Risk assessment for the open release of future biotechnology products: some important issues

Transcription

1 Risk assessment for the open release of future biotechnology products: some important issues Keith R Hayes, David Peel and Jessica Ford CSIRO Health and Biosecurity

2 Take home messages 1. What are the new risks? More relevant question: How do we assess risk in a scientific, comprehensive, adaptive and practical way 2. Do we need new risk assessment methods? [0, 5] yrs: No, existing tools and approaches are adequate [5, 20] yrs: Yes if case-by-case approach proves too cumbersome 3. Need to raise our game Comprehensive hazard analysis and testable risk predictions Monitor and evaluate predictions Develop entry and exit strategies Keith Hayes, NAS Washington, June 2016: Slide 2 of 14

3 Reflections from yesterday Product characteristics Diverse and rapidly expanding Some can survive, reproduce, spread and (presumably) evolve Familiarity highly variable, uncertainty and complexity generally high Desired risk assessment characteristics Yesterday: scientifically rigorous, adaptive and practical Add: comprehensive,... How do we do RA with these characteristics? Near term: raise our game on a case-by-case approach Med - long term: may need an alternative approach - e.g. consortia of GM microbes Keith Hayes, NAS Washington, June 2016: Slide 3 of 14

4 Hazard analysis for synthetic gene drive Scale Failure mode Possible effect Reference Individual Mutated grna causes Cas9 cleavage New phenotype; deleterious effect on host, Sander and of non-target sequence such as increased virulence Joung (2014) Cas9 fails to edit or target all alleles Mosaicism within organisms; reduced drive Araki et al. or gain of function polymorphism (2014) Population Community Mutations occur during repair of multiple cleavage sites Assortative mating between new phenotypes Intraspecific (admixture) and interspecific hybridization Unpredicted phenotypes arise due to gene by environment interactions CRISPR/Cas9 influences the innate immune response of the GDMO Suppression drive creates open ecological niche Incomplete suppression via (for e.g.) increase in drive resistant individuals Horizontal transfer of gene drive to distant species Multiple alleles leading to mosaicism in subsequent generations; reduced drive or gain of function polymorphism Drive is reduced or competitive advantage accrues to more virulent phenotype Gene drive is acquired by, and spreads within, non-target population Drive failure or failure to produce refractory organisms in the wild GDMO transmission of other pathogens is enhanced Sander and Joung (2014) Scott et al. (2002) David et al. (2013) Tabachinck (2003) Scott et al. (2002) Niche filled by a more detrimental species David et al. (2013) Loss of herd immunity and disease resurgence Webb (2011) Gene drive is acquired by, and spreads Wijayawardena within, non-target population et al. (2013) Keith Hayes, NAS Washington, June 2016: Slide 4 of 14

5 Comprehensive hazard analysis methods Method Application to Living Modified Organisms Reference Hazard and Operability Study (HAZOP) Modified version of HAZOP, termed GENHAZ recommended as hazard identification tool for LMOs by a United Kingdom Royal Commission on Environmental Pollution Watts (1989) Fault Tree Analysis (FTA) Event Tree Analysis (ETA) Hierarchical Holographic Modelling (HHM) Failure Modes and Effects Analysis (FMEA) Qualitative mathematical modelling (QMM) Applied as heuristic hazard identification tool for the release of genetically modified carp, and as a risk quantification tool to male sterile mosquitoes modified with I-PpoI construct Simple examples applied to biological systems - no known examples of application to LMOs Applied to identify hazards associated with breaches of HT Canola license conditions and male sterile mosquitoes modified with I- PpoI construct Modified versions applied to biological systems (hull-fouling introductions) - no known examples of application to LMOs Numerous examples of application within ecological systems, together with demonstration of application to the release of genetically modified carp in Australia Hayes et al. (2015, 2013) Ericson (2005) Hayes et al. (2004, 2015) Hayes (2002) Dambacher et al. (2003); Hayes et al. (2013) Keith Hayes, NAS Washington, June 2016: Slide 5 of 14

6 Risk assessment toolbox Keith Hayes, NAS, June 2016: Slide 6 of 14

7 Handling complexity via fault tree analysis Keith Hayes, NAS, June 2016: Slide 7 of 14

8 Handling uncertainty via elicitation and quantification FT2 Fx[subsetid] TMc Ind log10(x) Keith Hayes, NAS, June 2016: Slide 8 of 14

9 Scientific risk assessment The probability that a gene drive modified mosquito can be infected with a novel* blood borne disease is negligible. Is this a scientific risk prediction? *Novel for this species of mosquito - meaning it has never vectored this disease in the past National Academy of Sciences, June 2016: Slide 9 of 14

10 Scientific risk assessment The probability that a gene drive modified mosquito can be infected with a novel blood borne disease is negligible. Is this a scientific risk prediction? How many failed attempts* to infect a gene drive modified mosquito must I observe before I am 95% sure that this is true? Can you answer this question? *Assume that each attempt is independent National Academy of Sciences, June 2016: Slide 10 of 14

11 Zero numerator problem 7e+08 6e+08 5e+08 5e+08 4e+08 3e+08 2e+08 2e+08 8e+07 n Wilson Exact BayesLaplace Jeffreys Rule3 Rule4 Rule7 cbox 3e+06 1e 08 1e 07 2e 07 5e 07 8e 07 Upper CI probability of success Keith Hayes, NAS, June 2016: Slide 11 of 14

12 Entry and exit strategies Entry strategies Do stakeholders recognise the problem and its solution set? Is the Biotech product a member of their solution set? What values do stakeholders perceive to be threatened? Can they specify risk acceptance criteria? Exit strategies What does a successful BioTech solution look like? How will adverse outcomes be detected? When will absence of evidence be sufficient to stop monitoring? Keith Hayes, NAS Washington, June 2016: Slide 12 of 14

13 References Araki, M., Nojima, K., and Ishii, T. (2014). Caution required for handling genome editing technology. Trends in Biotechnology, 32: Dambacher, J. M., Li, H. W., and Rossignol, P. A. (2003). Qualitative predictions in model ecosystems. Ecological Modelling, 161: David, A. S., Kaser, J. M., Morey, A. C., Roth, A. M., and A, A. D. (2013). Release of genetically engineered insects: A framework to identify potential ecological effects. Ecology and Evolution, 3: Ericson, C. A. (2005). Hazard Analysis Techniques for System Safety. John Wiley and Sons, Hoboken, New Jersey, USA. Hayes, K. R. (2002). Identifying hazards in complex ecological systems, part 2: Infections modes and effects analysis for biological invasions. Biological Invasions, 4: Hayes, K. R., Barry, S. C., Beebe, N., Dambacher, J. M., De Barro, P., Ferson, S., and Ford, J. e. a. (2015). Risk assessment for controlling mosquito vectors with engineered nucleases, sterile male construct: Final report. Technical report, CSIRO Biosecurity Flagship, Hobart, Australia. Hayes, K. R., Greg, g. P. C., Gupta, V., Jessop, R., Lonsdale, W. M., Sindel, B., Stanley, J., and Williams, C. K. (2004). Identifying hazards in complex ecological systems. part 3: Hierarchical holographic model for herbicide tolerant oilseed rape. Environmental Biosa, 3: Hayes, K. R., Leung, B., Thresher, R., Dambacher, J. M., and Hosack, G. R. (2013). Meeting the challenge of quantitative risk assessment for genetic control techniques: A framework and some methods applied to the common carp (Cyprinus carpio) in Australia. Biological Invasions, DOI /s Sander, J. D. and Joung, J. K. (2014). Crispr-cas systems for editing, regulating and targeting genomes. Nature Biotechnology, 32: Scott, T. W., Takken, W., Knols, B. G. J., and Boete, C. (2002). The ecology of genetically modified mosquitoes. Science, 298: Tabachinck, W. J. (2003). Reflections on the Annopheles gambiae genome sequence, transgenic mosquitoes and the prospect for controlling malaria and other vector borne diseases. Journal of Medical Entomology, 40: Watts, S. (1989). Britons pioneer assessment of gene hazards. New Scientist, 1666:32. Webb, J. L. A. (2011). The first large-scale use of synthetic insecticide for malaria control in tropical africa: Lessons from liberia, Journal of the History of Medicine and Allied Sciences, 66: Wijayawardena, B. K., Minchella, D. J., and DeWoody, J. A. (2013). Hosts, parasites, and horizontal gene transfer. Trends in Parasitology, 29: Keith Hayes, NAS, June 2016: Slide 13 of 14

14 CSIRO Health and Bisecurity Keith R. Hayes t e Keith.Hayes@csiro.au w CSIRO Health and Biosecurity