T H E   N I H    C A T A L Y S T      J A N U A R Y  –  F E B R U A R Y   2005



text and photo
by Karen Ross


Intrigued by the Invisible: NEI Director Paul Sieving (left) and NHGRI tech development guru Jeffery Schloss (right), co-chairs of the NIH Roadmap Nanomedicine Implementation Group, flank Richard Fisher, director of the NEI Corneal Diseases Program and Nanomedicine Project team leader

The aim of nanomedicine, one of nine major NIH Roadmap initiatives, is to treat disease by intervening at a molecular level. It is a close cousin of nanotechnology, which is concerned with building devices that are 0.1 m or less in size. (For reference, the head of a pin is 2,000 m, a typical human cell is approximately 5 m, and a large protein complex is approximately 0.005 m.)

Nanomedicines, for example, could be tiny machines that compensate for the function of defective proteins or very precisely targeted pharmaceuticals that have no side effects.

Deeper Levels of Quantitation

Before these treatments can become a reality, scientists first need a detailed, quantitative understanding of cellular processes. Many of today’s approaches to biochemistry and molecular biology are much more descriptive than quantitative, says Jeffery Schloss, director of Technology Development Coordination, NHGRI, and one of the chairs of the implementation group that directs the Roadmap nanomedicine initiative.

The nanomedicine initiative, Schloss says, encourages scientists to take an engineer’s view of the cell—to think of molecular pathways as circuits and to make careful measurements of physical and chemical processes that take place.

Nanotechnology will contribute both the tools to make these measurements and, ultimately, the devices that can remodel molecular circuits. Furthermore, Schloss observes, biological pathways are themselves excellent examples of robust systems that operate at the "nano" scale.

But he does sound a cautionary note. However exciting and promising the field of nanomedicine may be, it is also a field in its infancy. It is extremely hard to predict what direction nanomedicine research will take in the near future, Schloss says, and this uncertainty has presented special challenges to the nanomedicine implementation group.

Nanomedicine is one of the five initiatives under the major NIH Roadmap theme "New Pathways to Discovery." The initiative is directed by an implementation group whose members are drawn from all over NIH.

Along with Schloss, the 16-member nanomedicine implementation group is chaired by NEI Director Paul Sieving, whose institute is responsible for administrative oversight of the initiative. The group’s primary mission is to develop a program that will fund the establishment of Nanomedicine Development Centers.

This initiative, Schloss and Sieving observe, has relevance to disciplines throughout the entire NIH. The tools and concepts that will emerge will enhance basic biological understanding and should eventually result in medical interventions that touch the mission of every institute.

Approaching a Visionary Center

No one is sure yet just what a Nanomedicine Development Center will look like. The investigators that make up a center could all be from the same institution, or there could be a core group at one institution that has collaborators in other places.

"They can also be virtual centers; there’s really no requirement for bricks and mortar," says Richard Fisher, director of the Corneal Diseases Program, NEI, and Nanomedicine Project team leader.

The idea, he says, is to bring in top investigators from many disciplines to work on a common problem. "They can work together across oceans; what’s important is their chemistry."

The requirements for a center have intentionally been sketched out only in rough outline:

A center should bring together scientists from a wide range of disciplines including biology, engineering, chemistry, physics, and mathematics.

The group of centers that is funded should form a collaborative network that shares both intellectual and physical resources.

The research should focus on developing quantitative approaches that are applicable to a wide range of biological problems.

The details have all been left to the creativity of the scientists who apply for funding. Says Sieving, "We want . . . the groups that are funded by this [initiative] to have free intellectual space to develop the concept of nanomedical technology in a way that we hope will speed its emergence."

A Unique Process

This degree of freedom is possible because of the unique process the implementation group devised for funding the centers.

Typically, when NIH program staff identify an area in biomedical science that needs investigation, NIH issues a request for applications (RFA), and interested scientists submit an application. Then, two levels of peer review, the study section and the advisory council of the funding NIH institute, are invoked to assess the scientific merit of the proposed work.

For the Nanomedicine initiative, however, the implementation team designed a multistep process whereby extramural investigators work collaboratively with NIH staff to craft the content of the Centers RFA that will be issued in April 2005.

The initiative was launched at a public meeting May 4, 2004, at NIH; approximately 300 scientists from all over the country attended. After this meeting, investigators were invited to submit a five-page "white paper" of their vision of a nanomedicine development center.

The implementation group received 81 such white papers, from which the members, in consultation with a group of extramural scientists, chose 20 to receive planning grants.

Criteria for judging the white papers included the characteristics of suggested model systems; the attention paid to quantitative measurements and engineering design principles; and the multidisciplinary nature of the team’s approach. Overall, the group sought to ensure the inclusion of a broad range of biomedical areas (see "Nanomedicine Sampler").

In another departure from the traditional grant-application process, in which investigators carefully guard the confidentiality of their proposals, representatives from each of the 20 groups will present more detailed 15-page proposals to each other and to members of the implementation group at a meeting to be held in March 2005.

This meeting, Fisher observes, will "really stimulate the interactive nature of the process." The cross-talk and ideas generated during the meeting, together with the applicants’ written proposals, will inform the implementation group’s final RFA for the Nanomedicine Development Centers.

In 2005, only the 20 groups that participated in the planning stages will be allowed to respond to the RFA and of those, three or four groups will receive five-year grants to establish their centers; the grants will total $6 million.

Beyond 2005

The implementation group anticipates another $6 million for a second round of Nanomedicine Development Center grants. Competition for this second round will be more traditional but "informed by everything we’ve done and learned this first round," Fisher says.

The team hopes that at the end of five years the first-round centers will have become productive, self-sustaining entities.

The centers are expected to have a cohesive set of investigators, to have a well-defined, workable topic of study, and to have made substantial progress in their research, says Sieving.

As for their financial future, it is possible that they will continue to be supported by the Roadmap, or they might be adopted by individual institutes at NIH. Alternatively, they could seek out funds from regular NIH grant programs or from private agencies.

"We’re hoping to build something so exciting," says Schloss, "that NIH and other agencies . . . can’t resist putting more money into it."



The 20 groups awarded nanomedicine development center planning grants reflect diverse scientific interests and approaches:

A group at Brown University, Providence, R.I., led by Clyde Briant plans to study the interactions between human tissues and foreign materials on a molecular level, with the goal of developing more biocompatible medical implants and devices.

Wah Chiu’s group at Baylor College, Houston, wants to examine how molecular chaperones help proteins to fold into their correct three-dimensional structures. This research could lead to the design of protein-folding machines that could be used to fight diseases, such as Alzheimer’s, that are thought to be caused by the accumulation of misfolded proteins.

On a similar theme, Yuri Lyubchenko’s team at the University of Nebraska Medical Center, Omaha, will explore what causes proteins to misfold and aggregate. They will develop tools to observe individual proteins as they aggregate and techniques to manipulate these proteins in the test tube.

James Baker’s group at the University of Michigan, Ann Arbor, proposes to study the structure and function of membranes using nanoscience tools. This work could lead to better strategies for delivering drugs to cells as well as a deeper understanding of agents that disrupt membranes.

Gang Bao of the Georgia Institute of Technology, Atlanta, leads a group that studies the biological nanomachines responsible for RNA synthesis and DNA repair. They will develop imaging tools that can reveal the behavior of single molecules inside cells.

Richard Wood and his group at the University of Pittsburgh will focus on the large protein complex responsible for nucleotide excision repair.

James Crowe and his team at Vanderbilt University, Nashville, Tenn., want to gain a detailed understanding of the signaling pathways triggered when the immune system encounters an invading microorganism. Ultimately they hope to be able to manipulate the immune response in individual cells or in the body of an organism.

Douglas Eaton of Emory University, Atlanta, and his group plan to use scanning probe microscopy techniques, which can zero in on structures as small as a molecule interacting with the surface of a cell, to study how cells communicate with each other.

A team at the University of Pittsburgh led by Susan Gilbert will investigate the motor proteins involved in mitosis at the nanometer level with the goal of developing better strategies for controlling cell proliferation.

Kevin Gillis’ group at the University of Missouri, Columbia, plans to study the protein and lipid machines that move material into and out of cells. These machines are implicated in many diseases, including cystic fibrosis and diabetes, and are prominent drug targets.

Chih-Ming Ho at the University of California, Los Angeles, and his colleagues will use tools to visualize and manipulate the cytoskeleton, whose dynamic rearrangements are critical for many cellular processes.

Samuel Stupp and his team at Northwestern University, Evanston, Ill., also plan to tackle the cytoskeleton on the nanoscale. The group will study the assembly of cytoskeletal structures and the involvement of the cytoskeleton in cell division and movement.

Ehud Isacoff’s team at the University of California, Berkeley, will study the membrane receptors that detect conditions in the extracellular environment and the signaling pathways that relay this information to the nucleus.

A group led by Eric Jakobsson at the University of Illinois, Urbana-Champaign, will embark on detailed studies of biological ion-conduction systems and apply this knowledge to the design of nanoconducting devices.

Gary Johnson and his team at the University of North Carolina, Chapel Hill, focus on the stressome, a multiprotein complex that responds to cellular stress. They have developed probes that can detect the conformation of individual components of the complex.

A group at the University of Connecticut School of Medicine and Dentistry, Farmington, Ct., led by Leslie Loew will address cellular processes on "supramolecular scale." These experiments will take a broader view than studies of individual molecules but provide more detail than studies done on a cellular level.

Edward Pugh and his colleagues at the University of Pennsylvania, Philadelphia, will study supramolecular cellular compartments (SMCCs) such as photoreceptors and nerve growth cones. They want to understand how these compartments assemble and eventually hope to develop artificial substitutes that can be used to treat diseases, including retinal degeneration, that are caused by defective SMCCs.

A group led by David Needham at Duke University, Durham, N.C., plans to apply engineering principles to the study of four biological problems: drug delivery, measurement of forces inside cells, inflammation, and orthopedic bioengineering. The knowledge they glean will be used to design nanoscale machines.

A Columbia University (New York, Morningside campus) team led by Michael Sheetz will explore the connections between cellular processes and physical factors such as spatial organization and mechanical force. Its work could lead to improved artificial tissues and therapies to enhance tissue repair.

Wendell Lim’s group at the University of California, San Francisco, plans to build machines that can direct cell movement.

Karen Ross



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