Stories from IMFAR 2014: A Refreshing Refocusing

CaptureIn addition to learning about autism awareness in Singapore, I got a lot out of the International Meeting for Autism Research, held a few weeks ago in Atlanta. I wrote a post for the Autism Science Foundation blog in which I share some of the major themes discussed at the meeting. Head on over to the ASF blog if you want to check it out!

Link: http://autismsciencefoundation.wordpress.com/2014/05/29/imfar-2014-a-refreshing-refocusing/

When Silver Bullets Hurt

The apparent increase in autism prevalence over the past decade has driven this disorder into the focus of our nation. This attention has led to a race for the cure, so to speak, a desperate search for a silver bullet to unlock the secrets of autism and cure its wide-ranging symptoms.

But this race is futile. Autism is extremely complex with both genetic and environmental factors, and no single treatment is likely to benefit everyone with autism or improve more than a few of its many symptoms. Searching for a silver bullet is not only pointless but also dangerous, as some of the proposed cure-alls may actually hurt more than they help.

The Food and Drug Administration recently released a consumer update warning families against false claims of cures for autism. Some of the treatments under question include removing important metals from the body in a process known as chelation and an ingestible “miracle mineral solution,” which turned out to be bleach. In the report, the FDA warns that these treatments are not only largely ineffective but could also lead to “serious and life-threatening outcomes.”

When the treatments above have proven fruitless, doctor-salesmen in Panama and other foreign countries have offered up therapies usually reserved for cancer treatment, such as stem cell and bone marrow transplants. These highly invasive, unregulated treatments are only informed by the preliminary results of exploratory animal studies published over the last few years. Although a clinical trial for stem cell therapy in autism is underway, a reminder is needed: autism is not cancer, and it will not be treated effectively if viewed as such.

Even an FDA-approved medication for aggression and irritability in autism, risperidone, has come into question for serious side effects. According to recent studies, this antipsychotic drug may cause metabolic dysfunction and significant weight gain, while only providing behavioral benefits for some individuals. A recent study exploring the combined results of many other studies led to the conclusion that risperidone and a similar drug, aripiprazole, have “substantial adverse effects and that each compound has a specific secondary effect profile that should be taken into account in treatment decision-making.”

The available treatments for autism, whether quack or FDA-approved, have a skewed cost-benefit ratio, in which the risk of harmful side effects outweighs the chance of true benefits. Scientists need to take treatment research back to the core symptoms of autism, especially social communication deficits. The utility of combo-therapies, in which medication and behavioral therapy are given together, should be further explored.

Treatments should stem not from a trial and error approach, but from a bottom-up approach, in which core symptoms and their potential underlying mechanisms inspire treatment ideas. Ultimately scientists and physicians need to focus solely on research-driven, patient-centered treatments. Any supposed silver bullet is really just a shot in the dark.

Take Your Vitamins: Is Folate Important for Future Dads, Too?

Women have been encouraged to take folate supplements during pregnancy since the early 1990s, but a new study suggests that men may also need to avoid folate deficiency for the sake of their future children.

“Currently prevention of birth defects is directed at the mother yet the male contributes 50 percent of the heritable information,” says Sarah Kimmins, associate professor of reproductive biology at McGill University and principal investigator of a new study published December 2013 in Nature Communications. “This mode of thinking that it’s all up to the mother to ensure the health of the offspring is outdated, as research is suggesting that a father’s reproductive health may be equally as important.”

Image by Christoph Bock (Max Planck Institute for Informatics) (Own work) [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Image by Christoph Bock (Max Planck Institute for Informatics) (Own work) [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0)%5D, via Wikimedia Commons

In their study, Kimmins and her colleagues explored how reduced dietary folate, also known as folic acid or vitamin B9, might affect male mice and their offspring. Folate is known to influence DNA methylation, the addition of a group of atoms containing one carbon and three hydrogens to the region of a gene that determines whether it is turned on or off. Through changes in DNA methylation, environmental factors, such as diet, are capable of causing changes in gene expression without altering the genetic code. These changes, called epigenetic modifications, can be passed from one generation to the next.

“This epigenetic information is dynamic and, unlike your DNA, can be altered by what you eat, smoke, and possibly even fear and stress,” says Kimmins.

The authors first exposed male mice to either a folate-sufficient diet, with the normal amount of folate a mouse needs to be healthy, or a folate-deficient diet, with only 14 percent of the normal amount of folate, from before birth through adulthood.

They then examined the reproductive health of these males and found that the folate-deficient mice had reduced fertility and that their offspring were less likely to survive as embryos. Additionally, the offspring of folate-deficient mice displayed developmental abnormalities, ranging from skeletal malformations in the skull, spine and limbs to muscular defects.

They also found 57 gene regions with altered methylation in the sperm of folate-deficient mice. Interestingly, these changes occurred primarily in genes related to development, the function of the brain and other organs, as well as genes associated with cancer and neurological conditions, such as autism and schizophrenia.

Furthermore, these epigenetic changes were transferred to the next generation of mice. The authors found that hundreds of genes within the placentas from the offspring of folate-deficient mice were expressed differently from those of folate-sufficient mice. Importantly, two of these genes were part of the original group of 57 genes that demonstrated altered methylation patterns.

These findings suggest that the sperm epigenome may be modified by the paternal diet, and that the effects of these changes have the potential to be passed onto future offspring. However, a mechanism behind the effect of diet on sperm DNA methylation is not yet clear, and there is the potential for alternative explanations of the findings.

“It may be speculated that some of the developmental defects observed in their study can be the result of inappropriate cellular metabolism and not necessarily an affected methylome,” says Rocio Rivera, assistant professor of developmental epigenetics at the University of Missouri.

This study also provides support for the idea that offspring are vulnerable to environmental conditions experienced not only by their mother during pregnancy, but also by their father before conception. Another recently published study has also demonstrated epigenetic changes related to paternal experience, in which fear associated with a specific scent was transferred from a male mouse to his offspring and even his grand-offspring.

Additionally, the altered gene expression and birth defects observed in the offspring of folate-deficient mice demonstrate a potential role of paternal folate levels in development. Although this study examined mice, the findings indicate the need for exploring the effects of folate deficiency in men.

“Even if a man eats enough folate, if he is overweight, or obese, or has a genetic mutation in an enzyme in the folate pathway . . . there is strong possibility that the sperm epigenome will be abnormal much like we saw in the mouse model,” says Kimmins.

In future studies, Kimmins and her colleagues plan to study folate levels in normal weight, overweight and obese men and follow the development of their children. Although the motherly reminder to take vitamins seems clichéd, it may turn out that folate supplements and good overall health may be just as important for future dads as it is for future moms.

References:

Lambrot R., Xu C., Saint-Phar S., Chountalos G., Cohen T., Paquet M., Suderman M., Hallett M. & Kimmins S. (2013). Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes, Nature Communications, PMID:

Dias B.G. & Ressler K.J. (2013). Parental olfactory experience influences behavior and neural structure in subsequent generations, Nature Neuroscience, PMID:

{This post was originally submitted as part of my application for the 2014 AAAS Science & Technology Mass Media Fellowship.}

Stories from IMFAR 2014: Autism (Un)awareness in Singapore

Photo source: Flickr

Photo source: Flickr

In Singapore, a highly developed, first-world country, autism awareness and educational support may be sorely lacking.

Over lunch today at the International Meeting for Autism Research in Atlanta, I sat next to Lela Iuorno from Singapore. Her eight-year-old son, Luca, has autism. Iuorno is at IMFAR hoping to learn more about available pharmacological and behavioral interventions for her son. She is particularly invested in autism research, as she is not only Luca’s parent but also his behavioral aide in school.

Behavioral aides, referred to as “shadow support” in Singapore, are not typically available in the school systems in Singapore. In fact, Iuorno has spent a lot of time trying to convince public schools in Singapore to provide access to behavioral aides in the classroom.

“It’s a lot of fighting,” she said. When Luca had attended three different schools before he finished preschool, Iuorno decided to take the reigns herself. She now attends school alongside Luca 5 days a week, providing the assistance he needs to stay focused during his classes. She works nights and weekends to offset the lost income she would have if she wasn’t serving as Luca’s aide. She’s constantly working to do what’s best for her son, she said.

“I feel like a one woman army,” she said.

Another obstacle Iuorno has encountered in Singapore is a lack of understanding amongst teachers and students about what autism actually is. There is a common misconception that autism is a temporary condition. Teachers have told Iuorno that when Luca “gets better” his experience at school will improve.

Additionally, students like Luca who have autism but do not display obvious behavioral symptoms, such as outbursts, are assumed to be fine. Thus, their individual barriers to learning are largely ignored.

“These children can’t survive [in public schools],” she said. Yet, there are few private special education schools in Singapore, and, of the ones that exist, getting in is difficult.

Despite its developed status, Singapore lacks well-organized special education systems for autism, in which trained behavioral aides are available. But, more importantly, Iuorno believes Singapore is in need of accurate awareness about autism and its heterogeneous symptoms. This unawareness is hurting the education of children like Luca.

“It’s true and it’s sad,” Iuorno said.

Give yourself a break and pick up a book

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Photo source: Wikimedia Commons

My husband is the kind of person who has to read a book before he sees a movie based on the book. It was a scramble to read all three books of the Hunger Games Trilogy before the first movie came out in 2012. He even re-read all of the Harry Potter books before their movies. Naturally, he’s finished the first book of the Divergent series with plenty of time before the movie comes out next month.

I, on the other hand, am not quite on track. Last week he casually yet admonishingly asked if I was going to read Divergent in time for the movie. Sadly, though, my first thought was, “Do I even have time to read a book right now?” I am often plagued with the well-ingrained grad student guilt that comes along with doing anything other than lab work or reading journal articles. “Surely I could spend the last few minutes of my time before bed doing something more productive than reading a teen fiction novel,” I thought.

However, as I read C.P. Snow’s The Two Cultures for my science communication class the other night, I came across a profound statement (amongst all the other profound statements in his influential piece) that changed my mind about my husband’s suggestion.

Writing about the scientific community’s perspective on literary works, he states: “It isn’t that they lack the [psychological, moral, or social] interests. It is much more that the whole literature of the traditional culture doesn’t seem to them relevant to those interests. They are, of course, dead wrong. As a result, their imaginative understanding is less than it could be. They are self-impoverished.”

“Self-impoverished” – such a powerful phrase to describe the state we, as scientists, put ourselves in when we refuse to consider the value of doing things like reading literary works. Snow points out that an “imaginative understanding” can be gained from reading books. Think about the ways our scientific ideas could become more innovative, integrative and cross-disciplinary if our minds were also being fueled by the works of imaginations that inspired Anne of Green Gables and Elizabeth Bennet.

Of course, in no way am I comparing Divergent to the works of Jane Austen, and I’m not saying you should skip lab tomorrow so you can dust off a copy of Moby Dick. But, the next time you feel drawn (or forced by your spouse) to pick up a book, give yourself a break and read. Let your mind relax into flowery turns of phrase or engage following chilling cliffhangers. Let your imagination unfurl, guilt-free. Your scientific ideas will thank you later.

 

Innocent Scientific Curiosity

I’m taking a science communication course designed for undergraduate science majors this semester, and I can’t help but think about how lucky these students are. Not only are they getting scientific training as undergrads, but MU has taken a step toward providing these young scientists with skills in how to communicate science to the public.

We’re starting out with reading the Science Times each week. This brings back fond memories for me, as reading this section of the New York Times my freshman year of college got me absolutely hooked on writing about science and learning how to do it. I remember reading Benedict Carey’s articles and being in awe of his ability to turn a complex scientific concept into a relatable idea with a well-crafted metaphor.

For today’s class we read a piece by George Johnson, entitled “New Truths That Only One Can See.” In this article, Johnson unpacks the theory of Dr. John P. A. Ioannidis in which he purports that most published scientific findings are false due to bias and the lack of replication in science.

In class one of the students expressed that he was surprised that some major scientific discoveries may in fact not be true. This feeling of surprise struck me in two conflicting ways. First, I was frustrated that the importance of replication of results and the real influence of statistical confounds such as Type I error are not being effectively conveyed to undergraduate science majors. It’s clear that the concept of unconscious bias in an experiment, while all too present, is often not acknowledged in science education.

But, then I was also relieved by the student’s surprise. Perhaps it’s my burned out grad student mindset, but I’m often too critical of my own findings in lab and those of others that are published. I think, “This is too good to be true! Something must be wrong.” I’ve lost a bit of the ability to believe that some discoveries can be true and, what’s more, change the world. Perhaps I’ll learn more in this class than I originally thought. Perhaps I’ll regain some of the innocent scientific curiosity that got squashed somewhere along the way of long hours spent banging my head against an SPSS output file. Perhaps I’ll remember why scientific inquiry is not just vitally important, but wholly exciting.

SfN Day 5: Finding an fMRI fingerprint

Photo source: Wikimedia Commons

Photo source: Wikimedia Commons

I had a chance to stop by a really intriguing poster this morning on Day 5 (the final day!) of Neuroscience 2013. Brian Mills, a co-author on a poster (765.01) entitled “Model-based functional brain connectivity,” talked me through the pretty complex methods of this project.

In general, functional connectivity studies involving resting state fMRI entail comparing connectivity patterns between different groups of participants (e.g., schizophrenia vs. typically developing). Instead, Mills and colleagues are exploring whether or not resting state fMRI can be used to identify connectivity patterns that are unique to a specific individual. They are seeking an fMRI fingerprint.

In their study, Mills and colleagues developed a model-based connectivity matrix for a set of regions of interest (ROIs) throughout the brain of a participant, in which each cell of the matrix represents not the connectivity between two ROIs (as is traditional in functional connectivity analyses), but instead the relative contribution of neighboring ROIs to the timecourse of a specific ROI. This matrix can be used to model and predict the connectivity patterns of a set of ROIs at another time, such as a second fMRI scan date.

Comparing different linear equations that produce these model matrices, Mills and colleagues have determined the best way to predict one’s resting state fMRI connectivity patterns. And by best, I mean pretty darn accurate. Using their modeling techniques, Mills and colleagues have been able to classify single participants at scans a week after their original scan with up to 100% accuracy.

Even better, this type of modeling only seems to require about 60 frames of resting-state fMRI data to achieve accurate classification of individual participants. These frames, totaling about 2.5 minutes of scanning, don’t even have to be in sequential order. This is especially useful for patient populations, such as autism, in which motion artifact is a particular concern. Mills noted that with this method you can use participants who may otherwise not be included in data analysis due to too much motion in the scanner. This classification method also works in monkeys, proving that human-specific behavior, such as mind-wandering, is not leading to the accuracy of this method.

Additionally, when looking across their pool of participants, Mills and colleagues were able to determine which brain regions were relatively stable, versus dynamic, in terms of connectivity patterns from individual to individual. It appears that connectivity in motor and sensory areas of the brain is conserved across individuals, whereas that of fronto-parietal areas and default mode network areas is more variable between individuals. These findings make natural sense, as I would think that the brain activity that makes someone unique would occur in more frontal, higher order networks of the brain, as opposed to more evolutionarily old regions, such as motor areas.

Mills noted that they hope to apply this method to explore how the classification of individuals changes across development and when patient populations such as ADHD are considered. Mills hopes that much like knowing the variability of one’s genetic makeup, this classification method will someday aid in predicting risk for different disorders as well as the likelihood of response to certain drugs.