Introduction

On October 1, 2007, scientists from Cornell University and the New York State Office of Science, Technology, and Innovation (NYSTAR) were joined by speakers from around the globe to discuss their research at the Eighth Annual Nanobiotechnology Symposium, organized by and held at Cornell's Nanobiotechnology Center (NBTC). The annual event is part of the Center's efforts aimed at "disseminating knowledge regarding [its] discoveries and ...enhancing the economic impact and commercialization of nanobiotechnology," said Robert Buhrman, Cornell's newly appointed Vice Provost for Research. The symposium was cosponsored by the NBTC, the Kavli Institute at Cornell, and the New York Academy of Sciences.

NBTC Director Harold Craighead noted in his welcoming remarks that in each of the eight years the symposium has been held, the program has changed in character, becoming increasingly outward looking with time. The themes for this year's event were:

• Improving medical imaging, diagnostics, and therapeutics
• Nanobiotechnology research and economic development
• Directions for sustainable energy

A hallmark of the Center has always been an effective integration of scientists—chemists, engineers, and physical and life scientists pursuing the relatively new area of nanobiotechnology. So it was not surprising that terms like collaboration, teamwork, interaction, interdisciplinary, and building bridges were heard repeatedly throughout the daylong symposium and were a common thread that wove many of the various presentations together.

Nanomedicine

A number of speakers shared their research discoveries in the rapidly developing field of nanomedicine. Nanomedicine utilizes engineered nanodevices and nanostructures in both the treatment and prevention of disease at the molecular level.

Abraham Stroock (Cornell), described a wound dressing with microfluidic properties that has all the characteristics of conventional dressings, but also has input (among these a mechanism for drug delivery) and output controls to tailor the environment and monitor the biochemical condition of the wound bed. The wound dressing was just one example of what Stroock calls "functional microphysiological structures that interface with biology." He listed some others as:

• prosthetics
• scaffolds for tissue engineering
• model tissues for basic biology, pharmokinetics, and toxicology

Another example of a novel approach to facilitating drug delivery through nanobiotechnology came from Philip Leopold (Weill Cornell Medical College) who relayed to the audience how viruses can be used as mentors or vehicles for this purpose. Comparing a virus with the space shuttle, Leopold said, "They both have three stages, get where they're going in just a few minutes, and deliver their payloads with an expectation of 100% efficiency." However, viruses are not ideal vectors for gene delivery, in part because they provoke an immune response.

The Nanobiotechnology Center (NBTC) was established in January 2000 with support from the National Science Foundation and NYSTAR to promote research in the intersection of biology and micro- and nanofabrication. It was the first national science and technology center devoted to the emerging field of nanobiotechnology. The NBTC is based at Cornell University in Ithaca, New York, and works in partnership with Clark Atlanta University, Howard University, Oregon Health and Science University, Princeton University, the New York State Department of Health's Wadsworth Center.

Leopold discussed a systematic way of thinking about the tools that viruses use for gene delivery. He noted that a virus uses cellular proteins to help it deliver its genome to the nucleus, carrying out what he calls "subcellular mimicry." In this process, the virus tricks the cell into thinking it is carrying out a normal function, such as nutrient uptake or organelle motility. From this observation, Leopold hypothesizes that we should be able to create an efficient nonviral vector with human proteins that can carry out those viral functions, exploiting normal cellular processes in the same manner. "Making an efficient nonviral gene transfer shouldn't be rocket science," he said in his concluding remarks. "It's just nanotechnology!"

Brian MacCraith (Dublin City University, Ireland) explained how fluorescence-based biochips could be used in revolutionary diagnostic devices for home use that provide early warning of life-threatening diseases, control of chronic diseases, and monitoring of well being. One such device—a myocardial infarction early warning system, if you will—that's based on the glucose testing paradigm, would track changes related to diet and general health to provide information as to whether or not an individual is at risk for future cardiac problems.

For this type of system to become a commonly used diagnostic, a number of hurdles have to be overcome. MacCraith described one of the challenges, that of optimizing fluorescence-based biochips so that the signal-to-noise ratio is higher, the signal is amplified, and detection of impending disease can occur before the condition becomes a problem. His work showed that one reason the sensitivity of these fluorescence-based chips is low is that most of the light hitting the chip gets trapped inside, and only a small fraction is emitted out of the bottom or above the chip, where can be detected by the optics system. By finding ways to get around this problem, the team was able to greatly enhance the biochip's sensitivity. MacCraith's group is working on other complementary approaches, including the development of advanced diagnostic biochips based on plasmon-enhanced fluorescence.

Nanotechnology can also be used in cell biological studies to mimic the complicated microenvironment in which cells function in the body. All cells interact with the extracellular matrix (ECM) via integrins, which are the cell surface receptors that mediate various intracellular signals to control migration, proliferation, and differentiation. However, said Claudia Fischbach-Teschl (Cornell), what is not very well understood is how these interactions contribute to another phenomenon—tumor vascularization, or the stimulation of new blood vessel growth by signaling from tumor cells. Tumor vascularization is a critical step both for tumor growth and for tumor cells to metastasize to distant organs.

Studies of cell-ECM interactions are usually conducted with two-dimensional culture systems in which petri dishes are coated with ECM components. But these systems are a poor substitute for the actual microenvironment of a tumor. Fischbach-Teschl is working on building polymeric systems to study the role of three-dimensional cell-ECM interactions in tumor vascularization. In one early indication that the structure of the culture matters, she has found that levels of growth factor secretion from tumor cells differ depending on whether the study is conducted in a two-dimensional or three-dimensional culture system.

Yosi Shacham-Diamand (Tel Aviv University) described whole cell bio-chips in which optical and electrochemical detection systems interface with living cells. The cells act as sensors while the electronic components provide a simple and sensitive way to report the output. Such systems have a number of potential applications, including acute toxicant detection in drinking water, screening drugs for activity or toxicity, diagnostic clinical information, basic neuroscience, and environmental engineering. Shacham-Diamand pointed out that using live cells in this manner is a modern day twist on the use of caged live canaries by Welsh coal miners to detect toxic fumes. "This is why sometimes our students call it the 'Canary Project,'" he said.

Nanobiotechnology and entrepreneurship

Steve Kresovich, Vice Provost for Life Sciences at Cornell, in his remarks introducing the afternoon program, reminded the audience that linking research with economic development and building bridges between the two is of the highest priority. "We see in the future closer collaborations, with research coming out of the University as an economic driver," Kresovich said.

"The new economy strategy talks about entrepreneurial activities and the importance of innovation in any firm regardless of its size," said Ed Reinfurt, acting executive director of NYSTAR. "If you can't embrace innovation, if you're not doing something better and different from your competitor, you're not going to succeed."

He continued, saying that New York State policy makers ask themselves four main questions when making policy decisions about research, innovation, and the economy: Where is New York today? Where does it need to go? How do we get the greatest impact from our investments? And how do we best position New York to thrive in a global innovation economy? "We need innovation to be the leader in economic development," he said.

Back row from left: Claudia Fischbach-Teschl, Brian MacCraith, Philip Leopold, Wolfhard Almers, Manfred Lindau, Larry Walker.
Front row from left: Watt W. Webb, Kimberly L. Jones, Dan Luo.

Universities are key, according to Reinfurt, to New York State continuing to thrive and to increase productivity and innovation since universities offer strong leadership, they support promising scientists and engineers, and, in partnership with the State, they can invest in research and innovation that is aligned with important industry clusters.

Advion is a good example of the kinds of partnerships to which Reinfurt was referring. Jack Henion, Advion's cofounder, chairman, chief scientific officer, and former Cornell University faculty member, started the company as a service business doing liquid chromatography/mass spectrometry analysis for the pharmaceutical industry. The company developed other services according to need from industry, such as sample management, metabolic identification, pharmacokinetic, and immunoassay services.

In the late 1990s, Advion became Advion Biosystems, a product business based on Henion's lab's work at Cornell, which used polymer-based chips to combine analytic chemistry with mass spectrometry. These chips have application to the pharmaceutical industry, which needed to analyze millions of samples quickly. New possibilities include combining data from the chips with PET and the new micro-PET technology for cancer diagnosis. "The key is an infrastructure and people that know what to do, a culture that fosters creativity," Henion said.

Other new biotechnologies

Dan Luo (Cornell) elicited a chuckle from the audience when he called NBTC one of the world's three most important inventions, the other two being polymers and DNA.

Luo uses DNA as a nanoscale material not only to do basic studies, but for applications in nanotechnology, medicine, materials science, and engineering. "We use DNA to construct nanoscale architecture," Luo said. "In other words we want to do DNA Lego or Tinkertoys." Luo's group has created DNA dendrimers, DNA-addressable molecules and materials, DNA-based barcode systems, DNA hydrogels, DNA liposomes, DNA-Au hybrid nanoparticles, and a DNA gel that can produce a large quantity of proteins without any living organisms.

Nanoscale technologies can be used to build new materials, and could play a role in environmental sustainability.

With the aforementioned DNA barcode they were able to detect anthrax bacteria, ebola virus, and SARS virus simultaneously. Using a form of the DNA encapsulated hydrogel, insulin was delivered to the cells of patients to treat type 1 diabetes. The latter was done in collaboration with researchers at Cornell Weill Medical Center.

Luo says that he and his partners have taken the first steps toward commercialization forming a company called DNANO. The group has received a $500,000 NYSTAR technology transfer award to support the barcode technology.

Concerns about energy costs and availability, and more recently issues of climate change, greenhouse gas emissions, national security, and global competition, have spurred the promotion of biofuels as one component of the nation's renewable energy portfolio. "Success in meeting the objective of developing 'green' industrial processes that are cost effective and sustainable requires coupling the core basic sciences with advanced materials, separation processes and, yes, nanobiotechnology to develop the next generation of bioconversion processes and systems," said Cornell's Larry Walker. "An emphasis on industrial biotechnology links us with nanobiotechnology, which in turn links us to biofuels."

A reception and lively poster session with more than 60 posters allowed meeting participants to probe the day's topics in more detail and exchange ideas about future collaborations.

Abstracts

The Nanomachines of Vesicle Tethering and Fusion

Speaker: Manfred Lindau
Professor, School of Applied and Engineering Physics
Cornell University

Inside the cell, vesicles are essential in the biosynthetic pathway from the endoplasmic reticulum and Golgi apparatus to insertion of components into the cell membrane. They are key components for the regulated release of neurotransmitters, hormones, or mediators of the immune system. They transport specific components inside the cell to specific sites, and are responsible for uptake of material into the cell from small molecules to viruses, bacteria, drugs, and nanoparticles. Vesicles are the sites to deal with toxic substances, to digest endocytosed material, and from which viruses may release their genetic code into the cell. Vesicles have even been shown to be capable of translocation from one cell to another via cellular processes named tunneling nanotubes. Most vesicles are of nanoscale dimensions with radii from 20 to 200 nm, although a few vesicle types may reach >1µm radius. Vesicles use an exquisite machinery for tethering at, and fusion with, a target membrane. We performed a functional characterization of these molecular nanomachines by measuring molecular forces of individual tethering events using optical traps as well as the opening of individual fusion pores using electrophysiological, electrochemical, and optical techniques in conjunction with microfabricated devices. Based on this characterization we utilize molecular manipulations to obtain a better understanding of molecular mechanics of vesicle tethering and fusion.

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Watching Vesicle Fusion and Fission in Live Cells

Speaker: Wolfhard Almers
Vollum Institute
Oregon Health Sciences University

Calcium-triggered exocytosis of synaptic vesicles forms the basis of communication between neurons, and the exocytosis of secretory granules mediates endocrine function. Through electrophysiologic recording, it has been possible for some time to detect the exocytosis of single organelles. But electrophysiology tells us only indirectly about events preceding and following exocytosis. In recent years it has become possible to image granules and synaptic vesicles by light microscopy in living endocrine cells and neurons. By total internal reflection fluorescence, one may detect in real time the minute mechanical changes attending endocytic events, as well as the recruitment and release of molecules mediating both membrane fusion and fission. Such studies have given new information about the nanomechanics of interaction at the level of single vesicles and single molecules.

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Physical Nanostructures for Biological Diagnostics

Speaker: Watt W. Webb
Professor, Applied & Engineering Physics
Cornell University

Zero-mode waveguides, composed of nanoscopic subwavelength tubes in thin metal chips, provide effective focal volumes of ~10 zeptoliters in which the dynamics of single molecule enzyme function can be measured, yielding, for example, a method for sequencing DNA with high speed and high processivity that is now under development. We recently found that filling these nanotubes with high refractive index dielectric material provides the potential to enable convenient non-destructive nearfield biological microscopy of <50 nm resolution at the exit from the nanoscopic waveguide.

Brightly fluorescent nanoscopic semiconducting nanocrystals called quantum dots have promised to provide potentially useful biophysical markers; however, their fluorescence emission blinks with broad ~1/f noise spectra, degrading the continuity of their signals. Silica nanoparticles as small as 10 nm diameter encapsulating dye molecules, created at Cornell (CU dots), provide comparable brightness of fluorescence emission without blinking.

Our most immediately effective nanoscopic biological diagnostic tool makes use of multiphoton laser scanning microscopy to image (with nanoscopic resolution) the in vivo molecular functioning of transcription factor molecules within the cellular nucleus. Binding of transcription factor molecules stimulates the expression of individual genes that can protect the organism from external stresses. The relevant proteins are labeled by inserting an associated fluorescent protein gene component that provides signals for nanoscopic molecular association detection.

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Whole Cell Biochips – Issues in Nano Bio Interfacing

Speaker: Yosi Shacham-Diamand
Department of Physical Electronics
School Of EE, Faculty of Engineering, Tel Aviv University

Recent developments in nano-bio interfacing allow integrated whole-cell sensing on a micro-chip level. Integrating living cells with microelectronics is a novel approach to produce intelligent devices. The merit of using living cells is to obtain functional information regarding the effect of a stimulus on living systems. In this talk we describe both optical and electrochemical interfacing in whole cell bio-chips where bacteria act as sensor elements. The "lab-on-a-chip" system could have a number of important applications including acute toxicant detection in drinking water, screening drugs for activity or toxicity, diagnostic clinical information, basic neuroscience, and environmental monitoring. Three families of devices will be discussed: photo-luminescent, bioluminescent, and electrochemical. We will present two examples: devices detecting acute toxicity in water, and "personalized medicine" devices with sensitive and high-throughput detection of colon cancer cells response to differentiation therapy. We will discuss the micro-fabrication issues, the optical modelling issues, the electrochemical sensing methods, and the principles for modelling signal and noise of such whole cell bio sensors.

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Strategies for Enhancing the Sensitivity of Fluorescence-based Biochips

Speaker: Brian D. MacCraith
Biomedical Diagnostics Institute
National Centre for Sensor Research
Dublin City University

This presentation will discuss emerging strategies that will yield substantial enhancements in the sensitivity (and, in particular, the signal-to-noise-ratio (SNR)) of fluorescence-based biochip platforms, especially for biomedical diagnostic applications. These strategies include exploitation of plasmonic effects and supercritical angle fluorescence (SAF) capture. The advantages offered by high-brightness labels will also be covered.

The presence of metallic nanoparticles or nanostructures in the vicinity of a fluorophore can dramatically alter the fluorescence properties of the fluorophore. The effect is associated with the localized surface plasmon resonance (LSPR) of the metallic nanoparticle/nanostructure, and depends on parameters such as metal type, particle size and shape, and the fluorophore-particle separation.

Our work is focused on establishing rational design rules for such applications. A particular feature of this work is the development of preparation methods to enable production of metal nanoparticles and nanostructures, which facilitate reproducible tunability of the LSPR at the optimal separation.

Based on an understanding of the anisotropic emission properties of a fluorophore at an interface, we have designed a range of novel, high-efficiency biochip platforms. This high efficiency is achieved by capturing the SAF component of the emission. Advanced optical design can also provide strict confinement of the fluorescence excitation to the surface. The combination of these two features yields significantly improved SNR and discrimination against bulk fluorescence in platforms that are compatible with mass production via micro-injection moulding.

Finally, novel doped nanoparticles (NPs) can provide substantial advantages when used as labels in biosensing systems such as fluoro-immunoassays. These advantages include improved SNR through the use of high-brightness, heavily-doped NPs, and both multiplexing and referencing capabilities.

All the enhancement strategies highlighted above will be illustrated with specific examples.

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Engineering Microvascular Structure within Macroscopic Tissues in vitro

Speaker: Abraham D. Stroock
Assistant Professor, Chemical and Biomolecular Engineering
Cornell University

Microvascular structure—a network of convective paths—is a ubiquitous element in living materials. The key function of vascular capillaries is to provide convectively-aided chemical and cellular exchange between the bulk of the tissue and centralized processes (e.g., in the lungs, liver, and GI tract); this exchange allows an organism to monitor and control the state of all of its tissues. In our laboratory, we are developing methods to embed and operate both synthetic and native microvascular structure within biomaterials in order to study biophysical aspects of its development and function, and to exploit its functionality in tissue engineering applications. I will present two examples to illustrate our efforts: 1) Direct fabrication of microfluidic networks within tissue scaffolds for culturing mammalian cells in three-dimensions. In this section, I illustrate how convective mass transfer via these networks enables spatial and temporal control of the biochemical environment experienced by the cells in the bulk of the scaffold. I will point toward applications of this technology for directing the development of functional tissue for clinical applications and modeling tissue-scale processes that involve cell-cell communication. 2) Directing growth of native capillary networks in cultures of endothelial cells in confined gels. In this section, I will present the initial results of our study of this spontaneous assembly process and discuss the possible role of mechanical interactions in directing collective cellular behavior.

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Biomimetic Microenvironments to Study Cancer Cell Angiogenic Capability

Speaker: Claudia Fischbach-Teschl
Assistant Professor, Biomedical Engineering
Cornell University

Three-dimensional microenvironmental conditions alter cancer cell signaling; however, the underlying mechanisms and importance of these conditions on tumor vascularization remain unclear. Polymeric systems based on alginate hydrogels have been utilized to more accurately recreate 3-D cell-microenvironment interactions and to examine the role of the transition from 2-D to 3-D culture, with and without integrin engagement, on cancer cell angiogenic capability. Our results indicate that 3-D culture enhances secretion of the pro-angiogenic factor interleukin 8 (IL-8) in an integrin dependent manner, whereas vascular endothelial growth factor (VEGF) secretion was unaffected by these conditions. IL-8 up-regulation was critical to tumor vascularization and progression in vivo, and mediated recruitment of bone marrow derived cells to the local vasculature via systemic signaling. In summary, 3-D integrin engagement alters the mechanisms of cancer cell angiogenic signaling, and blocking of both IL-8 and VEGF signaling may improve anti-angiogenic therapies.

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Positioning New York State in the Global Innovation Economy

Speaker: Ed Reinfurt
Acting Executive Director
NYS Foundation for Science, Technology and Innovation (NYSTAR)

Today's global economy demands innovative solutions and unprecedented levels of collaboration between academic institutions, industry and government. As competition for tomorrow's industries and high-paying jobs intensifies, solutions to complex problems will require the collective input from stakeholders, creative perspectives, and a talented workforce to execute these visions into reality.

This presentation will include an overview of New York's ranking in the 2007 State New Economy Index prepared by the Information Technology and Innovation Foundation along with a discussion of the report's recommendations on economic development strategies for the new economy. In addition, the presentation will address specific recommendations relating to enhancing the role of colleges and universities in regional innovation and growth.

Mr. Reinfurt will also share his insights into how New York can capitalize on its intellectual and capital investments through effective partnerships and how NYSTAR can align its programs with the state's priority research areas to harness this opportunity into economic growth.

The opportunities that the new global research environment creates for New York are significant. New York has a diverse technology base, almost 300 institutions of higher education, a talented and entrepreneurial workforce, and an Administration committed to growing its innovation economy. How these opportunities match the public's expectations for economic growth will be one of the challenges facing economic development specialists in the years ahead.

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The Advion Story: From Analytical Services to Chip-Based Nano Electrospray
Mass Spectrometry

Speaker: Jack Henion
Chairman and CSO
Advion BioSciences, Inc

Advion was founded in April, 1993, based upon experience and technology developed in my Cornell Analytical Toxicology laboratory which was based within the Diagnostic Laboratory of the Cornell College of Veterinary Medicine. The technology is called 'liquid chromatography/mass spectrometry' or LC/MS for short. This technology has provided a major positive impact upon the development of new drugs by the pharmaceutical industry as well as many other major industries ranging from environmental analysis to industrial chemicals and the characterization of proteins.

Following several collaborative relationships between my Cornell research laboratory and pharmaceutical companies in the early nineties, it was clear there was a market for contract analytical services involving the relatively new technique of LC/MS. After conducting a one-week market survey by traveling to five different pharmas where we received requests for our planned services from all five, we (Tom Kurz and I) began a search for startup monies. Within a few months we secured over $700,000 from two angel investors and opened our doors in a former shoe store in Lansing Village Place, Ithaca, NY, on April 1, 1993.

Within about six months we were profitable with our analytical services (now called Advion BioServices, Inc.) and grew to several tens of employees in the first few years. By the late nineties my Cornell research laboratory, collaborating in part with Harold Craighead's research group, had published several papers employing chip-based capillary electrophoresis/mass spectrometry (CE/MS) technologies. These were followed with several related chip-based studies, all employing mass spectrometry for a detector. Based upon the success of these studies I proposed undertaking R&D studies within Advion to further develop 'miniaturization' and to hopefully develop new technologies to build and broaden the base of Advion.

In late 1997 Advion had developed a novel silicon substrate multi-nozzle chip in collaboration with scientists at Kionex which was based in the Cornell Research Park in Ithaca. This chip was further improved and engineered to deal with the microfluidic demands of real-world analyses. Concurrently, we had to develop a robot to hold the chip and to sequentially deliver samples to the chip which was in turn positioned appropriately on a mass spectrometer for sample analysis. This robot developed into what is now called the TriVersa NanoMate and formed the basis of a new business unit now called Advion BioSystems, Inc. The TriVersa NanoMate robotic system has been sold to major academic and pharmaceutical research laboratories throughout the US, Canada, Europe, and Japan. The functionality of the system has grown from simple 'infusion' analysis of extracted biological samples to on-line LC/MS with concomitant fraction collection for subsequent infusion analysis for metabolite identification, protein characterization, and many other applications.

Our BioServices business unit has recently expanded its services to include immunoassay analyses for large molecule bioanalytical applications in a new laboratory in Manassas, VA. This laboratory will be certified to be GLP compliant and 'open for business' in early 2008. In addition, our original BioServices have been expanded in Ithaca to include metabolite identification employing our TriVersa NanoMate as well as a Sample Management Services (SMS) which provides kits for sample collection within the clinics.

Recently Advion acquired Nanotek, a small microfluidic synthesis system for the microsynthesis of PET reagents. This system expands and complements our microfluidic applications involving mass spectrometry since the PET reagents need to be analyzed for integrity and purity prior to administration to patients. The headquarters for this accelerated chemical synthesis business is located in Knoxville, TN. We also have other initiatives in the early stages of planning so we are confident that Advion will grow substantially in the future with the support of our premier investors and our employees who are excited to be in our new purpose-built building at 19 Brown Rd. within the Cornell Business and Technology Park.

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Engineering DNA as a Nano-scale Material

Speaker: Dan Luo
Professor, Biological and Environmental Engineering
Cornell University

Our research focuses on nucleic acid engineering: molecular engineering DNA as a nanoscale material. By taking advantages of the amazing chemical, physical, and biological properties of DNA, and by utilizing a myriad of DNA manipulating enzymes, we have created DNA dendrimers, DNA-based addressable molecules and materials, DNA-based nanobarcode systems, DNA hydrogels, DNA liposomes, DNA-Au hybrid nanoparticles, and a DNA gel that can produce a large amount of proteins without any living organisms. These examples illustrate the concept that DNA can be indeed utilized as a generic, designer material. In addition, they demonstrate the power of nucleic acid engineering as a link between biology and materials sciences and engineering in general and between molecular biology and molecular engineering in particular. New properties and applications are expected from DNA-based materials.

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Synthesis and Characterization of Nanoporous Organic and Inorganic Membranes: Applications in Biological Separations

Speaker: Kimberly L. Jones
Associate Professor of Civil Engineering
Howard University

Membranes can perform efficient upstream separation of complex biological mixtures. In addition, membranes have ease of integration, high surface area, and one-step selectivity, making them favorable choices for integration in biological separation processes. Membrane pore size can range from microporous microfiltration membranes to dense reverse osmosis membranes; other surface properties such as hydrophobicity, charge, and thickness vary with properties of the polymeric or inorganic thin film that comprises the selective layer of the membrane. Thus, physical–chemical properties of the membrane will affect the rejection and flux behavior. For specific separation applications, such as for the separation of DNA and heme, there is a need to develop membranes that will perform efficient, predictable, and rapid separation. To this end, we have developed and characterized two polymeric membrane systems, cellulose acetate and collagen, and one inorganic membrane, alumina, to elucidate the mechanisms that control transport across the membranes for the purpose of separating DNA and heme as well as other biological separations. Our goal is to develop tailorable membranes that can be applied to a wide range of biological separations, and this talk will discuss the links between membrane surface properties and performance and the promise of synthesizing tailorable membrane for target separations.

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Viruses as Mentors for Nano-scale Drug Delivery

Speaker: Philip L. Leopold
Associate Professor
Department of Genetic Medicine
Weill Cornell Medical College

As scientists, it is our job to generate new ideas, like nanoscale, intracellular drug delivery. But is that really novel? Viruses learned how to deliver genes to cells eons ago. Perhaps our best chance to catch up will be through the study and understanding of viruses. Viruses are capable of delivering a massive, hydrophilic macromolecule up a concentration gradient and through multiple hydrophobic and viscous barriers with tremendous efficiency. However, in attempting to harness viruses for the purpose of clinical gene transfer, it has become clear that our own immune system has evolved to defeat repetitive challenges from the same virus. Thus, in considering how to construct synthetic gene transfer vectors, the viral model may be instructive. In this presentation, I will discuss a systematic way for thinking about the tools that viruses use for gene delivery and how those tools might be harnessed in the clinic.

It is apparent that viruses accomplish the job of delivering genes to the nucleus through a series of molecular interactions between viral and cellular proteins. To accomplish these interactions, viral proteins have evolved to mimic cellular or extracellular proteins. But the simple concept of molecular mimicry does not adequately describe the functional importance of this strategy to viral infection. Taking adenovirus as an example, two capsid proteins are involved with establishing interactions with the cellular membrane using three distinct mechanisms. This multivalent interaction leads to endocytic uptake of the viral capsid into the endocytic pathway where a coordinated effort by four viral proteins results in lysis of the endosome membrane in a pH-dependent fashion. After escape to the cytosol, capsid interaction with cytoplasmic dynein leads to transport of the virus to the nuclear periphery, and interaction of the viral DNA and DNA-binding proteins with nuclear proteins and the nuclear import machinery results in nuclear import of the viral genome. It is clear that single viral proteins play multifunctional roles during infection. Furthermore, multiple viral proteins can be involved in accomplishing single steps in the infection pathway. These concepts will be discussed in terms of "subcellular mimicry," the idea that viruses purposefully mimic not only individual cellular molecules, but simultaneously mimic multiple cellular molecules for the purpose of participating in complex cellular activities. For some steps in viral infection, the parallels between the virus and its cellular counterparts are clear. For other steps in the infection pathway, the virus must rely upon novel viral properties, so-called "pure viral functions."

The challenge for nanoscientists will be to re-create the steps in viral infection using non-immunogenic elements (either non-immunogenic molecules/polymers or self-proteins) in such a way that the subcellular mimicry of pure viral functions occur with great efficiency and in proper sequence and context. We had better be patient. Viruses needed millions of years to accomplish this task.

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Nanobiotechnology as an Enabler for Biofuels Research and Development

Speaker: Larry P. Walker
Professor, Biological and Environmental Engineering
Cornell University

Biofuels are being promoted as one component of the nation's renewable energy portfolio. Two conversion platforms, industrial biotechnology and thermochemical, are receiving the bulk of the attention from the federal government and the energy sectors. Because of its life sciences research capacity, Cornell University is in an excellent position to develop enzymes, microorganisms, and plants to produce biofuels and bioproducts. The objective is to develop biotechnology approaches that will yield "green" industrial processes that are cost effective and sustainable. Success in meeting this objective partially hinges on exploiting breakthroughs in molecular biology, such as genomics, proteomics, and systems biology, to develop novel bioprocesses essential to converting plant carbohydrates to biofuels such as ethanol. However, complete success requires coupling the core basic sciences with advanced materials, separation processes, applied optics and, yes, nanobiotechnology to develop the next generation of bioconversion processes and systems. Nanobiotechnology offers the potential for accelerating the pace of scientific exploration into the function of biological systems and exploring new biological applications through the development of paradigms, methods and tools that focus a more concise and quantitative "eye" on molecular and cellular processes. For example, tools for single molecule detection employing sophisticated CCD cameras, coupled with nano-scale fluidics, will allow for the rapid analysis of DNA and RNA from environmental samples to give high temporal and spatial resolution of microbial communities; or it can be used for tracking the intrinsic binding and surface mobility of cell wall degrading enzymes. The NBTC commitment "to provide new insights into the function of biological systems and explore new biological phenomenon," makes it an enabling agent for the development of biofuels.