The First Cell

by Azra Raza

Scannell, J. W., et al. “Diagnosing the Decline in Pharmaceutical R&D Efficiency.” Nature Reviews Drug Discovery 11 (2012): 191–200.

  Chandrasekar, Thenappan. “Why Are We Losing the War on Cancer?” 2018 European Society for Medical Oncology Congress (#ESMO18), October 19–23, 2018, Munich, Germany. www.urotoday.com/conference-highlights/esmo-2018/esmo-2018-prostate-cancer/107789-esmo-2018-why-we-are-losing-the-war-on-cancer.html.

  Ehrenreich, Barbara. Bright-Sided: How the Relentless Promotion of Positive Thinking Has Undermined America. New York: Metropolitan Books, 2009.

  Baldwin, James. “Letter from a Region in My Mind.” New Yorker, November 9, 1962.

  Döhne, Hartmut, et al. “Diagnosis and Management of AML in Adults: 2017 ELN Recommendations from an International Expert Panel.” Blood 129 (2017): 424–447.

  LeBlanc, Thomas W., and Harry P. Erba. “Shifting Paradigms in the Treatment of Older Adults with AML.” Seminars in Hematology 56, no. 2 (2019): 110–117.

  Goldman, J. M. “Chronic Myeloid Leukemia: A Historical Perspective.” Seminars in Hematology 47, no. 4 (2010): 302–311.

  Lo-Coco, Francesco, and Laura Cicconi. “History of Acute Promyelocytic Leukemia: A Tale of Endless Revolution.” Mediterranean Journal of Hematology and Infectious Diseases 3, no. 1 (2011): e2011067. doi:10.4084/MJHID.2011.067.

  Mak, I. W., N. Evaniew, and M. Ghert. “Lost in Translation: Animal Models and Clinical Trials in Cancer Treatment.” American Journal of Translational Research 6, no. 2 (2014): 114–118.

  Wong, Chi Heem, Kien Wei Siah, and Andrew W. Lo. “Estimation of Clinical Trial Success Rates and Related Parameters.” Biostatistics 20, no. 2 (2019): 273–286. https://doi.org/10.1093/biostatistics/kxx069.

  Lowe, Derek. “A New Look at Clinical Success Rates.” Science Translational Medicine, February 2, 2018. https://blogs.sciencemag.org/pipeline/archives/2018/02/02/a-new-look-at-clinical-success-rates.

  Nixon, N. A. “Drug Development for Breast, Colorectal, and Non–Small Cell Lung Cancers from 1979 to 2014.” Cancer 123, no. 23 (2017): 4672. www.nature.com/articles/nrd1470.

  Hay, M., D. W. Thomas, J. L. Craighead, C. Economides, and J. Rosenthal. “Clinical Development Success Rates for Investigational Drugs.” Nature Biotechnology 32 (2014): 40–51.

  “95% of Promising Cancer Research Fails.” Dying for a Cure, July 10, 2016. http://dyingforacure.org/blogs/95-promising-cancer-research-fails/.

  Davis, C., et al. “Availability of Evidence of Benefits on Overall Survival and Quality of Life of Cancer Drugs Approved by European Medicines Agency: Retrospective Cohort Study of Drug Approvals 2009–13.” BMJ (2017): 359. https://doi.org/10.1136/bmj.j4530.

  Kola, I., and J. Landis. “Can the Pharmaceutical Industry Reduce Attrition Rates?” Nature Reviews Drug Discovery 3 (2004): 711–716. www.bmj.com/ content/359/bmj.j4530?_ga=2.220433373.434514445.1555067451-1576958994.1555067451; https://www.nature.com/articles/nrd1470.

  Hay, M., et al. “Clinical Development Success Rates for Investigational Drugs.” Nature Biotechnology 32, no. 1 (2014): 40–51.

  Thomas, D. W., et al. Clinical Development Success Rates, 2006–2015. www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates %202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf.

  Siegel, R. L., et al. “Cancer Statistics 2018.” CA 68, no. 1 (2018): 7–30.

  Siegel, R. L., et al. “Cancer Statistics 2019.” CA 69, no. 1 (2019): 7–34.

  “Cancer Death Rates Vary Greatly Among US Counties.” American Cancer Society. www.cancer.org/latest-news/cancer-death-rates-vary-greatly-among-us-counties.html.

  Mokdad, A. H., et al. “Trends and Patterns of Disparities in Cancer Mortality Among US Counties, 1980–2014.” JAMA 317, no. 4 (2017): 388–406. doi:10.1001/jama.2016.20324.

  Maeda, Hiroshi, and Mahin Khatami. “Analyses of Repeated Failures in Cancer Therapy for Solid Tumors: Poor Tumor-Selective Drug Delivery, Low Therapeutic Efficacy and Unsustainable Costs.” Clinical and Translational Medicine 7, no. 1 (2018): 11.

  Fojo, T., and C. Grady. “How Much Is Life Worth: Cetuximab, Non–Small Cell Lung Cancer, and the $440 Billion Question.” Journal of the National Cancer Institute 101, no. 15 (2009): 1044–1049.

  Kantarjian, Hagop M., et al. “Cancer Research in the United States: A Critical Review of Current Status and Proposal for Alternative Models.” Cancer 124, no. 14 (2018): 2881–2889.

  Carrera, P. M., et al. “The Financial Burden and Distress of Patients with Cancer: Understanding and Stepping-Up Action on the Financial Toxicity of Cancer Treatment.” CA, January 16, 2018. https://doi.org/10.3322/caac.21443.

  Fojo, T., et al. “Unintended Consequences of Expensive Cancer Therapeutics—The Pursuit of Marginal Indications and a Me-Too Mentality That Stifles Innovation and Creativity: The John Conley Lecture.” JAMA Otolaryngology—Head & Neck Surgery 140, no. 12 (2014): 1225–1236.

  Krummel, M. F., and J. P. Allison. “CD28 and CTLA-4 Have Opposing Effects on the Response of T Cells to Stimulation.” Journal of Experimental Medicine 182, no. 2 (1995): 459–465.

  Davis, Daniel M. “The Rise of Cancer Immunotherapy: How Jim Allison Saved a Whole World.” Nautilus, October 25, 2018.

  Hutchinson, Lisa, and Rebecca Kirk. “High Drug Attrition Rates—Where Are We Going Wrong?” Nature Reviews Clinical Oncology 8, no. 4 (2011): 189–190.

  Begley, G. C., and L. M. Ellis. “Raise Standards for Preclinical Cancer Research.” Nature 483 (2012): 531–533.

  Johnson, George. The Cancer Chronicles: Unlocking Medicine’s Deepest Mystery. New York: Alfred A. Knopf, 2013.

  Yong, Ed. “How to Fight Cancer When Cancer Fights Back.” Atlantic, April 26, 2017.

  Gilligan, A. M. “Death or Debt? National Estimates of Financial Toxicity in Persons with Newly-Diagnosed Cancer.” American Journal of Medicine 131, no. 10 (2018): 1187–1199.

  Baker, Monya. “1,500 Scientists Lift the Lid on Reproducibility: Survey Sheds Light on the ‘Crisis’ Rocking Research.” Nature, May 25, 2016.

  Cohen, J. D., et al. “Combined Circulating Tumor DNA and Protein Biomarker-Based Liquid Biopsy for the Earlier Detection of Pancreatic Cancers.” Proceedings of the National Academy of Sciences of the United States of America 114, no. 38 (2017): 10202–10207.

  Wang, Y., et al. “Detection of Tumor-Derived DNA in Cerebrospinal Fluid of Patients with Primary Tumors of the Brain and Spinal Cord.” Proceedings of the National Academy of Sciences of the United States of America 112, no. 31 (2015): 9704–9709.

  Bettegowda, C. “Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies.” Science Translational Medicine 6, no. 224 (2014): 224ra24.

  Vogelstein, Bert, Nickolas Papadopoulos, Victor E. Velculescu, Shibin Zhou, Luis A. Diaz, Jr., and Kenneth W. Kinzler. “Cancer Genome Landscapes.” Science 339, no. 6127 (2013): 1546–1558.

  “At the Forefront of Cancer Genetics, Bert Vogelstein, MD, Calls for Focus on Early Detection and Prevention.” ASCO Post, June 3, 2017. www.ascopost.com/issues/june-3-2017-narratives-special-issue/at-the-forefront-of-cancer-genetics-bert-vogelstein-md-calls-for-focus-on-early-detection-and-prevention/.

  DeVita, Vincent T., Jr., and Elizabeth DeVita-Raeburn. The Death of Cancer. New York: Sarah Crichton Books, 2015.

  Ehrenreich, Barbara. Natural Causes: An Epidemic of Wellness, the Certainty of Dying, and Killing Ourselves to Live Longer. New York: Twelve, 2018.

  CHAPTER 1: OMAR

  Sullivan, Thomas. “A Tough Road: Cost to Develop One New Drug Is $2.6 Billion; Approval Rate for Drugs Entering Clinical Development Is Less Than 12%.” Policy and Medicine. www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html.

  DiMasi, J., et al. “Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs.” Journal of Health Economics 47 (2016): 20–33.

  Wong, Chi Heem, Kien Wei Siah, and Andrew W. Lo. “Estimation of Clinical Trial Success Rates and Related Parameters.” Biostati
stics 20, no. 2 (2019): 273–286. https://doi.org/10.1093/biostatistics/kxx069.

  Kim, Chul, and Vinay Prasad. “Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival.” JAMA Internal Medicine 175, no. 12 (2015): 1992–1994.

  Maeda, Hiroshi, and Mahin Khatami. “Analyses of Repeated Failures in Cancer Therapy for Solid Tumors: Poor Tumor-Selective Drug Delivery, Low Therapeutic Efficacy and Unsustainable Costs.” Clinical and Translational Medicine 7, no. 1 (2018): 11.

  Kumar, Hemanth, Tito Fojo, and Sham Mailankody. “An Appraisal of Clinically Meaningful Outcomes Guidelines for Oncology Clinical Trials.” JAMA Oncology 2, no. 9 (2016): 1238–1240.

  Thomas, D. W., et al. Clinical Development Success Rates, 2006–2015. www.bio.org/sites/default/files/Clinical%20Development%20Success%20 Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion %202016.pdf.

  Philippidis, Alex. “Unlucky 13: Top Clinical Trial Failures in 2017.” Genetic Engineering & Biotechnology News. www.genengnews.com/a-lists/unlucky-13-top-clinical-trial-failures-of-2017/.

  Szabo, Liz. “Dozens of New Cancer Drugs Do Little to Improve Survival, Frustrating Patients.” https://khn.org/news/dozens-of-new-cancer-drugs-do--little-to-improve-survival-frustrating-patients/.

  Rupp, Tracy, and Diana Zuckerman. “Quality of Life, Overall Survival, and Costs of Cancer Drugs Approved Based on Surrogate Endpoints.” JAMA Internal Medicine 177, no. 2 (2017): 276–277. doi:10.1001/jamainternmed.2016.7761.

  Davis, C., C. Naci, E. Gurpinar, et al. “Availability of Evidence on Overall Survival and Quality of Life Benefits of Cancer Drugs Approved by the European Medicines Agency: Retrospective Cohort Study of Drug Approvals from 2009–2013.” BMJ (2017): 359.

  Hall, Stephen S. A Commotion in the Blood: Life, Death, and the Immune System. New York: Henry Holt, 1997.

  Sandomir, Richard. “Julie Yip-Williams, Writer of Candid Blog on Cancer, Dies at 42.” New York Times, March 22, 2018. www.nytimes.com/2018/03/22/obituaries/julie-yip-williams-dies-writer-of-candid-blog-on-cancer.html.

  Yip-Williams, Julie. The Unwinding of the Miracle: A Memoir of Life, Death, and Everything That Comes After. New York: Random House, 2019.

  Carrel, Alexis. “On the Permanent Life of Tissues Outside of the Organism.” Journal of Experimental Medicine 15, no. 5 (1912): 516–528.

  Friedman, David M. The Immortalists: Charles Lindbergh, Dr. Alexis Carrel, and Their Daring Quest to Live Forever. New York: Ecco/HarperCollins, 2007.

  Hayflick, L. “Mortality and Immortality at the Cellular Level: A Review.” Biochemistry (Moscow) 62, no. 11 (1997): 1180–1190.

  Hayflick, L. “The Limited In Vitro Lifetime of Human Diploid Cell Strains.” Experimental Cell Research 37, no. 3 (1965): 614–636.

  Scherer, W. F., J. T. Syverton, and G. O. Gey. “Studies on the Propagation In Vitro of Poliomyelitis Viruses, IV: Viral Multiplication in a Stable Strain of Human Malignant Epithelial Cells (Strain HeLa) Derived from an Epidermoid Carcinoma of the Cervix.” Journal of Experimental Medicine 97, no. 5 (1953): 695–710.

  Macville, M., E. Schröck, H. Padilla-Nash, C. Keck, B. M. Ghadimi, D. Zimonjic, N. Popescu, and T. Ried. “Comprehensive and Definitive Molecular Cytogenetic Characterization of HeLa Cells by Spectral Karyotyping.” Cancer Research 59, no. 1 (1999): 141–150.

  Landry J. J., P. T. Pyl, T. Rausch, T. Zichner, M. M. Tekkedil, A. M. Stütz, A. Jauch, R. S. Aiyar, G. Pau, N. Delhomme, J. Gagneur, J. O. Korbel, W. Huber, and L. M. Steinmetz. “The Genomic and Transcriptomic Landscape of a HeLa Cell Line.” G3: Genes, Genomes, Genetics 3, no. 8 (2013): 1213–1224.

  Skloot, Rebecca. The Immortal Life of Henrietta Lacks. New York: Crown/Random House, 2010.

  Ben-David, U., et al. “Genetic and Transcriptional Evolution Alters Cancer Cell Line Drug Response.” Nature 560 (2018): 325–330.

  Gillet, Jean-Pierre, Sudhir Varma, and Michael M. Gottesman. “The Clinical Relevance of Cancer Cell Lines.” Journal of the National Cancer Institute 105, no. 7 (2013): 452–458.

  Capes-Davis, A., G. Theodosopoulos, I. Atkin, H. G. Drexler, A. Kohara, R. A. MacLeod, J. R. Masters, Y. Nakamura, Y. A. Reid, R. R. Reddel, and R. I. Freshney. “Check Your Cultures! A List of Cross-Contaminated or Misidentified Cell Lines.” International Journal of Cancer 127, no. 1 (2010): 1–8.

  Wilding, Jennifer L., and Walter F. Bodmer. “Cancer Cell Lines for Drug Discovery and Development.” Cancer Research (2014). doi:10.1158/0008-5472.CAN-13-2971.

  Kolata, Gina. “Hope in the Lab: A Special Report—A Cautious Awe Greets Drugs That Eradicate Tumors in Mice.” New York Times, May 3, 1998.

  “EntreMed Stock Rides Wave of Optimism About 2 Drugs.” Los Angeles Times, May 5, 1998. www.latimes.com/archives/la-xpm-1998-may-05-fi-46397-story.html.

  “Background on the History of the Mouse.” National Human Genome Research Institute. December 2002. www.genome.gov/10005832/background-on-the-history-of-the-mouse/.

  Ericsson, Aaron C., Marcus J. Crim, and Craig L. Franklin. “A Brief History of Animal Modeling.” Missouri Medicine 110, no. 3 (2013): 201–205.

  Pound, P., S. Ebrahim, P. Sandercock, M. B. Bracken, I. Roberts, and Reviewing Animal Trials Systematically (RATS) Group. “Where Is the Evidence That Animal Research Benefits Humans?” BMJ 328, no. 7438 (2004): 514–517.

  Talmadge, J. E., et al. “Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer.” American Journal of Pathology 170, no. 3 (2007): 793–804.

  Perlman, R. L. “Mouse Models of Human Disease.” Evolution, Medicine and Public Health 2016, no. 1 (2016): 170–176.

  Eruslanov, Evgeniy B., Sunil Singhal, and Steven Albelda. “Mouse Versus Human Neutrophils in Cancer—A Major Knowledge Gap.” Trends in Cancer 3, no. 2 (2017): 149–160.

  Day, C. P., G. Merlino, and T. Van Dyke. “Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges.” Cell 163, no. 1 (2015): 39–53.

  Shoemaker, R. H., A. Monks, M. C. Alley, D. A. Scudiero, D. L. Fine, T. L. McLemore, B. J. Abbott, K. D. Paull, J. G. Mayo, and M. R. Boyd. “Development of Human Tumor Cell Line Panels for Use in Disease-Oriented Drug Screening.” Progress in Clinical and Biological Research 276 (1988): 265–286.

  Monks, A., D. Scudiero, P. Skehan, R. Shoemaker, K. Paull, D. Vistica, C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff, et al. “Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines.” Journal of the National Cancer Institute 83 (1991): 757–766.

  Monks, A., D. A. Scudiero, G. S. Johnson, K. D. Paull, and E. A. Sausville. “The NCI Anti-Cancer Drug Screen: A Smart Screen to Identify Effectors of Novel Targets.” Anti-Cancer Drug Design 12 (1997): 533–541.

  Grever, M. R., S. A. Schepartz, and B. A. Chabner. “The National Cancer Institute: Cancer Drug Discovery and Development Program.” Seminars in Oncology 19 (1992): 622–638.

  Seok, Junhee. “Genomic Responses in Mouse Models Poorly Mimic Human Inflammatory Diseases.” Proceedings of the National Academy of Sciences of the United States of America 110, no. 9 (2013): 3507–3512.

  Begley, C. G., and L. M. Ellis. “Drug Development: Raise Standards for Preclinical Cancer Research.” Nature 483, no. 7391 (2012): 531–533.

  Santarpia, L., et al. “Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer.” Oncologist 21 (2016): 1063–1078.

  DeVita, V. T., Jr., and E. Chu. “A History of Cancer Chemotherapy.” Cancer Research 68 (2008): 8643–8653.

  Sharpless, N. E., and R. A. Depinho. “The Mighty Mouse: Genetically Engineered Mouse Models in Cancer Drug Development.” Nature Reviews Drug Discovery 5 (2006): 741–754.

  Ben-David, Uri, et al. “Patient-Derived Xenografts Undergo Mouse-Specific Tumor Evolution.” Nature Genetics 49, no. 11 (2017): 1567–1575.

  Izumchenko, E., et al. “Patient-Derived Xenografts Effectively Capture Responses to Oncology Therapy in a Heterogeneous Cohort of Patients with Solid Tumors.” Annals of Oncology 28, no. 10 (2017): 259
5–2605.

  Tentler, John J., et al. “Patient-Derived Tumour Xenografts as Models for Oncology Drug Development.” Nature Reviews Clinical Oncology 9, no. 6 (2012): 338–350.

  Willyard, Cassandra. “The Mice with Human Tumours: Growing Pains for a Popular Cancer Model.” Nature 560, no. 7717 (2018): 156–157.

  van der Worp, H. B., et al. “Can Animal Models of Disease Reliably Inform Human Studies?” PLOS Medicine 7, no. 3 (2010): e1000245.

  Francia, Giulio, and Robert S. Kerbel. “Raising the Bar for Cancer Therapy Models.” Nature Biotechnology 28 (2010): 561–562.

  Ledford, Heidi. “Cancer-Genome Study Challenges Mouse ‘Avatars.’ Grafting Human Cancer Cells into Mice Alters Tumour Evolution.” Nature, October 9, 2017.

  “NCI Awards Champions Oncology $2M SBIR Grant for Prostate Cancer Research.” Genome Web. www.genomeweb.com/business-policy-funding/nci-awards-champions-oncology-2m-sbir-grant-prostate-cancer-research#.XJvLfFVKjIU.

  “Cancer Drug Benefits Are Overhyped.” Dying for a Cure, June 5, 2016. http://dyingforacure.org/blogs/cancer-drug-benefits-overhyped/.

  Rubin, Eric H., and D. Gary Gilliland. “Drug Development and Clinical Trials—The Path to an Approved Cancer Drug.” Nature Reviews Clinical Oncology 9 (2012): 215–222.

  “Pharmaceutical Companies Acknowledge the Failure of Animal Models in Their Drug Development Process, and Write About This Openly in the Scientific Literature.” For Life on Earth. www.forlifeonearth.org/wp-content/uploads/2013/05/Pharmaceutical-Company-Quotes2.pdf.

  Pippin, John J. “The Failing Animal Research Paradigm for Human Disease.” Independent Science News, May 20, 2014.

  O’Rourke, Meghan. “Doctors Tell All—And It’s Bad.” Atlantic, November 2014.

  Guwande, Atul. Being Mortal. New York: Metropolitan Books, 2014.

  Cochran, Jack. The Doctor Crisis. New York: PublicAffairs, 2014.

  Jauhar, Sandeep. Doctored: The Disillusionment of an American Physician. New York: Farrar, Straus and Giroux, 2015.

  CHAPTER 2: PER

  Buchanan, Mark. Ubiquity: The Science of History… or Why the World Is Simpler Than We Think. New York: Crown, 2001.