The Baltimore Sun recently ran a front-page article on autism and genetics (March 16, 2007), and it included a remark made by a parent of an affected child. She said that autism research may help, but she and other parents are more encouraged by the support and advice they provide to one another. "There's no magic bullet, but it's just a matter of steady and constant intervention," she said, That remark seemed a fitting point of introduction for a column focused on research in the field of intellectual and developmental disabilities.
"Research may help, but ..." is not a phrase that warms a scientist's heart, but in this case, it reflects the true sentiment of a good many people. They believe that research is fine, but if you have pressing needs, you want to invest your resources elsewhere. This attitude is understandable. As a parent, you have to use whatever you have on hand to deal with the many demands of the moment, and you can't wait around for years or decades or centuries for research to provide who knows what. On the other hand, it's no accident that those elusive magic bullets come along every so often, and investments in science today remain the best hope for a better future. While there are indeed no easy fixes for autism available today, it's clear that we will never have them without more research.
Even those "steady and constant interventions" of today are based on a long history of painstaking basic and applied research, and they are a vast improvement from the recent past. Admittedly, they are tedious and expensive and don't work 100 percent of the time, but think back to how different things were just a couple of decades ago. Autism was "known" to be a devastating disorder with no hope for anything other than a life of complete dependency, and today's early interventions are producing benefits that used to be mere fantasies. So, this one parent's comment makes it abundantly clear that there is a lot to cover in this monthly column.
There are some "big-picture" characteristics of science that merit review before jumping into the details of specific topics. This will entail a discussion of a key, defining feature of science: its unique way of going about its business. This involves inquiry, experimentation with the goal of discovering something we don't already know, and critical analysis. Researchers measure and describe, as objectively as possible, whatever it is they find of interest, and they formulate explanations of those observations. These explanations provide a basis for predicting what will happen in the future, and it must be possible to determine if these explanations are or are not correct. Further, descriptions of work have to include all the information needed to allow others to see for themselves if predicted things really do happen.
Nobody's word or work is taken on faith. This full transparency (at least outside of the for-profit and defense sectors) means that other people will be trying to replicate any new findings, especially things that generate major excitement. Often that proves to be easy (lots of things are easy, once someone shows you how it's done), and the new finding becomes the basis for the next steps in research or an application to improve practice. On the other hand, if replication doesn't work out, then explanations are sought and the reasons for inconsistency or misinterpretation are eventually found, avoiding excessive misdirected efforts.
That seems like enough foundation for now, so let's see how these principals translate to the specific example of fragile X syndrome, a condition that causes intellectual impairment and increases risk for many features of autism. Physical symptoms exist as well, and it affects one in every 3,600 boys and approximately one in every 5,000 girls who are usually less severely affected. We've known for a very long time that boys are more likely to have an intellectual impairment than girls; therefore, it was suspected that something genetic was involved. As you probably know, all genetic information is contained in the chromosomes that are present in every living cell. For humans, these are arranged in 23 pairs, with one member of each pair coming from the mother and the other from the father. These chromosomes are numbered from 1 to 22, going from largest to smallest in appearance under the microscope, plus a pair of sex chromosomes labeled X and Y. Males have one X and one Y, while females have two Xs, and for males, this has consequences. (Some conditions are associated with having a different number of chromosomes, the most well known being Down syndrome, but that will be a topic for a future column.)
Each chromosome has genes arranged along its length, and these genes essentially provide the recipes the cells in our bodies use to make proteins as they are needed to ensure healthy functioning. Occasionally, one of these genes becomes defective due to a mutation. Sometimes a single defective gene disrupts normal function, but in most cases, both copies of the gene in question have to be involved to cause problems. In these latter cases, people with just one defective gene will be unaffected because they have that second normal gene to provide the right protein. If a husband and wife each happen to have a matching defective gene (they are "carriers"), then their children face several possibilities. On average, one in every four will inherit both normal genes, and, of course, these children will be unaffected, as will their children and grandchildren. Two in every four will inherit one defective and one normal gene, and like their parents, they will be unaffected carriers. Finally, one in every four children will inherit both defective genes, and that can lead to problems. Depending upon the specific genes in question, these can be relatively mild, as in the partial absence of skin pigment in some forms of albinism, or catastrophic, as in Tay-Sachs disease.
Now, if a defective gene happens to be located on the X chromosome, females will have a second normal X to help compensate, but males, with their single X, will be out of luck. Because fragile X syndrome is caused by mutation of a gene on the X chromosome, more boys should be affected than girls, and that is indeed the case. However, another finding was totally unexpected. Classic X-linked patterns of inheritance predict that only females can be carriers of fragile X syndrome, but analyses of entire family histories (called pedigrees) showed that there were apparently unaffected male carriers, also. This generated a lot of double-checking, but the finding was replicated until everybody was satisfied that it was real. Alternative models of inheritance needed to be developed, and eventually, the family pedigrees for fragile X syndrome were explained. We now understand that it is one of a group of conditions called trinucleotide repeat disorders, and a very brief description of the chemical structure of chromosomes will help to explain how these disorders arise.
Each chromosome is a single giant molecule of deoxyribonucleic acid (DNA). It consists of sequences of millions of units, called bases, and these are always one of four compounds: adenine (A), thymine (T), cytosine (C) or guanine (G). Genes on the various chromosomes are composed of these bases arranged in very specific orderings (with flanking regions that mark their end points and regulate their activity), and mutations are, literally, changes in these orderings. It turns out that sequences of these bases can sometimes include a series of triplets that are repeated many times, and in the gene affected in fragile X syndrome (now identified and called the FMR1 gene) that happens to be CGG,CGG,CGG,CGG,CGG etc.. Normally, there will be less than 50--55 CGG repeats present, but when this expands to over 200-230, it causes fragile X syndrome. Men who are carriers will have a "premutation" consisting of between 50 and 200 repeats, and this explains why they are not themselves affected. However, when premutations are inherited by their daughters, instability in the series of CGGs can result in the occurrence of a full mutation during egg production.
This example nicely illustrates how observations incompatible with current understandings led to the discovery of a whole new family of conditions (that includes Huntington disease as well as fragile X syndrome). In a relatively short time, the gene involved was discovered along with the protein that gene encodes, and diagnostic tests are now available to identify affected individuals and carriers. While there are no direct treatments yet, promising avenues are under investigation.
Thus, research targeting fragile X syndrome has produced some remarkable successes, but it remains a work in progress. It is instructive to recognize that it has been some 60 years since Martin and Bell described some of the clinical features of a typical fragile X family without any real inkling of the underlying cause, and it was another 20+ years before Lubs made a breakthrough by noticing the unusual appearance of the X chromosome that characterizes the condition. Today, we know so much more about fragile X syndrome, but that's both good and bad news. It has taken researchers half a century to get this far, and we're still looking for effective treatments.
Because science is about the discovery of new knowledge, major advances are less predictable than we would like. The substantial improvements in practice these advances produce typically occur over decades rather than years, and while it is easy to recognize dramatic changes from that long-term perspective, you will rarely see much happening from month to month, and probably not even from year to year. History has shown, though, that while you can't predict when something important will be discovered, or, for that matter, exactly who will wind up doing the discovering, you can know that enormous payoffs are on the way.
In the field of intellectual and developmental disabilities especially, success depends upon partnerships. These include collaborations among scientists trained in distinct areas. It also includes the National Institute of Child Health and Human Development (NICHD), the part of the National Institutes of Health (NIH) most involved in supporting research focused on children's health, that has, in fact, established Fragile X Research Centers to encourage this type of team approach to address the complexities of this particular disorder. Additionally, other Centers are focused on intellectual and developmental disabilities, learning disabilities, and autism. However, our partnerships also must include educators, clinicians, and, certainly, people with intellectual and developmental disabilities and their families. Not long ago, Hillary Rodham Clinton famously wrote that it takes a village to raise a child, noting that we all have a role to play in nurturing the next generation. Similarly, it will take the efforts of us all to advance our understanding of intellectual and developmental disabilities, and that expanded knowledge will guarantee a brighter future for our children and grandchildren. Returning to the parent's quotation from The Baltimore Sun mentioned at the outset of this article, it just doesn't seem necessary to add that "but" to "research may help."
Wayne Silverman, Ph.D., has investigated the science of developmental disabilities for more than 30 years and currently serves as Director of Intellectual Disabilities Research at the Kennedy Krieger Institute in Baltimore, Maryland. An international leader in the fields of research, treatment, and education for disorders and injuries of the brain and spinal cord, Kennedy Krieger provides a wide range of services to over 12,000 children each year with developmental concerns from mild to severe. For more information, visit www.kennedykrieger.org.
By Wayne Silverman, Ph.D., Director of Intellectual Disabilities Research, Kennedy Krieger Institute
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|Publication:||The Exceptional Parent|
|Date:||May 1, 2007|
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