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Vol. LXI, No. 10
May 15, 2009
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Week-Long Event Builds Excitement
Just Past Infancy, Nanomedicine Takes 1st Steps at NIH

On the front page...

Like any 6-year-old, nanomedicine is just in primary school, learning its way in the world. And like any proud parent, NIH was raring to show what its offspring could already do. That was one of the main ideas behind the recent NIH NanoWeek 2009: Bring together some of nanotechnology’s early adopters. Share lessons learned. Point out pitfalls. Plan next steps. Network. Build teams.

“Nanomedicine is not yet in vogue right now,” said Dr. Kuan Wang, chief of NIAMS’s Laboratory of Muscle Biology and one of the event’s organizers. “It really did not exist. NIH is building its own brand of science. This is as creative as, say, Apple’s inventing the iPod for the music community. What we are doing with NanoWeek is using the chance to promote a much closer community with other fields of science like engineering and with other institutions like NIST. Interaction can be a lot more in-depth. Nanomedicine is going to have to involve everyone from clinicians to physicists.”

Continued...


  Dr. Mark Ratner of Northwestern University gives lead-off NanoWeek lecture.  
  Dr. Mark Ratner of Northwestern University gives lead-off NanoWeek lecture.  

First, a Review

NEI’s Dr. Richard Fisher, who introduced the first public session of NanoWeek on Apr. 8, offered a brief history of nanoscience at NIH. He recalled “Nanoscience and Nanotechnology: Shaping Biomedical Research,” a symposium on the then-new field’s potential in medical research that NIH held in 2000. NIH is one of 25 agencies in the National Nanotechnology Initiative that formed in 2001 to coordinate federal research and development in the field and to envision its future. NNI estimates that about 20,000 scientists worldwide are working in the nanotechnology realm now. The number is sure to increase as more potential applications and benefits are revealed.

The NIH Roadmap Nanomedicine Initiative funding began 4 years ago, after 2 years of planning, Wang added. He said NIH is ahead of the curve on nano applications, but lags behind institutions like NIST when it comes to fabrication of nano chips and instrumentation. Partnering up, then, benefits everyone, he said.
 

Fitness for molecules. With Dr. Kuan Wang (right), chief of NIAMS’s Laboratory of Muscle Biology, Dr. Jeffrey Forbes studies how molecules handle mechanical stress with nano tools such as atomic force microscope, single molecule fluorescence and molecular modeling of stressed molecules. “All molecules are elastic to some degree and would fail at some point when they are pushed too far, so it is very important to understand how nature designs the stress-handling capability,” Forbes said. “This is a fun place to do research...We developed and fabricated many of the nano tools we use.” Wang commented, “Since force is the most important function of muscles, the mechanical strength of the proteins that are used to assemble the contractile machinery is critical from a structural engineering point of view. This is an emerging field called mechanobiology that is propelled by nanotechnology.”

Freeze frame. Dr. Dennis Winkler (left), instrumentation specialist for Dr. Alasdair Steven’s Laboratory of Structural Biology Research, NIAMS, shows “nano tourists” how his lab uses cryo-electron microscopy and cryo-electron tomography techniques to study biological complexes such as viruses and cellular components. By using powerful computers to analyze the images from the electron microscopes, researchers produce highly detailed models of the specimens they are investigating, allowing them to explore life on the nano scale.

For their part, NIH’ers seem eager. Cosponsored by the trans-NIH nanotechnology task force and the Roadmap initiative—and assisted by the nano scientific interest group—NanoWeek is a “reflection of growth and interest in nanotechnology in the NIH community,” Fisher noted.
Dr. Kuan Wang

In addition to several days of lectures in Natcher Bldg., the week also included a poster session of current projects by researchers in the Baltimore- Washington area, lab tours (see photos/captions) of work under way at NIH and concurrent closed-session symposia with engineering industry scientists. Those talks, which involved pre-published research, intellectual property and other issues, were cosponsored off-campus by IEEE, a leading professional association for technology advances.

‘A Particular Kind of Small’

Dr. Mark Ratner, a physical chemist at Northwestern University, led off Apr. 7 with an overview of nano fundamentals. “Nano is not just small,” he said. “It’s a particular kind of small.”
Dr. Dennis Winkler, instrumentation specialist for Dr. Alasdair Steven’s Laboratory of Structural Biology Research, NIAMS, shows “nano tourists” how his lab uses cryo-electron microscopy and cryo-electron tomography techniques to study biological complexes such as viruses and cellular components. By using powerful computers to analyze the images from the electron microscopes, researchers produce highly detailed models of the specimens they are investigating, allowing them to explore life on the nano scale.

Nature designs at the nanoscale, he explained. Scientists are keenly interested in the process of assembly that occurs with particles this tiny. And tiny they are. A nano is one-billionth of a meter. A human hair is about 60 to 100 times bigger than a nano.

“But size is only the beginning of the nanoscience story,” said Ratner. “What pioneers in the field are trying to do now, and what medical researchers are most concerned with currently, is how nano particles behave. Turns out that once certain substances are examined at their nanoscale level, their properties and the ways they react to stimuli are vastly different than when they are viewed at their larger level.”

For example, look at the metal gold. “Take a piece of gold and cut it in half,” he said. “Nothing about the gold really changes. The melting point of it remains the same. The color remains the same.” However, if you repeat the halving maneuver 18 times, the metal “melting point changes and the color changes.”

Ratner described nanomedicine applications that are already showing promise in the lab. Researchers have developed nano particles that have repaired spinal cord injury in rats and theoretically regenerated the good cholesterol in blood samples.
Dr. Clare Waterman

Whole new views. NHLBI biologist Dr. Clare Waterman, also using a “homemade” TIRF (see Jin caption, at right) apparatus, studies how a cell moves and the dynamic assembly of proteins. “I can’t see dynamics with simple microscopy,” she says, explaining that the limit of a light microscope is about 250 nanometers. “‘The Beast’ here, which includes three cameras, several spinning disks and 6 different colors, allows us to push the limits of microscopy. I’m seeing [the protein-building process] alive. It’s a new twist to take it to the nano level. Obviously, it’s more physiologically relevant to be able to view 3-D organisms.”

He ended with slides showing how wide open the nanomedicine field remains. Security, education, environment, economics (globalization, training) and ethics (privacy, equality)—“all of these issues involve aspects of nanoscience,” he noted. “But in particular health and safety issues have come very much to the fore. There have been two recent studies out of the [National] Academy [of Sciences] and there will be more, because as these things come up in society, we have to worry about them—regulating them and figuring out when they’re safe and when they’re not…We really don’t quite understand what the capabilities of nanoscience and nanotechnology are. I think we’re just scratching the surface of what could actually happen in these structures and in these situations.”

Coming to Terms

At the opening Natcher session, NIH deputy director for intramural research Dr. Michael Gottesman said he had at first wondered if nanomedicine deserved its own field. Was it “sufficiently different from molecular biology, structural biology or the biochemistry of molecules at the nanoscale to give it a new name?” he asked. “I now realize that nanotechnology encompasses not only traditional nanoscale science, but [also] a whole new set of approaches to measuring nanoscale phenomena and to developing nano machines such as nano tubes and devices to interrogate and treat cells at a subcellular level.”

He also described how much there is to discover in the fledgling discipline. “Very little is known about the environmental effects of a growing number of nano particles that we’re using in everyday life,” Gottesman said. “They’re already being using in household cleaning materials and we’re beginning to use them in medicine. One of the challenges is to determine the effect on living organisms of novel nano particles that have never been seen in nature before and we need to assemble this information before there’s massive environmental release and medical use.”

So new is the field that even those working in it may not always speak the same language, he noted.

“Another problem is the need to find ways to describe the properties of nano particles and to standardize the terminology and the measurements,” Gottesman concluded. “This is essential so that scientists who work in the field can communicate meaningfully with each other. When they talk about a certain nano particle they’ll all be talking about the same thing. One of the goals of NanoWeek at NIH is to initiate this communication process.”

Dr. Albert Jin (r) has led the development of a comprehensive biological atomic force microscopy (called bio-AFM) facility with Dr. Emilios Dimitriadis (c) and Dr. Svetlana Kotova in the group of Dr. Paul Smith, chief of BIMIS/NIBIB. The facility now features a ForceRobot single molecule force spectroscope (shown in background), a PicoForce multimode high-resolution AFM-imaging platform, a total internal reflection fluorescence (TIRF) Bioscope Z AFM platform, and a multimodal Raman-TIRF-AFM platform. Using these nanotech tools and collaborating with scientists both inside and outside NIH over the last 10 years, the group has carried out a broad range of cutting-edge medical applications such as the nano-characterization of malaria vaccine components and DNA/HIV-integrase complexes. “At NIH, we deployed the first machine of this kind in the U.S. last year, and have obtained informative results on folding/unfolding of protein clathrin and malaria vaccine candidates,” said Jin. “Much of our work would not be possible at all without nanotechnology.”First in U.S. Dr. Albert Jin (r) has led the development of a comprehensive biological atomic force microscopy (called bio-AFM) facility with Dr. Emilios Dimitriadis (c) and Dr. Svetlana Kotova in the group of Dr. Paul Smith, chief of BIMIS/NIBIB. The facility now features a ForceRobot single molecule force spectroscope (shown in background), a PicoForce multimode high-resolution AFM-imaging platform, a total internal reflection fluorescence (TIRF) Bioscope Z AFM platform, and a multimodal Raman-TIRF-AFM platform. Using these nanotech tools and collaborating with scientists both inside and outside NIH over the last 10 years, the group has carried out a broad range of cutting-edge medical applications such as the nano-characterization of malaria vaccine components and DNA/HIV-integrase complexes. “At NIH, we deployed the first machine of this kind in the U.S. last year, and have obtained informative results on folding/unfolding of protein clathrin and malaria vaccine candidates,” said Jin. “Much of our work would not be possible at all without nanotechnology.”

With Dr. James R. Sellers (r), a senior investigator in NHLBI’s Laboratory of Molecular Physiology, Dr. Yasuharu “Harry” Takagi built the laser-computer-microscope-videocamera apparatus shown in the background, which is capable of “optical trapping”—viewing, tracing and monitoring—myosins, the motor proteins that move along actin filaments inside of cells. To capture perspectives at this nanoscale level, the researchers designed their own machines using mostly commercially available parts so they can now envision a single molecule at work. More importantly, they also wrote down the recipe for the elaborate “Lego-like” structure, so other scientists can make similar nanotools. “But that’s what NIH does, right? That’s exactly why we’re here,” Sellers points out.Recipe for nanotools. With Dr. James R. Sellers (r), a senior investigator in NHLBI’s Laboratory of Molecular Physiology, Dr. Yasuharu “Harry” Takagi built the laser-computer-microscope-videocamera apparatus shown in the background, which is capable of “optical trapping”—viewing, tracing and monitoring—myosins, the motor proteins that move along actin filaments inside of cells. To capture perspectives at this nanoscale level, the researchers designed their own machines using mostly commercially available parts so they can now envision a single molecule at work. More importantly, they also wrote down the recipe for the elaborate “Lego-like” structure, so other scientists can make similar nanotools. “But that’s what NIH does, right? That’s exactly why we’re here,” Sellers points out.

Working with Drs. Alioscka Sousa (c) and Maria Aronova, Dr. Richard Leapman (r) of the NIBIB Laboratory of Bioengineering and Physical Sciences emphasizes the interdisciplinary nature of the field. His lab uses nano techniques to localize and characterize particles via electron microscopy en route to helping to develop nano particles that can potentially deliver cancer therapy. For example, the group has been collaborating with Dr. Hemant Sarin, a physician and imaging sciences training fellow in NIBIB and the Clinical Center, and Dr. Gary Griffiths, a chemist and director of NHLBI’s Imaging Probe Development Center, in pre-clinical studies to develop dendrimer nano particles for glioma “theranostics” (combined therapy and diagnostics). They have also collaborated with Dr. J. Silvio Gutkind, biochemist Dr. Vyomesh Patel and colleagues in NIDCR, and Prof. James Rusling and Dr. Ashwin Bhirde, chemists at the University of Connecticut, to investigate pre-clinically the use of functionalized carbon nano tubes for targeted treatment of head and neck cancer. “Breakthroughs will come from teams—clinicians working with biologists working with chemists working with physicists,” Leapman said.Team-building paramount. Working with Drs. Alioscka Sousa (c) and Maria Aronova, Dr. Richard Leapman (r) of the NIBIB Laboratory of Bioengineering and Physical Sciences emphasizes the interdisciplinary nature of the field. His lab uses nano techniques to localize and characterize particles via electron microscopy en route to helping to develop nano particles that can potentially deliver cancer therapy. For example, the group has been collaborating with Dr. Hemant Sarin, a physician and imaging sciences training fellow in NIBIB and the Clinical Center, and Dr. Gary Griffiths, a chemist and director of NHLBI’s Imaging Probe Development Center, in pre-clinical studies to develop dendrimer nano particles for glioma “theranostics” (combined therapy and diagnostics). They have also collaborated with Dr. J. Silvio Gutkind, biochemist Dr. Vyomesh Patel and colleagues in NIDCR, and Prof. James Rusling and Dr. Ashwin Bhirde, chemists at the University of Connecticut, to investigate pre-clinically the use of functionalized carbon nano tubes for targeted treatment of head and neck cancer. “Breakthroughs will come from teams—clinicians working with biologists working with chemists working with physicists,” Leapman said.

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