The Verdict on Autism

Finally we can get down to some real issues regarding autism. As reported in this editorial in the Los Angeles Times, the US Court of Federal Claims has found no substantiated link between autism and the MMR vaccine or the vaccine additive thimerosal.

I have covered autism in two previous posts "The Question of Fragile X " (9/27/2008) and "Autism in the News " (4/4/2008). In both cases I have discussed some of the genetics behind this disease. For example Scientists know that autism is a multifactorial trait - meaning that it probably has both a genetic and environmental component. It is also most likely that autism is a disease that displays genetic heterogenity - meaning that it is actually several different diseases that express themselves the same way. Cancer is a good example of a disease with genetic heterogeneity - just because you get cancer does not mean that it is from the same cause.

Should we have never investigated the MMR vaccine or thimerosol? - of course not. It is always important for scientists to follow-up any leads as to a cause of a complex disease such as autism. However, numerous studies have indicated that the link between these and autism is almost insignificant. So why is this an issue? For too long the research community has been having to focus on only one cause - vaccines and their additives. This focus on one factor is not resource-friendly and it distracts from the search for a real cure. The results are in - time to move on.

There will be those individuals who accuse the government, CDC, and pharmaceuticals of a massive cover-up. Others will decide not to vaccinate their kids based on religious preferences. Neither of these two groups should be treated seriously since 1) our government is not smart enough to cover-up the simplest lie, and 2) the consequences of not being vaccinated far, far outweigh the risks.

We need to support autism research, even when the results do not match what we want. That is what science is all about.

Want more information - check out the National Institutes for Health pages on autism and the National Autistic Society page on autism genetics.

The Question of Fragile X

Geneticists really need to work on naming their genes. Drosophila geneticists are the worst - we give genes names such as Grunge, grim reaper, and swiss cheese (see a great link here), but sometimes the human geneticists can slip as well. One example - the fragile X syndrome. The name fragile X suggests that this version of the X chromosome is like a Ming vase...delicate and susceptible to fragmenting. But in reality, it causes a much worse condition.

What happens in fragile X is that there has been a duplication in a portion of the DNA on the X chromosome. Duplications happen all of the time, but unfortunately, this one happens to occur within the coding region for a gene. This gene is FMR-1, and it appears to be a very important gene for humans. FMR-1's gene product, the fragile X mental retardation protein (FMRP)is responsible for development of the neurons - the cells that conduct billions of electronic messages in our bodies, and brains, per second. In the mutated form of FMRP, there has been a repeat in one of the instructions, commonly called a codon. The repeat, called a trinucleotide repeat since it adds three new "letters" to the DNA message, causes the resulting protein to fold incorrectly. Proteins are all about folding, it is their three-dimensional shape that gives them their unique function. Imagine if you needed a wrench for a certain repair job, and the manufacturer mistakenly bent the top of the wrench at a 45 degree angle... it would make it very difficult to complete the task at hand. Proteins operate in much the same manner.

Another interesting aspect of repeats is the fact that they have the ability to increase in size from generation to generation. During the production of egg and sperm cells in humans (called meiosis), similar chromosomes line up with one another. The repeats can cause a misalignment, which can increase the size of the repeat. More repeats means a more severe form of the disorder. That is why everyone with fragile X does not have the same symptoms (what us geneticists call a phenotype).

Since Fragile X is on one of the sex-chromosomes, males (who are XY) are definitely more susceptible to its effects, since females (XX) at least have the chance to have a second, good copy of the chromosome. Fragile X syndrome can result in both mental retardation and a form of autism. In fact the recent attention to autism has resulted in some interesting discoveries about fragile X, specifically its relationship with a group of receptors on the cells in the brain called mGluR5. Identification of a receptor is a big deal, since drugs can be developed to interact directly with the receptor. Individuals with fragile-X also sometimes display aggressive behavior, but that is most likely believed to be a secondary result of the disease, probably brought on by speech difficulties, frustration, and anxiety - complications of the effects of mental retardation.

While drug studies are promising, a "repair" of fragile X is unlikely. Since the repeats in fragile X can be very large (200+ copies sometimes) it is unlikely, at least in 2008, that the defect could be repaired using any form of biotechnology, including gene therapy. Furthermore, since the gene product, FMRP, has already caused problems in the cells, it would probably not be possible to reverse the influence on the person. We should be able to treat the symptoms, and it appears that we are getting better at understanding how to do this, but this may be a good example of where our genetic limitation lie.

Autism in the News

Autism is once again in the news. In the past several weeks news agencies, such as CNN, have brought autism back into public thinking through coverage both on TV and the web. While the news network has done an adequate job of presenting the concerns of parents and the opinions of the scientists, they have done very little to present the basic scientific information about autism. From my perspective, most people are completely confused about autism. In the past, an autistic child was sometimes viewed as the fault of the parents, and in the current round of coverage the disease is sometimes being presented as a result of a medical community which prefers not to face the facts regarding vaccinations. Neither of which is really true. Instead, we need to recognize that autism is a very complicated disorder – and that complicated disorders can take some time to sort out.

First of all, and probably most importantly, autism is most likely not a single disease. Like Alzheimer’s disease and cancer, autism is a term that we have adapted to explain a related group of symptoms, in this case severe communication disorders. Alzheimer’s researchers now distinguish their disease using terms such as “late-onset” and “early-onset”. We need the same approach for autism. We need to develop a common set of classifications for the disease so that we all know what type of autism we are talking about. And these classifications need to be easily understood by the news organizations and general public. No scientific techno-babble please! For those who are trying to understand autism, we need to be able to distinguish the various forms so that we know if the news and the scientific community is talking about a common form or a rare form. Also, since autism is not a single disease, we can’t expect that the disease is caused by the same factors in each case. Which leads me to the second important point – genetics.

Autism is probably what geneticists call a multifactorial, or complex, disorder. What this means is not only is genetics involved, but also environmental factors. Those environmental factors are without doubt chemicals. While the news has been focusing on thimerosal, a chemical additive that was used in many vaccines, the truth is that we live in an increasingly chemical world. Some scientists estimate that we come in contact with over 70,000 man-made chemicals over the course of our lives. We have no idea how many of these chemicals interact with each other. In other words, our cells, and especially the easily influenced cells of a developing child’s nervous system, are being bombarded with a potentially hostile array of chemical compounds. Now, back to the genetics. Many of our genes have minor variations that go unnoticed until the cell is placed in a certain environmental condition. So say for gene X there are 2 variants, lets call them X-1 and X-2. When X-1 is exposed to a certain chemical cocktail, the gene continues to function normally. But when X-2 is exposed to the same group of chemicals, the environment alters the way the gene works, called gene expression by scientists, producing slight changes in the cells. In a complex trait it may be necessary to have many of these gene variants, say X-1, Y-4 and Z-2 acting at the same time to produce a disorder. Sorting out multifactorial complex traits takes time and patience by the scientific community.

So what can we do? As parents and concerned individuals we need to aggressively lobby our elected officials to increase funding to not only study this disease, but to make life better for the increasing number of kids who are being diagnosed with autism. In addition to long-term studies of people with autism, we need to start enrolling pregnant mothers in prenatal studies that examine everything from the genetics of the parents to the types of chemicals that the mother comes into contact with during her pregnancy. Only then will we be able to provide some real answers on what is causing autism, and maybe develop a means of reducing its impact on future generations.