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R&DA Conference October, 2008

Current work and new lipid strategies to combat warfighter stress

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PROGRAM GOALS

Contract with US Department of Defense to develop long shelf-lifetomatoes and lettuce using novel molecular breeding technologyTILLING®

DOD Program Goals– Increase shelf-life by 50-100% with no loss in nutrition, freshness,

color, crispness or taste – Grown domestically for military procurement– Available through normal commercial channels

Arcadia - using selective breeding technology to achieve program goals– Increasing firmness– Preventing over-ripening– Introducing better chilling tolerance – tomatoes and lettuce treated differently for shipping/storage

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DISTRIBUTION CHALLENGES

• Tomatoes are a soft fruit when ripe and easily subject to damage .

• Tomatoes are repeatedly handled throughout the distribution system.

Fruit suffers losses at very handling point as it softens and loses firmness

– HAND picked from plants– HAND and machine sorted over packing shed line– HAND packed into boxes– Resorted by HAND after 7 days of ripening– Resorted by HAND at point of delivery– Resorted by HAND at final destination

• Tomatoes suffer from chilling injury when stored below 55°F.– Most leafy greens, vegetables and fruits are stored below 40°F

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INCREASED FIRMNESS

Increased firmness using by our lead gene candidate

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REDUCED ROT

Candidate

Control

Candidate

Control

Harvest at Breaker

After 1 month

After 4 months

Candidate

Control

Using our lead long shelf life candidate (55F)

STUDIES IN PROGRESS

• Natick Soldier Center – Sensory evaluation of greenhouse and field

grown tomatoes 2008– Temperature storage studies

• Marita Cantwell at UC Davis Post Harvest Physiology– Firmness– Ethylene sensitivity– Shelf life studies

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By Stress Reduction Using Novel Dietary

Lipid Strategies

Enhancing Warfighter Performance

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Arcadia Biosciences, Inc.

Using agricultural biotechnology to develop plants that improve the

environment and human health

GLA – An Essential Omega-6

• Evening primrose and borage oil – traditional sources– Only 10% and 20% GLA– Supply inconsistent – high price

• GLA Safflower Oil

– > 50% GLA concentration– Supply consistency– Cost effective

Warfighter Stress

maximum of inducing factors

In Harm’s Way

No family - new associations

Climatic factors

Varied sleep patterns

New dietary regimens

Fatigue

Bodily injury

Physiological Stress

Psychological Stress

Hereditary based Stress

Essential Fatty Acids - Omega-3 & Omega-6

Essential ► your body can not make them

Essential ► you will perish without them

Essential ► offer vital inflammatory control

Essential ► providing immense systemic support

Essential ► proper brain development for infants

Essential ► many countries now establishing DVs

Discovered 1930’s - Burr & Burr

EFAs - the Omega Oils

Two primary classes - omega-3s and omega-6s

• Omega-3s > fish oil - high public profile ALA, EPA, DHA

• Omega-6s > varied and often confusing commentaryARA (arachidonic) for infants – excess is bad for adults

LA (linoleic) good for cholesterol - excess problematic?

• GLA – a vital metabolic omega-6 fatty acid

GLA + EPA = Synergy

Simplified EFA Pathway

• n-6 and n-3 paths > parallel

• Eicosanoids – signaling molecules effecting inflammation - immunity

• EPA and DGLA metabolites both act as inflammatory mediators

COX/LOX also metabolize ARA topro-inflammatory eicosanoids

Most ARA from animal product consumption

Parallel Pathways – Complimentary Efficacy

Benefits of either GLA or EPA are quite similar

Both offer dietary support for a host of similar conditions

» Inflammatory Control» Stress – Neurological Disorders» Arthritis – Joint Pain» Immune System Support» Skin diseases - rashes» Compulsive disorders, ADHD, cognitive functions» Cardiovascular Disease

Substantial clinical science supporting both GLA and EPA

Inflammatory Control is Critical

Uncontrolled inflammation - implicated in many diseases

Shubert R, et al, 2007, Influence of low-dose polyunsaturated fatty acids supplementation on the inflammatory response of healthy adults, Nutrition Oct;23(10):724-30

Autoimmune disorders Neurological disorders

Asthma – respiratory distress

Eczema, dermatitis, psoriasis

Cardiovascular disease

Diabetes and Metabolic Syndrome

Rheumatoid arthritis

EFAs in stress management

GLA shown to improve task performance under stress– Reduces blood pressure and heart rate responses to stress– Data suggests diet can alter stress reactivity in man1

EFA supplementation linked to reduced depression– Meta-analysis by Appleton et al2 2006 – Am. J of Clinical Nutrition– Depression – response to low-grade systemic inflammation– Supports: bipolar disorders, schizophrenia, mental acuity

GLA + EPA reduces antisocial behavior– Study of 231 incarcerated young men shows a 26 -37% decline3

– Study recently replicated in the NL – 34% decline

- Inflammatory Control -

Abbott Nutrition – Ross Labs

• OxepaTM Medical Food

• 4.0g/L GLA + 4.6g/L EPA daily

• Inflammatory modulation for ICU patients with respiratory distress syndrome

• As published in the Journal of Critical Care Med.– GLA + EPA reduced term of ICU confinement from

17.5 to 12.8 days ( > 25% reduction)

• Ross cited referencesGadek JE et al. Crit Care Med 1999;27(8):1409-1420.Singer P et al. Crit Care Med 2006;34(4):1033-1038.Pontes-Arruda A et al. Crit Care Med 2006;34(9):2325-2333.Murray MJ et al. Am J Physiol1995;269:H2090-H2099.Horrobin DF. Rev Contemp Pharmacotherapy 1990;1:1-45.Pacht ER et al. Crit Care Med 2003;31(2):491-500.

Inflammatory Sports Injuries

• Pharma Nord - ActiveComplex

• GLA plus EPA/DHA formulated with complimentary vitamins/minerals

• Used for 10 yrs. by Danish Olympic teams for treatment of inflammatory, over-use injuries

• Systemic and cellular balance of inflammatory versus anti-inflammatory eicosanoids

GLA/EPA and Joint Pain

• Clinicals show GLA + EPA tested on RA reduced: pain swelling inflammation morning stiffness

• Dozens of positive clinical results

• Reduces or eliminates need for NSAID medication• 1988, Belch JJ study – 450mg GLA + 240mg EPA

80% GLA+EPA - stopped or major reduction in NSAIDs 71% with just GLA 33% for placebo group

Belch JJ,et al. Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double-blind placebo-controlled study. Ann Rheum Dis 1988;47:96-104.

Reduced NSAID Usage

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12

Percentage of patients on full NSAID dosage

Months of GLA/EPA supplementation

Belch JJ et al. Annals Rheum Dis 1988 47: 96-104

COX Inhibitors

• Aspirin, naproxen and other non-selective inhibitors act on all COX enzymes (not just COX2)

• Inhibits important GLA/DGLA metabolite > PGE1

• PGE1 protects stomach lining – hence bleeding with excess aspirin, naproxen, NSAIDs.

• NSAID side effects – resulting from non-selective COX inhibition:

Stomach bleeding High blood pressure Headaches Extra platelet aggregation Fluid retention

20:4arachidonic acid

ARA

LOX115-HETrE

COX2

2-series prostanoids

5 LOX

pro-inflammatory

5

4-series LT’sltb4

EPA inhibits 5

20:3 DGLA

PGE1 COX1

EFAs and Skin Health

Warfighters develop skin irritations – multiple sources

• Climatic factors (hot dry air)

• Chemicals or pollutants as factors

• Stress factors

• Inherent disease – eczema, psoriasis

Reduced Eczema Symptoms by GLA Supplementation

Weeks of supplementation

Severity of symptoms

Itching

Vesicleformation

Inflammation

Oozing

Adapted from Adreassi, M. et al. Journal of International Medical Research, 1997 Vol. 25, pp 266-274

GLA/EPA for Respiratory Relief

Clinically proven to combat asthma

Mitigates bronchial tube inflammation

Further testing needed for field extremes

GLA/EPA for asthma treatment

Efficas – GLA/750mg + EPA/500mg as a medical food

Specific ratio – maximum inhibition of inflammatory leukotrienes

GLA and EPA working in concert to minimize ARA conversion to inflammatory leukotriene LTB4

Surette ME, Stull D, Lindemann J, The impact of a medical food containing gammalinolenic and eicosapentaenoic acid on asthma management and quality of life of adult asthma patients. Curr Med Res Opin. 2008 Feb;24(2):559-67

Department of Chemistry and Biochemistry, University of Moncton, Moncton, NB, Canada marc.surette@umoncton.ca

Other benefits of GLA/EPA for both military & civilian populations

• Conditions aggravated by inflammation

Osteoporosis

Cardiovascular health

Women’s health

General skin function

Decreased prospects of sepsis

Directions Forward

Establish a scientific basis to understand benefits of dietary uses of controlled GLA/EPA ratios in the military context

Develop palatable uses in food systems

Incorporate dietary antioxidants (Quercetin) to augment and enhance the control of inflammatory reactions under stress

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Thank You Ken Ardisson

ken.ardisson@arcadiabio.com

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Selected References

1. Mills DE, et al, 1989, Dietary fatty acid supplementation alters stress reactivity and performance in man. J Hum Hypertension Apr;3(2):111-6

2. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n–3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006;84:1308–16.

3. Gesch B, et al, Influence of supplementary vitamins, minerals and EFAs on the antisocial behavior of young adult prisoners. Brit J Psych, 2002 July;181:22-8

4. Arnold L et al. Gamma-linolenic acid for attention-deficit hyperactivity disorder: placebo-controlled comparison to d-amphetamine. Biol Psychiatry 1989;25:222-228.

5. Joshi K, Lad S, Kale M,et al, Supplementation with flax oil and vitamin C improves the outcome of Attention Deficit Hyperactivity Disorder (ADHD).Prostaglandins Leukot Essent Fatty Acids. 2006 Jan;74(1):17-21. Epub 2005 Nov 28.

6. Maida ME, et al, Cytosolic prostaglandin E2 synthase (cPGES) expression is decreased in discrete cortical regions in pyschiatric disease. Brain Res 2006, 1103:164-172

7. Lakhan SE, Vieira KF, Nutritional therapies for mental disorders Nutrition Journal 2008 7:2

8. Schachter HM, et al, Effects of Omega-3 Fatty Acids on Mental Health. Evidence Report/Technology Assessment AHRQ Pub. No. 05-E022-1 Rockville, MD: Agency for Healthcare Research and Quality. July, 2005