Nanoparticle-embedded microcapsules hold promise for multiple medical uses

(a) unlabeled alginate capsules, (b) alginate capsules labeled with Feridex, or ''magnetocapsules'' (note ferric oxide rust brown color).
(a) unlabeled alginate capsules, (b) alginate capsules labeled with Feridex, or
”magnetocapsules” (note ferric oxide rust brown color). Credit: Bulte Lab / JHU
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Graduate Students, Faculty Network at INBT Inaugural Retreat

Johns Hopkins Institute for NanoBioTechnology held its first annual pre-doctoral (graduate) student retreat at the Mount Washington Conference Center on Sunday, October 28, 2007.

Assistant professor David Gracias (ChemBE) describes self-assembled nanoliter containers.

Assistant professor David Gracias (ChemBE) describes self-assembled nanoliter containers.Credit: INBT / JHU

The retreat was arranged to engage students involved in both the National Science Foundation sponsored Integrative Graduate Education and Research Traineeship—or NanoBio IGERT—and the Howard Hughes Medical Institute (HHMI) sponsored Interdisciplinary Graduate Training in Nanotechnology for Biology and Medicine—or NBMed Program. Four faculty members affiliated with INBT presented their research during the morning speaker session. Speakers from the School of Medicine included Douglas Robinson, assistant professor of cell biology, and Jonathan Schneck, professor of pathology. Presenters from the Whiting School of Engineering included Hai-Quan Mao, assistant professor of materials science, and David Gracias, assistant professor of chemical & biomolecular engineering. Terrence Dobrowsky, a student in the HHMI program, also presented.

From left, Craig Schneider (HHMI), Mustapha Jamal (IGERT), and assistant professor Kalina Hristova (Mat. Sci. Eng.) networking during the retreat luncheon.

From left, Craig Schneider (HHMI), Mustapha Jamal (IGERT), and assistant professor Kalina Hristova (Mat. Sci. Eng.) networking during the retreat luncheon. Credit: INBT / JHU

Denis Wirtz, associate director of INBT and professor of chemical and biomolecular engineering, began the retreat by welcoming eight new students into the INBT’s graduate training programs. There are 15 students altogether in both programs, and they come from the departments of Materials Science and Engineering, Chemical an Biomolecular Engineering, Mechanical Engineering, Physics, and Biology.

About 45 students and faculty participated in a lively question and answer session in the morning, a chance to network during lunch, and further discussion during the afternoon poster session. INBT wishes to thank education program coordinator Ashanti Edwards for making the institute’s inaugural retreat such a huge success.

Janice Lin (IGERT), center, takes questions from Patrick Stahl (HHMI) left, and Tania Chan (IGERT), right.

Janice Lin (IGERT), center, takes questions from Patrick Stahl (HHMI) left, and Tania Chan (IGERT), right. Credit: INBT / JHU

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2008 Nanobio Symposium Preview: Andrew D. Maynard

Wilson Center Expert Says Public Dialog Key to Nanotech’s Future

Andrew D Maynard. Credit: Wilson Center.
Andrew D Maynard. Credit: Wilson Center.

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HHMI Student Profile: Alfredo Celedon

Alfredo Celedon, HHMI NanoBioMed graduate student.
Alfredo Celedon, HHMI NanoBioMed graduate student. Credit: INBT / JHU

Nanoparticless open up enormous possibilities for scientists and engineers to study biomolecules, says Alfredo Celedon, a NanoBioMed graduate (pre-doctoral) trainee at the Johns Hopkins University Institute for NanoBioTechnology (INBT).

“The ability to tailor magnetic nanoparticles, connect them to a biomolecule, and use the magnetic nanoparticle to manipulate the molecule is a very powerful concept. It will allow us to study the way different enzymes work, and it may even allow us to use them in new ways,“ Celedon says. “Proteins are perfect nanomachines, so it would be great to find ways to take advantage of their mechanisms.“

The molecule of most interest to Celedon is chromatin, the complex of histone proteins and DNA that make up chromosomes in the nuclei of eukaryotic cells. Celedon is studying the mechanical properties of chromatin by observing chromatin condensation under different biologically relevant conditions.

“If you modify the histones, you change the way the chromatin behaves,“ Celedon says. “When the chromatin condenses, the structure is tightly held, and there is no access to the DNA. If the chromatin is less condensed, the histones are more loosely held, and access to the DNA is permitted. Cells control gene expression in this way.”

Using nanoparticles and magnetic tweezers, Celedon has been able to exert forces on the chromatin fiber to study its response. He hopes these experiments will shed light on the generally held hypothesis that there is a “histone code“ that guides interactions between enzymes and DNA.

Modified histones are prepared in the lab of INBT affiliate Greg Bowman, assistant professor of biophysics at the Krieger School of Arts and Sciences. Magnetic nanoparticles are fabricated in the lab of Peter Searson, professor of materials science and engineering and director of INBT. Experiments using the magnetic tweezers experiments are conducted under an inverted optical microscope in the INBT’s laboratory located in the Whiting School of Engineering. Celedon’s advisors include INBT affiliate Sean Sun, assistant professor of mechanical engineering, and Denis Wirtz, professor of chemical and biomolecular engineering and INBT’s associate director.

“I had previously attempted to model these concepts theoretically,“ Celedon says. “Through the guidance of my advisors and INBT, we have developed a way to test these ideas experimentally. This is my first experience using nanotechnology, and we found that it is a unique way to observe the behavior of chromatin.“

Celedon, a native of Chile, earned both a bachelor’s and master’s degree in chemical engineering from Catholic University of Chile. He first came to the U.S. on a Fulbright Fellowship to University of California, Los Angeles, where he earned a second master’s degree in bioengineering.

The NanoBioMed program is sponsored by the Howard Hughes Medical Institute. To learn more about the NanoBioMed HHMI program, click here.

Computer Models Explore Nano-Machines

ATP synthase
Rotary motor ATP synthase manufactures ATP for the rest of the cell. Credit: Sun Lab / JHU

“Most molecular motors operate on principles that are very similar to the way the engine in your car works,“ says Sean Sun, an assistant professor in the Department of Mechanical Engineering in the Whiting School of Engineering at Johns Hopkins University and an affiliated faculty member of the Institute for NanoBioTechnology.
“They consist of a flexible protein that performs an action when it burns a fuel molecule.“

But understanding how nano-sized machines function or how they create forces is not always this straightforward. “In any system in biology, 90 percent of it is unknown,“ Sun says.

Sun recently encountered many unknowns while conducting computational research on the biological forces generated during the reproduction of single cell organisms. Sun, doctoral student Ganhul Lan and colleague Charles Wolgemuth of the University of Connecticut, have described how a kind of molecular nanomachine called a Z-ring facilitates bacterial cell division.
The team published their findings in the Proceedings of the National Academies of Science (Oct. 9, 2007). According to report, the Z-ring produces enough force to pinch the rigid cell wall to initiate division and also helps localize the proteins needed to form a new cell wall between the daughter cells. Exactly how this force is generated is still a mystery.

“Our lab works on nanomachines of all different kinds,“ Sun says. “The Z-ring is a protein conglomerate ensemble (and) one of the interesting discoveries about the process is that very little force was required to do the job.“

Sean Sun
Sean Sun. Credit: Will Kirk / JHU

Solutions to the puzzles presented by nanomachines can be found by exploiting the synergy between computational models and experimental observations, he says. Sun also draws upon his prior training in chemistry and physics.

“Biology is making a tremendous transition from an observational science into a quantitative science,“ Sun says. “This is an area where I can really make a contribution“

Computational theories on molecule fueled nanomachines can be tested experimentally in labs like that of INBT’s associate director, Denis Wirtz, professor in the Department of Chemical and Biomoleculuar Engineering. “With Denis, we are looking at many of the biochemical details to see if they match up to the computational models,“ Sun says.

Multidisciplinary collaborations initiated by INBT will shed light on these unknowns, Sun says. “Experiments are crucial in directing where your theories and modeling ought to go…They supply you with parameters. Even if you build equations, there are still unknowns that have never been measured. It is a synergistic process.“

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andre levchenko
Andre Levchenko with graduate student Hojung Cho holding innovative device with microscopic chambers. Credit: Will Kirk / JHU
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INBT Awards Seed Grants for Nanotechnology Diagnostics

Last August the Institute for NanoBioTechnology placed a call for proposals in the area of Diagnostics. This was the fourth funding opportunity supported by INBT in one of it’s core research areas.

The call for proposals related to diagnostics, which focussed on promising nanotechnology in the imaging of a specific disease, concluded the first year of the INBT seed grants. Five winning proposals by Johns Hopkins faculty have been selected to receive $20,000 each.

  • “Tumor imaging by silica nanoparticles: binding to prostate specific membrane antigen“ Howard Katz (MatSc) and Ronnie Mease (Radiology)
  • “Diagnosing colon cancer risk through direct experimentation on biopsied cells” Andre Levchenko (BioMed) and Andrew Feinberg (Medicine/Oncology)
  • “Nanomechanical techniques for cancer diagnosis“ Sean Sun (MechE), Greg Bowman (Biophysics) & Peter Searson (MatSc)
  • “Innovative technologies to study mechanisms of inflammation-induced CNS axonal degeneration“ Nitish Thakor (BioMed), Arun Venkatesan (Neurology) & Avindra Nath (Neurology)
  • “An integrated microfluidic nanosensor platform for point mutation detection of cancers” Jeff Wang (MechE) and Ie-Ming Shih (Pathology)

Nanowire Device Gives Insight in Cell Forces

Immunofluorescent micrograph of cell A under force stimulation by a magnetic micropost. (PNAS, Sept. 5, 2007)
Immunofluorescent micrograph of cell A under force stimulation by a magnetic micropost. (PNAS, Sept. 5, 2007)

A nanoscale device, developed by a team of researchers from Johns Hopkins University and the University of Pennsylvania, provides previously unknown information on how cells react to environmental forces.

The device offers a better understanding of cell mechanics and a potential means for scientists to compare how healthy and diseased cells react to forces. This knowledge, in turn, could spur the development of novel drug therapies, researchers say.
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Risk Assessment Minor in Development at JHU

Nanotechnology involving materials and devices at extremely small length scales—sometimes just a few atoms wide— is providing novel solutions to health and environmental problems. Nano-sized components are found in hundreds of applications, from targeted cancer therapies to stain-resistant clothing.

So that the scientists and engineers of the future will be better prepared to answer questions regarding nanotechnology, Johns Hopkins University faculty members specializing in disciplines ranging from engineering to public health are collaborating to develop a new undergraduate minor in nanotechnology risk assessment and public policy. Funding for development comes from a two-year, $200,000 National Science Foundation grant and will be administered through the Johns Hopkins Institute for NanoBioTechnology (INBT). If their work goes as planned, faculty members anticipate that the minor will be ready to accept its first students by the fall of 2009.

Students in the nano-risk minor will explore both the scientific properties of nanomaterials and the public policy ramifications of their use.

“We want them to learn about the potential risks associated with the development of nanotechnological solutions, as well as come to understand the risks presented by not developing some of these nanoscale solutions,“ says Justin Hanes, associate professor in the Whiting School of Engineering (WSE), who co-authored the grant with Edward Bouwer, WSE professor and director of the Center for Contaminant Transport, Fate, and Remediation, and Jonathan Links, professor in the Bloomberg School of Public Health (BSPH). All are INBT affiliated faculty members.

“Nanoparticles are small enough to cross cell membranes. They also possess a large surface area, which enhances their reactivity,“ Links says. “However, little research has been done to examine the toxicity potential of these ultrafine particles. Some concerns have been based only on the extrapolation of studies on other substances such as quartz, asbestos or particulate air pollution.“

Bouwer adds, “The proposal makes clear that the effects of nanoparticles on public health or the environment are not well understood. The program’s goal is to train scientists who are better prepared to lead research, development, and eventual commercialization of safe nanotechnologies.“

The new minor will likely involve a suite of courses on topics such as risk science and public policy; nanotechnology ethics, law and policy; environmental engineering; emerging environmental issues; environmental health; public health; and public health toxicology. Faculty members who will develop or teach the courses are affiliates of INBT, WSE, and BSPH, as well as the Risk Sciences and Public Policy Institute, Berman Institute of Bioethics, Center for Law and the Public’s Health, and Center for Educational Outreach (CEO).

“The program complements with the large group of students in the Public Health Studies major who also explore environmental health, health policy and other public health-related topics, but from a broader perspective,“ says James Yager, senior associate dean for academic affairs at BSPH.

A new course to be offered in the spring of 2008—Nanobiotechnology 101—and developed by INBT co-directors Peter Searson, professor of Materials Science and Engineering and Denis Wirtz, professor of Chemical and Biomolecular Engineering, will likely be a prerequisite of the nano-risk minor.

“The combination of leading faculty from across disciplines in the University exemplifies the mission of INBT by blending and leveraging expertise,“ Searson says. “It is a marvelous opportunity to bring together pre-existing, but largely separate, activities in nanotechnology within the university to impact our students and beyond.“

Additional INBT Training Opportunities

In addition to this new minor, INBT administers three other educational programs including the graduate Nano-Bio Medicine program funded by the Howard Hughes Medical Institute, the Integrative Graduate Education and Research Traineeship in Nanobiotechnology funded by the National Science Foundation, and a summer Research Experience for Undergraduates program.

Part of the proposal for the nano-risk minor requires that students from these graduate training programs be involved by training of K-12 classroom instructors through the Center for Educational Outreach (CEO). CEO will translate components of the coursework for use in science, technology, engineering, and mathematics curriculums in underprivileged school settings.

Also available in the JHU Gazette of Oct 8, 2007.

Integrated Imaging Center Brings It All into View

Seeing something as small as a nanometer—just about three to five atoms wide—requires highly advanced imaging techniques.

Top: Mutant Drosophila adult testis showing germ cells (red) and cell surface and fusome (green). Bottom: Early stage (third larval instar) wild-type (normal) Drosophila testis showing germ cells (red) and cell surface and pigment cell nuclei (green). Credit: van Doren Lab/JHU
Confocal image. Top: Mutant Drosophila adult testis showing germ cells (red) and cell surface and fusome (green). Bottom: Early stage (third larval instar) wild-type (normal) Drosophila testis showing germ cells (red) and cell surface and pigment cell nuclei (green). Credit: Van Doren Lab/JHU

Faculty affiliated with Johns Hopkins University’s Institute for NanoBioTechnology and researchers from a wide range of disciplines across divisions at JHU will find advanced, comprehensive, and highly precise methods of imaging at the Integrated Imaging Center (IIC) at JHU’s Homewood Campus.

Everyone is invited to see firsthand what IIC has to offer at the center’s annual open house, co-sponsored by Carl Zeiss and FEICO, on Sept. 21, 2007 from 3 to 6 p.m. IIC’s 2,500 square-foot facility is located on the first floor of Dunning Hall.

IIC’s facilities help scientists and engineers characterize nanomaterials at very small length scale as well as biologists studying complex cellular and subcellular interactions. Microscopy services at IIC also aid developers of medical applications investigate the interface between materials and biological systems and basic biomedical researchers describe nano-sized drug delivery systems.

The center boasts more than $3.5 million worth of state-of-the-art imaging equipment, including one of only two uniquely configured laser scanning microscopes in the United States. The goal of IIC, says center director J. Michael McCaffery, an associate research professor in the Department of Biology, is to provide the Johns Hopkins community, as well as other academic institutions, industry, and government, with resources for both conventional and advanced methods of light and fluorescence microscopy services.

Developing embryo of C. elegans. PIE-1 protein tagged with green fluorescent protein to monitor asymmetric cell division. Credit: Wirtz Lab/JHU.
Confocal image. Developing embryo of C. elegans. PIE-1 protein tagged with green fluorescent protein to monitor asymmetric cell division. Credit: Wirtz Lab/JHU

“As rapid advances have been made in the development of new techniques of fluorescence and electron microscopy, visualization and localization of biomolecules at the light and electron microscope level has become an essential component of any comprehensive study of molecular cell biology,“ McCaffery says. “This is because light and electron microscopy observations provide detailed information on the distribution, movement, and interaction of biomolecules or proteins within the cell that cannot be obtained by other methods.“

To anticipate the changing demands of research in a variety of disciplines, McCaffery says, IIC has added new equipment in recent months. A highlight includes a Zeiss laser scanning microscope (LSM) 510 VIS confocal with a Confocor 3 fluorescence correlation spectroscopy (FCS) module.

“There is only one other system of its kind in the U.S. that combines the FCS with confocal imaging and that is capable of cross-correlation,“ McCaffery says. “FCS allows for high-resolution spatial and temporal analysis of single biomolecules with respect to diffusion, binding, and enzymatic reactions in vitro and in vivo.“

Other new additions include a FEI Tecnai 12 TWIN 120kV high resolution (

Transmission electron miscroscope (TEM) image of self-assembled monolayer of spherical cobalt nanoparticles (~12 nm diameter) from a solution of hexane/octadecene. Credit: Searson Lab/JHU
Transmission electron miscroscope (TEM) image of self-assembled monolayer of spherical cobalt nanoparticles (~12 nm diameter) from a solution of hexane/octadecene. Credit: Searson Lab/JHU

The ESEM has proved to be very popular, McCaffery says, because of its ability to “image fully hydrated/wet samples with minimal preparation.“ In traditional scanning electron microscopy, samples must be dehydrated and coated with a metal prior to imaging. In the ESEM mode, McCaffery explains, “you can use a peltier stage to achieve relative humidity at any temperature or pressure in order to image live samples with minimal surface tension induced drying artifacts.“

The center features five suites devoted to specific imaging functions. These include a ultramicrotomy/tissue culture/cell prep room; a wet laboratory; “scanning room,“ which includes the Quanta ESEM and Typhoon phosphorimager; a transmission electron microscopy suite with two TEMs; and a multifunctional light microscopy suite, which includes the Marians 4D LM, Zeiss LSM 510 VIS confocal with Confocor 3 FCS, LSM 510 META UV confocal, and two Zeiss epifluorescence microscopes. Knowledgeable IIC staff members are available to answer questions or assist with the use of all equipment. Grants from the National Institutes of Health, National Science Foundation, and Howard Hughes Medical Institute help fund the additions to IIC.

Observation of green fluorescent nanoparticles (~90 nm in diameter) traveling through a micropost obstacle course. Credit: Drazer Lab/JHU.
Confocal image. Observation of green fluorescent nanoparticles (~90 nm in diameter) traveling through a micropost obstacle course. Credit: Drazer Lab/JHU

The Homewood campus IIC was established in 1998. Additional advanced imaging services have been available at the Montgomery County Campus IIC since 2004.

To learn more about the Integrated Imaging Center at JHU or to schedule an appointment to use the facilities, please go to the IIC Web site: http://www.jhu.edu/~iic/.

To view images from the IIC, click on the following link: http://www.jhu.edu/iic/gallery.htm

For other JHU research facilities visit our facilities page: http://inbt.jhu.edu/facilities.php