The end of innocence

So, 1 post into this blogging thing and I already broke my promise to write once a week. My only defence is to tell you that while I have been very busy over my last week before school, none of what I was doing made for very interesting photos or posts. Instead, I'm going to share with you a few favourite pieces of wisdom from the website I've been using to prepare for beginning my Ph.D. For the time being, I'm still filled with optimism about my field and becoming a graduate student. Google tells me that this naïveté will be short-lived and I will soon become a real Ph.D student - cynical, anxious and surviving on near lethal doses of caffeine.

The experience of getting a visa to study in the USA

This is so true it's sad. I've had more than one prof respond by simply typing a word or two in the 'Subject' line and leaving the email completely blank. Blank except for a long imposing automatic signature that includes all their various credentials.

Amongst all the meetings and orientations I've been attending this week, it's been drilled into me that over the next 4-6 years my perspectives on neuroscience will be significantly re-shaped by my advisor. Before work really begins and this 'thought refinement' starts to colour my views, I'd like to devote the rest of this post to my current ideas about brain development and developmental disorders (such as autism).

This is my fall-back plan. I've heard that making graphs can also buy you some time, in a pinch. Mom/dad/advisor please ignore this comic. 

Anyone who has ever tried using google to self-diagnose has realized that many symptoms are non-specific - a rare splitting headache can be a sign of hemorrhaging in the brain, or a cancerous growth or.... a sign of excessive enjoyment at last night's party. For many diseases modern medicine provides us with relatively easy, safe tests that can quickly sort out the most likely reason for your symptoms. Unfortunately, for most mental disorders there is no easy or definitive test to confirm a diagnosis. Instead, diagnosis is based largely on how the patient behaves, how they report feeling and the doctor's (and sometimes other family members') views of those behaviours. To be diagnosed with autism a child must (before the age of 3) show impaired social development, impaired communication skills and display repetitive behaviours (ie. preferring to repeat the same games over and over, rather than try a new one). This may seem like pretty clear criteria, however, it doesn't say anything about the causes for these behaviours. As soon as doctors first began to describe autism as a disorder, the quest for researchers has been to understand why and how it occurs.

Unlike most parts of the body, the brain continues to grow and develop after birth. Neurulation refers to the initial steps in creating the nervous system, which involves a complex series of signals that begin a process of folding that creates the brain and spinal cord structures. Other molecules secreted from the embryo's cells cause undifferentiated cells (stem cells) to take on the role of neurons. The brain has approximately 1 billion neurons, however, many more neurons are initially created and various chemical signals direct these new neurons to appropriate brain regions. Many of these neurons will later  be destroyed (via the process of apoptosis) leaving only those which are useful - better to have leftovers than not enough! The processes of neural migration and synaptogenesis, the formation of important synapses or communication points between neurons, seem to be significantly disrupted in autism.

Why and how are where mental disorders become particularly thorny. As autism has become a hot topic in the news thousands of clever people have tried to answer these questions and they have been successful! Sort of. Now, instead of no answer we have many answers: certain genes, exposure to heavy metals such as mercury, chemicals in certain beauty products (phthalates) have all been linked to an increased risk of autism. All of these answers have some truth in them, but none of them offer a complete explanation. Most scientists now believe that "autism" is likely caused by a variety of factors that have a common effect on brain development. The tricky part is that development includes a lot of different systems working in tandem, extremely quickly making it difficult to isolate exactly where these autism risk factors are having an effect. The easiest analogy is to imagine development of the nervous system as an organized government - many different branches of government are involved in creating and running the nervous system, and within each branch there is a chain of command. These branches of organization are commonly referred to as biological pathways and they are responsible for crucial operations involved in making each cell function properly (for example, gene regulation pathways arrange for new protein "workers" to perform cellular jobs and prevent more workers from being sent to systems that are already functioning at capacity). It seems likely that somewhere along the line, risk factors involved in autism are impacting the same biological pathway: corrupting the same branch of government, but infiltrating the system in different ways.

Microglia are the primary immune system cells in the nervous system, and are involved in a variety of functions in the brain. Note that the link to neurological and psychiatric disorders (including autism spectrum disorders) is still only hypothesized. With more research, hopefully this link can be confirmed and understood in more detail. It's important to also note that microglia can participate in destruction of neurons, which can be protective (sometimes neurons need to be removed from the brain, for example if they are injured or if they've formed synapses that are superfluous to efficient brain function). If this destructive ability is not tightly regulated by the immune system, this creates another point of potential problems for the brain and may also contribute to neurological issues.

Huge statistical studies crunching numbers about autism prevalence and risk around the world have repeatedly linked autism to disruptions in immune function during development. Immune system cells in the central nervous system actually outnumber the neurons, as the body places critical importance on protecting the brain and spinal cord. In adults, there are multiple lines of defence protecting these organs from foreign chemicals, viruses and bacteria but in the developing fetus these defences are still being organized and the perimeter of the nervous system is not yet secured. Immune cells in the fetus are more akin to traffic cops than a ruthless military - they play a key role in guiding newly formed neurons to appropriate brain areas and making sure they form the proper connections. As neuron production slows, the immune system "cleans up the streets" of the brain during a critical period that lasts approximately 1-2 years after birth, pruning away excess synapses that are not needed and removing any debris. If, during pregnancy or during that critical period after birth, the immune system is compromised the change in policy will take resources away from growth and development in order to fight the attackers. As well, it seems as though the immune conditions established during this time have a lasting effect on the organization of the immune system. This means that if there is a severe immune challenge during this time the immune system may always be imbalanced, set to different 'default' levels than in a typically developing infant.

Although deep understanding does require scientists to focus on very small, specific fields it is crucial to remember that the human body functions as a whole. The nervous and immune systems are constantly interacting and effects on one system can have unforeseen consequences on the other. It is crucial to keep these connections in mind!

There is a lot of really cool research implicating immune system involvement in autism and other mental disorders. One particularly compelling example was first noticed by parents who reported that their child's autism symptoms were significantly improved during times of illness. Some evidence has been found to support the idea that during illness, immune system responses in the autistic brain temporarily restore a more typical balance of immune molecules and this change is enough to improve behavioural symptoms. Other studies have shown that mothers who have auto-immune disorders such as rheumatoid arthritis, or experience a severe infection or flu during pregnancy are more likely to have their child suffer an autism spectrum disorder. Pregnant mice exposed to the same immune challenge at different times during gestation have offspring with varying behavioural symptoms, ranging from signs of schizophrenia to signs of autism. Blood samples from individuals with autism show unusual ratios of pro- and anti-inflammatory molecules compared to typically developing individuals, lending support to that idea of skewed 'default' immune settings in autism. But a lot of work remains to be done before anyone can claim that the immune pathways in the brain are the connecting feature driving autism spectrum disorders. Can all of the other research on autism risk factors really be linked to early disturbances in immune function and organization, or is evidence of dysregulated immune function simply another contributing factor?

If I am extremely clever and extremely lucky, I may be able to help put some of these puzzle pieces together over the next few years. I hope to conduct studies that can draw associations between immune system function and physical changes in the developing brain; can an attack on the fetal immune system cause neurons to make 'bad' synapses? Do autism risk genes have any effect on the immune system? If science can get to the heart of "what causes autism," only then can we begin to ask "how can this be fixed or prevented?" For now, the task at hand is to try and fit all the information collected into a big picture.



Side note:
I feel like it's important to mention here... autism has never been linked to vaccines, except by charlatans and uninformed but attractive celebrities. The immune system has a large number of components and the vaccines given to young children essentially give the immune system's information department a file on recognizing a wanted criminal. Vaccines are well-researched and carefully monitored to minimize risk and maximize protection, and having your children vaccinated is the smartest and safest thing to do. This isn't a debate, it's a fact.