Advances in biology are occurring at a breathtaking pace today, from genetic insights facilitated by the Human Genome Project and next generation DNA sequencing technologies, to global nucleic acid and proteomic expression measurement using new high-throughput methods. Less publicized in recent years, yet still the central driver of progress, are the steadily proceeding biological insights gained through tried and true hypothesis-driven investigation into the complex worlds of metabolism, growth, development, and regulation. Certainly, the basic science ecosystem is productive and this portends well for the myriad new applications that will benefit mankind; drugs, vaccines, devices, and related economic growth—or perhaps not—in stark contrast to the generation of fundamental biological knowledge are inefficiencies in applying this information to real-world problems, especially those of the clinic. While investigation hums along at light speed, translation often does not. The good news is that obstacles to progress are tractable. The bad news, however, is that these problems are difficult. The present paper examines translational research from multiple perspectives, beginning with a historical account and proceeding to the current state of the art. Included are descriptions of successes and challenges, along with conjecture on how the field may need to evolve in the future. 1. Introduction Our greatest glory is not in never failing, but in rising up every time we fail. (Ralph Waldo Emerson) Nothing exemplifies the quote above from Emerson more than the translation of a biological discovery into a new drug, device, or other intervention that helps society. This is no easy task. The stakes here are high—human health and wellbeing; thus it is important that the translational system is critically examined and understood in order to maximize the likelihood that basic research performed in the laboratory and clinic benefits the public [1–7] (see Appendix for relevant websites). Moreover, if positive economic activity is generated this strengthens the biotechnology and pharmaceutical company sectors, which in turn grows the scientific ecosystem writ large, ultimately making more funds available for research and training, creating high-level jobs, and increasing appreciation of the overall enterprise by the public [8–10]. At the outset, it is important to recognize three important aspects of translational research as it is performed today. First, the system is not broken per se as there are many advances to celebrate, exemplified by the discovery, production,
References
[1]
E. Abraham, F. M. Marincola, Z. Chen, and X. Wang, “Clinical and translational medicine: integrative and practical science,” Clinical and Translational Medicine, vol. 1, article 1, 2012.
[2]
D. G. Contopoulos-Ioannidis, G. A. Alexiou, T. C. Gouvias, and J. P. A. Ioannidis, “Medicine: life cycle of translational research for medical interventions,” Science, vol. 321, no. 5894, pp. 1298–1299, 2008.
[3]
H. H？rig, E. Marincola, and F. M. Marincola, “Obstacles and opportunities in translational research,” Nature Medicine, vol. 11, no. 7, pp. 705–708, 2005.
[4]
K. I. Kaitin and J. A. Dimasi, “Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000–2009,” Clinical Pharmacology and Therapeutics, vol. 89, no. 2, pp. 183–188, 2011.
[5]
M. J. Khoury, M. Gwinn, and J. P. A. Ioannidis, “The emergence of translational epidemiology: from scientific discovery to population health impact,” American Journal of Epidemiology, vol. 172, no. 5, pp. 517–524, 2010.
[6]
M. N. Liebman and F. M. Marincola, “Expanding the perspective of translational medicine: the value of observational data,” Journal of Translational Medicine, vol. 10, no. 1, article 61, 2012.
[7]
A. M. Feldman, “Does academic culture support translational research?” Clinical and Translational Science, vol. 1, no. 2, pp. 87–88, 2008.
[8]
M. Scudellari, “The profits of nonprofit. The suprising results when drug development and altruism collide,” The Scientist, article 25, 2010.
[9]
G. Will, Rev the scientific engine, Washington Post 2011.
[10]
J. C. Greenwood, “Biotechnology: delivering on the promise,” Science Translational Medicine, vol. 2, no. 13, p. 13cm1, 2010.
[11]
J. P. A. Ioannidis, “Materializing research promises: opportunities, priorities and conflicts in translational medicine,” Journal of Translational Medicine, vol. 2, article 5, 2004.
[12]
S. P. Mankoff, C. Brander, S. Ferrone, and F. M. Marincola, “Lost in translation: obstacles to translational medicine,” Journal of Translational Medicine, vol. 2, article 14, 2004.
[13]
F. M. Marincola, “The trouble with translational medicine,” Journal of Internal Medicine, vol. 270, no. 2, pp. 123–127, 2011.
[14]
R. B. Nussenblatt, F. M. Marincola, and A. N. Schechter, “Translational Medicine—doing it backwards,” Journal of Translational Medicine, vol. 8, article 12, 2010.
[15]
J. S. Pober, C. S. Neuhauser, and J. M. Pober, “Obstacles facing translational research in academic medical centers,” FASEB Journal, vol. 15, no. 13, pp. 2303–2313, 2001.
[16]
M. Hay, D. W. Thomas, J. L. Craighead, C. Economides, and J. Rosenthal, “Clinical development success rates for investigational drugs,” Nature Biotechnology, vol. 32, pp. 40–51, 2014.
[17]
I. G. Mills and R. B. Sykes, “Taking risks with translational research,” Science Translational Medicine, vol. 2, no. 24, p. 24cm10, 2010.
[18]
M. R. Emmert-Buck, “An NIH intramural percubator as a model of academic-industry partnerships: from the beginning of life through the valley of death,” Journal of Translational Medicine, vol. 9, article 54, 2011.
[19]
J. Kaiser, “Rejecting 'big science' tag, collins sets five themes for NIH,” Science, vol. 325, no. 5943, p. 927, 2009.
[20]
B. H. Littman, L. di Mario, M. Plebani, and F. M. Marincola, “What's next in translational medicine?” Clinical Science, vol. 112, no. 3-4, pp. 217–227, 2007.
[21]
X. Wu, F. M. Marincola, M. N. Liebman, and X. Wang, “A global resource to translational medicine: the International Park of Translational Medicine and BioMedicine (IPTBM),” Journal of Translational Medicine, vol. 11, no. 1, article 8, 2013.
[22]
T. A. Golper and H. I. Feldman, “New challenges and paradigms for mid-career faculty in academic medical centers: key strategies for success for mid-career medical school faculty,” Clinical Journal of the American Society of Nephrology, vol. 3, no. 6, pp. 1870–1874, 2008.
[23]
E. Dolgin, “Collins sets out his vision for the NIH,” Nature, vol. 460, no. 7258, p. 939, 2009.
[24]
C. Skarke and G. A. FitzGerald, “Training translators for smart drug discovery,” Science Translational Medicine, vol. 2, no. 26, p. 26cm12, 2010.
[25]
S. H. Woolf, “The meaning of translational research and why it matters,” Journal of the American Medical Association, vol. 299, no. 2, pp. 211–213, 2008.
[26]
D. M. Rubio, E. E. Schoenbaum, L. S. Lee et al., “Defining translational research: implications for training,” Academic Medicine, vol. 85, no. 3, pp. 470–475, 2010.
[27]
A. Fleming, “On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae,” Reviews of Infectious Diseases, vol. 2, no. 1, pp. 129–139, 1980.
[28]
F. Diggins, The True History of the Discovery of Penicillin by Alexander Fleming, Biomedical Scientist, Insititute of Biomedical Sciences, London, 2003, Originally published in the Imperial College School of Medicine Gazette.
[29]
I. Murray, “Paulescu and the isolation of insulin,” Journal of the History of Medicine and Allied Sciences, vol. 26, pp. 150–157, 1971.
[30]
P. G. Katsoyannis, K. Fukuda, A. Tometsko, K. Suzuki, and M. Tilak, “The synthesis of the B-chain of insulin and its combination with natural or synthetic A-chain to generate insulin activity,” Journal of the American Chemical Society, vol. 86, no. 5, pp. 930–932, 1964.
[31]
F. G. Banting, J. B. Collip, W. R. Campbell, and A. A. Fletcher, “Pancreatic extracts in the treatment of diabetes mellitus,” Canadian Medical Association Journal, vol. 12, pp. 141–146, 1922.
[32]
A. Wollmer, M. Federwisch, and P. de Meyts, Insulin & Related Proteins Structure to Function and Pharmacology, Kluwer Academic Publishers, Boston, Mass, USA, 2002.
[33]
M. F. Dunn, “Zinc-ligand interactions modulate assembly and stability of the insulin hexamer—a review,” BioMetals, vol. 18, no. 4, pp. 295–303, 2005.
[34]
B. T. Layden and W. L. Lowe Jr., “G-protein-coupled receptors, pancreatic islets, and diabetes,” Nature Education, vol. 3, article 13, 2010.
[35]
D. X. Brown, E. L. Butler, and M. Evans, “Lixisenatide as add-on therapy to basal insulin,” Drug Design, Development and Therapy, vol. 8, pp. 25–38, 2013.
[36]
D. Constantin-Teodosiu, “Regulation of muscle pyruvate dehydrogenase complex in insulin resistance: effects of exercise and dichloroacetate,” Diabetes and Metabolism Journal, vol. 37, pp. 301–314, 2013.
[37]
A. King, “Integrating advances in insulin into clinical practice: advances In insulin formulations,” The Journal of Family Practice, vol. 62, pp. S9–S17, 2013.
[38]
C. Maria Rotella, L. Pala, and E. Mannucci, “Role of insulin in the type 2 diabetes therapy: past, present and future,” International Journal of Endocrinology and Metabolism, vol. 11, pp. 137–144, 2013.
[39]
K. M. A. Gartland, F. Bruschi, M. Dundar, P. B. Gahan, M. P. Viola Magni, and Y. Akbarova, “Progress towards the 'Golden Age' of biotechnology,” Current Opinion in Biotechnology, vol. 24, no. 1, pp. S6–S13, 2013.
[40]
B. M. Silber, “Driving drug discovery: the fundamental role of academic labs,” Science Translational Medicine, vol. 2, no. 30, p. 30cm16, 2010.
[41]
A. J. Stevens, J. J. Jensen, K. Wyller, P. C. Kilgore, S. Chatterjee, and M. L. Rohrbaugh, “The role of public-sector research in the discovery of drugs and vaccines,” The New England Journal of Medicine, vol. 364, no. 6, pp. 535–541, 2011.
[42]
K. Debackere and R. Veugelers, “The role of academic technology transfer organizations in improving industry science links,” Research Policy, vol. 34, no. 3, pp. 321–342, 2005.
[43]
A. M. Boccanfuso, “Why university-industry partnerships matter,” Science Translational Medicine, vol. 2, no. 51, p. 51cm25, 2010.
[44]
G. Evans and F. Austin, “Collaborations among academia, government, and industry in the diagnostics space: barriers and some ideas for solutions,” Science Translational Medicine, vol. 2, no. 63, 2010.
[45]
L. M. Portilla and B. Alving, “Reaping the benefits of biomedical research: partnerships required,” Science Translational Medicine, vol. 2, no. 35, p. 35cm17, 2010.
[46]
K. Handelsman, “A translational research niche for small business innovation research grants,” Science Translational Medicine, vol. 1, no. 5, p. 5cm6, 2009.
[47]
R. Klausner, “Translational science: a view from a biotechnology investor,” Science Translational Medicine, vol. 2, no. 34, p. 34ed3, 2010.
[48]
L. Serrano, “Synthetic biology: promises and challenges,” Molecular Systems Biology, vol. 3, article 158, 2007.
[49]
H. O. Smith, C. A. Hutchison III, C. Pfannkoch, and J. C. Venter, “Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15440–15445, 2003.
[50]
D. J. Segal and J. F. Meckler, “Genome engineering at the dawn of the golden age,” Annual Review of Genomics and Human Genetics, vol. 14, pp. 135–158, 2013.
[51]
L.-Y. Zhang, S.-H. Chang, and J. Wang, “How to make a minimal genome for synthetic minimal cell,” Protein & Cell, vol. 1, no. 5, pp. 427–434, 2010.
[52]
M. A. O'Malley, A. Powell, J. F. Davies, and J. Calvert, “Knowledge-making distinctions in synthetic biology,” BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, vol. 30, no. 1, pp. 57–65, 2008.
[53]
D. Balke, C. Wichert, B. Appel, and S. Muller, “Generation and selection of ribozyme variants with potential application in protein engineering and synthetic biology,” Applied Microbiology and Biotechnology, vol. 98, no. 8, pp. 3389–3399, 2014.
[54]
H. Ye, D. Aubel, and M. Fussenegger, “Synthetic mammalian gene circuits for biomedical applications,” Current Opinion in Chemical Biology, vol. 17, no. 6, pp. 910–917, 2013.
[55]
A. V. Bryksin, A. C. Brown, M. M. Baksh, M. G. Finn, and T. H. Barker, “Learning from nature-novel synthetic biology approaches for biomaterial design,” Acta Biomaterialia, vol. 10, no. 4, pp. 1761–1769, 2014.
[56]
V. Singh, “Recent advancements in synthetic biology: current status and challenges,” Gene, vol. 535, pp. 1–11, 2014.
[57]
C. M. Agapakis, “Designing synthetic biology,” ACS Synthetic Biology, vol. 3, no. 3, pp. 121–128, 2014.
[58]
L. B. Scharff and R. Bock, “Emerging tools for synthetic biology in plants,” The Plant Journal, vol. 78, no. 5, pp. 783–798, 2014.
[59]
R. Rekhi and A. A. Qutub, “Systems approaches for synthetic biology: a pathway toward mammalian design,” Frontiers in Physiology, vol. 4, article 285, 2013.
[60]
K. H. Lee and D. M. Kim, “Applications of cell-free protein synthesis in synthetic biology: interfacing bio-machinery with synthetic environments,” Biotechnology Journal, vol. 8, no. 11, pp. 1292–1300, 2013.
[61]
H. Kim and E. Gelenbe, “G-networks towards synthetic biology: a brief review,” in Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society IEEE Engineering in Medicine and Biology Society Conference, pp. 579–583, 2013.
[62]
W. Bacchus, D. Aubel, and M. Fussenegger, “Biomedically relevant circuit-design strategies in mammalian synthetic biology,” Molecular Systems Biology, vol. 9, article 691, 2013.
[63]
M. Kalos and C. H. June, “Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology,” Immunity, vol. 39, no. 1, pp. 49–60, 2013.
[64]
B.-R. Lee, S. Cho, Y. Song, S. C. Kim, and B.-K. Cho, “Emerging tools for synthetic genome design,” Molecules and Cells, vol. 35, no. 5, pp. 359–370, 2013.
[65]
J. A. J. Arpino, E. J. Hancock, J. Anderson et al., “Tuning the dials of synthetic biology,” Microbiology, vol. 159, no. 7, pp. 1236–1253, 2013.
[66]
M. G. J. de Vos, F. J. Poelwijk, and S. J. Tans, “Optimality in evolution: New insights from synthetic biology,” Current Opinion in Biotechnology, vol. 24, no. 4, pp. 797–802, 2013.
[67]
J. A. Gimpel, E. A. Specht, D. R. Georgianna, and S. P. Mayfield, “Advances in microalgae engineering and synthetic biology applications for biofuel production,” Current Opinion in Chemical Biology, vol. 17, no. 3, pp. 489–495, 2013.
[68]
B. J. Karas, B. Molparia, J. Jablanovic et al., “Assembly of eukaryotic algal chromosomes in yeast,” Journal of Biological Engineering, vol. 7, article 30, 2013.
[69]
M. G. Montague, C. Lartigue, and S. Vashee, “Synthetic genomics: potential and limitations,” Current Opinion in Biotechnology, vol. 23, no. 5, pp. 659–665, 2012.
[70]
J. I. Glass, N. Assad-Garcia, N. Alperovich et al., “Essential genes of a minimal bacterium,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 2, pp. 425–430, 2006.
[71]
E. Pennisi, “Venter cooks up a synthetic genome in record time,” Science, vol. 302, no. 5649, article 1307, 2003.
[72]
M. Schmidt, H. Torgersen, A. Ganguli-Mitra, A. Kelle, A. Deplazes, and N. Biller-Andorno, “SYNBIOSAFE e-conference: online community discussion on the societal aspects of synthetic biology,” Systems and Synthetic Biology, vol. 2, no. 1-2, pp. 7–17, 2008.
[73]
A. Kelle, “Ensuring the security of synthetic biology-towards a 5p governance strategy,” Systems and Synthetic Biology, vol. 3, no. 1, pp. 85–90, 2009.
[74]
Y. Joly, G. Koutrikas, A.-M. Tassé et al., “Regulatory approval for new pharmacogenomic tests: A comparative overview,” Food and Drug Law Journal, vol. 66, no. 1, pp. 1–24, 2011.
[75]
S. H. Yim and Y. J. Chung, “Introduction to international ethical standards related to genetics and genomics,” Genomics & Informatics, vol. 11, pp. 218–223, 2013.
[76]
E. Shapiro, T. Biezuner, and S. Linnarsson, “Single-cell sequencing-based technologies will revolutionize whole-organism science,” Nature Reviews Genetics, vol. 14, no. 9, pp. 618–630, 2013.
[77]
C. H. Wade, B. A. Tarini, and B. S. Wilfond, “Growing up in the genomic era: implications of whole-genome sequencing for children, families, and pediatric practice,” Annual Review of Genomics and Human Genetics, vol. 14, pp. 535–555, 2013.
[78]
T. Pang, “Genomics for public health improvement: relevant international ethical and policy issues around genome-wide association studies and biobanks,” Public Health Genomics, vol. 16, no. 1-2, pp. 69–72, 2013.
[79]
E. R. Mardis, “Next-generation sequencing platforms,” Annual Review of Analytical Chemistry, vol. 6, pp. 287–303, 2013.
[80]
B. Dan and P. Baxter, “Paediatric neurology: a year of DNA technology,” Lancet Neurology, vol. 13, pp. 16–18, 2014.
[81]
V. G. Sankaran and P. G. Gallagher, “Applications of high-throughput DNA sequencing to benign hematology,” Blood, vol. 122, pp. 3575–3582, 2013.
[82]
Y. Yang, R. Liu, H. Xie et al., “Advances in nanopore sequencing technology,” Journal of Nanoscience and Nanotechnology, vol. 13, no. 7, pp. 4521–4538, 2013.
[83]
R. Normand and I. Yanai, “An introduction to high-throughput sequencing experiments: design and bioinformatics analysis,” Methods in Molecular Biology, vol. 1038, pp. 1–26, 2013.
[84]
F. S. Ong, J. C. Lin, K. Das, D. S. Grosu, and J.-B. Fan, “Translational utility of next-generation sequencing,” Genomics, vol. 102, no. 3, pp. 137–139, 2013.
[85]
M. Levy-Sakin and Y. Ebenstein, “Beyond sequencing: optical mapping of DNA in the age of nanotechnology and nanoscopy,” Current Opinion in Biotechnology, vol. 24, no. 4, pp. 690–698, 2013.
[86]
J. F. Thompson and J. S. Oliver, “Mapping and sequencing DNA using nanopores and nanodetectors,” Electrophoresis, vol. 33, no. 23, pp. 3429–3436, 2012.
[87]
B. Merriman, I. Torrent, and J. M. Rothberg, “Progress in ion torrent semiconductor chip based sequencing,” Electrophoresis, vol. 33, no. 23, pp. 3397–3417, 2012.
[88]
M. Tuna and C. I. Amos, “Genomic sequencing in cancer,” Cancer Letters, vol. 340, pp. 161–170, 2013.
[89]
S. Fox, S. Filichkin, and T. C. Mockler, “Applications of ultra-high-throughput sequencing,” Methods in Molecular Biology, vol. 553, pp. 79–108, 2009.
[90]
Y. Bromberg, “Building a Genome Analysis Pipeline to Predict Disease Risk and Prevent Disease,” Journal of Molecular Biology, vol. 425, pp. 3993–4005, 2013.
[91]
J. M. Johnsen, D. A. Nickerson, and A. P. Reiner, “Massively parallel sequencing: the new frontier of hematologic genomics,” Blood, vol. 122, pp. 3268–3275, 2013.
[92]
D. C. Koboldt, K. M. Steinberg, D. E. Larson, R. K. Wilson, and E. R. Mardis, “The next-generation sequencing revolution and its impact on genomics,” Cell, vol. 155, pp. 27–38, 2013.
[93]
I. R. Watson, K. Takahashi, P. A. Futreal, and L. Chin, “Emerging patterns of somatic mutations in cancer,” Nature Reviews Genetics, vol. 14, pp. 703–718, 2013.
[94]
L. Wang and D. A. Wheeler, “Genomic sequencing for cancer diagnosis and therapy,” Annual Review of Medicine, vol. 65, pp. 33–48, 2014.
[95]
Y. R. Li, J. E. Levine, H. Hakonarson, and B. J. Keating, “Making the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation,” European Journal of Human Genetics, vol. 22, pp. 715–723, 2014.
[96]
K. Davies, “The era of genomic medicine,” Clinical Medicine, vol. 13, pp. 594–601, 2013.
[97]
E. K. Bancroft, “How advances in genomics are changing patient care,” The Nursing Clinics of North America, vol. 48, pp. 557–569, 2013.
[98]
F. B. de Abreu, W. A. Wells, and G. J. Tsongalis, “The emerging role of the molecular diagnostics laboratory in breast cancer personalized medicine,” The American Journal of Pathology, vol. 183, pp. 1075–1083, 2013.
[99]
L. G. Biesecker, “Hypothesis-generating research and predictive medicine,” Genome Research, vol. 23, no. 7, pp. 1051–1053, 2013.
[100]
S. Kamalakaran, V. Varadan, A. Janevski et al., “Translating next generation sequencing to practice: opportunities and necessary steps,” Molecular Oncology, vol. 7, no. 4, pp. 743–755, 2013.
[101]
J. J. McCarthy, H. L. McLeod, and G. S. Ginsburg, “Genomic medicine: a decade of successes, challenges, and opportunities,” Science Translational Medicine, vol. 5, no. 189, p. 189sr4, 2013.
[102]
R. Simon and S. Roychowdhury, “Implementing personalized cancer genomics in clinical trials,” Nature Reviews Drug Discovery, vol. 12, no. 5, pp. 358–369, 2013.
[103]
L. A. Garraway, “Genomics-driven oncology: framework for an emerging paradigm,” Journal of Clinical Oncology, vol. 31, no. 15, pp. 1806–1814, 2013.
[104]
S. Tsuji, “The neurogenomics view of neurological diseases,” JAMA Neurology, vol. 70, no. 6, pp. 689–694, 2013.
[105]
M. J. Annala, B. C. Parker, W. Zhang, and M. Nykter, “Fusion genes and their discovery using high throughput sequencing,” Cancer Letters, vol. 340, pp. 192–200, 2013.
[106]
R. R. Gullapalli, K. V. Desai, L. Santana-Santos, J. A. Kant, and M. J. Becich, “Next generation sequencing in clinical medicine: challenges and lessons for pathology and biomedical informatics,” Journal of Pathology Informatics, vol. 3, article 40, 2012.
[107]
C. Brander and F. M. Marincola, “AAAS joins the Translational Medicine family,” Journal of Translational Medicine, vol. 7, article 32, 2009.
[108]
X. Chen, R. Andersson, W. C. Cho et al., “The international effort: building the bridge for translational medicine: report of the 1st International Conference of Translational Medicine (ICTM),” Clinical and Translational Medicine, vol. 1, no. 1, article 15, 2012.
[109]
J. A. DiMasi, R. W. Hansen, H. G. Grabowski, and L. Lasagna, “Cost of innovation in the pharmaceutical industry,” Journal of Health Economics, vol. 10, no. 2, pp. 107–142, 1991.
[110]
J. A. DiMasi, R. W. Hansen, and H. G. Grabowski, “The price of innovation: new estimates of drug development costs,” Journal of Health Economics, vol. 22, no. 2, pp. 151–185, 2003.
[111]
M. E. Hughes, J. Peeler, and J. B. Hogenesch, “Network dynamics to evaluate performance of an academic institution,” Science Translational Medicine, vol. 2, no. 53, Article ID 53ps49, 2010.
[112]
M. Qian, D. Wu, E. Wang et al., “Development and promotion in translational medicine: perspectives from 2012 sino-american symposium on clinical and translational medicine,” Clinical and Translational Medicine, vol. 1, article 25, 2012.
[113]
A. Cambrosio, P. Keating, S. Mercier, G. Lewison, and A. Mogoutov, “Mapping the emergence and development of translational cancer research,” European Journal of Cancer, vol. 42, no. 18, pp. 3140–3148, 2006.
[114]
A. Rajan, R. Sullivan, S. Bakker, and W. H. van Harten, “Critical appraisal of translational research models for suitability in performance assessment of cancer centers,” The Oncologist, vol. 17, no. 12, pp. e48–e57, 2012.
[115]
W. Trochim, C. Kane, M. J. Graham, and H. A. Pincus, “Evaluating translational research: a process marker model,” Clinical and Translational Science, vol. 4, no. 3, pp. 153–162, 2011.
[116]
E. A. Zerhouni, “Space for the cures: science launches a new journal dedicated to translational research in biomedicine,” Science Translational Medicine, vol. 1, no. 1, p. 1ed1, 2009.
[117]
E. G. Nabel, “On board with the cures acceleration network,” Science Translational Medicine, vol. 2, no. 32, p. 32ed2, 2010.
[118]
H. J. Falk-Krzesinski, K. B？rner, N. Contractor et al., “Advancing the science of team science,” Clinical and Translational Science, vol. 3, no. 5, pp. 263–266, 2010.
[119]
K. B？rner, N. Contractor, H. J. Falk-Krzesinski et al., “A multi-level systems perspective for the science of team science,” Science Translational Medicine, vol. 2, no. 49, p. 49cm24, 2010.
[120]
D. C. Mowery, B. N. Sampat, and A. A. Ziedonis, “Learning to patent: institutional experience, learning, and the characteristics of U.S. University patents after the Bayh-Dole Act, 1981–1992,” Management Science, vol. 48, no. 1, pp. 73–89, 2002.
[121]
V. Loise and A. J. Stevens, “The Bayh-Dole act turns 30,” Science Translational Medicine, vol. 2, no. 52, p. 52cm27, 2010.
[122]
A. Colaianni and R. Cook-Deegan, “Columbia university's axel patents: technology transfer and implications for the Bayh-Dole Act,” Milbank Quarterly, vol. 87, no. 3, pp. 683–715, 2009.
[123]
R. Dalton, “Berkeley's energy deal with BP sparks unease,” Nature, vol. 445, no. 7129, pp. 688–689, 2007.
[124]
R. Jensen and M. Thursby, “Proofs and prototypes for sale: the licensing of University inventions,” The American Economic Review, vol. 91, no. 1, pp. 240–259, 2001.
[125]
S. A. Mian, “US university-sponsored technology incubators: an overview of management, policies and performance,” Technovation, vol. 14, no. 8, pp. 515–528, 1994.
[126]
N. R. Council, Managing University Intellectual Property in the Public Interest, The National Academies Press, Washington, DC, USA, 2010.
[127]
R. G. Phillips, “Technology business incubators: how effective as technology transfer mechanisms?” Technology in Society, vol. 24, no. 3, pp. 299–316, 2002.
[128]
J. Gertner, The Idea Factory: Bell Labs and the Great Age of American Innovation, Penguin, New York, NY, USA, 2012.
[129]
M. Riordan and L. Hoddeson, Crystal Fire: the Invention of the Transistor and Birth of the Information Age, WW Norton, New York, NY, USA, 1998.
[130]
W. F. Brinkman, D. E. Haggan, and W. W. Troutman, “A history of the invention of the transistor and where it will lead us,” IEEE Journal of Solid-State Circuits, vol. 32, no. 12, pp. 1858–1864, 1997.
[131]
S. J. Steele, “Working with the CTSA consortium: what we bring to the table,” Science Translational Medicine, vol. 2, no. 63, p. 63mr5, 2010.
[132]
J. G. Thursby and M. C. Thursby, “Intellectual property. University licensing and the Bayh-Dole Act,” Science, vol. 301, no. 5636, p. 1052, 2003.
[133]
D. Blumenthal, E. G. Campbell, N. Causino, and K. S. Louis, “Participation of life science faculty in research relationships with industry,” The New England Journal of Medicine, vol. 335, no. 23, pp. 1734–1739, 1996.
[134]
R. Fini, N. Lacetera, and S. Shane, “Inside or outside the IP system? Business creation in academia,” Research Policy, vol. 39, no. 8, pp. 1060–1069, 2010.
[135]
R. A. Lowe and C. Gonzalez-Brambila, “Faculty entrepreneurs and research productivity,” Journal of Technology Transfer, vol. 32, no. 3, pp. 173–194, 2007.
[136]
A. Aneja, R. Esquitin, K. Shah et al., “Authors' self-declared financial conflicts of interest do not impact the results of major cardiovascular trials,” Journal of the American College of Cardiology, vol. 61, pp. 1137–1143, 2013.
[137]
S. V. Sharma, D. A. Haber, and J. Settleman, “Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents,” Nature Reviews Cancer, vol. 10, no. 4, pp. 241–253, 2010.
[138]
J. Mattern, M. Bak, E. W. Hahn, and M. Volm, “Human tumor xenografts as model for drug testing,” Cancer Metastasis Reviews, vol. 7, no. 3, pp. 263–284, 1988.
[139]
J. N. Weinstein, “Drug discovery: cell lines battle cancer,” Nature, vol. 483, no. 7391, pp. 544–545, 2012.
[140]
R. H. Shoemaker, “The NCI60 human tumour cell line anticancer drug screen,” Nature Reviews Cancer, vol. 6, no. 10, pp. 813–823, 2006.
[141]
U. McDermott, S. V. Sharma, and J. Settleman, “High-throughput lung cancer cell line screening for genotype-correlated sensitivity to an EGFR kinase inhibitor,” Methods in Enzymology, vol. 438, pp. 331–341, 2008.
[142]
J. Barretina, G. Caponigro, N. Stransky et al., “Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity,” Nature, vol. 483, pp. 603–607, 2012.
[143]
G. Kari, U. Rodeck, and A. P. Dicker, “Zebrafish: an emerging model system for human disease and drug discovery,” Clinical Pharmacology and Therapeutics, vol. 82, no. 1, pp. 70–80, 2007.
[144]
C. Chakraborty, C. H. Hsu, Z. H. Wen, C. S. Lin, and G. Agoramoorthy, “Zebrafish: a complete animal model for in vivo drug discovery and development,” Current Drug Metabolism, vol. 10, no. 2, pp. 116–124, 2009.
[145]
S. B. Hedges, “The origin and evolution of model organisms,” Nature Reviews Genetics, vol. 3, no. 11, pp. 838–849, 2002.
[146]
M. Jucker, “The benefits and limitations of animal models for translational research in neurodegenerative diseases,” Nature Medicine, vol. 16, no. 11, pp. 1210–1214, 2010.
[147]
C. G. Begley and L. M. Ellis, “Drug development: raise standards for preclinical cancer research,” Nature, vol. 483, no. 7391, pp. 531–533, 2012.
[148]
D. Alishekevitz, R. Bril, D. Loven et al., “Differential therapeutic effects of anti-VEGF-A antibody in different tumor models: implications for choosing appropriate tumor models for drug testing,” Molecular Cancer Therapeutics, vol. 13, pp. 202–213, 2014.
[149]
J.-P. Gillet, S. Varma, and M. M. Gottesman, “The clinical relevance of cancer cell lines,” Journal of the National Cancer Institute, vol. 105, no. 7, pp. 452–458, 2013.
[150]
A. F. Gazdar, B. Gao, and J. D. Minna, “Lung cancer cell lines: useless artifacts or invaluable tools for medical science?” Lung Cancer, vol. 68, no. 3, pp. 309–318, 2010.
[151]
A. F. Gazdar, L. Girard, W. W. Lockwood, W. L. Lam, and J. D. Minna, “Lung cancer cell lines as tools for biomedical discovery and research,” Journal of the National Cancer Institute, vol. 102, no. 17, pp. 1310–1321, 2010.
[152]
J. Gandhi, J. Zhang, Y. Xie et al., “Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines,” PLoS ONE, vol. 4, no. 2, Article ID e4576, 2009.
[153]
J. L. Wilding and W. F. Bodmer, “Cancer cell lines for drug discovery and development,” Cancer Research, vol. 74, pp. 2377–2384, 2014.
[154]
J. Heyer, L. N. Kwong, S. W. Lowe, and L. Chin, “Non-germline genetically engineered mouse models for translational cancer research,” Nature Reviews Cancer, vol. 10, no. 7, pp. 470–480, 2010.
[155]
K. Garber, “From human to mouse and back: “tumorgraft” models surge in popularity,” Journal of the National Cancer Institute, vol. 101, no. 1, pp. 6–8, 2009.
[156]
S. Rottenberg and P. Borst, “Drug resistance in the mouse cancer clinic,” Drug Resistance Updates, vol. 15, no. 1-2, pp. 81–89, 2012.
[157]
H. C. Denroche, W. L. Quong, J. E. Bruin et al., “Leptin administration enhances islet transplant performance in diabetic mice,” Diabetes, vol. 62, pp. 2738–2746, 2013.
[158]
H. Dong, H. Huang, X. Yun et al., “Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation,” Endocrinology, vol. 155, no. 3, pp. 818–828, 2014.
[159]
U. H. Neumann, S. Chen, Y. Y. Tam et al., “IGFBP2 is neither sufficient nor necessary for the physiological actions of leptin on glucose homeostasis in male ob/ob mice,” Endocrinology, vol. 155, no. 3, pp. 16–25, 2014.
[160]
H. J. Do, T. Jin, J. H. Chung, J. W. Hwang, and M. J. Shin, “Voglibose administration regulates body weight and energy intake in high fat-induced obese mice,” Biochemical and Biophysical Research Communications, vol. 443, pp. 1110–1117, 2014.
[161]
C. E. Koch, C. Lowe, D. Pretz, J. Steger, L. M. Williams, and A. Tups, “High fat diet induces leptin resistance,” Journal of Neuroendocrinology, vol. 28, no. 2, pp. 58–67, 2013.
[162]
K. M. Gamber, L. Huo, S. Ha, J. E. Hairston, S. Greeley, and C. Bj？rb？k, “Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity,” PLoS ONE, vol. 7, no. 1, Article ID e30485, 2012.
[163]
C. Clemmensen, J. Chabenne, B. Finan et al., “GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet,” Diabetes, vol. 63, no. 4, pp. 1422–1427, 2014.
[164]
T. Roszer, T. Jozsa, E. D. Kiss-Toth, N. de Clerck, and L. Balogh, “Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration,” Cell and Tissue Research, vol. 356, no. 1, pp. 195–206, 2013.
[165]
R. Guzman-Ruiz, N. Gomez-Hurtado, M. Gil-Ortega et al., “Remodeling of energy metabolism and absence of electrophysiological changes in the heart of obese hyperleptinemic mice. New insights into the pleiotropic role of leptin,” Frontiers in Endocrinology, vol. 4, article 175, 2013.
[166]
J. Benzler, Z. B. Andrews, C. Pracht et al., “Hypothalamic WNT signalling is impaired during obesity and reinstated by leptin treatment in male mice,” Endocrinology, vol. 154, pp. 4737–4745, 2013.
[167]
L. Zabeau, F. Peelman, and J. Tavernier, “Antagonising leptin: current status and future directions,” Biological Chemistry, vol. 395, no. 5, pp. 499–514, 2014.
[168]
P. D. Taylor, A. M. Samuelsson, and L. Poston, “Maternal obesity and the developmental programming of hypertension: a role for leptin,” Acta Physiologica, vol. 210, no. 3, pp. 508–523, 2014.
[169]
M. D. Klok, S. Jakobsdottir, and M. L. Drent, “The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review,” Obesity Reviews, vol. 8, no. 1, pp. 21–34, 2007.
[170]
J. Grasman, “Reconstruction of the drive underlying food intake and its control by leptin and dieting,” PloS ONE, vol. 8, Article ID e74997, 2013.
[171]
R. Muniyappa, R. J. Brown, A. Mari et al., “Effects of leptin replacement therapy on pancreatic beta-cell function in patients with lipodystrophy,” Diabetes Care, vol. 37, no. 4, pp. 1101–1107, 2014.
[172]
R. Z. Tom, P. M. Garcia-Roves, R. J. Sjogren et al., “Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice,” Diabetes, vol. 63, no. 5, pp. 1560–1571, 2014.
[173]
N. Chapnik, Y. Genzer, A. Ben-Shimon, M. Y. Niv, and O. Froy, “AMPK-derived peptides reduce blood glucose but lead to fat retention in the liver of obese mice,” The Journal of Endocrinology, vol. 221, no. 1, pp. 89–99, 2014.
[174]
E. Tuduri, H. C. Denroche, J. A. Kara, A. Asadi, J. K. Fox, and T. J. Kieffer, “Partial ablation of leptin signaling in mouse pancreatic alpha-cells does not alter either glucose or lipid homeostasis,” American Journal of Physiology Endocrinology and Metabolism, vol. 306, no. 7, pp. E748–E755, 2014.
[175]
H. C. Denroche, J. Levi, R. D. Wideman et al., “Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling,” Diabetes, vol. 60, no. 5, pp. 1414–1423, 2011.
[176]
J. P. A. Ioannidis, “Contradicted and initially stronger effects in highly cited clinical research,” Journal of the American Medical Association, vol. 294, no. 2, pp. 218–228, 2005.
[177]
M. Wadman, “NIH mulls rules for validating key results,” Nature, vol. 500, pp. 14–16, 2013.
[178]
K. K. Tsilidis, O. A. Panagiotou, E. S. Sena et al., “Evaluation of excess significance bias in animal studies of neurological diseases,” PLoS Biology, vol. 11, no. 7, Article ID e1001609, 2013.
[179]
F. S. Collins and L. A. Tabak, “Policy: NIH plans to enhance reproducibility,” Nature, vol. 505, pp. 612–613, 2014.
[180]
Y. Huang and R. Gottardo, “Comparability and reproducibility of biomedical data,” Briefings in Bioinformatics, vol. 14, pp. 391–401, 2013.
[181]
J. Couzin-Frankel, “When mice mislead,” Science, vol. 342, pp. 922–925, 2013.
[182]
R. J. Traystman and P. S. Herson, “Misleading results: translational challenges,” Science, vol. 343, pp. 369–370, 2014.
M. Bissell, “Reproducibility: the risks of the replication drive,” Nature, vol. 503, pp. 333–334, 2013.
[185]
J. P. A. Ioannidis, “Why most published research findings are false,” PLoS Medicine, vol. 2, no. 8, Article ID e124, 2005.
[186]
B. ] Alberts, M. W. Kirschner, S. Tilghman, and H. Varmus, “Rescuing US biomedical research from its systemic flaws,” Proceedings of the National Academy of Sciences, vol. 111, pp. 5773–5777, 2014.
[187]
F. M. Marincola, “Translational medicine: a two-way road,” Journal of Translational Medicine, vol. 1, article 1, 2003.
[188]
S. K. Chatterjee and M. L. Rohrbaugh, “NIH inventions translate into drugs and biologics with high public health impact,” Nature Biotechnology, vol. 32, pp. 52–58, 2014.
[189]
S. Khot, B. Soon Park, and W. T. Longstreth Jr., “The vietnam war and medical research: untold legacy of the U.S. doctor draft and the NIH “yellow berets”,” Academic Medicine, vol. 86, no. 4, pp. 502–508, 2011.
[190]
M. M. Gottesman, “The role of the NIH in nurturing clinician-scientists,” The New England Journal of Medicine, vol. 368, no. 24, pp. 2249–2251, 2013.
[191]
S. Broder, “Twenty-five years of translational medicine in antiretroviral therapy: promises to keep,” Science Translational Medicine, vol. 2, no. 39, p. 39ps33, 2010.
[192]
K. Lewis, “Platforms for antibiotic discovery,” Nature Reviews Drug Discovery, vol. 12, no. 5, pp. 371–387, 2013.
