Drazer wins NSF Career Award

German Drazer

German Drazer (Photo: Will Kirk)

German Drazer, assistant professor in the Department of Chemical and Biomolecular Engineering and affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology was recently named a recipient of the National Science Foundation Faculty Early Career Development (CAREER) awards, given in recognition of a young scientist’s commitment to research and education. Drazer was given the award for “Deterministic and Stochastic Transport of Suspended Particles in Periodic Systems: Fundamentals and Applications in Separation Science.” The grant will support his investigations into the transport phenomena that arise in the motion of suspended particles in spatially periodic systems, and the translation of these phenomena into new principles for the manipulation of suspended particles in fluidic devices.

Read more about the work in the Drazer Lab here.

INBT researchers use LEGO to study what happens inside lab-on-a-chip devices

New Hopkins materials science faculty to explain ‘flash nanoprecipitation’

Margarita Herrera-Alonso

Margarita Herrera-Alonso

Margarita Herrera-Alonso, a new assistant professor in Johns Hopkins Department of Materials Science and Engineering, will present the talk, “Block Copolymer Nanoparticles by Flash Nanoprecipitation: Prodrug Strategies,” on Feb. 3, 2010, at 3 p.m. in Maryland Hall 110. This talk is part of the Materials Science seminar course (EN 510.804), but all Hopkins students, faculty and staff are invited to attend.

Abstract

Colloidal particles are proven effective carriers for therapeutic and imaging agents. Protection of solutes (therapeutic and/or imaging) by encapsulation in colloidal particles enhances their biodistribution and pharmacokinetics, prevents degradation during transport, and allows for triggered/controlled release. Choice of the carrier–dendrimer, micelle, liposome, nanoparticle– is largely determined by its loading efficiency, drug content, and delivery rate. Polymer-based carriers are particularly useful given their chemical, compositional and architectural versatility. We are interested in the formulation of drug-loaded polymer-based nanoparticles. The uniqueness of these nanoparticles relies on the method by which they are produced: Flash Nanoprecipitation. Successful encapsulation of solutes in polymer nanoparticles by Flash Nanoprecipitation depends on establishing rapid micromixing conditions and balancing the kinetics of block copolymer self-assembly and solute precipitation. While Flash Nanoprecipitation is an extremely versatile method for solute encapsulation, the resultant nanoparticles are not exempt from undergoing solvent-mediated interparticle mass transfer. This instability can be attenuated by the use of prodrugs. Specific examples of estradiol prodrugs and their encapsulation in a series of poly(ethylene glycol)-based copolymers will be discussed.

Whiting School of Engineering Department of Materials Science and Engineering

Princeton physicist to discuss physics of cancer cell resistance

Physics professor Robert Austin, right, and graduate ¬student Guillaume Lambert observe prostate cancer cells growing on chips of silicon and silicon-based plastic. (Princeton Office of Communications)

The fact that cancer cells frequently re-emerge after initial therapeutic attempts has dogged the efforts of oncologists to save patients’ lives for decades. According to Princeton physicist, Robert H. Austin, cancer cell resistance is primarily a biological reaction to stress and “one of the great unsolved, and deadly, problems in oncology.”

On Thursday, February 4, Austin will discuss, “The Physics of Cancer,” during a 3 p.m. joint colloquium hosted by Johns Hopkins University departments of Physics and Astronomy and Biophysics in the Schafler auditorium of the Bloomberg Center on the Homewood campus. The talk is free and open to the public.

Austin is principal investigator for Princeton’s Physical Science-Oncology Center and a trans-network partner with Johns Hopkins Engineering in Oncology Center, both of which are National Cancer Institute funded organizations.

Austin will address the general principles of physics, ecology, and biology and why recurrence of resistant cancer cells seems to be a universal phenomenon in cancer. He says that “evolution in small, stressed habitats is key to the rapid and inevitable re-emergence of resistance of cancer cells” (and) “that modern techniques of physical probes, genomics, proteomics and nanotechnology will allow us to analyze the evolutionary path of these emergent resistant cells.”

Related Links

Johns Hopkins Engineering in Oncology Center

Flyer for  Prof. Austin’s colloquium

Physical Sciences in Oncology Centers of the National Cancer Institute

Animator, scientist partner to illustrate cover of Advanced Materials

AM_3_U1resizeThe cover of the January 19, 2010 issue of the journal Advanced Materials features a photo illustration executed by Martin Rietveld, web director and animator at Johns Hopkins Institute for NanoBioTechnology. Rietveld’s work illustrates an article about chemomechanical actuators—grippers that open and close like a hand in response to chemical reactions. The paper is based on the research of lead author, doctoral student Jatinder Randhawa in the laboratory of David Gracias, associate professor of chemical and biomolecular engineering and faculty affiliate of the Institute for Nanobiotechnology. Randhawa conceptualized the illustration of his research for the journal cover.

Says Gracias, “Chemomechanical actuation is intellectually appealing since it is widely observed in nature, but chemomechanical actuation is relatively unexplored in human engineering where the dominant strategy to actuate structures is based on electromechanical actuation (i.e. with electrical signals). Here, microstructures open and close reversibly in response to chemical surface oxidation and reduction without the need for any wires or batteries.”

Related links:

Chemomechanical Actuators: Reversible Actuation of Microstructures by Surface-Chemical Modification of Thin-Film Bilayers. Jatinder S. Randhawa, Michael D. Keung, Pawan Tyagi, David H. Gracias.

Johns Hopkins Institute for NanoBioTechnology Animation Studio

David Gracias INBT Faculty Profile

Environmental, health impacts of engineered nanomaterials theme of INBT’s annual symposium

By 2015, the National Science Foundation reports that the nanotechnology industry could be worth as much as $1 trillion. Nanomaterials have many beneficial applications for industry, medicine and basic scientific research. However, because nanomaterials are just a few atoms in size, they also may pose potential risks for human health and the environment.

Cross-sectional autoradiograms of rodent brains showing (A) control physiological state; and (B) and (C) showing distribution of brain injury from an injected neurotoxicant. Red areas indicate the highest concentrations of a biomarker that identifies brain areas that are damaged by the neurotoxicant. (Guilarte Lab/JHU)

Cross-sectional autoradiograms of rodent brains showing (A) control physiological state; and (B) and (C) showing distribution of brain injury from an injected neurotoxicant. Red areas indicate the highest concentrations of a biomarker that identifies brain areas that are damaged by the neurotoxicant. (Guilarte Lab/JHU)

To increase awareness of Hopkins’ research in this emerging area of investigation, the theme for the fourth annual symposium hosted by Johns Hopkins Institute for NanoBioTechnology (INBT) will be environmental and health impacts of engineered nanomaterials. INBT’s symposium will be held Thursday, April 29, from 8 a.m. to 3 p.m. at the university’s Bloomberg School of Public Health in Baltimore, Md.

Morning talks in Sheldon Hall by eight Hopkins faculty experts will discuss neurotoxicity, exposure assessment, manufacture and characterization of nanomaterials, policy implications and many other topics. In the afternoon, a poster session will be held in Feinstone Hall featuring nanobiotechnology research from across the university’s divisions.

INBT is seeking corporate sponsorships for the symposium. Interested parties should contact Thomas Fekete, INBT’s director of corporate partnerships at tmfeke@jhu.edu or 410-516-8891.

Media inquiries should be directed to Mary Spiro, INBT’s science writer and media relations director, at mspiro@jhu.edu or 410-516-4802.

A call for posters announcement will be made at a later date.

More:

Biodegradable nanoparticles ideal carrier for drug delivery

Johns Hopkins University researchers have created biodegradable nanosized particles that can easily slip through the body’s sticky and viscous mucus secretions to deliver a sustained-release medication cargo. The researchers say that these nanoparticles, which degrade over time into harmless components, could one day carry life-saving drugs to patients suffering from dozens of health conditions, including diseases of the eye, lung, gut or female reproductive tract.

The mucus-penetrating biodegradable nanoparticles were developed by an interdisciplinary team led by Justin Hanes, a professor of chemical and biomolecular engineering in Johns Hopkins’ Whiting School of Engineering*. The team’s work was reported recently in the Proceedings of the National Academy of Sciences. Hanes’ collaborators included cystic fibrosis expert Pamela Zeitlin, a professor of pediatrics at the Johns Hopkins School of Medicine and director of Pediatric Pulmonary Medicine at Johns Hopkins Children’s Center.

Individual biodegradable nanoparticle developed by the Justin Hanes Lab at Johns Hopkins University (shown here at microscale for easier imaging) displaying polymer coating as a red fluorescent glow. Hanes' biodegradable nanoparticles have the ability to penetrate mucus barriers in the body to deliver drugs. (Photo by Jie Fu/JHU)

Individual biodegradable nanoparticle developed by the Justin Hanes Lab at Johns Hopkins University (shown here at microscale for easier imaging) displaying polymer coating as a red fluorescent glow. Hanes’ biodegradable nanoparticles have the ability to penetrate mucus barriers in the body to deliver drugs. (Photo by Jie Fu/JHU)

These nanoparticles, Zeitlin said, could be an ideal means of delivering drugs to people with cystic fibrosis, a disease that kills children and adults by altering the mucus barriers in the lung and gut. “Cystic fibrosis mucus is notoriously thick and sticky and represents a huge barrier to aerosolized drug delivery,” she said. “In our study, the nanoparticles were engineered to travel through cystic fibrosis mucus at a much greater velocity than ever before, thereby improving drug delivery. This work is critically important to moving forward with the next generation of small molecule– and gene-based therapies.”

Beyond their potential applications for cystic fibrosis patients, the nanoparticles also could be used to help treat disorders such as lung and cervical cancer and inflammation of the sinuses, eyes, lungs and gastrointestinal tract, said Benjamin C. Tang, lead author of the journal article and a postdoctoral fellow in the Department of Chemical and Biomolecular Engineering. “Chemotherapy is typically given to the whole body and has many undesired side effects,” he said. “If drugs are encapsulated in these nanoparticles and inhaled directly into the lungs of lung cancer patients, drugs may reach lung tumors more effectively and improved outcomes may be achieved, especially for patients diagnosed with early stage non–small cell lung cancer.”

“If drugs are encapsulated in these nanoparticles and inhaled directly into the lungs of lung cancer patients, drugs may reach lung tumors more effectively and improved outcomes may be achieved, especially for patients diagnosed with early stage non–small cell lung cancer.” ~ Ben Tang

In the lungs, eyes, gastrointestinal tract and other areas, the human body produces layers of mucus to protect sensitive tissue. But an undesirable side effect is that these mucus barriers can also keep helpful medications away.

In proof-of-concept experiments, previous research teams led by Hanes earlier demonstrated that latex particles coated with polyethylene glycol could slip past mucus coatings. But latex particles are not a practical material for delivering medication to human patients because they are not broken down by the body. In the new study, the researchers described how they took an important step forward in making new particles that biodegrade into harmless components while delivering their drug payload over time.

“The major advance here is that we were able to make biodegradable nanoparticles that can rapidly penetrate thick and sticky mucus secretions, and that these particles can transport a wide range of therapeutic molecules, from small molecules such as chemotherapeutics and steroids to macromolecules such as proteins and nucleic acids,” Hanes said. “Previously, we could not get these kinds of sustained-release treatments through the body’s sticky mucus layers effectively.”

The new biodegradable particles comprise two parts made of molecules routinely used in existing medications. An inner core, composed largely of polysebacic acid, or PSA, traps therapeutic agents inside. A particularly dense outer coating of polyethylene glycol, or PEG, molecules, which are linked to PSA, allows a particle to move through mucus nearly as easily as if it were moving through water and also permits the drug to remain in contact with affected tissues for an extended period of time.

In Hanes’ previous studies with mucus-penetrating particles, latex particles could be effectively coated with PEG but could not release drugs or biodegrade. Unlike latex, however, PSA can degrade into naturally occurring molecules that are broken down and flushed away by the body through the kidney, for example. As the particles break down, the drugs loaded inside are released.

This property of PSA enables the sustained release of drugs, said Samuel Lai, assistant research professor in the Department of Chemical and Biomolecular Engineering, while designing them for mucus penetration allows them to more readily reach inaccessible tissues.

Biodegradable nanoparticles produced by the Justin Hanes Lab at Johns Hopkins University visualized under a scanning electron microscope. (Photo by Ben Tang and Mark Koontz/JHU)

Biodegradable nanoparticles produced by the Justin Hanes Lab at Johns Hopkins University visualized under a scanning electron microscope. (Photo by Ben Tang and Mark Koontz/JHU)

Jie Fu, an assistant research professor, also from the Department of Chemical and Biomolecular Engineering, said, “As it degrades, the PSA comes off along with the drug over a controlled amount of time that can reach days to weeks.”

PEG acts as a shield to protect the particles from interacting with proteins in mucus that would cause them to be cleared before releasing their contents. In a related research report, the group showed that the particles can efficiently encapsulate several chemotherapeutics, and that a single dose of drug-loaded particles was able to limit tumor growth in a mouse model of lung cancer for up to 20 days.

Hanes, Zeitlin, Lai and Fu are all affiliated with the Johns Hopkins Institute for NanoBioTechnology. Other authors on the paper are Ying-Ying Wang, Jung Soo Suk and Ming Yang, doctoral students in the Johns Hopkins Department of Biomedical Engineering; Michael P. Boyle, an associate professor in Pulmonary and Critical Care Medicine at the Johns Hopkins School of Medicine; and Michelle Dawson, an assistant professor at the Georgia Institute of Technology.

This work was supported in part by funding from the National Institutes of Health, a National Center for Research Resources Clinical and Translational Science Award, the Cystic Fibrosis Foundation, the National Science Foundation and a Croucher Foundation Fellowship.

The technology described in the journal article is protected by patents managed by the Johns Hopkins Technology Transfer Office and is licensed exclusively by Kala Pharmaceuticals. Justin Hanes is a paid consultant to Kala Pharmaceuticals, a startup company in which he holds equity, and is a member of its board. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

(*At the time that this research was published, Hanes had his primary affiliation with the Whiting School of Engineering Department of Chemical and Biomolecular Engineering. Hanes’ current primary affiliation is with the Johns Hopkins School of Medicine Department of Ophthalmology.)

Related Links

Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. PNAS 2009 106:19268-19273; published online before print November 9, 2009.  [Institutional access required.]

Hanes Lab

Johns Hopkins Children’s Center

Institute for NanoBioTechnology

Story by Mary Spiro and Jacob Koskimaki with materials provided by Johns Hopkins Technology Transfer.

Follow INBT on Twitter.

Chemical and biomolecular engineer Denis Wirtz named Smoot professor

Denis Wirtz. Photo by Will Kirk/JHU

Denis Wirtz. Photo by Will Kirk/JHU

Denis Wirtz, Johns Hopkins University professor of chemical and biomolecular engineering and director of the Engineering in Oncology Center, has been named the Theophilus Halley Smoot Professor in the Whiting School of Engineering. University president Ronald J. Daniels and the Board of Trustees determined the recipient.

Wirtz is the founding associate director of the Johns Hopkins Institute for NanoBioTechnology. He was recently named a 2009 fellow of the American Academy for the Advancement of Science in the Engineering Section for his contributions to cell micromechanics, cell adhesion, and for the development and application of particle tracking methods that probe the micromechanical properties of living cells.

He is on the Editorial Boards of Biophysical Journal, Cell Adhesion and Migration and J. Nanomedicine. In 2005, he was named a fellow of the American Institute for Medical and Biological Engineering. Wirtz won the National Science Foundation Career Award in 1996 and the Whitaker Foundation Biomedical Engineering Foundation Award in 1997.

Wirtz came to Johns Hopkins faculty in 1994 and completing a postdoctoral fellowship in Physics and Biophysics at ESPCI (ParisTech). Wirtz earned his PhD in Chemical Engineering from Stanford University in 1993.

An announcement from the Whiting School’s dean Nick Jones stated that, “Throughout his time at Johns Hopkins, Denis has distinguished himself as an outstanding scholar and teacher. Additionally, Denis’ role as a catalyst for interdisciplinary research and collaboration at the university has proven extremely effective, both in terms of the research he conducts and the support he has attracted over the years. I am confident that his current research into the physical basis for cell adhesion and de-adhesion will prove critical to our understanding of the metastasis of cancer and enable important breakthroughs in the diagnosis and treatment of cancer in the years to come.”

The Smoot Professorship was established in 1981 through the estate of Theophilus H. Smoot, who joined Johns Hopkins as a research assistant in the Department of Mechanical Engineering in 1942 and later a research associate in the department in 1946. Upon the passing of Mr. Smoot in 1976 and his widow, Helen A. Smoot in 1980, the Theophilus Halley Smoot Fund for Engineering Science was created.  The first Smoot Professorship was awarded in 1981 to Stanley Corrsin, a professor and former chair in the department of mechanical engineering. Robert E. Green, Jr., professor in the department of materials science, held the professorship from 1988 through 2007.

Presentation of the Smoot professorship will occur in the spring.

Wirtz Lab

Named Professorships of The Johns Hopkins University

Johns Hopkins Institute for NanoBioTechnology

Johns Hopkins Engineering in Oncology Center

Story by Mary Spiro and from materials provided by the Whiting School of Engineering.

INBT, EOC directors named AAAS 2009 Fellows

The Johns Hopkins Whiting School of Engineering faculty members who direct the Institute for NanoBioTechnology and Engineering in Oncology Center both have been awarded the distinction of AAAS Fellow. Election as a Fellow is an honor bestowed upon AAAS members by their peers.

Peter Searson, INBT director. Photo by Will Kirk/JHU

Peter Searson, INBT director. Photo by Will Kirk/JHU

Denis Wirtz, EOC director. Photo by Will Kirk/JHU

Denis Wirtz, EOC director. Photo by Will Kirk/JHU

Peter C. Searson, the Joseph R. and Lynn C. Reynolds Professor of Materials Science and Engineering, was named for distinguished contributions to the field of surface chemistry and nanoscience. His research interests include surface and molecular engineering, and semiconductor quantum dots.

Searson directs the interdivisional Institute for NanoBioTechnology launched in May 2006, which brings together researchers from medicine, engineering, the sciences, and public health to create new knowledge and develop new technologies to revolutionize health care and medicine. INBT currently has more than 190 affiliated faculty members. Searson has secondary appointments in the Krieger School of Arts and Sciences Department of Physics and Astronomy and the Johns Hopkins School of Medicine Department of Oncology.

Denis Wirtz, the Theophilus H. Smoot Professor of Chemical and Biomolecular Engineering, was elected for his contributions to cell micromechanics and cell adhesion. He also was distinguished for his development and application for particle tracking methods to probe the micromechanical properties of living cells in normal conditions and disease state. Wirtz studies the biophysical properties of healthy and diseased cells, including interactions between adjacent cells and the role of cellular architecture on nuclear shape and gene expression.

Wirtz directs the newly formed Johns Hopkins Engineering in Oncology Center. The EOC is a Physical Sciences in Oncology program center of the National Cancer Institute launched in October 2009 with a $14.8 million grant from the National Institutes of Health. EOC brings together experts in cancer biology, molecular and cellular biophysics, applied mathematics, materials science, and physics to study and model cellular mobility and the assorted biophysical forces involved in the spread of cancer. Wirtz also serves as co-director of the Institute for NanoBioTechnology and has a joint appointment in the Johns Hopkins School of Medicine Department of Oncology.

A total of seven Johns Hopkins faculty members were elected to AAAS this year. Read about all of them in a Johns Hopkins University press release listed in the links below.

This year 531 members have been awarded this honor by AAAS because of their scientifically or socially distinguished efforts to advance science or its applications. New Fellows will be presented with an official certificate and a gold and blue (representing science and engineering, respectively) rosette pin on Feb. 20 at the AAAS Fellows Forum during the 2010 AAAS Annual Meeting in San Diego.  AAAS Fellows were announced in the AAAS News & Notes section of the journal Science on Dec. 18,  2009.

Story by Mary Spiro with materials provided by AAAS.

Seven Johns Hopkins Researchers Named 2009 AAAS Fellows

Searson Group Lab page

Wirtz Group Lab page

Johns Hopkins Institute for NanoBioTechnology

Whiting School of Engineering

On new lab chip, heart cells display a behavior-guiding ‘nanosense’

Johns Hopkins biomedical engineers, working with colleagues in Korea, have produced a laboratory chip with nanoscopic grooves and ridges capable of growing cardiac tissue that more closely resembles natural heart muscle. Surprisingly, heart cells cultured in this way used a “nanosense” to collect instructions for growth and function solely from the physical patterns on the nanotextured chip and did not require any special chemical cues to steer the tissue development in distinct ways. The scientists say this tool could be used to design new therapies or diagnostic tests for cardiac disease.

Leslie Tung, left, and Andre Levchenko, right, both of the Department of Biomedical Engineering, with Deok-Ho Kim, a doctoral student in Levchenko’s lab, who holds a nanopatterned chip able to cue heart cells to behave like natural heart tissue. Photo: Will Kirk/homewoodphoto.jhu.edu

Leslie Tung, left, and Andre Levchenko, right, both of the Department of Biomedical Engineering, with Deok-Ho Kim, a doctoral student in Levchenko’s lab, who holds a nanopatterned chip able to cue heart cells to behave like natural heart tissue. Photo: Will Kirk/homewoodphoto.jhu.edu

The device and experiments using it are described in this week’s online Early Edition issue of Proceedings of the National Academy of Sciences. The work, a collaboration with Seoul National University, represents an important advance for researchers who grow cells in the lab to learn more about cardiac disorders and possible remedies.

“Heart muscle cells grown on the smooth surface of a Petri dish would possess some, but never all, of the same physiological characteristics of an actual heart in a living organism,” said Andre Levchenko, an associate professor of biomedical engineering in Johns Hopkins’ Whiting School of Engineering. “That’s because heart muscle cells—cardiomyocytes—take cues from the highly structured extracellular matrix, or ECM, which is a scaffold made of fibers that supports all tissue growth in mammals. These cues from the ECM influence tissue structure and function, but when you grow cells on a smooth surface in the lab, the physical signals can be missing. To address this, we developed a chip whose surface and softness mimic the ECM. The result was lab-grown heart tissue that more closely resembles the real thing.”

Levchenko said that when he and his colleagues examined the natural heart tissue taken from a living animal, they “immediately noticed that the cell layer closest to the extracellular matrix grew in a highly elongated and linear fashion. The cells orient with the direction of the fibers in the matrix, which suggests that ECM fibers give structural or functional instructions to the myocardium, a general term for the heart muscle.” These instructions, Levchenko said, are delivered on the nanoscale—activity at the scale of one-billionth of a meter and a thousand times smaller than the width of a human hair.

Levchenko and his Korean colleagues, working with Deok-Ho Kim, a biomedical engineering doctoral student in Levchenko’s lab and the lead author of the PNAS article, developed a two-dimensional hydrogel surface simulating the rigidity, size and shape of the fibers found throughout a natural ECM network. This biofriendly surface made of nontoxic polyethylene glycol displays an array of long ridges resembling the folded pattern of corrugated cardboard. The ridged hydrogel sits upon a glass slide about the size of a U.S. dollar coin. The team made a variety of chips with ridge widths spanning from 150 to 800 nanometers, groove widths ranging from 50 to 800 nanometers and ridge heights varying from 200 to 500 nanometers. This allowed researchers to control the surface texture over more than five orders of magnitude of length.

“We were pleased to find that within just two days the cells became longer and grew along the ridges on the surface of the slide,” Kim said. Furthermore, the researchers found improved coupling between adjacent cells, an arrangement that more closely resembled the architecture found in natural layers of heart muscle tissue. Cells grown on smooth, unpatterned hydrogels, however, remained smaller and less organized, with poorer cell-to-cell coupling between layers. “It was very exciting to observe engineered heart cells behave on a tiny chip in two dimensions like they would in the native heart in three dimensions,” Kim said.

Collaborating with Leslie Tung, a professor of biomedical engineering in the Johns Hopkins School of Medicine, the researchers found that after a few more days of growth, cells on the nanopatterned surface began to conduct electric waves and contract strongly in a specific direction, as intact heart muscle would. “Perhaps most surprisingly, these tissue functions and the structure of the engineered heart tissue could be controlled by simply altering the nanoscale properties of the scaffold. That shows us that heart cells have an acute ‘nanosense,’” Levchenko said.

Johns Hopkins researchers developed this chip to culture heart cells that more closely resemble natural cardiac tissue. Photo: Will Kirk/homewoodphoto.jhu.edu

Johns Hopkins researchers developed this chip to culture heart cells that more closely resemble natural cardiac tissue. Photo: Will Kirk/homewoodphoto.jhu.edu

“This nanoscale sensitivity was due to the ability of cells to deform in sticking to the crevices in the nanotextured surface and probably not because of the presence of any molecular cue,” Levchenko said. “These results show that the ECM serves as a powerful cue for cell growth, as well as a supporting structure, and that it can control heart cell function on the nanoscale separately in different parts of this vital organ. By mimicking this ECM property, we could start designing better-engineered heart tissue.”

Looking ahead, Levchenko said that he anticipates that engineering surfaces with similar nanoscale features in three dimensions, instead of just two, could provide an even more potent way to control the structure and function of cultured cardiac tissue.

In addition to Kim, Levchenko and Tung, authors on this paper are postdoctoral fellow Elizabeth A. Lipke and doctoral students Raymond Cheong and Susan Edmonds Thompson, all from the Johns Hopkins School of Medicine Department of Biomedical Engineering; Michael Delannoy, assistant director of the Johns Hopkins School of Medicine Microscope Facility Center; and Pilnam Kim and Kahp-Yang Suh, both of Seoul National University.

Tung and Levchenko are affiliated faculty members of the Johns Hopkins Institute for NanoBioTechnology. Thompson is a member of INBT’s Integrative Graduate Education and Research Traineeship in nanobiotechnology. Funding for this research was provided by the National Institutes of Health and the American Heart Association.

Related Web sites

Andre Levchenko’s Lab

Leslie Tung’s Lab

Johns Hopkins Institute for NanoBioTechnology

Story by Mary Spiro

Cell’s ‘cap’ of bundled fibers could yield clues to disease

Newsletter readers! If you are looking for the 2010 NanoBio Symposium story go to: http://inbt.jhu.edu/outreach/symposium
Doctoral student Shyam Khatau, left, and Denis Wirtz, director of the Johns Hopkins Engineering in Oncology Center, played a key role in finding a bundled “cap” of thread-like fibers that holds a cell’s nucleus in its proper place. Photo by Will Kirk, Homewoodphoto.jhu.edu.

Doctoral student Shyam Khatau, left, and Denis Wirtz, director of the Johns Hopkins Engineering in Oncology Center, played a key role in finding a bundled “cap” of thread-like fibers that holds a cell’s nucleus in its proper place. Photo by Will Kirk, Homewoodphoto.jhu.edu.

It turns out that wearing a cap is good for you, at least if you are a mammal cell.

Researchers from the Johns Hopkins Engineering in Oncology Center have shown that in healthy cells, a bundled “cap” of thread-like fibers holds the cell’s nucleus, its genetic storehouse, in its proper place. Understanding this cap’s influence on cell and nuclear shape, the researchers say, could provide clues to the diagnosis and treatment of diseases such as cancer, muscular dystrophy and the age-accelerating condition known as progeria.

“Under a microscope, the nucleus of a sick cell appears to bulge toward the top, while the nucleus of a healthy cell appears as a flattened disk that clings to the base,” said principal investigator Denis Wirtz, professor of chemical and biomolecular engineering and director of the Engineering in Oncology Center. “If we can figure out how and why this shape-changing occurs, we may learn how to detect, treat or perhaps even prevent some serious medical disorders.”

Scientists have known that misshapen nuclei are an indicator of disease, Wirtz said, but they were not certain how a cell controlled the shape of its nucleus, the structure in mammal cells where genetic material resides. In a study published in the Nov. 10 issue of the Proceedings of the National Academy of Sciences, however, the research team led by Wirtz reported the discovery of a fibrous structure that holds the nucleus in its place. The researchers call this new network structure the perinuclear actin cap.

“In healthy cells, the perinuclear actin cap is a domed structure of bundled filaments that sits above the nucleus, sort of like a net that is tethered all around to the perimeter of the cell membrane,”

Wirtz said. This configuration pushes the nucleus down toward the base of the cell and also creates the distinctive flattened shape of normal cells. Cells with cancer, muscular dystrophy or progeria, however, lack this distinctive cap, allowing the nucleus to float upward toward the top of the cell’s membrane. These diseased cells may appear more rounded and bulbous.

“The cap controls the shape of the nucleus by controlling the shape of the cell itself,” Wirtz said.

The perinuclear actin cap was discovered while the team was trying to find out if cell shape controls nucleus shape. By growing cells on a surface with alternating sticky and non-sticky stripes, the researchers noticed that as cells grew along a sticky stripe, their nuclei elongated as well. Using a confocal microscope — a special kind of microscope that can view an object one “slice” at a time — doctoral student Shyam Khatau was able to reconstruct the cell in three dimensions. By stacking the confocal microscope images together, Khatau, who is affiliated with the Johns Hopkins Institute for NanoBioTechnology, was able to produce short movies showing the 3-D structure of the cells, the nucleus and the perinuclear actin cap. (The movies are online here or below.)

“That’s when we saw the cap,” Khatau said, “and Dr. Wirtz realized we were on to something.”

The cap’s role in disease became evident when Khatau tested cells without the gene to produce lamin A/C, a protein found in the membrane of the nucleus of normal cells but absent in the nuclear membrane of cells from people with muscular dystrophy. Cells without lamin A/C failed to produce the perinuclear actin cap.

“We next plan to study how the cap’s effect on the shape of the nucleus affects what genes the cells express,” said Wirtz.

Khatau, who is pursuing his doctorate in the Department of Chemical and Biomolecular Engineering, is lead author of the journal article.

Additional Johns Hopkins authors on this paper are Wirtz; doctoral student Christopher M. Hale and senior Meet Patel from the Whiting School of Engineering’s  Department of Chemical and Biomolecular Engineering; and Peter C. Searson, a professor in the school’s Department of Materials Science and Engineering. Other co-authors were P. J. Stewart-Hutchinson and Didier Hodzic from the School of Medicine at the Washington University in St. Louis and Colin L. Stewart from the Institute of Medical Biology, Singapore.

This work was funded by the National Institutes of Health and the Muscular Dystrophy Association.

Story by Mary Spiro

PNAS journal article.

Johns Hopkins Engineering in Oncology Center

Johns Hopkins Institute for NanoBioTechnology

Department of Chemical and Biomolecular Engineering