Tuesday, April 25, 2006

MOVING BEYOND SIMPLICTY TOWARD THE RIGHT ANSWERS

I often say that neither science nor law (my field) should be inscrutable. But for scientific writing (or legal writing for that matter) to be understandable to lay people, it must make sense. Dr. Martha Herbert, a pediatric neurologist, makes sense when she speaks or writes. She is never one to overstate the case; indeed, she was one of the researchers who asked to have her name removed from a Generation Rescue advertisement lest her work be touted as definitive proof of a mercury-autism connection.

Dr. Hebert’s article, Autism: A Brain Disorder, or a Disorder That Affects the Brain?(link to pdf here), does not break any new ground, but it does clarify where we are and, more importantly, where we should be going. In the piece, Dr. Herbert convincingly suggests that the scientific evidence now supports a departure from a “strongly genetic, brain-based” model of autism in favor of a “genetically influenced, systemic” model. Her model seeks exploration of the interplay between brain connectivity issues and biological factors. Somatic symptoms that some call “comorbidities” are hypothesized to “be integrally related to what have been considered ‘core’ or defining symptoms, and both are likely to derive from the same or related underlying pathophysiology.”

It is important to note that Dr. Herbert does not specifically identify mercury as the biological factor triggering the genetic predisposition. Rather, her article references “heterogeneous” biological underpinnings. That certainly matches my own opinion that autism is not dependent on thimerosal exposure, but thimerosal exposure may be a trigger or contribute to the development of autism. Autism, again in my opinion, predated the introduction of thimerosal into vaccines, but the expansion of the vaccine schedule and the use of thimerosal are the primary factors in the skyrocketing numbers of diagnosed autism. In other words, the fact that the development of autism in an individual does not mean it is not primarily responsible for the current epidemic (oh dear, there I go using the “E” word again).

For a while now, those of us who believe that vaccines played a role in our children’s autism have been split into three basic camps. (This is a gross overgeneralization given the various permutations on the hypotheses, but I am culling it to three to keep this post manageable.)

First is the group that believes thimerosal exposure to be the cause of autism, a view which is sometimes oversimplified into an equation of autism = mercury poisoning. Those who doubt the vaccine connection (i.e., those that proclaim autism is totally genetic and that the unprecedented increase in diagnosed cases is due wholly to broadened diagnostic criteria and increased awareness) tend to lump anyone who disagrees with them into either this category or into some vague classification of “anti-vaxers.” Although admittedly controversial and not universally accepted, laboratory testing often indicates that mercury may not be properly excreted by some autistic children.

The second group focuses more on the effects of MMR vaccinations and the development of enterocolitis. The connection is easy enough to make given the gastro-intestinal problems many autistic children have. Like the thimerosal hypothesis, there are laboratory findings ⎯ again controversial and not universally accepted ⎯ to suggest that live viruses are causing problems in these children.

The third group, which I would place myself in, sees validity in both the thimerosal and MMR hypotheses, but don’t believe either can give a full answer in isolation. The key to understanding is to classify autism ⎯ at least the form of autism we see in our children ⎯ as an autoimmune disorder. Although there is a genetic predisposition underlying everything, the actual autoimmune process in most children might start with mercury poisoning from thimerosal-laden shots (see the recent study from the M.I.N.D. Institute). With the immune system damaged by the mercury, it becomes understandable how attenuated live viruses, particularly those given in combination and simultaneously with thimerosal-containing vaccines (e.g., my son received the MMR, polio, and DTP shots all in one visit to the pediatrician) can not only fail to create an immunity, but might also cause the kind of biological damage of which Dr. Herbert writes.

As we learn more and more, this third hypothesis is getting more attention beyond the scientific community. Witness the new articles in Dan Olmsted’s excellent and thought-provoking “Age of Autism” series for UPI. Like all of his articles, Mr. Olmsted is very careful to avoid representing his writing as scientific, but the questions he raises cannot be ignored. His recent series entitled “Pox” (see here and here) examines some of the results of a Merck-sponsored trial of the “ProQuad” vaccine. The ProQuad combines the MMR with a vaccine for chicken pox. Some of the children on whom the vaccine has been tested, have developed autism. The common thread among the children, other than they all reside in the area of Olympia, Washington, where the trials occurred, is that they all have a family history in which relatives had problems with chicken pox (e.g., multiple cases of the disease or the subsequent development of shingles) that might suggest a susceptible immune system.

It may yet turn out that mercury is the only problem, or that the MMR is the only problem, or that vaccines are not involved at all and it is all genetics. It would be far easier to believe any of those scenarios than to look at a multiplicity of possible environmental triggers acting on genetic predisposition. Most of us, however, would rather reach the right answer. Dr. Herbert’s model provides a framework for finding the right answer. And an answer that points to autoimune processes makes sense.

73 Comments:

Anonymous Mary Webster said...

Coconuts.

4/25/06, 9:50 PM  
Blogger Kristina Chew said...

Thanks for the link to Dr. Herbert's article. We are indeed in "camp 3." When I look back and think about Charlie's early months--and even earlier, to before he was born--I can remember things that tell me Charlie was the Charlie he already was, but what--in addition to/besides genes--"made" him so is yet up for grabs.

One thing to note: Though a big baby and vigorous, Charlie spent his first 36 hours of life in the ICU. He had contracted an infection in being born and was given antibiotics through an IV in the middle of his forehead (he kicked off the one on his ankle). He seemed so robust compared to the preemies in the incubators, and yet has always been curiously weak.

May we all keep on moving, forward, upward, onward.

4/25/06, 10:13 PM  
Blogger María Luján said...

Hi Wade
As you know I like very much the Martha Herbert work, even when I see it as a first step in an integrative view of what autism is.I think she is very open minded and he has provided a good basis where to begin working ahead.
I hope that research in the topic of thimerosal and vaccines can be seen in the next years with other light-beyond the controversy- and under the analysis of the Dr HErbert´s work with high tech equipment and high scientific procedures and methodology.
I know that perhaps I am being too much emphatic in the point but, although I include myself in the same group as you and Kristina, I think that every parent has his/her personal view because all autistic children are different and all experiences with autism are different. I also think that if xenobiotics management is altered in autism, therefore What our children breath and eat and drink can have chemicals difficult to handle properly (heavy metals, PCBs, PAHs, organic compounds, etc).I think that immune/autoimmune issues are of paramount importance in autism,looking at the published evidence, and related with these issues with viruses and bacterian infections- and their treatments.

With my son, he was very healthy-almost never ill- apparently up to the vaccines of the 12 to 18 months and 24 months. We never noticed before a different development up to 2 years although now we can not be sure that some signs were not present (memory is very tricky).

María Luján

4/25/06, 11:31 PM  
Blogger Ian Parker said...

Hi Wade,

I also appreciate the link to Dr. Herbert's article. I'm not totally sure that I'm in the third group, but only because of I'm not necessarily one "who believe that vaccines played a role in our children’s autism". I accept it as a possibility rather than believe it, which is a subtle difference but a difference nonetheless. Regardless, I am definitely a believer in the "genetically influenced, systemic" model, and I'd still sign up to buy the team jacket if one were offered.

While I still consider myself new to the autism issue, I’ve already seen too many children with the same diagnosis as my daughter who have many issues that she does not have, and who have escaped many of my daughter’s issues. The only major commonality other than some broad categorical umbrellas under which they all fit (e.g. “communications issues”) is the diagnosis itself. Dr. Herbert’s ‘final common pathways’ argument makes a great deal of sense given the range of symptoms and issues that get squeezed into the autism category, suggesting the possibility of ‘autisms’ rather than ‘autism’. It also potentially explains a questions about autism as a purely genetic condition, i.e. from an evolutionary standpoint, how does it continue to exist?

Unfortunately the ‘debate’ has – at least in some quarters - become so polarized between ‘all autism = mercury’ vs. ‘all autism is genetic/natural variation’ – arguments that have become almost ideological in nature - that I’d suggest that there are some who do not want to consider the possibility of a genetically influenced, systemic model. They may see it as a slippery slope that could undermine their absolutist arguments and give at least a minimum of credibility to the ‘other side’. That would be a shame, because this alternate approach to the questions behind autism may ultimately offer 'solutions' that are palatable to all sides.

4/27/06, 10:14 AM  
Blogger Wade Rankin said...

Ian: I’m not totally sure that I’m in the third group, but only because of I’m not necessarily one “who believe that vaccines played a role in our children’s autism”. I accept it as a possibility rather than believe it, which is a subtle difference but a difference nonetheless.

I was certainly overgeneralizing, but mostly because vaccines are the big issue. One of the appealing things about Dr. Herbert’s model is that it is not vaccine-dependent. I believe that vaccines were the primary triggering factor in my son’s autism. Also, I think changes in the vaccine schedule and the use of thimerosal are a likely cause of the rise in the numbers of diagnosed ASD cases because (a) there is a biologically plausible connection, (b) the timing fits, and (c) vaccines may be the most pervasive environmental factor among the affected children. That being said, if autism does have an autoimmune basis, there is no reason to believe that thimerosal, mercury, or live viruses must be the only possible trigger.

And while I’m addressing Ian’s comment, let me thank him for linking to his fine post that addresses many of these issues. It’s worth checking out.

4/27/06, 11:28 AM  
Blogger Joseph said...

from an evolutionary standpoint, how does it continue to exist?

From an evolutionary standpoint, how does mental retardation continue to exist, to give you another example? (You can substitute that with anything really).

Yet, about 3% of the population scores in the mentally retarded range, and about 1% can be classified as mentally retarded.

This is just a consequence of IQ test norming. It would be impossible to eliminate mental retardation, just as it would be impossible to eliminate giftedness (both equally "abnormal" conditions).

I can repeat the same argument with any behavioral spectrum.

4/27/06, 4:02 PM  
Blogger Joseph said...

I believe that vaccines were the primary triggering factor in my son’s autism. Also, I think changes in the vaccine schedule and the use of thimerosal are a likely cause of the rise in the numbers of diagnosed ASD cases because (a) there is a biologically plausible connection, (b) the timing fits, and (c) vaccines may be the most pervasive environmental factor among the affected children.

Unfortunately, the only paper that attempts to show a correlation between the administrative prevalence of autism and the average dose of thimerosal per child turns out to have a number of fatal and suspect errors. You should really check that out.

4/27/06, 4:08 PM  
Blogger Ian Parker said...

Joseph said:

"From an evolutionary standpoint, how does mental retardation continue to exist, to give you another example? (You can substitute that with anything really)."

Well, actually there's a bit of a difference between MR (which can have many causes, some potentially genetic mutations and some environmental) and a genetically based inheritable autism that either has to adhere to the rules of population genetics and evolution or re-write them.

4/27/06, 4:44 PM  
Blogger Joseph said...

Well, actually there's a bit of a difference between MR (which can have many causes, some potentially genetic mutations and some environmental) and a genetically based inheritable autism that either has to adhere to the rules of population genetics and evolution or re-write them.

The argument holds if you consider only the genetic causes of mental retardation. When it comes to behaviors and skills, nothing is 100% heritable anyway.

Autistic behavior may similarly result from a variety of subtle and complicated things, and I don't believe this is going to be as simple as "vaccines".

There's nothing to suggest that autism (the phenotype, not the diagnosis) is not adhering to the rules of population genetics.

4/27/06, 5:24 PM  
Blogger Wade Rankin said...

Joesph: Unfortunately, the only paper that attempts to show a correlation between the administrative prevalence of autism and the average dose of thimerosal per child turns out to have a number of fatal and suspect errors. You should really check that out.

Joseph,

Do you mean that you think the only studies performed to support the kind of hypothesis we’re discussing are the Geiers’ papers? Although I might disagree with you about the relative worth of their work, we could disregard the Geiers altogether (which I do not think necessary except to make a point), and we would still have lots to argue about. If you mean that most of the epidemiological reports fail to support a vaccine connection, you are right, but I have yet to see any epidemiology on either side of the debate that seems to have any reliability whatsoever. That leaves us with the biological evidence. If you mean to say that there is no single study to put all the pieces together, I would agree, but there is a steadily mounting body of work by quite a few scientists and clinicians that tend to support this developing hypothesis. We’ve both seen them listed countless times, and I really don’t want to open up a huge debate on each of the studies here. I have no problem with the fact you disagree with the methodology or conclusions of those studies, but you can’t ignore the fact that there is some basis for the argument any more than I can ignore the fact that you have a basis for stating the contrary.

Autistic behavior may similarly result from a variety of subtle and complicated things, and I don’t believe this is going to be as simple as “vaccines”.

I don’t disagree that this is not as simple a problem as “vaccines.” Indeed, I think I've said as much before. But the hypothesis that vaccine-induced damage may be the single biggest problem, at least for certain age cohorts, is not only plausible but likely.

I can only interpret your suggestion that the autism phenotype is adhering to the rules of population genetics as a continuation of your long-standing argument that we are not really seeing a dramatic increase in the numbers or relative severity of ASD. With all due respect to the interesting writing you have done on the subject, I don’t believe we have any reliable means of measuring the increase, but too many factors point to the conclusion that we are in the midst of an epidemic. “Diagnostic substitution” cannot explain away the numbers we see, and it certainly can’t explain away the non-scientific observations of those who most closely work in the pertinent fileds.

4/27/06, 5:47 PM  
Blogger María Luján said...

Hi Joseph
I appreciate very much your work, but the epidemiology can not dismiss at individual level negative effects.
A recent example about genetics.
There are certain kinds of polymorphisms that have not been studied in autistic children yet ( such as CPOX or BNDF), except GMST1 and the results were positive for correlation (2006, recently published)
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=16472391

GMST1 is a part of a sequence.From the reaction between a xenobiotic and glutathione, several enzymes are involved: glutathione S transferase-(GSM), gama glutamyl transpeptidase, cisteynil glicinase, N acetyl transferase and finally conjugates with mercapturic acid is formed. This sequence needs adequate levels of essential amino acids, pantothenic acid for Coenzyme A and phosphorus for the synthesis of ATP.
So I wonder if besides/ beyond glutathione , that needs aminoacids , the transformation to mercapturic acid somewhat can be hindered because of problems in some of these enzymes or nutritional problems affected by genetics and epigenetics in ASD? Nobody has published never a complete study on ASD children about this, although there are attempts by Dr Jill James/Dr Boris about GSH status and also the manuscript I mentioned above.

MAría Luján

4/27/06, 5:55 PM  
Blogger Ian Parker said...

Joseph said:

"The argument holds if you consider only the genetic causes of mental retardation. When it comes to behaviors and skills, nothing is 100% heritable anyway."

By quoting my "genetically based inheritable autism" before stating this it appears that you are implying that autism is not 100% heritable. If so then we agree. But are you suggesting that autism does not have a very significant genetic component? If so, that would put you in a very definite minority (in the same camp as your nemesis?).

If autism does have a significant genetic component then for it to continue to exist as a genetically based condition, the rules of population genetics require that people with the alleles that contribute to autism either procreate at the same or higher rate than the rest of the population or that the condition will 'breed out'. Clearly autism still exists, so either the individual alleles must have a significant natural advantage to overcome the reduced ‘fitness’ inherent in autism (notice I did not say that autistics do not procreate – only that their rate of procreation is assumed to be below ‘average’), or the alleles in the combinations that today cause autism did not historically produce this outcome to nearly the same degree to which they do today (supporting a ‘second hit’), If these alleles do contribute a significant natural advantage then they would have to also demonstrate this advantage over time, i.e. in the millennia prior to civilization during which they would have had to exist to allow for the geographic and haplogroup distribution of autism found today. If they cannot do this then they are not adhering to the rules of population genetics.

Joseph said:

"Autistic behavior may similarly result from a variety of subtle and complicated things, and I don't believe this is going to be as simple as "vaccines".

If you're arguing against my point on this then let's agree that I also have not said that it will be as simple as vaccines. Otherwise you clearly have not read what I said above or in my post. But going from there, I'll agree that "Autistic behavior may similarly result from a variety of subtle and complicated things". We may not agree on what those subtle and complicated things may be, however.

4/27/06, 6:09 PM  
Blogger Joseph said...

Do you mean that you think the only studies performed to support the kind of hypothesis we’re discussing are the Geiers’ papers?

No, I mean the only paper to attempt to correlate administrative prevalence with thimerosal dose per child. (I think this is correct).

If you mean that most of the epidemiological reports fail to support a vaccine connection, you are right, but I have yet to see any epidemiology on either side of the debate that seems to have any reliability whatsoever.

I actually agree with you that there needs to be some replication of findings, if only to address the concerns in your side of the debate. This, of course, can only go so far.

That leaves us with the biological evidence. If you mean to say that there is no single study to put all the pieces together, I would agree, but there is a steadily mounting body of work by quite a few scientists and clinicians that tend to support this developing hypothesis.

None of it convincing though.

But the hypothesis that vaccine-induced damage may be the single biggest problem, at least for certain age cohorts, is not only plausible but likely.

I'm not sure what you're basing this assertion on.

I can only interpret your suggestion that the autism phenotype is adhering to the rules of population genetics as a continuation of your long-standing argument that we are not really seeing a dramatic increase in the numbers or relative severity of ASD. With all due respect to the interesting writing you have done on the subject, I don’t believe we have any reliable means of measuring the increase, but too many factors point to the conclusion that we are in the midst of an epidemic.

It's difficult to go back in time and check. But you might have seen my post on the 1982 paper and another recent paper that screened mentally retarded populations for autism; both found similar results, 38-39% prevalence in that population, which is much higher than any current administrative recognition of autism in that population.

I'd also suggest that it's possible to check if regional differences in prevalence are real. This could be done by, again, screening the population with mental retardation and by providing an autism spectrum screening questionnaire to children in an age cohort.

“Diagnostic substitution” cannot explain away the numbers we see, and it certainly can’t explain away the non-scientific observations of those who most closely work in the pertinent fileds.

No, it can't, particularly in certain regions where diagnostic substitution is a minor factor compared to increasing recognition in the population without cognitive deficits.

Regarding anecdotal observations, it's hard to judge what their value is. For example, has the number of "geeks" increased in the last generation? I doubt it. But I'm sure more children with an autistic label are attending mainstream schools these days.

4/27/06, 6:17 PM  
Blogger Joseph said...

I appreciate very much your work, but the epidemiology can not dismiss at individual level negative effects.

I tend to agree. But there are a number of issues. First, when arguing causes, people don't generally say, "my child suffers from X". They say, "my child has an autism diagnosis" and "autism is caused by X". Often, anything medically wrong with the autistic child is assumed to be part of the autism. There needs to be better research to support correlations. Even so, it's not necessarily true that co-morbidities of the condition cause the condition. Genotypes can have higher incidence of certain co-morbidities, and this is not surprising.

4/27/06, 6:25 PM  
Blogger María Luján said...

Hi Joseph
You say
Often, anything medically wrong with the autistic child is assumed to be part of the autism.

But What if it is? How can we assure for sure that the gene expression hindered/disturbed by epigenetics has not this manifestation if not enough studies are for now? We are not therefore at an individual level, you do not know until you
1-test properly to detect
2-treat adequately to do the best you can with the medical condition, if it is treatable. There are a lot of detected comorbilities by anecdotical evidence that can/can not be related to the core of what autism is.I think that , as in the case of the epidemics debate, we can not say nothing for sure today with the information available, BUT we have clues in that direction. If you are interested, I can send to you a recent review about that perhaps you can find interesting.

There needs to be better research to support correlations.

I agree with you that correlation is not causation, therefore I prefer the word comorbilities.

Even so, it's not necessarily true that co-morbidities of the condition cause the condition.

Agree, but with the available information it can not be discarded that are a result of the condition. Even more, we can not know at individual level how much is result of genetics (brain structure) or produced by ( neurotransmitters problems for example because of environmental insult) because the diagnosis is only based on behaviors and these can have many different routes, even with mixed causality.

Genotypes can have higher incidence of certain co-morbidities, and this is not surprising.

But the individual presentatioin of the comorbilities is , at least or at least must be, enough suspicious to encourage high tech and high level research about, if open minded to the issue is present.

María Luján

4/27/06, 6:38 PM  
Blogger Joseph said...

By quoting my "genetically based inheritable autism" before stating this it appears that you are implying that autism is not 100% heritable. If so then we agree. But are you suggesting that autism does not have a very significant genetic component? If so, that would put you in a very definite minority (in the same camp as your nemesis?).

It's undisputed that autism is not 100% heritable, but at the same time autism is extremely heritable. It's difficult to find any behavior or skill clearly more heritable than autism.

Evidently, there must be an environmental reason as to why autism is not 100% heritable. There must also be an environmental reason why intelligence and personality are not 100% heritable. This doesn't have to be a brain insult necessarily, but can be random, subtle and uncontrollable. Camille explains it well in the comments section of my post about this.

If autism does have a significant genetic component then for it to continue to exist as a genetically based condition, the rules of population genetics require that people with the alleles that contribute to autism either procreate at the same or higher rate than the rest of the population or that the condition will 'breed out'.

This is not necessarily true if autism results from multiple alleles, which individually don't have significant liabilities (and perhaps even some advantages).

Also, the frequency of these alleles can be low, without being zero.

have to also demonstrate this advantage over time, i.e. in the millennia prior to civilization during which they would have had to exist to allow for the geographic and haplogroup distribution of autism found today. If they cannot do this then they are not adhering to the rules of population genetics.

And again, I believe it did exist. It just wasn't labeled 'autism' and in many cases not even labeled at all. (It's also possible autistics in the past had lower life expectancy. See this for example.)

If you're arguing against my point on this then let's agree that I also have not said that it will be as simple as vaccines. Otherwise you clearly have not read what I said above or in my post. But going from there, I'll agree that "Autistic behavior may similarly result from a variety of subtle and complicated things". We may not agree on what those subtle and complicated things may be, however.

Right, I'm thinking random, early, subtle, uncontrollable. The same kinds of things that make intelligence and personality not be 100% heritable.

4/27/06, 6:49 PM  
Blogger Do'C said...

"But the hypothesis that vaccine-induced damage may be the single biggest problem, at least for certain age cohorts, is not only plausible but likely.

I'm not sure what you're basing this assertion on."


Post Hoc fallacy. A occurs, then B occurs, somehow A caused or influenced B. It is plausible, but there is no evidence to quantify likely. If you think there is today, you be bleevin. Roosters crow 5 minutes before sunrise, then the sun rises. How likely is it that the crowing of the roosters actually causes the sun to rise?

"If autism does have a significant genetic component then for it to continue to exist as a genetically based condition, the rules of population genetics require that people with the alleles that contribute to autism either procreate at the same or higher rate than the rest of the population or that the condition will 'breed out'."

That's a possibility, but requires evaluation on an evolutionary timescale. Unless time-travel really was developed by the Geiers, we will be unlikely to know the answer to this one.

4/27/06, 7:49 PM  
Blogger Ian Parker said...

Joseph said: "This is not necessarily true if autism results from multiple alleles, which individually don't have significant liabilities (and perhaps even some advantages).

Actually, even in the case of multiple alleles, which most assume is the case in autism, the combinations of alleles that cause autism would detract from the maintenance of the frequency of each individual allele if the 'autism cases' did not reproduce at the same rate.

To simplify, if an allele frequency is 50% and there is no variation in reproduction (hold for genetic drift for a moment) then the frequency in the next generation should be 50%. But if 4% of those with the allele (2% of the pop) have the combination of multiple alleles - i.e. autism - and only half procreate then the replication is only 49% (100% of 48% + 50% of 2%). At that rate it doesn't take too many generations for the frequency to approach 0%. For the frequency not to approach 0% there is a requirement for the alleles in their non-autistic combinations to reproduce at a higher than average rate, or for the autism combination to reproduce at the average rate.

Joseph said: "And again, I believe it did exist. It just wasn't labeled 'autism' and in many cases not even labeled at all. (It's also possible autistics in the past had lower life expectancy. See this for example.)

Mathematically the allele combinations must have existed. If they did not then autism would have no genetic component. On this we're agreed. But the rules of population genetics require that either the combination reproduces at the average rate or that the uncombined or partially combined alleles reproduce at a higher than average rate to take up the slack, which requires that they have a natural advantage to overcome genetic drift. And that natural advantage would have to endure over time (through a long pre-civilization period).

As for autistics having lower life expectancy (even or especially if externally caused), that again would raise the hurdle rate for the individual alleles unless death came a) post-procreation and b) did not impact the ability of the offspring to survive to maturity and reproduce again.

Joseph said: "I'm thinking random, early, subtle, uncontrollable. The same kinds of things that make intelligence and personality not be 100% heritable."

But again, we're still stuck with the fact that regardless of the allele expression, the allele frequency must either increase, be maintained, or suffer decline. Even if the combinations of alleles that cause autism result in the condition only 50% of the time, or even 1% of the time, that only changes the rate of decline, not the decline itself. We're still stuck with the math, requiring either a corresponding natural advantage, or a long term decline. As for totally random autism, any random non-genetic form would become the dominant expression of the condition, as the genetically caused autism would disappear. Clearly this has not happened.

The only exception to this duality(natural advantage or extinction) would be if the combination did not have any significant negative reproductive impact, i.e. that genetics is not enough to explain autism, but that the condition requires one or more additional exogenous factors.

4/27/06, 7:51 PM  
Blogger Ian Parker said...

This comment has been removed by a blog administrator.

4/27/06, 7:58 PM  
Blogger Ian Parker said...

DoC said: "That's a possibility, but requires evaluation on an evolutionary timescale. Unless time-travel really was developed by the Geiers, we will be unlikely to know the answer to this one."

Given the world-wide prevalence of autism and clear evidence of historical migration patterns through mitochondrial DNA and Y chromosome analysis, the alleles that contribute to autism would have to be at least 40,000 years old (see here)

I'm not sure why the Geiers would have anything to do with it, but I would hope that if they did they'd prove the case before applying for the patent.

4/27/06, 8:01 PM  
Blogger María Luján said...

Hi DoC
You say

Post Hoc fallacy. A occurs, then B occurs, somehow A caused or influenced B. It is plausible, but there is no evidence to quantify likely.

The first step in every known scientific method is observation of anecdote. The anecdote itself is useful , the main point is the analysis of. Under a TOTAL CAUSAL relation, you always can be done a Post hoc fallacy with everything, even with medical conditions that after replication demonstrated to be proven. Medical conditiond need testing to be correlated with an even under this there are several options available in general.

If you think there is today, you be bleevin. Roosters crow 5 minutes before sunrise, then the sun rises. How likely is it that the crowing of the roosters actually causes the sun to rise?

The problem I have with this argument is that is not applicable here. There are a lot of work that is not being actually considered about HM susceptibility and environmental factors and also from viral infections in other fields than autism that are given a lot of clues about. I do think that nothing has been proven for sure today, beyond that in autism the genetic component is important, nothing can be assured for sure , nothing can be discarded from what are we talking about as environmental insult and effect in gene expression/epigenetics.

4/27/06, 8:07 PM  
Blogger Wade Rankin said...

Dad o’ Cam,

If all I was relying upon were my own observations, I would have to agree that the possibility of engaging in an ad hoc fallacy should deter me from stating an opinion on causation. But we are talking about a hypothesis that was, in part, labeled “plausible” by the IOM before they decided it would be a good idea to shut down the debate based on one American epidemiological study that even its author called, “neutral,” together with a few badly designed foreign epidemiological studies. There is a growing body of biological evidence that seems to support a connection with vaccines, particularly those containing thimerosal. What has puzzled me from day one is the relative lack of interest in performing biological studies by any agency, company, or person who might have an interest in disproving the connection. Now you might call that a “red herring,” and it certainly proves nothing, but it just seems to me that the best way to shut people like me up would be to prove me wrong.

4/27/06, 8:25 PM  
Blogger Do'C said...

Ian, I enjoyed your genetics post, thanks for the link.

Maria said: "The first step in every known scientific method is observation of anecdote."

Anecdote? I know it's a question of semantics, stick with "observation" and I'm with you.

Maria said: "The problem I have with this argument is that is not applicable here. There are a lot of work that is not being actually considered about HM susceptibility and environmental factors and also from viral infections in other fields than autism that are given a lot of clues about."

Clues may be important, but do not constitute scientific evidence.

Maria said: "I do think that nothing has been proven for sure today, beyond that in autism the genetic component is important, nothing can be assured for sure , nothing can be discarded from what are we talking about as environmental insult and effect in gene expression/epigenetics.

Then we are not in disagreement. I support research focused on understanding the multiple etiologies of the many autisms, it does need to be destined for real peer-reviewed scientific publication.

Wade said: "If all I was relying upon were my own observations, I would have to agree that the possibility of engaging in an ad hoc fallacy should deter me from stating an opinion on causation. But we are talking about a hypothesis that was, in part, labeled “plausible” by the IOM before they decided it would be a good idea to shut down the debate based on one American epidemiological study that even its author called, “neutral,” together with a few badly designed foreign epidemiological studies."

I don't see how being labeled "plausible" by the IOM says anything other than they saw it "plausible".

Wade said: "There is a growing body of biological evidence that seems to support a connection with vaccines, particularly those containing thimerosal."

Hmm, we could go in circles on what's valid that constitutes such evidence if we don't accept a common standard for scientific acceptability or relevance. Until then, we'd be arguing belief, which would be pointless. Thimerosal is well on its way to irrelevance (even the trace amounts).

Wade said: "What has puzzled me from day one is the relative lack of interest in performing biological studies by any agency, company, or person who might have an interest in disproving the connection."

Your begging the question Wade - "disproving the connection". It's possible that it's puzzling to you because you (and many others) have made an assumption that many have not.

Now you might call that a “red herring,” and it certainly proves nothing, but it just seems to me that the best way to shut people like me up would be to prove me wrong.

I don't see any point in trying to shut you up or prove you wrong, I'm not making an assumption that you're right in the first place. To prove you wrong would require that you prove your hypothesis first. I'm not going to assume you are wrong either. When you prove your hypothesis, I'll be all ears.

I also think an effort to shut people up who are speaking from belief is fruitless. You can believe whatever you want, it's a free country.

By the way Wade, you're quite the polite commenter out there in the blogosphere, please don't ever let that deteriorate.

4/27/06, 10:35 PM  
Blogger María Luján said...

Hi Dad of Cameron

Clues may be important, but do not constitute scientific evidence.

It depends on the analysis of. At an individual level. Clues provided by published reports can be extremely important.


Then we are not in disagreement. I support research focused on understanding the multiple etiologies of the many autisms, it does need to be destined for real peer-reviewed scientific publication.

Again, there are a lot of reports of the non most controversial authors about HM susceptibility (Dr Woods and Echeverria) and from MMR effects (as inmunosuppresant) for example that are not being commonly discussed/or considered in the analysis.



María Luján

4/28/06, 7:19 AM  
Blogger Joseph said...

To simplify, if an allele frequency is 50% and there is no variation in reproduction (hold for genetic drift for a moment) then the frequency in the next generation should be 50%. But if 4% of those with the allele (2% of the pop) have the combination of multiple alleles - i.e. autism - and only half procreate then the replication is only 49% (100% of 48% + 50% of 2%). At that rate it doesn't take too many generations for the frequency to approach 0%. For the frequency not to approach 0% there is a requirement for the alleles in their non-autistic combinations to reproduce at a higher than average rate, or for the autism combination to reproduce at the average rate.

According to your model, no low-frequency inherited alleles associated with liabilities should ever exist. You'd have a hard time explaining something such as Fragile-X or the Ashkenazi Jewish race for that matter.

Or consider the DRD4-7R allele associated with ADHD. It has a pretty high frequency in Europe (something like 20%). Some of the alleles associated with autism also appear to have relatively high frequencies, even though more work is needed in this area to confirm.

So basically, an allele can be advantageous to some extent and maintain a non-zero frequency.

4/28/06, 9:28 AM  
Anonymous anonimouse said...

Wade,

While I certainly think it's plausible that some variants of autism have an environmental component, I think you are making a huge reach when you suggest that thimerosal-containing vaccines are the primary environmental culprit. There are many "environmental toxins" out there that could theoretically cause neurological damage, why thimerosal and thimerosal only?

If you're suggesting that these children have a general susceptibility to environmental factors that then manifest as autistic-like behaviors. that's one thing. I'd suggest that's a pretty darn difficult thing to prove.

I'm not sure why the focus on thimerosal-containing vaccines, though. There are plenty of other things that children are widely exposed to that could be factors. I admit to having cynical reasons for thinking that TCV's are the main target.

I think that if environmental factors are to play in autism, they're most likely pre-natal during critical periods of brain development, where it's far more plausible brain structures could be altered. So I would love to see continued research of things mothers do and/or exposed to during the first trimester, and see what correlates there are with autism. We already know mothers who contract rubella during the first trimester, for example, have a higher risk of delivering children who end up being on the spectrum.

4/28/06, 9:41 AM  
Blogger Wade Rankin said...

Joseph, Dad of Cameron, and anonimouse,

I cannot state that I am right and you are wrong. Like all of you, I am trying to make sense of a very complicated situation, and my opinions are based on what makes sense. What I like about Dr. Herbert’s model (you remember Dr. Herbert, don’t you; that’s where we began this little discussion) is that it provides a good framework for exploring all of the environmental possibilities. The work going on at the M.I.N.D. Institute should help us understand better the basic processes, which will help us determine the relative dangers of specific insults.

Before we go any farther in this discussion, I just wanted to thank everyone for maintaining a respectful tone.

4/28/06, 10:03 AM  
Blogger Joseph said...

why thimerosal and thimerosal only?

I echo that question. May I suggest that this is a trigger that can be blamed on a specific corporation and the goverment?

There's very little said about the association between administrative prevalence of autism and degree of urbanization, for example. There's very little uproar over environmental pollution, which is probably not as easy to blame on someone specific.

The difference in administrative prevalence between Los Angeles and Fresno is pretty much equivalent to the size of the "epidemic". I would think this is where most of the focus of the environmental trigger proponents should go to. Instead, they focus on causes that can be more easily pursued through litigation.

4/28/06, 10:07 AM  
Blogger Ian Parker said...

Joseph said: "According to your model, no low-frequency inherited alleles associated with liabilities should ever exist. You'd have a hard time explaining something such as Fragile-X or the Ashkenazi Jewish race for that matter."

No, what I said was the following:

"For the frequency not to approach 0% there is a requirement for the alleles in their non-autistic combinations to reproduce at a higher than average rate, or for the autism combination to reproduce at the average rate."

Fragile X is a mutation occurring in 1 in 4000 males and 1 in 6000 females. Mutations by definition can occur randomly and spontaneously (that’s why they’re mutations). It is the same with Down’s Syndrome.

Ashkenazi exist because they have historically tended to marry within the culture/faith/tribe/group (pick your favorite descriptor). If you’re going to go to Ashekanzi diseases next (e.g. Tay-Sachs), there is considerable speculation that they exist because in their carrier form they actually provide a natural advantage (Tay-Sachs in this form may enhance dendrite growth and promote higher intelligence).

Genetic diseases can exist due to founder effect and genetic drift, but the high hurdle rate for serious liabilities usually means such diseases are confined to small subsections of the population and are geographically isolated. Autism is neither.

As for ADHD, it can have both serious liabilities and significant advantages. My boss at a previous employer was ADHD, and in terms of quickness and range of intellectual thought he was a wonder to behold. His income, lifestyle, and family all reflected this. From an evolutionary 'fitness' POV we should all be so lucky.

Joseph said: ” So basically, an allele can be advantageous to some extent and maintain a non-zero frequency”.

I believe that is close to what I said here: ” Clearly autism still exists, so either the individual alleles must have a significant natural advantage to overcome the reduced ‘fitness’ inherent in autism (notice I did not say that autistics do not procreate – only that their rate of procreation is assumed to be below ‘average’), or the alleles in the combinations that today cause autism did not historically produce this outcome to nearly the same degree to which they do today (supporting a ‘second hit’)”

4/28/06, 10:15 AM  
Blogger Joseph said...

The work going on at the M.I.N.D. Institute should help us understand better the basic processes, which will help us determine the relative dangers of specific insults.

I should let you know that the MIND Institute has been looking at the CDDS data for several years, and are apparently drawing similar conclusions to what I have. They have access to confidential-level info I don't have access to and can probably draw conclusions I'd like to be able to. I understand a paper is in the works.

This is what Paul Choate of CDDS told me:

Fortunately Irva Hertz-Picciotto has done just that, not only rebutting Geier but exposing several things that we are concerned about but don’t understand, such as the highly concentrated prevalence of our Autistic caseload in LA. We have also made clear to her group the Autism population shifts we see in MR diagnosis as well as the persistent drop in problem behavior. Irva is prominent in this field, and she wants to publish in a leading journal like Lancet or JAMA; this would establish clear scientific precedence over Geier and Geier.

So basically, the dropping client characteristics and regional differeces I've posted about will soon hit the mainstream literature.
This is pretty compelling evidence, hard to explain or refute.

4/28/06, 10:16 AM  
Blogger Joseph said...

Fragile X is a mutation occurring in 1 in 4000 males and 1 in 6000 females. Mutations by definition can occur randomly and spontaneously (that’s why they’re mutations). It is the same with Down’s Syndrome.

Fragile X is most often inherited. I'm not sure how often a brand new mutation occurs, but it must be quite infrequently. Autism alleles could also appear as mutations occasionally.

Then we get into whether autism provides certain advantages or not. This is disputed and I don't want to get into an argument as to whether Einstein and Bill Gates are autistic. But you might want to check the research of Dr. Mottron.

4/28/06, 10:30 AM  
Blogger Ian Parker said...

That autism potentially provides some advantages is not an issue. The issue is whether autism provides advantages that enhance 'fitness', i.e. the extent to which an organism is adapted to or able to produce offspring in a particular environment.

Again, obviously some autistics procreate. That is not in question. What is an issue is whether they do so at the same rate as the rest of the population.

4/28/06, 10:42 AM  
Blogger Do'C said...

Ian said: "Again, obviously some autistics procreate. That is not in question. What is an issue is whether they do so at the same rate as the rest of the population."

Autistics may not be the only relevant factor. What about predispositioned carriers of a likely myriad of influential/susceptible genetics that are not by today's definition, "autistic"?

4/28/06, 11:32 AM  
Blogger Joseph said...

Again, obviously some autistics procreate. That is not in question. What is an issue is whether they do so at the same rate as the rest of the population.

This is not the issue really. The issue is whether people with autistic alleles in general procreate at a rate similar to that of the rest of the population. It not relevant if they have a diagnosis of autism or not.

Consider the parents of autistics. How often do they procreate? I don't believe there are studies on this. Anecdotally, I believe it's common for autistics to have many siblings. (I'm trying to remember a study of 15 families where the dad was autistic, and each family had 3, 4 kids).

There's some question about higher risk of autism in twins. Perhaps autism comes with a fertility advantage? I'm just speculating, of course.

4/28/06, 12:07 PM  
Blogger María Luján said...

Hi
About environmental insult, it is certain that there are a lot of potential ones, but it seems that the key to understand the impact are
1-the detox system
2-the immune system-
For me
a-There is individual susceptibility to toxicants based on genetics
b-There are biochemical imbalances related to the expression of these genes
c-The epigenetics plays a role in terms also of compensating mechanisms that can be disrupted
Perhaps you know this manuscript but I found it extremely interesting.

http://ehp.niehs.nih.gov/
members/1999/suppl-5/767-
775el-fawal/el-fawal-full.html

Neuroimmunotoxicology: Humoral Assessment of Neurotoxicity and
Autoimmune Mechanisms
Environ Health Perspect. 1999 Oct;107 Suppl 5:767-75.

In the management of xenobiotics, factors affecting the toxicity of reactive metabolites are
1-Levels of activating enzymes
2-Levels of conjugating enzymes
3-Levels of cofactors or conjugating chemicals. Glutathione depletion potentiates covalent binding and hepatotoxicity…Reduced glutathione plays an important protective role rapping electrophilic metabolites and preventing binding to hepatic proteins and enzymes.
The toxic sequelae will vary with developmental stage, nutritional status, health or physiological previous status:
In sequence, from the reaction between a xenobiotic and glutathione, several enzymes are involved: glutathione S transferase-(GSM), gama glutamyl transpeptidase, cisteynil glicinase, N acetyl transferase and finally conjugates with mercapturic acid is formed. This sequence needs adequate levels of essential amino acids, pantothenic acid for Coenzyme A and phosphorus for the synthesis of ATP.In the case of Hg susceptibility, there is a wide distribution of resistance in NT people. Some people have no evidences with very high blood values and other have with low
blood values
There is a manuscript about the lap time between exposure and symptoms

Silent Latency Periods in Methylmercury Poisoning and in Neurodegenerative Disease
Bernard Weiss,1 Thomas W. Clarkson,1 and William Simon2

http://www.ehponline.org/
members/2002/suppl-5/851-854weiss/weiss-full.html
Dr Woods studied Hg interaction with humans since 1977. There are more than 50 manuscripts cited in Pubmed.
These kinds of polymorphisms have not been studied in autistic children yet, except GMST1 and the results were positive for correlation (2006, recently published)
http://www.pubmedcentral.gov/
articlerender.fcgi?tool=pubmed&pubmedid=16472391
Manuscripts of Echeverria and Woods et al present the idea of susceptibility.
Descotes, Piyasirisilp S, Hemachudha T., Shoenfeld Y, Aron-Maor A. have published on concerns about genetically susceptible people in terms of reactions to vaccines in general.

Again, there have been no complete effort to correlate findings about detox system, immune system and nutritional status to know about the biochemistry of autism as a different example of how genetic differences impact at a systemic form the overall interaction with the environment.

Again Joseph, what is demonstrated is that these CCDS data can not be used to say that an epidemics have taken place during the last 30 years, but also can not discard it for sure. AND at an individual level, why only MR? what if there are another better markers unknown today? What about speech delay and learning problems?What about related problems with the detox/immune system such as asthma or allergies? Because of the wide deffinition, there are an enormous variation of potential medical problems that could be related to related polymorphisms, such as GSMT1 showed.


What do you think?
Sincerely
María Luján

4/28/06, 1:13 PM  
Blogger Joseph said...

Again Joseph, what is demonstrated is that these CCDS data can not be used to say that an epidemics have taken place during the last 30 years, but also can not discard it for sure.

A small real increase over decades cannot be discounted, but it cannot be asserted either. Furthermore, a small increase is not incompatible with genetics.

AND at an individual level, why only MR? what if there are another better markers unknown today? What about speech delay and learning problems

I can tell you there doesn't appear to be an increase in the prevalence of speech delay. There's limited info on this though.

4/28/06, 1:34 PM  
Anonymous anonimouse said...

why thimerosal and thimerosal only?

I echo that question. May I suggest that this is a trigger that can be blamed on a specific corporation and the goverment?

There's very little said about the association between administrative prevalence of autism and degree of urbanization, for example. There's very little uproar over environmental pollution, which is probably not as easy to blame on someone specific.


My "cynical" belief echoes yours - that the rush to indict thimerosal has more to do with a convenient, lucrative boogeyman than anything else. That's why I often wonder how much research is really done in the name of scientific inquiry and how much is being done to pad the reference list for an impending lawsuit.

That being said, I will suggest that the choice of thimerosal does make sense at some level. While other environmental factors are likely to vary substantially from location to location, vaccine uptake is fairly consistent. It's one of the few things with the potential to cut through regional (and perhaps socio-economic) boundaries.

4/28/06, 3:15 PM  
Blogger Ian Parker said...

Okay, this is starting to get a little circular here. All thread long, since Joseph called me on the evolutionary argument, I've been proposing the following:

"If autism does have a significant genetic component then for it to continue to exist as a genetically based condition, the rules of population genetics require that people with the alleles that contribute to autism either procreate at the same or higher rate than the rest of the population or that the condition will 'breed out'. Clearly autism still exists, so either the individual alleles must have a significant natural advantage to overcome the reduced ‘fitness’ inherent in autism (notice I did not say that autistics do not procreate – only that their rate of procreation is assumed to be below ‘average’), or the alleles in the combinations that today cause autism did not historically produce this outcome to nearly the same degree to which they do today (supporting a ‘second hit’)"

Joseph said: "Then we get into whether autism provides certain advantages or not. This is disputed and I don't want to get into an argument as to whether Einstein and Bill Gates are autistic. But you might want to check the research of Dr. Mottron.?"

I then answered specificially the question of autistic procreation, assuming that the stuff I wrote previously still holds, and now I'm being called to account for not considering the carriers, i.e. those with autistic alleles as distinct from autistics themselves, and their level or degree of procreation.

I guess what I'm trying to say is that I've already covered this above.

Specifically on "Anecdotally, I believe it's common for autistics to have many siblings. (I'm trying to remember a study of 15 families where the dad was autistic, and each family had 3, 4 kids).", (humor) are we allowed to use the "a" word?(/humor).

I would suggest based on the studies I identified on my blog that autistics tend to procreate less average than often, and based on these studies, apparently infrequently enough to overwhelm any potential examples of some autistic families. Unfortunately this is an unknown, because it has not been extensively studied as part of 'autistic outcomes', which themselves have not exactly been researched to death.

Personally, I'd love to read that autistic outcomes match those of non-autistics in terms that can loosely apply to the biological concept of 'fitness'. I'll then give up blogging and spend more time with my daughter, which is probably where I should be anyway.

As for twins, there were a couple of studies here and here suggesting that DZ twinning increased the risk of autism, but they were explained/refuted here.

4/28/06, 3:36 PM  
Blogger Wade Rankin said...

. . . why thimerosal and thimerosal only?

Okay, someone help me out here. Who in this discussion has said that thimerosal is the only possible environmental insult?

That's why I often wonder how much research is really done in the name of scientific inquiry and how much is being done to pad the reference list for an impending lawsuit.

I’ve spent over 20 years blaming plaintiffs’ lawyers for cooking up wild claims. Although they tend to be a pretty well organized, and often well-financed, group, they would not go about concocting science in these cases ⎯ at least not in the manner the body of science is developing.

First, the M.O. of the plaintiffs’ bar is to wait until something is a little more established before moving into the territory. Moreover, they would not choose this target considering they have to go through vaccine court first. In other words, this is not necessarily the target of choice for those opportunistic fellows.

Second, if the plaintiffs’ bar were influencing the science, they wouldn’t rely on reductionist biological studies. They would be more interested in funding epidemiological work that would be easier to manipulate. The biological studies, if they are concocted, would be far easier to refute for the defense. In other words, epidemiology would give them more bang for the buck.

4/28/06, 4:20 PM  
Blogger Ian Parker said...

Meanwhile, getting a bit closer to the original subject of this post...

It is an easy fallback to suggest that the motivation on the 'bio-med' side is a litigation payoff, but it is also a sweeping and - just maybe - an unfair generalization? There is also the slight possibility that some may actually believe - correctly or incorrectly is another matter - that this offers a) an explanation of the causes of autism and b)potentially a route to amelioration of some of the symptoms. You don't have to believe that another's viewpoint is correct to believe that it may be genuinely held.

Just a thought.

One reason that there is not much research done on autism and the degree of urbanization or environmental pollution may be the strength of the ‘autism as genetics’ paradigm. None of the mainstream doctors we’ve encountered (there have been more than a few, and they appear to be representative of a more general view) believe that autism is anything other than purely genetic. That’s not a conspiracy, but it is a pretty firm belief structure, and to the extent that this view is shared, doctors, researchers, and those controlling funding - being human - are probably more likely to explore the avenues of approach that match their belief structure than those that do not. Dr Herbert’s attempt to redefine the paradigm in systemic terms is not unique, but it is a departure from this view, and may increase the amount of research in other areas.

4/28/06, 4:25 PM  
Blogger María Luján said...

Hi anonimouse
Thank you for your comment
" While other environmental factors are likely to vary substantially from location to location, vaccine uptake is fairly consistent. It's one of the few things with the potential to cut through regional (and perhaps socio-economic) boundaries"
I do not want to bother you with an idea you can be not interested on, therefore I wonder if you would be interested to know what is my thinking about the potential role of vaccines in general in susceptible children and based published science.
Do you know the Descotes, Piyasirisilp S, Hemachudha T., Shoenfeld Y, Aron-Maor A. works and the Echeverria works I mentioned? Do you want to comment them?
Ian
My experience was very much like yours. In fact it was worse. We were told Autism=Hell, Autism =Cancer literally by almost every doctor we contacted (except 2, the current doctors of my son).
We need a change of mind in researchers and doctors about what autism is, considering different the individual presentation of autism and the possibilities of comorbilities (please let me call them this way for now Wade) to conduct serious research about these issues:heavy metals, vaccines, possibility of bioaccumulation and negative effects of viruses in autistic children. Unfortunately, in no other field, the mistakes a researcher can do in methodology or interpretation-and publish-, even if it is well intentioned, have a lot of impact about the topic of the research itself. Today, many of what it has been published is out of date and however is still being mentioned once and again. But for me is part of the history of the topic. I have found useful and totally useless published research in autism from serious peer review journals. I think that we need a new approach to autism , perhaps even from different fields than autism itself-because of this locked in concept- from immunology, virology, toxicology, xenobiotics management,etc working with geneticists in collaboration with open mind and open to the analysis of the observation.

María Luján

4/28/06, 4:34 PM  
Blogger Joseph said...

I would suggest based on the studies I identified on my blog that autistics tend to procreate less average than often, and based on these studies, apparently infrequently enough to overwhelm any potential examples of some autistic families. Unfortunately this is an unknown, because it has not been extensively studied as part of 'autistic outcomes', which themselves have not exactly been researched to death.

It's hard to quantify. But check this, then this and this. Interesting? Maybe or maybe not.

On outcomes, there are only a couple of studies. Some portion of autistics are classified as having good outcomes (even "recovered").

4/28/06, 5:37 PM  
Blogger Do'C said...

Wade said: "I’ve spent over 20 years blaming plaintiffs’ lawyers for cooking up wild claims. Although they tend to be a pretty well organized, and often well-financed, group, they would not go about concocting science in these cases ⎯ at least not in the manner the body of science is developing."

Wade, why would you assert that 'science' is not being concocted in these cases?

Are you VERY familiar with the 2003 ASU chelation study that resulted in the Bradstreet paper, and the current SCNM chelation study?

Do you know all of the reasons why ASU sent the second chelation study walking?

4/28/06, 5:54 PM  
Blogger Joseph said...

The question on triggers is this: There is a huge focus and uproar over vaccines (be it thimerosal or MMR). The plausibility of the vaccine hypothesis is no better than that of any other environmental trigger hypothesis, such as environmental pollution. Is this simply where the research has just happened to be focused on?

4/28/06, 6:01 PM  
Blogger Joseph said...

they would not go about concocting science in these cases

I again refer you to Geier & Geier (2004) and how the carefully selected data strangely fits the desired findings.

4/28/06, 6:05 PM  
Blogger Do'C said...

Hey Joseph,

Wouldn't you know it? Geier and Geier were in on the first chelation study with Bradstreet and Adams. Coincidence?

Maybe.

4/28/06, 6:11 PM  
Blogger María Luján said...

Hi joseph
Probably the point of the timing and the way of exposure (injection) in genetically susceptible individuals is what for me I found of concern in vaccines in general.
But again, from other fields of neurobiology neuroimmunotoxicology , etc there are several clues about potential dysfunctions. What is lacking is a systemic study about the potential or actual impact of vaccines in ADS children, not in the general population, but in ASD children.
I wonder if the research would not be more productive if the focus if given to the biological process of xenobiotics management more than to the xenobiotics one per one. The same with biological process of how vaccines can affect immune system and how combination of insults can affect the detox immune and digestive systems in combination- from here the systemic view and not a reduccionist one.
MAría Luján

4/28/06, 6:19 PM  
Blogger Joseph said...

Geier and Geier were in on the first chelation study with Bradstreet and Adams.

Hmm, I guess it's time to look for literature by Bradstreet and Adams as well.

4/28/06, 6:44 PM  
Blogger Ian Parker said...

Hi Joseph,

I get your implication with the studies. Some thoughts though:
a) The viral study looks like it selected for families with siblings as controls (so what is the average family size for families with 2+ children?)
b) The AS study shows a child rate at 2.1 vs. 1.86 for the Census data (total US with own children under 18). The under 18 category understates current family size (how many families have children at home or at school over 18 but not classed as independent?). The AS study suggests that the AS families are ‘older’ (average age of AS subjects is 13.34) with i) all siblings counted, regardless of age and ii) a higher probability than the average Census family of having reached their ‘final’ size. The 1.86 family size is a work in progress, not a final count (many of those families will have another child). The ‘final’ family size in the US I believe is still above the replacement rate (I seem to recall it is also a bit higher than 2.1, but I could be wrong).
c) Even assuming apples to apples on the AS study vs. Census data, the difference in family size is 2.10 (incl the AS child) vs. 1.86. The AS children will have to have a reproductive rate at > 75% of the average to maintain allele frequency.
d) Even if families carrying the alleles that contribute to autism have a higher rate of procreation today, they i) have to have had an increased rate sufficient to account for any potential fitness gap in the autistic offspring, and ii) have to have had this increased rate through the last 40,000 plus years, with the assumption that their current ‘fitness’ advantage was historically valid (i.e. the ancestors of today’s IT professional or engineer had to have possessed this advantage pre-civilization? Maybe, maybe not).
e) I’m trying too hard. :-)

4/28/06, 7:30 PM  
Blogger María Luján said...

Hi Joseph
You say
Some portion of autistics are classified as having good outcomes (even "recovered").

Please let me give you another explanation. Even if there is an environmental component, development brings important changes in the immune system at ages such as 7-8 and also in puberty. Therefore , these changes can bring improvement related to the partial resolution of the immmune/detox issues in some cases and under certain circunstances.
I think that "recovered" is a label in terms of " not fitting DSMIV criteria"... but this does not imply for me that the recovering is equal to the cure of the underlying condition, especially if it is genetics. This would not imply that my child, for me, would be non-autistic, it it happens. It would imply that the most evident ( in terms of language and interactions) and behaviorally important criteria for would not be met.Nothing more and nothing less.

4/28/06, 7:58 PM  
Blogger Joseph said...

María,

I think autistic children are always developing. Autism is not a developmental halt. Recent placebo-controlled studies on Secretin clearly show this. I'm skeptical of your proposition that it's because of improvements in the immune system or anything of that sort. The autistic brain is simply different and, not surprisingly, it develops differently.

Also, I think the timing is a bit off. Autistic children who become verbal seem to do so around the ages of 4 to 7.

4/28/06, 8:04 PM  
Blogger Ian Parker said...

Hi DoC,

You said:"Do you know all of the reasons why ASU sent the second chelation study walking?"

I'm interested in knowing why. I was wondering that myself because I was looking forward to someone doing a 'proper' study that - regardless of findings - would stand up to scrutiny. I was disappointed to hear that it vanished, but never tried to track down why.

4/28/06, 8:19 PM  
Blogger Do'C said...

Ian,

It didn't vanish. It was taken up by the Naturopaths at the Southwest College of Naturopathic Medicine. I'd be utterly surprised if it ever turned up in a real peer-reviewed journal.

You can read a little more in a post here.

Regardless of my take on this, I'd encourage you to read the comments by Prometheus, especially option [b].

I had commented on that option with some additional information, but removed it for respect of the desired anonymity of a person who likely wants to remain far away from this as possible.

4/28/06, 8:42 PM  
Blogger Ian Parker said...

Hi DoC,

Thanks for the link. I have to admit that 'naturopath' does not inspire the same level of confidence as a study out of ASU, and the IRB rejection does not exactly inspire confidence. If the goal was really proof of concept then they should be moving heaven and earth to get the study approved by a recognized institution.

4/28/06, 9:47 PM  
Blogger Wade Rankin said...

DoC,

Call me ignorant, but what does ASU removing itself from the chelation study have to do with litigation? I read your post on the subject, and understand your ctiticisms, many of which seem valid enough. But I don't see how ASU dissassociating themselves from the study supports this vast plaintiff-lawyer conspiracy theory I keep hearing. I mean, we're supposed to be the tin-foil hat people, not you guys, right?

4/28/06, 10:51 PM  
Blogger Joseph said...

I get your implication with the studies. Some thoughts though:

Yep, you pretty much arrived at the same data objections I had. But it looks like a question a study might look into: Do autistic families have more children than average?

4/28/06, 11:10 PM  
Blogger Do'C said...

ASU rejecting this study doesn't support a plaintiff-lawyer conspiracy theory in and of itself. However, it's possible that non-disclosed events that may or may not have occurred during the first study, do or do not support such a theory. That's all I can legally and ethically say about that, no tin foil hat required.

How was that for ambiguity? Not proof of anything - I'm not interested in proving any conspiracy theory, IMHO the 'scientists' involved are committing career suicide all by themselves, but it's a free country. I just want people to ask questions - questions like, "Why didn't the first study go to a real peer-reviewed journal?", and, "If this is legitimate science, why would ASU can study #2?". If it's not legitimate, why is it taking place? Why did I only hear back from Jim Adams and not the Principal Investigator or the Pediatrician in our entire 4-day discussion? I got read receipts from all of them for our communications.

Sticking only with publicly-available fact, here's how I see it Wade. If the study was ethical, had scientific merit, was legal and safe, and there were no 'problems' during the first study that could affect the second, it should have been approved.

Incidentally, I don't necessarily see it as a conspiracy. I think it's entirely possible that it's more of a group delusion to some degree, in which they've allowed belief to interfere with good science. Also, I don't mind wearing a tin-foil hat at a party just for fun or as a conversation starter.

4/29/06, 1:42 AM  
Blogger Joseph said...

There's a big difference between a vast conspiracy, which is very difficult (perhaps impossible) to carry out, and scientific misconduct by a few bad apples.

4/29/06, 8:51 AM  
Blogger Wade Rankin said...

Thanks for the thoughtful comments, everybody, including those with which we cannot agree. Feel free to keep leaving comments, but I will be out of pocket for a couple of days. It's JazzFest time in the Big Easy!

4/29/06, 9:27 AM  
Blogger Do'C said...

Thanks for being a gracious host of the wandering conversation Wade.

4/29/06, 11:37 AM  
Blogger Do'C said...

Joseph said: "There's a big difference between a vast conspiracy, which is very difficult (perhaps impossible) to carry out, and scientific misconduct by a few bad apples."

I couldn't agree more. It's near infinitely unlikely that there is any vast conspiracy - that would require thousands of families (and this handful of 'scientists') to truly understand all of the science, and purposefully ignore it.

Litigants are more likely acting on what they believe in, which they have every right to. That belief does not create scientific reality though.

More along the lines of the original theme of this post, I'd be curious about your take on this phrase Wade, "The multiple etiologies of the many autisms".

4/29/06, 11:50 AM  
Blogger María Luján said...

Hi Joseph
You say
think autistic children are always developing. Autism is not a developmental halt.

Yes, I agree with this

Recent placebo-controlled studies on Secretin clearly show this.

I have some problems with these kind of studies, where only ONE intervention is tried at once. There is no such a thing as THE treatment of autisms ( I included the s in purpose)

I'm skeptical of your proposition that it's because of improvements in the immune system or anything of that sort.

Please let me explain. I think that development/placebo effects are important. Only I am saying that they can be part of the improvements.
I think that development bring changes in immune system/hormonal system/detox system that can be benefic and include a partial resolution of even unknown or undetected medical problems.

The autistic brain is simply different and, not surprisingly, it develops differently.

I agree partially. I think that the autistic brain is different but during growth all aspects emotional ( the love and acceptance we receive) physical ( the nutritional status) and physiological are important.

Also, I think the timing is a bit off. Autistic children who become verbal seem to do so around the ages of 4 to 7.

I mentioned the 7-8 years that is known for a NT. I think that developmental steps can be altered at individual level in ASD therefore I am not surprised of the 4 to 7 years range. Besides, the changes are systemic, with interrelations between different systems.
If you are interested, I have some information about.
Sincerely
María Luján

4/29/06, 3:05 PM  
Blogger María Luján said...

Hi
This is a recent manuscript I just found in Pubmed from Dr Herbert
Neurotoxicology. 2006 Mar 28;
Autism and environmental genomics.
Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG, Cremer L, Hatchwell E.
Pediatric Neurology, Massachusetts General Hospital, Harvard Medical School, USA.
Autism spectrum disorders (ASD) are defined by behavior and diagnosed by clinical history and observation but have no biomarkers and are presumably, etiologically and biologically heterogeneous. Given brain abnormalities and high monozygotic concordance, ASDs have been framed as neurobiologically based and highly genetic, which has shaped the research agenda and in particular criteria for choosing candidate ASD genes. Genetic studies to date have not uncovered genes of strong effect, but a move toward "genetic complexity" at the neurobiological level may not suffice, as evidence of systemic abnormalities (e.g. gastrointestinal and immune), increasing rates and less than 100% monozygotic concordance support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors. We review this evidence and also use a bioinformatic approach to explore the possibility that "environmentally responsive genes" not specifically associated with the nervous system, but potentially associated with systemic changes in autism, have not hitherto received sufficient attention in autism genetics investigations. We overlapped genes from NIEHS Environmental Genome Project, the Comparative Toxicogenomics Database, and the SeattleSNPs database of genes relevant to the human immune and inflammatory response with linkage regions identified in published autism genome scans. We identified 135 genes in overlap regions, of which 56 had never previously been studied in relation to autism and 47 had functional SNPs (in coding regions). Both our review and the bioinformatics exercise support the expansion of criteria for evaluating the relevance of genes to autism risk to include genes related to systemic impact and environmental responsiveness. This review also suggests the utility of environmental genomic resources in highlighting the potential relevance of particular genes within linkage regions. Environmental responsiveness and systems impacts consistent with system-wide findings in autism are thus supported as important considerations in identifying the numerous and complex modes of gene-environment interaction in autism.

MAría Luján

4/30/06, 8:52 AM  
Blogger Joseph said...

evidence of systemic abnormalities (e.g. gastrointestinal and immune), increasing rates and less than 100% monozygotic concordance support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors.

María: Obviously this is where the paper can't make a good case as far as I'm concerned.

4/30/06, 9:36 AM  
Blogger María Luján said...

Hi Joseph
I think that the overall manuscript is very interesting to read, more than some particular points related to incidence/prevalence.
Sincerely
María Luján

4/30/06, 10:08 AM  
Blogger María Luján said...

Hi Joseph
I think the epidemiology part is discussed neutrally in the manuscript and is a short part.
MA Luján

4/30/06, 10:18 AM  
Blogger Do'C said...

Maria,

I'm curious about your opinion. Obviously, science will provide a lot more insight in the next 10-20 years. But, baseon what you've been reading the past year, how many different etiologies would you guess lead up to the DSMIV diagnosis of autism. How many different potential clinical manifestations of whatever kind do suppose could lead to categorization as "autistic" by behaviour?

4/30/06, 11:54 AM  
Blogger María Luján said...

Hi Dad of Cameron
Thank you for your interest in my opinion. Please give me a bit of time to think properly about your questions to give you the best answer I can, with the right references. I will return ASAP.
Ma Luján

4/30/06, 12:00 PM  
Blogger María Luján said...

Hi DoC
You say
But, based on what you've been reading the past year, how many different etiologies would you guess lead up to the DSMIV diagnosis of autism.

First I think that a lot of different etiologies could be present, in combination, to provide a fit with the behavioral diagnosis under the DSMIV.
I am very interested on the science behind and I have contacted several researchers around the world, working in these fields. However, as I always tell, I consider myself a student of what autism is, in my son in particular and in general. I am not saying that I am right, I am telling you an opinion about, based on a high amount of published research I have revisited and my personal experience. In this sense, I am open to constructive criticisms to improve my personal view. How do we learn if we do not discuss our ideas?
In my mind, I consider three different main groups
a-Purely genetically based- a detected chromosomic fault-, with a clear correlation in biochemistry, known in manifestations and symptomatology and biochemically detected by known clinical analysis, such as
Phosphoribosylpyrophosphate (PRPP) synthetase superactivity (very rare), an Xq chromosomal fault exacerbated by impaired proline metabolism. PRPP is the sugar template on which purine and pyrimidine nucleotides are assembled, and superactivity of the synthase imbalances nucleosides/nucleotides.
Adenylosuccinate lyase deficiency is a 22q 13.1 chromosomal fault which impairs purine formation before inosine monophosphate formation and after adenylosuccinate formation. Elevated “succinylpurines” occur, adenosine, AMP, ADP, ATP imbalances occur and immune dysregulation is likely.
Histidinemia is a chromosomal fault at 12q22-23 which causes deficiency of formiminoglutamate (“FIGlu”) and consequently, limited amounts of special folate forms needed for purine synthesis. Occurrence is about one in 10,000 and victims may have poor auditory memory and poor response to verbal input.
Lesch-Nyhan disease, a fault at Xq26-27 with mutant activity of hypoxanthine-guanine-phosphoribosyltransferase. Occurrence is about one in 10,000 male births; purines are wasted as urate, and formation of cytidine triphosphate, CTP, is deficient in certain cells. Victims are typically self-destructive.
Fragile X syndrome has faults at Xq27-28. The problem was originally considered to be deficiency of 5,10-methylene THF which is required in pyrimidine metabolism to form thymidine from uridine. Fragile X is a leading genetic cause for mental retardation in males; some become autistic.
Rett Syndrome, a fault at Xq28 seen in females (males do not survive), with 21 different possible genetic mutations. Incidence is about one in 12,000 females. Gene binding of methylated cytosine and guanine is disordered, and progressive regression occurs starting at 6 to 18 months.
Dihydropyrimidine dehydrogenase (DPD) deficiency, a chromosomal fault at 1p22, results in uracil not forming enough dihydrouracil and thymine not forming enough dihydrothymine. Elevated uracil/thymine occurs in urine. Mild heterozygous DPD is common; severe cases with autism are uncommon.
Tuberous sclerosis, a fault at 16p13.3, results in formation of a protein called “tuberin”. Tuberin has homology for GTPase activating protein, and it can deplete guanosine as GTP, GDP, GMP by dephosphorylation. Incidence is one in 10,000 births with 25 to 60% featuring autistic traits.
Superactivity of pyrimidine 5’-nucleotidase (P5N) with several chromosomal links (4q26 cytosolic, 17p11.2 mitochondrial). This causes accelerated depletion of uridine monophosphate (UMP) and cytidine monophosphate (CMP); urate is typically subnormal. Incidence is unknown.
Phenylketonuria with possible faults at 12q22-24 and at 4q15.1-16.1 (biopterin), which is now a rare autism condition due to diagnosis and treatment in early infancy. Without treatment, as many as 40% of PKUs could become autistic. In PKU there is futile use (wasting) of GTP to form biopterin.
Prader Willi syndrome, Angelman syndrome, CHARGE, congenit hypothyroidism-untreated
This is not an exhaustive list. Only I am presenting to you the most cited chromosomic faults that have manifestations that are diagnosed potentially under the DSMIV. You can find information about each one (and others) in pubmed.

b-Related to certain polymorphisms in certain genes, in different number depending on individual, in combination- form 5 to up to 20, that because of gene expression, environmental insult and epigenetics, produce the symptomatology that is diagnosed as autism in all forms under the DSMIV. The child for me in these cases is born different biochemically and systemically because of these polymorphisms expression (in brain structure, immune and detox system for example).
In this group I think that for the weak detox system due to genetics the xenobiotics to consider would be
i-Heavy metals from all sources and all kinds (Hg, Pb, Cd, As), other (Al)
ii-Chemicals in general (Dioxins, PCBs, PAHs, additives, etc)
iii-Antibiotics, that could be an insult for genetically susceptible children.
About the immune system, the potential insults to consider would be
i-vaccines as a whole, considering that they would be a combination of insults (including here HepB, DTP, MMR, etc) depending on the individual circunstances.
ii-herpes infections
iii-streptococus infections-considering the PANDAS group
iv-bacterian infections in general and their treatments.
I think that some ASD children could have problems with xenobiotics, with viral/bacterian infections in general or with both. I hope that further research will give more insights about. I have included antibiotics in xenobiotics-because of the metabolism- but also they affect the immune system. The same with heavy metals. For me the problem is the COMBINATION of insults, before the 2 years of age.
Honestly, I think that instead to focus on the amount of potential insults ( and their effects) that would be a 100 years study, to know about the immune, GI and detox system in ASD children in comparison with NT children would be more important –and is giving- more clues. The problem is what to study-because I think that many things are unknown-, the question to answer, the methods used and the conclussions obtained. Other problem is that we do not know today what child can be susceptible until the supposed damage has been done, therefore a certain biochemical finding is the result of the prenatal plus postnatal effects therefore very difficult to discriminate.

I have found in the last 2 years a growing amount of published manuscripts about Heavy metals susceptibility (Dr Echeverria and Dr JS Woods work), vaccine effects in genetically susceptible people ( you can find in pubmed the works of Piyasirisilp S, Hemachudha T., Shoenfeld Y, Aron-Maor A. and Vial T, Descotes J.) and also in neuroimmunotoxicology (Dr Hogdson book on toxicology, http://ehp.niehs.nih.gov/members/
1999/suppl-5/767-775el-fawal/el-fawal-full.html
Neuroimmunotoxicology: Humoral Assessment of Neurotoxicity and
Autoimmune Mechanisms
Environ Health Perspect. 1999 Oct;107 Suppl 5:767-75.)
The potential of autoimmunity reactions of different presentation is very important related to genetically susceptible people exposed to neurotoxicants of many different sources.
This is a good review about
http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt
=Abstract&list_uids=
16126512&query_hl=29&itool=
pubmed_DocSum

Therefore, for me, because of “autistic” genetics or polymorphisms, HM , infections (and treatments of) and vaccines can be an insult for autistic children.
In this field therefore, the correct diagnosis of comorbilities with the adequate and safe and accurate tests in trustable labs I think will be of paramount importance to attenuate and to treat the effects of the environmental impact. These comorbilities can range from the nutritional defficiencies, problems in Ca+2 channels, purine and pyrimidine disorders, porphyrine problems, mitochondrial dysfunction, oxidative stress to the HM poisoning to the GI issues (of all kinds) to the particular autoimmune presentation and others unknown today. For me, these are results of the interaction (extremely complex) between autistic genetics and autistic gene expression with the environmental insult/epigenetics. How much they are/they are not related to the core of gene expression and how much of the core of the symptomatology causes the adequate treatment can ameliorate depends on the accuracy of the diagnosis of the comorbility, the kind of treatment and the individual response and it is not predictable for now.
c-Related to prenatal environmental insult, in form of prenatal infection with certain viruses or bacterian in mother, xenobiotics (alcohol, drugs, certain medication,other,unknown today) that can affect negatively the NS development, with or without a genetic predisposition, producing damages to brain/NS/immune system.
How many different potential clinical manifestations of whatever kind do suppose could lead to categorization as "autistic" by behaviour?
For me, there are as many autisms as autistics. I think that the individual presentation can be a combination of what I presented you above, being genetics of paramount importance always, depending on prenatal and posnatal effects at an individual level.

What do you think?
Sincerely
María Luján

4/30/06, 1:34 PM  
Blogger Do'C said...

You know Maria, I think the most important thing you said was,
"How do we learn if we do not discuss our ideas?"

I could not agree more.

You bring up a lot of potential starting points, and the thing I appreciate about your discussion the most is the acknowledgement of the daunting nature of the task and the need for good science and methodology.

I think the long run numbers (10, 20, and 50 years out) will reveal a much larger number of etiologies than people currently imagine. (How's that for a generalization/assumption?) I also think it possible that it will be a moving target to some degree (environmental, genetic, and lifestyle factors change constantly too).

4/30/06, 3:33 PM  
Blogger María Luján said...

Thank you DoC
You say
I think the long run numbers (10, 20, and 50 years out) will reveal a much larger number of etiologies than people currently imagine
I agree with you in this sense. In the same way, environment and lifestyle and social attitudes have changed last 40 years therefore this component is very important to analyze when data on neurodevelopmental problems are considered/analyzed.

You say
You bring up a lot of potential starting points, and the thing I appreciate about your discussion the most is the acknowledgement of the daunting nature of the task and the need for good science and methodology.

They are starting points for me to reach a globalized approach of the different components that can be collaborating ( let´s go to present this way for now)in a child diagnosed with ASD under the DSMIV in the symptomatology. These are starting points to develop an integrative view of autism, in the sense of Dr Martha Herbert, with scientifically and medically based evidence published to confirm ( or not) the relative importance of each one ( and of others that will come) at a general level for ASD. But there are a lot of published research about all these different issues, analyzed with different view and without focus in ASD. Under this light-and because the focus is mainly genetics in current approach- I think that there is a lack of research of all the environmental insults I listed in autistic people ( children/teens and adults). You find research in HM effects, viruses/bacterian and vaccines effects in previously NT people.
Where is the research on the genetically susceptible people, especially autistics of the biochemical/physiological/immune/neurological impact of the potential insults?
At an individualized level, depending as ever on the tests done, the labs,the doctor/s in the team and the approach, the situation can be different. The problem for me is the extrapolation of individual cases to the general population of ASD and also the generalization based on certain limited number of studies for all children with ASD.

A personal example. When my son was diagnosed the doctor told us "nothing to test" because EEG of 7 hours was OK and no epilepsy signals were evident and common tests were OK.
After personal research and consultation with mainly foreign doctors and bibliography, we found celiac disease, several allergies and many many other comorbilities in my son, mainly in local labs.For me it all depends in individual cases of the approach.
For me, under a rational and coherent and based on science approach for my autistic son, many of the potential insults I listed to you I found were such for my son. If you are interested on more details about why I think so, I have no problems that you contact me by e-mail.

Sincerely
María Luján

4/30/06, 5:11 PM  
Blogger Ian Parker said...

Joseph, you left a msg on my blog:
"The number of children in families with at least 2 children is 2.46. I might do some additional research and blog about this." This is presumably connected with procreation of those with the alleles that may contribute to autism. I'll respond here since this is where the discussion has been.

Just some thoughts:

1. It is obvious that autism still exists, so the contributing alleles have been with us over the last 40,000 years or more. So by definition the allele frequencies must be reasonably stable, i.e. those possessing the alleles must be procreating at a rate sufficient to maintain the alleles’ continuing existence.

2. The rate of procreation of families with autistic children or families with autistic parents in a post-industrial world is not necessarily indicative of historical rates of procreation in an agricultural (less than 10,000 years) or pre-agricultural world (i.e. 30,000 of the past 40,000 years).

3. The current rate of procreation within families with autism may be biased due to 'stoppage', which is quite likely a modern phenomenon, while the current rate of autistic survival to reach maturity may also be considerably higher than that of most of our history.

4. Even if the current rate of procreation within families with autism is consistent with historical patterns, this rate is not indicative of the underlying allele frequencies.

Assuming that the rate of a subsequent child also having autism is between 2% and 10% (I've seen quotes of 2%, 5% and 10%), then either having an autistic child changes the odds of subsequent children being autistic (conceivable but definitely not proven, or even accepted as likely by most) or the autism rate of that parental combination is between 2% and 10% for any child. If this rate can be extrapolated to all combinations of parents who possess the 'right' allele combinations, then at an average of 2.x children per family, the vast majority of families with the potential to produce autistic offspring will never know their risk. So until the alleles that contribute to autism are known and counted, it will be impossible to know or measure even current frequencies, let alone frequencies over time, since we don't know who or what to count.

5. The real question is 'how much of a fitness liability has autism historically been?' "Either the individual alleles must have a significant natural advantage to overcome the reduced ‘fitness’ inherent in autism (notice I did not say that autistics do not procreate – only that their rate of procreation is assumed to be below ‘average’), or the alleles in the combinations that today cause autism did not historically produce this outcome to nearly the same degree to which they do today (supporting a ‘second hit’)". To simplify, this is a series of algebraic equations over time in which we need to know either the degree of natural advantage over time to determine the degree of liability, or we need to know the degree of liability to determine the benefit of the natural advantage.

So, the current fecundity of families with autistic members may be interesting in its own right, but it does not answer the questions that autism poses of population genetics and evolution. The answers to those questions will flow through the knowledge of the definitive causes of the condition(s), be they genetic, systemic, or other.

4/30/06, 6:30 PM  
Blogger Joseph said...

Ian,

I think I've addressed your points in my latest post. Let's continue the discussion there if you'd like.

5/1/06, 1:48 PM  

Post a Comment

Links to this post:

Create a Link

<< Home