Genes and Environment, Developmental and Chronic: An Inclusive Approach to Autism Science

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Genes and Environment, Developmental and Chronic
An Inclusive Approach toAutism Science

• Martha Herbert, MD, PhD
• TRANSCEND Research Program
• Pediatric Neurology
• Martinos Center for Biomedical Imaging
• Center for Morphometric Analysis
• Massachusetts General Hospital
• Harvard Medical School
• www.transcendresearch.org

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Autism A Behaviorally Defined Syndrome

• DSM-IV Criteria for Autistic Disorder (299.0)
• Impaired social interaction
• Delayed and disordered communication
• Markedly restricted repertoire of activities and
  interests
• Autism SPECTRUM Disorder(s)

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Autism A Behaviorally Defined SyndromeBiology
is not part of the definition(and neither is
prognosis)

• DSM-IV Criteria for Autistic Disorder (299.0)
• Impaired social interaction
• Delayed and disordered communication
• Markedly restricted repertoire of activities and
  interests
• Secondary Features of Autism
• Seizures (30), cognitive deficits,
  sensorimotor abnormalities, savant skills, immune
  impairments, GI distress(50-75), food allergies
  (50)
• No biological markers exist to identify autism at
  this time
• Autism is presumably Heterogeneous biologically
• But autism is biological

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Conventional Modular Model
Gene Brain module
Behavior
AUTISM
Behaviors
Brain C
Social Interaction
Brain B
Communi- cation
Brain A
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Static model of autism
Genes Prenatal Brain Hopeless

• Inevitable
• Fixed
• Hardwired
• Unchangeable

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Multi-system from the start? Kanner 1943 on
body symptoms

• Case 1 Eating has always been a problem ..
  for him. He has never shown a normal appetite.
• Case 2 large and ragged tonsils.
• Case 3 diarrhea and fever following smallpox
  vaccination . healthy except for large tonsils
  and adenoids.
• Case 4 vomited a great deal during his first
  year feeding formulas were changed frequently
  tonsils were removed
• Case 5 nursed very poorly quit taking any kind
  of nourishment at three months tube-fed five
  times daily up to one year of ageAt camp she
  slid into avitaminosis and malnutrition but
  offered almost no verbal complaints.
• Case 7 vomited all food from birth through the
  third month.
• Case 8 feeding formula caused concern. colds,
  bronchitis, streptococcus infection, impetigo
• Case 9 none of the usual childrens diseases.
  ? Overactive immune system?
• Case 10 frequent hospitalizations because the
  feeding problem repeated colds and otitis media
• Case 11 was given anterior pituitary and thyroid
  preparations for 18 months
• Kanners original paper, discussed in Jepson 2007

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EmergingSystemsApproach
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Distributed Genetic ContributorsBeyond clear
gene-brain-behavior relationships
No obvious single genes of strong effect Lots of
different combinations of genes Rzhetsky, 2007,
PNAS Probing genetic overlap among complex human
phenotypes
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Environmentally responsive geneshigh frequency,
low penetrance modulation of vulnerability
http//www.niehs.nih.gov/envgenom/egp6.htm

• cell cycle
• cell division
• cell signaling
• cell structure
• DNA repair
• gene expression
• homeostasis
• metabolism
• immune and inflammatory response
• hormone metabolism
• nutrition
• oxidative metabolism and stress
• membrane pumps and/or drug resistance
• signal transduction

AUTISM AND ENVIRONMENTAL GENOMICSHerbert MR,
Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG,
McCoy L, Ziegler DA, Hatchwell E
Neurotoxicology, 2006
Brain effects may be downstream of genetic
vulnerabilities or gene-environment interactions
that affect other organs or the whole system
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Distributed brain volume changes Beyond Modular

• Widespread volume increases
• Widespread asymmetry alterations
• Multiple regions showing variable changes

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Distributed Physical FindingsFrom brain
condition to systemic condition

• GI, Immune and Metabolic/Systemic problems

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Distribution of active changes across the
lifespan

• Brain volume changes during life course

• Cellular changes during life course

Bauman and Kemper

• Persistence of active tissue pathology during
  life course

Vargas and Pardo
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Whats making autistic brains bigger?

• Abnormal brain growth
• Disproportionate increase of white matter (e.g.
  frontal lobe)

Herbert M. 2005
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Brain ConnectivityNetworking in your head
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Distributed neurofunctional disturbancesBeyond
local circuits
Murias, 2007
Just, 2004

• Widely distributed connectivity and coherence
  abnormalities
• Broadly distributed atypical responses to
  functional paradigms
• Many different ways of responding differently

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Widely distributed brain tissue changes
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Inflammation and Oxidative Stress in Autism
chronic, ongoing postnatal medical problems,
not confined to brain

• Neuroglial activation and neuroinflammation in
  the brain of patients with autism
• Vargas et al, 2005, Annals of Neurology

Oxidative stress in brain tissues from autistic
patients Increased concentration of
isoprostanes Vargas et al, 2005, Annals of
Neurology

• These changes were found at similar intensities
  in brain aged 5-44 years
• Greater intensity of inflammation in a 3-year
  olds brain

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Pardo Immune activation in Radiate White
MatterImmune Activation as a Chronic Medical
Problem
Astrogliosis
Microgliosis
Herbert Large Brains from Radiate White Matter
Enlargement
Pardo
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Gastrointestinal System

• 16-96 of autistic children have GI disease
• Number is higher in prospective studies, lower in
  retrospective chart reviews
• Not always the same across individuals
• constipation, diarrhea, inflammatory bowel
  disease, abnormal intestinal organisms

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Protein-calorie malnutrition due to
malabsorptionIntrinsic static comorbidity or
treatable medical condition?

• This will chronically
• Deplete nutrients
• Circulate substances to body and brain
• These can worsen brain and body metabolic
  shortfalls until treated

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Not just human metabolism
Abnormal Clostridial bacterial species in
autistic childrens stool. Finegold S, 2002
Extended GenomeHost and gut-microbial
co-metabolome interactionJ Nicholson, Nature
Review Microbiology, 2005

• Abnormal gut flora metabolism can
• deplete vital nutrients
• alter metabolism of
• xenobiotics
• Alter immune function
• This can cause or worsen metabolic stress.

Published Transient improvement in core symptoms
with antibiotic Rx. (Finegold)
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Pain-based behavior pressure on abdomen
Krigsman
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TheEvery Day of Some Autisms
What we need Clinical labs that will detect and
report pertinent gut pathogens
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Immune signs and symptoms and measures in autism
Eczema
Recurrent infections Autoantibodies Family
history of autoimmune disease Autoimmune
features Food allergies and sensitivities Atypical
cytokine and chemokine levels Abnormal
immunoglobulin levels
Onychomycosis
Allergic Facies
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Cross-talk between the immune system and the CNS

• What we know
• The immune system and the nervous system maintain
  extensive communication, including 'hardwiring'
  of sympathetic and parasympathetic nerves to
  lymphoid organs.
• Bidirectional cross-communication mediated by
  signal molecules exists between the nervous and
  the immune systems
• e.g. 5-HT, opioids peptides, vasopressin,
  oxytocin, VIP, cytokines, chemokines.
• Products of immune cell activation including
  inflammatory cytokines IL-1, IL-6 and TNF-a can
  affect mood and sleep.
• Activation of the immune system may affect the
  function of both afferent nerves and the CNS.

Ashwood
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Immune system and CNS cross-talk
Ashwood
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Short-term immune triggers cause long-term brain
inflammation

• TNF-a increases are triggered by bacterial and
  other exposures.
• In the bloodstream this increase lasts 9 hours
• In the liver it lasts 1 week
• IN THE BRAIN IT LASTS 10 MONTHS
• This means that someone who gets exposed to a
  trigger of TNF-a every now and then could look
  like they have a chronic and untreatable brain
  problem.
• Qin et al., GLIA, 2007

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Metabolism and cellular function
Impairment of glutathione synthesis and
replenishment
Cellular Damage
Metabolic endophenotypes and related genotypes
are associated with oxidative stress in children
with autism S. Jill James et al. American Journal
of Medical Genetics Part B Neuropsychiatric
Genetics, 2006
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Rubenstein Merzenich,Genes, Brain and Behavior
(2003) 2 255-267

• Comments
• Increased excitation/inhibition ratio may
  explain many features of autism, such as
• Sensory sensitivities
• Sleep disturbances
• Seizures, epilepsy

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The Blood-Brain Barrier is not an absolute
barrier
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Distributed MechanismsMechanisms Without Borders

Brain/Nervous System
GUT BRAIN Vagus afferents Gut
neuropeptides
BRAIN GUT Endorphins Neuropeptides
IMMUNE BRAIN Cytokines microglia
activation
BRAIN IMMUNE Endorphins Neuropeptides
Cortisol
IMMUNE GUT Cytokines GALT
Immune System
GUT IMMUNE Gut neuropeptides microbial
products
Gut
Kahler/James/Herbert
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Implications of inflammation and oxidative stress
findings

• Ongoing chronic abnormality
• Rather than only early developmental changes that
  change wiring and then are static
• Environmental factors can cause both problems
• Persistent into adulthood
• Autism now keeps company with a different class
  of neurological diseases, not just developmental
  disorder
• Including Alzheimers, Parkinsons, and HIV
• Suggests a pathophysiological cascade with
  upstream causes and downstream consequences
• (more complex than genetic determination)
• Inflammation and oxidative stress are potentially
  medically treatable

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Rabbit or duck?
Is autism a BRAIN DISORDER or a DISORDER THAT
AFFECTS THE BRAIN?
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TRANSCEND - LADDERSWhole-Body Infants at Risk
Study

• A Multisystem Evaluation of Infants At Risk for
  Autism
• The first Baby Sibs study to look at MEDICAL
  development alongside behavioral and brain
  development
• New functional measures
• EEG
• Metabolic, Immune, Toxics, Nutrition
• Autonomic nervous system (stress measure)

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Example of TRANSCEND WorkInfants at Risk --
Continued

• QUESTIONS
• Do biological abnormalities precede behavioral
  abnormalities?
• Are there biological predictors?
• Are there things we could treat very early that
  might reduce severity or prevent autism
  altogether?

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Conventional Modular ModelAutism as
Genetically Caused Brain Disorder
Gene Brain module
Behavior
AUTISM
Behaviors
Brain C
Social Interaction
Brain B
Communi- cation
Brain A
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To Systems Autism as a Disorder that Affects the
Brain
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To a Whole-Body Understanding of Autism
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Autism RatesCalifornia Data
http//www.dds.ca.gov/Autism/pdf/AutismReport2003.
pdf
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Is autism really all genetic?Twin studies
support genetic influence, not genetic
determination.
Major Twin Study Data

• Twin Study Implications
• More identical than fraternal twin pairs are
  concordant (share an autism diagnosis)
• But concordance is only 60 for full autism
• 90 concordance is for broad autistic spectrum
  (i.e., milder) in one of the twins
• What accounts for the incomplete concordance?

• KEY POINTS
• These autism twin studies were all done before
  the rates went up
• Increased recurrence risk with families could
  have environmental components

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Gene-Environment Interactions not Either-Or,
but Both-And

• G and E probably affect most cases
• ASD can be 80 genetic AND 80 environment
• Example if everyone smoked, then who gets cancer
  is genetic

AUTISM AND ENVIRONMENTAL GENOMICSHerbert MR,
Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG,
McCoy L, Ziegler DA, Hatchwell E
Neurotoxicology, 2006
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Autism Rates California Data http//www.dds.ca.g
ov/Autism/pdf/AutismReport2003.pdf

• Diagnostic substitution Calling something autism
  that would previously have been labeled something
  else
• Diagnostic oversight people we didnt notice due
  to low awareness
• Diagnostic expansion expanded diagnostic
  criteria
• No proof that these fully account for the
  massive increase in diagnosis of autism.

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No proof that these arguments thoroughly explain
ALL the increase

• New paper from UC Davis (Epidemiology,Hertz-Piccio
  tto and Delwiche, 2009)
• 600 increase 1990 ? 2001
• 200 can be explained by non-environmental
  factors
• 24 age at diagnosis
• 56 inclusion of milder cases
• 120 Change in DSM diagnostic criteria
• The rest of the increase may have environmental
  contributors
• Even some of the earlier cases could have been
  environmental

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Modifications of neuronal networks that increase
susceptibility to autism spectrum conditions

• Inappropriate numbers and/or morphologies of
  synapses may lead to a too weakly or too strongly
  connected network. Such abnormal synaptic
  connectivity is frequently observed in mental
  retardation (MR), a condition present in 75 of
  individuals with ASC.
• 2. An imbalance between GABA and glutamate may
  lead to an abnormal inhibition or excitation
  associated with epilepsy, a condition present in
  30 of individuals with ASC.
• 3. An increased number of neurons may cause
  macrocephaly, observed in 30 of individuals with
  ASC.
• 4. High levels of serotonin are observed in at
  least 25 of individuals with ASC. This abnormal
  neuromodulation may alter network properties, as
  observed in patients with OCD and mutations of
  the serotonin transporter.
• Belmonte Bourgeron, Nature Neuroscience, 2006

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Defective/deficient GABAa Receptors in
AutismsPesticides that antagonize GABAa
ReceptorsGene x Environment InteractionIncreas
ed Excitation/Inhibition Ratio
Schematic illustration of a GABAA receptor with
its binding sites
Non-Competitive GABA antagonists
(4-alkyl-1-phenylpyrazole)
Fipronil
800 tons applied in 2000
Regent Goliath Nexa Adonis
Chipco Choice Frontline
From Pessah
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Why are immune disorders, or chronic diseases, on
the rise?
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Trends in U.S. Chemical Production, 19201980
Pesticide use more than doubled between 1964 and
1982 (USDA)
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Rise in Autism Prevalence v. Other Major Chronic
Conditions in US
Autism
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Texas autism rates, by school districts
Potential association between autism rates,
environmental mercury other toxins in
TexasPalmer, et al., Health and Place, 12 (2006)
203209
1990-1993
1998-2000
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On average, for each 1000 lb of environmentally
released mercury, there was a 43 increase in the
rate of special education services and a 61
increase in the rate of autism.Palmer et al.
Health Place 12 (2006) 203209
Autism rates
Proximity to point sources of environmental
mercury release as a predictor of autism
prevalence. Palmer et al. Health Place 2008
Total toxicity
Chemicals-TRI (Toxic Release Inventory)
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Air Pollution over China
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Body Burden The Pollution in NewbornsA
benchmark investigation of industrial chemicals,
pollutants and pesticides in umbilical cord
bloodEnvironmental Working Group, July 14,
200510 newborns, 10,000/baby for study

• Chemicals and pollutants detected in
• human umbilical cord blood
• Mercury (Hg) - tested for 1, found 1
• Polyaromatic hydrocarbons (PAHs) - tested for 18,
  found 9
• Polybrominated dibenzodioxins and furans (PBDD/F)
  - tested for 12, found 7
• Perfluorinated chemicals (PFCs) - tested for 12,
  found 9
• Polychlorinated dibenzodioxins and furans
  (PBCD/F) - tested for 17, found 11
• Organochlorine pesticides (OCs) - tested for 28,
  found 21
• Polybrominated diphenyl ethers (PBDEs) - tested
  for 46, found 32
• Polychlorinated Naphthalenes (PCNs) - tested for
  70, found 50
• Polychlorinated biphenyls (PCBs) - tested for
  209, found 147

• Of the 287 chemicals detected in umbilical cord
  blood
• 180 cause cancer in humans or animals
• 217 are toxic to the brain and nervous system
• 208 cause birth defects or abnormal development
  in animal tests

http//www.ewg.org/reports/bodyburden2 See also
Centers for Disease Control and Prevention.
(2005) Third National Report on Human Exposure to
Environmental Chemicals. Atlanta (GA) CDC
Available at http//www.cdc.gov/exposurereport/re
port.htm
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Status of Developmental Toxicity Testingfor the
2,863 ChemicalsProduced Above 1 million
pounds/year
Some Data On Developmental Toxicity
20-30 Tested for Neurodevelopmental Toxicity Acco
rding to EPA Guidelines This testing is NOT
REQUIRED.
No Data On Developmental Toxicity
To test these 2,863 chemicals in combinations of
3 would require 85 BILLION tests.
In Harms Way, www.preventingharm.org
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EPA To Drop 'E,' 'P' From Name

• EPA To Drop 'E,' 'P' From Name WASHINGTON,
  DC-Days after unveiling new power-plant pollution
  regulations that rely on an industry-favored
  market-trading approach to cutting mercury
  emissions, EPA Acting Administrator Stephen
  Johnson announced that the agency will remove the
  "E" and "P" from its name. "We're not really
  'environmental' anymore, and we certainly aren't
  'protecting' anything," Johnson said. "'The
  Agency' is a name that reflects our current
  agenda and encapsulates our new function as a
  government-funded body devoted to handling
  documents, scheduling meetings, and fielding
  phone calls." The change comes on the heels of
  the Department of Health and Human Services'
  January decision to shorten its name to the
  Department of Services.

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Major change in understanding impacts of
chemicalsLOW DOSE EXPOSURE ISSUES

• Synergies
• Two or more chemicals in combination can have
  effects not seen from individual exposures (e.g.
  paraquat and maneb together increase relative
  risk of Parkinsons Disease)

• Biomimesis
• At doses far below cytotoxic levels, chemicals
  can alter or disrupt signaling mechanisms,
  including by acting like the bodys own
  molecules but at inappropriate times or sites
  (e.g. endocrine disruption).

• Compound and chronic exposures can
• Alter set points of affected metabolic pathways
• Overwhelm pathways (particularly detox pathways)
• http//www.ourstolenfuture.org/

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• Risk of exposed mother having child develop
  autism increased with the poundage of
  organochlorine applied and decreased with
  distance from field sites.
• (Odds ratio 6.1)

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FINAL COMMON PATHWAYS
Environmental Inputs
RADIATION
CHEMICALS
ALLERGENS
HEAVY METALS
TOXINS
NOISE
DRUGS
STRESS
INFECTIONS
Overflowing the Levees
The bodys generic reactions Inflammation Oxidat
ive Stress
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BEES Colony Collapse Disorder
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UN Report by 1360 scientists Ecosystem damage
is so severe that we can no longer be confident
that the Planet Earth can support human life for
more than two generations.
The planet is not stable.

• http//www.millenniumassessment.org

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Complete story http//www.theonion.com/content/no
de/38901
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Terminus Brain Environmental Threats to Human
Intelligence and the Physical Capacity for
Integrative Brain Functions
And the immune system as well.
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Autism as a consequence of cellular-level
functional changes
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Rabbit or duck?
CRITICAL QUESTIONS Is there a connection between
neuroinflammation and network problems in brain
processing? Is the brain defective? Or Is the
brain physically sick?
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Chronic mechanisms can affect cells which impact
brain FUNCTION
Functional Vulnerabilities

• Energy Production
• NMDA plasticity
• Lipid Membranes
• Transmitter Specificity
• Glial Support

• Free Radicals
• Calcium Upregulation
• Peroxidation
• Toxic Mediators
• Chronic Inflammation

• Cellular
• Widespread
• Impact timing, signal intensity, coordination
• Model Metabolic dysregulation can influence
  neural systems function

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What do we know about glial cells and brain
functioning?

• What metabolic and other impacts might
• white matter astrogliosis have on
• neural and neural systems function?
• Astroglia cells participate in a tripartite
  synapse, surrounding neuronal synapses and
  modulating their activity
• Astroglial cells play critical roles in neuronal
  metabolism
• Activated astroglia are larger and can reduce
  capillary lumen up to 50
• Immune-activated glial cells may contribute to
  excitotoxicity.
• Glial cells participate in chemical signaling
• NO WORK YET ON IMMUNE DYSFUNCTION IMPACT ON
  GLIAL MODULATION OF NEURAL SYNCHRONY
• (in anything, not just in autism research)

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Abstract The enteric nervous system is composed
of both neurons and glia. Recent evidence
indicates that enteric gliawhich vastly
outnumber enteric neuronsare actively involved
in the control of gastrointestinal functions
they contain neurotransmitter precursors, have
the machinery for uptake and degradation of
neuroligands, and express neurotransmitter-
receptors which makes them well suited as
intermediaries in enteric neurotransmission and
information processing in the ENS. Novel data
further suggest that enteric glia have an
important role in maintaining the integrity of
the mucosal barrier of the gut. Finally, enteric
glia may also serve as a link between the nervous
and immune systems of the gut as indicated by
their potential to synthesize cytokines, present
antigen and respond to inflammatory insults. The
role of enteric glia in human disease has not yet
been systematically studied, but based on the
available evidence it is predictable that enteric
glia are involved in the etiopathogenesis of
various pathological processes in the gut,
particularly such with neuroinflammatory or
neurodegenerative components.
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A Different Model of Autism

• Autism could be a consequence of challenges to
  cellular function throughout the body, including
  the brain
• These cellular changes may be related to
  environmental insults
• Altered cellular response could be at the root of
  brain and body problems

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Autism The Centrality of Active
Pathophysiologyand the Shift from Static to
Chronic Dynamic Encephalopathy

• By Martha R. Herbert, MD, PhD
• Autism
• Oxidative stress, inflammation and immune
  abnormalities
• Chauhan A, Chauhan V, Brown T, eds., in press,
• 2009, Taylor Francis/CRC Press.

Learning from the autism catastrophe Key
leverage points Martha Herbert Altern Ther Health
Med. 2008 Nov-2008 Dec 31 14(6)28-30.
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Sensory disturbances Modulated by metabolic
impacts on neurotransmitters and receptor
function?Commonly observed hyper and/or
hyposensitivity in one or more modalities

• Cortical auditory processing abnormalities
• Visual sensory processing deficits
• Abnormal synchrony
• Cross-modal sensory integration difficulties
• Common hypersensitive to external sensory
  stimuli, hyposensitive to internal sensory stimuli

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Autism Electrophysiological Abnormalities (n28)
Laboratory challenge 15 of these patients had no
seizures and would be considered normal.
Increased VEP amplitude standard deviation was
2.42-8.92 SD (average 5.4 SD)
Martien Duffy
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Autonomic nervous system dysregulation

• Tendency to be highly stressed physiologically

Higher baseline HR and less variance to challenge
in ASD Goodwin, Groden et al, 2005
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Gene ? Brain ? Behavior model
Genetics
Brain
Communication Social interaction Restricted
behavior
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Whole Body Model Vicious circles in brain and
body
Physical environment
Genetics
Cellular Dysfunction Energy, Signaling,
Metabolism
Body
Brain
Sensory Sleep Seizures
Gastro Immune Hormones etc.
Communication Social interaction Restricted
behavior
More easily OVERWHELMED
Pain, Poor function Sickness
Frustration
Overload! STRESS!
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Much more comprehensive than Gene ? Brain ?
Behavior
Genetics
Brain

• This model is too linear
• It leaves out too many important things

Communication Social interaction Restricted
behavior
77
Capacity of cellular dysfunction to be reversed
78
Improvement in core autism behaviors in setting
of fever
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Regression, Fluctuation and ImprovementBeyond
static encephalopathy

• Variable severity with transient striking
  improvements and recovery of function in some
  cases
• Transient improvement w fever (Zimmerman A
  Pediatrics in press)
• Spikes in function in stress or emotional
  situations
• Transient improvement on antibiotics (Sandler,
  Finegold, Bolte, JCN 2000)
• Improvement on allergy medications
• Variability in function related to food, allergen
  and toxic exposures

• Treatment-responsiveness
• Stable improvement can follow treatment
• Published reports of loss of diagnosis (Fein D
  Sutera, Kelley JADD 06,07)
• Recovery documentation studies in process

Neurobiological Implications NEUROMODULATORS
and/or NEURODYNAMICS, not just wiring.
80
Implications of clinical observations of good
days/bad days and improvement/recovery
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Improvement in brain function after treatment

• Example
• Depakote was given for spike-waves during sleep
  that did not meet criteria for CSWS (continuous
  spike-wave during sleep)
• Substantial improvement resulted in speech and
  cognition
• This was measurable in brain by techniques not in
  standard use
• Research measures need to become part of clinical
  practice

Before treatment
After treatment
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Reversal in Mouse Models
83
Rapid reversal of Alzheimers symptoms by drug
that inhibits TNF-a and therefore inhibits
inflammation
84
Short-term immune triggers cause long-term brain
inflammation

• TNF-a increases are triggered by bacterial and
  other exposures.
• In the bloodstream this increase lasts 9 hours
• In the liver it lasts 1 week
• IN THE BRAIN IT LASTS 10 MONTHS!!!
• This means that someone who gets exposed to a
  trigger of TNF-a every now and then could look
  like they have a chronic and untreatable brain
  problem.

Qin, GLIA, 2007
85
What to Do
86
Step OneADMIT THAT WE HAVE A PROBLEM!
87
Our national faith so far has always been
Theres always more. Our true religion is a
sort of autistic industrialism.-Wendell Berry,
Harpers, May 2008
88
A Perspective on the Autism Spectrum Tip of
the Iceberg, Canary in the Coal Mine
89
Give Biology a Big Place in the Autism Agenda
90
Realize that autism has a lot of company in other
chronic illnesses with similar underlying
mechanisms
91
Disease co-morbiditiesRzhetsky, 2007, PNAS
92
Autism comorbiditiesRzhetsky, 2007, PNAS

• Pervasive Developmental Disorders
• PDD, Fragile X
• Neurological disorders
• Attention deficit, epilepsy, cerebral palsy,
  schizophrenia, bipolar disorder,
  neurofibromatosis, Parkinsons Disease, Migraine
• Bacterial, viral, protozoan
• Viral infections of CNS, tuberculosis, viral
  infections of other systems, staphylococcal and
  Helicobacter pylori infections
• Allergies, Autoimmune disorders
• Allergic rhinitis, eczema, psoriasis
• Benign and Malignant Neoplasms
• Other
• Kawasakis disease, acanthosis nigricans,
  aberrations of carbohydrate metabolism

93
Genes that had biggest impact and/or occurred
most commonly across 9 comorbid conditions
largely had immune function

• Substantial overlap in genes implicated in
  multiple co-morbid conditions
• Many of the genes highly ranked in multiple
  conditions have immune relevance

ADHD cerebral palsy depression schizophrenia t
uberculosis allergic rhinitis bipolar
disorder Parkinson's
Method GeneSelectAssist service in CDC's HuGE
website
94
Realize that practical day-to-day things may be
of some help
95
MIND InstituteSacramentoThur-Fri Nov
2-3,2006Clinical Implications of Environmental
Toxicology for Childrens Neurodevelopment in
Autism
96
complex, heterogeneous, multileveled, interactive

• Clinical vicious circles with
• amplifying feedback loops across levels

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Self-reinforcing or vicious circles

• Genes modulate vulnerability to toxic, immune and
  infectious stress
• Toxics impair immunity
• Infection and immune stress alter gene expression

• Increased excitation/inhibition contributes to
  sensory overload and sleep disruption
• These contribute to stress
• Stress worsens the HPA axis contribution to
  biological factors increasing the I/E ratio
• (HPA hypothalamic-pituitary-adrenal)

Toxics
Infection/Immune
? E/I Ratio
Sensory/Sleep
Genes
HPA Axis
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Chilling out vicious circles and allowing
adaptive self-re-regulation

• Less toxic exposure
• Better ability to detoxify
• Improved nutritional status
• Immune support
• Reduce/avoid infection
• Behavioral organization and stress reduction

Toxics
Infection/Immune
Genes
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TRANSCEND Research Program
Study of tissue properties in brain
enlargement Study of altered sensory processing
Study of metabolism and brain processing Study
of onset of brain, body, metabolism in
infants Characterization of brain change from
treatment
www.transcendresearch.org transcend_at_partners.org
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Autism-Environment CME Executive Summary

• Concerning increases in autism as well as
  allergies, asthma, learning disabilities and
  other pediatric conditions, all suggest a
  contributory role for environmental factors.

• Understanding mechanisms of environmental
  toxicology has the potential to improve how we
  treat affected individuals.

• Research findings support consideration of immune
  abnormalities, gene-environment interactions and
  enhanced vulnerability to toxins and infection in
  autism.

• Autism can be reframed as a medical condition
  with features that affect the whole body
  including the brain.

• Low dose, chronic and combined exposures can have
  significant impact on neurodevelopment and
  children's health.

• Environmental exposures exact an enormous and
  preventable economic and social impact.

Herbert, Future Neurology, March 2007 v2, no2.
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We all live downstreamEveryone, Everywhere
102
Will Women Lead the Environmental Health
Movement?

• How can we imagine that ordinary people might be
  able successfully to challenge the overwhelming
  internal logic of the global economic system
  because of concern over environmental health?
• There is an Ethiopian proverb that when spider
  webs unite they can tie up a lion. The lion of
  the globally destructive patterns of production
  and consumption may one day be ensnared and
  ultimately domesticated by the gossamer webs of
  human consciousness and community action. What
  will happen when ordinary people, whose lives are
  often mortally wounded by the destruction of the
  biosphere, come to understand that their wounds
  are so often intimately related to the wounds of
  the earth?
• What will happen when a working woman comes to a
  realization that her own breast cancer, her
  husband's lymphoma, her brother's melanoma, her
  son's learning disability, his best's friend's
  attention deficit disorder, her daughter's
  endometriosis, her niece's cleft palate, her
  cousin's chronic anxiety and panic disorder, her
  best friend's severe chemical sensitivity, her
  best friend's daughter's asthma, her uncle's
  infertility, her neighbor's son's testicular
  cancer, and her sister's daughter's childhood
  leukemia, may form a pattern?

103

• What will happen when this working woman begins
  to understand that these new human pandemics,
  that affect her family and her community
  directly, may be profoundly connected to what is
  happening to the fish in the sea, the birds in
  the sky, and the animals of the earth?
• I believe this working woman will understand that
  the cancers and infertility of the fish, the
  disappearance of the frogs, the cleft palates of
  the mice, the shifts in gender orientation of the
  birds, the susceptibility to viruses and
  infections of the seals, the disappearance of the
  songbirds, -- that all this and much, much more
  may be telling us a story that is also our story.
• The story that the birds and the fish and the
  mice are telling us is the story of InterBeing --
  the story that all life on earth is truly,
  breathtakingly, concretely connected right now,
  and that what we do to the mice of the field and
  the birds of the forest, we also ultimately do
  also to ourselves and our families right now.
• I do not believe that we can hide from this story
  much longer. It is among the great stories of our
  time.
• Michael Lerner, http//www.commonweal.org/pubs/ler
  ner/article_extinction.html
• The Age of Extinction and The Emerging
  Environmental Health Movement

104
Making our own hopecontinued from Lerner, Age of
Extinctions

• This very human protest against a massive
  entrenched and toxic global system of production
  and consumption may seem unrealistic economically
  and politically. But is it any less realistic
  than the Quaker protests in Europe and the United
  States that played such a key role in ending the
  350-year-old slave trade? I do not invoke the
  parallel to ending the slave trade lightly. For
  we are as enchained by toxic chemicals and ozone
  depletion and climate change and the destruction
  of nature as we were once enchained by slavery. I
  believe environmental health may be one of the
  greatest human rights issues of the millennium.
  That is our best hope.

105
TRANSCEND Research ProgramTreatment Research And
Neuroscience Evaluation of NeuroDevelopmental
Disorders
TRANSCEND Tal Kenet Katherine Martien Matt
Anderson Matthew Belmonte Eva Ratai Nancy
Snidman Nandita Shetty Suzanne Maness Annette
Robichaud Emily Mott Nikki Meribela Alyssa
Orinstein Avi Ringer Jerome Kagan
Center for Morphometric Analysis, MGH Verne
Caviness David Kennedy Nikos Makris
Other Collaborators Liam OBrien Curt Deutsch
Nosology Project Isabelle Rapin David
Ziegler Deborah Fein Pauline Filipek Doris A.
Allen Michelle Dunn Robin Morris Lynn Waterhouse
Tran.scend Verb To rise above or across surpass
exceed To pass beyond the limits of To be greater
than, as in intensity or power To be greater in
scope or size than some standard To exist above
and independent of To be transcendent
excel www.transcendresearch.org
Foundations and Grants Cure Autism Now
Foundation National Alliance for Autism
Research Autism Speaks NINDS Bernard Fund for
Autism Research Nancy Lurie Marks Family
Foundation
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(No Transcript)