This blog post is by Richard Fauth
It didn’t come from me. I have to admit I could never pull it off like he does. It must be because he’s half-French (his mother’s half.) Last Sunday, we had a cook-out with a family of friends at Fort Wilderness in Disney World. My 8-year-old son Lucas was at it again. Smooth. It didn’t take him long to catch the eye of a college-age girl. He took her shoes off. Before long he was riding around the campground in a golf cart with the other kids. She was driving; he was riding shot-gun. That’s my boy. The cutest little boy on the planet. Although he can say only a few words, I knew he couldn’t be happier.
Lucas has autism and some researchers find him interesting. A sample of Lucas’ DNA was tested by a commercial lab a few years ago for three autism suspect genes. Sequencing tests for the genes (CDKL5, Cntnap2 and Shank 3) were among the first to be performed. The results are what researchers find interesting — unusual variants or mutations in two of the genes-Shank3 and Cntnap2. These results also changed our lives — we left a world where things were increasingly desperate and entered a world of new found hope. Some now say Lucas may be one of the most researched children with autism in the country.
Like many parents, Marie and I spend a lot of effort trying to get the best for our child. Like many kids, Lucas’ day is filled with “activities,” although if he could speak well enough, I think he would call it “work.” He puts in a tough week – long hours of special education, speech therapy, occupational therapy, and applied behavioral therapy. But he also has some fun — “special kids” dance class on Saturday and some gym classes.
As I write this, skin cells from Lucas, Marie and me are being converted to Pluripotent stem cells at a laboratory at Stanford University. From these stem cells, the researchers will grow neuronal tissue. The research is aimed at developing drugs to improve the outcomes of many children. Another study, a paper concerning a variant in Lucas’ Shank3 gene, has already been published. We have been invited to join another study and there is other interest-full Exomic sequencing of autism suspect genes in Lucas.
Lucas has been to Boston Children’s Hospital-Harvard, Stanford University, Mt. Sinai Hospital in New York, and the Dan Marino Center in Miami. We have visited the Kennedy Krieger Center in Baltimore. Every time I see one of those “my kid made the honor roll at…” bumper stickers, I want to put a sticker on the back of my car listing all the places my kid has been to, followed by “so there!”
He’s my boy and I’m proud of him. Daddy knows; I tell him so when he gets real frustrated because he can’t speak. As hard as it is on Marie and me, it is incredibly difficult for him. We fear that this will not get any easier for him. What we know is that without effective research, it likely won’t.
Lucas can swim in our pool here in Orlando. He also loves his trampoline. The “It’s a small world after all” ride at Disney World is now second on Lucas’ list of cool things to do. First is going to the beach -especially during a “Surfers for Autism” event. These are closely followed by long airplane flights and jumping on hotel beds. The last time we went for a weekend at the beach, he threw a fit when we left-he’d just as soon hang out there indefinitely. I know the feeling.
But it is another feeling that stays with me most days. It is the feeling that when the day comes when I leave this world, I will have not done enough to make the difference needed for Lucas. This has got to be every parent’s worst nightmare — failing to be a good enough advocate. At 52, I already believe that I will never retire. I could spend my time fighting for insurance reform so that Marie and I wouldn’t have to come up with $25,000 to $35,000 each year for Lucas’ therapies and someday I could retire. Or I can spend more time doing what I can to advocate for the bigger agenda: finding effective therapeutics for children with autism.
So Marie and I pour over autism research. As part of the ongoing research concerning Shank 3 mutations, I am a proud member of the Phelan McDermid Syndrome (PMS) Research Support committee along with a group of very smart parents fighting with me to find help for our kids. Lucas does not have the deletion in chromosome 22 that causes PMS, but rather mutations in the Shank3 gene which researchers believe may cause autism.
I only wish that more parents would push for research into the dozens, if not hundreds, of autism suspect genes and the pathways that variants in these genes disrupt. I also have hopes. Hopes that more sequencing will be available and affordable in the near future. That Pluripotent stem cell, brain imaging and genetics research will answer many of the questions needed to move into effective drugs. And that research concerning speech, occupational and ABA and other psychological therapies yields improved outcomes for our children.
After watching a WWII movie last Memorial Day, I began pondering the notion of “the greatest generation.” I also recently read The Immortal Life of Henrietta Lacks about He La cells and the Herculean effort our country undertook to beat polio. I believe it is this generation’s challenge to beat the developmental disability that is autism. We are on the cusp of major findings into the causes and potential treatments for autism. Trials are underway using experimental drugs to combat Fragile X and Rett syndromes. Research is implicating mutations in many of the same genes affected in other disorders with disrupted chromosomes, disorders in which classic autism exists- such as PMS. Common pathways are emerging in the literature. For a segment of the population, we now know what causes autism. The first studies concerning children and multiple autism suspect gene mutations have been published.
It matters. What we know, where we go, how we get there. That is the sentiment on the faces of parents we meet involved in research and support for their children on the spectrum. Parents who would move heaven and earth to help their kids. A hope that comes with research.
“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community. We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.
Scientists have long wondered how experiences during a person’s lifetime can alter behavior and body functioning. In the early 1800’s Jean Batiste Lamarck suggested that giraffes’ necks grew long through many generations of stretching to reach distant leaves. That theory eventually fell to evolution–pressures from the environment selectively amplify or quiet certain traits that are variably present within a population. Later, the DNA code was found to be the mechanism for inheritance and the level at which selective pressure acts.
Today’s scientists see hints of Lamark as they peer into the molecular biology of inheritance.
Consider DNA to be a library of books that encode genes. These “genetic books” must be read so that proteins can be formed from the code. Some genetic books are open and available for reading by the cell’s molecular machinery. Others maybe temporarily unavailable and still others are in the restricted section—essentially permanently unreadable.
Experiences throughout an individual’s life create tags on the genetic code, marking it as available or not for reading. The molecular methods that control the availability of the genetic code are collectively referred to as epigenetic mechanisms. Literally meaning “above the genome”, epigenetic mechanisms tag DNA with different chemical marks, such as methyl or acetyl groups. Certain tags can increase the reading frequency, resulting in more protein building-blocks transcribed from the DNA code, and more of that gene “expressed”. Other tags result in a particular piece of the genetic code to be skipped during reading.
A host of environmental agents and interactions may leave epigenetic marks on the genome. Early life stress, smoking, exposure to toxins may all leave epigenetic marks either creating or removing barriers for protein creation.
Here is where Lamark comes in. Most epigenetic marks are removed before the sperm and egg meet to form an embryo, but sometimes, epigenetic marks remain. This is one mechanism by which environmental exposures can be passed along from parent to child.
The study of epigenetics and gene expression in autism is underway and early findings are exciting. Some of the genetic syndromes associated with autism, such as Angelman and Prader-Willi syndrome, result from epigenetic marks that render one parent’s genetic contributions unreadable. Recently, gene expression studies from the blood and even brain tissue of individuals with autism have shown differences in the activity of patterns of genes that are involved in brain development and function.
This is an exciting area of research and we look forward to sharing more details as we learn more from the science.
Read more about epigenetics on or blog.
5|25: Celebrating Five Years of Autism Science Day 19: First Successful Autism Genome-Wide Association Study Results
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 19th item, First Successful Autism Genome-Wide Association Study Results, is from Autism Speaks’ Top 10 Autism Research Events of 2009.
Advances in technology and analytical methods over the past several years have enabled a better understanding of genetic risk factors for ASD. The human genome has over 6 billion DNA nucleotides. Until recently, it has been extremely difficult for scientists to compare two groups of individuals – one affected by a condition versus a comparison group – in terms of their detailed DNA because such comparisons require the analysis of at least half a million to a million individual locations in the genome of thousands of people. New methods, called Genome-Wide Association Studies (GWAS), have now made it possible to perform such comparisons and identify single changes in DNA nucleotides as specific genetic risk factors. Although this powerful technology has already produced exciting findings in other complex diseases, it wasn’t until 2009 that GWAS studies finally began to bear fruit for autism. In the Spring and again in the Fall, researchers reported successful application of GWAS technology to ASD.
GWAS is a powerful analysis technique that allows researchers to sift through hundreds of million of bits of genetic data to identify changes to the genetic code that are associated with a disease. Because the approach is not based on any specific biological hypothesis, scientists can cast the broadest experimental net possible, and use sophisticated statistical methods to establish the disease association. In recent years, GWAS has been successful in identifying susceptibility genes for such diverse conditions as macular degeneration, diabetes, rheumatoid arthritis, Crohn’s disease, and bipolar disorder. In April 2009, a large team of scientists led by investigators at Children’s Hospital of Philadelphia, reported results from the first successful GWAS study in autism. Tens of thousands of DNA samples are required for GWAS to produce meaningful results, so working with collaborators that included members of the Autism Genome Project, the researchers pooled samples from the Autism Speaks-funded Autism Genetic Resource Exchange (AGRE) combined with many other collections. The result was identification of a DNA variant associated with the genes cadherin 10 and 9, which are responsible for creating molecules that facilitate the formation of neural connectivity. This finding is consistent with accumulating evidence suggesting abnormal interactions between neurons may be at the core of the deficits seen in autism.
The idea that faulty connections between neurons plays a major role in ASD was further supported with the publication of the second autism GWAS study in October. Also working with AGRE and members of the Autism Speaks-funded Autism Genome Project, a collaboration led by investigators from Boston’s Autism Consortium and Johns Hopkins University used a very different statistical approach to discover an association between ASD and the gene semaphorin-5A. Similar to the cadherins identified in the first study, semaphorin 5A is thought to play an important role in neural development.
Taken together, these two groundbreaking studies confirm the potential for GWAS to make successful contributions to our understanding of autism genetics. Remarkably, out of the approximately 20,000 different human genes the experiments could have identified, the genetic variations that were uncovered are genes involved in brain development, serving to expand and reinforce our current thinking about biological mechanisms of autism. Like all new findings, they continue to focus the attention of the scientific community on the next directions for research and exploration.
Update since this story was published: DNA technology has once again advanced dramatically. New high-throughput techniques have finally made it possible to sequence entire stretches of genes, known as exons, in large numbers of patients. At the end of 2009, stimulus funds from the American Recovery and Reinvestment Act were awarded to investigators from the Autism Genome Project and the Autism Consortium who will use these new techniques to conduct a very detailed examination of 1,000 different genes linked to autism using several thousands of families who have kindly provided their DNA.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our ninth item, Copy Number Variations, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Three studies published in 2007 pointed autism researchers toward the importance not only of mutations within the DNA code of specific genes, but also of variations in the number of copies of genes, known as Copy Number Variations (CNV). Created by submicroscopic deletions or duplications of DNA sequences, recent advances have only now allowed CNV to become routinely detectable, establishing an entirely new avenue of genetic research.
Armed with the latest technology and three different collections of patient DNA, including Autism Speaks’ Autism Genetic Resource Exchange (AGRE), researchers at Cold Spring Harbor scanned the genome for the presence of CNV in autism. In February 2007 they reported that not only do individuals with autism have more CNV than individuals without autism, but that CNV in autism occur more often as “de novo” or spontaneous mutations (mutations not found in the DNA of either parent). They also found that these spontaneous CNV appear to be more common in families with only one child with autism (simplex) than those with multiple affected children (multiplex).
With their data suggesting that genetic mechanisms may be different in different types of autism, the researchers then carefully studied the inheritance pattern of autism in the many families in Autism Speaks’ AGRE and IAN databases. In July they published that they could fit the data to a model in which there are at least two distinct ways that genes may play a role in the development of autism: spontaneous CNV might help to explain autism in simplex families, whereas inherited gene mutations may be at the root of autism spectrum disorders in a greater portion of multiplex families. Such a model is significant because although autism has been thought to have a strong genetic component, so far it has not been shown to be as clearly inherited as other simple genetic disorders.
The team from Cold Spring Harbor has provided a new theory of autism risk that stands to influence how future autism genetic research is conceptualized. Although their results require replication, it also now leads to the question of what causes this increase in spontaneous CNV, opening the door to an exploration of the interplay between genetics and environmental factors. Possible risk factors include age of the parents, specific toxicological factors and accumulated exposures, as well as genetic predisposition.
Update since this story was first run: Improvement in DNA technology since the publication of this first major autism CNV study has meant that new insights into the role of CNV are actively being pursued. The largest and most comprehensive autism CNV study to date was published in April 2009 in the top research journal, Nature. The new study focused on inherited rather than spontaneous CNV, with the researchers finding CNV variations in genes important for neural development [for more details, see http://www.autismspeaks.org/science/science_news/top_ten_autism_research_events_2009_cnv.php]. Researchers in autism are continuing to lead geneticists in other fields with an intense focus on CNV and early recognition of their importance as potential disease risk factors.