nanotechnology: emerging developments national cancer...

Disease Markers 18 (2002) 153–158 153IOS Press

Foreword

Nanotechnology: Emerging Developmentsand Early Detection of CancerA Two-Day Workshop sponsored by theNational Cancer Institute and the NationalInstitute of Standards and Technology,August 30–31 2001, on the National Instituteof Standards and Technology Campus,Gaithersburg, MD, USA

Steven J. Zulloa, Sudhir Srivastavab, J. Patrick Looneyc and Peter E. Barkerd

aChemistry and Life Sciences Division, Advanced Technology Program, National Institute of Standards andTechnology, Gaithersburg, MD 20899-4730, USAbCancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 ExecutivePlaza North, Suite 3142, Bethesda, MD 20892, USAcProgram Office, National Institute of Standards and Technology, Gaithersburg, Md 20899-8311, USAdNIST-NCI Biomarkers Validation Laboratory, DNA Technology Group/ Biotechnology Division, National Instituteof Standards and Technology, 100 Bureau Drive, Gaithersburg, MD 20899-8311, USA

Abstract. A recent meeting jointly sponsored by the National Cancer Institute (NCI) and National Institute of Standards andTechnology (NIST) brought together researchers active in nanotechnology and cancer molecular biology to discuss and evaluate theinterface between disciplines. Emerging areas where nanotechnologies may impact cancer prevention and early cancer detectionwere elaborated by key researchers who catalyzed interdisciplinary dialogue aimed at fostering cross-discipline communicationsand future collaboration.

Keywords: Biomarker, cancer detection, nanotechnology, high throughput, microarray, mitochondria

1. Meeting Report

At the workshop (August 30–31, 2001) organizedby the National Cancer Institute (NCI) and the Na-

tional Institute of Standards and Technology (NIST)

on “Nanotechnology in Early Detection of Cancer”,

nanotechnology experts from academia, industry and

government institutions discussed state of the art tech-

ISSN 0278-0240/02/$8.00 2002 – IOS Press. All rights reserved

154 S.J. Zullo et al. / Foreword

nologies and evaluated current and prospective appli-cations of nanotechnology for early cancer detection.Experts from both cancer research and nanotechnologypresented examples from their own research and com-mented on potential impact of novel nano-scale toolsas applied to cancer research.

The workshop of cancer researchers, molecular bi-ologists, chemists, physicists, nanotechnologists, andother scientists, convened at the NIST campus, wasjointly sponsored by the Cancer Biomarkers ResearchGroup of the Division of Cancer Prevention (DCP) ofthe NCI, the DNA Technologies Group/ Chemical Sci-ences and Technology Laboratory (CSTL) of NIST andthe NIST Advanced Technology program (ATP Pro-gram). Dr. Lee Hood, President and Director, In-stitute for Systems Biology, chaired the session Nan-otechnology Devices for Early Detection of Cancer,and Dr. George Whitesides, Professor, Department ofChemistry and Chemical Biology, Harvard University,chaired Nanotechnology Platforms for High Through-put Identification of Biomarkers.

Nanotechnology is defined as the creation of func-tional materials, devices and systems through controlof matter at the scale of 1 to 100 nanometers, and ex-ploitation of novel properties and phenomena at thesame scale. Advances in nanotechnology are the im-petus for the “Next Industrial Revolution” by the Na-tional Nanotechnology Initiative (NNI). One potentialapplication highlighted in the NNI is the detection ofdiseases. This might obviate patient care with a shifttowards early detection and prevention.

The purpose of the workshop was to determine howand when advances in nanotechnologycould be appliedto the early detection of cancer. Topics included lasersto measure optical deformability in cancer cells, detec-tion, sensing and therapeutics through sensors basedon nanoporesand nanomaterials, molecular combing todetect genomic instability, molecular nanomechanicsfor detection of biomolecular interactions, dendrimers,nanodevices and nanotechnology platforms for sens-ing, delivery and therapeutic applications. The Work-shop highlighted the potential nanotechnology has tomake significant contributions to cancer prevention anddetection in addition to diagnosis and treatment. Theconsensus was that, nanotechnology offers importantnew tools for detection at a time when existing moreconventional technologies might be approaching theirlimits. Nanotechnology was identified as a possiblemeans to provide direct readout of genomic and pro-teomic information both at the single-cell and single-molecule level. Its utility in analyzing and characteriz-

ing extremely limiting amounts of biological materialwas also explored. This commentary summarizes thehighlights of the workshop and the recommendationsmade by the leading proponents of nanotechnology.

Dr. Peter Greenwald (Director, Division of CancerPrevention, National Cancer Institute) described DCPgoals that could be reached with the help of advancesin nanotechnology: (1) research on biomarkers, and (2)clinical trials in early detection and prevention of can-cer, with the aims of reducing the incidence and mortal-ity rates of cancer. Nanotechnology offers to help refineearly detection and diagnostics to provide endpointsfor cancer prevention and help drive improvements incancer therapy.

Dr. Hratch Semerjian (Director, CSTL) describedbiotechnology-related research conducted in NISTlaboratories, particularly in the NIST BiotechnologyDivision, including the Center for Advanced Re-search in Biotechnology (CARB), a joint University ofMaryland-NIST endeavor. Dr. Semerjian describedthe long history of collaboration between NIST and theNCI, especially in the area of clinical laboratory qualityassurance programs. He noted that this meeting wasbeing held on the first anniversary of the interagencyagreement on biomarker validation that involves NISTand the NCI.

2. NCI Vision of Nanotechnology

Cancer is a series of diseases rather than one singledisease. All of these diseases involve changes in thegenetic code of cells, resulting in altered expression ofgene products, RNA, and protein. Protein interactionsare critical to the genesis of the cancerous cells and tothe response to therapy and interventions. Understand-ing these critical interactions enables researchers to de-velop the technologies needed to take the next steps inthe discovery process.

Cancer currently is being missed at its earliest stages,in part because detection methods are not directed atcellular changes of carcinogenesis. The NCI is encour-aging discovery and elaboration of those early cellularchanges. The NCI will further derive information onbiomarkers as well as define significant opportunities todefine diagnostically useful signatures for determiningthe next step of therapy, treatment, or prevention. NCIis also supporting identification of new biological tar-gets for treatment and prevention at the molecular level.To shift from therapeutic to a preventive mode, a newnano-scale tool kit is needed to: (1) detect biomark-

S.J. Zullo et al. / Foreword 155

ers, signatures, and targets; (2) determine their bestuses; (3) apply them in the early stages of cancer de-velopment; and (4) measure, analyze, and manipulatemolecular processes at scale and in context.

Nanotechnology will help define cancers by molec-ular signatures denoting processes that reflect funda-mental changes in cells and tissues that lead to cancer.To support the measurement, analysis, and manipula-tion of molecular processes at scale and in context, newtechnologies will be needed. These ultimately will be-come the first wave of clinical tools to examine tissuesand samples, pushing towards an entirely new methodof addressing cancer that integrates detection, diagno-sis, and intervention on a common technology plat-form. A series of questions arose: (1) Can nanotech-nology enable the cancer research community to meetthe challenges associated with early detection, (2) Whatare the promising novel technologies, (3) How can theintegration of nanotechnology development in cancerresearch be encouraged and fostered, and (4) How canthe cancer and nanotechnology research communitiesbe brought together?

There are a number of NIH-sponsored programs thatsupport development of new technologies for this toolkit, including the Innovative Molecular Analysis Tech-nologies Program (IMAT) (URL: http://otir.nci.nih.gov/tech/imat.html). Advancing the technology ofearly cancer detection to enable new applications andallow for higher throughput at reduced cost requires in-creased automation, increased parallel processing, andminiaturization with reductions in scale. In develop-ing molecular analysis technologies, the push to reducescale has proceeded through the range of microdynam-ics and microfluidics into the realm of nanotechnology.It is hoped that this push will extend into detection, giv-ing clinicians and researchers the opportunity to detectcancerous processes inside the body at an early stage ina noninvasive or minimally invasive manner. Advancesin nanotechnology hopefully will allow researchers todevelop biomolecular sensors that will enable informa-tive feedback loops to: (1) find early signatures of dis-ease; (2) diagnose what intervention is needed; and (3)determine the effectiveness of treatments.

The trend toward technology reductions of sizeapproaching the nano-scale is driven by the advan-tage of working in a size context compatible withuse in the human body. Nano-technological ad-vances have expanded understanding of the struc-ture, function, and relationships of biological macro-molecules as well as the creation of new devices thathave the capabilities for producing functional ma-

terials at scale, although their role is still emerg-ing. Three NCI-sponsored programs that are uti-lizing nanotechnological advances in biomarker ex-periments include the Unconventional InnovationsProgram (URL: http://otir.nci.nih.gov/tech/uip.html );the NCI/National Aeronautics and Space Administra-tion Collaboration on Biomolecular Sensors (URL:http://nasa-nci.arc.nasa.gov/), and the NCI Early De-tection Research Network (EDRN)(URL: http://www3.cancer.gov/prevention/cbrg/edrn/).

3. NIST Activities in Nanotechnology

NIST laboratories are organized primarily by dis-cipline, although many NIST programs are interdis-ciplinary and span laboratories. The primary role ofNIST is in measurement science and measurementsof fundamental physical phenomena. Thus nanotech-nology presents tremendous challenges to ongoing re-search and applications at NIST. The NIST role in nan-otechnology is to develop measurements and standardsthat will guide and expedite the development of newnanotechnologies. As manufacturing nano-devices de-velops, NIST will help develop benchmark measure-ments that will be critical for understanding the perfor-mance of nano-devices and nanoscale phenomena.

Current NIST nano-scale activities include workin photolithography, molecular electronics, materi-als characterization, chemical imaging, and biologicalmeasurements. For example, NIST recently developeda nano-scale physics facility, at which researchers fab-ricate structures on surfaces under strictly controlledconditions and ask fundamental questions about whathappens when one or more atoms are put together.This work ranges from quantum mechanical phenom-ena to macroscopic phenomena, and holds the poten-tial for new science to emerge as novel capabilitiesare developed in response to newly established bench-marks. Private sector firms, often teamed with univer-sity collaborators, are funded by the Advanced Tech-nology Program (ATP) to conduct much of the extra-mural NIST nanotechnology research. ATP supportsa wide range of innovative, advanced technologies viacompetitive peer-reviewed government-industry cost-share awards. These include nano-structured ma-terials, nano-diagnostics, and nano-fabrication. Inthe most recently completed competition (Fiscal Year2001), awards were made for nano-scale technologies(http://www.atp.nist.gov/awards/2001list.htm).


4. Nanotechnology Devices for Early Detection ofCancer

Dr. Hood commented that cancer diagnosis, cancertherapy, and cancer prevention must be closely inte-grated, as all deal with similar sets of biological infor-mation. This will lead to individualized medicine incancer diagnosis and treatment. Thus, there are differ-ent dimensions of stratification and progression that re-searchers must address. Prostate cancer, for example,may have three or four biologically different stages,each with the different ability to progress. Multi-parameter analyses can be used to distinguish these twoprocesses from each other. The ability to comprehen-sively profile proteins in blood would be a tremendousadvance. However, a significant challenge to high-precision multi-parameter analyses in blood is dealingwith large amounts of serum albumin. DNA arrayscombined with nano-devices can identify moleculesthat are tissue-specific, which would allow for the iden-tification of tissue-specific markers for diagnostic pur-poses and ultimately, create an antibody molecule thatactivates the innate immune system. Nanotechnologyoffers the ability to interrogate cells, in blood, and inbiopsies in the future. The nanotechnology approachto diagnostics and therapeutics combines genomics,proteomics, protein engineering, and cellular manip-ulation. Nanotechnology opportunities emerging forcancer diagnostics, therapeutics, and prevention willinvolve single-molecule analysis, single-cell analysis,small cell populations, and multi-parameter analysis.Microfluidics and microelectronics will provide keyand striking opportunities, and these technologies willmove down in scale to the nano-realm. With the PSAtest (prostate specific antigen, or kallikrein 3), cancercan be identified relatively early. With nanotechnologymultiple biopsies may become possible, and with thisthe ability to analyze specific and multiple analytesinvivo.

Nanotechnology provides new ways to decipher bi-ological information. One possibility is application ofnanopores to sequence DNA and characterize proteinsand other molecules. The ability to genotype at veryhigh throughputwill be exceptionally important. Meet-ing participants noted that it might be necessary to ex-amine 100,000–500,000 genetic markers in an individ-ual to carry out a comprehensive sophisticated detailedgenetic analysis. Current conventional techniques areexpensive, costing up to $1.50 per marker. Dr. Hoodnoted that nanotechnology offers possibilities for de-tection of RNA splicing, examining proteins, and as-

saying cellular behaviors at the level of single cells.He closed his remarks by stating that members of thebreakout group felt strongly that the progression ofmicro-fluidics and micro-electronics into nanotechnol-ogy is a powerful and exciting development. This de-velopmenthas potential to transform the areas of cancerdiagnostics, therapeutics, and prevention.

To be useful, technology must move towards in-creased miniaturization, offer parallel analyses and in-tegration in an automated system. Particular opportu-nities will offer a view of single molecules, single cells,and in small samples. Multiplex analyses will be im-portant; and all the advantages of micro-fluidics, mi-crostructure, and nanotechnology will be needed. Forexample, in prostate cancer, there can be two differenttypes of prostate cancer cells. In one, the localizedcancer cell is virtually identical to a luminal cell, whilein metastatic cancer, the cell is virtually identical byphenotype to normal stem cells. There are different cellsurface markers on these two cell types. It is possibleto identify a whole series of cell surface markers

Researchers, when developing technology at thenanometer scale, should bear in mind dynamic range,techniques for RNA expression and RNA splicing. Par-ticularly in cancer, detection methods capitalize on am-plification technologies, while proteomics initiativesare disadvantaged by the lack of appropriate tech-nology for protein amplification, although phage dis-play technologies do offer potential in that the detec-tion molecule can be amplified. In this and other ap-proaches, sensitivity of detection is preeminent.

Thus, nanotechnology may enable detection of sin-gle cell phenotype. Indeed, analysis, diagnosis, treat-ment, and ultimately prevention are all interrelated.The current approach begins with microarrays to inter-rogate multiple tissues to determine specific geneticallydetermined characteristics, or cellular phenotypes. Thepower of proteomics is then brought to bear on the sys-tem under examination, for example, by finding a tissuespecific cell surface molecule against which to raise anantibody to detect the errant cell. The ultimate goalthen of the genomics, proteomics, protein engineeringand cellular manipulation, is to activate the innate im-mune system, utilizing the molecular specificity andengineering of the living organism in a coherent inte-grated systems approach to diagnosis and treatment ofcancer.

S.J. Zullo et al. / Foreword 157

5. Nanotechnology Platforms for HighThroughput Identification of Biomarkers

Pursuing advances in nanotechnology is worthwhile,as the research science holds potential for significanttechnical contributions to the prevention, detection, di-agnosis, and treatment of cancer. Dr. Whitesidesnoted that these are areas in which tools are desperatelyneeded, and mechanisms to support the developmentof tools should be improved, particularly on the partof the NIH. The support roles of the NIST intramurallaboratories, and the extramural ATP, also address andpromote this expressed need for nanotechnology tooldevelopment.

Nanotechnology holds promise for providing newtools for understanding the cell, the differences be-tween normal and abnormal cells, and the mechanismsof communication between them. This informationis fundamental to design of cancer detection and pre-vention strategies. Nanotechnology may also providenondestructive “windows” into cells, with the ability tomanufacture particles or probes that are small enoughto be inserted into cells and monitor in real time withoutdamaging the cell. Nanotechnology offers the chanceto explore the mechanical properties of the cell, in-cluding energy metabolism, morphology, cytoskeletaldevelopment, internal fluid flows, transport of compo-nents, and signaling pathways. In diagnosis and treat-ment, single cell analysis, characterization of tumormargins, isolation of rare cells from blood, and newtools for imaging may be possible with advances innanotechnology. Dr. Whitesides noted that it wouldbe difficult to determine whom to screen with this newtechnology, if it develops to an appropriate level.

One of the major challenges to developing this po-tential synergy is finding ways to bring the physics andengineering communities together with biologists andclinicians in a more productive social milieu. There is afundamental distinction between the physical sciences,which tend to be mathematical and quantitative, and thebiological sciences, which tend to be non-quantitative.Institutional processes that bring all of these types ofscientists together are needed, but there is no clear con-sensus on how to achieve this. Systems that requirethese disciplines and individuals to work together col-lectively may be required. Dr. Whitesides added thateducation is key. These groups will have to learn newvocabularies of other scientific fields and understandtheir strengths and weaknesses. Workshops, exchangesof students and more senior researchers, and better ac-cess to published literature may help address the cul-

tural divide between biology and engineering. Also,there is need of more effective information dissemi-nation explaining the specialized NIH programs avail-able to researchers, especially those in engineering andphysics. There is a general perception among the sci-ence and engineering communities that the hypothesis-driven NIH is not receptive to the needs of technologydevelopers. This perception needs to change on bothsides. Steps must be taken to ensure that this occurs,so that the NIH can support new technologies earlier intheir development.

Dr. Whitesides commented that one technology thathas made the difference in the approach to cancer, in-deed to biology, has been the technology of arrays, atechnology not initially supported by NIH. The NISTATP funded a number of companies that were earlymajor players in developing the microarray technology.

6. Discussion of Meeting Results

Dr. Hood elaborated six paradigm shifts in biol-ogy that have resulted from the human genome project,and how these changes may affect the development ofnanotechnology.

1. Discovery science. The challenge “discovery sci-ence” raises is how discovery can and should beintegrated with hypothesis-driven research. Thiswill be a challenging mandate for academic in-stitutions if they are to take advantage of the ad-vances resulting from the human genome project,and potentially, from nanotechnology.

2. Biology is, at its core, information science. Thereare two basic kinds of information in the genome:information contained in the genes, and informa-tion in the regulatory networks that specify howthe genes operate. One of the key and primaryintellectual challenges of the 21st century willbe solving the question of regulatory networks.This understanding is central to evolution, de-velopment, and complicated physiologic mecha-nisms. Biological information is hierarchicallyorganized. To fully understand living systems,the capability to integrate the different types ofhierarchical information is crucial.

3. High throughput biology. From the first capil-lary sequencer in 1986 to the DNA sequencinginstruments of today, there has been a 2,000-foldincrease in throughput, an increase in the qualityof the sequence data, and a decrease in the cost


per base pair. Those changes have all come as aresult of incremental improvements in chemistry,engineering, and software. The next generationof instruments likely will be microfluidics-based.

4. Accrual to biology of the tools for mathematicsand statistics. Biology is unique in that it is theonly science whose core information is digital innature. In more than 4 billion years of evolution,organisms have evolved to encode digital infor-mation in an incredibly complex, efficient andhierarchical manner. Unraveling this will haveinteresting implications.

5. Model organisms have been developed. Theseare critical in deciphering biological complexityand common, evolutionarily conserved biologi-cal themes. They do so via: (1) a genetics partslist, and (2) the ability to limit the parts list andexamine the regulatory networks while startingto decipher the logic of life for a given organ-ism. Comparative genomics will be a very pow-erful tool and an incredibly important one, be-cause evolution is not well understood. Evolu-tionary mechanisms, once unraveled, provide therationale for biological design.

6. The genome has provided access to human vari-ability. The genome has allowed access to poly-morphisms, the variations that distinguish indi-viduals from one another, a very small fractionof which predispose to diseases such as cancer.The science now is in a reactive medicine phase,but it is moving towards a predictive phase. Forsome diseases and disorders, researchers can be-gin to developdetailed probabilistic histories, andhopefully, generate preventive therapies.

Each of these paradigm shifts is facilitated by a sys-tems biology approach. The concept behind systemsbiology is that biological systems can be interrogatednot one gene or one protein at a time, but from the con-text of how all genes or all proteins behave. Accordingto Dr. Hood, the field of biology appears to be goingthrough a series of paradigm changes that are funda-mentally different from previous changes to the field.Biomedical science needs to change and co-evolve as

well. Three suggestions were made: (1) change theeducation of students and physicians; (2) emphasizetool development, because shifting from predictive topreventive medicine will require a vast array of newglobal technologies; and (3) marry the bioengineering,computer science, engineering, and physical sciencecommunities, with biology, so those cross-disciplinaryscientists can gain a deep understanding of what theproblems are and focus on them. Also, it was suggestedthat the scientists should be allowed to take larger stepsand gamble on developing technologies.

A predominant view of the workshop is that the fun-damental progress of the NIH depends on the develop-ment of tools so that researchers can explore hypothe-ses that previously were intractable before nanotech-nology. It was mentioned that the NIH should be reach-ing out to researchers to a greater degree. Participantsdiscussed the role of the ATP and the interplay be-tween private industry, academia, and the governmentin terms of matching funds and intellectual property inbringing the day and a half activity to a close.

Acknowledgements

The authors wish to thank the ATP and the DNATechnologies Group at NIST, and the Division of Can-cer Prevention at NCI for supporting this meeting.

About the Authors

Steven J. Zullo is Project Officer with the Chem-istry and Life Sciences Division of the NIST AdvancedTechnology Program. Sudhir Srivastava is the Chief,Cancer Biomarkers Group, Division of Cancer Pre-vention, National Cancer Institute. Dr. Srivastava di-rects the DCP program Early Detection Cancer Net-work (EDRN). Patrick Looney is a Physicist with theProgram Office, Office of the Director at NIST; Pe-ter Barker is Biologist and Project Leader at the DNATechnologies Group, Biotechnology Division of CSTLat NIST.

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