SAB Temporary Working Group on the Convergence of Chemistry & Biology

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1 OPCW Scientific Advisory Board Briefing BWC Meeting of States Parties, Geneva, 11 th December 2012 SAB Temporary Working Group on the Convergence of Chemistry & Biology Robin Black

2 OPCW SAB TWG on Convergence of Chemistry & Biology Focusing on: Biomediated production of chemicals Chemical synthesis of molecules of biological origin, and replicating systems Toxins & bioregulators Benefits and threats TWG includes BWC and industrial experts Invited experts for specific topics 2

3 OPCW SAB TWG on Convergence of Chemistry & Biology Topics addressed at 2nd meeting, Sept 2012: Emerging trends & drivers in global biotech industry (Richard Johnson invited speaker) Synthetic biology (Scott Mohr invited speaker) Industrial examples of SB Benefits of convergence to the CWC decon, medical countermeasures, detection, diagnostics Impact of nanotechnology Bioregulators / peptides 3

4 Biomediated production of bulk chemicals Synthetic Biology new/modified biological systems Production of proteins, complex drug molecules in novel systems green chemistry renewable resources improved enzymes Convergence of chemistry & biology cheaper, better drugs Chemical synthesis of replicating systems for beneficial purposes Optimistic view Chemical synthesis of biological molecules e.g. peptide drugs, DNA

5 Biomediated production of bulk chemicals toxic chemicals & precursors? Synthetic Biology new/modified BW agents? Convergence of chemistry & biology Production of proteins, complex drug molecules in novel systems toxins, bioregulators? Chemical synthesis of replicating systems Enhanced/new BW agents? Pessimistic view Chemical synthesis of biological molecules toxins, bioregulators,

6 Decontamination: modified enzymes for mild decon Medical countermeasures: modified enzymes as scavengers Examples of beneficial applications to CB defence Detection: antibodies, aptomers, other affinity materials Diagnostics: POC devices CW/BW devices in development Convergence with Nanotechnology CWA/BW devices in development

7 Enzymes in therapy against nerve agent poisoning: biopharming Nerve agents act by inhibiting the enzyme acetylcholinesterase Butyrylcholinesterase (BuChE) present in plasma reacts similarly with nerve agents but with no known physiological penalty Endogenous BuChE acts as a partial scavenger of nerve agents Exogenously administered BuChE is being investigated as a scavenger for therapy and prophylaxis Expensive & impractical to isolate large amounts from human blood Recombinant BuChE has been produced in the milk of transgenic goats an example of biopharming (but recently discontinued?) 7

8 Enzymes in therapy against nerve agent poisoning Disadvantage of BuChE is that it reacts stoichiometrically 1:1 with the nerve agent, thus requiring the administration of a large amount of protein Modified enzymes are being engineered that will react catalytically with the nerve agent, or which are rapidly reactivated by the co-administration of oximes 8

9 Point of care diagnostic devices for exposure to nerve agents Several devices are in development for the rapid POC diagnosis of exposure to nerve agents Some of these devices include, e.g. monoclonal antibodies, combined with nanoparticulate transducers and reporting systems The shortage of selective molecular recognition materials, for capture or for detection, is a limiting factor As these devices become more sophisticated, diagnosis in the field may partially replace laboratory-based analysis 9

10 Bioregulators & toxins: overlap between the Conventions peptides lipid derived: eicosinoids, leukotrienes, PAF the largest group Bioregulators Small molecule neurotransmitters Interleukins etc acetylcholine, noradrenaline, dopamine, histidine, serotonin etc larger molecules 10

11 Peptide bioregulators Peptide bioregulators have a diverse range of central and peripheral activities Some observers fear peptides as prototypes for new centrally acting incapacitants But they have significant disadvantages cost of manufacture, reaching their target organ (particularly the brain), metabolic lability For pharmaceutical use (high value products), these are being overcome, but at the expense of increased complexity and cost, e.g. metabolically resistant analogues analogues with increased lipophilicity encapsulation or incorporation in a nanocarrier or they look for a peptide mimic! What appear to be two of the most toxic peptide bioregulators reported in the literature, endothelins and substance P + peptidase inhibitor, exert their toxic effects without crossing the BBB 10 December 2012

12 Proteinaceous, e.g. botulinum, ricin highly toxic Can be produced in quantity by natural organism Toxins as CBW agents low mol mass animal & marine toxins, e.g. saxitoxin, tetrodotoxin Chemical synthesis difficult, natural source impractical for large amounts Peptides, e.g. conotoxins, scorpion toxins etc Chemical synthesis moderately difficult & expensive Ricin & saxitoxin are Schedule 1 chemicals low mol mass fungal toxins Readily produced by natural organism but modest toxicity 12

13 Some ambiguities? The BWC includes bioregulators and toxins and their analogues After what degree of modification does an analogue cease to come under this definition? Many drugs are derived from neurotransmitters or other bioregulators e.g. related to dopamine (anti-parkinsons disease), acetylcholine, prostanoids, modified peptides Many drugs are derived from toxic alkaloids such as atropine & morphine are toxic alkaloids viewed as toxins under the BWC? the Schedule 2 CW agent/incapacitant BZ is an analogue of atropine! 13

14 Summary The increasing convergence of chemistry & biology offers major advances for humankind including health care, renewable energy, cleaner industrial production, food... Also offers potential improvements in CB defensive countermeasures therapeutics, detection, diagnostics, verification, decon There are potential threats to the Conventions, e.g. from synthetic biology but would probably require substantial and covert R&D programmes OPCW TS need to build & maintain knowledge in areas of overlap e.g. bioregulators & toxins 14

Convergence of Chemistry and Biology

Convergence of Chemistry and Biology OPCW Temporary Working Group Report Summary 8/6/2014 W. Kane, OPCW Scientific Advisory Board 1 Outline Background/Overview: OPCW Temporary Working Group (TWG) on Convergence