Maine CDC Autism Conference: Genes and Environment, Developmental and Chronic: An Inclusive Approach to Autism Science by Martha Herbert, MD, PhD

Maine CDC Autism Conference 2009
Genes and Environment, Developmental and Chronic: An Inclusive Approach to Autism Science, followed by Q&A
Martha Herbert, MD, PhD
Pediatric Neurologist
Massachusetts General Hospital
Harvard Medical School



Next Session:
Looking Forward Beyond Vaccines: How Do We Know What Autism IS NOT if We Do Not Know What Autism IS? by Jon Poling, MD, PhD

Adversomics: The Emerging Field of Vaccine Adverse Event Immunogenetics

We are emerging from the dark frozen winter of the vaccine extremists. This warm sunbeam on our faces brought to you by the wise and reasonable folks at the Pediatric Infectious Diseases Journal:

"We believe that adversomics (the immunogenetics and immunogenomics of vaccine adverse events at the individual and population level, respectively) is critical to understanding and preventing serious adverse vaccine-related events, developing the next generation of vaccines, and to improving public confidence in vaccine safety."

It is like a breath of fresh air.

"Nonetheless, the field of adversomics is growing due to scientific interest in understanding the basis for vaccine reactions, “push” from the growing field of individualized medicine, and consumer demand for safer vaccines."

Ahhhh.... I hear birds chirping and can smell the new flowers of spring.

Adversomics: The Emerging Field of Vaccine Adverse Event Immunogenetics

Gregory A. Poland, MD,* Inna G. Ovsyannikova, PhD,† and Robert M. Jacobson, MD‡

Key Words: genetic association, immunogenetics, vaccine adverse events

(Pediatr Infect Dis J 2009;28: 431–432)

Vaccines have enabled tremendous decreases in infectious diseases, eradication of smallpox, saved lives, and remain among the most effective and cost-effective of our public health initiatives.1 At the same time, as an ever larger number of vaccines are administered globally, increasing concerns about adverse events and reactions have been raised and threaten the public health successes attributable to vaccines. For example, the controversy surrounding measles-mumps-rubella (MMR) vaccine and thimerosal are emblematic of public concerns and perceptions regarding vaccine safety and vaccine adverse reactions (AEs). With current and future technologic advances such as high throughput whole-genome scanning, transcriptomics, epigenetics, proteomics, and new biostatistical approaches to understanding huge databases of information, we can better understand associations and mechanisms by which genetically- mediated individual variations in vaccine response and reactivity occur. Armed with such knowledge, the ability to predict such AEs, or to design new vaccine approaches that minimize or eliminate serious vaccine-related reactions could be devised, consistent with a more personalized or individual approach to vaccine practice which we have called adversomics (the immunogenetics and immunogenomics of vaccine adverse events at the individual and population level, respectively).

CURRENT KNOWLEDGE

Immune, inflammatory, idiosyncratic, and other responses to a vaccine are determined by a host of known and unknown factors, including individual characteristics (age, gender, race, medical condition, etc.), the quality and quantity of vaccine antigen(s), the number of doses administered, route of immunization, and host genetics. Although tremendous work has gone into understanding genetic susceptibility to infectious diseases,2 attention now needs to turn toward understanding genetic susceptibility to vaccine-related AEs. Indeed in the case of live vaccines, one might simplistically envision administration of such vaccines as an “infection” and conceptually study the susceptibility to such reactions in the same manner. To further develop this construct, we have hypothesized that adverse reactions and events may not be random, but may in fact be, in part, genetically predetermined. For example, early studies demonstrated that certain populations are unusually susceptible to measles vaccine reactions with post-vaccine febrile reactions among 11 different Amerind populations 0.4°C higher than in Caucasian populations.3 It was speculated that genetic differences in Amerinds were associated with intensified reactions to measles vaccine. Studies of Native American children revealed higher risks for invasive Haemophilus influenzae type b infection than white children. Decreased IgG2 and IgG4 antibody responses to H. influenzae type b polysaccharide vaccine were observed in healthy Apache children, compared with white children, potentially explaining the higher incidence of H. influenza type b infections in Apache populations. 4 Later studies revealed specific Km and
Gm genetic allotypes associated with poorer immune response.5

More recent studies have investigated the role of cytokines in the pathogenesis of AEs associated with live viral vaccines. A large study of AEs, including fever, lymphadenopathy, and localized or generalized rash, after smallpox immunization was associated with increased levels of IFN-!, TNF-", IL-2, IL-5, and IL-10, whereas individuals who did not report an AE demonstrated increased IFN-! levels only during the acute phase compared with baseline levels after immunization.6 Concerns regarding myopericarditis after smallpox vaccine has resulted in studies which are examining possible genetic associations.7,8

Additional insights into identification of genetic markers that affect immune and physiological responses to viral vaccines emerged from a study which examined the genetic basis for adverse events after smallpox vaccination.9 The hypothesis was that subjects experiencing AEs exhibited unique genetic polymorphisms associated with AE reactions in response to smallpox vaccination. To test the hypothesis 346 smallpox (Dryvax) immunized individuals were genotyped for single-nucleotide polymorphisms (SNPs) in 19 candidate genes and assessed for the development of fever associated with the receipt of vaccine. This study showed that fever following smallpox vaccination was associated with specific haplotypes on the IL1 gene complex, and in the IL18 and IL4 genes. Importantly, these findings raise the possibility that the same genetic polymorphisms linked to fever after smallpox vaccine may also influence fever risk after other live virus vaccines, including MMR.9,10 For example, a small percentage of children who get vaccine-induced fever after MMR will develop febrile seizures. Knowledge of a genetic association could allow the development of predictive tests or preventive therapies that could be administered with vaccine to prevent such AEs.

In another study 131 healthy volunteers from 2 independent smallpox vaccine studies were genotyped across 386 genes and assessed for local and systemic AEs.11 The authors reported that genetic polymorphisms in genes expressing an enzyme previously associated with adverse reactions to a variey of pharmacologic agents (ie, the methylenetetrahydrofolate reductase, MTHFR, gene) and an immunologic transcription factor (ie, the interferon regulatory factor-1, IRF1, gene) were associated with local and systemic AEs (an oral temperature !38.3°C, generalized skin eruptions, or enlarged or tender regional lymph nodes) after smallpox vaccination.

Our own laboratory has done extensive work in identifying genetic associations with HLA, cytokine, cytokine receptor, innate receptors, innate immune response genes, and signaling molecules and both humoral and cell-mediated immune responses.12,13 This work has been fundamental to identifying and understanding associations between genetic polymorphisms and variations in immune responses. Such methods must now be turned toward understanding adverse events associated with vaccination. An example is that epidemiologic studies have quantified the risk of immune thrombocytopenic purpura (ITP) and anaphylaxis, attributable to the MMR vaccine in the second year of life as 1 case per 40,000 vaccinated children.14,15 Recently France et al demonstrated that 76% of ITP cases in children ages 12 to 23 months were related to MMR vaccination.15 Identification of a genetic association between MMR vaccine and ITP would be important and would inform attempts at developing preventive strategies or improved vaccines. A further example is the expanding recommendations for the use of seasonal influenza vaccine and the potential use of pandemic vaccines globally; studies of the genetic susceptibility to Guillain-Barre Syndrome (GBS) would be important.16

SUMMARY
We believe that adversomics (the immunogenetics and immunogenomics of vaccine adverse events at the individual and population level, respectively) is critical to understanding and preventing serious adverse vaccine-related events, developing the next generation of vaccines, and to improving public confidence in vaccine safety. Significant difficulties in the growth of the field of vaccine immunogenetics include the difficulty of studying large enough numbers of subjects (rare AEs are, by definition, rare), lack of research funding, the complexity and extensive polymorphic nature of immune response genes, statistical issues of multiple comparisons and statistical power, issues of multigenic and other gene interactions such as complementation and epigenetic DNA modifications, and gender, racial, and ethnic differences. Nonetheless, the field of adversomics is growing due to scientific interest in understanding the basis for vaccine reactions, “push” from the growing field of individualized medicine, and consumer demand for safer vaccines. The capability to reproduce statistical associations in independent population-based studies remains essential to assessing the generalization of such studies. Clearly more comprehensive studies are needed to determine if there are
associations between genetic variations among individuals and susceptibility to serious adverse events in response to vaccination. These factors combined with technologic ability will lead to a new era in vaccinology and better, safer vaccines.

REFERENCES
1. Centers for Disease Control and Prevention. Ten
Great Public Health Achievements—United States,
1900–1999. MMWR. 1999;48:241–243.
2. Kaslow R, et al. eds. Genetic Susceptibility to
Infectious Diseases. New York, NY: Oxford University
Press; 2008:1– 447.
3. Black FL, et al. Intensified reactions to measles
vaccine … J Infect Dis. 1971;124:306 –317.
4. Siber GR, et al. Impaired antibody response to
Haemophilus influenzae type b polysaccharide…
N Engl J Med. 1990;323:1387–1392.
5. Goldblatt D, et al. Association of Gm allotypes
with the antibody response … J Immunol. 1994;
153:5316 –5320.
6. Rock MT, et al. Adverse events after smallpox
immunizations … J Infect Dis. 2004;189:1401–
1410.
7. Halsell JS, et al. Myopericarditis following smallpox
vaccination … JAMA. 2003;289:3283–3289.
8. Wilson CB, et al. Vaccine safety–vaccine benefits
… Nat Rev Immunol. 2001;1:160 –165.
9. Stanley SL, et al. The immunogenetics of smallpox
vaccination. J Infect Dis. 2007;196:212–219.
10. Usonis V, et al. Reactogenicity and immunogenicity
of a new live …. Pediatr Infect Dis J.
1999;18:42– 48.
11. Reif DM, et al. Genetic basis for adverse events
after smallpox vaccination. J Infect Dis. 2008;
198:16 –22.
12. Poland GA, et al. Heterogeneity in vaccine immune
response … Clin Pharmacol Ther. 2007;
82:653– 664.
13. Poland GA, et al. Vaccine immunogenetics ….
Vaccine. 2008;26:6183– 6188.
14. Stratton KR, et al. Adverse events associated with
childhood vaccines other than pertussis and rubella
… JAMA. 1994;271:1602–1605.
15. France EK, et al. Risk of immune thrombocytopenic
purpura … Pediatrics. 2008;121:e687–
e692.
16. Juurlink DN, et al. Guillain-Barre syndrome after
influenza vaccination in adults … Arch Intern
Med. 2006;166:2217–2221.
Concise Reviews The Pediatric Infectious Disease Journal • Volume 28, Number 5, May 2009
432 ©

Mito/DNA/Autism/GFCF/Glutamate Thoughts From A Food Process Engineer

Now THIS is the kinda thing I was talking about in my fantasy "Responsible Government" piece. Medical professionals hearing the mito/autism news and applying their understanding from other fields to the autism problem! It even has autism gene theory with, get this, real world application that can be of use for helping kids today!

Except in my fantasy she would not have to be posting this to a CNN site, because NIH would have called her when she sent it into them months ago.

Another fascinating Dr. Gupta comment:

Dr. Gupta,

Here is what I wrote to the NIH in January. It still sums up my thoughts. It should be noted that one of the genes for autism discovered last year codes for a MITICONDRIAL aspartate/glutamate carrier.

I am a former food process engineer who believes, because recent studies have implicated genes which code for glutamate synapses in ASD, we should investigate the effects of both INGESTED and INJECTED excitatory free amino acids (glutamic acid and aspartic acid) on children with these autism genes.

If excitatory free amino acids affect ASD children, it would explain both the impact of GF-CF diets AND a vaccine link. Vaccines have free glutamic acid added to preserve the virus. I have created and attached a chart showing where free glutamic acid comes from. It is found in extremely high amounts in processed wheat and dairy products so much so that food manufacturers use these two items routinely to produce free glutamic acid in foods but with a clean label.

Consequently, a child may not improve on a GF-CF diet alone, because it doesn’t limit all potential sources of free glutamic acid like soy. Children are tested at birth for PKU and phenylalanine is limited until the brain is hardwired by the age of 7. Why not treat the predisposition for autism similarly and limit the glutamic and aspartic amino acids in the diets of children with autism genes?

ASD also includes errors of metabolism for sulfur containing amino acids like cysteine. Cysteine is converted to taurine and glutathione by the liver. Taurine regulates heartbeat and osmotic balance as well as bile production and was found to be low after a seizure. In ASD, symptoms include arrhythmias, digestive disorders and a high rate of epilepsy, suggesting that taurine production may be compromised. Glutathione levels are also lower in ASD leading one to conclude that possibly, cysteine metabolism may be responsible for the myriad and seemingly unrelated additional symptoms of ASD. It should be noted that glutamate interferes with the handling of cysteine. When cysteine metabolism is compromised, homocysteine levels may increase. The lower levels of glutathione may put ASD individuals at risk of mercury poisoning, since glutathione helps eliminates mercury from the body.

It should be noted that the NMDA receptors that respond to both glutamate and aspartate are found in the amygdala - part of the limbic system involved in the perception of taste and smell as well as fear. Activating the amygdala in ASD, causes gaze avoidance. ASD children may also over-react to smells and tastes and face to face encounters can overwhelm them with fear. Limiting excitatory amino acids that target the amygdala may help.

Japan consumes more MSG, and fish (a dietary source of mercury) than nearly any other country. Compared to the amount of mercury consumed in fish and the amount of MSG consumed in the diet, the MMR contribution was probably small compared to a typical Japanese diet. In Japan, the MMR vaccine was stopped in 1993. Autism rates still increased. Perhaps in Japan, the diet plays more of a role in autism than the vaccines. Children from other countries with a lower consumption of fish and MSG may find a stronger correlation between vaccines and autism.

New research studies into ASD should include people who are sensitive to the food additives MSG and aspartame. MSG-sensitive persons have reported a distinct lessening of symptoms by using taurine, ibuprofen, CoQ10, Vitamins B6 and B12, carbohydrate, foods high in butyric acid like butter, and Magnesium. Perhaps they share some of the same genes that predispose a child to ASD. New treatment studies should look into these easily available, inexpensive and relatively safe compounds.

Based on what I have observed, here are my recommendations:

1. Treatment of ASD?

REMOVAL of excitatory amino acids (glutamate, aspartate) from VACCINES.
Glutamate and aspartate restricted diet (similar to treatment for PKU) in addition to GF/CF diet.

Supplementation of taurine, glutathione, vitamins B6, C, magnesium, CoQ10.
Increased carbohydrate.

Labeling of free glutamic and aspartic acid on food labels.
Glutamate blockers, anti-histamines and leukotriene blockers for children already suffering or getting vaccinated.

We should calm their surroundings, encourage quiet tasks and less-threatening contact to enhance communication. We need to give them space and not overwhelm them.


2. Diagnosis of ASD?

Test for autism genes preferably AT BIRTH like PKU.

Tests for aspartic acid, glutamic acid, glutathione, taurine, cysteine, homocysteine.


3. Risk factors for ASD?
Autism Genes
Sensitivity to excitatory amino acids
Low taurine, Low glutathione
Sulfite Sensitivity
Vaccination with glutamic acid as a preservative
Damage to the microglia
Overactive immune system
Junk food diet
Aspartame in medications or vitamins or foods
Multiple food allergy


4. Biology of ASD?

Excess CNS sensitivity,

Inability to handle sulfur-containing amino acids,

Overactive immune response linked to Nerve Growth Factor


5. Other areas of ASD research?

Common genes in Alzheimer’s, Parkinsons, ALS, MS, and excitatory amino acid sensitivity.

Study persons without ASD who suffer from overactive CNS or neurodegenerative disease and sensitivity to excitatory amino acids. See if they share same genes.

Could Alzhemier’s sufferers simply be ADS children whose brains were hard-wired before damage by the environment?


Thank you for this opportunity to share my ideas on this very important topic,

Please see this webpage that clearly shows why a wheat and dairy based processed food diet may be very harmful to a child sensitive to excitatory amino acids:
http://www.msgtruth.org/avoid.htm

HT:Here in HP

Genetic Causation Theory Leads to Autism Eugenics

I missed a lot of stories on my break last year. This is an important one.

Do the proponents of the genetics only theory realize that this is the consequence?

A US example of this fallout is evident in yesterday's LA Times piece by a man whose wife selectively aborted two of the four babies that she was carrying. They aborted the two boys and kept the two girls. One of the reasons they they cited was because boys are more likely than girls to be autistic.

The Eliminators
By Chuck Colson
Thursday, August 3, 2006

British medical researchers recently announced plans to use cutting-edge science to eliminate a condition my family is familiar with: autism. Actually, they are not “curing” autism or even making life better for autistic people. Their plan is to eliminate autism by eliminating autistic people.

There is no in utero test for autism as there is for Down syndrome. As I have previously told “BreakPoint” listeners, that testing, combined with abortion-on-demand, has made people with Down syndrome an endangered population. By some estimates, 90 percent of these people—who, if allowed to live, can live happy and healthy lives—are aborted.

In the absence of such a test for autism, researchers at University College Hospital London are settling for what they call a “close enough” solution. They have applied for permission to use pre-implantation genetic diagnosis, or PGD, to screen out male embryos in families with a history of autism.

Their “logic” is that since 90 percent of all autistic people are males, their testing would allow families with autistic children “to have a daughter free from the condition.” Of course, they would have also killed males who were not autistic. Talk about wholesale gender cleansing.

The critics are not convinced. Simone Aspis of the British Council of Disabled People drew the what-should-be obvious inference: “Screening for autism would create a society where only perfection is valued.” In the brave new world of the researchers, it is reasonable to fear “that anyone who is different in any way will not be accepted.”

Here in the states, bioethicist Ben Mitchell said that “if unborn children are being eliminated for a genetic disposition to autism, no one is safe . . . Today autism, tomorrow intelligence below 70 I.Q., the next day male pattern baldness. When will this madness stop?”

The only way to avoid this is to understand that we have no business deciding “who should live and who should die.” And that’s exactly where proposals like this are leading us.

Once a disability is “diagnosed” in utero, women are subject to enormous pressures to have an abortion. According to a recent Business Week article, there’s even a name for women who refuse to have an abortion in these circumstances: “genetic outlaws.”

Despite all the rhetoric about “alleviating suffering,” the bottom line in targeting the disabled in utero is the bottom line. As Business Week puts it, “the social cost of accommodating [their] birth is increasingly being seen as exceeding [their] worth.”

Oh my! This utilitarian view of life inevitably leads us exactly where the Nazis were creating a master race. Can’t we see it?

My heart goes out to parents who are raising autistic children. I know what they face because my daughter is raising a 15-year-old autistic son. But I also know firsthand the joy and blessing these children can bring into our lives. The answer is not to play God and keep them from being born—rather we need to help them and their parents. That’s what “alleviating suffering” really means.