Michael Csukai

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  • 2010 corn – USA no 1 (316 MT), China no 2 (176 MT)15% of global productionOver a third of all cropland is degraded to some extent24% of all land is degraded, and 18% of this degraded land is crop land13 bn ha of land hence 560 Mha is degraded croplandTotal cropland ~ 1560 Mha (PNAS 2011, 3465)
  • The second challenge is a disease – soybean rust – caused by a fungus called Phakopsorapachyrhizi. This organism has been known for over 100 years without causing any significant problems. Then in 2001 a highly virulent strain of the disease was first observed in Paraguay. The spores are spread by the wind and within a couple of years the disease was endemic throughout South America. In 2004 it is believed that Hurricane Ivan in the Caribbean blew spores from Venezuela up to the United States where the disease now has a foothold but struggled to really establish (winters are too cold). Nevertheless we now have the situation where all elite lines of soybeans are susceptible to infection to a disease which can cause complete yield loss if left untreated and which is endemic or threatens all of the major soybean producing regions of the world. Treatment with fungicides is the only line of defence, but none of the fungicides available were invented with control of soybean rust in mind. They just happen to be effective, and if the disease develops resistance then we are in big trouble!
  • Aral Sea – used to be the fourth largest lake in the world, 68,000 square km1960s Soviet irrigation projects diverted feeding rivers, down to 10% of its original sizeBetween Kazakhstan and Uzbekistan
  • 2003 – 3.6 degree temperatureanomoly52,000 people diedCorn yields down by 30-40%Wheat yields down by 20%
  • Uk averages 8 t/ha for wheat. Ukraine averages 3 t/ha.Raising yields in Ukraine to the UK average would produce an extra 33 Mt wheat per year (5% of world production)UK produces ~ 14 Mt per yearWorld produced 685 Mt in 2009 C4 photosynthesis has evolved independently ~ 40 times – convergent evolution
  • Uk averages 8 t/ha for wheat. Ukraine averages 3 t/ha.Raising yields in Ukraine to the UK average would produce an extra 33 Mt wheat per year (5% of world production)UK produces ~ 14 Mt per yearWorld produced 685 Mt in 2009
  • Holistic picture of where MIP2 fits in and complements the forward and reverse genetics efforts. Receptor-ligand interaction based MIP2 approach is useful both for unbiased MoA diagnosis (if Fwd and rev genetics do not yield promising results) but also validating mutant cell lines employed by genetics teams.
  • Holistic picture of where MIP2 fits in and complements the forward and reverse genetics efforts. Receptor-ligand interaction based MIP2 approach is useful both for unbiased MoA diagnosis (if Fwd and rev genetics do not yield promising results) but also validating mutant cell lines employed by genetics teams.
  • Holistic picture of where MIP2 fits in and complements the forward and reverse genetics efforts. Receptor-ligand interaction based MIP2 approach is useful both for unbiased MoA diagnosis (if Fwd and rev genetics do not yield promising results) but also validating mutant cell lines employed by genetics teams.
  • Michael Csukai

    1. 1. Sustainably growing more with less:fungal control solutions and technology gapsBioDundee Classification: PUBLIC
    2. 2. Outline● Global food security challenges● Syngenta● Fungicide Active Ingredient Pipeline - MoA diagnosis Issues! - Biokinetics Gaps! - Resistance assessment● Knowledge gap2 Classification: PUBLIC
    3. 3. Increasing demand for food● World population growth - 7.0 billion today - 9.3 billion by 2050 • Large error bars!● Increasing wealth driving increased demand for animal products - Significant effect on primary crop demand - 80% of agricultural land is used for animal production● Bottom line: food demand in 2050 will be 70% higher than in 2006 - Ignoring impacts of climate change, biofuels and the additional production required to eliminate hunger3 Classification: PUBLIC
    4. 4. Pressures on existing global farmland● Pressures on farmland from urbanisation● Reduction in soil fertility due to poor agronomic practices● Pressures to satisfy demand for non-food crops - Food, feed, fibre, fuel, feedstocks, fine chemicals - 40% of the US corn crop in 2011 was used to produce biofuels● It would be an ecological disaster to convert wild lands to farmland on a significant scale● Bottom line: Large increases in global farmed area are unlikely - Indeed we may struggle to retain the amount of farmland we currently have! 4 Classification: PUBLIC
    5. 5. Pressures from pests● Evolution of resistance in existing pests - Weed resistance to glyphosate● Evolution of new pests - Soybean rust, Ug-99● Hopelessly unscientific pesticide legislation! - Hazard-based cut-offs - Preferential treatment of natural products● Bottom line: Agricultural pests are evolving to become more virulent - The political situation is making things worse5 Classification: PUBLIC
    6. 6. Pressures on farming inputs● Fertiliser - Nitrogen prices are linked to the price of oil - Phosphorus supplies are concentrated in North Africa (> 75%)● Water - 70% of the world’s fresh water is used by agriculture - Already 25% of the world’s rivers do not reliably reach the sea!● Economic inputs & infrastructure - Credit and insurance are increasingly difficult to obtain● Bottom line: Current practices are unsustainable6 Classification: PUBLIC
    7. 7. Uncertainties around climate change● Crop yields - Probably already being impacted● Global farmed area - Shifts in cropping regions - Sea level rise● Extreme weather events● Economic, social and political stability Science 9 January 2009: vol. 323 no. 5911 240-244● Bottom line: There are significant uncertainties about the degree of impact of climate change on agriculture, and the timescale of impact - But it could well be “profoundly negative” and “soon”!7 Classification: PUBLIC
    8. 8. How to produce more food? New and better technologies● Three strategies - Increase intrinsic yield Stresses potential Crop yield • Convert annual to Pests perennial crops Actual • C3 to C4 photosynthesis yield • Understanding and de- Current Future? bottlenecking yield - Understanding and mitigating against abiotic stresses • Drought, heat stress, cold stress, nutrient deficiency - New and better crop protection technologies • More effective, resistance management, new MOA8 Classification: PUBLIC
    9. 9. It is not necessarily all about yield....● Technologies to reduce agricultural inputs and impacts - “Precision” technologies - Water & nutrient use efficiency • Crops producing their own nitrogen - Technologies to reduce GHG emissions • Increase soil carbon● Technologies to produce “better” food - More nutritious, better tasting, more “appealing”9 Classification: PUBLIC
    10. 10. Outline● Global food security challenges● Syngenta● Fungicide Active Ingredient Pipeline - MoA diagnosis - Biokinetics - Resistance assessment● Knowledge gap10 Classification: PUBLIC
    11. 11. Helping the world grow more from lessOur ambition:To bring greater food security in an environmentally sustainable way toan increasingly populous world by creating a worldwide step-change infarm productivity. 8M large-scale 450M smallholder farms farms >100 Ha ~1.0 Ha World 11 Classification: INTERNAL USE ONLY
    12. 12. Market overview 2010Global market: ~ $75 bn Conventional Seeds (~ $17 bn) 25% 51% 16% GM Seeds (~ $12 bn) Crop Protection* 8% (~ $40 bn) Non-Crop Chemicals (~ $6 bn) *Includes Seed Treatment Source: Syngenta Analysis, Philips McDougall Classification: PUBLIC12
    13. 13. Competitors in 2010 14000 12000 10000$ mill. sales 8000 6000 4000 2000 0 CP Seeds/Traits L&G Sources: Companies Annual/Quarterly reports, Phillips McDougall, Agreworld, Syngenta Analysis Classification: PUBLIC 13
    14. 14. Syngenta sales 2010: $ 11.6 bn Crop Protection Seeds $ 8.8 bn (77%) $ 2.8 bn (23%)Crop Protection Seeds Selective Herbicides (26%) Corn & Soybean (58%) Non-selective Herbicides (11%) Diverse Field Crops (23%) Fungicides (30%) Insecticides (17%) Vegetables (10%) Seed Care (9%) Flowers (9%) Professional Products (5%) Other (2%) Classification: PUBLIC14
    15. 15. Syngenta R&D Over 5000 Syngenta employees work in Research and Development We spent around $1 billion in 2010 on R&D15 Classification: PUBLIC
    16. 16. Global R&D capabilities GOA Chemistry JEALOTT’S HILL Chemical Discovery Weed Control Formulation Bioscience Major R&D sites Environmental Science located on three continents BEIJING BiotechnologyGREENSBORO R&DFormulationEnvironmentalScience SBI Biotechnology Other sites R&D ● Marker-assisted and seed breeding capabilities STEIN Fungicides, Insecticides & ● Global field station network Professional Products Classification: PUBLIC 16
    17. 17. 17 Classification: PUBLIC
    18. 18. Syngenta was focused three businessesCrop Protection Seeds Lawn & Garden*Selective herbicides Corn & Soybean FlowersNon-selective herbicides Diverse Field Crops Growing Media**Fungicides Vegetables Chemical Controls**Insecticides Turf & Ornamentals**Seed care * Newly established in 2008 - Financial reporting for product lines in 2008 under Crop Protection and Seeds respectively ** Reported as Professional Products under Crop Protection Classification: PUBLIC18
    19. 19. New Syngenta strategy is crop focused Specialty Rice Divers Field Crops Cereals Sugar cane Soybean Vegetables Corn19 Classification: PUBLIC
    20. 20. Innovating across technologies to transform the way crops are grownIntegrated solutions addressing growers’ needs comprehensively Growers’ needs Weed Insect Disease Nematode Yield Nitrogen Drought Quality Labor Post Technology control control control control potential efficiency traits shortage harvest Breeding Native traits Biological solutions GM traits Seed care Chemical solutions Crop protection Nutrients, w ater Machinery Services 20 Classification: PUBLIC
    21. 21. Outline● Global food security challenges● Syngenta● Fungicide Active Ingredient Pipeline - MoA diagnosis - Biokinetics - Resistance assessment● Knowledge gap21 Classification: PUBLIC
    22. 22. Why look for novel fungicides● Likely to remain the mechanism to deliver fungal control of disease complexes in many crops● Looking for novel Modes of Action (MoA) - resistance management - cleaner toxicological & environmental profile - broader antifungal spectrum● New products sell better than old products22 Classification: PUBLIC
    23. 23. Screening up to 300,000 compounds a year23 Classification: PUBLIC
    24. 24. Discovery pipeline Activity? Activity Profile Performance Profile Tox Profile Financial profile Registration requirements Hits leads candidates Research Development launch24 Classification: PUBLIC
    25. 25. Discovery pipeline Activity? Activity Profile Performance Profile Tox Issues Regulatory issues Financial profile Registration requirements Hits leads candidates Research Development launch25 Classification: PUBLIC
    26. 26. Outline● Global food security challenges● Syngenta● Fungicide Active Ingredient Pipeline - MoA diagnosis - Biokinetics - Resistance assessment● Knowledge gap26 Classification: PUBLIC
    27. 27. MoA impact on AI pipeline● MoA determination: - Intrinsic potency measurement - Structure based design strategies - Valuable for Tox and resistance risk assessment27 Classification: PUBLIC
    28. 28. Mode of action diagnosis Early projects Known UnknownTools will generally Collect and review information on MoA MoA “physiological effects”be available.Use external collaboration MoA1 “symptomology”for speed, in-house capability Haploinsufficiency / OERfor SAR support Spectrum Phys Chem 28 Classification: PUBLIC
    29. 29. Target site elucidation  More than 25 assays  Identify activity at known target sites (+/-)  Identify hits with interesting activity or symptomology M M M29 Classification: PUBLIC
    30. 30. Mode of action diagnosis Early projects Known UnknownTools will generally Collect and review information on MoA MoA “physiological effects”be available.Use external collaboration MoA1 “symptomology”for speed, in-house capability Haploinsufficiency / OERfor SAR support Spectrum Phys ChemStructure Activity Relationships (SAR)plant pathogen vs mammalian intrinsic potency 30 Classification: PUBLIC
    31. 31. Haploinsufficiency and over-expression induced resistanceHaploinsufficiency and over-expression induced resistance both exploit gene dosage methods31 Classification: PUBLIC
    32. 32. Basis of the assaysHaploinsufficient  More sensitive to 25ppm Normal cell Target protein IC50 25ppm  Less sensitive to 25ppmOverexpressing 32Classification: PUBLIC
    33. 33. Haploinsufficiency and OEIR are complementary Chemical Target identified Haploinsufficiency OEIR Tunicamycin   F-2003-035   Cerulenin   Rapamycin   Oxytriazine  ND Flutriafol   Fenpropimorph   Soraphen   Eupolauridine  33 Classification: PUBLIC
    34. 34. How do we utilise Haploinsufficiency and OER dataTypically a small gene group is identified. Which is target? • Data and literature review • Express proteins and determine if small molecule interact • Mutate genes and determine if resistant clone can be producedCould a data integration approach improve this process?Would like to have the ability to do OER in appropriate plant pathogens34 Classification: PUBLIC
    35. 35. Mode of action diagnosis Early projects Known UnknownTools will generally Collect and review information on MoA MoA “physiological effects”be available.Use external collaboration MoA1 “symptomology”for speed, in-house capability Haploinsufficiency / OERfor SAR support Spectrum Phys Chem Reverse Genetics Testable, quality yes Sustained interest yes MoA hypothesis? in Chemistry? Test using reverse genetics S. cerevisiae M. graminicola P. Infestans Etc. 35 Classification: PUBLIC
    36. 36. Mode of action diagnosis Early projects Known UnknownTools will generally Collect and review information on MoA MoA “physiological effects”be available.Use external collaboration MoA1 “symptomology”for speed, in-house capability Haploinsufficiency / OERfor SAR support Spectrum Phys Chem Reverse Genetics Testable, quality yes Sustained interest yes MoA hypothesis? in Chemistry? no Test using reverse genetics Generate resistant strain S. cerevisiae S. cerevisiae M. graminicola M. graminicola P. infestans, P. Infestans M. grisea Etc successful Forward Genetics Collaboration with researchers at the Identify mutant gene James Hutton Institute & Dundee University instrumental to Phytophthora infestans work 36 Classification: PUBLIC
    37. 37. Mode of action diagnosis Early projects Known UnknownTools will generally Collect and review information on MoA MoA “physiological effects”be available.Use external collaboration MoA1 “symptomology”for speed, in-house capability Haploinsufficiency / OERfor SAR support Spectrum Phys Chem Reverse Genetics Testable, quality yes Sustained interest yes MoA hypothesis? in Chemistry? no Test using reverse genetics Generate resistant strain Develop affinity assay S. cerevisiae S. cerevisiae M. graminicola M. graminicola P. infestans, Affinity Based successful P. Infestans M. grisea Etc unsuccessful Forward Genetics Generate SAR and Embark on protein correlate to biology purification directed by affinity assay or affinity chromatography supported by proteomics 37 Classification: PUBLIC
    38. 38. Plant pathogen platform for MoA DiscoveryEfficient transformation methodGood homologous recombination efficiency – for reverse genetics construct generationInducible/titratible promoter – for protein expression, overexpression induced resistance screens and lethal KO determinationGood predicted protein database – for peptide mass fingerprinting in affinity purification studiesAbility to map resistant mutants – direct identification of target protein by forward genetics38 Classification: PUBLIC
    39. 39. M. graminicola, the most important cereal disease in northern European countries ● ~17% of cultivated land is planted with wheat (worldwide) ● Estimated annual yield loss between 30 and 50% during an outbreak - It represents loss of >9 millions tons worldwide ● Ascomycete (Dothedomycete, like : Alternaria, Pyrenophora, Stagnospora) ● Pathogen is semi-biotrophic with a stealth growth ● Infection and spread via ascospores (airborne) and conidiospores (water splash) - Germ tube hyphae penetrate the leaves via stomata - First phase: biotrophic almost no growth, no symptoms for ~1 to 2 weeks - Second phase: necrotrophic, mediate PCD in plants, fast growth Non treated TreatedPhoto: GHJ Kema, Wageningen Univerisity and Research Centre,Plant Research International B.V., Wageningen, The Netherlands. 39 Classification: PUBLIC
    40. 40. M. graminicola plant pathogen platformEfficient transformation methodGood homologous recombination efficiencyInducible/titratible promoter – inducible promoter still neededGood predicted protein databaseAbility to map resistant mutants40 Classification: PUBLIC
    41. 41. Published – methods and tools to stimulate external research41 Internal use only
    42. 42. Outline● Global food security challenges● Syngenta● Syngenta seeds and R genes● Fungicide Active Ingredient Pipeline - MoA diagnosis - Biokinetics - Resistance assessment● Knowledge gap42 Classification: PUBLIC
    43. 43. Biokinetics and Microscopy The study of all processes which occur following initial contact between a pesticide and a target crop / fungus and delivery of the toxophore to the target site What they do …  spray droplet characteristics and behaviour (microscopy)  leaf surface redistribution  foliar spray retention, uptake, rainfastness, uv photo-stability  vapour movement  xylem and phloem systemicity and movement to new growth  metabolism in model systems and target organisms (maize cell culture, SEPTTR cell culture – looking to expand these to wheat and oomycete)  biokinetics in the lab, glasshouse, field, and on the farm43 Classification: PUBLIC
    44. 44. Biokinetics and Microscopy The study of all processes which occur following initial contact between a pesticide and a target crop / fungus and delivery of the toxophore to the target site What they do …  spray droplet characteristics and behaviour (microscopy)  leaf surface redistribution  foliar spray retention, uptake, rainfastness, uv photo-stability  vapour movement  xylem and phloem systemicity and movement to new growth  metabolism in model systems and target organisms (maize cell culture, SEPTTR cell culture – looking to expand these to wheat and oomycete)  biokinetics in the lab, glasshouse, field, and on the farm44 Classification: PUBLIC
    45. 45. Biokinetic issues● Gaps - Ability to follow movement of compounds within cell! - Range of efflux reporter strains in a plant pathogen - Range of metabolism reporter strains in a plant pathogen - Understanding metabolic capacity of plant pathogens45 Classification: PUBLIC
    46. 46. Outline● Global food security challenges● Syngenta● Fungicide Active Ingredient Pipeline - MoA diagnosis - Biokinetics - Resistance assessment● Knowledge gap46 Classification: PUBLIC
    47. 47. Resistance assessment● Frequently asked to address if a new compound have a high or low resistance risk?● UV mutagenesis and selection – but limited numbers are covered compared to the field.Gap: Tools for better quality resistance assessment47 Classification: PUBLIC
    48. 48. Guide selection of chemical inputsHistorically driven by diverse inputs (Combi-chem approaches)Can we be smarter at identifying biologically relevant chemical space?● Target based screening still not popular concept !● Stronger focus on hypothesis driven starting point - including relevant Pharma targets & chemistry as starting points48 Classification: PUBLIC
    49. 49. Outline● Global food security challenges● Syngenta● Syngenta seeds and R genes● Fungicide Active Ingredient Pipeline - MoA diagnosis - Biokinetics - Resistance assessment● Knowledge gap49 Classification: PUBLIC
    50. 50. Major gaps in fundamental understanding of Fungal Biology S. cerevisiae Neurospora crassa ~ 1200 ~ 1200 Systematic KO projects show similar numbers of lethal genes50 Classification: PUBLIC
    51. 51. Major gaps in fundamental understanding of Fungal Biology S. cerevisiae Neurospora crassa 500 Overlap is surprisingly poor!!! • Crude calculations, BlastP, 25% identity cut-off so very permissive • Rounded numbers!51 Classification: PUBLIC
    52. 52. Major gaps in fundamental understanding of Fungal Biology S. cerevisiae Neurospora crassa 350 Compare Lethals to M. graminicola 1000/1200 Neurospora lethal are in M. graminicola 850/1200 Yeast lethal are in M. graminicola Overlap = 350 • Crude calculations, BlastP, 25% identity cut-off so very permissive • Rounded numbers!52 Classification: PUBLIC
    53. 53. Major gaps in fundamental understanding of Fungal Biology S. cerevisiae Neurospora crassa 150 350 500 750 M. graminicola 1000/1200 Neurospora lethal are in M. graminicola 850/1200 Yeast lethal are in M. graminicola• Crude calculations, BlastP, 25% identity cut-off so very permissive• Rounded numbers! 53 Classification: PUBLIC
    54. 54. 54 Classification: PUBLIC
    55. 55. General areas of interest for Syngenta Biological Sciences● Weed, insect and fungal resistance (including mathematical modelling)● Metabolism in fungi, plants, nematodes and insects (including modelling and prediction)● Predictive toxicology and selectivity between pest and non-target organisms● Chemical biology approaches to agricultural science● Systems and synthetic biology in agriculture● Assay development and target identification● Microscopy – micro-localisation of chemicals in plant, fungal and insect tissues● In-vitro assay to whole organism translation● Plant phenotyping● Movement of chemicals in soil and uptake into roots● Genetics - translation into pests from models & marker identification● Protecting seeds from insect and fungal attack● Plants and abiotic stress55 Classification: PUBLIC
    56. 56. A web portal to submit innovative ideas - opportunities and collaboration www.syngentathoughtseeders.com56 Classification: PUBLIC
    57. 57. 57 Classification: PUBLIC
    58. 58. Key pathogens (no particular order)● Mycosphaerella graminicola (Zymoseptoria tritici)● Fusarium graminearum, oxysporum & verticillioides● Botrytis cinerea● Blumeria graminis tritici● Puccinia graminis tritici● Alternaria● Cercospora● Magnaporthe grisea● Rhizoctonia● Phytophthora infestans● Plasmopara● Pythium● Phakopsora pachyrhizi● No genome yet58 Classification: Confidential
    59. 59. Syngenta Seeds Position on R genesNative traits approach● Genetic resistances against fungus in plants are used for decades.● In many crops, resistance traits have been identified and characterized. Some genes have been identified● A range of commercial varieties exhibiting high or intermediate resistances against obligate or necrotrophic fungus.● Frequently these resistances are linked to active immunity pathogen recognition by the plant triggers plant resistance - often seen as a hypersensitive response.59 Classification: PUBLIC
    60. 60. Resistance genes used in Tomato (Solanum lycopersicum)Some resistance loci commonly used in commercial varieties:● Ve Verticilium dahliae and Verticilium albo-atrum● Frl Fusarium oxysporum radici-lycopersici● I1,I2,I3 Fusarium oxysporum lycopersici● mlo Oïdium neolycopersici● Lv Leveillula taurica● St Stemphylium solani● Ph1,Ph2,Ph3 Phytophthora infestansNot an exhaustive list60 Classification: PUBLIC
    61. 61. Issues● Necrotrophic fungus are more complex to control by genetic means and only intermediate resistance are currently available.● Despite the high frequency of resistance in the natural plant diversity, some groups of pathogens such as Oomycetes are more complex to control only from genetic factors● In some pathosystems, resistance traits spread in commercial germplasm are durable whereas in some others it’s not.● Continuous effort required to provide resistant variety to growers.61 Classification: PUBLIC
    62. 62. Perception of many!● Pathogen diversity and evolution allow rapid breaking resistance – Making GM approaches risky and unattractive● “Engineering would take much longer than the defeat of the R-gene in the field”. Methods to deliver Durable Resistance Methods to assess Durability of Resistance Mutagenesis approaches – numbers game is a problem62 Classification: PUBLIC
    63. 63. 63 Classification: PUBLIC
    64. 64. 64 Classification: PUBLIC
    65. 65. Resistance breeding activitiesThe classical approach● Search for phenotypic variability in diverse natural germplasm.● Genetics of the most favorable phenotype is characterized via the construction of a genetic map and BSA or QTL studies according to the genetic complexity of the resistance.New approach● Utilize fungus effectors to identify host receptor in natural or induced germplasm diversity.65 Classification: PUBLIC
    66. 66. Issues/gaps summary● Data integration approach for yeast work?● OER in appropriate plant pathogens● Inducible promoter for M. graminicola work● Ability to follow movement of compounds within cell!● Range of efflux reporter strains in a plant pathogen● Understanding metabolic capacity of plant pathogens● Range of metabolism reporter strains in a plant pathogen● Tools for better quality resistance assessment● Tools for target prioritisation/compound follow up66 Classification: Confidential

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