This week in Neurochem we talked about a very controversial and growingly prevalent topic – autism. As most people know, autism is a disorder characterized by a difficulty in verbal/nonverbal communication, social interactions, relationships, and disinterest/extreme interest in various activities. And, interestingly, the disorder is becoming more and more prevalent. According to the article, “How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis,” by Deth et al. of Northeastern University, the incidences of autism have grown from 3 in every 10,000 children in 1970 to 66 in 10,000 children in 2002. This shocking increase has many people (especially mothers) wondering…why? What are we doing differently that is causing this drastic increase? While some attribute the increase to advanced diagnosis ability and awareness, it still leaves you wondering if there are other reasons as well.
When talking about the causes of autism, it’s hard not to mention the thimerosal debate. Thimerosal is an inorganic mercury compound that has been used as a preservative in vaccines since the 1930’s. In 1999, new research on the toxicity of thimerosal was conducted by the FDA, and, although research didn’t suggest anything to cause alarm, it was still decided to phase out thimerosal as a precautionary measure due to its structural relatedness to methylmercury.3 In 2000, parents of autistic children started forming groups based on the belief that vaccines had caused their children’s disorders. Although much research has disproved the thimerosal/autism link, the debate still lives on today.3
While thimerosal, a heavy metal derivative, seems not to cause autism, there is reason to believe that heavy metals could still be a culprit of the disorder. According to this week’s article, a redox/methylation hypothesis of autism is still a valid argument and explanation. This is based on the tendency of heavy metals to inhibit an important protein of sulfur metabolism, methionine synthase.
Homocysteine is an amino acid derivative of cysteine. In sulfur metabolism, HCY can be converted to three other molecules – S-Adenosyl-L-homocysteine (SAH), methionine (MET), or cystathionine, a glutathione precursor. In times of oxidative stress due to heavy metal exposure, most of this HCY is shunted to cystathionine production due to glutathione’s role as a powerful antioxidant. Essentially, methionine synthase is shut down to deal with more pressing issues – the oxidative stress. This leads to all sorts of effects for the cell.
One effect is SAH accumulation, since the reaction between HCY and SAH is reversible and no HCY is being utilized by methionine synthase. This inhibits two types of methylation reactions in the cell – DNA methylation and phospholipid methylation. DNA methylation is very important in turning certain genes on and off, so this can have astounding effects on the cell. Phospholipid methylation is related to dopamine release and neural synchronization which is responsible for attention and focus-related thinking skills. Genetic factors are very important in predisposing an individual in autism, however, they don’t totally cause autism, supporting this heavy metal hypothesis. Many genetic mutations and polymorphisms in autism appear in molecules related to this redox/methylation hypothesis.
Although the exact mechanisms of autism have yet to be elucidated, the redox/methylation hypothesis seems quite likely considering the joint environmental/genetic factors. Since it seems quite likely that the environmental part of autism could be causing the dramatic increase in cases seen in recent decades, further research in this area is in dire need. Furthermore, as rates increase, advocating for increased awareness about the disorder is desperately needed as well. Autism creates new educational/social challenges which will require novel methods of interpersonal interaction and treatment for these individuals.
http://www.morphonix.com/software/education/science/brain/game/specimens/wet_brain.html
http://www.boloji.com/index.cfm?md=Content&sd=Articles&ArticleID=1098
http://www.webmd.com/brain/autism/autism-symptoms
Deth, R., Muratore, C., Benzecry, J., Power-Charnitsky, V., and Waly, M. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. Neurotoxicology 2008;29:190-201.
http://www.nationalautismassociation.org/thimerosal.php
Final Reflections
I enjoyed this Neurochemistry capstone course firstly, because of the interesting and fascinating topics that we covered. In the beginning part of the course, we discussed more of the biochemistry aspects and learned about different pathways, receptors, and substances within the human body that would provide us with a foundation for understanding the articles that were later to come. I don’t think that I would have gotten nearly as much out of the papers if we hadn’t discussed some of these pathways and mechanisms beforehand. The topics of the papers we discussed included concussions, addiction, obesity, bipolar, autism, and others. These were great articles to discuss because they covered a broad spectrum of disorders and they were also things that most of us have heard of and encountered at some point in our lives. However, I think that the most important skill I learned in this course is how to dissect these papers, and investigate different aspects of them in order to understand more about the whole picture. This will be a valuable skill as I continue my education and need to know how to investigate every aspect of a topic in order to fully understand it. Other aspects of this course such as the discussion of our individual areas of investigation, class discussions, and writing blog posts are all important skills to being a scientist. Concordia prides itself in “sending out thoughtful and informed individuals to influence the affairs of the world.” In order to be an effective scientist, one needs to share their area of expertise with other scientists, and know how to communicate their knowledge and discoveries both with other scientists and the general public. In this way, ideas and knowledge can be shared, and scientific advances and further discoveries can be made. This course has taught me how to do that through class discussions, investigations, and writing blog posts for the public to see.
Synchronized Dance Therapy for Autism
A new hypothesis in the cause of Autism is that of a dysfunctional motor neuron system. Motor neurons were discovered in the early 1990s while studying the brains of macaque monkeys. Researchers found that a group of neurons in the front part of their brains known as the ventral premotor cortex (just in front of the brain’s motor area) were activated when the monkey performed different tasks. The big shocker however, was that these same neurons were activated when the monkey watched someone else do the same action, just as if it had been doing the task itself. Much more research has been done since their discovery, and motor neurons are now known to be important to the tasks of empathy and socializing with other people, including communicating our emotions through facial expressions. In fact, it has been found that people with autism have dysfunctional mirror neuron systems. A characteristic of the disorder is difficulty socializing with others, and dysfunctional mirror neurons play a role in their inability to understand the intentions of others based on the action they observe. It has also been shown that the more severe the symptoms of autism are, the more inactive their mirror neurons are. The finding of these correlations has led to new therapeutic approaches that include autism patients imitating the actions of others.
V.S Ramachandran is a neuroscientist at the University of California, San Diego and is very well known and respected in the field of behavioural neurology. I have read is book: Phantoms in the Brain: Probing the Mysteries of the Human Mind that describes different neurological disorders, some of which are very rare and phenomenal, and how these “abnormalities” help us to understand how the brain is suppose to function under “normal” circumstances. I would highly recommend it to anyone fascinated by the mysteries of the human brain. Ramachandran has been studying this theory of autism that has come to be known as the “Broken Mirror” theory of autism. In a recent correspondence in Medical Hypotheses, Ramachandran and his colleague E.L. Seckel proposed a type of dance therapy for autism based on the theory that the mirror neuron system in autistic patients is not missing, but merely “dormant”. In Phantoms in the Brain, Ramachandran describes a therapy that he developed for patients with phantom limb involving mirrors. In a similar fashion, the therapy for autism that Ramachandran proposes is that an autistic patient would be in a room with multiple mirrors at different angles, and three neurotypical people. These people would dance to a rhythm and the autistic patient would mimic their movements and be able to watch themselves performing these actions in the many mirrors. In addition, Ramachandran and Seckel propose that various patterns of touch be administered to the autistic patient while they are watching themselves in the mirror, because of the existence of mirror neurons that fire when you watch someone else being touched. I would assume that the goal with this therapy is that the multiple ways to stimulate the mirror neurons would aim to restore the function of dormant mirror neurons in autistic patients.
This is a fascinating and novel therapy, and it will be interesting to see the future of therapies of this kind. Our paper with week was about the other pathways that may be a cause for autism. I think that future research should look at the theory of mirror neurons in conjunction with this article. Could the redox/methylation hypothesis be linked to these dormant mirror neurons, or can environmental factors impact mirror neurons in the same way that they can harm other pathways leading to autism? Findings about this link would also help to create combination treatments, which often seem to work better for many disorders, than one treatment alone.
For more information of mirror neurons and this new treatment, read the full articles that I have described, they’re very interesting!: http://www.sciencedirect.com.cordproxy.mnpals.net/science?_ob=MiamiImageURL&_cid=272414&_user=1822410&_pii=S0306987710004603&_check=y&_origin=search&_zone=rslt_list_item&_coverDate=2011-01-31&wchp=dGLzVlS-zSkzS&md5=499e9bc883e9a5c8121decf6c6450459/1-s2.0-S0306987710004603-main.pdf ; http://www.sfn.org/index.aspx?pagename=brainbriefings_mirrorneurons
Amyloid Beta Plaques: Destructive or Protective?
Contrary to popular “scientific” belief, we aren’t really that sure what causes the neurodegeneration of brain tissue in Alzheimer’s Disease (AD) patients. Thus, amyloid beta (AB) plaques are not nearly as deserving a scapegoat as is often thought.
If we investigate the chemical properties of AB depositions, we find that AB doesn’t exhibit the ability to make reactive oxygen species; rather AB exhibits anti-oxidant properties, implying that AB should be neuroprotective.
If AB is neurotoxic, we might expect to observe deleterious affects whenever AB production is increased, however AB increases are observed after instances of neuronal stress, as in cases of hypoglycemia and brain trauma. This result gives merit to the hypothesis: AB increases serve as a neuroprotective pathway due to physical stresses. So what is the role of AB plaques in the brain?
An alternative hypothesis to the origin of AB is that neuronal energy shortages coupled with Ca2+ overloads promote a fundamental switch in the metabolism route of Amyloid-Beta Precursor Protein (ABPP) from a non-amyloidogenic to an amyloidogenic pathway, i.e. it switches from the body making no AB plaques to the body making AB plaques. Since AB plaques show up after neuronal stress, induced by decreased energy production and higher Ca2+ concentrations (key symptoms exhibited by concussion patients), it appears that AB plaques play a protective role in the brain, and that ABPP is the necessary built-in protective system that is always on standby ready to create protective plaques.
So, even though AB plaques are always observed in AD patients, the presence of AB plaques is not unique to AD patients and thus is likely a bystander of the damaging effects of AD. Considering this information and that of the AD article we read, there are obviously mixed opinions regarding the role AB plays in AD. The article focused on in our neurochemistry course suggests that AB plaques are toxic, while other literature sources claim that AB is either a benign byproduct of AD or that it plays an active role in protecting the brain from the neurodegenerative nature of AD. Only future research will illuminate the true role AB plays in AD.
A Rotating Obsession: Autism Diagnosis and Treatment
As of 2002 autism affected 66 out of 10,000 people in the United States. With its growing prevalence, it is becoming even more important to get a proper diagnosis for autism so that the children can receive the best treatment available. Even though autism is not curable it can be managed and children can learn how to cope if therapy is introduced early. Autism is characterized by lack of social skills, impairments in communication or particular obsessions. Since a large part of autism is a lack of empathy, a lot of the therapy that is offered for autistic individuals is behavioral therapy.
I am personally affected by autism because my youngest brother who is now 17 years of age was diagnosed with Asperger’s, a subset of autism approximately 2 or 3 years ago. Asperger’s is not as severe as autism, and individuals with this disorder are very often viewed as normal individuals, they just don’t have as many social networks because they lack the capability to relate to others in the same capacity. My brother does lack some social skills, throughout elementary school and junior high school he was often made fun of for being different. But I think one of the most distinguishing characteristics looking back now was his obsessions. His obsessions often changed over the years, but during them he was totally and completely absorbed. During his toddler years he was totally and completely obsessed with Superman, for about a year and a half he even insisted that everyone call him Superman. The next phase of his obsessions was horses; he had imaginary horses that he would call to so they could follow us every time we drove anywhere. Next was Hotwheel cars, he had over 300 at one point. Then he started collecting fishing lures, which was an odd obsession because he hates eating fish, putting worms on the hook grossed him out, and he refused to take the fish off the line. As a 10 year old, his tackle box collection would make any seasoned fisherman jealous. His current obsession is archery, no one in our family has ever introduced him to bows and arrows, but he spent his entire summer working to make money to buy a very expensive bow to just practice with since he isn’t a hunter. Often times children have passions and hobbies, but few are as dedicated and committed to them as my brother, or other autistic individuals. Perhaps their dedication is something we should envy? To have such passion about something, anything, maybe we could accomplish so much more in life and have so much more depth to our learning.
The Cure for Alcoholism….
This week’s article was about alcohol abuse, alcoholism and the mechanisms behind it. The purpose of this article was to figure out what happens when alcohol enters the brain and what parts of the brain are affected. If scientists can figure out what happens, they may be able to find drugs that can reduce alcohol dependency in alcoholics, repair brain regions that have been damaged due to alcohol and even find drugs that can cause an aversion to alcohol. However, can there really be a cure for alcoholism?
Currently there are three drugs that are approved by the FDA for alcohol treatment. The first is called Campral and it is used to reduce the withdrawal symptoms experienced by long term alcohol abusers when they stop using. It is also believed that it helps the brain return to its normal cognitive function. However this drug has many side effects such as diarrhea, vomiting and nausea. Another drug is Antabuse and when this drug is taken in conjunction with alcohol, it causes headaches, nausea, vomiting, chest pain, sweating, choking and difficulty breathing. The last medication that has been approved is called Trexan, and it inhibits the “good feeling” that people get from drinking. The downsides of this drug are that it may worsen withdrawal symptoms from alcohol and it can only be used in treatment programs.
Although there are numerous drugs on the market, I don’t think that any one of them can really be used to treat alcoholism. I personally know a recovering alcoholic and after talking to her, she said that the only thing that really truly works is when the person wants to change, and is fully committed to making that change. She has been involved in Alcoholics Anonymous for three years now and even though there have been great struggles, it has been well worth the time. When I talked to her about easy fixes and the drugs that are now available to help, she is extremely skeptical on whether or not these drugs will work on the person long term. Sure you could easily take a drug that makes you puke when you drink, but people that truly desire the alcohol, will just not take the drug. The drug that improves your brain function, could be used as an excuse to just continue drinking, because in the end, you can take a pill and be cured from any brain damage.
Therefore in my opinion, alcoholism is not an easy fix. You can’t just magically take a pill and no longer desire alcohol. Recognize that you have a problem, desire change, and take action yourself to make those changes. We can’t always rely on medicine and science to fix our problems, the power rests in our own will.
If you are or known someone who is an alcoholic and would like more information about the program Alcoholics Anonymous, you can visit their website and find a meeting location near you by clicking here: http://www.aa.org/
Heavy Metal Autism
Our paper this week talked about environmental effects and how they play into theories for how autism starts in kids. One factor that is thought to cause autism is the toxicity of heavy metals. A few examples of these metals and where they are commonly found are:
Lead – petrol, paint, batteries, certain water mains
Mercury – fillings in teeth, fish, paint, some appliances, nasal sprays and eye drops, certain vaccines.
Cadmium – Cigarettes, tires, metal plating
Arsenic – Pesticides, chicken feeds, rice, treated wood
Antimony – Carpets, flame retardant clothes
It is believed that Methyl Mercury contributes mainly to autistic development in children.
(see our class wiki)
So how then do we treat heavy metal poisoning?
Just like any other illness, we treat it with pills! Current treatments involve chelating agents. These agents bind with the heavy metals selectively and then the complex that is formed is expelled from the body by the kidneys. Some examples of Chelating agents are EDTA, DMSA, DMPS, and TTFD. EDTA however, is not used for treating autism because it can be harmful to children, and EDTA is not good for binding mercury, what is thought to be the main heavy metal poison in autistic children. DMSA and DMPS are both used and given orally. They both chelate mercury, lead and cadmium well. So they are the pills of choice for treating autism in children.
Other treatments for autism
Dr. James Neubrander has injected methlycobalamin (a form of Vitamin B12 pictured above) into patients and they have shown improvements in language ability social skills as well as in attentiveness. http://www.drneubrander.com/index.php
So there is still hope out there for parents with autistic children. It is still hard guarantee improvement however, and I’m not sure which direction we should be going with treatment. However, from what I understand, this seems to be the best hypothesis for the origins of autism. There also seems to be some treatments available that keep this theory in mind. We will see what the future brings us.
Further information can be found at http://www.autism.com
The Diversity of Alcoholism
I have for you two scenarios (These stories are not based on any person in particular, but are just general possible scenarios.)
First is a story about Edward. Edward has been a respectable CPA for the same business for the last 12 years. His family consists of his wife of ten years. A few evenings a week after a stressful day, Edward and some of his colleagues go out for a few drinks. By the time the night is over, Edward has consumed six or seven drinks and heads home. When he gets there, his wife has gone to bed. It’s late and he didn’t answer his phone. Edward storms into the bedroom and he screams and cusses at her supposed incompetence. His fury builds in the wake of his drunkenness. He takes a swing at her face. Edward is an aggressive and abusive alcoholic.
Second is a story about Lenny. Lenny is and has been a hardworking man doing construction for 25 years. He has a beautiful family of two sons, a daughter, and wife of 24 years. His family appears normal from the outside. No neighbors see any issues with the family across the street. They are just a normal working class family with a moderate income. But what cannot be seen from the outside is that each night before Lenny comes home. He stops at the bar with his buddies and has a few…then drives home. When he gets there supper’s on the table. His wife offers to make his plate, but he politely refuses. He goes back outside and underneath his workbench in the garage takes out a can beer…and another…and another…and another. Until it’s almost time for bed. This takes place day after day, week after week. Lenny is a passive alcoholic.
These two stories are different on so many levels. But the one common link between the two is the alcohol. How is it possible that alcohol can have such polar-opposite effects on two individuals as similar as these? This is a difficult question to answer and to be honest experts still don’t know.
Image from: http://usdrugstore.blog.com/alcoholism-learn-about-alcoholism-symptoms-stages-and-how-are-alcoholism-treated/
This week our neurochemistry class explored the reasons behind the behaviors that alcohol causes. Biochemically alcohol (ethanol) has an effect on all parts of the body including the nervous system. Alcohol’s complex impact on the body makes it difficult to pin point the reasons for certain behaviors. However, one effect that alcohol always seems to be true to is that of becoming uninhibited. Individuals who have had only a couple of drinks tend to show signs of uninhibitedness and “loosen up.” The truth starts coming out. Individuals become unafraid and senseless. They lose their reasoning for making good decision making. This may be the point where individuals differ in their actions. This may be why there are passive drunks, funny drunks, aggressive drunks, etc. Perhaps their own personality and history is what leads them to their choices—good or bad—after a few drinks. Generally speaking, alcoholism tends to be a common (so-called) disease across the United States. However alcoholism has many shapes and molds. Alcohol can result in many different and often opposing behaviors depending on the person it is acting within.
Alcohol is commonly consumed beverage throughout the world. According to the CDC about 52% of the US population over the age of 18 are considered regular drinkers (12 or more drinks per year). Alcohol is the drink of choice for celebrations, break-ups, deaths, divorce, marriage, any event under the sun (minus a child’s birthday party). So why is it that with a beverage so common that there are addictive qualities that come along with it? Why is it that certain individuals are more prone to alcohol addiction than others? I mean, drinking is not illegal, so there must be a reason. The prohibition in the thirties didn’t work so well so the lawmakers learned better. People like alcohol and there’s nothing wrong with that. But, there’s nothing good about alcohol addiction either. So where so we draw the line?
If you or someone you know need help in an abusive situation please call the National Domestic Violence Hotline at 1-800-799-7233 (SAFE)
Or get help online at:
http://www.helpguide.org/mental/domestic_violence_abuse_help_treatment_prevention.htm
For more information about statistics of alcohol addiction please see:
http://www.cdc.gov/nchs/fastats/alcohol.htm
Alcohol as a social issue
This week’s discussions centred around ethanol and it’s many different pathways that it effects. This is relatively new research, and not much is known about how this knowledge can be used to fight issues surrounding alcohol use. For me, the biggest issues with alcohol use and abuse are societal issues. I have known many foreign exchange students from Germany and other European countries. Many of them say that the difference between the United States and other countries’ drinking practices is that because alcohol is so much a part of their society, in Europe they drink for social reasons, and in America a lot of young people drink to get drunk. This is where a lot of problems come in, when alcohol is drunken for its effects. I think that alcohol will always be a substance that is both legal and widely used because it is so engrained into our society. Knowing how alcohol takes its effects is useful from the point of view of simply “knowledge is power,” but until we can find a helpful use for this knowledge, it doesn’t help those that are using alcohol all that much. Perhaps the scientific community can develop a sort of pill that can be taken while drinking to stop the aversive effects before they start. Most people continue to drink because they like the initial feel of relaxation and disinhibition, but if we can stop the pathway of ethanol before it inhibits reasoning and decision making this would be a very beneficial use of the knowledge we have.
Brain to Fat Communication
A steamy slab of steak lies on a plate soaked in steak sauce accompanied by garlic-mashed potatoes and cheese-covered broccoli. You reach for your fork and take a bite. Little by little the massive helping of food is soon demolished. Already feeling full and a bit lethargic, you stare at a luscious piece of strawberry cheesecake. You think to yourself, “I don’t need this… I definitely shouldn’t eat it… But wait, it looks so good. I’ll just have a bite.” Before you know it, you’ve eaten the whole thing and moved onto another piece. Feeling bloated and almost sick, you sit back and relax as the lump of food sitting in your stomach begins to travel through your digestive system.
To many, this may seem like an exquisite meal. However, those that eat this excessively on a regular basis, usually combined with other unhealthy choices, commonly experience obesity. Fact is, eating like this has a huge impact on not only the digestive system but adiposity signaling as well. Adiposity signaling is communication between the brain and body fat stores in the body via the bloodstream. The way in which adiposity signaling functions has become an area of scientific interest.
For a molecule to be considered for adiposity signaling it must meet certain conditions. It must be able to secrete into the plasma relative to the fat stores, move from the brain into the bloodstream, show expression in the brain of signaling molecules that are involved with energy homeostasis, and decrease food intake. As of now, only two molecules are known to be directly associated with adiposity signaling, leptin and insulin. The effects of the molecules’ actions on neurons occur in the hypothalamus of the brain. More specifically, the region most concerned with these effects is called the hypothalamic arcuate nucleus. This area contains two neurons, proopiomelanocortin (POMC) and neuropeptide Y (NPY) with agouti related protein (AgRP), that express insulin and leptin receptors. However, POMC and NPY/AgRP have different effects depending on the levels of leptin and insulin. POMC is activated by insulin and leptin and reduces food intake and increases energy usage. NPY/AgRP also reduces food intake but is inhibited by leptin and insulin. In other words, if NPY/AgRP is secreted, food intake is stimulated.
Although the mechanism in which fat stores and the brain are connected is much more complicated than what has been explained, POMC and NPY/AgRP play an integral role. It is their existence that tells the body to eat more food or not. Even though regular exercise combined with a healthy diet should deter obesity, not everyone is able to maintain such a lifestyle. If scientists are able to engineer a drug capable of inhibiting NPY/AgRP and promoting POMC, weight loss could become more efficient.