more extensive plan for a Nanomedicine Center. The award could be used to assemble potential team members, hold workshops, etc. in order to facilitate the planning and writing of the more extensive concept development plan (step 2). The final solicitation for the Nanomedicine Development Centers will be generated by extracting the best features of the submitted plans and will be published shortly after the concept development plans are submitted. Only applicants who have submitted both the concept and a plan will be eligible to apply for funding for a Nanomedicine Development Center in 2005 (step 3). Pending availability of funds, Nanomedicine Development Centers may also be funded in 2006, and if so, a new round of applications will be accepted that, again, will be open to the entire research community.

*** This description is not a complete, formal description of the process. Session 4 at the upcoming May 4 meeting will be dedicated to a more detailed discussion of this initiative, the timeline, and the requirements at each step of the process.