Abstract
A basic mission of NASA is to use the United States’ segment of the International Space Station (ISS), designated a national laboratory, to facilitate the growth of a commercial marketplace in low Earth orbit for scientific research, technology development, observation and communications. Protein crystallization research has long been promoted as a promising commercial application of the ISS for drug development. In this paper we examine the case for microgravity protein crystallization under different private and public investment scenarios. The analysis suggests that sustaining investment is unlikely to come from individual companies alone. Public and private investment must be combined and managed to overcome a number of challenges including the need to integrate microgravity crystallization into the complex system of technologies involved in structure-based drug design. Multiple risks related to transportation costs/frequency, risk for cargo and research crew, and uncertainty about the longevity of the ISS complicate the calculus.
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Notes
On the transformative nature of these two drug classes, see Kesselheim et al. (2015). On the role of structure-based approaches in the development of these and other drugs see Kubinyi (1999), Redig (2001), Wlodawer (2002), Stevens (2003), Hardy and Malikayil (2003), Noble et al. (2004), and Vijayakrishnan (2009).
In his historical review of protein crystallography, Giegé (2013, p. 6474) finds: “Overall, space grown crystals grow larger, and have more regular external morphology and better internal order with reduced mosaic spread, although contradictory results have been reported.” Giegé cites the review by Judge et al. (2005) of the first 20 years of microgravity protein crystallization, as well as Snell et al. (1995), Ng et al. (1997), Declercq et al. (1999), Carter et al. (1999), and Ng (2002). For contradictory results, he cites Sauter et al. (2012).
This ‘virtuous cycle’ effect is essentially an indirect network externality benefitting earth-based crystallography, analogous to a dominant computer operating system for which commercial software is developed.
This message was emphasized repeatedly by the industry experts we interviewed.
Pharmaceutical and biotechnology companies do of course accept high levels of technical risk in developing new drugs; that is essential to their business models. By contrast, solving the structure of a specific protein is never essential to a single company, and solving the most recalcitrant proteins’ structures does not fit within the business models of most companies.
Based on correspondence with CASIS, the 2018 International Space Station (ISS) commercial resupply contract provides for a total of seven launches and five returns: five SpaceX launches, each of which carry cargo to the ISS and return cargo to earth, and two Orbital launches which only carry cargo to the ISS. NASA ISS National Laboratory office has spoken publicly about expecting at least one launch per month having return capability beginning in late 2019.
To allow continuous discounting, a 10.5% annual discount rate is converted to a 9.98% continuously compounded annual discount rate (the natural log of 1.105 is 0.09985). Then, $1,000,000e−0.09985(3/12) = $975,348, so the cost of a 3-month delay is $24,652, and $1,000,000e−0.09985(6/12) = $951,303, so the cost of a 6-month delay is $48,697.
Resolutions at all less than 1.0 Å are considered excellent; resolutions less than 2.5 Å are very good. For many drug-development applications the improvement from 3.0 to 2.5 Å is especially meaningful.
References
Anderson, A. C. (2003). The process of structure-based drug design. Chemistry & Biology, 10(9), 787–797.
Aritake, K., Kado, Y., Inoue, T., Miyano, M., & Urade, Y. (2006). Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase. Journal of Biological Chemistry, 281(22), 15277–15286.
Callaway, E. (2015). The revolution will not be crystallized. Nature, 525(7568), 172.
Carter, D. C., Lim, K., Ho, J. X., Wright, B. S., Twigg, P. D., Miller, T. Y., et al. (1999). Lower dimer impurity incorporation may result in higher perfection of HEWL crystals grown in microgravity: A case study. Journal of Crystal Growth, 196(2), 623–637.
Chandonia, J. M., & Brenner, S. E. (2006). The impact of structural genomics: Expectations and outcomes. Science, 311(5759), 347–351.
Declercq, J. P., Evrard, C., Carter, D. C., Wright, B. S., Etienne, G., & Parello, J. (1999). A crystal of a typical EF-hand protein grown under microgravity diffracts X-rays beyond 0.9 Å resolution. Journal of Crystal Growth, 196(2), 595–601.
DeLucas, L. J., Suddath, F. L., Snyder, R., Naumann, R., Broom, M. B., Pusey, M., et al. (1986). Preliminary investigations of protein crystal growth using the space shuttle. Journal of Crystal Growth, 76(3), 681–693.
DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, 47, 20–33.
Edwards, A. (2016). Reproducibility: Team up with industry. Nature, 531(7594), 299–301.
Gerlits, O., Fajer, M., Cheng, X., Blumenthal, D., Taylor, P., Radić, Z., et al. (2016). Crystallographic studies of human acetylcholinesterase reactivation by oximes: Towards a neutron structure. The FASEB Journal, 30(1 Supplement), 1191.1.
Giegé, R. (2013). A historical perspective on protein crystallization from 1840 to the present day. FEBS Journal, 280(24), 6456–6497.
Gileadi, O., Knapp, S., Lee, W. H., Marsden, B. D., Müller, S., Niesen, F. H., et al. (2007). The scientific impact of the Structural Genomics Consortium: A protein family and ligand-centered approach to medically-relevant human proteins. Journal of Structural and Functional Genomics, 8(2–3), 107–119.
Hardy, L. W., & Malikayil, A. (2003). The impact of structure-guided drug design on clinical agents. Current Drug Discovery, 3, 15–20.
Jorgensen, W. L. (2004). The many roles of computation in drug discovery. Science, 303(5665), 1813–1818.
Judge, R. A., Snell, E. H., & van der Woerd, M. J. (2005). Extracting trends from two decades of microgravity macromolecular crystallization history. Acta Crystallographica Section D: Biological Crystallography, 61(6), 763–771.
Kesselheim, A. S., Tan, Y. T., & Avorn, J. (2015). The roles of academia, rare diseases, and repurposing in the development of the most transformative drugs. Health Affairs, 34(2), 286–293.
Kovalevsky, A., Blumenthal, D. K., Cheng, X., Taylor, P., & Radić, Z. (2016). Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning. Annals of the New York Academy of Sciences, 1378(1), 41–49.
Kubinyi, H. (1999). Chance favors the prepared mind-from serendipity to rational drug design. Journal of Receptors and Signal Transduction, 19(1–4), 15–39.
Ledford, H. (2010). Consortium solves its 1,000th protein structure. Nature News, September. https://doi.org/10.1038/news.2010.500.
Link, A. N., & Maskin, E. S. (2015). Does information about previous projects promote R&D on the International Space Station? In P. Besha, & A. MacDonald (Eds.), Economic development of low Earth orbit (pp. 43–59). Washington, DC: National Aeronautics and Space Administration.
Link, A. N., & Scott, J. T. (2011). Public goods, public gains: Calculating the social benefits of public R&D. New York: Oxford University Press.
Link, A. N., & Scott, J. T. (2019). The economic benefits of technology transfer from U.S. federal laboratories. Journal of Technology Transfer. https://doi.org/10.1007/s10961-019-09734-z.
Littke, W., & John, C. (1984). Protein single crystal growth under microgravity. Science, 225, 203–205.
McPherson, A., & DeLucas, L. J. (2015). Microgravity protein crystallization. npj Microgravity, 1, 15010.
Moraes, I., Evans, G., Sanchez-Weatherby, J., Newstead, S., & Stewart, P. D. S. (2014). Membrane protein structure determination—The next generation. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1838(1), 78–87.
National Research Council. (2000). Future biotechnology research on the international space station. National Academies Press. https://www.nap.edu/catalog/9785/. Accessed March 23, 2017.
Ng, J. D. (2002). Space-grown protein crystals are more useful for structure determination. Annals of the New York Academy of Sciences, 974(1), 598–609.
Ng, J. D., Lorber, B., Giegé, R., Koszelak, S., Day, J., Greenwood, A., et al. (1997). Comparative analysis of thaumatin crystals grown on earth and in microgravity. Acta Crystallographica Section D: Biological Crystallography, 53(6), 724–733.
Noble, M. E., Endicott, J. A., & Johnson, L. N. (2004). Protein kinase inhibitors: Insights into drug design from structure. Science, 303(5665), 1800–1805.
Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R., et al. (2010). How to improve R&D productivity: The pharmaceutical industry’s grand challenge. Nature Reviews Drug Discovery, 9(3), 203–214.
Redig, A. (2001). Gleevec: Highlighting the power of rational drug design. Journal of Young Investigators, 5(3). http://legacy.jyi.org/volumes/volume5/issue3/features/redig.html.
Roth, B. L., Sheffer, D. L., & Kroeze, W. K. (2004). Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery, 3(4), 353–359.
Sauter, C., Lorber, B., McPherson, A., & Giegé, R. (2012). Crystallization—General methods. In E. Arnold, D. Himmel, & M. Rossman (Eds.), International tables for crystallography, Volume F: Crystallography of biological macromolecules (pp. 99–121). Chichester: Wiley.
Scannell, J. W., Blanckley, A., Boldon, H., & Warrington, B. (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nature Reviews Drug Discovery, 11(3), 191–200.
Snell, E. H., & Helliwell, J. R. (2005). Macromolecular crystallization in microgravity. Reports on Progress in Physics, 68(4), 799.
Snell, E. H., Weisgerber, S., Helliwell, J. R., Weckert, E., Hölzer, K., & Schroer, K. (1995). Improvements in lysozyme protein crystal perfection through microgravity growth. Acta Crystallographica Section D: Biological Crystallography, 51(6), 1099–1102.
Stevens, R. C. (2003). The cost and value of three-dimensional protein structure. Drug Discovery World, 4(3), 35–48.
Tassey, G. (2015). Selecting policy tools to expand NASA’s contribution to technology commercialization. In P. Besha, & A. MacDonald (Eds.), Economic development of low Earth orbit (pp. 1–21). Washington, DC: National Aeronautics and Space Administration.
U.S. Food and Drug Administration (FDA). (2006). Innovation or stagnation: Critical path opportunities report. https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/UCM077254.pdf. Accessed June 15, 2017.
Vijayakrishnan, R. (2009). Structure-based drug design and modern medicine. Journal of Postgraduate Medicine, 55(4), 301.
Vonortas, N. S. (2015). Protein crystallization for drug development. In P. Besha, & A. MacDonald (Eds.), Economic development of low Earth orbit (pp. 23–42). Washington, DC: National Aeronautics and Space Administration.
Wlodawer, A. (2002). Rational approach to AIDS drug design through structural biology. Annual Review of Medicine, 53(1), 595–614.
Woodcock, J., & Woosley, R. (2008). The FDA critical path initiative and its influence on new drug development. Annual Review of Medicine, 59, 1–12.
Acknowledgements
The authors acknowledge research funding from NASA (Grant NNX16AH09G) for this project. The content of this paper reflects the opinions of the two authors and not those of NASA. We are grateful to the many scientists in the pharmaceutical industry, academia, and government who took the time to educate us on the issues and share their insight and perspectives. These contributors are too many to list by name. We are especially grateful to Lynn Harper, Patrick Besha, and Alex McDonald from NASA as well as to Warren Bates and Debbie Wells from CASIS for invaluable insights and advice over the course of the project. Discussant comments during the Workshop “Entrepreneurship in the Public and Nonprofit Sectors” at the US National Academies of Science (October 2018) were highly appreciated and helped us rethink some arguments. Vonortas acknowledges the infrastructural support of the Institute of International Science and Technology Policy at the George Washington University for carrying out this research. He also acknowledges support from the Basic Research Program at the National Research University Higher School of Economics within the framework of the subsidy to the HSE by the Russian Academic Excellence Project ‘5–100’. None of the organizations mentioned above is responsible for the contents of this paper. Remaining mistakes and misconceptions are solely the responsibility of the authors.
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Scott, T.J., Vonortas, N.S. Microgravity protein crystallization for drug development: a bold example of public sector entrepreneurship. J Technol Transf 46, 1442–1461 (2021). https://doi.org/10.1007/s10961-019-09743-y
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DOI: https://doi.org/10.1007/s10961-019-09743-y