IOM to Hold Workshop on Autism and the Environment
On April 18 and 19, 2007, the Institute of Medicine, or IOM, will host a workshop in Washington, D.C. entitled: “Autism and the Environment: Challenges and Opportunities for Research.” This workshop, organized in response to a request from the U.S. Secretary of Health and Human Services, will be hosted in collaboration with the IOM’s Roundtable on Environmental Health Sciences, Research, and Medicine.
The workshop will feature presentations and discussions on strategies for research focusing on the potential relationship between autism and an array of environmental exposures. This will be a stand-alone workshop and is not part of an ongoing study by the IOM.
A publicly available summary of the presentations and discussions made during the workshop will be prepared by a rapporteur and will reflect what transpired at the workshop. It will be prepared in accordance with institutional policy and procedures and published by the National Academies Press. All views presented in the report will be those of workshop participants. The report will not contain findings or recommendations by the planning committee.
To see the agenda for the workshop, click here (PDF). Click here to register for the workshop.
This PDF is available at http://nap.edu/11946
Autism and the Environment: Challenges and Opportunities for Research: Workshop Proceedings (2008)
358 pages | 6 x 9 | PAPERBACK
ISBN 978-0-309-10881-2 | DOI 10.17226/11946
Forum on Neuroscience and Nervous System Disorders; Board on Health Sciences Policy; Institute of Medicine
Institute of Medicine 2008. Autism and the Environment: Challenges and Opportunities for Research: Workshop Proceedings. Washington, DC: The National Academies Press. https://doi.org/10.17226/11946.
Autism and the Environment: Challenges and Opportunities for Research
Board on Health Sciences Policy
Institute of Medicine
of the National Academies
WORKSHOP ON AUTISM AND THE ENVIRONMENT CHALLENGES AND OPPORTUNITIES FOR RESEARCH PLANNING COMMITTEE*
ALAN LESHNER (Chair), American Association for the Advancement of Science, Washington, D.C.
DUANE ALEXANDER, National Institute of Child Health and Human Development, Bethesda, Maryland
ERIC FOMBONNE, McGill University, Montreal, Canada
STEVEN HYMAN, Harvard University, Cambridge, Massachusetts
JUDY ILLES, University of British Columbia, Vancouver, Canada
DAVID SCHWARTZ, National Institute of Environmental Health
Sciences, Triangle Park, North Carolina
SUSAN SWEDO, National Institute of Mental Health, Bethesda,
CHRISTIAN ZIMMERMAN, Neuroscience Associates, Boise, Idaho
BRUCE ALTEVOGT, Project Director
SARAH HANSON, Senior Program Associate AFRAH ALI, Senior Project Assistant
LORA TAYLOR, Senior Project Assistant
FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS
ALAN LESHNER (Chair), American Association for the Advancement of Science, Washington, D.C.
HUDA AKIL, University of Michigan, Ann Arbor
MARC BARLOW, GE Healthcare, Inc., Buck, United Kingdom
DANIEL BURCH, CeNeRx Biopharma, Research Triangle Park, North
DENNIS CHOI, Emory University, Atlanta, Georgia
TIMOTHY COETZEE, National Multiple Sclerosis Society, New
DAVID COHEN, Columbia University, Society for Neuroscience
representative, New York
RICHARD FRANK, GE Healthcare, Inc., Princeton, New Jersey
RICHARD HODES, National Institute on Aging, Bethesda, Maryland
STEVEN HYMAN, Harvard University, Cambridge, Massachusetts
JUDY ILLES, University of British Columbia, Vancouver, Canada
STORY LANDIS, National Institute of Neurological Disorders and
Stroke, Bethesda, Maryland
TING-KAI LI, National Institute on Alcohol Abuse and Alcoholism,
MICHAL OBERDORFER, NIH Neuroscience Blueprint, Bethesda,
KATHIE OLSEN, National Science Foundation, Arlington, Virginia
ATUL PANDE, GlaxoSmithKline, Inc., Research Triangle Park, North
STEVEN PAUL, Eli Lilly and Company, Indianapolis, Indiana
WILLIAM POTTER, Merck Research Laboratories, Inc., North Wales,
PAUL SIEVING, National Eye Institute, Bethesda, Maryland
RAE SILVER, Columbia University, New York, New York
WILLIAM THIES, Alzheimer’s Association, Chicago, Illinois
ROY TWYMAN, Johnson and Johnson Pharmaceutical Research and
Development, Inc., Titusville, New Jersey
NORA VOLKOW, National Institute on Drug Abuse, Bethesda,
FRANK YOCCA, AstraZeneca Pharmaceuticals, Wilmington, Delaware
CHRISTIAN ZIMMERMAN, Neuroscience Associates, Boise, Idaho
STEVIN ZORN, Pfizer Global Research and Development, Ann Arbor,
BRUCE ALTEVOGT, Project Director
SARAH HANSON, Senior Program Associate
LORA TAYLOR, Senior Project Assistant
IOM Anniversary Fellow
LISA BARCELLOS, University of California, Berkeley
Independent Report Reviewers
These workshop proceedings have been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Coun- cil’s Report Review Committee.
The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published workshop proceedings as sound as possible and to ensure that the proceedings meet institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.
We wish to thank the following individuals for their review of these proceedings:
Lisa Croen, Kaiser Permanente Northern California, Oakland, CA
Gary W. Goldstein, Kennedy Krieger Institute and Johns Hopkins
University School of Medicine and School of Hygiene and Public
Health, Baltimore, MD
Carlos A. Pardo-Villamizar, Johns Hopkins University School of
Medicine, Baltimore, MD
Lyn Redwood, National Autism Association, Nixa, MO
Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the final draft of the workshop proceedings before their release.
The review of these proceedings was overseen by Dr. Floyd E. Bloom, The Scripps Research Institute, Professor Emeritus. Appointed by the National Re- search Council, he was responsible for making certain that an independ- ent examination of these proceedings was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of these workshop pro- ceedings rests entirely with the institution.
Autism spectrum disorders (ASD) constitute a major public health problem, affecting one in every 150 children and their families. Unfortunately, there is little understanding of the causes of ASD, and, despite their broad societal impact, many people believe that the overall research program for autism is incomplete, particularly as it relates to the role of environmental factors. One reason for that may well be that there have been relatively few occasions that have brought together all the key stakeholders⎯scientists, clinicians, parents of autistic children, patient advocates, and major sponsors of autism-related research⎯to engage in a full discussion of autism causality and scientific research priorities.
In response to these challenges, the U.S. Secretary of Health and Human Services (HHS) asked that the Institute of Medicine’s (IOM) Forum on Neuroscience and Nervous System Disorders (the Forum) host a workshop that would bring together the key public and private stakeholders to discuss potential ways to improve the understanding of the ways that environmental factors may affect ASD. The Forum provided an ideal setting to facilitate this request, since it is designed to provide its members⎯representatives from government, industry, academia, and patient advocacy organizations⎯with a venue for openly exchanging information and discussing critical scientific and policy issues related to nervous system functioning.
Thus, on April 18 and 19, 2007, the Forum hosted a workshop, “Autism and the Environment: Challenges and Opportunities for Research” organized by an ad hoc planning committee. This workshop and its development epitomized what is called by many people “public engagement” by and with the scientific community. Members of the broader public were involved in every aspect of the workshop.
The planning committee included not only academic leaders and top government scientists, including three institute directors from the National Institutes of Health, but also four members of the autism advocacy community, three of whom are parents of autistic children. Many of the workshop participants and invited speakers were members of the advocacy community.
The result was an activity that fully explored from all angles the range of issues surrounding environmental factors and ASD, and resulted in an array of new ideas for research projects and programs. There is no question that this workshop and its product, this volume, were greatly enriched by this broad participation.
As chair of the Forum and the workshop planning committee, I want to acknowledge the hard work and dedication displayed by every member of the planning committee, Forum, and workshop participants. I would also like to thank the leadership of the IOM and HHS for providing the Forum with the opportunity to host this very important event.
This workshop was a huge success, both in helping to identify potential scientific opportunities and in demonstrating the utility of moving from a strategy of public education about science toward fuller public engagement, with science where both sides—scientists and members of the public—listened and learned from each other.
Alan Leshner, Chair Workshop Planning Committee Forum on Neuroscience and Nervous System Disorders
This workshop originated at the suggestion of advocates for patients with autism. In a meeting with the two of us, they broached the idea of engaging with the scientific community to help shape a new research agenda. The Institute of Medicine’s Forum on Neuroscience and Nervous System Disorders provided a neutral venue to bring together key stakeholders—scientists, parents of autistic children, other patient advocates, and major sponsors of autism-related research—specifically to identify scientific opportunities to further the understanding of environmental factors that may contribute to autism.
The presentations and discussions at the workshop identified a number of promising directions for research on the possible role of different environmental agents in the etiology of autism. Equally important was the opportunity for dialogue and the exchange of ideas that took place in an atmosphere of mutual respect and learning.
The payoff will be new directions for scientific research that are more fully informed by different perspectives on the reality of autism. From that, everyone stands to gain.
William F. Raub, Ph.D.
Science Advisor to the Secretary Department of Health and Human
Harvey V. Fineberg President Institute of Medicine
On April 18 and 19, 2007, the Institute of Medicine’s (IOM’s) Fo- rum on Neuroscience and Nervous System Disorders (the Forum), in re- sponse to a request from the U.S. Secretary of Health and Human Services, hosted a workshop called “Autism and the Environment: Chal- lenges and Opportunities for Research.” The goal of the workshop was to provide a venue to bring together scientists, members of the autism community, and the major sponsors of autism-related research to discuss the most promising scientific opportunities (Box I-1). The focus was on improving the understanding of the ways in which environmental factors such as chemicals, infectious agents, or physiological or psychological stress can affect the development of the brain. In addition, discussions addressed the infrastructure needs for pursuing the identified research opportunities—tools, technologies, and partnerships.
Chaired by Alan Leshner, chief executive officer of the American Association for the Advancement of Science and executive publisher of Science, the workshop represented a partnership among members of the autism advocacy community, scientists, and policy makers. The autism community was involved in the early discussions that led to the Secre- tary’s request for this workshop and subsequent sponsorship by the Fo- rum and supplemental sponsorship by the National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and the Centers for Disease Con- trol and Prevention. Four of the thirteen members of the workshop plan- ning committee⎯which was solely responsible for organizing the workshop, identifying topics, and choosing speakers⎯were members of the autism community. Furthermore, a number of members of the autism community were speakers, discussants, and workshop attendees, who reminded workshop participants about their sense of urgency in address- ing this serious health issue.
The publication of the workshop proceedings provides the Forum with a broader mechanism to inform not only the membership of the Fo- rum, but also other interested parties about what transpired at the work- shop. The workshop proceedings should not be confused with a National Academies consensus report. The proceedings do not contain findings or recommendations endorsed by the National Academies or the IOM, the Neuroscience Forum, or the Planning Committee. Opinions and state- ments included in the proceedings are solely those of the individual per- sons or participants at the workshop, and are not necessarily adopted, endorsed, or verified as accurate by the National Academies. What fol- lows in Chapter 2 are the proceedings of the meeting. Embedded in this are important lessons for the reader. Proceedings have been edited to eliminate redundancy and grammatical errors. In addition, workshop
Statement of Task
The Forum on Neuroscience and Nervous System Disorders was estab- lished by the IOM to provide an opportunity for continuing dialogue and dis- cussion among representatives of all relevant sectors about scientific and policy issues related to neuroscience and nervous system disorders.
In response to a request from the U.S. Secretary of Health and Human Services, the IOM Forum on Neuroscience and Nervous System Disorders, in collaboration with the IOM Roundtable on Environmental Health Sciences, Research, and Medicine, will host a workshop on Autism and the Environ- ment: Challenges and Opportunities for Research. The workshop will feature presentations and discussions on strategies for research focusing on the potential relationship between autism and an array of environmental expo- sures. An ad hoc planning committee will organize a public workshop that will focus on the following three questions:
• What are the most promising scientific opportunities for improving the understanding of potential environmental factors in autism?
• What scientific tools and technologies are available, what interdisci- plinary research approaches are needed, and what further infrastructure in- vestments will be necessary in the short and long term to be able to explore potential relationships between autism and environmental factors?
• What opportunities exist for public–private partnerships in the sup- port and conduct of the research?
PERSPECTIVES OF THE ADVOCACY COMMUNITY
Ms. Laura Bono
Ms. Bono: I am Laura Bono, founding board member and past chair of the National Autism Association. I have been asked to talk about the perspectives of the advocacy community. My time is short, so I will get right to the point of what many in the advocacy community want and think.
Declare autism a national health emergency under the Public Health
1Throughout Ms. Bono’s presentation, she may refer to slides that can be found online at http://www.iom.edu/?id=42455.
Act and treat it with urgency. Thirty-six thousand children, who should be living normal lives, will succumb to the diagnosis this year alone, affecting the trajectory of their lives and that of their parents forever. Autism is estimated to cost $3.2 million per child over a lifetime. Using the conservative estimate in the United States of 500,000 children means this epidemic will cost society close to $2 trillion.
Autism is both economically and emotionally devastating to the children and their families. Many families are on the brink of bankruptcy as they struggle to get insurance and the medical attention their children need. Murder/suicides of parents and their autistic children are on the rise.
I can’t discuss the perspectives of the advocacy community without citing the failings of the CDC. We believe the CDC has a performance and credibility problem. Their failure to declare an epidemic beginning with the 1989 birth cohort to study the time trend data or to examine the toxic and viral body burdens of children are why we are here today, over 15 years too late.
Julie Gerberding, director of the CDC, said recently in a February 8, 2007, CDC press release when they announced the 1-in-150 rate that she wasn’t sure if the rates are truly rising or if they are getting better at studies. “Our estimates are becoming better and more consistent, though we can’t tell yet if there is a true increase in ASDs [autism spectrum disorders] or if the changes are the result of our better studies.” This denial thwarts research into environmental factors and just isn’t acceptable. How many autistic individuals did you know when you were under the age of 21?
Since it is impossible to have a genetic epidemic, literally hundreds of millions of taxpayer dollars could have been appropriately directed to gene–environment and other susceptibility initiatives. Even more could have been spent on learning about the critical mechanisms involved in response to environmental neurotoxicants. We could have been focusing on what changed in the environment and when. We could have been investigating the environmental trigger for years and successfully helping suffering children. We urgently need to begin these initiatives now.
Many in the advocacy community are thankful because starting today, the government is finally going to make environmental research a priority, which will lead to better treatments and recovery. Because if autism is environmental, then it is treatable and preventable. It is no longer hopeless, or lifelong. It is hopeful, with a possible cure.
Recent clinical investigations have identified numerous comorbid disease states in children with autism. These include immune system abnormalities; inflammatory bowel disease; oxidative stress; disordered urine and serum chemistries, including elevated porphyrins; methylation disturbances; increased body burdens of metals, including mercury and lead; chronic viral, fungal, and bacterial infections; and microglial activation in the brain.
Studies must be initiated as soon as possible to increase the focus on the identification of these comorbid disease states. Parents and clinicians alike are reporting that when these problems are acknowledged and treated, it can result in marked improvement in children’s learning and behavior. Some children recover completely. This should be a wakeup call to us all.
The research paradigm needs to shift from autistic children are genetically defective to autistic children are sick and treatable. We should only grant money to genetic vulnerability and epidemiology studies that have a clear environmental hypothesis.
Research detoxification treatments; identify and validate biomarkers; study biomedical imbalances and treatments that are working; investigate the role of vaccines, including thimerosal, aluminum, and live viruses; research the role of the immune, gastrointestinal, and endocrine systems; and study the recovered children’s pre- and post-diagnosis medical files for clues.
Because it is the environment, we need to leave no stone unturned. There is a growing body of evidence implicating vaccine overload, mercury and aluminum from vaccines. Thousands of parents agree with this research. They watch their children regress after being vaccinated. Their autistic children have been diagnosed with heavy metal poisoning and immune system dysfunction and when treated, get better. Regardless of controversy surrounding any theory, we must research and produce successful antioxidant, methylation, and blood-brain barrier chelation treatments, as well as immune system, detoxification, and inflammation interventions.
I want to remind you that you are tasked with setting in motion the crucial environmental research that hundreds of thousands of children are silently waiting for now. The guiding principles should be to pursue research and treatments that will impact the most lives as quickly as possible and follow clues provided by treatments currently working in children. Such an agenda would best be served by a translational research protocol where clinicians who care for children with autism advise research into the most promising areas of intervention.
It is imperative that the working group proceed with urgency and follow the truth wherever it leads. Recovery happens every day to some, but our goal should be for all. We need to accelerate environmental research; demand even more money to address the problem; issue RFAs [request for applications] and have research proposals scored according to autism matrix goals; get answers; interpret them expediently; and continue to work the problem until we beat it.
We can do this. And our hope starts with you. Thank you.
Dr. Leshner: Thank you very much for your very powerful statement setting the stage. I would like to respond that we share the sense of urgency.
We share the sense that science and research will be the hope, and we of course share the goal of bringing the full power of science to bear on this public health problem of great urgency in tremendous proportion.
I hope that we will live up to the charge that you have just given us to look at the full array of environmental factors and the ways in which they can cause this disorder, affect its progression and then, of course, the variety of ways in which we can approach it.
I think that your point about the need to both inform clinical practice, but also to listen to clinical practice is a very important charge and I assure you that we are planning to take advantage of that and listen to that carefully.
So, I really tremendously appreciate the statement you have just made and I promise you that we will do our best to respond to it.
DEFINING AUTISM: BIOMARKERS AND OTHER RESEARCH TOOLS6
Dr. Martha Herbert
Dr. Herbert: I am happy to be here and I want to reiterate that our instructions have been to give a broad and general overview of what we
know and what we need to know. I want to comment that the issue of biomarkers is very pertinent for research and it is also very pertinent to those of us in clinical practice.
Why biomarkers in autism? Right now we have no biomarkers for diagnosis. Biomarkers would help in identifying pathophysiological mechanisms. Different biomarkers in different subgroups would be very helpful in multiple regards—identification of treatable features and prediction and tracking of treatment response.
Overall, we need to focus on biology and pathophysiology, and there are multiple levels of the biological hierarchy at which we need to measure, and we need to make a more concerted effort to coordinate measures across these levels of the biological hierarchy.
I would like to propose from the point of view of learning more about autism pathophysiology, more than the thimble that Pat Levitt showed in his slide show, that we consider taking a middle-out approach. Bottom up could be genes up and top down could be behavior down. We have been using in autism research a gene–brain behavior model and I think that what we are talking about here is, and everyone has been saying more than that, it is genetically influenced, not just genetically determined and it is a whole organism.
It is a systems model where pathogenesis is now gene–environment and epigenetics, and the biology needs to be broken out in details of molecular and cellular mechanisms, tissue and metabolism, altered connectivity and processing to get to the phenotype. It is the mechanisms that yield the phenotype. They may be caused or triggered by the pathogenesis, but it is the mechanisms that lead to what we call autism.
This involves again breaking out the biology in more detail and it is also at the level of pathophysiological mechanisms that will identify biomarkers and also that will identify biomedical treatment targets. We have been talking about involvement of more than the brain in autism and I think it is interesting to go back to the very first paper on autism by Leo Kanner. Kanner commented on somatic symptoms in almost all of his cases, and I have highlighted, in red, eating problems, tonsils, diarrhea and fever, more tonsils and adenoids, frequent vomiting, tonsils, tube feeding, avitaminosis, malnutrition, vomiting, feeding, bronchitis, colds, streptococcus, infection, impetigo.
One child who didn’t have any infections, which would be a question of overactive immune system, frequent hospitalizations because of feeding, colds and otitis media, hormonal problems. These were measurements across the levels of biological hierarchy.
This may provide fresh and unique opportunities to get a grip on
what is going on in autism.
Biomarker challenges in autism—critical issues are involved in terms of recognizing what is going on with the phenotypes so that we understand and measure things that are appropriate to the challenge. Many autistic children—not all, but many— have striking variations in their severities, striking good hair days, bad hair days and I will get back to that in a minute.
There are also chronic features, oxidative stress, inflammation, metabolic perturbations. These are ongoing problems. They raise the question of what environmental factors do on an ongoing basis and not just to perturb development. How do they affect neuronal functioning on an ongoing basis? Treatment responsiveness—I will get back to that in a minute. We are seeing some stable improvement following treatment, multisystem involvement. It has been mentioned and, again, whether this impacts the brain primarily parallel or downstream.
The heterogeneity is enormous and that has been mentioned, autisms, leaving the question open of where are the commonalities and final common pathways and how can that question influence our research agenda. Finally, some of the chronic pathophysiological features, such as the inflammation and the oxidative stress, appear nonspecific so that insofar as these are potentially treatment responsive, it is important to remember that what may be treatable may not be specific to autism.
A particular thing that is important to remember is to not characterize autism as a static encephalopathy. There is a paper in press in pediatrics by Andy Zimmerman and others reporting transient marked improvement with fever, children who will start making eye contact and talking during the course of a fever and then it goes away when the fever resolves or somewhat afterward. Some children will have spikes in function sometimes under conditions of stress or emotional stimulation or they will say something quite articulate when they are normally not verbal, demonstrating a neurological capability of performing at that level, but which for some reason is suppressed, which raises the question of whether treatment is removing inhibition or giving skills or both.
Transient improvement on antibiotics has been reported and I will get back to that. Improvement on allergy medications, variability in function related to food, allergen and toxic exposures and also treatment responsiveness, including published reports of loss of diagnosis with recovery documentation studies in process. Overall, this raises the
question that this is not just a disorder of neurological development. It is also a disorder of ongoing neuromodulator impact on brain function. This is a slide from Sidney Finegold at UCLA (University of California– Los Angeles) and the veteran’s hospital in Los Angeles.
He is one of the authors of the study that demonstrated that oral vancomycin could transiently improve symptoms in autism. This was a follow-up study showing nine variants of clostridial bacteria found only in autistic subjects and three variants of clostridia found only in controls.
These abnormal variants of bacteria can deplete vital nutrients, alter metabolism of xenobiotics, and affect immune function. All of this can cause or worsen metabolic stress. This suggests that in order to characterize subgroups and treat these children, we need to go beyond human metabolites and human genome to look at an extended metabolome.
This is a delectable slide of a child standing in his own diarrhea and I don’t think the day of autism is complete without looking at this, but the point here is that if you send a stool sample from this child to a clinical laboratory, it would probably come back negative.
The measures that allow these bacteria to be identified are done in research labs, and they are not available to help practicing physicians. This is something that needs to change, and this is not just a research question.
There are two reasons why measurements need to be coordinated across levels. It is not just that there is a great deal of variability among results of genetic studies. There is variability in behavior and now that we know that the genetics are not the only thing, we need to confront the variability at multiple levels. We don’t know where the commonality is, where it fans in and what is stable across different people with autism. Is it connectivity? Is it more at the tissue metabolism level? Do all children have inflammation in their brains or only some? We don’t know this. We need to get systematic about looking for this across all levels.
Also, toxins, infection/immune, genes, and other things function clinically in a vicious cycle. Genetic susceptibility sets up vulnerability to toxins, which impairs immune systems, sets up infection, which alters gene expression and it becomes a self-amplifying vicious-circle feedback loop.
So, conclusions. First, I would propose that metabolism needs to be a core focus in autism. We know that environmental factors perturb metabolism, even at low levels of exposure. We know that some of the same mechanisms and pathways get hit in the metabolic disorders as in
inborn errors of metabolism. But the spectrum and intensity of effect differs. We need to learn about multisystem and multilevel impacts. Metabolism is a target for biomedical treatments and also metabolic changes are a final common pathway on which can converge multiple different genetic mutations. What we need to do is to study how environmental perturbation of metabolism, which is not a disease category that we are taught about in medical training at this time, has different patterns and thresholds than inborn errors of metabolism and we need to develop practice parameters around this.
Also what is needed is to develop infrastructural support of the study of metabolism. It is daunting because of the state sensitivity and the sensitivity to handling of sampling. I think we need consensus meetings to identify measures that are less sensitive to these problems. We should consider “omics” and other profiles, develop standard operating procedures, and in particular have a special focus on environmentally responsive metabolism.
As these questions get clarified, we should develop a repository for metabolic samples of many kinds as determined by consensus with multicenter participation and encourage, strongly encourage, participation with contributions from research projects with well- phenotyped subjects.
With regard to brain and metabolism, we know that brain and metabolism are both abnormal in autism and we also know that this is not consistent in its details between subjects. What we need is to learn how metabolism modulates brain and vice-versa. This requires integration and integration requires infrastructure.
I would particularly suggest that in our studies of the brain, we have a much more concerted focus on characterization of brain as a physical organ, characterization of brain tissue. I also propose that we use more high-temporal-resolution brain function measures since the abnormalities in temporal measures, EEG, MEG, at the millisecond level are closer to being indicators of synaptic dysfunction and particularly that since synaptic dysfunction can be metabolically modulated, this is important.
We need, as I have said, systematic metabolic characterization and we need to have an extended metabolome and also extended genome looking at gut microecology and its disruptions.
We also need to have better characterization of change and treatment, which we know are possible. We need better tools to track treatment and change biologically. We should be studying n’s of 1,
repeated measures to see in the same individuals see what can change. We do not have good measures of change. We can study individuals who are diagnosed over time. We can study children at risk for autism over time, children undergoing treatment over time, and the marked good hair, bad hair days, for example, a child with a fever who improves or other phenomena like that, children who are off fluids and function better.
We need subgrouping to identify mechanisms and to predict treatment response. We do not have published studies showing the separation of groups, such as the illustration that I have shown, which is a separation of Lou Gehrig’s disease, Alzheimer’s, and Parkinson’s, but this kind of work needs to be done in autism.
There is no reason to think that there will be one biomarker for autism. What we need is profiles of vulnerability and treatability. Environmental perturbation of metabolism is widespread in the organism, but its thresholds are different and the reference ranges we use will not pick it up. Autism’s sensitive physiology also may mean trouble for the individual, even when labs are within the population normal ranges. So, clinical reference ranges need to be rethought for this kind of complex disorder as part of our process.
Finally, it has been pointed out that the environmental influences on autism suggest treatability and prevention and even though the focus of today’s discussion is not on treatment, I think it is very important to understand that what we are talking about is also very much about identification of treatment targets and of treating them.
Dr. Spence: Are there questions for Dr. Herbert?
Dr. Levitt: I just wanted to comment that there are many patients
with clear-cut primary genetic disorders like the Fragile X syndrome and Rett syndrome and many, many others, who have good hair days and bad hair days and you have a lot of this kind of variation, even though they have a primary underlying genetic condition.
Dr. Herbert: I would also like to point out that many or most people with some of those primary conditions don’t have autism and people with genetic conditions have high vulnerability to environmental perturbation. So, it doesn’t exclude an environmental role, even when there is a known genetic factor.
Dr. Levitt: I am not arguing there is no environmental role. I think there is an environmental role and that these people are suspect and subject to these kind of perturbations, but they are particularly—they areprofoundly susceptible to these.
Dr. Herbert: That is very telling. That is very interesting. So, this is
a question of using controlled clinical settings to study change using systematic systems, biology, and biomarkers.
Dr. Insel: Martha, I really liked your presentation a lot, but could I get you to just expand a little bit for us so that we understand what you mean about some of the studies you would like to see done? For instance, in metabolomics, what would be the tissue and for the microecology, microbiomics, it sounds like you would focus on gut, but can you give— where would you go? What would be the targets for some of these things?
Dr. Herbert: At the moment, I think we haven’t explored even blood and urine samples. I am mentioning gut because I wanted to show that this is more than a human metabolism problem. It is also our pathogens or our commensals, but I think we should have—I do not pretend to be the one who can unilaterally dictate what an appropriate profile should be, but I think there is a lot that could be done with blood and urine samples and with a protocol for suitable spinal fluid, even when you don’t have a standard study for children who may for one reason or another get a lumbar puncture, they should have available to them a standard operating procedure that can be used in a clinical setting to send samples to a repository.
I really propose consensus meetings to make that decision. I think this is a very complicated area. I have been asked singlehandedly to offer certain organizations the answer to this and I just don’t think it is appropriate. I think planning procedures are what we really need to have happen here.
Dr. Spence: Martha, I actually had a question. As a clinician we do get abnormal labs sometimes and I know in metabolism that the state of the child at the time that the lab is drawn is very important. So, do you want to just speak to the challenges of kind of the reliability of some of these biomarkers and standardization?
Dr. Herbert: I think there are some measures that are more state dependent than others. If we are going to organize a repository, we need to get people whose day job and 24/7 specialty is to handle these things, to identify a set of measures, which are most stable. It may be a limited set of measures. There are some measures where if you don’t freeze it within 15 minutes and so forth and if you have it at a different time of day, it is very different. But by no means all of them. So, I think the first step would be to get specialists in multiple disciplines to identify measures, which are more and which are less state sensitive, and I think we owe it to the children to really put the effort into doing that.
Dr. Schwartz: You talked about biomarkers as a way of linking pathogenesis to phenotype in terms of mechanisms, but biomarkers could also be used as a way of biologically phenotyping the disease, and in particular this disease strikes me as a disease that is made up of several subtypes. I just wanted your comments and thoughts in terms of using biomarkers as a way of biologically phenotyping autism.
Dr. Herbert: Absolutely. That was on my first slide and I further would expand what I am saying—what I said about that, which is that treatment response measured with biomarkers is an even further way of subtyping. Some of the nutritional treatments that are used in autism in certain settings are relatively low risk and a difference in response to those could be related to a genetically modulated environmentally sensitive set of differences in pathophysiology. That is a great opportunity to learn more about disease mechanisms as a research probe.
Ms. Bono: I just wanted to make a comment that in the blue folder in front of everyone, I made copies of an algorithm that some of the DAN practitioners—that is Defeat Autism Now—use when they get children into their offices and they start subtyping them by blood and urine markers and how they would treat a child based on gut, based on immune problems. It is in the packet. So, if anyone wants to look at that, it is a good start. It is based on about 4,000 or 5,000 children.
Dr. Spence: Great.