Generativism

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Epigenetics and phenotypic plasticity: Methods of assessment and actionable consequences.

PETER J. D’ADAMO, ND, MIFHI

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

P4 Medicine

Leroy Hood Institute For Systems Biology Seattle Washington Predict

Prevent Personalize

Participate

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

GENERATIVISM

(PREDICT)

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

GENERATIVE SCIENCE

Generative

Adjective /ˈjenərətiv/ /-ˌrātiv/ /ˈʤɛnəˌreɪdɪv/

Able to produce • the generative power of the life force

4 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Generative Medicine

• Is the interdisciplinary and multidisciplinary specialty that explores life at the physical, biological and social levels as emergent processes

• Shows how deterministic and ﬁnite rules and parameters in the natural processes interact with each other to generate indeterministic and inﬁnite results

• Explores complex life processes as generating through continuous interactions between elemental entities on parsimonious and simple universal rules and parameters • Embodies the fundamental principles of holism • Basic unit is the Complex Adaptive System 5

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

The Paradigm

• The generative paradigm is a meta-model of how and why events occur in living systems • Embodies the fundamental principles of holism, • Result from the phenomena of emergence • A tendency for complex interactions to produce unanticipated, or even counterintuitive, results • Basic unit is the complex adaptive system

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

The Paradigm

• Dominated by scale-free networks and power-law probabilities (80/20 rules) • Not gaussian (bell-shaped) probabilities • Usually features a large number of interacting components, such as agents, variables and processes • Known as the state-space of the system

8 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

GAUSSIAN (MEDIOCRISTAN)

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

NORMALISTAN

Number of cities population >500,00

0 2 3 4 5 Number of connecting interstates 11

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

POWER-LAW (EXTERMISTAN)

12 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Why the rich always get richer

1 10 10 100 100 1000

Power-law J shaped probability curve

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Power laws in life

• Pareto’s Distribution: 80% of the wealth is owned by 20% of the population • Zipf’s Law: The distribution of words ranked by their frequency in a random body of text is generally a power-law distribution • Size of sand granules • Google rankings • Ritualization : repetitive use of pathways • Hebb's rule: cells that ﬁre together wire together

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

3/4 POWER LAW

The ﬁrst accurate measurements of body mass versus metabolic rate by Kleiber in 1932 shows that the metabolic rate R for all organisms follows exactly the 3/4 power-law of the body mass, i.e.,

¾ R0 ~ M 15

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

4/3 POWER LAW

16 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

FRACTAL TREES

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

LIVING SYSTEMS SHRED-OUT

Cell Membrane James Grier Miller, Living Systems. McGraw Hill, New York, NY. (1978)

Parenchyma

Integument (skin)

Customs

Miller’s shred-out is an early example of Membership what is now known as a scale free network

Border

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

THINKING IN NETWORKS

• Graph theory is the study of graphs: mathematical structures used to model pairwise relations between objects from a certain collection. • A network is a directed graph (digraph) with weighted edge. • Network theory is an area of computer science and network science and part of graph theory. • Systems biology is the study of biologic circuitry

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

A SIMPLE GRAPH NETWORK

• Analyzing networks involves graph theory • Connectors are known as nodes • Connections are known as edges • Edges can be directed or undirected

20 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

DANCING WITH NETWORKS

(PREVENT / ANTICIPATE)

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Perturbations and robustness

• Perturbation synonymous with disturbance • Robust systems respond efﬁciently to perturbations • Extrinsic (environmental) or Intrinsic (homeodynamic) • Fragile Systems: • Cannot handle basic perturbations • Are over-optimized for speciﬁc perturbations • Antifragile systems actually improve with disruption

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

System fragility

• A system that is optimized for a speciﬁc perturbation inevitably entails extreme fragility for unexpected perturbations • These kind of trade-offs are common in biological systems

24 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Fine-tuning

• Properties that are not robust are called ﬁne-tuned • Each is the opposite of the other • These properties change signiﬁcantly when biological parameters are altered • Fine-tuning usually involves some aspect of noise reduction

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

The more you anticipate the needs of a complex network the more you risk increasing its fragility.

'Sometimes too much good is no good.'

James D'Adamo

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

KEGG (Kyoto Encyclopedia of Genes and Genomics)

Diseases are perturbations of the molecular system

Drugs are peturbants of the molecular system

Please note paradox here.

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Network Medicine

• Hubs • None-essential disease genes tend to avoid hubs • In-utero essential genes tend to be associated with hubs • Local hypothesis • Proteins involved in the same disease have an increased tendency to interact with each other • Mutations in interacting proteins often lead to similar disease phenotypes

28 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Disease networks • Disease module hypothesis • Cellular components associated with a speciﬁc disease phenotype show a tendency to cluster in the same network neighborhood • In-utero essential genes tend to be associated with hubs • Network parsimony principle • Causal molecular pathways often coincide with the shortest molecular paths between known disease associated components • Shared components hypothesis • Diseases that share disease associated cellular components (genes, proteins, metabolites, micro RNA) show phenotypic similarity and comorbidity 30

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Noise and information

• Most noise in complex adaptive systems stems from random (stochastic) events • Cellular noise: entropy, thermal variants, collisions etc. • Intrinsic cellular noise: variation in regulated quantities inside a single cell • Extrinsic cellular noise: variation between identical cells in a population • Living systems either export their entropy (negentropy) or use information to resolve uncertainty

32 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Noise and information

• Information could be treated very much like any other physical quantity such as mass or energy via its ability to surprise • To understand how information can be quantiﬁed we need to divorce ourselves from the all-too-human tendency to equate information with meaning

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Generative Strategies

• Increasing robustness is a good strategy in an unstable system • Fine-tuning is a good strategy in stable systems that function in stochastic type environments • Dithering: the intentional application of perturbation • Can help ﬁne-tuning mechanisms 'unstick' due to ratcheting error where an intended mechanism may lack sufﬁcient free energy to continue • Simulated annealing: adding stochastic noise to a system to improve improve information carrying capacity 34

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Generative Entrenchment

• Term coined by William Wimsatt in 2007

• The adoption and propagation of sub-optimal solutions in a ﬁtness landscape can lead to generative entrenchment

• A genetic mutation or recombination that affects the earliest stage of development will have more side effects down the road than would one which ﬁrst acted later and many of these would likely be maladaptive.

• VHS cassette tape format versus Sony Betamax

• ‘Small World Phenomena’

• Accumulation of epimutations in aging 36 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

The goal should not be to eliminate errors, but to recognize and metabolize them.

-William Wimsatt

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

EPIGLYCOMIC PHENOTYPES

( PERSONALIZE )

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Glycoconjugates are increasingly gaining recognition as important operative high-density information coding systems and as an elaborate enzymatic machinery enabling cells to be versatile enough to produce a glycan proﬁle (glycome) as characteristic as a ﬁngerprint. (1)

Gabius HJ and Wu AM. The emerging functionality of endogenous lectins: A primer to the concept and a case study on galectins including medical implications. , 2006.Chang Gung Medical Journal, 29(1), pp. 37-62.

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Aberrant N-linked glycosylation O-linked

‘Hard glycosylation’ ‘Soft glycosylation’ • Endoplasmic reticulum/ Golgi • Mucins • Receptor glycosylation • Barrier defenses • Protein tagging • Adhesion molecules • Tumor antigens

40 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Factors inﬂuencing glycosylation

• Animal species • Blood group speciﬁcity • Age • Site in the intestines • Position along the crypt/ villus axis • Diet • Pathology • Cancer • Inﬂammation • State of differentiation and maturation • Bacterial status

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

N-glycans and protein folding • Interact with chaperone proteins in the endoplasmic reticulum • Chaperone proteins aid the folding of the attached protein • Decreased in Alzheimer’s Disease • ER stress • Unfolded Protein Response • Hormesis

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Protein Tagging

Ubiquitination Epigenetic modiﬁcation

Aberrant N-linked glycosylation Transcription factor inactivation Autophagy

Housekeeping Apoptosis ER Stress

Programmed cell death Drugs, xenobiotics, Receptor lectins etc agonism Unfolded Heat Shock Protein Response Most receptors Response heavily glycosylated

Autoimmune disease Hormetic Response Neurodegenerative Aging

Molecular chaperones Phenotypic canalization 43

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

O-linked glycans

• Glycan attached to the oxygen atom of serine or threonine side chains • Most common O-linked glycoproteins are often termed mucins • Ubiquitous in mucous secretions on cell surfaces and in body ﬂuids

44 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Transcription factor inactivation Epigenetic Histone Ubiquitination modiﬁcation acetylation

N-linked Aberrant Autophagy glycosylation O-linked ER Stress

Apoptosis

Unfolded Heat Shock Protein Receptor Dysbiosis Response Response agonism Tumor Hormetic antigens Response

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Blood groups and microbiome

• Colonic bacteria degrade ABH mucins • ABH mucin breakdown byproducts → bacterial substrate + source of free colonic SCFA

• Degradative colonic bacteria also blood group speciﬁc • Some strains are 50,000x more likely in particular ABO groups

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

ABH antigen distribution

• Tongue, salivary glands • Thyroid • Lung and pericardium • Endothelium • Liver and pancreas • Stomach • Intestines • Ovary and prostate • Mucosal surfaces 47

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Secretor status

• ABO is the blood group system • ABH describes the antigens • A secretor (FUT2+) possesses the gene to secrete unbound, free-form ABH antigen into body ﬂuids • A non-secretor does not (FUT2-) • Non-secretors are about 20% of the population, but will comprise about 80% of your difﬁcult, hard-to-manage cases (think power-law)

48 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Secretor genetics

• Secretor status controlled by two autosomal dominant alleles, Se and se • 80-85% are phenotypically secretors (SeSe or Sese) • The secretor gene FUT2 codes for the glycosyltransferases • Downstream from FUT1 O (H) antigen • FUT2 knockout are called non-secretors (‘nonnies’) • Link with Lewis Blood Grouping System (secretor: Lewis a-b+ /non- secretor: Lewis a+b-)

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Predictive aspects of secretor status • Brush border hydroxylases • Intestinal alkaline phosphatase activity • Bacterial ﬂora / Candida carriage • Gut mucosal defense/ IgA • Breast milk components • Blood clotting • Dental caries • Diabetes • Crohn's disease • Heart disease • Alcoholism and alcohol protective beneﬁts • Metabolic Syndrome X • Serum B12 Levels • CRP 50

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Why study phenotype?

Constraints! Genotype Phenotype Familial epigenome Prenatal environment 51

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

EPIGENETICS

• Reversible, heritable changes in gene regulation that occur without a change in DNA sequence (genotype) • Usually seen along developmental trajectories • Methods of biological inheritance that do not directly relate to the inheritance of collections of genes

52 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

FITNESS LANDSCAPES

Fitness landscapes are state-spaces that can be searched by optimization algorithms

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

The evolution of the embryo to the fetus is a series of narrowing ﬁne-tunable choices or canalizations, as genotype gives way to phenotype.

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Waddington's epigenetic landscape I

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

56 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

‘Reactive’ vs ‘Receptor’ vs ‘Thrifty’ epigenotypes

• Function of epigenetics and tissue glycomics

• Reactor epigenotypes have less fetal and prenatal phenotypic plasticity and greater opportunities for auto-immunity

• Receptor epigenotypes have greater phenotypic plasticity and greater opportunities for antigenic mimicry leading to microbial overgrowth and immune over-tolerance

• Thrifty epigenotypes are typically prone to excessive glycation

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Predictive Adaptive Response

• Gluckman and Hanson propose that the thrifty phenotype is adaptive in the longer-term - by preparing the organism for its likely adult environment • However windows of plasticity close early during human development and subsequent environmental changes may result in the selected trajectory becoming inappropriate

Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12759-62

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

“Disease occurs if an environmental challenge exceeds the ability of an individual to mount an effective adaptive response to it.”

Gluckman and Hanson. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12759-62

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

30% Household genes - immutable by environment

70% Luxury genes - mutable by environment

60 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Two main components of the epigenetic code DNA methylation/ histone acetylation

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Other epigenetic mechanisms

• Ubiquinylation via S26 proteosome • Most common method of transcription factor deactivation • SUMOlylation • Hairpin RNA • Stop tRNA/ Ribosome translation

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Natural products involved in methylation epigenetics

Methyl donation • Methylcobalamine • SAMe • Methionine • Betaine • Folate

Reversal of hypermethylation • Genistein and related soy isoﬂavones • Green tea polyphenols • Caffeic acid, chlorogenic acid (coffee) 63

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

PHENOTYPIC INTERPRETATIONS

64 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Markers of phenotype plasticity • Biometrics • Indexes • Leg-torso • Upper-lower leg • D2/D4 • Dermatoglyphics • Pattern matching • White like • Assymetry 65

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Three basic ridge patterns

Whorl Arch Loop

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Fingerprint topology: The triradii

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Ridge height and atrophy • Although ridge patterns are permanent, ridge height is quite dynamic • Ridge hypoplasia: epidermal ridges are reduced in height giving a ‘worn off’ appearance • White lines are ﬂexion creases on ﬁngerprints • Ridge height and white lines can tell a lot about the state of health of the gut mucosa • White lines correlate with gluten, gliadin and lectin sensitivity 68 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Pleiotropy

Occurs when a single gene inﬂuences multiple phenotypic traits.

Consequently, a new mutation in the gene may have an effect on some or all traits simultaneously.

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Epistasis

In genetics, epistasis is a phenomenon in which the expression of one gene depends on the presence of one or more 'modiﬁer genes'.

ABO is perhaps the most active epistatic locus

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Fluctuating asymmetry

• Refers to random, small deviations from perfect bilateral symmetry in morphological traits • These minor deviations reﬂect environmental and genetic stress experienced during ontogeny • FA has been associated with negative health outcomes and many developmental disorders in humans • FA is a ‘pure measure’ of developmental instability

72 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

D2-D4 index

• The ratio of the lengths of the second to fourth digit • Appears to correlate with prenatal exposure to androgens • Some reﬂection of HOX2 gene

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

2D:4D Digit Ratio Traits

Manning, J. T. (2002). Digit ratio: A pointer to fertility, behavior and health. NJ: Rutgers University Press.

Low 2D:4D ratio High 2D:4D ratio Presumably due to relatively greater Presumably due to relatively greater fetal exposure to testosterone in the fetal exposure to estrogen in the 1st 1st trimester. trimester. More fertile Higher lifetime reproductive success Males More aggressive and assertive Higher risk of early heart disease Greater proclivity toward homosexuality/ bisexuality Higher musical and sports aptitude Greater proclivity toward More fertile Females homosexuality/ bisexuality Higher lifetime reproductive success More aggressive and assertive Higher risk of breast cancer

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

THE TWO-FOLD ASPECT OF EVERYTHING

( PARTICIPATE )

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

76 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Hierarchies

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Protein Folding

• Protein folding is greatly inﬂuenced by stresses, such as • Temperature changes • Exercise • Oxidative damage • Chemical toxins • Aging

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

‘It is thus not surprising that a number of pathological conditions, such as cancer as well as neurodegenerative and cardiovascular diseases, are associated with an abundance of mutated and misfolded proteins that overwhelm or deregulate chaperone activity.’

Ahmed Chadli, PhD Center for Molecular Chaperone / Radiobiology and Cancer Virology Molecular Oncology Program, Chaperone Biology http://www.georgiahealth.edu/cancer/people/chadlilab.html

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Endoplasmic reticulum

• Central place of lipid synthesis, protein folding and protein maturation • Proteins fold into their ultimate structure in the ER • The ER is the major signal transducing organelle that senses and responds to changes of the homeostasis • Conditions interfering with the function of ER are collectively called ER stress

80 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

ER Stress

• Induced by accumulation of unfolded protein aggregates or by excessive protein trafﬁc (viral infection) • Stress conditions lead to decreased rate of protein translation to prevent further accumulation of unfolded proteins • Transcription factors are activated in order to induce the expression of ER-resident chaperones to deal with accumulated protein aggregates • Protein-degrading apparatus becomes activated and eliminates denatured proteins • If the stress cannot be resolved, the cell dies by apoptosis 81

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

ER Stress, UPR and Disease

• Obesity, insulin and type 2 diabetes • Inﬂammation • Crohn’s • Ulcerative colitis • Inﬂammatory bowel disease • Neurodegenerative disorders • Alzheimer's disease • Parkinson's disease • Bipolar disorder • Liver disease • Cancer

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

HEAT SHOCK PROTEINS

• Induced by various physical, chemical, and biological stresses • Bind glucocorticoid receptors in cytoplasm • Function as molecular chaperones • They not only regulate various processes of protein biogenesis but also function as lifeguards against proteotoxic stresses • Critical for synthesis, folding, translocation, assembly and degradation of proteins

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

‘The Hsp90 stress response protein is an ancient, abundant and nearly ubiquitous protein chaperone that supports an essential group of conserved signal transduction proteins in nearly every organism and cell type examined.’

Milton CC, Ulane CM, Rutherford S (2006) Control of Canalization and Evolvability by Hsp90. PLoS ONE 1(1): e75. doi:10.1371/ journal.pone.0000075

84 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

HSP-90

• Heat shock protein 90 implicated in the epigenetic control of phenotype, a process known as canalization • A balance between Hsp90 buffering and the expression of morphological traits is most likely moderated in nature by environmental stress • Stress-damaged proteins titrate Hsp90 from signal transduction proteins • Severe stresses in nature can temporarily overwhelm the Hsp90 chaperone system

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Heuristic

• If your patient has been prescribed a steroid they have some element of ER stress and UPR • They are glycosylating in some aberrant manner

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

What is a lectin?

• ‘Multivalent carbohydrate-binding proteins or glycoproteins’ • A more ﬂexible interpretation would be ‘lectins are proteins which speciﬁcally bind (or cross link) carbohydrates’ • Think velcro

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Agglutination / Hemolysis

Image source: Random House Encyclopedia (first edition, 1977)

88 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Lectins in the world/ lectins in the diet

36 of 88 lectins identiﬁed in common 50% of over 2000 plants investigated foodstuffs showed some ABO contained lectins speciﬁcity

Link 89

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Foods With Known Dietary Lectins • Adzuki Beans • Eel • Onion, all types • Scallion • Alfalfa Sprouts • Egg Whole, Chicken • Orange • Sesame Oil • Allspice • Eggplant • Oyster • Sesame Seed • Aloe Vera • Fava Bean • Papaya • Snail, Escargot • Amaranth • Filbert, Hazelnut • Parsley Soybean • Apple • Garbanzo Bean, Chickpea • • Parsnip • Soybean Flour • Artichoke • Garlic Peanuts • Soybean Meal • Asparagus • Goat • Peas • Soybean, tofu • Asparagus Pea • Grapefruit • • Pepper, Bell • Squash • Avocado • Green, String Bean • Pepper, Red Flakes • Strawberry • Banana • Haddock • Perch • Sunflower Seed • Barley • Hake • Perch, Ocean • Swiss Chard • Beet • Halibut • Pinto Bean • Tamarind Bean • Blackberry • Herring • Plantain • Tempeh • Buckwheat, Kasha, Soba • Honeydew • Plum • Tomatillo • Carrot • Jack Fruit • Pomegranate Tomato • Celery • Kidney Bean • • Potato, White With Skin • Tomato juice • Chayote, Pipinella • Leek • Quail • Trout, rainbow, wild • Cherimoya • Lemon • Quince • Walnut • Cherry • Lentils • Quorn Wheat, • Chestnut, European • Lima Bean • • Radish • Wheat,, Bram • Chicken • Marjoram • Raspberry • Wheat, Durum • Chicory • Milk, Soy • Rhubarb • Wheat, White Flour • Clam • Miso • Rice flour, brown • Wheat, Whole Grain • Corn • Mung Bean • Rice flour, white • Wheat, Whole Grain • Cornmeal, Hominy, Polenta • Mushroom, Oyster • Rice, Basmati Emmer • Cornstarch • Mushroom, Straw • Rice, Brown • Wheat, Whole Grain Kamut • Cucumber • Mushroom, White • Rice, White • Wheat, Whole Grain Spelt • Currants • Navy Bean • Salmon Roe • Zucchini • Durian • Nutmeg 90

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Dietary lectins and colon cancer

• Dietary lectins can alter the proliferation of colonic cells • Differentiation is regulated by adhesion molecules which, being glycosylated, are targets for lectin binding • VFA (broad bean lectin) Agaricus bisporus (mushroom) lectin stimulated an undifferentiated colon cancer cell line to differentiate into gland like structures

Dietary or therapeutic VFA may slow progression of colon cancer. Gut 1999 May;44(5):709-14

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Modern wheat and inﬂammation

• Inflammatory states = altered glycosylation • Galactosyl groups hinge the Fc region of the IgG and IgA molecule • In auto-immune diseases, galactosyl groups replaced with NAG or mannose MAN • Termed galactose deficient antibodies • Avoidance of wheat may suffice for therapy - especially in the early stages

92 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Wheat Germ Agglutinin (WGA)

• Total protein content of wheat 3-12% • Lectin (WGA) part of the protein fraction • Rather small lectin - easily endocytosed • Heat resistant - resists proteolysis • Speciﬁc for (NAG) amino sugar • Over-represented in the digestive tract of • Blood group O • Non-secretors • Hyper-inﬂammatory states 93

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Soy: not so simple • Soy Bean Agglutinin or SBA • SBA speciﬁcity • Purges marrow after stem cell therapy • Phytoestrogens • Endothelial protection • Saponins • Anti-cancer • Anti-mutagen • Side chain cleaving enzymes de-cloak cancer • Lignans

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Lectins and dietary absorption • Most lectins in our diet are resistant to breakdown • Bound and endocytosed by epithelial cells. • Powerful exogenous growth factors for the small intestine • Induce dramatic shifts in its bacterial ﬂora • Interfere with its hormone secretion. • Lectins which are transported across the gut wall into the systemic circulation can modulate the body's hormone balance, metabolism and health

• Eur J Clin Nutr. 1993 Oct;47(10):691-9. 95

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Lectins and Allergy

• Most lectins given orally are immunogenic • Lectins can modulate IgE responses to other antigens • Dietary lectins can induce the release of IL-4 and IL-13 from human basophils • Dietary lectins are known to prime TH2 helper lymphocytes. • Most humans carry antibodies to common dietary lectins

96 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Lectins and Gut Permiability

• Lectins can overstimulate and exhaust the capacity of goblet cells to synthesize mucin • Endocytosis in the small intestine greatly enhanced by the presence of large numbers of commensal bacteria • Endocytosis of lectins is more extensive in the colon where bacterial counts are high

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

The philosophy of hormetism is based upon harnessing this biologicalphenomenon in a deliberate and systematic way in order to increase strength and resilience.

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

100 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Impact of hormesis on basic concepts

• Low-dose stimulation is a measure of biological performance • The magnitude of the response is a reﬂection of biological plasticity • Hormetic response highly conserved • Compensatory stimulation is a fundamental aspect of adaptation • Low-level stress optimizes system performance

101

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Biological performance

• Cell proliferation • Growth • Longevity • Strength • Disease resistance • Increase in cognition • Generative/ regenerative functions

102

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Even small hormetic improvements can have a big effect on the quality of life The effects are primarily due to re-stabilization of the biological networks

103

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Hormesis and Aging • Good news: • There are no genes made with a speciﬁc purpose to limit life span • No gerontogenes that limit lifespan and which need to be neutralized • Even death mechanisms (apoptosis) are as much a part of growth as they are of death

104 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Homeodynamic space

• Buffering capacity in homeodynamic space • Counteracts disturbances • Determinant of survivability • Aging is a progressive shrinkage of the homeodynamic space • High degree of individualization

105

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Shrinkage of the homeodynamic space • Accumulation of molecular damage • Mutations • Epimutations • DNA damage • RNA damage • Protein damage • A repair systems are not perfect • Damage can and dose appear in the repair mechanisms themselves

106

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Maintenance and repair systems (MARS)

• Genomic stability • Epigenomic stability • Protein stabilization • Macromolecule stability • Free-radical counteraction

107

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

HORMETIC AGENTS

• Heat • Radiation • Ozone • Pro-oxidants • Exercise • Hypergravity • Food restriction • Micronutrients • Hormetins 108 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

EFFECTS OF THERMAL HORMESIS

• ↓ in oxidatively and glyco-oxidatively damaged proteins • ↓ in the induction of sugar induced protein damage • ↑ wound healing • ↑ telomeric function • ↑ resistance to other stresses • H2O2 • ETOH • UV-A • Sugar

109

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

• Curcumin (HSP) • Saffron • Resveratrol • Milk Thistle • Trehalose • Cinnamomum cassi PHYTO HORMETINS • Paeoniﬂorin (chaperone inducer) • Podophyllotoxin • Glycyrrhizin (chaperone co-inducer) • Ergots, galls and smuts (neurovascular hormetics) • Radix Angelicae Sinensis • Radix Astragali • Rosmarinic acid • Scutellaria biacalensis (wogonin) • Clove • Ashwagandha (Withania somnifera) • Kinetin (plant growth factor) • Adaptogens 110

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

• CoQ 10 (H2O2 pro-oxidant) • Lipoic acid (H2O2 pro-oxidant) • Vitamin C (DNA oxidant) • Periodic fasting NUTRI-HORMETINS • Ethanol • Green tea (catechins proxidants) • Iron, copper, selenium, iodine, zinc, cadmium • Caffeic acid • Falcarinol (carrots) • Sulforaphane, glucosinolates, isothiocyanates • Homocysteine

111

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Heat shock stress response • Long-term hormesis studies on aging human ﬁbroblasts and keratinocytes • ↓ age -related changes • ↑ lifespan • ↑ tolerance to stress • ↑ functionality • ↑ wound healing • ↑ differentiation • ↑ blood vessel formation • ↑ bone differentiation

Suresh Rattan, PhD, DSc. Hormesis In Aging Research and Interventions . http://www.dose-response.org/podcasts/agingresearch.htm 112 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Multivariate data

A collection of procedures which involve observation and analysis of more than one statistical variable at a time.

113

Africa Asia Europe America Australia

Rh* D- 20% 15% 36% 20% 0%

ABO * O 69% 60% 65% 90% 76%

FY*A 11% 60% 42% 70% 99%

Explained Variance (Eigenvalues) Correlation Matrix

Value PC 1 PC 2 PC 3 PC 4 PC 5 Africa Asia Europe America Australia

Eigenvalue 3.799 1.201 0.000 0.000 0.000 Africa 1.000 0.370 0.942 0.613 0.154

% of Var. 75.975 24.025 0.000 0.000 0.000 Asia 0.370 1.000 0.660 0.961 0.975

Cum. % 75.975 100 100 100 100 Europe 0.942 0.660 1.000 0.842 0.477

America 0.613 0.961 0.842 1.000 0.875

Australia 0.154 0.975 0.477 0.875 1.000

114

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Food/ Nutrient Values.

115

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Now the fun starts.

116 CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Men n=126

117

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Women n=290 (median)

118

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

Subject Values.

119

CENTER OF EXCELLENCE IN GENERATIVE MEDICINE

SWAMIGenoType

Software platform computes Epigenotype and specific diet plan Variety of biometric, dermatoglyphic and serologic markers 16 Program Modules, 32,000 lines of source code 12.9 million computations per diet ‘Genoharmonics’ Mealplanner Doctor has final control of the ultimate food value Chart report can be kept in file or given to client for extra detail/ value

120