Pediatr Radiol (2014) 44:935–939 DOI 10.1007/s00247-014-2958-4
RESEARCH FORUM
Basic science research in pediatric radiology — how to empower the leading edge of our field Heike E. Daldrup-Link
Received: 28 May 2013 / Revised: 12 December 2013 / Accepted: 26 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Basic science research aims to explore, understand and predict phenomena in the natural world. It spurs the discovery of fundamentally new principles and leads to new knowledge and new concepts. By comparison, applied research employs basic science knowledge toward practical applications. In the clinical realm, basic science research and applied research should be closely connected. Basic science discoveries can build the foundation for a broad range of practical applications and thereby bring major benefits to human health, education, environment and economy. This article explains how basic science research impacts our field, it describes examples of new research directions in pediatric imaging and it outlines current challenges that we need to overcome in order to enable the next groundbreaking discovery.
Basic science research is the quest for the truly unknown [1]. It is motivated by a deep intellectual curiosity, without an immediate purpose in mind or expectation of commercial gain [1]. It assumes that cause and effect are non-linear, paths are not straight. There are numerous examples where basic science led researchers to unexpected results. Sir Alexander Fleming discovered penicillin after deciding to study the mold on a Petri dish that had apparently contaminated and killed staphylococcus bacteria growing on that dish [2]. Fleming had the inner curiosity and flexibility to deviate from his initial experimental plan toward studying the unexpected. Penicillin remains one of the most important therapeutic drugs in medical practice. Wilhelm Conrad H. E. Daldrup-Link (*) Pediatric Radiology, Lucile Packard Children’s Hospital, Stanford School of Medicine, 725 Welch Road, Stanford, CA 94305-5614, USA e-mail: [email protected]
Röntgen studied cathode rays, the phosphorescent stream of electrons used today in televisions and fluorescent light bulbs. During his experiments, he accidently discovered new rays with different properties than the cathode rays; these new rays had the ability to penetrate solid structures such as the human body. His discovery was recognized with one of the first Nobel prizes in history and remains the foundation for our profession today [3]. Because basic science research ventures down new paths of endeavor, its immediate value is not immediately apparent. It takes time, intellectual flexibility and persistence to explore new ideas and produce new discoveries. Thomas Edison claimed 1,093 U.S. patents, including the light bulb, the phonograph and the motion picture camera. Upon the critique that 1,000 of his inventions failed, he responded: “I have not failed. I discovered 1,000 ways that did not work.” Great discoveries include many setbacks. Anybody investing time or money in basic science research has to accept this. For this reason, especially in economically difficult times, it is sometimes argued that research efforts should focus primarily on applied research, which provides direct benefit and return to our society. However, applied research utilizes existing concepts over and over again and thereby can only produce incremental advances and returns. Major innovations that fundamentally advance our field require generation of new knowledge via basic science research and ultimately lead to innovation-based economic growth. Even though the outcome of individual research endeavors is uncertain, federally supported academic research ultimately leads to approximately 30% of the total NASDAQ value, and the yearly National Institutes of Health budget (for new and competing awards) of $28 billion generates at least 100–120 inventions each year [4].
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According to the philosophy of sciences, the discipline of physics is considered to be more fundamental than all other sciences, such as chemistry, biology, psychology and economics [1]. The basic science of physics includes the fundamental nature of matter, space, time and energy. Medical imaging technology is based on physics principles and plays an increasingly important role in elucidating basic science questions in biomedical research. The development of CT and MRI together has been regarded as the most important innovation in medicine [5]. The pediatric radiology community would add that US imaging has had a major impact on our field as well. Further development of these and other new imaging technologies is the future of our field. In the past, applied pediatric radiology research consisted mainly of anatomical descriptions of imaging findings with surgical or pathological correlations. That era is over. Today, advanced functional and molecular imaging technologies are becoming available for the benefit of pediatric patients. The clinical need for more specific information along with the success of molecular imaging innovations in adults is slowly penetrating into pediatric imaging applications [6]. Examples of ongoing basic research efforts with potentially high clinical impact include developments of novel US technologies such as advanced blood flow quantifications and tissue perfusion maps, advanced US data post-processing and 3-D reconstruction algorithms, and developments of targeted and theranostic (combined diagnostic and therapeutic) microbubbles, among many others [7–10]. Integration of US technologies with other imaging modalities is a relatively unexplored area that could be of value for improved tissue characterization, planning of interventional procedures and more efficient workflows. Other technological advances include intraoperative MR scanners, which allow image-guided resection of central nervous system tumors [11], simultaneous functional MRI (fMRI) and electroencephalographic (EEG) scans for co-localization of epileptogenic foci [12], integration with high-frequency focused sonography for targeted tumor ablations [13, 14] and hyperpolarized MR imaging, which allows for dynamic mapping of biological processes such as tumor glycolysis [15] or mitochondrial dysfunction in cardiac diseases [16]. Integrated positron emission tomography (PET)/MRI systems open opportunities to sequentially or simultaneously evaluate a variety of physiological processes toward comprehensive one-stop diagnostic exams, which can be utilized to validate new biomarkers, to combine tracer quantification with functional assessment (e.g., tissue concentration and activation of theranostic drugs) or to investigate successive physiological processes (e.g., receptor density and therapeutic drug uptake) [17–19].
Pediatr Radiol (2014) 44:935–939
New child-adapted molecular imaging approaches can be expected to substantially improve our knowledge of the biology of pediatric disease and support the development of fundamentally child-adapted (personalized) diagnostic and therapeutic approaches. Examples include radiation-free optical imaging technologies for the diagnosis and treatment-monitoring of rheumatoid arthritis [20, 21], radiation-free photo-acoustic imaging technologies for diagnosing brain oxygenation [22, 23], novel approaches for imaging stem cell therapies [24, 25] and noninvasive tumor ablations with high-intensity focused sonography [26]. Optical imaging is based on the detection of fluorescent light and is very attractive for pediatric imaging applications because it is radiation-free, very fast and has molecular sensitivity [22, 27]. A recently developed clinical optical imaging scanner allows for evaluation of inflamed joints of the hands in patients with rheumatoid arthritis via detection of tissue fluorescence after intravenous injection of the FDA-approved fluorescent contrast agent indocyanine green [21]. Other developments in optical imaging instrumentation include hand-held probes (similar to those used in sonography), dual-axes endoscopes fitted with fluorescence confocal microendoscopes [28] and optical imagers for intraoperative tumor delineation [29]. Photo-acoustic imaging relies on delivery of non-ionizing, pulsed laser light into a tissue of interest, which leads to thermo-elastic expansion of the target tissue and emission of US waves, which can be detected with a US transducer (“light in – ultrasound out”) [22]. The technique is highly sensitive for measurement of tissue hemoglobin (Hb) concentrations and oxygen saturations based on differential absorption of light by oxygenated and deoxygenated Hb, and thus it is of high interest for monitoring infants in neonatal intensive care units. Relatively new research disciplines that need to be integrated into the development of imaging technologies include genomics (study of genes), proteomics (study of proteins produced by an organism) and bioinformatics (computational methods for organizing and analyzing biological data). These disciplines shift our diagnostic efforts from an observational–descriptive process (what is) to predictive–imaginative operations (what will be), thereby fundamentally changing the way we approach human pathophysiology, i.e. from detecting and treating disease to maintaining human health. The most underutilized resource in this context is the patient. Our patients and their parents want to be involved in evaluations of their health status and they embrace developments of self-measuring devices [30–33]. Examples include personalized genomics services [30], wireless, non-invasive glucose and other blood biomarker
Pediatr Radiol (2014) 44:935–939
measuring devices [33], wireless blood pressure, EEG and electrocardiographic sensors in removable body patches, and pressure sensors in textiles for people with paraplegia [31], among many others. These new patientdriven health-monitoring devices have great potential as screening tools and need to be validated against and integrated with traditional diagnostic approaches. The driving force for pediatric imaging research is the people who invest their time and energy in initiatives and who are ready to face and overcome obstacles along the way (Fig. 1). There are at least three major challenges related to the human workforce that drives pediatric imaging research, and in particular basic science research:
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intrinsic motivation. Although people seem to be productive under these circumstances, they cannot deliver their most creative work because their fear obstructs their imagination. (3) Limited opportunities for creativity and training. In order to ensure predictable, well-controlled and safe conditions in a clinical context, the clinical environment enforces the maintenance of norms and regulations and discourages questioning or changing the status quo. However, true advancements are built on provocative thoughts, controversial ideas and openness to change. What inspires us to engage in research activities? We want to pursue truly exciting ideas and create something new. Everybody can relate to this core impulse of life: explore the unknown, learn, grow—and create enduring value. Providing access to novel, cutting-edge technologies and actively encouraging creative and diverse ideas would create a stimulating, innovative and collaborative environment where true advancements could take place.
(1) Disconnection between clinicians and basic scientists. Very few pediatric radiology teams include basic scientists dedicated to pediatric imaging research. Although several major institutions have basic scientists working on topics related to pediatric imaging research, many of these scientists are not well connected to clinical teams. This disconnection significantly obstructs the translation of novel basic science discoveries to clinical practice and needs to be addressed. (2) Increasing work-related pressures. Increasing clinical demands make it difficult for clinical radiologists to engage in research in general and high-impact basic research in particular. Lim et al. [34] reported that only 11% of all original research articles published in Radiology and the American Journal of Roentgenology during the last 10 years were related to basic science research and only 5% of original research articles were related to pediatric radiology. In addition, performance pressures for clinician–scientists and basic scientists, such as the fear of not advancing or losing a job, destroys
National Institutes of Health (NIH) funding issues significantly impede progress of pediatric imaging research. There are limited requests for applications (RFAs) specifically tailored to questions relevant to pediatric imaging and there are limited NIH grant opportunities related to pediatric imaging. Because of the salary cap on NIH budgets, the actual salary for clinician–scientists is not supported by the NIH. The difference between NIH-funded and actual salary has to be funded by the respective university. Training grants are not well tailored toward the needs of clinician–scientists either. The mandatory 75% research effort required for NIH’s K career development awards is too much for a junior radiologist to
Fig. 1 Research fellows in Daldrup-Link Lab, where researchers are developing cellular imaging technologies (a). b Confocal microscopy of an FITC-nanoparticle-labeled (green) mesenchymal stem cell. Courtesy
of Daldrup-Link Lab (http://daldrup-link-lab.stanford.edu). c Sagittal T2weighted MR scan of a knee joint after transplantation of iron oxide nanoparticle-labeled stem cells into cartilage defects (arrows)
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develop his or her clinical competencies at the same time. This is an unfortunate one-size-fits-all approach to research training, because there is evidence that awardees of the Radiological Society of North America’s early investigator awards (40% effort) and the Association of University Radiologists’ GE Radiology Research Academic Fellowship awards (50% effort) are as good or sometimes better than the general pool of NIH K awardees at winning larger research grants later in their career (personal communication with Michael Kalutkiewicz, Academy of Radiology Research). Flexibility per medical discipline in NIH training awards would be welcome. In addition, funding agencies tend to favor worthy but incremental research over risky but potentially transformative work, thereby discouraging the kind of research that could most advance our field. Once a grant finally comes through, a large amount of the budget routinely gets cut while actual expenses have increased in the meantime, making it impossible to conduct the project as proposed. While funding agencies focus on maintaining funding opportunities for trainees and junior investigators, funding opportunities for mid- and senior-level investigators have decreased dramatically, thereby leading countless trainees into dead-end science careers and late transfers to other fields, after thousands and millions of dollars have been invested. We need to provide better longterm resources for science careers to ensure monetary and intellectual return to our society. All points above impede our ability to establish the next generation of basic science researchers and expert clinician– scientists, who are essentially needed to advance our field. Besides scarcer funding opportunities, another important limitation is the unavailability of experienced educators. There is a substantial lack of qualified mentors who can motivate and guide capable trainees toward successful and productive research experiences. Although we prepare trainees for clinical rotations with via instructions by clinical experts and appropriate teaching materials, research activities are expected to occur intuitively and automatically. Journal editors, program directors and mentors have to foster thorough research education and guide trainees toward high-impact research projects and scientific publication, which lead to relevant information and discoveries that truly matter. Basic scientists and clinicians should work together to understand the theoretical and practical value of new imaging technologies; pediatric radiologists and pediatricians should collaborate more closely to better connect imaging procedures and patient management; trainees could form teams to explore different aspects of novel imaging technologies; and pediatric imaging centers should collaborate to generate more significant results. Although funding for NIH as a whole is expected to continue to see downward pressure, the prolonged austerity may actually present an opportunity for radiology research to distinguish itself in a positive way. A recent study by
Pediatr Radiol (2014) 44:935–939
Kalutkiewicz and Ehman [4] showed that of all NIH institutes, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) produces patents/inventions at the highest rate (per $100 million in funding), yet maintains one of the smallest budgets within the NIH portfolio. In addition, early data show that imaging study sections are among the most prolific patent generators, providing an argument for all institutes that giving favorable administrative consideration for imaging projects may engender the ability to increase NIH patent outputs, in addition to answering important scientific questions. As a community, we must set higher standards, utilize modern communication resources to learn from one another and strive to become the very best we can be. We must not confuse enforced academic performance with inspired scientific progress. Producing enduring value requires passion, collaboration and hard work. A close interaction of basic science and clinical research teams along with access to cutting-edge technologies can provide a unique platform to truly transform the field of pediatric radiology toward more efficient, less traumatic and less expensive diagnostic procedures that would enable more accurate diagnoses and individualized treatments for our pediatric patients. Conflict of interest None
References 1. Davis BD (2000) The scientist’s world. Microbiol Mol Biol Rev 64:1–12 2. Ligon BL (2004) Penicillin: its discovery and early development. Sem Pediatr Infect Dis 15:52–57 3. Andreae H (1973) The discoverer of X-rays and first Nobel prize winner for physics, Wilhelm Conrad Rontgen, died 50 years ago. Photographie 26:195–197 4. Best Practices in Transforming Research into Innovation: Creative Approaches to the Bayh-Dole Act. Hearing before the House Committee on Science, Space, and Technology, Subcommittee on Technology and Innovation. United States House of Representatives. 112th Cong., 2nd Sess. (2012). (Statement of Todd T. Sherer, PhD, CLP, Association of University Technology Managers) 5. Fuchs VR, Sox HC Jr (2001) Physicians’ views of the relative importance of thirty medical innovations. Health Aff (Millwood) 20:30–42 6. Daldrup-Link H, Gambhir SS (2013) Pediatric molecular imaging. In: Treves ST (ed) Pediatric nuclear medicine and molecular imaging, 4th edn. Springer, Heidelberg 7. Kiessling I, Bzyl J, Kiessling F (2011) Molecular ultrasound imaging and its potential for paediatric radiology. Pediatr Radiol 41:176–184 8. Lindner JR (2004) Microbubbles in medical imaging: current applications and future directions. Nat Rev Drug Discov 3: 527–532 9. Willmann JK, Cheng Z, Davis C et al (2008) Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice. Radiology 249: 212–219
Pediatr Radiol (2014) 44:935–939 10. Willmann JK, Paulmurugan R, Chen K et al (2008) US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice. Radiology 246:508–518 11. Pamir MN, Ozduman K, Dincer A et al (2010) First intraoperative, shared-resource, ultrahigh-field 3-tesla magnetic resonance imaging system and its application in low-grade glioma resection. J Neurosurg 112:57–69 12. Jacobs J, Rohr A, Moeller F et al (2008) Evaluation of epileptogenic networks in children with tuberous sclerosis complex using EEGfMRI. Epilepsia 49:816–825 13. Auboiroux V, Petrusca L, Viallon M et al (2012) Ultrasonographybased 2D motion-compensated HIFU sonication integrated with reference-free MR temperature monitoring: a feasibility study ex vivo. Phys Med Biol 57:N159–N171 14. Sung HY, Jung SE, Cho SH et al (2011) Long-term outcome of highintensity focused ultrasound in advanced pancreatic cancer. Pancreas 40:1080–1086 15. Hu S, Balakrishnan A, Bok RA et al (2011) 13C-pyruvate imaging reveals alterations in glycolysis that precede c-Myc-induced tumor formation and regression. Cell Metab 14:131–142 16. Malloy CR, Merritt ME, Sherry AD (2011) Could 13C MRI assist clinical decision-making for patients with heart disease? NMR Biomed 24:973–979 17. Drzezga A, Souvatzoglou M, Eiber M et al (2012) First clinical experience with integrated whole-body PET/MR: comparison to PET/CT in patients with oncologic diagnoses. J Nucl Med 53:845–855 18. Samarin A, Burger C, Wollenweber SD et al (2012) PET/MR imaging of bone lesions—implications for PET quantification from imperfect attenuation correction. Eur J Nucl Med Mol Imaging 39: 1154–1160 19. Schwenzer NF, Stegger L, Bisdas S et al (2012) Simultaneous PET/MR imaging in a human brain PET/MR system in 50 patients—current state of image quality. Eur J Radiol 81: 3472–3478 20. Meier R, Krug C, Golovko D et al (2010) ICG-enhanced imaging of arthritis with an integrated optical imaging/X-ray system. Arthritis Rheum 62:2223–2227 21. Meier R, Thuermel K, Moog P et al (2012) Detection of synovitis in the hands of patients with rheumatological disorders: diagnostic
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performance of optical imaging in comparison to MRI. Arthritis Rheum 64:2489–2498 James ML, Gambhir SS (2012) A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 92:897–965 Wang X, Chamberland DL, Xi G (2008) Noninvasive reflection mode photoacoustic imaging through infant skull toward imaging of neonatal brains. J Neurosci Methods 168:412–421 Khurana A, Nejadnik H, Chapelin F et al (2013) Ferumoxytol: a new, clinically applicable label for stem-cell tracking in arthritic joints with MRI. Nanomedicine 8:1969–1983 Castaneda RT, Boddington S, Henning TD et al (2011) Labeling human embryonic stem-cell-derived cardiomyocytes for tracking with MR imaging. Pediatr Radiol 41:1384–1392 Popert R (2011) High-intensity focussed ultrasound. Clin Oncol 23: 114–116 Sutton EJ, Henning TD, Pichler BJ et al (2008) Cell tracking with optical imaging. Eur Radiol 18:2021–2032 Liu JT, Mandella MJ, Ra H et al (2007) Miniature near-infrared dualaxes confocal microscope utilizing a two-dimensional microelectromechanical systems scanner. Opt Lett 32:256–258 Zhao Q, Jiang H, Cao Z et al (2011) A handheld fluorescence molecular tomography system for intraoperative optical imaging of tumor margins. Med Phys 38:5873–5878 Swan M (2009) Emerging patient-driven health care models: an examination of health social networks, consumer personalized medicine and quantified self-tracking. Int J Environ Res Public Health 6: 492–525 Chenu O, Vuillerme N, Bucki M et al (2013) TexiCare: an innovative embedded device for pressure ulcer prevention. Preliminary results with a paraplegic volunteer. J Tissue Viability 22:83–90 Torrado-Carvajal A, Rodriguez-Sanchez MC, RodriguezMoreno A et al (2012) Changing communications within hospital and home health care. Conf Proc IEEE Eng Med Biol Soc 2012:6074–6077 Ali SM, Aijazi T, Axelsson K et al (2011) Wireless remote monitoring of glucose using a functionalized ZnO nanowire arrays based sensor. Sensors 11:8485–8496 Lim KJ, Yoon DY, Yun EJ et al (2012) Characteristics and trends of radiology research: a survey of original articles published in AJR and Radiology between 2001 and 2010. Radiology 264:796–802
RESEARCH FORUM
Basic science research in pediatric radiology — how to empower the leading edge of our field Heike E. Daldrup-Link
Received: 28 May 2013 / Revised: 12 December 2013 / Accepted: 26 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Basic science research aims to explore, understand and predict phenomena in the natural world. It spurs the discovery of fundamentally new principles and leads to new knowledge and new concepts. By comparison, applied research employs basic science knowledge toward practical applications. In the clinical realm, basic science research and applied research should be closely connected. Basic science discoveries can build the foundation for a broad range of practical applications and thereby bring major benefits to human health, education, environment and economy. This article explains how basic science research impacts our field, it describes examples of new research directions in pediatric imaging and it outlines current challenges that we need to overcome in order to enable the next groundbreaking discovery.
Basic science research is the quest for the truly unknown [1]. It is motivated by a deep intellectual curiosity, without an immediate purpose in mind or expectation of commercial gain [1]. It assumes that cause and effect are non-linear, paths are not straight. There are numerous examples where basic science led researchers to unexpected results. Sir Alexander Fleming discovered penicillin after deciding to study the mold on a Petri dish that had apparently contaminated and killed staphylococcus bacteria growing on that dish [2]. Fleming had the inner curiosity and flexibility to deviate from his initial experimental plan toward studying the unexpected. Penicillin remains one of the most important therapeutic drugs in medical practice. Wilhelm Conrad H. E. Daldrup-Link (*) Pediatric Radiology, Lucile Packard Children’s Hospital, Stanford School of Medicine, 725 Welch Road, Stanford, CA 94305-5614, USA e-mail: [email protected]
Röntgen studied cathode rays, the phosphorescent stream of electrons used today in televisions and fluorescent light bulbs. During his experiments, he accidently discovered new rays with different properties than the cathode rays; these new rays had the ability to penetrate solid structures such as the human body. His discovery was recognized with one of the first Nobel prizes in history and remains the foundation for our profession today [3]. Because basic science research ventures down new paths of endeavor, its immediate value is not immediately apparent. It takes time, intellectual flexibility and persistence to explore new ideas and produce new discoveries. Thomas Edison claimed 1,093 U.S. patents, including the light bulb, the phonograph and the motion picture camera. Upon the critique that 1,000 of his inventions failed, he responded: “I have not failed. I discovered 1,000 ways that did not work.” Great discoveries include many setbacks. Anybody investing time or money in basic science research has to accept this. For this reason, especially in economically difficult times, it is sometimes argued that research efforts should focus primarily on applied research, which provides direct benefit and return to our society. However, applied research utilizes existing concepts over and over again and thereby can only produce incremental advances and returns. Major innovations that fundamentally advance our field require generation of new knowledge via basic science research and ultimately lead to innovation-based economic growth. Even though the outcome of individual research endeavors is uncertain, federally supported academic research ultimately leads to approximately 30% of the total NASDAQ value, and the yearly National Institutes of Health budget (for new and competing awards) of $28 billion generates at least 100–120 inventions each year [4].
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According to the philosophy of sciences, the discipline of physics is considered to be more fundamental than all other sciences, such as chemistry, biology, psychology and economics [1]. The basic science of physics includes the fundamental nature of matter, space, time and energy. Medical imaging technology is based on physics principles and plays an increasingly important role in elucidating basic science questions in biomedical research. The development of CT and MRI together has been regarded as the most important innovation in medicine [5]. The pediatric radiology community would add that US imaging has had a major impact on our field as well. Further development of these and other new imaging technologies is the future of our field. In the past, applied pediatric radiology research consisted mainly of anatomical descriptions of imaging findings with surgical or pathological correlations. That era is over. Today, advanced functional and molecular imaging technologies are becoming available for the benefit of pediatric patients. The clinical need for more specific information along with the success of molecular imaging innovations in adults is slowly penetrating into pediatric imaging applications [6]. Examples of ongoing basic research efforts with potentially high clinical impact include developments of novel US technologies such as advanced blood flow quantifications and tissue perfusion maps, advanced US data post-processing and 3-D reconstruction algorithms, and developments of targeted and theranostic (combined diagnostic and therapeutic) microbubbles, among many others [7–10]. Integration of US technologies with other imaging modalities is a relatively unexplored area that could be of value for improved tissue characterization, planning of interventional procedures and more efficient workflows. Other technological advances include intraoperative MR scanners, which allow image-guided resection of central nervous system tumors [11], simultaneous functional MRI (fMRI) and electroencephalographic (EEG) scans for co-localization of epileptogenic foci [12], integration with high-frequency focused sonography for targeted tumor ablations [13, 14] and hyperpolarized MR imaging, which allows for dynamic mapping of biological processes such as tumor glycolysis [15] or mitochondrial dysfunction in cardiac diseases [16]. Integrated positron emission tomography (PET)/MRI systems open opportunities to sequentially or simultaneously evaluate a variety of physiological processes toward comprehensive one-stop diagnostic exams, which can be utilized to validate new biomarkers, to combine tracer quantification with functional assessment (e.g., tissue concentration and activation of theranostic drugs) or to investigate successive physiological processes (e.g., receptor density and therapeutic drug uptake) [17–19].
Pediatr Radiol (2014) 44:935–939
New child-adapted molecular imaging approaches can be expected to substantially improve our knowledge of the biology of pediatric disease and support the development of fundamentally child-adapted (personalized) diagnostic and therapeutic approaches. Examples include radiation-free optical imaging technologies for the diagnosis and treatment-monitoring of rheumatoid arthritis [20, 21], radiation-free photo-acoustic imaging technologies for diagnosing brain oxygenation [22, 23], novel approaches for imaging stem cell therapies [24, 25] and noninvasive tumor ablations with high-intensity focused sonography [26]. Optical imaging is based on the detection of fluorescent light and is very attractive for pediatric imaging applications because it is radiation-free, very fast and has molecular sensitivity [22, 27]. A recently developed clinical optical imaging scanner allows for evaluation of inflamed joints of the hands in patients with rheumatoid arthritis via detection of tissue fluorescence after intravenous injection of the FDA-approved fluorescent contrast agent indocyanine green [21]. Other developments in optical imaging instrumentation include hand-held probes (similar to those used in sonography), dual-axes endoscopes fitted with fluorescence confocal microendoscopes [28] and optical imagers for intraoperative tumor delineation [29]. Photo-acoustic imaging relies on delivery of non-ionizing, pulsed laser light into a tissue of interest, which leads to thermo-elastic expansion of the target tissue and emission of US waves, which can be detected with a US transducer (“light in – ultrasound out”) [22]. The technique is highly sensitive for measurement of tissue hemoglobin (Hb) concentrations and oxygen saturations based on differential absorption of light by oxygenated and deoxygenated Hb, and thus it is of high interest for monitoring infants in neonatal intensive care units. Relatively new research disciplines that need to be integrated into the development of imaging technologies include genomics (study of genes), proteomics (study of proteins produced by an organism) and bioinformatics (computational methods for organizing and analyzing biological data). These disciplines shift our diagnostic efforts from an observational–descriptive process (what is) to predictive–imaginative operations (what will be), thereby fundamentally changing the way we approach human pathophysiology, i.e. from detecting and treating disease to maintaining human health. The most underutilized resource in this context is the patient. Our patients and their parents want to be involved in evaluations of their health status and they embrace developments of self-measuring devices [30–33]. Examples include personalized genomics services [30], wireless, non-invasive glucose and other blood biomarker
Pediatr Radiol (2014) 44:935–939
measuring devices [33], wireless blood pressure, EEG and electrocardiographic sensors in removable body patches, and pressure sensors in textiles for people with paraplegia [31], among many others. These new patientdriven health-monitoring devices have great potential as screening tools and need to be validated against and integrated with traditional diagnostic approaches. The driving force for pediatric imaging research is the people who invest their time and energy in initiatives and who are ready to face and overcome obstacles along the way (Fig. 1). There are at least three major challenges related to the human workforce that drives pediatric imaging research, and in particular basic science research:
937
intrinsic motivation. Although people seem to be productive under these circumstances, they cannot deliver their most creative work because their fear obstructs their imagination. (3) Limited opportunities for creativity and training. In order to ensure predictable, well-controlled and safe conditions in a clinical context, the clinical environment enforces the maintenance of norms and regulations and discourages questioning or changing the status quo. However, true advancements are built on provocative thoughts, controversial ideas and openness to change. What inspires us to engage in research activities? We want to pursue truly exciting ideas and create something new. Everybody can relate to this core impulse of life: explore the unknown, learn, grow—and create enduring value. Providing access to novel, cutting-edge technologies and actively encouraging creative and diverse ideas would create a stimulating, innovative and collaborative environment where true advancements could take place.
(1) Disconnection between clinicians and basic scientists. Very few pediatric radiology teams include basic scientists dedicated to pediatric imaging research. Although several major institutions have basic scientists working on topics related to pediatric imaging research, many of these scientists are not well connected to clinical teams. This disconnection significantly obstructs the translation of novel basic science discoveries to clinical practice and needs to be addressed. (2) Increasing work-related pressures. Increasing clinical demands make it difficult for clinical radiologists to engage in research in general and high-impact basic research in particular. Lim et al. [34] reported that only 11% of all original research articles published in Radiology and the American Journal of Roentgenology during the last 10 years were related to basic science research and only 5% of original research articles were related to pediatric radiology. In addition, performance pressures for clinician–scientists and basic scientists, such as the fear of not advancing or losing a job, destroys
National Institutes of Health (NIH) funding issues significantly impede progress of pediatric imaging research. There are limited requests for applications (RFAs) specifically tailored to questions relevant to pediatric imaging and there are limited NIH grant opportunities related to pediatric imaging. Because of the salary cap on NIH budgets, the actual salary for clinician–scientists is not supported by the NIH. The difference between NIH-funded and actual salary has to be funded by the respective university. Training grants are not well tailored toward the needs of clinician–scientists either. The mandatory 75% research effort required for NIH’s K career development awards is too much for a junior radiologist to
Fig. 1 Research fellows in Daldrup-Link Lab, where researchers are developing cellular imaging technologies (a). b Confocal microscopy of an FITC-nanoparticle-labeled (green) mesenchymal stem cell. Courtesy
of Daldrup-Link Lab (http://daldrup-link-lab.stanford.edu). c Sagittal T2weighted MR scan of a knee joint after transplantation of iron oxide nanoparticle-labeled stem cells into cartilage defects (arrows)
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develop his or her clinical competencies at the same time. This is an unfortunate one-size-fits-all approach to research training, because there is evidence that awardees of the Radiological Society of North America’s early investigator awards (40% effort) and the Association of University Radiologists’ GE Radiology Research Academic Fellowship awards (50% effort) are as good or sometimes better than the general pool of NIH K awardees at winning larger research grants later in their career (personal communication with Michael Kalutkiewicz, Academy of Radiology Research). Flexibility per medical discipline in NIH training awards would be welcome. In addition, funding agencies tend to favor worthy but incremental research over risky but potentially transformative work, thereby discouraging the kind of research that could most advance our field. Once a grant finally comes through, a large amount of the budget routinely gets cut while actual expenses have increased in the meantime, making it impossible to conduct the project as proposed. While funding agencies focus on maintaining funding opportunities for trainees and junior investigators, funding opportunities for mid- and senior-level investigators have decreased dramatically, thereby leading countless trainees into dead-end science careers and late transfers to other fields, after thousands and millions of dollars have been invested. We need to provide better longterm resources for science careers to ensure monetary and intellectual return to our society. All points above impede our ability to establish the next generation of basic science researchers and expert clinician– scientists, who are essentially needed to advance our field. Besides scarcer funding opportunities, another important limitation is the unavailability of experienced educators. There is a substantial lack of qualified mentors who can motivate and guide capable trainees toward successful and productive research experiences. Although we prepare trainees for clinical rotations with via instructions by clinical experts and appropriate teaching materials, research activities are expected to occur intuitively and automatically. Journal editors, program directors and mentors have to foster thorough research education and guide trainees toward high-impact research projects and scientific publication, which lead to relevant information and discoveries that truly matter. Basic scientists and clinicians should work together to understand the theoretical and practical value of new imaging technologies; pediatric radiologists and pediatricians should collaborate more closely to better connect imaging procedures and patient management; trainees could form teams to explore different aspects of novel imaging technologies; and pediatric imaging centers should collaborate to generate more significant results. Although funding for NIH as a whole is expected to continue to see downward pressure, the prolonged austerity may actually present an opportunity for radiology research to distinguish itself in a positive way. A recent study by
Pediatr Radiol (2014) 44:935–939
Kalutkiewicz and Ehman [4] showed that of all NIH institutes, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) produces patents/inventions at the highest rate (per $100 million in funding), yet maintains one of the smallest budgets within the NIH portfolio. In addition, early data show that imaging study sections are among the most prolific patent generators, providing an argument for all institutes that giving favorable administrative consideration for imaging projects may engender the ability to increase NIH patent outputs, in addition to answering important scientific questions. As a community, we must set higher standards, utilize modern communication resources to learn from one another and strive to become the very best we can be. We must not confuse enforced academic performance with inspired scientific progress. Producing enduring value requires passion, collaboration and hard work. A close interaction of basic science and clinical research teams along with access to cutting-edge technologies can provide a unique platform to truly transform the field of pediatric radiology toward more efficient, less traumatic and less expensive diagnostic procedures that would enable more accurate diagnoses and individualized treatments for our pediatric patients. Conflict of interest None
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