Investment in imaging exploits trends in genetics, nanotech

Necessity is not always the mother of invention. If you are Dr. Roderic Pettigrew, director of the National Institute of Biomedical Imaging and Bioengineering, invention can germinate from any number of sources. The likelihood of its ultimate adoption increases with the help of federal funds and the guidance that comes from an interdisciplinary approach to medical research and development.

Pettigrew, the first director of NIBIB, has been at its helm since the year of its first Congressional appropriation in 2002.

With an operating budget of close to $300 million in fiscal 2008, NIBIB is as close as radiology gets to having a federal research agency devoted to its advancement at the National Institutes of Health. Closely allied with NIH director and radiologist Dr. Elias Zerhouni, Pettigrew has pointed the agency in a direction that is consistent with the chair's vision of medical research that exploits recent discoveries in genetics, molecular biology, and nanotechnology.

In an interview with Diagnostic Imaging, Pettigrew discussed NIBIB-supported initiatives that promise to establish a set of standards and goals for medical imaging practice.

DI: When NIBIB was created in 2002, it was billed as radiology's institute at the National Institutes of Health. Has that proved to be the case?

Pettigrew: The institute certainly does give radiology a home at the NIH, but our mission is broader than strictly radiology. I think of NIBIB as the interface of physical sciences and the life sciences. Radiology and bioengineering are at the core of the nexus of the quantitative sciences and the life sciences.

DI: What other fields does this encompass?

Pettigrew: Twentieth-century medicine was reactive in that actions were taken after symptoms appeared. In the 21st century, medicine will become proactive. We will detect disease at its very earliest stages to either preempt its development or minimize the serious consequences that would otherwise follow. All of the physical sciences factor into realizing this vision: chemistry, biology, genetics, mathematics, computer sciences, material science, and engineering, along with the quantitative sciences that form much of the foundation of radiology.

My view of the institute is that it operates at the intersection of the quantitative sciences and the life sciences, with the radiological sciences being one of the key components.

DI: What did you plan to achieve as NIBIB director when you first took the post?

Pettigrew: I wanted NIBIB to have the most profound impact possible on improving human health. I wanted it not only to effect major advances in the treatment of disease, but also to add to the understanding of disease and disease mechanisms by leading the development of emerging medical technologies.

DI: What did you identify that could make a difference?

Pettigrew: It was important to first become a champion for integrating the two major constituencies that led to the creation of the institute: imaging and bioengineering.

I wanted to facilitate interdisciplinary science and a strong interaction between multiple disciplines, aiming for a greater degree of interdisciplinary research. We organized the institute with [a team] concept in mind. Our scientific program includes a division of discovery science and a division of applied science without calling out specific scientific disciplines.

That was done intentionally because multiple disciplines are involved in discovery, in the application of discovered information, and in tools development.

Our division of interdisciplinary training emphasizes the development of a new generation of scientists who will have areas of focus but are cognizant of an array of fields.

The second objective had to do with the management of the institute. It is the first NIH institute to focus specifically on emerging technologies, with imaging and engineering as key areas. Many radiologists have been successful in getting NIH funding for their research, but we had no way of really predicting what the response would be, what level of growth or demand to expect.

DI: How did the research community respond to funding opportunities made available through NIBIB?Pettigrew: We had a tremendous response. In 2003, our first full year of funding, we had over 1000 applications in response to requests and 500 additional investigator-initiated requests. The budget of $280 million more than doubled from the startup budget of $112 million in the spring of 2002, but the applications increased by almost a factor of 4. In the next year we had an additional increase in investigator-initiated applications of about 100%. In our fourth year, applications rose another 20%.

DI: What innovations have thus far grown out of NIBIB funding?

Pettigrew: There have been several. Our most dramatic scientific innovations are likely to come from our Quantum Grants program, [which] I refer to as an effort to achieve medical "moon shots." I see this as a complement to the normal way in which the NIH does business. We fund a large number of research activities involving the development of techniques and technologies that lead to incremental improvements but are not transformative. Here, we are taking a small part of our budget and concentrating those dollars on a few well-chosen technological developments that could really transform healthcare.

DI: What are the projects?

Pettigrew: One involves principal investigator Karen Hirschi, Ph.D., from Baylor College of Medicine and collaborators from Rice University, the University of Cambridge in England, and multiple corporate partners. The focus is on developing a treatment for stroke. The concept is to engineer a stem cell-based functional neurovascular unit that could be implanted in an area of the brain that has been damaged by an ischemic stroke or hemorrhage. The implanted device would stimulate the regeneration of cerebral tissue to ameliorate some of the neurological consequences of a stroke.

The second is a project with Mehmet Toner, Ph.D., a professor of surgery and bioengineering at Massachusetts General Hospital. He is developing a microfluidics-based device specifically for detecting circulating cancer cells, with the goal of being able to identify one circulating cancer cell in a sample of a billion normal cells.

The third involves a collaboration between Wake Forest University and the University of Miami to develop a curative treatment for type 1 diabetes using amniotic fluid-derived stem cells to engineer insulin-producing pancreatic islet cells, which would then be transplanted into the patient and essentially regenerate a functioning pancreas. The principal investigator is Dr. Anthony Atala.

The fourth project supports the work of bioengineer Shuvo Roy, Ph.D., at The Cleveland Clinic to develop an implantable dialysis unit that some are calling an artificial kidney.

The fifth is led by Raoul Kopelman, Ph.D., at the University of Michigan. He is developing multifunctional nanoparticles that are capable of penetrating the blood-brain barrier. These nanoparticles will be linked to a blue dye and a photosensitizer. The dye will allow surgeons to visualize brain tumors during excisional surgery, and upon laser stimulation, the photosensitizer will enable the ablation of residual tumor cells.

DI: What NIBIB projects have direct implications for diagnostic imaging?

Pettigrew: We supported the development and implementation of high-speed MR imaging, including Dr. Daniel Sodickson's work on parallel imaging. Dr. Simon Cherry at the University of California, Davis has received our support to develop PET/MRI instrumentation. We're supporting projects relating to image-guided focused ultrasound at Brigham and Women's Hospital and Dr. Richard Ehman's work at Mayo Clinic Rochester on MR elastography. That approach is really looking great, both for imaging liver fibrosis and also as a potential application for distinguishing benign from cancerous breast lesions.

Our grantee Dr. John Boone at the University of California, Davis has had some early success with a dedicated breast CT scanner. It is able to detect a lesion that's about a third the size of lesions detectable with mammography with the same radiation dose.

We also support groups in the bioinformatics and neuroimaging arenas. For example, we are helping fund the work of Dr. John Mazziotta at the University of California, Los Angeles on the imaging of Alzheimer's disease. Along with the National Institute of Arthritis and Musculoskeletal Disease, we are funding a multi-institutional effort to find imaging-based biomarkers for the development and progression of arthritis.

James S. Duncan, Ph.D., at Yale University is a shining example of a researcher who uses interdisciplinary science to solve real-world problems. His work relates to epilepsy. Many patients troubled by seizures never undergo a definitive treatment because their brain lesions are difficult to identify and hard to reach. Jim and his colleague Dr. Dennis Spencer, chief of neurosurgery at Yale, assembled a huge multidisciplinary team-including biologists, mechanical engineers, computer visualization experts, radiologists, and bioengineers-to develop an intraoperative, real-time guidance technique. Presurgical imaging, including conventional contrast-enhanced MRI, functional MRI, and MR spectroscopy, is combined with electroencephalography to identify the exact location of the epileptic focus. This integrated 3D data set is then updated in real-time during surgery to adjust in 3D for the shifting position of the brain.

Spencer estimates that over 30% more patients can undergo surgery because of this new image-guidance technology. The surgical procedures now typically take 90 minutes less time to perform, and postoperative neurologic deficits essentially have been eliminated.

DI: What are NIBIB's other accomplishments in its first six years?

Pettigrew: Among the recent ones is our bilateral agreement with India's Department of Biotechnology of the Ministry of Science and Technology to develop low-cost healthcare technologies aimed at medically underserved populations.

NIBIB is also one of three NIH institutes working with the Department of Defense in the development of the Armed Forces Institute of Regenerative Medicine. This is an effort to repair battlefield injuries by integrating therapies that optimize the self-regenerative capacity of the body with biomaterials to create engineered tissues and organs.

DI: How have funding levels at NIBIB changed in recent years?

Pettigrew: Funding growth has been slow, 1% or less for the most recent years.

DI: Are you concerned that the projects that you've helped create will be funded long enough to find a practical application?

Pettigrew: We are concerned about some long-term projects if institute funding is not on par with inflation, though we try to plan for the "out" years. Part of the management of the institute involves assuring the long-term support of the projects we undertake.

DI: You've mentioned NIBIB support of "moon shots," technologies that could transform medicine. Does NIBIB support projects that are closer to earth, ones that have a high probability of influencing medical practice?Pettigrew: We've established a point-of-care technologies research network to drive development of appropriate diagnostic technologies through collaborations that merge scientific and technological capabilities with clinical need. Currently, we fund four centers: the Center for Emerging Neuro Technologies at the University of Cincinnati, the Center for Point-of-Care Technologies for Sexually Transmitted Diseases at Johns Hopkins University, the Rapid Multipathogen Detection for POCT and National Disaster Readiness at the University of California, Davis, and the Center to Advance POC Diagnostics for Global Health at the Program for Appropriate Technologies in Health (PATH) in collaboration with the University of Washington.

DI: What diseases are first in line for this type of point-of-care treatment?

Pettigrew: I'll give you an example: the UCLA urosensor for treating urinary tract infections, which are quite common. The patient is typically first placed on a broad-spectrum antibiotic, while a urine sample is cultured in the lab. This approach involves a number of problems. Culturing the sample delays the start of a definitive treatment, and the initial use of a broad-spectrum antibiotic raises the risk of increasing the bacteria's resistance to therapy. The urosensor is a chip-based technology about the size of a conventional microscope slide. It contains a dozen or so electrodes and electroplated centers. On each of these is a molecular probe specific to the DNA sequence for a range of potential pathogens that might be responsible for a urinary tract infection. Detection is based on identifying the bacteria RNA.

DI: How will medical imaging practice change in the next five to 10 years because of the work of NIBIB?

Pettigrew: We will move from reactive to proactive medicine, an approach that is home-based rather than hospital-based and minimally invasive instead of invasive. Imaging will play a critical role in early diagnosis and personalizing the therapy for optimal effectiveness.

I mentioned earlier the potential for identifying breast tumors now that are about a third the size of the tumors that can be identified with conventional mammography. New modalities, such as MR elastography, will determine if small lesions are malignant. Molecular medicine will take hold as diagnostics and therapeutics such as gene-based treatments are developed. Nanomedicine platforms will combine imaging and therapy.

DI: You've led NIBIB for nearly all of its six-year history. Can we expect you to stay on?

Pettigrew: I have no plans to leave the institute at this time. My long-term plans are to continue to do and support science that will have a lasting impact on healthcare. NIBIB was created to assist the development of emerging technologies. It is exciting to be able to do what I've wanted to do from my earliest days. I've always had a great love for the physical sciences. This job allows me to apply them in a way that can improve the lives of everyone.