Somewhere Over the Rainbow - The Search for an Autism Cure
July 31st, 2005
To a humble biologist, like myself, the idea of “a cure for autism” is as simplistic as “a cure for cancer.” This isn’t because I think that either autism or cancer are necessarily “incurable”, it’s just that both ideas demonstrate a serious lack of knowledge.
The “cure” part isn’t the problem - it’s the “a” part.
You see, like cancer, autism is not a single disorder. Genetic studies point to several disorders, with linkages on several different chromosomes. Even a casual reading of case histories and parental anecdotes shows an amazing range of severity, types of disabilities, progression, and accompanying signs and symptoms.
If I wrote up ten or twelve case histories of autism today and tried to conclude that they were all suffering from the same disorder, I would be laughed at. Yet there are people - the autism-mercury cabal foremost among them - that insist (”demand” would be more like it) that autism is a single disorder.
Think about cancer. If we were to lump all cancers together, we would have the same sort of mess that is currently seen in autism. There would be no consistent presentation, no consistent progression of the disease and there would certainly be no treatment that would work on all (or even most) “cancer”.
Yet, in a startling parallel, there are people in the world who claim to have found a cause for all cancer and even a cure for all cancer. Like the people who have found the cause for all autism and its cure, they are all - at the very least - terribly mistaken.
So, before we all run off like headless chickens looking for an autism cure, perhaps we ought to spend at least a few minutes making sure we know what autism is. After all, except for the autism-mercury experts, nobody knows what causes autism.
That’s right, we don’t know what the pathology in autism is. We don’t even know, for sure, what part of the brain is involved (we are pretty confident that it is a brain disorder, rather than, say, a liver problem). There are those who feel that it is probably a disorder of the amygdala, but nobody has found any consistent abnormalities in the amygdala of autistic people. In fact, no physical abnormality - genetic, biochemical, radiological or other - has been consistently found in all autistic people.
This, of course, is just more evidence that autism is not a single disorder. To extend the cancer analogy, that would be like trying to find a consistent biopsy in all cancer patients - doing, for example, a lung biopsy in everyone. It would come as no surprise to us that a lung biopsy would fail to show cancer in someone with basal cell carcinoma, just as a skin biopsy would be highly unlikely to reveal lung cancer. So why is it that otherwise intelligent people can’t see the reason there is no consistent pathology in autism?
And since we aren’t even sure if we’re dealing with a single disorder (except that some of us, myself included, are very sure that we aren’t), it would seem extremely foolish to start looking for causes and treatments. Going back to the cancer analogy, looking at UV exposure as a cause for all cancers would fail to show a relationship, since pancreatic, lung, liver and kidney cancer are not correlated wth UV exposure - and would miss the cancers that are UV-caused, like basal cell and melanoma because of the “background” of non-UV-related cancers.
Likewise, treatments that might help a sub-set of cancers would not show any benefit when tested against all cancers because of the large number of non-responding cancers included in the subject mix. So too, a treatment that might be effective for a certain sub-type of autism will have its benefits “drowned out” by all the other disorders that don’t respond to it.
In the final analysis, it does little good - and probably a good deal of harm - to go chasing off after various hypothetical causes and cures of autism at this point. First, we need to find out what the abnormalities (that’s right, plural) in autism are and then sort the patients into their proper diagnostic groups. Otherwise, we’re going down the rabbit hole after the “cure for all autism”, which - like chasing the pot of gold at the end of the rainbow - is very engaging but never profitable.
Prometheus
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Dr. Hornig’s Autistic Mice
July 29th, 2005
The September 2004 issue of Molecular Psychiatry (may not have been available at your local news-stand) contained an article by Dr. M. Hornig et al titled, “Neurotoxic effects of postnatal thimerosal are mouse strain dependent”. Athough the title doesn’t give any hints (other than the mention of thimerosal), the article is all about autism. This struck me as strange, since I had a hard time imagining how you would tell if a mouse was autistic. But, I digress.
The Autism Diva has already addressed the topic of autistic mice and Dr. Hornig in some detail in her delightful post, “Rain Mouse?”, so I’ll try not to cover the same ground. Instead, I would like to address some of the technical aspects of the study.
In a nutshell, Dr. Hornig and her colleagues gave intramuscular (i.m.) injections of either thimerosal or a placebo to newborn mice. The mice were from three different strains - one that was susceptible to autoimmune disorders (SJL/J) and two that were not (C57BL6/J and BALB/cJ).
In order to simulate the immunization schedule given to human infants (see where they’re going with this?), they gave the injections on the 7th, 9th, 11th and 15th days of life. For reference, human infants receive their immunizations at ages 2 months, 4 months, 6 months and 12 months (one year). However, mouse infancy is much more accelerated than human infancy, requiring the injections to be spaced closer together in order to happen during the same developmental stages.
A plan of overdosage:
The timing of the injections is the first flaw that I would like to address. While it is true that this dosing schedule allows the thimerosal to be administered in the same neurodevelopmental stage as in human infants, it overlooks a big fact of biology.
The plasma half-life (time that it takes for the plasma concentration to decrease 50%) of methylmercury in humans is variously reported as being between 40 and 56 days. There are no published studies of the half-life of thimerosal in humans, but animal studies make it likely that it will be longer. The half-life of methylmercury in mice is much shorter - 158 hours.
So, a dose of mercury given to a human will be half gone in about 50 days and, in a mouse, 6 1/2 days. Let’s look at what this means in the context of this study:
If an infant is given a mercury dose at time zero (0) that produces a blood mercury level of 1.0 (arbitrary units), that blood level will be down to 0.44 after 60 days. A second dose at 60 days (see where I’m headed?) will bring the blood level to 1.44. In another 60 days, the level will be down to 0.63 and another dose will bring it up to 1.63. After waiting 180 days (about three half-lives), the blood level is down to 0.13 and a fourth dose will raise it to 1.13.
Now let’s look at it from the perspective of the mice in this study. If they receive a dose at time zero that produces a blood level of 1.0 (arbitrary units), after two days, the blood level will only be down to 0.81. Another dose raises the blood level to 1.81 and, after another two days, it is down to only 1.46. Another dose raises the blood level to 2.46, which is down to 1.61 when the final dose raises it to 2.61.
So, the human experiences a maximum blood level of 1.63 (arbitrary units) and the mouse - since it is being dosed at a smaller fraction of its half-life - sees a maximum blood level of 2.61. In short, the mouse gets to a blood level 60% higher than the human.
The case of the underweight child:
Now, this all assumes that the mouse and the infant are not growing - which is not true - and that the doses they are getting are equivalent on a microgram per kilogram body weight basis, which also is not true. The study dosed the mice on a per kilogram basis equivalent to what a human infant would have received had they received their vaccinations on schedule. However - and this is a curious thing - they used the 10th percentile (10% of children that age weigh less, 90% weigh more) body weights for children at ages 2, 4, 6 and 12 months.
I found myself wondering, “Why didn’t they use the 50th percentile (50% weigh more than this weight, 50% weigh less - sort of an ‘average weight’)?” I have no answer - but I have an idea. By using the 10th percentile, they were able to give the baby mice an even bigger dose of mercury. Let’s run the numbers, as they say on NPR:
Dosing is based on the child receiving 62.5 micrograms of thimerosal at 2,4 and 6 months and 50 micrograms at 12 months. Using the numbers for 10th percentile weights and 50th percentile weights, this works out to doses of:
2 months
10th - 4.4 kg - 14.2 ug/kg
50th - 5.3 kg - 11.8 ug/kg (17% less)
4 months
10th - 5.7 kg - 10.8 ug/kg
50th - 6.8 kg - 9.2 ug/kg (15% less)
6 months
10th - 6.8 kg - 9.2 ug/kg
50th - 7.9 kg - 7.9 ug/kg (14% less)
12 months
10th - 9.0 kg - 5.6 ug/kg
50th - 10.3 kg - 4.9 ug/kg (13% less)
So, by using the 10th percentile weights, the authors were able to give the mice about 15% more thimerosal. This goes nicely with the dosing schedule to significantly raise the dose the mice receive.
The show must go on!:
What Dr. Hornig didn’t show in her article, but is showing to concerned parents of autistic children, is the video of her autistic mice. The study article adresses such prosaic behavioral changes as decreased spontaneous movement, decreased exploration and decreased streotypic behaviors, but the video (CAUTION: large file) she shows includes such titillating tidbits as one mouse grooming another to death and another mouse biting its own tail. These, she says, are evidence that these mice have become autistic….
Hold the phone! Grooming is a social activity mice engage in, and autistic people are supposed to be averse to social interactions! And although self-injurious behavior is seen in autism, there are other, better explanations that were overlooked.
In fact, I felt a strange hot flush come over me as I watched the video (maybe it was just a hot flash). I have seen exactly this type of behavior before - but not associated with mercury.
Many years ago, I was associated with a group studying treatments for chronic neuropathic pain. The model we used was a rat model in which we injured the sciatic nerve and let it heal. A number of the rats would develop what was assumed to be neuropathic pain - evidenced (so we thought) by biting and chewing on the affected hind limb. It was a grisly sight and, what was worse, it wasn’t really neuropathic pain.
Another group discovered that anything that caused abnormal sensation would cause rats (and other animals) to bite and gnaw on the affected limb. What I saw in these mice was exactly what we saw in the partially denervated rats. And - oh, by the way - mercury causes parasthesias (numbness and tingling). Dr. Hornig has probably managed to make these mice so neurotoxic that they are experiencing parasthesias - a common sign of mercury poisoning.
And now, a word from our sponsors!:
These days, no discussion of mercury and autism is complete without a thorough exposition of who paid for the study and who might have a conflict of interest. So, you might ask, who paid for this study?
The UC Davis M.I.N.D. Institute
The Coalition for Safe Minds
To remind you, the Coalition for Safe Minds’ mission statement is:
“Our mission is to end the health and personal devastations caused by the needless use of mercury in medicines. “
But I’m sure that didn’t influence the outcome of the study.
Happy reading!
Prometheus
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If you want to drive the Bus…
July 27th, 2005
Postponing my showdown with Dr. Hornig’s autistic mice yet again, I would like to address a phenomenon that is nearly ubiquitous in the “alternative” medicine world. I am speaking of the concept that anybody - regardless of their education, training or experience - is qualified to speak knowingly and render expert opinion on scientific and medical matters, as long as they have personal experience of the subject under discussion.
This is a phenomenon that defies common sense - the very same people who take offense at being told they lack the proper education to make scientific and medical assertions are often “professionals” of another stripe - MBA’s (and here), lawyers, and stock brokers - who would be aghast at the suggestion that a neophyte off the street could do their job with equal skill. Imagine their outrage (or amusement) if I, a humble biologist, announced that I was as competent as they were to, say, formulate a business plan for a multinational corporation, set up a tax-sheltered annuity or render an opinion on federal law.
The sad fact of the matter is that it takes a certain amount of education to be a scientist, or even a doctor. There are facts to learn, techniques to practice, skills to acquire and mental habits to develop. You can’t get these from watching “ER”, “CSI Miami” or even the Discovery Channel.
This is not unique to science. Lawyers, MBA’s, stock brokers, plumbers, electricians, truck drivers, firefighters, bicycle racers, and even the folks flipping hamburgers all have to spend a certain amount of time learning how to do their job. If your education, training and experience is solely in business, law or marketing, then you have no more expertise in science than you have in firefighting - and what’s your plan if the stove catches on fire tonight, eh?
So, why is it that people who wouldn’t think about redoing the plumbing in their bathroom suddenly feel that they have innate skills in science? Part of it has to do with our education system, which gives everyone a small taste of “science” in the primary and secondary grades but fails to instruct them in the real methods of science. The average person thinks that a scientist is just a huge repository of “facts”, since that was what their “science” classes in high school were all about. That couldn’t be farther from the truth.
A real scientist has to learn a prodigious amount of information, true enough, but the real emphasis is on learning how to think. It is much easier to teach a student the Periodic Table than it is to teach them how to formulate a testable hypothesis. And it is far easier to teach the Kreb’s Cycle than it is to teach how to draw an accurate and supportable conclusion from experimental data. This is probably why most college graduates with “science” degrees don’t end up doing any research - they end up selling or being technicians or technical advisors.
Although there have been some excellent self-taught scientists in history, they are few and far between. And there haven’t been too many of them since the middle of the last century. So, it seems pretty unlikely that someone is going to read a few semi-technical books and emerge able to compete head-to-head with an educated and experienced scientist when it comes to, say, critical evaluation of a scientific study. Yet there are numerous people who claim to be able to do this very thing.
I once witnessed an amazing exchange between a research physician and a parent of an autistic child. The parent had a degree in business and had been a fairly successful business person for many years. The physician had been researching autism for over thirty years. The discussion I overheard (and oversaw) was about - couldn’t you just guess - whether or not autism was caused by mercury.
After the physician had explained the reasons why he felt that mercury didn’t cause a majority of the cases of autism - along with the caveat that the research so far couldn’t eliminate mercury as a minority cause, the parent said:
“Well, my assessment of the data is that mercury is the only cause of autism and that genetics has nothing to do with it.”
The physician paused for a moment, clearly debating whether or not to reply, and finally said:
“You’ll excuse me if I feel that you lack the qualifications to give that assertion much weight.”
The parent then retorted, angrily:
“That’s just typical physician arrogance - I’m just as qualified as you to decide what causes autism!”
I was stunned. Not because this parent “talked back” to a physician - I actually enjoyed that part - but I was stunned by the appalling ignorance of that statement. I was stunned that someone with no significant scientific education and a few years experience as a parent of an autistic child could honestly think that they were equal in qualifications to someone with an advanced degree inscience and thirty years of research in the field!
OK, this isn’t “PC” - it’s not “polite” to tell people that they don’t know what they’re talking about. But it’s true! Just because someone has an autistic child does not make them an expert in the science of autism. Sure, they know a whole lot about raising an autistic child, but that does not give them any insight into the biochemistry or neurophysiology of autism.
In other words, if you want to drive the bus, you need to go to bus-driver school, first.
Prometheus.
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Men of Straw, Invisible Black Sheep and the Tale of Two Lemmas
July 26th, 2005
In the rather short time that I have been writing this blog, I have become acutely aware of the deplorable state of reasoning skills among the supporters of “alternative” medicine. Today’s lesson will be on Logic.
The Straw Man Fallacy:
Detailing the logical errors in most of their arguments would require a book, but there is one logical fallacy that the “alties” seems particularly fond of: the “straw man.” For those who didn’t take Professor Petersen’s Logic class, the straw man fallacy is simply attacking an argument that your opponent didn’t make. Usually, this is done by implying (or asserting) that your opponent has argued something easy to refute - usually something extreme and indefensible - and then attacking that argument instead of the one your opponent actually made.
As a hypothetic example, if your opponent said that there is no data supporting a causal connection between autism and mercury, you could attack them for saying that mercury is completely safe. You could ask them, “Do you think that mercury is a good thing to inject into children?”
This tactic does not refute your opponent’s argument - it doesn’t even address it - but it is a good way to switch the discussion from an argument you can’t win (since you don’t have any decent data) to one that you can win. It’s not intellectually honest, but it works more often than not. Just watch any political campaign.
Some of the more popular straw man arguments that I’ve seen used in “alternative” medicine are:
[1] “People should be allowed to make medical decisions for themselves.”
This straw man is usually used to dodge the issue of practitioners failing to be honest about the data supporting their treatments (usually none). By making it appear to be an issue of personal autonomy, rather than an issue of truth in advertising, the builders of this straw man hope to avoid the tough questions about a practitioner’s obligation to be honest and open about what they are selling.
[2] “You’re trying to take away our right to free speech!”
The First Amendment of the US Constitution, and similar constitutional guarantees in other countries, does not grant carte blanche rights to say anything one wants. Libel, slander, and mail fraud are all offenses that involve the improper use of speech. The right to freedom of speech and press is not a license to lie, deceive and defraud.
Argument from Ignorance:
Another favorite “altie” fallacy is usually expressed as, “You don’t have any proof that it doesn’t work (or cause cancer/autism/terminal moraine).”
This fallacy - the argument from ignorance - is used in much the same way as a straw man. It is much easier to argue that something isn’t proven to never happen than to argue that it does. A classic story of this (told to me by the aforementioned Prof. Petersen) is the story of the two logicians:
On a train through Scotland, a senior logician and his junior colleague were observing the countryside. Upon sighting a huge flock of grazing sheep, the junior colleague casually remarked, “There’s not a single black sheep in that whole flock.”
The senior logician, roused from his doze, retorted, “You can’t say that - you don’t know if you can see the whole flock!” Chastened, the junior logician replied, “Well, all the sheep in view are white.” The senior logician snorted into his mustache and said, “You can’t say that, either!” “Well!” said the exasperated junior member, “What can I say?” With a smug look, the senior logician replied, “That all the sheep in view are white, on at least one side!”
So, the absence of visible black sheep does not eliminate the possibility of black sheep - no matter how many sheep are observed - because the presence of a single black sheep somewhere in the Universe (Past, Present or Future) firmly establishes the existence of black sheep.
However, in biology, it is not usually important to know if black sheep exist, as long as you know that they are exceedingly rare. For example, while it has not been possible to definitively prove that power lines do not cause brain cancer in children, it has been shown that the risk is between zero and a risk so small that it blends into zero (i.e. the uncertainty range includes zero).
Likewise, it may not be possible to prove that Dr. Alt’s Sure-Fire Cancer Cure doesn’t ever cure cancer, but it is possible to show that it happens less often than with other, more established treatments (or placebo, or the spontaneous remission rate of the cancer). So, even if it is true that someone (or even two or three someones) had their cancer “disappear” after taking Dr. Alt’s treatment, it doesn’t mean that it actually works.
False Dilemma:
One logical fallacy that shows itself time and again in “alternative” medicine is the false dilemma. This fallacy is basically a failure to consider (or present) all of the possible alternative choices. In “alternative” medicine, this fallacy is often somewhat hidden, as in the following:
“If we let the government regulate vitamins and supplements, then you won’t be able to buy them anymore.”
In this case, the false dilemma presented is between the following two options:
[1] Unregulated advertisement and sale of vitamins and “supplements”.
[2] Vitamins and supplements being banned from sale.
In reality, there are many other possible choices, such as:
[3] Vitamin and supplement retailers being required to provide sufficient data to support any claims they make in advertising or on the label.
[4] Limiting sales of vitamins and supplements to only those items whose safety has been established by legitimate studies.
[5] Requiring that vitamin and supplement makers (and sellers) make no health-related claims about their products.
[6] … etc.
By using a false dilemma - an “either this or that” type of framework for the debate - the “alties” manage to make their preferred stand at least the lesser of two evils. However, they can do so only by picking an extreme option and making it appear to be the only other choice. If all the potential options are placed on the table, their preferred choice is the one that looks extreme.
Well, that’s all for now. Class dismissed!
Prometheus.
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An Embarassment of Riches
July 21st, 2005
I can’t believe it! I locked my door when I left for lunch and, when I returned, there were two articles on the floor of my office. Forensic evidence suggests that they had been inserted under the door. The Facilities Maintenance people have refused to put a tighter threshold on the doorway, so I guess I will have to adjust to this rich source of material (and amusement).
The first article was from a newspaper in Seattle, the Seattle Post Intelligencer and was titled, “The Abortion Debate that Wasn’t“. Despite the eye-catching title, the article really wasn’t about abortion - except indirectly - it was about eugenics.
Eugenics is an old concept, dating back to at least the late 1800’s. For those who aren’t familiar with the concept, it is the idea that we can “improve the breed” (i.e. the human breed) by preventing “abnormal” people from reproducing. This has been tried in a number of places and in a number of ways, from “euthenasia” (an nice way of saying “murder”) of the “unfit” to forced sterilization.
I don’t want to debate the morality of eugenics - which could take decades and is rather beyond my area of expertise - but the reality of it. Although I may not be an expert in medical ethics, I can speak rather expertly about the genetic practicality of eugenics. Apart from the very real question of how to determine who is “unfit” to reproduce (refer that to the bioethicists), the bigger issue is that eugenics doesn’t work.
The Seattle Post Intelligencer article focused on how aborting fetuses that have genetic defects is both unfair to the disabled (a good argument, but beyond my ken) and may cause our species to lose valuable genetic variations (my area of interest). This part of the argument, which was not well articulated, is a case of needless worrying.
Even in a simple autosomal recessive trait (see here for a good tutorial), eliminating all of the homozygous individuals (those who show the trait in question) will not necessarily eliminate the “abnormal” gene. Only by detecting all the people who carry the gene and preventing them from reproducing can you eliminate the gene. Even if detection of all the carriers is possible, it would be a much bigger problem to convince people of normal physique and intelligence that they can’t have children.
If this seems a bit hard to believe, how about a large long-term (tens of thousands of years, at least) “study”? Does everyone know about Sickle Cell Disease (SSD)? This is an autosomal recessive disorder of the red blood cells that, until very recently, was rapidly fatal in homozygotes (i.e. they died well before they could have children). Despite this “natural” eugenics program, SSD is still with us.
SSD’s persistence is due, in part, because the people carrying only one copy of the gene (heterozygotes) are somewhat less susceptible to malaria than people with zero copies of the gene. However, once the gene became established, it can only disappear if there is a strong selection pressure against not only homozygotes (two copies) but also heterozygotes (one copy). Without that selection pressure, the gene frequency will drift randomly. Over time, if malaria becomes a less significant health threat, the gene for SSD may decrease because of genetic drift, but this will take thousands of generations - if it happens at all.
So, people arguing for (or against) sterilization or murder of the disabled will have to do without the support of genetics. Eugenics doesn’t work - either to eliminate genetic disorders or to eliminate “useful” genes.
Prometheus.
Coming up… Dr. Hornig’s Autistic Mice (the second article)
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