Center for Cancer Nanotechnology Excellence
and Translation (CCNE-T)
Stanford University has made significant investments in several key areas that directly impact this CCNE-T research proposal. Stanford University has strongly believed that its strengths in the School of Medicine, Engineering, and Humanities & Sciences (home of Chemistry Department) need to be leveraged towards advancing biomedical sciences. For this reason a key effort known as the Bio-X Program was established and a new building of 225,000 square feet known as the James H. Clark Center was constructed (see above figure). This was an investment of over $175 million in construction costs and infrastructure that brings together scientists from many disciplines including Chemistry, Applied Physics, Bioengineering, Computer Science, Developmental Biology, Molecular Pharmacology, Medicine, Surgery, and Radiology. All the Bio-X Program Scientists share a common goal to advance Biomedical Science. The CCNE-T proposal will tremendously benefit from the environment at Stanford and the Bio-X that fosters highly multidisciplinary efforts including nanotechnology research. It is through the structure of the Bio-X program that many of the Stanford based researchers in this proposal were brought together (e.g., Drs. Gambhir, Rao, Dai, Wang, Felsher, Nolan). Dr. Matthew Scott, Director of the Bio-X Program, and Dr. Arthur Bienenstock, Stanford Dean of Research overseeing the Bio-X Program, are highly supportive of this CCNE-T as it is the exact type of collaborative effort that the Bio-X would like to foster.
In 2001, Drs. Gary Glazer (chair of Radiology) and Philip Pizzo (Dean, School of Medicine) initiated a nation-wide search to bring leadership in multimodality molecular imaging of living subjects to Stanford. Dr. Gambhir was recruited and appointed as the Director of the Molecular Imaging Program at Stanford (MIPS) and moved to Stanford in 2003. Dr. Gambhir, who was also appointed Head of Nuclear Medicine, immediately began recruitment of new faculty in molecular imaging and has already recruited 6 new MIPS faculty.
Drs. Glazer and Pizzo were supported in their efforts by the University as a whole, including Dr. John Hennessy (President, Stanford University), Dr. Sharon Long (Dean of Humanities and Sciences), Dr. Jim Plummer (Dean of Engineering), and Martha Marsh (President & CEO of Stanford Hospital), This same senior leadership is also highly supportive of the CCNE-T as this grant is a perfect example of what the University leadership would like to see happen on campus .
Stanford University has made major commitments to the Molecular Imaging Program at Stanford (MIPS). The recruitment of Dr. Gambhir to Stanford was a top-down effort with significant commitments in new space, renovation of existing space, equipment, new faculty billets, startup packages for new faculty, and funds for infrastructure development. The University committed $45,000,000 in total towards the MIPS effort. Many different Departments and individuals were committed to ramping-up molecular imaging, therefore facilitating the recruitment of Dr. Gambhir.
Construction of the new Lucas Expansion building of 14,000 net square feet finished in February 2005. This building houses the new cyclotron facility, radiochemistry labs, chemistry labs, and cell/molecular biology labs. This was an investment of over $23,000,000 by Stanford University to ensure the proper infrastructure for Molecular Imaging Chemistry on campus in the form of space for the new Lucas Expansion building. In addition, approximately 7,000 square feet were allocated within the Clark Building to house a portion of the MIPS. Space was also committed to the Nuclear Medicine clinic to double its size from approximately 6,000 to 12,000 net sq. feet. This is existing space that we will finish renovating in 2007 and which will allow for a significant clinical component to the program. The renovated space will house 2 PET/CT's, 4 new SPECT/CT cameras, and 2 existing SPECT cameras.
Resources & Facilities Linked to The Stanford Comprehensive Cancer Center (SCCC):The SCCC provides expert support services and state-of-the-art equipment to all Cancer Center members through a number of core facilities. Each facility conducts its own research and development to ensure that investigators have access to the most sophisticated technologies and research protocols available today.
Animal Tumor Models and Histopathology Facility: The Animal Tumor Models and Pathology Core Facility supports state-of-the-art in vivo tumor biology research through a number of specialized services, including animal tumor modeling, experimental pathology, clinical diagnostics, embryo cryopreservation/rederivation and assisted reproduction. The facility additionally ensures the effectiveness of these studies through the standardization of drug injections, tumor inoculations and other technical procedures.
Cancer Biostatistics Core: This Facility provides statistical support to assist researchers at each stage of a study’s lifecycle, including project design, mid-study evaluation and the interpretation and reporting of results. The facility also assists with the statistical review of proposed studies and the planning of research-related data management systems. All services are provided under the direction of the Division of Biostatistics within the Department of Health Research and Policy.
Cancer Imaging Core: The Cancer Imaging Core supports the in vivo structural and functional analysis of animal models of cancer through state-of-the-art imaging instrumentation and variety of services. Existing technologies include a number of in vivo optical bioluminescence/fluorescence imaging systems offering 3D images of cellular and molecular processes. As part of the Molecular Imaging Program at Stanford (MIPS), the core also serves as a test bed for advances in molecular imaging that have preclinical and clinical applications.
See additional details of the Stanford Cancer Center in the Cancer Centers section.
The Bio-X Program supports, organizes, and facilitates interdisciplinary research connected to biology and medicine, and brings to bear Ideas and methods embodied in engineering, computer science, physics, chemistry, and other fields to important challenges in bioscience. In turn, bioscience creates new opportunities in other fields. In this environment, significant discoveries and creative inventions are accelerated through formation of new collaborative teams. Students and faculty are broadening and enriching their training in science and technology to more fully integrate fields, departments, and schools at Stanford. Educational events for Bio-X participants and for the public are planned to motivate thoughtful discussions of social and ethical issues connected with scientific advances.
The James H. Clark Center, the hub for the Bio-X program, fosters an unprecedented degree of collaboration between scientists from different disciplines in order to meet some of the most pressing scientific and medical challenges of the coming decades. Such challenges can no longer be met by individual disciplines working in isolation, but require the combined expertise of multi-disciplinary teams. The Clark Center lies at the heart of the Stanford campus between the core campus science engineering buildings and the hospital and medical facilities. Located on primary routes between the campus and the medical center, the building acts as a social magnet encouraging chance encounters and informal meetings between lecturers, researchers and students from diverse academic backgrounds. The lab interiors are a dramatic departure from tradition. The building has been turned inside out, with 'corridors' replaced by external balconies, enabling completely flexible lab layouts. The three-story building takes the form of three wings of laboratories centered on an open courtyard overlooked by balconies. The Clark Center is home to approximately one half of the Radiology 3D Imaging Laboratory, the Molecular Imaging Lab, and the small animal imaging.
The Radiological Sciences Laboratory (RSL), located in the Lucas Center and is directed by Dr. Gary H. Glover, is a section within the Stanford University Department of Radiology, and is located in the Lucas Center. The RSL is comprised of 13 full-time basic science faculty, averages 50 predoctoral and postdoctoral students, and hosts numerous other fellows and visiting scholars. The mission of the RSL is to support basic research in imaging science, provide a nurturing environment for students and postdocs, and collaborate with others within and outside of the Department.
The Molecular Imaging Program at Stanford (MIPS), directed by Dr. Sam Gambhir, also a section within the Department of Radiology with labs located in the Clark Center, the Alway Building, the Edwards Building, and in the recently opened Lucas Center Expansion. Approximately 10,000 nasf of the new Lucas facility is used for radiochemistry and labeling procedures. Two MIPS faculty and approximately 20-25 staff, postdocs, and graduate students carry out research experiments in the wet lab space and have access to cyclotron-produced isotopes on a daily basis.
Stanford Library Facilities: Stanford's libraries have amassed collections of books, journals, scores, sound and video recordings, and printed reference works numbering more than eight million volumes. These collections continue to grow at a rate of roughly 110,000 volumes per year. Stanford University Libraries and Academic Information Resources (SULAIR) develops and implements resources and services within the University libraries and academic technology units that support research and instruction.
The total space in the School of Medicine utilized for organized research programs is approximately 600,000 sq. ft. The Lane Library serves the Medical Center. In approximately 40,000 sq. ft., there are over 375,000 total volumes. Of those, the estimated number of book titles is 175,000. Lane Library subscribes to more than 2,500 serial publications and provides full-text online versions of over 1,100 journals. The library also provides access to computerized databases for PubMed, Medline, Biological Abstracts, Chemical Abstracts, Toxline, Cancer Lit, AIDSline, PDQ, CINAHL (nursing), Citation Index, and UNCover. Some of these databases are available to trainees on their personal workstations.
There are sixteen Stanford University Libraries:
- Cecil H. Green Library, the main research library with collections in the humanities, social sciences, area studies, and interdisciplinary areas,
- J. Henry Meyer Memorial Library, which houses Academic Computing and the East Asia Library,
- thirteen research branch libraries serving the sciences, engineering, education, art, music, and East Asia studies, and
- Stanford Auxiliary Libraries, which house infrequently used materials from the collections of Stanford University Libraries.
- In addition, Stanford has five coordinate libraries:
- Hoover Institution Library and Archives,
- J. Hugh Jackson Business Library,
- Lane Medical Library,
- Robert Crown Law Library, and
- Stanford Linear Accelerator Center Library.
The Lane Medical Library & Knowledge Management Center's (KMC) research collections cover clinical medicine and its specialties, basic sciences, public health, and related fields. Lane serves as one of twelve resource libraries for the Pacific Southwest Region of the National Network of the Library of Medicine. The Library & KMC house a physical collection of materials, subscribe to electronic resources needed to support the mission of SUMC, and provide access to the computer labs.
Stanford Core Research Facilities:
Stanford supports many facilities to support research. The following is a partial list of Core that serve as resources to all faculty and students participating in research on the Stanford campus.
The Stanford Center for Innovation in In-vivo Imaging (SCI3) is located one floor below the Contag Laboratory in the Clark Center at Stanford University. This resource houses the fiber-based confocal microscopes that can be used as validation of the new instrument designs. The Imaging laboratory is 2800 sq. ft. with divided rooms for MRI, PET/SPECT, and computer analyses. The imaging laboratory is connected via an animal surgery room to two animal holding rooms that have been designed as radioactive, viral vector and infectious agent (BL-2) animal holding areas. A two-door autoclave is located between these holding rooms and the rest of the animal facility for the Clark Center. The equipment that is currently available for this project includes two 10 mm dual axes microscopes, a CellViszio fiber-based confocal and a standard fluorescence microscope. There is a backup and storage system for the image data, which is used as the general data server for the facility. The computer space is intended for software development and to house the server as well as data analysis machines. This computer room is adjacent to office space for an administrator and a scientific director.
The Stanford Cell Sciences Imaging Facility (CSIF) provides access to and training in high-resolution, state-of-the-art fluorescence and electron microscopy services. The facility has three advanced imaging systems that provide confocal, deconvolution and 2-photon fluorescent light microscopy technologies. For electron microscopy, the facility has a full-service laboratory that offers sample preparation and training for both transmission and scanning electron microscopy technologies. Specific goals include acquisition of cutting-edge light and electron imaging instrumentation, training in the proper application and use of available equipment and technical assistance and consultation in the application of advanced immuno- and histo-chemical techniques. The CSIF is also dedicated to providing access to multi-dimensional (3D, 4D) imaging technology for volumetric analysis of cell and tissue architecture and continues to obtain and make available advanced 3D, 4D volume rendering, image-analysis software.
The Stanford Fluorescence Activated Cell Sorting (FACS) Core Facility, located at the Stanford University School of Medicine. Biomedical research requires an ability to separate and describe unfolding events in complex surroundings. Since the mid 1980’s, the Stanford Shared FACS Facility (SSFF) has provided a state-of-the-art flow cytometry facility for immune system studies, molecular biology research, pre-clinical research, HIV-1 studies and a host of other enterprising studies in a variety of fields. The recent upgrades to these systems have increased the capabilities of the SSFF by adding a 9-color, 3-laser high speed cell sorter and a 6-color, 2-laser non-sorting analyzer, and upgrading the central data store, data management and data access system of the facility. This will be useful for cross-validation of our results with the DAC microscopes in tissue models where we can predetermine the fluorescence of a given population of cells prior to embedding in tissue phantoms.
The Bioinformatics Resource Center, located in the Beckman Center (between the Lucas and Clark Centers) provides workshops, consultation and hardware and software access for Mac, PC and UNIX for use in biomedical research.
The Functional Genomics Facility, located in the Center for Clinical Sciences Research (between the Lucas and Clark Centers), provides high quality gene expression microarrays, production support and analysis, and bioinformatics support. Products and services include: human and mouse microarrays, grade "C" human and mouse microarrays, poly-l-lysine coated glass, custom array printing, Agilent scan, array hybridization, Biomek FX, Biomek FX programming, hybridization course, and Axon scan.
High-Throughput Drug Screening Facilities, located in Center for Clinical Science Research (CCSR) provide researchers at Stanford with the ability to run high-throughput chemical, siRNA, cDNA, and high-content screens for the purpose of drug and/or target discovery. The HTBC is a Stanford University School of Medicine core facility for the Stanford Comprehensive Cancer Center and the Digestive Disease Center. This highthroughput screening (HTS) laboratory allows Stanford researchers and others to discover novel modulators of targets that otherwise would not be practical in industry. The center incorporates instrumentation (purchased with NCRR NIH Instrumentation grant number 1S10RR019513-01), databases, compound libraries, and personnel whose previous sole domains were in industry. Among our instrumentation are a Molecular Devices ImageXpress Micro fluorescence microplate imager, with live cell option, a Caliper Life Sciences SciClone ALH3000 microplate liquid handler and the Molecular Devices Analyst GT and FlexStation II 384 fluorescence, luminescence and absorbance microplate readers. We have over 130,000 small molecules for compound screens, 15,000 cDNAs for genomic screens, and the siARRAY whole human genome siRNA library from ThermoFisher Scientific (formerly Dharmacon) targeting 21,000 genes.
The Proteomic & Integrative Research Facility, located in the Edwards Building (adjacent to the Clark Center), is based in the Department of Pathology at the Stanford University School of Medicine. The facility provides a fee for service component to support the needs of the Stanford research community. In addition, the facility has a mandate to promote research through collaborative projects spanning both basic and clinical research efforts at Stanford. Services offered encompass standard protein/peptide identification, identification of protein complex components, identification of proteins in lysates, etc.
The Stanford Tissue Bank, located at 800 Welch Road adjacent to the Stanford University Hospitals and Clinics, provides service to Stanford researchers by facilitating the collection, storage, distribution, and study of human tissues. Services and products include: frozen tissue pickup, frozen tissue from bank, H&E stained frozen section, and review of slides.
The Stanford Tissue Procurement Facility of the Stanford Cancer Center, adjacent to the Stanford University Hospitals and Clinics, supports collection and provision of needed tissue specimens to Stanford Cancer Center investigators to support their cancer-related research. TPF activities and services include collecting and banking freshly frozen tumor and normal tissues from excess surgical material and from autopsy, providing fresh tumor tissue for viable cell studies, processing and banking serum specimens from cancer patients, maintaining a tissue database with links to clinicopathological data, providing histological staining and pathological review, coordinating patient consent and ensuring regulatory compliance.
The Office of Information Resources & Technology (IRT) provides information technology, informatics and knowledge management services in support of the School of Medicine's clinical, research and educational missions. The Infrastructure Services Group provides school-wide networking (wired and wireless), data center, desktop support and multimedia/AV services. The Educational Technology Services provides a highly coordinated set of educational planning and support services to support the innovative and appropriate use of teaching technology throughout the School of Medicine. The Privacy and Data Security provides school-wide data security and ensures compliance with HIPAA and other privacy mandates. IRT also provides server hosting and support services for a monthly fee.
The Stanford Cancer Center focuses the world-class expertise of more than 240 researchers and clinicians on the most critical issues in cancer research and medicine today. These dedicated individuals work together in multidisciplinary teams to unravel cancer’s secrets and to transform the latest detection, diagnosis, treatment and prevention discoveries into the most advanced patient care available. Combining these advances with comprehensive support services, the SCC is committed to giving patients every clinical and technological advantage in the prevention and treatment of cancer.
The Veterinary Service Center serves all aspects of the Department and assures that the use of all animals is humane and complies with all relevant policies and legal requirements. The functions of the VSC include: the procurement of animals for research and teaching; the provision of veterinary care; the provision of animal husbandry services; the oversight of animal holding facilities; and the provision of special services that facilitate animal research.
Uncommon in the world, Stanford has world-class nanotechnology infrastructure centrally located at the Science and Engineering Quadrangle but adjacent to the School of Medicine (Figure 1). The two communities are physically and intellectually connected via the Clark Center and the Bio-X Program. The Stanford Nanofabrication Facility (SNF) in the Paul Allen Center for Integrated Systems, just next to the Clark Center, is a 10,000 square foot, Class 100 clean-room housing a complete suite of over 75 processing tools for the micro- and nano- fabrication of devices. A full-time staff of engineers and technicians provide equipment and process support to keep the facility operational 24 hours a day, 7 days a week. SNF, in partnership with twelve other university facilities across the country, form NSF’s National Nanotechnology Infrastructure Network (NNIN), which is committed to providing nanofabrication resources to researchers across the country, in industry as well as academia. As one of the original Network sites, SNF now has over ten years of experience as an open user facility. Over 600 lab members are registered at SNF. About 30 new researchers join SNF each month. Although more traditionally known for its strengths in silicon device fabrication, SNF has expanded its capabilities to serve other disciplines as well. Specifically, SNF now supports a large cadre of internal and external users with interests in biology, chemistry, MEMS, optics, and physics in addition to the traditional areas of electronics, materials, and process characterization. SNF lab members routinely develop processes requiring 10 to 15 or more patterning steps and hundreds of individual process steps. Thus, the SNF has extensive infrastructure for operating a large lab, training new researchers, and allowing them to fabricate complex devices. Of particular relevance to the CCNE grant is e-beam, for nanopattern definition, currently Raith system in operation and a brandnew Leica system expected to be on line in 2010.. Through the Network, SNF also has access to more advanced tools, such as the Leica VB6 at Cornell’s Nanofabrication Facility and the Jeol 9300 at Georgia Tech. These tools are for electron-beam lithography used in nanofabrication. Valued at $10M, they represent the very best of top-down approaches to nanofabrication, as opposed to bottom-up nanofabrication with chemical synthesis. Still, SNF recognizes the need to improve its own e-beam capability and so is in the process of acquiring a state-of-the-art, direct write e-beam system that offers both the required nanoscale resolution and write speed. However, even with the most advanced tools, e-beam is limited by extremely long processing time and the kinds of materials that can be direct-written. Nanoimprinting methods, though, allow high-fidelity, fast transfer or replication of nanopatterns obtained by direct-write e-beam into a broad range of materials. SNF has recently acquired an EV Group MA 620 Nanoimprint system and is in the process of developing protocols for its use and for fabricating nano-imprint stamps.
Stanford Science and Engineering Quadrangle where SNL, SNF and new Nano Center are located.
As part of Stanford Advanced Materials Initiative, Stanford Nanocharacterization Lab (SNL) is established with University, private and public funds to maintain a state of the art facility for nanomaterials characterization. SNL already operates as a successful user facility within the Stanford University community. Our system works well for a wide range of users such as materials scientists, mechanical and electrical engineers, physicists, chemists, biologists, etc.. The SNL facility has a high degree of utilization by the researchers developing the nano-scale structures. One additional point worth noting is the synergy that is provided by the SNL design layout. The transmission electron and scanning electron microscopes, surface analysis and X-ray equipment all exist side-by-side in an open working environment. Accordingly, researchers carrying out measurements with one piece of advanced equipment encounter, and often engage with, their counterparts working on a quite different analytical strategy. This has led to significant cross-fertilization of ideas across multiple disciplines. We have already experienced many occasions on which this transfer of ideas has substantially benefited and indeed developed a new research approach. One such example is the collaboration between the Wang and Gambhir lab that resulted in a Nature Medicine publication (Gaster R et al, “Matrix-insensitive protein assays: pushing the limits of biosensors in medicine” In press; 2009).
Blueprint of the renovated SNL facilities
A brand new Nano Center with 100,000 sf of space is scheduled to open at 1Q2010, in which 6000 sf of low-vibration laboratory will be dedicated for nano-characterization and nano-patterning and 3000 sf of clean room for nandevice fabrication. The creation of this Stanford Nano-Synthesis Facility (SNS) will further boost our capability to integrate nanomaterials with advanced device concepts and biomedical applications.
The combination of investments by Stanford University in the Bio-X Program, MIPS, the Cancer Center, the Stanford Nanofabrication Facility, and the Advanced Materials Initiative has tremendously helped the in-place CCNE-TR program to launch successfully. This is because the infrastructure that has been invested in by the University is highly suited for interdisciplinary research, and the links to ongoing efforts in clinical cancer care are ideal.