This is the first in an occasional series of interviews with key figures in the science and autism fields.
At a recent NIH Interagency Autism Coordinating Committee (IACC) meeting, the member of the committee representing the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) was the only federal member to abstain from voting to reverse a previously voted-on decision to approve objectives relating to vaccine safety research as part of its deliberations for the Strategic Plan for Autism Research. Autism Speaks' Chief Science Officer, Geraldine Dawson, Ph.D., spoke with Duane Alexander, M.D., Director of the NICHD to seek clarification on their position regarding the research on the role of environmental factors in autism.
Dr. Geraldine Dawson: Dr. Alexander, can you provide us with some background regarding what the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is and its mission?
Dr. Duane Alexander: The mission of the NICHD is to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, that all children reach adulthood as free of disease and disability as possible and able to achieve their full potential for healthy and productive lives, and that the health, productivity, independence, and well-being of all people is fostered through optimal rehabilitation. As one of the 27 Institutes and Centers of the National Institutes of Health, our fundamental precept is that many adult characteristics, such as overall health and behavior, have their origins during the formative childhood years of life. Therefore, we focus on developmental processes, from before birth to adulthood, rather than on a specific disease or illness. NICHD believes that the combined efforts of biomedical, biobehavioral, and social science research can provide a better understanding of human development, and a greater opportunity for finding prevention and treatment methods for many conditions.
Dr. Dawson: What aspects of autism spectrum disorders (ASD) research are either being funded or encouraged by the NICHD?
Dr. Alexander: The NICHD is one of the five NIH Institutes sponsoring the Autism Centers of Excellence (ACE). The ACE program supports studies covering a range of autism research, such as early identification and intervention in infants at risk for ASD, early brain abnormality and functioning, potential environmental risk factors and biomarkers, intensive early behavioral intervention, long term effects of early intervention, multidisciplinary studies of insistence on sameness, and possible new medication treatments.
Additionally, the NICHD supports a variety of investigator-initiated research projects in areas such as identifying early risk markers, epigenetic pathways of gene regulation, potential metabolic phenotypes, postmortem tissue study, longitudinal familial studies, treatment studies using psychosocial or functional analysis approaches, risk factors for obesity, community-based programs for youth, a computer-based course of behavior intervention for parents, and validation of a screening instrument for early detection.
Also, the NICHD has funded a Brain and Tissue Bank since 1991 to provide a research resource to increase knowledge of the etiology and pathogenesis of neurodevelopmental disorders. The bank serves the critical role of collecting, preserving, and distributing human tissues to qualified scientific investigators who are dedicated to the improved understanding, care and treatment of people with neurodevelopmental disorders, including ASD. We recently released a Request for Information to notify the community that a Request for Proposals for continuation of the bank will be published and to provide all interested parties an opportunity to comment. We received close to 100 comments, mostly from the investigators who had received tissues from the bank. The comments are very helpful and unanimously affirm the value and contribution of the bank. We plan to award the contract to continue and expand the bank, with an increased emphasis on ASD, in 2009.
Dr. Dawson: What is the mission of NICHD with respect to understanding the etiology of developmental disorders, including ASD? Does this include the role of environmental factors?
Dr. Alexander: The NICHD studies normal developmental processes as well as things that can go wrong and result in developmental disorders. In the course of this research, our scientists study the inherent processes that direct the development of a fertilized egg into a multicellular organism and eventually into a fully functioning adult individual. We study this in a wide range of laboratory animal models as well as humans. We look at genetic abnormalities as well as exposures prenatally and postnatally to environmental chemicals or physical agents, medications and vaccines, foods and additives, illnesses, and behavioral and cognitive influences, all of which combine to produce health/illness, and function/dysfunction, in children and eventually in adults. These developmental variations range from physical abnormalities (e.g., birth defects) to chromosome abnormalities and genetic disorders (e.g., Down syndrome) to cognitive and intellectual disabilities and communication disorders of known or unknown cause. ASDs fall into this latter group. In addition to looking for causes of these disorders, we also look at diagnosis, treatment, cure, amelioration, and prevention for all of these developmental disabilities.
Study of environmental factors as causes or ameliorations of developmental disorders is a major component of our research program. Part of this research goes beyond environmental factors acting alone to look at gene-environment factor interactions. In some cases virtually everyone has a genetic make-up that renders them susceptible to adverse consequences of a given environmental exposure, with only a few protected. In other instances a given environmental exposure may have an adverse effect only on a relatively few people who have a variant genetic constitution that leaves them susceptible to adverse consequences from an environmental exposure; these are difficult to detect, especially if only a few people have this genetic variant that makes them susceptible. In this instance, large numbers of individuals need to be studied to find enough people with the rare variant. This situation is where the National Children's Study (NCS) has a potentially valuable role to play. Of the 100,000 children being recruited, we expect 600 to 700 will be diagnosed with ASD by 3 years of age. We will be able to study the genetic constitution of the children with autism in relation to many environmental exposures (illness, home chemicals, medications, vaccines, and many others) and compare them to a control group in the sample without ASD on this whole range of exposures. If there are genetic variations linked to autism related to any of these exposures, this study should identify them if they are not too rare.
Dr. Dawson: What are examples of legitimate scientific questions that remain to be considered with respect to the role of vaccines as a cause or risk factor for ASD? Why is it important to address those questions?
Dr. Alexander: One question that still remains to be addressed in a study of adequate size and precision is the one described in the preceding response, which is whether there is a subgroup in the population that, on a genetic basis, is more susceptible to some vaccine characteristic or component than most of the population, and may develop an ASD in response to something about vaccination. We know that genetic variations exist that cause adverse reactions to specific foods, medications, or anesthetic agents. It is legitimate to ask whether a similar situation may exist for vaccines. No clear evidence yet exists to implicate a specific relationship, but questions persist about whether there may be subpopulations unable to remove mercury from the body as fast as others, some adverse or cross-reacting response to a vaccine component, a mitochondrial disorder increasing the adverse response to vaccine-associated fever, or other as-yet-unknown responses.
The history of vaccine use holds numerous examples of risk reductions made when research demonstrated vaccine-associated adverse events, even if they were uncommon or only hypothetical. These include stopping smallpox vaccination not long after the disease was eliminated, switching from live polio vaccine to the killed vaccine, shifting to purified antigen rather than whole organism pertussis vaccine, and many others, including removal of Thimerosal as a preservative from children's vaccines. All these changes came from continued research and the desire to maximize public safety even when the adverse events were rare (polio) or hypothetical (Thimerosal). There are still legitimate questions to ask about possible vaccine-associated events, and such questions need to be pursued in the interest of both public safety and maintaining public trust.
Dr. Dawson: What sort of findings from vaccine-related studies might be useful in terms of advancing prevention, diagnosis and treatment for ASD?
Dr. Alexander: Both vaccine- and environment-related studies hold out the possibility of breaking down the group of ASDs into different subgroups based on cause or response to different treatment approaches. Diagnosis can be used not just for autism overall but for the subtype within the spectrum. Knowing causes can permit research to develop different prevention/intervention/ treatment approaches that could personalize care and markedly improve outcomes.
Dr. Dawson: What do you believe is NICHD's role in pursuing studies that address such questions?
Dr. Alexander: The NICHD, in common with the other Institutes doing research on autism, shares an urgent interest in stimulating creative new approaches and testing of a wide variety of hypotheses related to causes and treatments of ASD. The emphasis from NICHD will be largely on factors that interfere with typical development to produce ASD, and careful evaluation of medical, behavioral or educational interventions to improve function.
Dr. Dawson: How could Autism Speaks and NICHD work collaboratively to address parents' concerns about the potential role of vaccines or other environmental agents as a cause or risk factor for ASD?
Dr. Alexander: A collaborative relationship/partnership between Autism Speaks and NICHD is in the best interests of both organizations. Like any research organization, NICHD and the scientists it supports depend on the willingness of parents, children, and adults to agree to participate in research on autism when asked. Encouragement and reassurance from Autism Speaks could facilitate that participation enormously. We see that already in our joint collaboration in the Baby Sibs Project. Another is assistance with the Brain and Tissue Bank, where Autism Speaks can help encourage donations of tissue from individuals with ASD as well as other neurodevelopmental disorders, and help publicize the availability of this research resource and its importance. With regard to vaccines or other environmental agents as risk factors for ASD, it is important that there be agreement on the message that no clear causative link has yet been established, although research continues on the question just as it does for other questions related to vaccines.
Dr. Dawson: As the Director of the NICHD, are there any lessons you have learned about the research process that may be of comfort to parents who have concerns and are anxious for results for their children?
Dr. Alexander: The research process at its best is open and constantly questioning. It even reevaluates things that have been accepted for a long time, and is honest enough to be self-correcting when new information develops. What is important is that the scientific inquiry moves ahead unfettered but free of conflict of interest so that the public can have confidence in the results. When there is evidence that research may not be free of bias, it is the role of the research community and the public to raise questions and concerns, assure that corrective measures are taken to be sure that results are valid and untainted, and provide assurance to the public that their trust is earned and deserved.