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

Podcast: Nanotech method to study cell detachment could lead to improved cancer therapies

Peter Searson

Peter Searson

Cancer spreads from organ to organ when cells break free from one site and travel to another. Understanding this process, known as metastasis, is critical for developing ways to prevent the spread and growth of cancer cells. Peter Searson, Reynolds Professor of Materials Science and Engineering in the Whiting School of Engineering and director of the Institute for NanoBioTechnology, led a team of engineers who have developed a method to specifically measure detachment in individual cells.

The method, which uses lab-on-a-chip technology, allows researchers to observe and record the exact point when a cell responds to electrochemical cues in its environment and releases from the surface upon which it is growing. Better knowledge of the biochemistry of cell detachment could point the way to better cancer therapies. In this “Great Ideas” podcast, Elizabeth Tracey, communications associate for the School of Medicine, interviews Searson about this current research.

“…We know that processes like cell detachment are important in cancer metastasis, where cells become detached from tumors…” Peter Searson

Click here to listen:  Great Ideas Podcast: Peter Searson

Related links:

You can watch a video and read more about Searson’s method of studying cell detachment here.

Peter Searson’s INBT profile page.

This podcast was originally posted to the Johns Hopkins University “Great Ideas” web page. To view the original posting, click here.

Maitra’s Cancer Preventive Nano-Spice Featured on WJZ-TV

The spice, turmeric, contains a substance that has shown promise in the prevention and treatment of several diseases, including cancer. The only drawback is that the substance—curcumin—does not easily enter the bloodstream. Now, Anirban Maitra, associate professor at the Johns Hopkins School of Medicine and affiliated faculty member of the Institute for NanoBioTechnology, has created tiny, nano-curcumin particles so small they can be absorbed into the bloodstream through the stomach. Maitra was interviewed October 28, 2008 by Kellye Lynn of WJZ-TV in Baltimore.

[flash http://inbt.jhu.edu/video/maitra-wjz13.flv W=425 H=318 f={image=http://inbt.jhu.edu/images/newsimages/maitra-wjz.jpg} mode=2]


New Postdoc Program in Nanotechnology for Cancer Medicine Launched at Johns Hopkins

New postdoc program in nanobiotechnology at Johns Hopkins University. Credit: HIPS/JHU.

The Institute for NanoBioTechnology (INBT) has recently launched a postdoctoral fellowship in Nanotechnology for Cancer Medicine (NTCM). Funded by the National Cancer Institute, the goal of this new postdoctoral training program is to ensure that a diverse and highly trained workforce is available to assume leadership roles in biomedical, behavioral and clinical research. This is the first T-32 grant awarded in the Whiting School of Engineering. Applications are now being accepted for this one-of-a-kind program that will allow two new postdoctoral fellows to enter the program each year.

Denis Wirtz, professor of Chemical and Biomolecular Engineering in the Whiting School of Engineering, and Kenneth Kinzler, professor of Oncology at the School of Medicine will co-direct the NTCM training program. Wirtz is associate director of INBT and Kinzler is a member of INBT’s executive committee.

Postdoctoral fellows will learn new methods for molecular imaging, develop high-throughput diagnostic tools, and engineer novel drug, antibody, or genetically based delivery systems to treat human cancers, Wirtz explains. “They will be laying the foundations for technologies that will enable an inside-view of cancer cell functions, as opposed to the limited ‘blackbox’ input-output techniques currently used,“ Wirtz says.

NTCM fellows will view interactions between nanostructures and biological systems in physical, biological, and biomedical terms and will become adept at emerging concepts in biomolecular engineering, protein engineering, materials synthesis and surface modification. Fellows will be able to take advantage of research and clinical resources at the Johns Hopkins Hospital, the National Cancer Institute-designated Sidney Kimmel Comprehensive Cancer Center, the Ludwig Center for Cancer Genetics and Therapeutics, The Sol Goldman Pancreatic Cancer Center, and the In Vivo Cellular and Molecular Imaging Center, as well as the educational resources and experimental facilities available through INBT.

Each fellow will be supported for two years and will be co-advised by a faculty member in oncology or medicine and a faculty member in engineering. (There are 20 participating faculty members, please go to http://inbt.jhu.edu/postdoc-faculty.php to view the full list.) Fellows will take a core lecture course in either nanotechnology or cancer biology, a core laboratory course in nanobiotechnology for cancer medicine, and will attend a weekly journal club. In addition, fellows will participate in an annual retreat in the fall and the annual NanoBio Symposium in the spring. After two, 6-week rotations in the laboratories of participant faculty, fellows will embark on co-advised research in nanotechnology for cancer medicine.

Only U.S. citizens and permanent residents are eligible to apply for the NTCM program. Requirements for admission include a PhD in an engineering discipline or biological/oncology discipline or an MD degree. A concentration in cancer is helpful. Interested applicants should send their C.V. and two letters of recommendation to: Ashanti Edwards / Prof. Denis Wirtz, Institute for NanoBioTechnology, Johns Hopkins University, NEB 100, 3400 N. Charles St. Baltimore, MD 21218. For more information, e-mail aedwards@jhu.edu.

The Institute for NanoBioTechnology at Johns Hopkins University brings together internationally renowned expertise in medicine, engineering, the sciences and public health to foster the next wave of nanobiotechnology innovation. Faculty members affiliated with INBT are members of the Johns Hopkins Krieger School of Arts and Sciences, Whiting School of Engineering, School of Medicine, Bloomberg School of Public Health and Applied Physics Laboratory. For more information about INBT, go to http://inbt.jhu.edu.

Story by Mary Spiro