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Advances in nanotechnology research, development, translation and regula= tion are currently impeded by the lack of an informatics infrastructure tha= t permits greater collaboration among the different disciplines, entities a= nd stakeholders engaged in nanoscience and nanotechnology. Despite ample pr= ecedent in related fields, only recently has a consensus begun to emerge ab= out specific needs in nanoinformatics and possible collaborative approaches= to satisfy them. An exchange of ideas on informatics requirements among th= e various communities of interest would be helpful in developing a broader = consensus. The purpose of this note is to initiate such a dialogue, but in = the actionable context of identifying pilot projects in areas of critical n= eed, critiquing the pilot=E2=80=99s capabilities with respect to realistic = user scenarios, and collaboratively iterating their design, functionality, = and interfaces to satisfy the community of interest=E2=80=99s requirements.= The definition of =E2=80=9Ccommunity of interest=E2=80=9D is therefore the= collection of stakeholders with a need for the pilot=E2=80=99s capability = with resources available to develop it and a willingness to engage collabor= atively. This note will present a high-level view of some expressed needs a= nd =E2=80=9Cseed=E2=80=9D pilot projects which may be especially pertinent.= Finally, this document is intended to be a working document which will be = updated with input from others interested in nanoinformatics. The current d= ocument stresses nanobiology and nanomedicine, whereas the goal is to colla= boratively produce a document with a more comprehensive scope. Please addre= ss any comments to Martin Fritts (frittsmj@mail.nih.gov) or Raul= Cachau (cachaur@mail.nih.gov).
Currently there is fairly wide agreement that there is a lack of reliabl= e, curated data in nanotechnology. Discussion of =E2=80=9Cminimum required = characterization=E2=80=9D for nanomaterial has continued over the last few = years, and interlaboratory testing has been initiated to quantify the accur= acy of current measurement methods and protocols. However, because of a pre= vious lack of adequate characterization of nanomaterial, especially with re= spect to its structure, polydispersity, purity, stability and lot-to-lot va= riability, the amount of publicly available data that can be used to correl= ate the structure of a nanomaterial with its activity is small. Furthermore= , there remains a lack of:
Without such data concerning the linkage between the structure of nanoma= terial and its activity, rational design of nanotechnology-enabled products= is not possible.
The most urgent need for a nanoinformatics infrastructure is therefore t= o collect, curate, annotate, organize and archive the available data. There= must be a common understanding of the characterization required to provide= sufficient knowledge of both a material=E2=80=99s structure and its activi= ty in different biological environments, cell lines and animal models, inte= rlaboratory testing to quantify the error, uncertainty and sensitivity of t= he data, and study materials to support those tests as well as instrument a= nd method calibration. In addition to archiving the data, expert annotation= s and analysis regarding its quality and extent of validity, the infrastruc= ture should allow for a federated system of public/private databases with a= dequate, layered access control to allow aggregation among public and priva= te data where possible. For example, in nanomedicine this data would includ= e the results of pre-clinical and (blinded) clinical trails to allow for es= tablishing correlations of benefit and risk across populations and sub-popu= lations.
The second requirement for the informatics infrastructure is to provide = a semantically rich mechanism to search for and retrieve data within a set = of federated databases and systems. This implies methods to map among the k= eywords, vocabularies, taxonomies and ontologies describing the metadata em= ployed by each of the database systems as well as advanced methods that all= ow for building logically linked, range-limited searches using valid values= for nanomaterial properties and measurement data, and including curated an= notation and comment. Ontology development for different namespaces is ther= efore a critical requirement. A key capability to specify nanomaterial stru= ctural motifs of interest would provide the capability to discern correlati= ons among nanoparticle structures and functionalizations and their activity= in specific environments. A nanomaterial registry would be mandatory to be= gin to establish the link between metadata descriptions and the actual nano= material tested, the effect of differences in similar structures on their a= ctivity, the lot-to-lot variation in manufacture and resultant difference i= n test results, and the establishment of unique identifiers for study mater= ial and standard reference material. The nanoinformatics system should also= aid in establishing nanomaterial repositories to be used in storing and de= livering study material for interlaboratory tests, in conducting those test= s and analyzing their results. Again, in the example of nanomedicine, searc= hes based on patient genetic and diagnostic information would enable the de= velopment of personalized, targeted treatments and a reduction in undesirab= le side-effects.
The third requirement is for an infrastructure to support modeling and s= imulation. A predictive capability based on the nanomaterial=E2=80=99s stru= cture and the underlying physical, chemical and biological mechanisms of it= s interaction with its environment provides methods to test hypotheses and = to advance both the science and the technology. Without that capability we = have at best good observation, but no method other than testing to guide de= velopment. Previous examples of scientific and technology development clear= ly indicate that combining characterization and test with modeling and simu= lation accelerates the development cycle and translation to market. There i= s no indication that nanotechnology is an exception to that paradigm. What = is need, therefore, are freely available structural models for nanomaterial= as well as free, open-source methods for model sharing and development. Th= e current cycle for duplicating a modeling result reported through the lite= rature is measured in years: sharing code establishes collaborations in day= s. Again, to use the field of nanomedicine, the development of small-molecu= le drugs accelerated only when the basic structural motifs for those molecu= les could be identified and correlated with their effects so that modeling = of mechanism could be used to augment test. The required nanoinformatics in= frastructure must support such collaborative efforts.as well as links to re= quired computational resources.
By satisfying these three basic requirements for the nanoinformatics inf= rastructure we can establish the larger communities of interest in differen= t applications of nanotechnology. If we continue to progress application by= application, agency by agency, and institution by institution we will nece= ssarily realize slow progress. But if we establish viable communities of in= terest =E2=80=93 by definition, each participant actively supporting their = collaborative ventures =E2=80=93 then we will accrue great benefit. In addi= tion to more rapid progress due to more facile teaming, access to extensive= resources, and shared expertise, we will be able to benefit from shared re= sults and expertise among related collaborations. For example, partnering i= n instrument development would make available both broader markets and more= specific requirements by linking requirements for research with those for = nanomaterial development, for quality assurance in large scale manufacture,= and for regulatory and field testing, thereby providing longer term planni= ng for increasing market size with maturing capability.
In the following sections examples of existing capability and promising = pilots are mentioned. In addition, there have been attempts at establishing= different communities of interest in these project areas. They are referen= ced in connection with ongoing or evolving projects rather than being liste= d separately.
Definition: In this document =E2=80=9Ccharacterization=E2=80=9D includes= physico-chemical, in vitro and in vivo testing to determine the structure = and properties of nanomaterials and their effects in relevant biological en= vironments.
Most existing public nanomaterial databases gather, organize and archive= published papers on nanomaterial characterization or references to those p= apers. Although publications provide an overview of an experiment, analysis= or computation, they rarely provide sufficient data and information to all= ow rapid duplication of the published results. This is particularly true in= nanotechnology: for example, nanoparticles are generally both polymorphic = and polydisperse, and detailed knowledge of the sensitivity of the results = of a characterization on the variation in structure of the subpopulations i= s generally not reported. Instead, results are frequently attributed to an = ideal, monodisperse structure. Finally, there currently exists no generally= accepted mechanism for sharing proprietary nanomaterial data. As a result,= the raw data and supplementary data that would be so useful in evaluating = error, uncertainty and sensitivity are lacking.
There have been some efforts made to rectify these shortcomings in the a= vailable data.
Standard measurement protocols for nanomaterials are now being becoming = available through the standards development organizations (SDOs). Standards= have been completed and are under development at both ATSM and ISO. Althou= gh many laboratories have developed protocols which include controls to tes= t for interference by different classes of nanomaterials, there is generall= y little incentive for providing the resources necessary to turn those prot= ocols into a viable standard. NCI=E2=80=99s Nanotechnology Characterization= Laboratory (NCL) is one of the exceptions to that rule: NCL has published = its protocols on its website and many of the developing standards at ISO an= d ASTM are based on those protocols. However, the resources available to de= velop standard protocols are limited. Although the pool of experts in stand= ard development is generally shared among the different SDOs, collaborative= standard development is hindered by competition among the SDOs. A pilot ef= fort has been proposed to establish a collaborative =E2=80=9Cpre-standards= =E2=80=9D protocol development using shared electronic tools, but that conc= ept has been embraced solely by ASTM at present.
The utility of a given standard characterization protocol is limited if = the error and uncertainty associated with the result in unknown. The determ= ination of the error and uncertainty of the test results for a new standard= are provided by conducting an interlaboratory study (ILS) through a sponso= ring organization, although ASTM provides the management and financial reso= urces for an ILS for any of the standard protocols it develops. A new organ= ization, the International Alliance for Harmonization in Nanotechnology (IA= NH), has recently been formed to close the gap in sponsorship of ILS and to= provide a quantitative measure of the reliability and repeatability of sta= ndard protocols. Several ILS studies are currently underway through sponsor= ship by the IANH, ASTM, and other participating organizations.
At present it is difficult (in some instances impossible) to correlate t= est results found in the literature on similar nanomaterials. Any given typ= e of nanomaterial may be manufactured through a number of different procedu= res involving different precursors, reagents and excipients, producing diff= erent products and contaminants. Even when a given procedure is repeated by= the same hands, results may vary because of uncontrolled environmental con= ditions, variability in reagents, reactivities and timings, as well as inst= rument drift and calibration error. As a result, a given nanomaterial may h= ave a very significant lot-to-lot variability even when produced by the sam= e expert. In addition, material stability and storage conditions may increa= se its variability. For that reason large lots of reference materials are n= ecessary for use in interlaboratory studies to ensure that, as nearly as po= ssible, all tests are performed using aliquots of the same material. This i= s true for determining the physical and chemical properties of the material= s themselves, but even more so for in vitro or in vivo tests which also mus= t contend with a large variability in cell lines and animal models. As a re= sult there is a great need for certified reference materials, standard refe= rence materials and study materials to provide instrument calibration, prot= ocol controls and reference measurements to track similarities and differen= ces among lots. Without the reference points, correlating results on the = =E2=80=9Csame=E2=80=9D nanomaterial produced by different labs can be extre= mely difficult.
Just two years ago NIST produced its first batches of standard reference= nanomaterial, gold colloids with nominal sizes of 10, 30 and 60 nanometers= . That material was used for the ASTM ILS studies concluded one year ago an= d is available at moderate cost for other laboratory and interlaboratory st= udies. The OECD has called for the initiation of similar interlaboratory st= udies using large batches of material, and some of those studies are curren= tly underway under the sponsorship of different participating labs as well = as by the IANH. It should be noted that these materials are in general obta= ined through commercial vendors of the materials in large lots, perhaps by = blending several smaller lots. An initial characterization is performed on = the materials by the providers.
To provide for some uniformity in how nanomaterial characterization is p= erformed, several new pilot efforts are underway to standardize the number = and types of protocols that should be performed on nanomaterials to establi= sh some meaningful measure of the quality and reliability of published and = private data. These efforts tend to follow the spirit of the MIAME (Minimum= Information About a Microarray Experiment) standard by the MGED Society wh= ich =E2=80=9Cspecifies all the information necessary to interpret the resul= ts of the experiment unambiguously and to potentially reproduce the experim= ent.=E2=80=9D For example the Min Char (Minimum Information for Nanomateria= l Characterization) Initiative has published a suggested minimum list of pa= rameters necessary to characterize nanomaterial as well as some supplementa= ry considerations that should be considered for completeness- http://characterizationmatters.org/ . Other organizations such as the = OECD and several SDOs are considering other recommendations for additional = characterizations. However, there is not yet movement toward an overall cla= ssification scheme for different levels of characterization that would be u= seful in annotating nanomaterial data as to its degree of quality and relia= bility. Some of the underlying issues, such as aggregating information on t= he interference produced by certain nanomaterial types, sizes and functiona= lizations, and the effects of sample preparation are actively being conside= red, and have initiated other efforts in data characterization standards su= ch as that of caBIG=E2=80=99s Nanotechnology Working Group. In particular O= NAMI is developing a Nanomaterial-Biological Interaction Knowledgebase to a= id in interpretation of the effects of nanomaterial exposures as well as in= novative rapid in vivo assessments of potential toxicity at multiple levels= of biological organization (molecular, cellular, system and organism) usin= g embryonic zebrafish.
While structural motifs such as alpha helices and beta sheets and strand= s have provided insight into protein folding, function, and interaction, th= ere exists no similar body of knowledge concerning structural motifs for na= nomaterial and their interactions with other molecules and assemblies. Furt= hermore, there currently is no recognized repository for nanomaterial struc= tures similar to the PDB for proteins. In addition, real nanomaterials are = polydisperse and polymorphic, creating a further complexity due to the need= to develop structures for each of the material=E2=80=99s subpopulations. F= inally, nanomaterial is frequently functionalized through the attachment of= ligands, other molecules such as drugs or antibodies, or even other nanopa= rticles. Because of this inherent complexity, nanotechnology currently does= not have a structural database to serve as a common resource and focus for= research on the biological interactions of nanomaterial. Over the past few= years Raul Cachau of the NCI=E2=80=99s Advanced Biomedical Computing Cente= r and his collaborators at the University of Talca in Chile, Bowie State Un= iversity in Maryland have developed a pilot database for nanoparticles whic= h an annotation facility to aid in the identification of structural motifs = in nanomaterial and elucidation of their role in biological interactions. T= he pilot database is part of the Collaboratory for Structural Nanobiology (= CSN) (aka. The Linnaeus Project) and serves as a focus for several projects= in nanoinformatics and modeling discussed below. The CSN also incorporates= a wiki to permit rapid annotation of the structures and to facilitate coll= aboration, an ISBN number to ensure permanent archiving of material develop= ed on the site, and a capacity for storing and sharing computer models.
An important area of activity involving new pilots is that of database f= ederation. Although currently nanotechnology databases cite and link to eac= h other, only recently have there been discussions of federating different = databases to permit common searches through all the databases in a federati= on. Such federation would provide more than ease of search: with sufficient= capability to safeguard proprietary data, federation would permit searches= over both public and private data in a controlled manner, greatly expandin= g the amount of data available, and creating a mechanism for expert annotat= ion and curation of data at its source. This is particularly important due = to the fact that most nanomaterial data is available through publications a= nd that it will be otherwise difficult to annotate this data with regard to= its quality and reliability (as discussed above) lacking such a mechanism.= The topic has been discussed at several recent workshops including the 200= 8 NanoHealth Enterprise Workshop (now the NanoHealth and Safety Enterprise)= and the October 10, 2008 NIST Nanoinformatics Workshop, as well as ongoing= work in caBIG;s Nanotechnology Working Group. Databases currently being co= nsidered for a pilot federation include NCI=E2=80=99s caNanoLAB, the CSN, O= NAMI, NNI=E2=80=99s NanoHUB (http://nanohub.org/ ) and the National Nanom= anufacturing Network (http://www2a.cdc.gov/niosh-nil/), and N= IOSH=E2=80=99s Nanoparticle Information Library (http://www2a.cdc= .gov/niosh-nil/) with possible participation by both the EPA and FDA. L= inks to ICON (http://www.goodnanogu= ide.org/tiki-index.php?page=3DHomePage ) and Nanowerk (http://www.nanowerk.com/phpscripts/n_dbsearch.php ) are = also being discussed.
It is important to realize that there is a need for access to better ins= trumentation for characterization of nanomaterial and determination of its = structure. Although NIH has traditionally provided access to US national fa= cilities as Light and Neutron Sources necessary for diffraction studies, th= e usage of these facilities has been low. Raul Cachau (NCI, ABCC) has propo= sed a new effort to establish user centers to help scientists access these = facilities by providing help with the detailed and sometime onerous demands= required for sample preparation, remote operation and data archiving and a= nalysis. Such resources could greatly increase the utility of these facilit= ies for scientists involved in nanotechnology for the biological sciences a= nd medicine. There is also a related need that has not yet resulted in a pi= lot application, and that is for collaborative development of new instrumen= tation for more detailed characterization of nanomaterial including ligand = distributions. There are several very promising new methods which could aid= biological; and medical applications of nanotechnology, especially low ene= rgy electron microscopy, terahertz spectroscopy, and single molecule spectr= oscopy. Collaborative development of such instrumentation between manufactu= rers and researchers could accelerate their availability. By developing com= prehensive requirements for research, scale-up, full-scale manufacture, and= regulation, manufacturers would be aware of the extent of the market for t= his instrumentation and the differing requirements for each stage of develo= pment while the field could benefit from early testing to advance promising= research and applications more quickly
A semantic search capability offers very significant advantages over key= word search. Because search terms are not only defined but also have define= d relations to other search terms, the number of false returns is greatly r= educed. Furthermore, since valid values are also defined, searches such as = =E2=80=9Cpegylated gold nanoparticles with size between 20 and 60 nm=E2=80= =9D become possible. Although the infrastructure required to institute such= capability is significant, the development of ontologies for nanomaterial = is proceeding with several notable examples. As the Semantic Web comes clos= er to realization, =E2=80=9Cnamespaces=E2=80=9D consisting of practitioners= with identifiable disciplines (e.g. toxicologists, cell biologists, =E2=80= =A6) will begin to formulate their own ontologies which could be adapted fr= eely. Indeed, nanomaterial ontologies have already reached some maturity wi= th the Nanoparticle Ontology (NPO) at Washington University, caNanoLAB=E2= =80=99s ontology, and the Japanese Nanomateria Platform ontology and are be= ing used in conjunction with pilot databases. These activities take advanta= ge of existing expertise and organizational bodies such as Open Biomedical = Ontologies (OBO) as well as new tools for mapping among ontologies such as = Biomed GT. Other activities are also underway such as ASTM and ISO developm= ent of standard ontologies and Norway=E2=80=99s new Ontolution Nano Project= . Finally, the need for a nanomaterial registry to aid in relating specific= nanomaterial lots to the ontology terms describing their composition and s= tructure is now recognized with NIBIB issuing a new RFA for development of = a nanomaterial registry.
Support for modeling and simulation in nanotechnology has largely been p= roceeding piecemeal with separate efforts within different agencies and ins= titutions, The prime major exception to that rule is NanoHUB which hosts se= lected applications and tools for use on demand throughout the nanotechnolo= gy community and which has seen continually increasing usage of their resou= rces. Another is the previously mentioned CSN which hosts over 150 structur= al nanoparticle models currently that are freely available for use in model= ing and simulation codes. The CSN will also make available computer codes, = run parameters and validation suites for open source codes in the future, t= ogether with the wiki forum for collaborative development of tools and soft= ware. The EPA=E2=80=99s National Center for Computational Toxicology - h= ttp://www.epa.gov/ncct/ - provides relevant models but is not currently= nano-related. The ACTION-Grid, a EU 7th Framework project invol= ving nanoinformatics, personalized medicine and grid computation, is a rece= nt promising addition in this area. As mentioned above, new pilot activitie= s are currently being discussed for modeling and simulation activities rang= ing from structure/activity relationships through quantum-based first princ= iples applications and models for exposure and risk.