2011 Johns Hopkins Nano-Bio Magazine

JOHNS HOPKINS

NANO-BIO The Magazine of Johns Hopkins Institute for NanoBioTechnology | Spring 2011

Nanotech Versus Cancer Three Big Ways Tiny Tools Will Change Cancer Cells Get Ready For Their Close-up IIC Brings Data Into Focus

nbt

INBT Goes To The Fair

CONTENTS

FEATURED STORIES Johns Hopkins University Institute for NanoBioTechnology Suite 100, New Engineering Building 3400 North Charles Street Baltimore, MD 21218 Phone: (410) 516-5634 Fax: (410) 516-2355 http://inbt.jhu.edu Leadership Peter C. Searson DIRECTOR;

10

18

Beyond the Bench: Johns Hopkins Cells Studied in 3-D Technology Transfer Puts Results May Reveal Novel Cancer Targets to Work

27

Jargon-Free Zone: Science, Engineering Fest Forces Tech Talk Out the Window

JOSEPH R. AND LYNN C. REYNOLDS PROFESSOR

Denis Wirtz ASSOCIATE DIRECTOR; THEOPHILUS H. SMOOT PROFESSOR

Staff Ashanti Edwards

SYMPOSIUM 2 3 4

Welcome Agenda Cancer Nanotechnology: Three Big Ways Tiny Tools Will Change Cancer

ACADEMIC PROGRAM ADMINISTRATOR

PARTNERSHIPS

Thomas Fekete

8 10 13

DIRECTOR OF CORPORATE PARTNERSHIPS

Christie Johnson

Weaving Novel Tissue Engineering Templates Beyond the Bench: Johns Hopkins Technology Transfer Puts Results to Work Corporate Sponsored Fellowship Puts Engineer on Industry Fast Track

RESEARCH SERVICE ANALYST

6XVDQQDK 3RUWHUÀHOG ADMINISTRATIVE MANAGER

Martin Rietveld DIRECTOR, WEB/ANIMATION

Tracy Smith ADMINISTRATIVE COORDINATOR

Mary Spiro SCIENCE WRITER; EDITOR-IN-CHIEF, NANO-BIO MAGAZINE

Graphic Design Danielle Peterson BRIO DESIGN

Additional Photography Homewoord Photography Johns Hopkins Pathology Photography

RESEARCH 14 18 20 22

More Than Pretty Pictures: Johns Hopkins Integrated Imaging Center Brings Data Into Focus Cells Studied in 3-D May Reveal Novel Cancer Targets Electric Tweezers Put Nanowires Right Where They’re Needed Dissecting the Nanomotor That Packages the Genome

EDUCATION 25 26

aRE YoU Ready for Some Research?

Students Organize Cancer Nanotech Mini-Symposium

OUTREACH 27 28 31

Jargon-Free Zone: Science, Engineering Fest Forces Tech Talk Out the Window Extreme Makeover: ‘Boys Hope Girls Hope’ Home Edition INBT: The Movie

ON THE COVER +HDOWK\ PRXVH ÀEUREODVWV LPDJHG ZLWK KLJK PDJQLÀFDWLRQ ÁXRUHVFHQFH PLFURVFRS\ 7KLV DOWHUHG LPDJH VKRZV WKH QXFOHXV LQ JUHHQ DQG DFWLQ ÀODPHQWV LQ SXUSOH Illustration by Martin Rietveld

Spring 2011

1

Symposium

WELCOME

Denis Wirtz

Anirban Maitra

Welcome to the fifth annual symposium of Johns Hopkins Institute for NanoBioTechnology. The focus of today’s symposium is cancer nanotechnology. It’s also the theme of the second edition of our annual publication, Nano-Bio Magazine.

As co-chairs of today’s event, we have prepared a slate of expert faculty speakers for the morning session to discuss cancer metastases and the variety of exciting and innovative ways that this collection of diseases can be detected, treated and possibly even cured using nanotechnology. Our symposium poster session this afternoon offers a chance to explore the numerous advanced ways that researchers across Johns Hopkins University are using nanotechnology to study the problem of cancer metastases, as well as other problems in the basic biological sciences, health and medicine. Nanotechnology has truly provided scientists, engineers and clinicians with an amazing toolbox of devices to gain a better understanding of this dreaded disease we call cancer.

The pages of our 2011 Nano-Bio Magazine have a compendium of articles describing the latest research, outreach activities and educational programs of INBT. In particular, our editor has chosen to highlight research efforts devoted to elucidating the processes of metastasis and to discovering ways we might potentially diagnose and treat cancer in the future with nanotechnology. Our feature story on the ways that nanotechnology will impact cancer is a fitting introduction to updates on the progress being made at the Johns Hopkins Physical Sciences-Oncology Center, also known as the Engineering in Oncology Center, as well as our brand new Center of Cancer Nanotechnology Excellence. Both centers are funded through grants from the National Cancer Institute. There is also a section showcasing our unique educational programs, including the training occurring at the new Cancer Nanotechnology Training Center.

INBT was founded in May 2006. So, today’s symposium represents something of a mini-milestone— a celebration of our fifth anniversary as a research entity. We thank you for joining in this celebration, and we hope that you also share our expectation that we shall have many more anniversaries in the years to come. Thanks also to our corporate partners for their ongoing support of our endeavors throughout the year and to our media sponsors for making this event and publication possible.

Please let one of us, an INBT staff member, or one of our student volunteers know if there is anything that we can do to make your experience with us here today more pleasant. We hope you enjoy the day!

Denis Wirtz Theophilus H. Smoot Professor Whiting School of Engineering Department of Chemical and Biomolecular Engineering Director, Johns Hopkins Physical Sciences-Oncology Center Anirban Maitra Professor Johns Hopkins School of Medicine Department of Pathology Co-director, Cancer Nanotechnology Training Center

2

Johns Hopkins University Nano-Bio Magazine

Symposium

AGENDA 9:00-9:05 am

CANCER NANOTECHNOLOGY | May 13, 2011, Shriver Hall The annual symposium of Johns Hopkins Institute for NanoBioTechnology

Welcome/Introduction of Speakers,

10:35-10:50 am

Break

10:50-10:55 am

Welcome/Introduction of Speakers

Denis Wirtz KEYNOTE ADDRESS 9:05-9:35 am

Anirban Maitra

“Why develop sensitive detection systems for abnormal DNA methylation in cancer?”

10:55-11:15 am

“Cancer Cell Motility in 3-D”

Stephen B. Baylin is deputy director of The Sidney

Denis Wirtz is the Theophilus H. Smoot Professor

Kimmel Comprehensive Cancer Center at Johns

of Chemical and Biomolecular Engineering in the

Hopkins and the Virginia and D.K. Ludwig profes-

Whiting School of Engineering at Johns Hopkins

sor of oncology and medicine. He is chief of the

University. Wirtz is associate director of INBT and

Cancer Biology Division and associate director for

director of the Johns Hopkins Physical Sciences-

research of the center.

Oncology Center, also known as the Engineering in Oncology Center.

9:35-9:55 am

“Enabling cancer drug delivery using nanoparticles” Anirban Maitra is a professor at Johns Hopkins

11:15-11:35 am

“MRI as a Tool for Developing

School of Medicine with appointments in Pathol-

Vaccine Adjuvants”

ogy and Oncology at the Sol Goldman Pancreatic

Hy Levitsky is a professor of Oncology, Medicine

Research Center and secondary appointments in

and Urology at the Johns Hopkins School of Medi-

Chemical and Biomolecular Engineering at the

cine and the Scientific Director of the George Santos

Whiting School of Engineering and the McKusick-

Bone Marrow Transplant Program.

Nathans Institute of Genetic Medicine.

11:35-11:55 am 9:55-10:15 am

10:15-10:35 am

“Genetically Encodable FRET-based Biosensors

“Epithelial Morphogenesis

for probing signaling dynamics”

in Cancer Metastasis”

Jin Zhang is an associate professor at Solomon

Gregory Longmore is a professor at the Washington

H. Snyder Department of Neuroscience at Johns

University in St. Louis School of Medicine, Depart-

Hopkins School of Medicine with primary appoint-

ment of Medicine, Oncology Division, Molecular

ments in Pharmacology and Molecular Sciences and

Oncology Section and the Department of Cell Biol-

secondary appointments in Neuroscience, Oncology,

ogy and Physiology.

and Chemical and Biomolecular Engineering.

“A Translational Nanoparticle-Based Imaging

11:55-12:00 pm

Adjourn/Concluding Remarks

Method for Cancer”

Thomas Fekete, director of corporate partnerships,

Martin Pomper is a professor at Johns Hopkins

INBT

School of Medicine with a primary appointment in Radiology and secondary appointments in Oncology, Radiation Oncology, and Pharmacology and Mo-

1:30-3:30 pm

Research Poster Session, Clipper Room, Shriver Hall

lecular Sciences, as well as Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health.

Spring 2011

3

Symposium

Cancer Nanotechnology: Three Big Ways Tiny Tools Will Change Cancer

BY MARY SPIRO

The National Cancer Institute estimates that more than 1.5 million new cases of cancer were diagnosed in 2010, not including certain skin cancers. Although progress has been made in the treatment of many types of cancer, more than 1,500 people a day still die from cancer, which is the second leading cause of death in America behind heart disease.

Nanotechnology, whether used as a basic research tool or as part of a therapy, is expected to impact cancer diagnosis and treatment in many ways. In the past two years, Johns Hopkins Institute for NanoBioTechnology has established two research centers devoted to combating cancer.

In the fall of 2009, NCI awarded INBT $14.8 million over five years to launch a Physical Sciences-Oncology Center (PS-OC) aimed at unraveling the physical underpinnings that drive the growth and spread of cancer. The Johns Hopkins Engineering in Oncology Center is led by Denis Wirtz of the Whiting School of Engineering and Gregg Semenza of the Johns Hopkins School of Medicine. Then, in the fall of 2010, INBT received a $13.6 million 5-year grant to create the Johns Hopkins Center of Cancer Nanotechnology Excellence (CCNE). This center brings together a multidisciplinary team of scientists, engineers and physicians to develop nanotechnology-based diagnostic

4

Johns Hopkins University Nano-Bio Magazine

platforms and therapeutic strategies for comprehensive cancer care. Peter Searson of the Whiting School of Engineering and Martin Pomper of the Johns Hopkins School of Medicine codirect this research entity. Both centers support the philosophy that to find solutions to the challenges of cancer, researchers must revise their way of thinking.

“Genetic approaches provide important insight to cancer, but it is not enough,” said Wirtz, who is the Theophilus H. Smoot Professor in the Department of Chemical and Biomolecular Engineering. “The cell’s microenvironment, and in particular, its physical properties play a critical role in tumor growth and metastasis. We have the opportunity to develop never-before imagined solutions to cancer’s challenges by integrating physics principles with cancer biology.”

Likewise, the tools and materials being developed in nanotechnology have just begun to be employed to study basic cellular interactions, let alone be used for drug delivery vehicles or tumor eradication methods, added Searson, the Joseph R. and Lynn C. Reynolds Professor in the Department of Materials Science and Engineering.

“The focus of the CCNE will be strongly translational,” Searson said. “We want to develop innovative nanotechnology-based

+XPDQ HQGRWKHOLDO SURJHQLWRU FHOOV DOLJQ RQ PLFURQ ZLGH ÀEURQHFWLQ

Nanotechnology will become important in imaging cells like these

patterns, elongate, and assemble into tubular structures in vitro after

KHDOWK\ PRXVH ÀEUREODVWV 8QGHU KLJK PDJQLÀFDWLRQ à XRUHVFHQFH

Ă€YH GD\V LQ FXOWXUH /DXUD 'LFNLQVRQ *HUHFKW /DE

PLFURVFRS\ WKH QXFOHXV DSSHDUV EOXH DQG DFWLQ ÀODPHQWV DUH VKRZQ LQ green. (Christopher Hale/Wirtz Lab)

solutions to cancer diagnosis and therapy and then shepherd them through to clinical trials via corporate partnerships and creative pathways to commercialization.�

Understanding stem cell biology As part of PS-OC, Sharon Gerecht leads an investigation on how cancer spreads by analyzing the physical properties of the extracellular matrix, the three-dimensional framework upon which cells grow. Gerecht, an assistant professor of chemical and biomolecular engineering in the Whiting School of Engineering, studies stem cells and in particular endothelial progenitor cells, which have the potential to generate new blood vessels. Both healthy and cancerous tissues require vascularization to bring them cell-renewing oxygen. “Nanotechnology and nanoscale materials are and will continue to impact the field of stem cell engineering as they offer a unique opportunity for the basic understanding of cell fate decision at the sub cellular level,� Gerecht said. “For example, using nanotechnology one can control and manipulate the interactions of a cell with the surface topography onto which it is attached.�

Gerecht’s team uses hydrogels—polymer-based cell cultur-

ing platforms—with nanoscale features, patterned surfaces and attached growth factors to coax endothelial progenitor cells to grow and differentiate. Some of her recently published work demonstrates that by manipulating the fabricated substitute for the extracellular matrix, one can cause cells to behave in vitro much the same as they would in living tissue. “These technological advantages enable us to mimic the surrounding environment of the cells in healthy and diseased tissues to study cellular responses such as differentiation and growth. Clinical applications include the guidance of tissue regeneration as well as the inhibition of tumor growth,� Gerecht said. “Through surface modification we can control the cellular organization of endothelial progenitors and guide them to assemble into unidirectional tubular structures. This approach allows us to engineer the formation of well-organized vascular structures in vitro.� Gerecht said that if well-defined, functional vascular networks can be achieved in a Petri dish, it may one day lead to methods to improve the growth and survival of implanted cells and tissues in patients.

Quantum dots for early diagnosis Tza-Huei “Jeff� Wang, associate professor of mechanical

Spring 2011

5

Cy5 labeled molecules brought close to quantum dot (gold) through

Mucus-penetrating particles (red) improve particle distribution in the

biotin streptavidin interaction. The laser excites the quantum dot which

airway mucus that lines the respiratory tract. Conventional particles

transfers energy to the Cy5 labeled target molecules (red). (Yi Zhang/

(green) are adhesively stuck in mucus. (Craig Schneider/Hanes Lab)

Wang Lab)

engineering in the Whiting School of Engineering leads a research project with the CCNE that seeks methods to screen bodily fluids such as blood or urine for cancer indicators found outside of the genetic code, indicators called epigenetic markers.

Working with Stephen Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research in the School of Medicine; and James Herman, Wang’s project will use semiconductor nanocrystals, also known as quantum dots, and silica superparamagnetic particles to detect DNA methylation. Methylation adds a chemical group to the exterior of the DNA and is a biomarker frequently associated with cancer.

Nanoparticles, such as quantum dots, possess “well defined shapes, sizes, and compositions as well as a high surface to volume ratio,” Wang said. That means a nanosensor using quantum dots can be more efficient in binding molecules associated with epigenetic markers and therefore, is better able to detect very low volumes of these indicators in bodily fluids.

Quantum dots, which range from a few nanometers up to a couple hundred nanometers in diameter, work by capturing molecular targets and, something like a light switch, transducing

6

Johns Hopkins University Nano-Bio Magazine

the molecular binding events into fluorescent signals, in a process called fluorescence resonance energy transfer (FRET), Wang explained. “Quantum dots make excellent FRET donors that overcome pitfalls associated with conventional molecular FRET,” he said.

Because quantum dots of different sizes absorb different wavelengths of light, measurable fluorescence is emitted even at the single molecule level of detection. QD-based DNA nano sensors easily filter out background “noise” to perceive circulating biomarkers including single point mutations to the genetic code and DNA methylation in clinical samples.

“The quantum dot assays, and other nanomaterials enabled assays, possess ultrahigh sensitivity that address the challenge in rare markers in bodily fluids such as blood, present a promising solution for non-invasive disease screening and monitoring in the near future,” said Wang.

Nano-scale ‘smart bomb’ cancer therapies Drugs contained in nanosized particles could direct chemotherapeutic agents to attack cancer cells located among many

healthy ones, preventing the common side-effects that occur when toxic chemicals enter a cancer patient’s bloodstream. Craig Peacock, an assistant professor of cancer biology at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins School of Medicine, is part of a team at the CCNE using mucus-penetrating nano-particles to deliver drugs to small cell lung cancer cells. Peacock said the use of nanotechnology could help overcome some of the challenges of traditional chemotherapies. “The success of improved cancer treatments has been eclipsed by the fact that many cancers become resistant to therapies over time,� Peacock said. “This is especially true for small cell lung cancer (SCLC), an extremely aggressive tumor that is strongly linked to tobacco exposure, and which is frequently responsive to chemotherapy when treatment first begins.�

Peacock said the majority of SCLC patients die within two years of diagnosis due to the rapid reappearance of chemoresistant disease. This suggests that a small number of tumor cells resist the toxic effects of the chemotherapy drugs, and subsequently generate enough drug-resistant progeny to permit the cancer to be reestablished. “My research is concerned with interrupting this source of tumor recurrence,� Peacock said. Studies of SCLC cells grown in the lab indicate that even “resistant� cells can be killed with sufficiently high doses of chemotherapy drugs, Peacock added. “However, achieving these doses in patients using traditional approaches produces intolerable toxicity in normal, healthy tissues,� he said. Working with Justin Hanes’ group, Peacock seeks to circumvent this obstacle by using specialized mucus-penetrating nanoparticles (MPP) to encapsulate the chemotherapeutic agents and deliver them directly to the site of the tumor within the lung. Hanes is a professor in the Department of Ophthalmology at the Johns Hopkins School of Medicine. “This permits targeted exposure of the cancer to high, sustained doses of chemotherapy, while sparing normal tissues from the worst effects of these drugs,�

Peacock said.„

Johns Hopkins Cancer Nanotechnology Training Center (CNTC) Launched

BY MARY SPIRO

To train new scientists and engineers to combat the spread of cancer, Johns Hopkins Institute for NanoBioTechnology (INBT) has established a pre-doctoral (PhD) training program in Nanotechnology for Cancer Medicine. Together with the institute’s previously established Nanotechnology for Cancer Medicine postdoctoral fellowship, these two training programs comprise the Johns Hopkins Cancer Nanotechnology Training Center (CNTC).

Similar to the postdoctoral program, the PhD training in nanotechnology for cancer medicine will educate graduate students to use nanotechnology solutions to diagnose, treat, manage, and hopefully one day, even cure cancer, said the CNTC’s director Denis Wirtz, the Theophilus H. Smoot professor of Chemical and Biomolecular Engineering in the Whiting School of Engineering.

7KH &17& ZDV IXQGHG E\ D PLOOLRQ JUDQW RYHU Ă€YH \HDUV IURP WKH National Cancer Institute. Launched in the fall of 2010, the pre-doctoral WUDLQLQJ SURJUDP KDV DOUHDG\ DWWUDFWHG KLJKO\ TXDOLĂ€HG VWXGHQWV ZLWK EDFKelor’s degrees in diverse backgrounds such as biochemistry, genetics, molecular and cellular biology, as well as those who majored in engineering or physics. By attracting students with these sorts of educational backgrounds,Wirtz said, INBT will help develop what he calls “hybrid scientists, engineers, and clinicians.â€? “We are seeking to train people who can develop new nanoscale materials and nanoparticles that will address biological functions related to the growth and spread of cancer, or metastasis, at a mechanistic level,â€? said Wirtz, who also directs INBT’s Engineering in Oncology Center and is INBT’s associate director.

Anirban Maitra, professor of pathology and oncology at the Johns Hopkins School of Medicine and co-director of the CNTC, said research will IRFXV RQ WKH LGHQWLĂ€FDWLRQ DQG SUHFOLQLFDO YDOLGDWLRQ RI WKH PRVW FDQFHU VSHFLĂ€F QDQRWHFKQRORJ\ EDVHG WKHUDSLHV SDUWLFXODUO\ XVLQJ WKH ZHDOWK of knowledge on the cancer genome emerging from CNTC participant scientists such as Kenneth Kinzler and Bert Vogelstein, both School of Medicine faculty. “The CNTC is uniquely poised to leverage this information for developing molecularly targeted nanotechnology-based tools for cancer therapy,â€? Maitra added. *HQHUDOO\ IHOORZV WDNH Ă€YH WR VL[ \HDUV WR FRPSOHWH WKH FDQFHU QDQRtechnology for medicine PhD program. INBT will support CNTC trainees for two years, after which, the students will be funded by their primary departments from which their degrees will be conferred.

As many as six outstanding pre-doctoral fellows may enter the CNTC program per year.Candidates from under-represented groups in the science and engineering disciplines, including women and minorities, are encouraged to apply.

For more information about the CNTC programs, please contact INBT’s Ashanti Edwards, at ashanti@jhu.edu.

Spring 2011

7

Partnerships

Weaving Novel Tissue Engineering Templates

BY MARY SPIRO

Secant’s woven spacer fabric designed for use in spinal stabilization.

Imagine a fabric based on centuries old weaving, knitting, and braiding methods, but which coaxes tissue or bone to grow where needed. Secant Medical® pushes the boundaries of biomedical textiles, helping device engineers transform their ideas into prototypes and solve myriad clinical challenges.

Located outside Philadelphia in Perkasie, Pa., a town steeped in textiles manufacturing tradition, Secant Medical’s engineers consult with researchers at universities and in industry to develop advanced biomaterials that resemble fabrics you might find in a craft store, except these fabrics use filaments on the nano- and micro-scale.

“Most clients don’t know the difference between a woven or knitted textile,” said Jeff Koslosky, Secant Medical’s director of technology and product development, “but fabrics do a nice job of mimicking tendons, ligaments and tissues in addition to having the ability to shape transform. Our job is to educate the client as to what’s possible.”

Secant Medical’s expertise in textiles manufacturing dates back to 1943 and their parent company Prodesco Inc. “We take good, basic, fundamental, elegant design to create really interesting applications that can potentially save lives and improve the quality of life,” Koslosky said.

Secant Medical develops textiles for both tissue engineering and medical devices.

8

Johns Hopkins University Nano-Bio Magazine

“Textiles used for tissue engineering scaffolds possess a high surface area (similar to terry cloth or velour) and promote rapid regeneration and repair,” Koslosky said. This kind of textile might be found in an “annular cuff” used to prevent leakage around a replacement heart valve.

Other medical fabrics promote ordered, controlled tissue regeneration. “Textiles with an open weave work well for localizing osteobiologic inducing (bone-growing) materials in a confined area, yet are porous enough to allow for cellular and tissue integration,” Koslosky added. This results in bone regeneration that retains the bone shape.

Some of Secant Medical’s biomedical textiles allow part or all of its material to dissolve in vivo. So-called “hybrid” biomaterials pair biodegradable polymer with stable filament, creating a product that serves a purpose, but is later subsumed by a patient’s own tissue. The company also seeks to develop textiles that combine filaments that degrade at different rates, that include cell growth factors or that can deliver drugs.

Secant Medical is among INBT’s corporate partners. To learn about INBT’s Corporate Partnership Program, contact Tom Fekete at 410-516-8891 or at tfekete1@jhu.edu. To learn more about Secant Medical LLC, visit www.secantmedical.com.

PHOTOGRAPHY COURTESY OF SECANT MEDICAL

Spring 2011

9

Partnerships

Beyond the Bench:

Johns Hopkins Technology Transfer Puts Results to Work

BY BENJAMIN GIBBS

Translational research might seem like an academic or industry buzzword, but scientists traditionally focused on basic research now understand that thinking beyond the bench can put science in the marketplace or at the patient’s bedside.Viewing their work through a translational lens, scientists can interpret results, develop devices, or establish protocols that consider potential clinical or industrial applications. Johns Hopkins Technology Transfer is the place to go for answers to common questions about translational research.

10 Johns Hopkins University Nano-Bio Magazine

ILLUSTRATION BY MARTIN RIETVELD

1.

2.

3.

that gives us the ability to obtain the best possible patent protection. Next, we conduct an analysis of the patent landscape and pertinent scientific literature to help identify potential commercial partners who can help turn the science into products.

What is translational research?

Translational research takes scientific discoveries from laboratories, and systematically transforms them from a scientific concept or hand-built research tool into a readily available commercial product that can be purchased off a shelf from a vendor. Another way to view it is as scientific evangelism: first you make a discovery, then you translate that discovery into a product by convincing ever larger non-scientific groups of its value.

Why consider translating basic scientific knowledge into the marketplace?

Translational research increases the number of people positively impacted by research. One measure of research impact is being published in a peer-reviewed academic journal. The number of times other researchers reference an original academic paper becomes a measure of how much the underlying research influences the body of scientific knowledge. This measure is relevant in the academic world, but has little impact on wider society. A more tangible way to measure research impact is to examine how many people the research helps. In translational research, a basic scientific concept is systematically developed until it can be put into a product and then into someone’s hands. In other words, what would be more meaningful to someone plagued by malaria-infested mosquitoes: an academic paper describing a new way to design an antimalarial mosquito net or a crate full of the mosquito nets manufactured from the design? Scientists also are legally required to translate their findings. The Bayh-Dole Act of 1980 mandates that any institutions generating research with a potential commercial application and using federal funding (usually from the National Institutes of Health or the National Science Foundation) must put forth their best efforts to see that research becomes available on the market.

What are the typical steps in bringing a new idea to the market place?

New ideas should be protected. By submitting an invention disclosure to the Technology Transfer office (even before the research is published) we can file a provisional patent

Commercialization requires management of two related timelines: development of technology from an esoteric scientific concept to a full-fledged product and development of associated patents to protect the product. Discovering something new is not enough; you have to build a fully functional prototype and prove it works. The design is refined until it is ready to be tested in a “real world” environment. The goal is to develop a “production prototype” or design ready to be mass-produced.

4.

What are some of the challenges to translational research?

One challenge to translation is traction: can you convince people that your research is valid? You need to have solid data describing how your technology offers significant advantages over what’s currently available on the market.

Another challenge is identifying the optimal path for commercialization. This may be apparent for certain types of technologies, such as those that require FDA approval.

More customized approaches are required for others.

Finally, what’s the exit strategy, the plan that will capture value for investors? Will you commercialize the technology through a start-up company that will be purchased by a big industry player? Will you license directly to large, established industry players? Investors in early-stage technology want to know how they can generate positive returns from their investments, so it is critical to begin to understand this, even at a very early stage.

Visit the Johns Hopkins Technology Transfer web site for more information about bringing new ideas to market. http://www. techtransfer.jhu.edu/ Benjamin Gibbs is a technology commercialization representative for Johns Hopkins Technology Transfer.

Spring 2011

11

12 Johns Hopkins University Nano-Bio Magazine

Partnerships

.DWH /DÁLQ ZRUNV LQ WKH ODE RI 'DYLG *UDFLDV

and offered some additional money for lab resources. Teamed with researchers at Northrop Grumman, one of the nation’s largest defense contractors, Laflin developed a research project with goals mutually beneficial to her, Gracias, and the company. She also is on track to obtain her security clearance so that she may apply to work with the defense contractor after graduation.

Laflin’s project involves developing a microscale “gripper” with hinges that flex when ultra low volumes of certain molecules, such as those associated with biological or chemical warfare agents, are detected. “It is very difficult to make a hinge sensitive to the parts per million or parts per billion concentration levels of these chemicals,” she said.

Ideally, when the hinge material encounters the chemical trigger, the hinge flexes to close the gripper down around the threatening matter. The challenge, Laflin says, has been in creating a hinge thin enough to perceive low volumes of chemical trigger, yet strong enough to keep the gripper open until activated. Such a device, she said, could also have medical applications by detecting molecules produced by tumors.

In addition to funding her research and helping map her career path, Laflin says INBT’s Corporate Sponsored Fellowship with Northrop Grumman has benefitted her in some unexpected ways. Recently, she and Gracias presented a talk for researchers at Northrop Grumman where she met some of her potential future work colleagues.

“I think it is wonderful when companies get interested in doctoral students. It benefits us and it benefits them because they get students who are specifically trained in fields the companies are interested in,” Laflin said.

Laflin also values being part of INBT. “Interacting with students from other disciplines through INBT’s journal club has been a tremendous benefit,” Laflin said. “I know I can go to them if I have question outside my expertise.”

Companies interested in establishing a Corporate Sponsored Fellowship with INBT should contact, Tom Fekete, INBT’s director of corporate partnerships at tfekete1@jhu.edu or call 410-516-8891.

Corporate Sponsored Fellowship Puts Engineer on Industry Fast Track

BY MARY SPIRO One day, the research of Kate Laflin, a pre-doctoral student in chemical and biomolecular engineering at Johns Hopkins University, may help detect, trap or locate biological or chemical warfare agents, such as anthrax. Laflin’s work on “threat-activated grippers with microelectronics” is funded in part through the Corporate Sponsored Fellowship program at Johns Hopkins Institute for NanoBioTechnology.

Laflin came to Johns Hopkins with a degree in chemical engineering from Virginia Tech seeking defense-related research.

“I have always known that I wanted to work for industry. I had previously started a collaboration with the U.S. Army Research Laboratory, so my work was already heading in that direction,” she said.

Her advisor, David Gracias, associate professor of chemical and biomolecular engineering, urged Laflin to apply for INBT’s Corporate Sponsored Fellowship with Northrop Grumman, which covered part of the cost of her tuition, provided a stipend,

PHOTOGRAPHY BY MARY SPIRO

Spring 2011

13

Research

Shyenne Yang, PhD, of Mark Van Doren’s biology lab positions Drosophila HPEU\RV IRU ÁXRUHVFHQW LPDJLQJ

More Than Pretty Pictures: Johns Hopkins Integrated Imaging Center Brings Data into Focus

BY MARY SPIRO

Heavy, black curtains and dimmed lights shroud the core of the Johns Hopkins Integrated Imaging Center (IIC). Yet researchers who peer through the advanced microscopes cloaked by these dark draperies view experimental samples more clearly than ever thanks to a combination of the high-tech equipment and the creative expertise offered by the center’s seven-member staff.

When describing Johns Hopkins University’s showpiece microscopy facility, it’s easy to rattle off a laundry list of available

14 Johns Hopkins University Nano-Bio Magazine

equipment and laboratory space able to prepare samples with nearly any contrasting agent found in the literature. The Homewood-based center contains devices that can image a sample in virtually any manner in 2-D, 3-D and even 4-D. IIC’s 3,500 square-foot facility comprising space in Dunning, Jenkins, and Olin Halls, boasts more than $7.5 million worth of stateof-the-art imaging equipment, including a Zeiss laser scanning microscope (LSM) 510 VIS confocal with a Confocor 3 fluo-

PHOTOGRAPHY BY MARTY KATZ/BALTIMOREPHOTOGRAPHER.COM

rescence correlation spectroscopy (FCS) module—one of only a very few such uniquely configured laser scanning microscopes in the United States.

Director J. Michael McCaffery, a research professor in the Department of Biology at the Krieger School of Arts and Sciences, said the Hopkins community is thrilled to have access to such a versatile microscope that combines FCS that is capable of cross-correlation analysis, with confocal imaging and a fully enclosed environmental system for dynamic/live imaging.

Researchers affiliated with Johns Hopkins Institute for NanoBioTechnology (INBT) are also glad to have access to IIC’s menu of facilities.

“Fluorescence correlation spectroscopy allows for highresolution spatial and temporal analysis of single biomolecules with respect to diffusion, binding, as well as enzymatic reactions in vitro and in vivo,” McCaffery said. In other words, you can see and measure a lot of really tiny stuff with it, something INBT researchers working at micron/nanometer resolutions are finding incredibly useful.

The center features multiple suites devoted to specific microscopy/imaging functions. These include a ultramicrotomy/ tissue culture/cell prep room; a wet laboratory; a “scanning room”, which includes the FEI Quanta environmental scanning electron microscope and Typhoon phosphorimager; two transmission electron microscopy suites with four TEMs including an analytical CM 300 FEG in Olin Hall and a Tecnai 12 cryo-TEM in Dunning Hall. A multifunctional light microscopy suite includes the Marianas 4D light microscope, the Zeiss LSM 510 VIS confocal with Confocor 3 FCS (mentioned above), LSM 510 META UV confocal, and two Zeiss epifluorescence microscopes. The Homewood Flow-Cytometry Resource includes a FACSVantage SE with DIVA option, a FACSCalibur, and a FACSCanto. Lastly, there is the Homewood Center for Macromolecular Crystallography equipped with a Rigaku RU-H3R X-ray generator. All these advanced tools help scientists and engineers characterize nanomaterials; and image cells, sub-cellular organelles, and biomolecules/ proteins at very small dimensions.

None of this fancy equipment would be of much use to researchers without the expertise of McCaffery and the IIC staff.

McCaffery brings years of experience and a background in cell biology and microbiology. The center’s associate director, William Wilson, an associate research professor in the Department of Materials Science and Engineering at the Whiting School of

Engineering, describes himself as a “chemist, turned physicist, who became an electrical engineer, who is now a materials scientist.”

Staff scientist Kenneth J.T. Livi, director of the IIC’s HighResolution Analytical Electron Microbeam Facility located in Olin Hall, offers his unique perspective on earth and planetary sciences. Researchers can also consult with microscopy specialist/ trained biologist and FACS supervisor Erin Pryce, the FACS manager Yorke Zhang, computer/IT specialist Marcus Sanchez, and research assistants Leah Kim and Adrian Cotarelo, who both are currently earning their bachelor degrees in biology at Johns Hopkins.

“Sometimes young researchers haven’t contemplated all the possibilities of how to use and apply an instrument; and don’t realize there are many different ways to utilize familiar tools in order to obtain new, in some cases better, information,” McCaffery said. “Our desire is always to approach a problem from many disparate perspectives to generate convergent data that corroborates each particular assay. Hopefully, results from each individual assay, allows the scientist to arrive at a convergent perspective that yields confidence in the results and conclusions.”

One of the easiest ways to obtain different microscopy data and improve corroboration among assays is simply to change the contrast mechanism.

“The most common contrast mechanisms used to image something are optical contrast (transparent versus opaque), polarization, and fluorescence,” said Wilson. “But there are many different ways you can manipulate how light interacts with the specimen and what you detect out of an objective.”

For example, ultrafast laser sources have made nonlinear optical forms of contrast an exciting new tool. Techniques like twophoton excited fluorescence and second harmonic generation (both available in the IIC), produce excellent spectral and structural information about samples because a smaller effective photon volume is excited. Wilson explained it like this: “Imagine turning your stereo all the way up and hearing the sound distorted. That distortion is created by the higher order acoustic harmonics from your stereo. The same happens with intense laser light resulting in new “colors” being generated from the object irradiated. The cool thing here is that the different nonlinear processes are often sensitive to different physical properties or structural features, offering complementary information about your sample.”

In some cases, getting more detailed information simply requires looking at the right color range. The two-photon fluo-

Spring 2011

15

rescence and second harmonic signals appear at different wavelengths. If you excite a sample with enough energy to generate third order harmonics, that signal is detected at an even bluer wavelength, Wilson said. “With third harmonic generation, you only get signals from the interface of structures with no interference from anything else. This means you can simultaneously image fluorescence, polar order, and interface dynamics just by popping in a few filters and beamsplitters,” he said.

“Over the past ten or so years, physicists and engineers focused on advanced microscopy, have produced better and more advanced laser and optical technologies, generating techniques that many researchers in the biological and biomedical sciences might not know exist,” Wilson said. “There also are a lot of applied physicists who are developing and using these new technologies who don’t know what an interesting sample is.

We hope to help bridge this gap, becoming a place where these collaborative synergies can flourish.”

Sample preparation is another area where the center can help researchers. “Cell fractionation, for example, which is the breaking down of whole cells and separating them into their individual components, when combined with biochemical techniques and microscopy, can often allow researchers to pose more precise questions and to better analyze a biological problem,” McCaffery said.

“It is common for someone to come in and want to use a particular instrument or technique they read about in a paper,” McCaffery said. When that happens, McCaffery and Wilson are likely to give researchers “homework.”

“It’s important to remember that the goal is not to make a pretty picture,” Wilson said. “The goal is to answer a question, so sometimes we have to ask them, ‘What is your research question?’”

An enviable set of microscopy tools combined with a team that brings years of training and experience from a variety of disciplines sets Johns Hopkins Integrated Imaging Center apart from the microscope on the individual researcher’s lab bench, as well as from facilities nationwide. Wherever possible, McCaffery said, IIC staff tries to be engaged in all of the research that is carried out in the center. “Simply, our involvement leads to better results and better science”, McCaffery added.

Researchers confirm this successful combination.

“The facilities at the IIC have allowed us to obtain critical information about the internal structure of our peptide nanomaterials that would have remained unknown without careful electron and fluorescence microscopy,” said J.D. Tovar, assistant professor of Chemistry. “Equally important, the scientific IIC staff members were vital participants making sure collaborative experiments were done meaningfully and students were trained competently. Our collaboration with Dr. Wilson has given some nice insights and at the same time has posed many more questions for future research.”

Praise like that for the IIC is always nice to hear, staff members say, but they emphasize that the services and tools they provide are just part of the job. “Part of being a scientist is learning not only how to gather information from a wide variety of tools but also understanding how to pose clear questions that lead to the right tools, in a nutshell, how to not waste time. If we can help you do that, then we have achieved our goal,” Wilson said.

To read more about IIC’s facilities and services, go to http://www.jhu.edu/iic/.

From left, IIC director Michael McCaffery, FACS supervisor Erin Pryce, and associate director William Wilson with the BD FACSVantage SE.

16 Johns Hopkins University Nano-Bio Magazine

PHOTOGRAPHY BY MARY SPIRO

Research

Cells Studied in 3-D May Reveal Novel Cancer Targets

BY MARY SPIRO

3-D makes movies more fun, but it turns out that looking at cells in 3-D yields more accurate information that could help develop drugs to prevent cancer’s spread.

“Finding out how cells move and stick to surfaces is critical to our understanding of cancer and other diseases, but most of what we know about these behaviors has been learned in the 2-D environment of Petri dishes,” said Denis Wirtz, director of the Johns Hopkins Physical Sciences-Oncology Center (Engineering in Oncology Center). The Wirtz lab has demonstrated for the first time that cell movement inside a three-dimensional environment, such as the human body, is fundamentally different from the behavior seen in conventional flat lab dishes.

This discovery implies that results produced by common high-speed methods of screening drugs to prevent cell migration on flat substrates are, at best, misleading, said Wirtz, who also is the Theophilus H. Smoot Professor of Chemical and Biomolecular Engineering at Johns Hopkins. This is important because cell movement is related to metastasis, Wirtz said. “Our study identified possible targets to dramatically slow down cell invasion in a three-dimensional matrix.”

When cells are grown in two dimensions, Wirtz said, proteins help form long-lived attachments called focal adhesions on surfaces. Under 2-D conditions, adhesions last several seconds to several minutes. The cell also develops a broad, fan-shaped protrusion called a lamella along its leading edges to move it forward. “In 3-D, the shape is completely different,” Wirtz said.

18 Johns Hopkins University Nano-Bio Magazine

“It is more spindlelike with two pointed protrusions at opposite ends. Focal adhesions, if they exist at all, are so tiny and so short-lived they cannot be resolved with microscopy.”

Lead author Stephanie Fraley, a Johns Hopkins pre-doctoral student in Chemical and Biomolecular Engineering, said the shape and mode of movement for cells in 2-D are an “artifact of their environment.” which could produce misleading results when conducting drug screens. “Typically, any kind of drug study that you do is conducted in 2D cell cultures before it is carried over into animal models. Sometimes, drug study results don’t resemble the outcomes of clinical studies. This may be one of the keys to understanding why things don’t always match up,” Fraley said.

Even in studies that are called 3-D, Wirtz said, the tops of the cells are still located above the matrix. “Most of the work has been for cells only partially embedded in a matrix, which we call 2.5-D,” he said. “Our paper shows the fundamental difference between 3-D and 2.5-D: Focal adhesions disappear, and the role of focal adhesion proteins in regulating cell motility becomes different.”

Wirtz added that loss of adhesion and enhanced cell movement are hallmarks of cancer. His team’s findings should radically alter the way cells are cultured for drug studies. For example, the team found that in 3-D culture, cells possessing zyxin moved in a random way, exploring their local environment. But when the zyxin gene was disabled, cells traveled in a rapid and persistent,

8VLQJ D WHFKQLTXH FDOOHG UHĂ HFWLRQ FRQIRFDO PLFURJUDSK\

Lead author Stephanie Fraley works in the lab of Denis Wirtz.

FROODJHQ ÀEHUV LQ D ' PDWUL[ FDQ EH VHHQ ZLWK FDQFHU cells embedded.

one-dimensional pathway far from their place of origin. Fraley said such cells might even travel back down previously explored routes. Since zyxin is often misregulated in cancer, Fraley said, an understanding of how it functions in a 3-D cell culture is critical to understanding how cancer spreads.

To study cells in 3-D, the team coated a glass slide with a collagen-enriched gel. Collagen, the most abundant protein in the body, forms a network of cross-linked fibers similar to the natural extracellular matrix scaffold upon which cells grow. Researchers then mixed cells into the gel before it set. They viewed cells traveling in the matrix from below using an inverted confocal microscope. The displacement of tiny beads embedded in the gel was used to show movement of the collagen fibers as the cells extended protrusions in both directions and then pulled inward before releasing one fiber and propelling themselves forward. Fraley compared the movement of the cells to a person trying to maneuver through an obstacle course crisscrossed with bungee cords. “Cells move by extending one protrusion forward and another backward, contracting inward, and then releasing one of the contacts before releasing the other,� she said.

On a 2-D surface, the cell’s underside remained in constant contact with a surface, where large and long-lasting focal adhesions formed. Cells moving in 3-D environments, however, only made brief contacts with the surrounding collagen network–

contacts too small to see and too short-lived to even measure, the researchers observed. “We think the same focal adhesion proteins identified in 2-D situations play a role in 3-D motility, but their role in 3-D is completely different and unknown,� Wirtz said.

Fraley said her future research will focus specifically on the role of mechanosensory proteins like zyxin on motility, as well as how factors such as gel matrix pore size and stiffness affect cell migration in 3-D. Co-investigators on this research from Washington University in St. Louis were Gregory D. Longmore, a professor of medicine, and his postdoctoral fellow Yunfeng Feng, both of whom are affiliated with the university’s BRIGHT Institute. Longmore and Wirtz lead one of three core projects that are the focus of the Johns Hopkins Engineering in Oncology Center, a National Cancer Institute-funded Physical Sciences in Oncology Center.

Additional Johns Hopkins authors, all from the Department of Chemical and Biomolecular Engineering, were Alfredo Celedon, a recent doctoral recipient; Ranjini Krishnamurthy, a recent bachelor’s degree recipient; and Dong-Hwee Kim, a current doctoral student.

Funding for the research was provided by the National Cancer Institute. This study appeared in the June 2010 issue of Nature Cell Biology. „

PHOTOGRAPHY BY STEPHANIE FRALEY (LEFT) AND HOMEWOOD PHOTOGRAPHY (RIGHT)

Spring 2011

19

Research

Drug-carrying nanowires can be driven toward selected biological cells using electric tweezers.

Electric Tweezers Put Nanowires Right Where They’re Needed

BY JACOB KOSKIMAKI

20 Johns Hopkins University Nano-Bio Magazine

ILLUSTRATION BY ERIK ZUMALT/FACULTY INNOVATION CENTER, UT-AUSTIN

Imagine how a single eyelash might move in an Olympic-sized swimming pool. Viscous forces exerted by water would prevent the lash from moving very far through the liquid in which it sits.

Now imagine a structure only one millionth the size of the eyelash, something on the scale of nanometers. Overcoming these forces is a problem researchers face when attempting to manipulate gold nanowires, small rods that can be used to construct tiny devices or to deliver drugs to cells. At such a small scale, the viscous force water exerts on the wire becomes extremely problematic, akin to a swimmer moving through molasses. Controlling movement with any precision or accuracy has eluded researchers for decades, stifling potential applications of nanowire technology.

Recently, Johns Hopkins University researchers in Physics and Astronomy in the Krieger School of Arts and Sciences, and Biomedical Engineering at Johns Hopkins School of Medicine have developed a way to manipulate these thin rods using a technique called electric tweezers. The tweezers use electric fields to rotate and position wires with high accuracy.

“Many experts in fluid mechanics said moving such small particles in liquid would be fruitless,” said Chia-ling Chien, a principle investigator on the study. Chien is the Jacob L. Hain Professor of Physics and director of Johns Hopkins Materials Research Science and Engineering Center. “We wanted to see how difficult it would be and if we can precisely control and manipulate their rotation and movement,” he said.

Donglei Fan, a PhD graduate and postdoctoral fellow in the Whiting School of Engineering Department of Materials Science and Engineering, developed the electric tweezers technology.

Fan, Chien and professor of materials science and engineering Robert Cammarata joined forces with Zhizhong Yin, a former postdoctoral fellow in Biomedical Engineering and his adviser, Andre Levechenko, an associate professor of biomedical engineering at Hopkins. The latter two were spearheading use of micro/nanotechnology for biomedical applications, and this collaboration helped realize the great potential of using this technology for precise drug delivery. They published a paper on this technology in the July 2010 Nature Nanotechnology, along with doctoral candidate in biomedical engineering, Raymond Cheong and former postdoctoral fellow in physics and astronomy, Frank Q. Zhu. A soon-to-be-published review article written by Fan, Zhu, Cammarata and Chien illustrates the electric tweezers technique and its application to deliver a dose of a potent anti-cancer molecule to a single cell. The

tweezers work by positioning two electrodes and applying a voltage, which creates an electric field. Nanowires can be made to carry a charge, and can be held, translated and rotated by controlling the direction of the field, and generating the appropriate force.

“Previous work has tested optical or magnetic techniques to similarly manipulate smaller entities, however, these techniques are limited in that they can only capture particles in their field, but cannot move them. The electric technique is also relatively simple to set up and does not require extensive instru-mentation as required by optical and magnetic systems,” Chien said.

Although tissues and cells are susceptible to damage by strong electric fields, Chien stresses the electric fields are well within range of biological tolerance.

Another advantage of using electric tweezers is its extreme precision, where it’s possible to specifically target one cell in a plate of hundreds of thousands—roughly equivalent to a cargo plane guiding a parachute to one person in a crowd. One can also target different locations of the cell, such as the cytoplasm or nucleus for site-specific drug delivery, Chien explains. This can be guided by light microscopy.

Before the advent of electric tweezers and nanowire technology, guiding small molecules to individual cells would have been virtually impossible. “We can observe how a single cell might communicate with its neighboring cells, and how it might respond to a very low dose of a drug,” Chien said.

Researchers predict this will improve our understanding of cell biology, and cell targeting. For example, some drugs are difficult to get across the cellular membrane, but delivery can be improved by attachment to gold nanowires. Beyond biological applications, Chien said electric tweezers could be used in other materials-based applications, such as constructing circuits. Carbonbased structures, such as carbon nanotubes, have unique electrical properties, and can similarly be controlled using electric tweezers.

“Using electric tweezers, it is now possible to assemble structures piece-by-piece,” Chien said, which was previously difficult to do with physics at the nanoscale. Electric forces can rotate small wires to create nanomotors that can mimic small protein motors in cells. Although potential in vivo applications are far off, the technique will undoubtedly improve our understanding of cell-to-cell communication, and the tools researchers have to study drug responses.

Jacob Koskimaki is a pre-doctoral fellow in Biomedical Engineering at Johns Hopkins University.

Spring 2011

21

Research

Dissecting the Nanomotor That Packages the Genome

BY MARY SPIRO

The way that DNA is packaged into chromosomes plays a major role in determining whether genes are “on” or “off” in both normal and diseased cells. Although a number of factors that participate in this packaging have been identified, relatively little is understood regarding how these factors actually work.

Biophysicists from Johns Hopkins Krieger School of Arts and Sciences have described how one of the nano-scale packaging motors can turn itself on and off.

In the cells of humans and other mammals, DNA coils tightly around spool-like structures called histones and must be freed up so that the genes can be transcribed, said Gregory D. Bowman, assistant professor of biophysics at Johns Hopkins. To accomplish this, tiny multi-protein structures called chromatin remodeling complexes interact with these DNA spools and either slide them along DNA or remove them from the DNA entirely. To move the histones along the DNA, the remodeling complex uses a motor protein called ATPase, a nano-scale machine that uses the molecule ATP as fuel.

“The DNA wraps around the histone core, somewhat resembling a bike chain on a gear,” Bowman said. “To move the histone core along DNA, the chromatin remodeling complex has to somehow loosen the grip of the histones on the DNA. There are two popular ideas for how this might occur,” Bowman said.

“In one model, the remodeler holds the histone core in place while actively walking along the DNA, pushing the DNA with enough force to break contacts with the histone core. In the other model, histone-DNA contacts are broken simply by the remodeler binding and severely distorting the wrapped DNA. Once distorted, the DNA may be able to then easily slip past

22 Johns Hopkins University Nano-Bio Magazine

Crystal structure of Chd1 chromatin remodeler showing chromodomains (yellow) packed against the central cleft of ATPase motor (blue and red surface).

the histone core. At this point, however, we really just don’t know exactly how this process works,” said Bowman.

Bowman’s team, which included biophysics and biology doctoral students Glenn Hauk and Jeffrey McKnight and research associate Ilana Nodelman, described how a particular chromatin remodeler called Chd1 found in yeast regulates its own access to DNA. “By allowing or preventing sections of DNA from being transcribed, chromatin remodeling complexes have a profound influence on gene expression,” Bowman added. “Our genetic information–our chromosomes–are packaged into millions of these histone spools, and these spools are often used to block cellular machinery from transcribing genes that should remain off. When genes are activated, histones must typically be removed from regulatory elements in the gene promoter. Disrupting the delicate balance of gene expression by, for example, improperly moving histones or unpackaging DNA, has been shown to lead to various diseases such as cancer.”

Bowman’s team has shown that two so-called chromodomains of Chd1, which resemble a bent dumbbell, can prevent the ATPase motor from interacting with DNA. By packing against

ILLUSTRATION BY GREGORY BOWMAN

the DNA-binding site of the ATPase motor, the chromodomains can therefore regulate the ability of the remodeling complex to move histones along DNA. Bowman’s team showed that mutating the chromodomains actually improved the speed at which the motor could move histones along DNA and burn ATP. “This role of the chromodomains in negatively regulating the ATPase motor was completely unexpected,” Bowman said. “Most chromodomains bind to histone tails and help attach associated factors to chromatin. In Chd1, the chromodomains can also block the DNA binding site of the motor, which means that they can influence not only the localization of the remodeling complex, but also when it’s activated.”

Bowman’s team plans to use the knowledge of this regulatory mechanism to better understand how Chd1 and other remodeling complexes choose particular histone cores, and how the complexes determine which direction the histone cores should be shifted. Bowman said a thorough understanding of how the mechanism works not only gives scientists insight into the socalled “black-box” of how cells function normally, but also provides valuable information to those seeking to control or prevent disease.

“There are many different subgroups of chromatin remodelers,” Bowman said, “Chd1 is just one specific kind of chromatin remodeler, but we don’t really know the fundamentals of how any of them work.”

Understanding this one type of chromatin remodeler and how the ATPase motor is turned on and off will go a long way in helping researchers comprehend how the other types of remodelers may function” he added.

In addition, the finding that a histone-binding element like the chromodomains possesses the ability to turn remodelers on and off could provide researchers with additional therapeutic or diagnostic targets, he said.

This research was funded by the National Institutes of Health/National Institute of General Medical Sciences and published in the September 10, 2010 issue of the journal Molecular Cell.

Spring 2011

23

Education

Obafemi Ifelowo worked on nonviral gene

At right, Makeeda Moore (GSU) learned to culture and assess stem cells in the Sharon Gerecht lab.

delivery in the Jordan Green lab.

aRE yoU Ready for Some Research?

BY SARAH GUBARA

Every summer Johns Hopkins Institute for NanoBioTechnology hosts undergraduates from different universities in the Research Experience for Undergraduates (REU) program. This highly competitive National Science Foundation-funded program offers an intensive 10-week, hands-on experience culminating in a university-wide poster session. Undergraduates are paired with faculty members, graduate students, and postdoctoral fellows willing to guide them in a project to be completed before summer’s end. When it’s over, most students have a pretty good idea if a research career is in their future or not.

Quinton Smith, a chemical engineering major from the University of New Mexico, was drawn to Hopkins because of its top-ranked biomedical engineering program and the opportunity to interact with world-famous scientists, engineers and clinicians. Working in the lab of Sharon Gerecht, an assistant professor of Chemical and Biomolecular Engineering, Smith found that his research directly coincided with his career interests. “The graduate students show us what’s entailed in doing research and how to learn in a laboratory environment,” Smith said.

Makeda Moore, a biochemistry major from Georgia State University who also worked in the Gerecht lab, had never done research before. She learned to do stains, evaluate cell growth, and take care of cell cultures.

PHOTOGRAPHY BY SARAH GUBARA

Kameron Black of the University of California, San Diego is double majoring in Neuroscience and Physiology. What attracted him to Hopkins wasn’t just the prestigious name, but research tailored specifically to his interests. Black said he was humbled by the opportunity to work alongside PhDs who were locating and mapping the binding domain of a certain protein in the lab of Ted Dawson, professor of neurology and neuroscience at the Johns Hopkins School of Medicine.

Obafemi Ifelowo, a molecular biology and bioinformatics student from Towson University worked in Jordan Green’s lab on nonviral gene delivery. Green is an assistant professor of biomedical engineering. Originally, Ifelowo was med school bound, but after spending time in a lab, he said he wants to add a research component to his career path.

Alfred Irungu, a mechanical engineering major from UMBC, is interested in the biomedical engineering applications of his research. He found working in the German Drazer lab to be a great experience. Drazer is an assistant professor of Chemical and Biomedical Engineering.

“I got to see how a grad student’s life is and see what I’m going to be doing for the next five years of my life,” Irungu said.

Sarah Gubara is a graduating senior in Psychology at Johns Hopkins University.

Spring 2011

25

Education

Students Organize Cancer NanoTech Mini-Symposium MARY SPIRO

Johns Hopkins Institute for NanoBioTechnology hosted the first student-coordinated mini-symposium on cancer nanotechnology on March 23 in Hackerman Hall Auditorium.

The symposium showcased current research from nine students affiliated with Johns Hopkins Physical Sciences-Oncology Center (PS-OC) and Johns Hopkins Center of Cancer Nanotechnology Excellence (CCNE). Johns Hopkins Physical Sciences-Oncology Center, also known as the Engineering in Oncology Center, is funded by a grant from the National Cancer Institute and aims to unravel the physical underpinnings involved in the growth and spread of cancer. Johns Hopkins Center of Cancer Nanotechnology Excellence, also funded by a grant from the NCI, aims to use a multidisciplinary approach to develop nanotechnology-based tools and strategies for comprehensive cancer diagnosis and therapy and to translate those tools to the marketplace.

“We become so focused on our own research that we sometimes don’t know what other students are working on,” said Stephanie Fraley, a pre-doctoral candidate in chemical and biomolecular engineering who helped organize the event.

“The beauty of an event like this is that we get to see work from across the campuses and across disciplines, all in one morning.”

In addition to the research presentations John Fini, director of intellectual property for the Homewood campus schools, also spoke. Organizers plan to hold the cancer nanotechnology mini-symposiums each spring and fall.

26 Johns Hopkins University Nano-Bio Magazine

Presenters included: z Eric Balzer, PhD, (Konstantinos Konstantopoulos Lab, PS-OC): Migrating tumor cells dynamically adapt to changes in environmental geometry z Venugopal Chenna (Anirban Maitra Lab, CCNE): Systemic delivery of polymeric nanoparticle encapsulated small molecule inhibitors of hedgehog signaling pathway for the cancer therapy z Laura Dickinson (Sharon Gerecht Lab, PS-OC): Functional surfaces to investigate cancer cell interactions with hyaluronic acid z Stephanie Fraley (Denis Wirtz Lab, PS-OC): Role of dimensionality in focal adhesion protein localization and function z Kelvin Liu, PhD, (Jeff Wang Lab, CCNE): Decoding circulating nucleic acids in serum using microfluidic single molecule spectroscopy z Jeaho Park (Peter Searson Lab, CCNE): Quantum dots for targeting cancer biomarkers z Craig Schneider (Justin Hanes Lab, CCNE): Mucuspenetrating particles for the treatment of lung cancer z Sam Walcott, PhD, (Sean Sun Lab, PS-OC): Surface stiffness influences focal adhesion nucleation and decay initiation, but not growth or decay z Yi Zhang (Jeff Wang Lab, CCNE): A quantum dot enabled ultrahigh resolution analysis of gene copy number variation

Outreach

Pre-doctoral fellow Justin Galloway helps youngsters at USASEF.

Pre-doctoral fellow Garrett Jenkinson used magnets to demonstrate self assembly.

Jargon-Free Zone: Science, Engineering Fest Forces Tech Talk Out the Window

BY GARRETT JENKINSON

A dozen graduate students affiliated with Johns Hopkins Institute for NanoBioTechnology volunteered to talk to children and adults about their research at the first annual USA Science and Engineering Festival. Held on the National Mall in Washington, D.C., the event attracted 500,000 visitors over two days in October 2010.

What was the benefit of talking to the public at the USA Science and Engineering Festival about my research?

There is, of course, the clichéd bit about children being the future scientists and world leaders, or the more pragmatic argument that the public funds much of our research. These points are as valid as they are unoriginal. To me, however, the USA Science and Engineering Festival was a challenging and thus, engaging experience.

The first challenge was to simply and effectively convey scientific concepts to a general audience without falling back on years of deeply entrenched scientific jargon and mathematics.

PHOTOGRAPHY BY MARY SPIRO

A mistake that I have made in the past is explaining to the public that, “My research investigates dynamical processes on complex networked systems.”

During the festival, I instead emphasized the practical applications of my research, telling people, “I am currently using math and computers to understand how to develop better drugs to fight cancer, or to combat the spread of infectious diseases like SARS or HIV.” Although the latter statement definitely sparked more interest from listeners, such a statement was surprisingly difficult for me to formulate. To a scientist, it is vague, unsubstantiated and addresses only a small subset of potential applications. Despite this, the latter yields interest and inquiry, where the former returns glazed looks and yawns.

The festival brought other unexpected challenges. For example, our exhibit included floating Styrofoam pieces that congregate See Jargon-Free on page 30

Spring 2011

27

Outreach

Extreme Makeover: ‘Boys Hope Girls Hope’ Home Edition

BY MARY SPIRO

Four Baltimore city high school students from Boys Hope Girls Hope of Baltimore spent Summer 2010 working in Johns Hopkins University medical research laboratories, as well as helping build a new home for some of their fellow scholars. The young men were supported by Johns Hopkins Institute for NanoBioTechnology. The producers of ABC’s “Extreme Makeover: Home Edition” also put the boys to work helping construct a spacious home for the scholars of Girls Hope.

Boys Hope Girls Hope of Baltimore is a privately funded, non-profit multi-denominational organization offering at-risk

children with “a stable home, positive parenting, high quality education, and the support needed to reach their full potential.”

INBT hosted Matthew Green-Hill, Donte Jones and Durrell Igwe from Archbishop Curley High School; and Dwayne Thomas II from Loyola Blakefield. Doug Robinson, associate professor of cell biology at the School of Medicine, originally spearheaded the effort to bring Boys Hope Girls Hope scholars to Hopkins through INBT in 2009. This most recent program session concluded, for the first time, with a research poster session for family and faculty.

Scholars participated in active research projects. For example, Thomas worked in Robinson’s laboratory on cytokinesis of the organism Dictyostelium. In the lab of Caren Meyes, assistant professor of Pharmacology and Molecular Sciences at the School of Medicine, Jones conducted work related to malaria.

Igwe spent his summer in the neuroscience laboratory of Howard Hughes Medical Institute investigator Alex Kolodkin. GreenHill participated in neurodegenerative disease research in the laboratory of Craig Montell, professor of biological chemistry at the medical school.

Although not required, many participants choose to live in the organization’s group homes with their fellow scholars. Boys Hope Scholars told producers of “Extreme Makeover: Home Edition” that there was no house for the Girls Hope scholars.

Before long, several city blocks along Fleetwood Ave. were cordoned off and filled with construction equipment and workers.

A Girls Hope home was built in just nine days, despite severe rainstorm setbacks.

Top: From left, Boys Hope Scholars Matthew Green-Hill, Dwayne Thomas II, Donte Jones, Durrell Igwe.

Bottom: Dwayne Thomas II shows off his summer research efforts.

28 Johns Hopkins University Nano-Bio Magazine

PHOTOGRAPHY BY MARY SPIRO (TOP) AND CHRISTIE JOHNSON (BOTTOM)

Jargon-Free from page 27

on the surface of the water—an excellent macroscopic analogy to self-assembly at the nanoscale. However, it was not the selfassembly that prompted questions from the children, but the magnetic stir bar steadily spinning away at the bottom of the container in which the pieces were floating.

I had planned on talking about how cool it would be to throw all the parts of a Ferrari into a room only to come back to a shiny new sports car, but my plan was foiled. Instead, I was given the opportunity to improvise and discuss how magnets are used in MRI so doctors can look inside the body without ever touching a patient—like Superman’s X-ray vision, minus the ionizing radiation!

At a scientific conference one can usually predict the questions long before arriving. My advice? Try a real challenge. Discard the technical jargon and talk with a child whose questions and curiosities are truly unforeseeable.

Garrett Jenkinson is a pre-doctoral fellow in Electrical Engineering at Johns Hopkins University.

30 Johns Hopkins University Nano-Bio Magazine

Outreach

Thanks to all 41 individuals who appeared in our video.

INBT: The Movie Johns Hopkins Institute for NanoBioTechnology has moved to new headquarters in Suite 100 of the New Engineering Building on the Homewood Campus. As part of the open house that was held February 25 to show off our new digs, we premiered a sixminute video on the history, philosophy and mission of INBT. The video includes interviews with more than 20 INBT affiliated faculty and students.

The project was produced and directed by INBT’s web/

animation director Martin Rietveld and science writer/media relations director Mary Spiro. Jay Corey, the university’s director of video strategy and his multimedia production coordinator David Schmelick handled filming and editing. The video, featured on INBT’s YouTube Channel, gives a comprehensive overview of what the institute is all about, what it hopes to achieve and where it is going.

To watch, go to http://www.youtube.com/user/JHUINBT

Spring 2011

31