This Made Me Laugh...

Age of Autism is sponsoring a contest to "win" lunch with "Doctor" Andrew Wakefield...

While I have no money to bid in an auction, I think that a coalition of legitimate scientists should band together and try to win it--if only to spend the awkward lunch hour grilling him on medical ethics and sound science practice.

Vaccination: A Love Story

(Dear reader, I apologize in advance for the rather cliche topic of this post...I'm just fed up with all of my comments getting moderated off of age of autism.)

Perhaps one of the most pernicious aspects of the culture war is the anti-vaccination movement. Driven by charismatic celebrities such as Bill Maher and Jenny McCarthy, an army of soccer moms, and a handful of ethically dubious fringe scientists, the "anti-vaxers" represent one of the greatest extant immediate threats to general public health in the developed world. Since its modern beginnings in the early 1990's to the present day, the movement has accrued a cult-following of otherwise well-meaning people that has done nothing but hinder the progress of science and cause unnecessary human fatality. Contributing to the movement is both a general lack of understanding of the science behind vaccines among the general public and clinicians, and a not-wholly-irrational public distrust of the pharmaceutical industry. Addressing this issue will require effective and persuasive communication of vaccine science to both the general public and practicing clinicians.

As a safe and effective preventative counter-measure to infectious disease, vaccination is far from a modern concept. Primitive vaccination protocols can be found in ancient aryuvedic texts from India, and the procedure was widely practiced in the Muslim world until it was introduced to western medicine by Lady Mary Montague and (more famously) Edward Jenner in the 18th century. While the technology of vaccine production and delivery has changed over time, the basic concept that a specific immune response can be "primed" in a person to render immunity to a pathogen prior to exposure remains. In order to properly explain the mechanism at play here, it is first necessary to briefly explain how immunity works.

In the most reductive sense, the human immune system differentiates between things that are supposed to be in the body (e.g. one's own serum proteins and cells) and things that are not (e.g. viral coat proteins, bacteria, and even cancer). To accomplish this task, and eliminate those items that fall into the latter category, human immunity functions through two broad mechanisms. Innate immunity is just that, innate, upon contact with any foreign biotic material, it functions to quickly and efficiently eliminate it. Sometimes, however, this non-specific first line of defense is breached and, in the case of infectious disease, the body needs to break out the heavy artillery.

The components of adaptive immunity represent the body's version of guided missiles and surgical strike commandos. Upon exposure to an antigen, macrophages (the "storm troopers" of innate immunity) present the antigen to adaptive immune cells and trigger proliferation of cells specific to that antigen. These adaptive immune cells fall into two categories, B-cells and T-cells. B-cells produce antibodies, proteins capable of recognizing a specific antigen and facilitating its destruction; once the body starts producing antibodies against a specific antigen, it will continue to do so--granting immunity--throughout life. T-cells are a bit more diverse, and fall into several subcategories, but their general role is to recognize and kill infected and pathogenic cells. Following exposure to a specific antigen, "memory T-cells" specific to that antigen persist throughout life and can proliferate quickly to mount a specific response in the event of re-exposure. Vaccines induce adaptive immunity to a particular pathogen so that, upon exposure, the body already has a specific response.

Modern vaccines fall into five broad categories, attenuated, killed, subunit, toxoid, and conjugate.

Killed and attenuated vaccines are technically the simplest to produce and the earliest vaccines generally all fall under these two categories. These vaccines work by introducing killed, noninfectious, or weakly infectious versions of the infectious pathogen into the body thereby simulating infection and inducing an adaptive immune response. While certain attenuated vaccines may cause infection in immunocompromised individuals, and many of these vaccines must be refrigerated to be kept "fresh", they have become one of the safest and most reliable counter-measures to infectious disease in use today.

Subunit, toxoid, and conjugate vaccines work by introducing biomolecules specific to a given pathogen rather than the pathogen itself. Vaccines in this category can be used to develop an adaptive immune response against bacterial lipopolysaccharides and even small organic molecules. Because, with the exception of some toxoid vaccines, recombinant DNA technology is required to produce them, vaccines in these three categories did not enter wide-spread clinical use until the latter half of the 20th century. Because they contain no potentially infectious particles, these vaccines pose no risk of causing infection. Additionally, some of them can even be stored "dry", greatly increasing their shelf-life. These vaccines are highly safe, with the clinical trials for a few of them producing no statistically significant life-threatening effects.

Re-enter the anti-vaxers. The most common ailment blamed on vaccinations is autism. Much of the momentum for this belief was provided by a now-retracted-and-thoroughly-disproven paper published in the Lancet in 1998. No peer-reviewed publications have ever presented even a hypothetical pathogenic mechanism for such a causal linkage; in fact, much of the anti-vaccination fervor has focused on pseudoscientific vagueries such as "toxic load" and "vaccine load."

"Toxic load" as defined by the anti-vaxers refers to the idea that trace chemicals or preservatives present in the vaccine induce autism. Several studies have thoroughly discounted this concept. The only potentially scientifically valid tenet underlying this idea is several public health studies that have shown a (barely) statistically significant correlation between environmental mercury content (defined variously as soil concentration, drinking water concentration and atmospheric concentration) and local prevalence of autism. Unfortunately, a biologically insignificant amount of mercury given as a bolus (as in a vaccine) and environmental exposure throughout development are still two very different things, and treating autism as heavy metal poisoning can have lethal consequences.

"Vaccine load" is the idea that the normal vaccine schedule gives too many vaccines at once, thereby overwhelming a child's immune system. This concept blatantly disregards that the human body is constantly under attack from pathogens and has evolved to survive under constant attack from pathogens--the human body is more than capable of dealing even with a relatively high titre of thousands of antigens at once. Not only is the normal vaccine schedule safe, adhering to it is necessary for the maintenance of "herd immunity" and general public health.

Vaccination is one of the oldest medical procedures still in use today, and continues to be one of the most effective tools available against infectious disease. Outlining the flaws in the anti-vaccination movement would produce a blog entry far longer than I am willing to write, but there will certainly be more to follow on this topic.

The Arizona Bill: A Good Place to Start the Conversation

After sitting through months of hype on CNN and Faux news, I finally made time to read through Arizona's infamous S.B. 1070. Having expected to see a work of tea-stained Beck-isms and back-door racism, I was actually quite surprised to encounter a perfectly constitutional, surprisingly impotent, politically neutral law.

From an enforcement standpoint, the law really does not change all that much. Actually, from its wording, it seems plausible that the law was explicitly written to incite controversy and discussion--not racial profiling.

Legally, S.B. 1070 primarily accomplishes three things:

1. It sets a state-wide standard of enforcement of already-existing federal law.

2. It authorizes law-enforcement officers to question the immigration status of persons suspected to be in violation of other local, state, and federal laws (but, outside of suspected human smuggling, immigration status alone explicitly does not constitute probable cause under this law).

3. It adds the potential for an additional 500$ fine to be imposed on persons found to be here illegally.

The caveat here that prevents racial profiling is that in order for a person's immigration status to be questioned in the first place they have to be legitimately stopped by a law-enforcement officer for some other reason. An illegal immigrant walking down the street, not causing any trouble cannot--and would not--be stopped. Even passengers in a car subjected to a traffic stop, so long as the driver is cooperative and able to produce his license, registration, and proof of insurance, cannot be questioned because, unless the passengers provide it, the officer would not have probable cause.

Most foreigners carry a passport with them at all times, most adult legal residents have driver's licenses as do most adult citizens. If, as a citizen, I am stopped by a police officer for any reason, even on the street (as I recently was when a friend of mine was caught urinating on the sidewalk), the first thing they ask to see is my driver's license. Failure to produce it or any other form of identification would be suspicious and, were I driving, would earn me a fine. A person who is in the United States legally who is stopped legitimately should be able to produce some form of identification--S.B. 1070 simply allows for the arrest of suspicious persons found violating the law so that they may be identified. So long as they behave themselves, even illegals have nothing to worry about.

The purpose of S.B. 1070 was not to stop the flow of immigrants across our borders--with the exception of a very small minority, this entire country was built by immigrants--the purpose of this bill was to catalyze a discussion about the changes that need to be made to existing American immigration policy. For that effect, the bill has worked beautifully; the American people have put immigration reform back on the front burner. Now is the time, let's work together to figure out how we can best continue to welcome the "huddled masses" of the "tempest tossed" into the land of the free.

My histones made me do it!

Unraveling the biochemistry of behavior is one of the most difficult ongoing scientific ventures. The brain develops nearly continuously from shortly after implantation to early adulthood. Much of the molecular biology of normal brain development remains elusive; even less is known how genetic and environmental cues could potentially interact to cause psychopathology later in life.

A news focus appears in this month's Science, discussing the work that has been done to date on the role of epigenetics in human behavior and the promise of future research in that field.

http://www.sciencemag.org/cgi/content/short/329/5987/24 (link to abstract)

For those of you unfamiliar with molecular biology, epigenetics is the term used to describe the correlation between gene regulation and phenotype. (methinks I'll add a glossary page)

Individual chromosomes are LARGE molecules--stretched end to end, the 46 chromosomes in a single human cell would be roughly two meters long. Obviously, this is an inconvenient way for cells to store genetic data--cells get around this problem by compactly packaging DNA around proteins called histones.

With the exception of certain types of blood cells, every cell in the human body contains a complete copy of the host genome. As cells differentiate throughout development and adult life, each cell type only needs to actively use a minority of the genes it its genome. Mechanically, genes that are packaged around histones cannot be actively expressed--therefore histone modification allows the "unpacking" and "repacking" of genes according to developmental and physiological need.

The important thing to remember regarding the role of epigenetics in development is that development is not a static program. Owing to environmental factors, even identical twins can manifest markedly different physical phenotypes (e.g. I'm an inch taller than my own identical twin). Based on environmental and physiological cues, expression level of any given gene in a particular tissue can vary widely from individual to individual. The variability of development is known as phenotypic plasticity.

Inappropriate epigenetic regulation of gene expression has been implicated in several human diseases ranging from cancer to metabolic disorders to autism. As the age of monogenic disease gene hunting draws to a close, scientists are increasingly coming to understand the role of differential gene regulation in human disease.

Regarding the role of epigenetics in human behavior and psychopathology, there was a more complete review published in Frontiers of Neuroendocrinology last year.

Much of the work that has been done to date in behavioral epigenetics has focused on the role of epigenetic factors in creating brain sex differences and favoring sex-specific behaviors in rodent animal models.

The potential link between autism and epigenetics is tantalizing. Gregory et al. (2009) found a significantly higher rate of histone methylation (silencing) within the oxytocin receptor (OXTR) promoter region in samples taken from the temporal lobe of autistic patients versus age and sex matched controls.

Polymorphisms within the regulatory region of the OXTR gene have been previously correlated with autism. Additionally, exogenous administration of oxytocin to autistic patients has been shown to temporarily attenuate many of its outward behavioral signs.

These finding, coupled with the recent correlation of gene copy number of various genes with autism, imply that autism could conceivably be a disorder of transcriptional regulation rather than the direct result of one or more "broken" genes.