THE UNIVERSITY OF CHICAGO
Department of Psychiatry
5841 S. Maryland Avenue
Chicago, IL 60637
Child and Adolescent Psychiatry
Laboratory of Developmental Neuroscience
April 3, 2000
Honorable Dan Burton
Committee on Government Reform
House of Representatives
Congress of the United States
2157 Rayburn House Office Building
Washington, DC 20515-6143
Dear Representative Burton and Colleagues:
Thank you for the opportunity to testify on the topic of autism. I am speaking as the brother of the late Kenneth Wade Cook who had many of the problems of children and adults with autism, as a physician who cares for many patients with autism, and as a researcher trying to increase our knowledge of the causes of autism and to increase our ability to treat this devastating disorder.
I recall being an 8 year-old boy with a 2 year-old brother that my family had just realized was not developing normally. I remember the pain of my parents vividly. I further recall that we went to a meeting where, to my recollection, we were told that "patterning," a special diet, rebreathing through a mask, and related methods still practiced today would cure his problems. I remember our family being skeptical for part of the meeting. By the end of the meeting, we and the other families in the group were sold on this treatment because it was too painful to accept what we knew was happening. If there is anything I have not forgotten, it is that hope is something essential in working with children with severe challenges. I am thankful to those who were interested enough in children to spend so much time with my brother and my family. They knew that providing us the tools to work to teach my brother the basics of communication and motor skills was helpful and I suspect that many of them were practicing this method for the same reason we were. They had to try.
I could complain about the 5 AM mornings in which it was physically exhausting to perform the patterning, but I'm sure it was at least good training for the schedule of a physician-scientist and provided a shared task for our family. However, I'm not pleased that there wasn't more time spent teaching me to play with my brother instead of trying to teach him to read, when it wasn't close to being an appropriate next step. Our family learned to accept and love my brother deeply. I am thankful that children today more opportunity for education due to Congressional legislation. Excellent community support was vital to my family during my brothers last years in St. Louis. Mostly I miss him since his death at the age of 29. His death remains as unexplained as his original problem, although the two are likely to be related. It reminds me that there is mortality as well as morbidity associated with autism and related developmental disorders.
We have an extremely long way to go to provide full access to adequate care for children, adolescents, and adults with autism. It is very difficult to confront attitudes as a physician that I only suspected as a child. Insurance companies, state agencies, school administrators, and other physicians continually turn away from caring for people with autism. Much more attention is given to paperwork than provision of care and services. This is not the main purpose of our meeting today, but I can not speak without mentioning this. Although many of the most severe problems are emotional and behavioral, insurance companies discriminate against the best treatments by the most qualified providers, with the result often being time lost from work for parents, depression in parents, and most importantly, suffering would otherwise be treatable.
The needs of the patients and problems in the systems of care and education have seemed overwhelming since I started my practice in the mid 1980s, so the thought of an increase in the prevalence of autism is probably something I wouldn't want to confront. However, comment on changes in systems that are largely responsible for the apparent increase is appropriate. An increase in autism in Illinois schools has been cited as evidence a rise in autism prevalence rates, but autism is still underestimated in Illinois schools. The increase is based on the introduction of autism as a possible educational classification in autism. In addition to many educational systems not recognizing autism, many diagnosticians didnt recognize it in the past. Autism spectrum disorders are only beginning to be accurately estimated. Based upon its widespread ethnic distribution, it has most likely been challenging people with autism and their families for thousands of years, but it has taken us this long to recognize what it is. Thus, the committee's ongoing work is important and a sense of urgency is necessary to catch up for lost time.
This brings to mind the medical saying, "first do no harm." One harm worse than doing nothing was blaming mothers because of their physical and emotional closeness to their children. Not only were individuals hurt by blaming mothers for their child's autism, but we probably lost a couple of decades following an impression of causation rather than focusing on the same science that was leading to improved treatments in cancer and heart disease. Without evidence to support a relationship between vaccinations and autism, we need to be careful about wasting precious resources on another case of guilt by association. Mothers were guilty because they were physically close to children with autism. Now vaccinations are being blamed largely because they are given at the same time as the regressions that occur for a substantial minority of children with autism (between the first and second birthday). Certainly, GI findings that have not been demonstrated to be specific for autism do not provide support for MMR vaccinations as a cause of autism. Data may be provided today which are credible in support of a connection, but the data to date do not support the hypothesis of MMR vaccination caused autism.
It has been a privilege to be involved in the development of new treatments for children with autism. Lost in the media's overfocusing on "miracle" cures over the more than three-and-a-half decades I have been involved, are small changes in our available treatments. Although limited to improving aggressive behavior, anxiety, and depression, medications that potently inhibit the reuptake of serotonin into nerve terminals (SSRIs)(e.g. Prozac, Luvox, Paxil, Zoloft, Celexa) have provided the first medication class that reduces the core symptoms of repetitive behavior leading to distress for many people with autism. Of course, it isn't enough, but it demonstrates that improvements through development of effective medications are possible. As far as research challenges and needs are concerned, pharmacological treatment research needs to be enhanced so that we have better data about whether each of these drugs works in autism, for which symptoms, at what ages, and for which patients. In addition, it would be extremely helpful to know which patients will worsen on small doses and what treatments to provide such patients.
As many know, not all of our attempts to improve treatment have been successful. A relatively classic story is that of fenfluramine, originally thought to raise I.Q. and reduce symptoms of autism. After considerable work, fenfluramine was found to be a good placebo. Although we were hopeful that secretin would be serendipitous powerful treatment, at least two carefully controlled trials have shown it to be similar in effect to fenfluramine in providing a good placebo effect. Further studies are ongoing to make sure a positive effect is not present under certain circumstances, but it may be about to end up as part of the long history of good, honest attempts to hit a home run in autism treatment that struck out. There is no reason not to try, except that we have to be careful about the risks to the children and the costs to the families if we overly promote treatments without evidence from controlled trials.
There is a problem when thousands of doses of secretin from pigs could be administered to children with claims of benefit while clinical trials to study safety and efficacy were being delayed by federal policies against expediting research review for secretin clinical trials. This ironic situation allowed the supply of secretin to be depleted, thus delaying initiation and completion of our multi-site trial.
Having several hats as brother, physician and scientist can be very painful. I recall my anger as a child when investigators found that patterning wasn't effective. How could they do such a thing and how could I now be in their shoes in contributing to data about the lack of efficacy of secretin? All I have to say is that I shed a tear when the data were analyzed for secretin, much as I shed many tears when I came to the realization that "patterning" was not going to let me know my brother without his severe problems.
I suppose it is obvious why so much of my time is devoted to research reaching down to basic mechanisms. On the one hand, I am desperate to improve the situation for my patients, many of whom are reminders of my brother. On the other hand, for some of my patients I have seen medical treatments provide relief I didn't think possible before our first use of Prozac in autism shortly after its release in 1988. By the way, there is no reason to have lengthy discussions about who tried it first, since I know I had parents discuss it around the same time or before professionals were considering it.
The riskiest thing for a physician-scientist to do is translational research, especially when it is from the bedside to the bench. Basic science has a much more appealing longitudinal logic. Clinical science has relevance. As much as both are pioneering, translational research often requires almost autistic perseverance. However, eventually the bridge has to be crossed.
Our laboratory has worked on neurochemisty, neuroimmunology, neuroendocrinology, neuroimaging, and neurogenetics of autism. The reason for our current focus on genetics is that the data, not impressions, show it to be the most powerful influence in the etiology of autism. It is not the only influence and it is not a simple, single gene disorder. However, it is a rare event in my lifetime to realize that suddenly that molecular genetic study of autism spectrum disorders provides one of the best scientific opportunities in medicine. Of course, this would not be possible without the considerable basic science advances and applied science advances ranging from sequencing of the human genome, to development of rapid methods of genotyping, to the development of powerful statistical approaches. It is new for established researchers in other fields to be drawn into autism and related disorders because of the scientific opportunity.
It is unlikely that gene therapy will be the result of genetic research in autism. It is also unlikely that genetics of autism will explain a relatively recent increase in measured autism prevalence. The point of genetic research is to develop treatments that will correct the missing or abnormal signals for a small set of nerve cells in the amygdala, hippocampus, and cerebellum so that the nerve cells mature. If we knew the signals, what has long been a too complicated puzzle of autism will become simple enough for us to understand. Although the simple idea is to provide gene therapy, oral delivery of more traditional small molecules is likely to be more feasible and preferable.
Even more important has been the emerging voice of families of children with autism. I can not begin to list and thank the parents, brothers, sisters, aunts, uncles, and grandparents who are not only taking on the extraordinary challenge of caring for their family members, but who are speaking for people with autism who because of their communication problems are not as able to speak for themselves as we wish they could.
The need to learn more about autism is self-apparent and the scientific opportunities are abundant. The challenges are in learning about something as complicated as the developing brain and development of some of the most uniquely human qualities of higher level communication and social behavior.
Two recent developments in the broader field of developmental disorders show that complex situations may be better understood through molecular genetics. The first is the finding of the gene for FRAXA mental retardation. This is very relevant to autism since a substantial proportion of children with FRAXA have autism spectrum disorders. Although one wishes knowledge of a gene will lead to new treatment sooner, the results of a decade of research to understand the mechanism of this disorder is leading to an almost exponential growth in understanding of complex interactions of molecules in the process of learning. Another development is the recent cloning of the gene for Rett syndrome. This is actually one of the most severe autism spectrum disorders. It is notable that it is caused by a single gene, MECP2, but that it has a course of regression in social behavior and communication between the first and second birthday. Knowing the gene has led to a breakthrough in the systematic approach to investigation of Rett syndrome in terms of how it affects the development of the brain. Study of both FRAXA and Rett syndrome will lead to basic knowledge about how autism and related conditions develop.
Although we don't know the specific genes involved, several groups have been finding evidence that an extra part of chromosome 15 leads to a high risk for autism, especially if inherited from the mother. Although responsible for less than 4% of cases of autism, these 15q11-q13 duplications, like Rett syndrome and FRAXA, are likely to help us understand autism more generally. Several laboratories, including our own, are searching for a gene in this region. As an example of our concern about not wanting to waste precious resources, the probability of there not being a gene in this region is about 5 in 100,000, but we're not sure yet. Of course, we'll have to get beyond regions with likely autism genes to actually finding the specific genetic changes and then getting on with the work of using the information to improve treatment. (More information about molecular genetic studies and autism is available at our web site at: http://psychiatry.uchicago.edu/ldn ).
It's a good thing there are people doing good clinical research and trying to improve educational and other interventions while we are working out the fundamental causes. It's also good that people are asking questions about prevention and even taking shots to improve medication delivery, either trying to hit for average with medications like Prozac, or swinging for the fences with an occasional secretin trial. However, it's important not to think we have more of an effect than we can back with controlled data. History teaches us that zeal without skepticism may have negative consequences (e.g. false accusation of fathers of children with autism who underwent facilitated communication).
The challenges of autism research are obvious. In terms of needs, I mostly want to thank Congress for the appropriation of increased funds for biomedical research. All of the pertinent NIH institutes are now engaged in active support of autism research. A simple statement of needs is that there are many important and feasible questions about autism not able to be asked with current resources. There are not enough well-trained researchers in the field, partly because the area was almost totally unfunded five short years ago. Most importantly, questions that are being asked well and efficiently, such as in the area of molecular genetics, are not being answered at an optimal rate given current funding in the area. Again, this is not meant as a criticism, but as a statement of scientific opportunity.
Thank you for the opportunity to communicate.
Edwin H. Cook, Jr., M.D.
Associate Professor of Psychiatry and Pediatrics