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Proceedings Day 1 April 18, 2007 WELCOME, INTRODUCTIONS, AND WORKSHOP OBJECTIVES: Dr. Alan Leshner Dr. Leshner: Good morning everyone. I am Alan Leshner. I am the CEO (Chief Executive Officer) of the American Association for the Advancement of Science and Executive Publisher of Science magazine, but I am here in my role as chair of the Institute of Medicine’s (IOM’s) Forum on Neuroscience and Nervous System Disorders. I am delighted to welcome everyone. This is the workshop Autism and the Environment: Challenges and Opportunities for Research. The major purpose of this workshop is to work together to try to figure out how we can do a better job to bring the full power of science to bear on a public problem of tremendous magnitude and tremendous import. The IOM’s Forum on Neuroscience and Nervous System Disorders has the purpose of building partnerships and discussions to further understand the brain and the nervous system, to understand disorders and their structure and function, as well as clinical prevention and treatment strategies. What the forum does is to bring together leaders from the public and private sectors, including federal agencies, the pharmaceutical industry, advocacy organizations, and the academic community to have conversa- tions about these general critical issues. 5
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6 AUTISM AND THE ENVIRONMENT In addition, we try to serve an educational function, educating the press, the public, and policy makers about neuroscience and nervous system disorders. One of the mechanisms through which we operate is workshops like the one today that provide a venue for discussion about key challenges and opportunities in the field. The Forum was asked to host this workshop by the U.S. Secretary of Health and Human Services, and William Raub will speak in a moment to help explain its origins, but it came about as a result of a series of discussions among members of the autism community, the Office of the Secretary, and Dr. Harvey Fineberg, president of the Institute of Medicine. I do want to specifically thank Kelli Ann Davis, Jim Moody, and Mark Blaxill—Mark has also been a member on our planning committee—who were instrumental members of the advocacy community in all of these discussions. Let me say a few words about the format for today’s meeting. You all have a copy of the agenda and I won’t read it to you, but let me just reiterate that the workshop objectives are to look to the future, to look for and try to identify the most promising scientific opportunities for improving the understanding of potential environmental factors in autism, to talk about what infrastructure, what tools and technologies are available and what is needed, what kinds of interdisciplinary approaches are needed and other kinds of infrastructure, investments and then to talk about exploring potential partnerships that are needed to support and conduct autism research. The format that we are using, if you look at the agenda (Appendix B), is to have a series of speakers in each of numerous settings. There actually are way too many speakers for a normal workshop, but we were unable to figure out how to keep this in proportion and make sure that we covered this very complex issue fully. So, we are going to be rather ruthless in maintaining the organization of the workshop. Each speaker has been given 15 minutes. We will have one or two minutes for what I will call critical questions of clarification right after each talk, but really we mean critical clarification, not a discussion and not a discourse. Then at the end of each session, we have allocated actually a substantial amount of time for discussion among the session participants and then we have allocated time at the end of the day for continued discussion, but also an opportunity for members of the audience to participate at that time as well.
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7 PROCEEDINGS I would ask those people who are planning to ask questions or develop questions over the course of the day’s events or the 2 days’ events, please, no statements, no long harangues. This is about questions. This is a scientific meeting and we are looking for scientific opportunities and ways that we can move the science forward. So, I remind you of that, but I will surely remind you of that again. Again, the purpose of the workshop is to stimulate discussion about how best to move research on autism and the environment forward and I need to make some, I apologize, bureaucratic announcements on behalf of the IOM. One, this is not a consensus conference. We are not, in fact, expecting to come to a consensus by the end of the meeting. What we are expecting to do is to hear an array of opportunities, an array of needs, an array of challenges that will be identified. A proceeding of the workshop will be written. (NOTE: This is the pub- lished document to which Dr. Leshner refers in his remarks.) It will not, again, be an official consensus statement or consensus report of the Institute of Medicine. It is outside our authority as a forum to produce those kinds of reports, but, hopefully, what it will do is set the stage for a research agenda moving forward, and that is really what our goal is today. I do want to thank the planning committee, which has been so instrumental in this workshop. It could not have been done without the joint activity of people from many different sectors with interest in this. One request of the speakers before we move on and that is—and I apologize for doing this late, but we are a little bit concerned that with all the discussion and all the talk, it may be a bit difficult to capture each speaker’s view of what a major opportunity or a major gap to be filled might be. Therefore, if it is not too late to do that organizationally in your head, if at the end of your talk you could articulate at least one, just so the recorders can write down, here is one potential gap in scientific knowledge or potential scientific opportunity that needs to be filled. If we can focus in that way toward the future, I think we can make a larger contribution than we could otherwise. I don’t want to take too much time. We are already a bit constrained and I, again, want to thank the members of the planning committee, who did such a wonderful job of pulling this together. I want to thank all the speakers, who will be with us today and tomorrow, and all of you who are participating in this.
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8 AUTISM AND THE ENVIRONMENT Let me turn now to Dr. William Raub, science advisor to the Secretary of the Department of Health and Human Services (DHHS), who just will make some additional comments about the workshop and its origins and its particular charge. CHARGE TO WORKSHOP PARTICIPANTS Dr. William Raub Dr. Raub: Good morning everyone. I add my welcome to Dr. Leshner’s. I am delighted at the wonderful turnout. The journey that brought us here began almost 2 years ago with a protest action directed against the Executive Branch. Parents of autistic children and other advocates were mindful of a reelection campaign promise to eliminate mercury-based compounds from vaccines. Staff of the Domestic Policy Council asked me to host a meeting whereby representatives of the advocates could state their concerns in person. I did so and had the privilege of meeting a group of impressive individu- als, several of whom are here today. I would like to be able to say that the protest event, the follow-up meeting at Health and Human Services, and the subsequent communica- tion from the Council back to the advocates left everyone satisfied. But that was not the case, and deep divisions remain over the matter of vaccine safety. Nevertheless, several of the advocates asked if I would be amenable to hosting further meetings, whereby they could lay out additional concerns about how the institutions of science have approached the problem of autism. I quickly agreed, having been moved deeply by the quality of the advocates’ preparedness, the sincerity of their representa- tions, and the power of their testimony regarding the crushing burden that autism places on not only the affected children, but also the entire family. That led to a series of meetings with various combinations of repre- sentatives from the autism advocacy community—but always focused on what science has or has not done and what more it can or should do. Last October, at one of those sessions, Dr. Harvey Fineberg, president of the Institute of Medicine, joined Mark Blaxill, Kelli Ann Davis, Jim Moody, and me to discuss the IOM’s studies of vaccine safety and related
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9 PROCEEDINGS activities. Out of that meeting arose the notion that some sort of IOM- anchored, autism-oriented event could make a uniquely important contribution to shaping the research agenda against this dreaded disease. During the weeks that followed, Dr. Fineberg and I posed this generic concept to Dr. Thomas Insel, director of the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH) and chairman of the HHS Interagency Autism Coordinating Committee. Then we widened the circle to include two other NIH leaders: Dr. David Schwartz, director of the National Institute of Environmental Health Sciences (NIEHS), and Dr. Duane Alexander, director of the National Institute of Child Health and Human Development. This team quickly determined that an IOM-hosted workshop focused on potential environmental factors contributing to the etiology or pathogenesis of autism would make for a highly desirable and value-added contribution to ongoing NIH-based efforts to develop a strategic plan for autism research. Without equivocation, Drs. Fineberg and Leshner affirmed that the IOM neuroscience forum would host such a workshop. Drs. Bruce Altevogt and Andrew Pope and their staff recruited and facilitated the deliberations of a first-class planning committee. The three institutes that I have already mentioned, plus the National Institute of Neurological Disorders and Stroke and the Centers for Disease Control and Prevention (CDC), agreed to provide the requisite funding. As indicated by the agenda and the advanced materials on the IOM website, the planning committee tried to ensure that no potentially important environmental contributor to autism has been overlooked or excluded. Although the workshop is not intended to reprise the analysis of the epidemiological evidence related to vaccine safety, the planning committee recognized that vaccine constituents, especially organic chemicals used as preservatives or adjuvants, obviously qualify as environmental agents that warrant attention. In other words, our research agenda should include studies of any and all environmental agents that plausibly might contribute to causing or exacerbating autism, irrespective of the medium of exposure. I am hopeful that the next 2 days will prove to be an important milestone for autism research—not only because this workshop is addressing vitally important questions about the cause or causes of the disease, but also because the agenda is the product of collaboration between advocates for autistic children and their families and the scientific community. To be sure, other aspects of the autism challenge deserve similar
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10 AUTISM AND THE ENVIRONMENT attention, especially the paucity of effective treatments, and autism advocates and the scientific community have much further to go to achieve the full measure of mutual understanding and trust. But our challenge here and now is clear: to step together onto the path to a better day, to set the stage for other important steps to come, and to make other advocates and scientists want to be part of that advancing throng. Thank you for being here. Dr. Leshner: Thank you, Bill, and thank you very much for your important efforts in getting this meeting organized, getting it stimulated, and setting the appropriate stage for it. I do want to, again, thank the planning committee. I neglected to mention that the importance of this meeting from a scientific and a public health perspective is reflected by the very large number of members of our forum, who came today, in spite of it not being an official regular meeting of the forum. I really very much appreciate the help and support. Almost the entire forum has come today from many different sectors. I think that is an important statement. I also want to reiterate William Raub’s thanks to Bruce Altevogt, Sarah Hanson, and their colleagues from the IOM, who have done a phenomenal amount of work putting this all together and making sure that it happens. Let me not take more time, but rather turn to Laura Bono, who has been a member of our workshop planning committee, is a board member of the National Autism Association, and has agreed to bring to the group the perspectives of the advocacy community. PERSPECTIVES OF THE ADVOCACY COMMUNITY1 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 1 Throughout Ms. Bono’s presentation, she may refer to slides that can be found online at http://www.iom.edu/?id=42455.
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11 PROCEEDINGS 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.
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12 AUTISM AND THE ENVIRONMENT 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
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13 PROCEEDINGS 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.
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Session I Autism—The Clinical Problem: “What Do We Know? What Do We Need?” Dr. Leshner: I would like to turn to a discussion of the clinical problem and introduce Sarah Spence, who will serve as the session chair. I would like to point out that we are on time. So, don’t feel any pressure, Dr. Spence, or speakers in this session. Dr. Spence is staff clinician at NIMH, where she works in the Pediatrics and Developmental Neuropsychiatry Branch. Thank you. Dr. Spence: Thank you, Dr. Leshner. I think we may have one of the most difficult sessions to do, which is to introduce the clinical problem and do it in an hour and 20 minutes and no more. So, I am not going to spend a lot of time on the introduction. I think the most important thing to keep in mind during this session is that it is about what we know and what we need. It is about introducing the main issues to set the stage for a productive discussion later on today and getting a diverse audience, kind of onto a level playing field about what the issues are. So, to start with the clinical problem, I am going to introduce my boss, Dr. Susan Swedo, the chief of the branch that I work in at the NIMH. CLINICAL OVERVIEW: HOW CAN THE CLINICAL MANIFESTATIONS OF AUTISM SHED LIGHT ON POTENTIAL ENVIRONMENTAL ETIOLOGIES?2 Dr. Susan Swedo Dr. Swedo: Since I only have 15 minutes today to describe all of autism to you and why we believe that the environment plays such a crucial role in this disorder, I’m going to be using videos to show you in a few seconds what it would take me a very long time to try to explain. 2 Throughout Dr. Swedo’s presentation, she may refer to slides that can be found online at http://www.iom.edu/?id=42456. 15
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154 AUTISM AND THE ENVIRONMENT do, anyway. I would propose from a sociological point of view that there could be usefully some support for the self-organization of the parents and some of the treating physicians, like the DAN docs, like Nancy and others, to have more support to build a platform of communicating what classes of data are available, a status report of what is being collected. It is not enough for you to stand up and say for 30 seconds that you have these kind of data. I think it would be really nice if we could have support for a description in more detail of what is going on, focusing in classes of data to facilitate the interface with NDAR and other kinds of data collection mechanisms. I’m not clear that it would work coming from NDAR to the parent and treating community. I think there needs to be some support for the treating community, which is exhausted and overworked beyond all description with this incredible burden of cases. It is not just people coming in and mining data. There needs to be preparation for that, so that there is some kind of a systematic approach. So I think to make this happen, in order to meet in the middle, there can be a transitional infrastructure of setting up what it would mean to do that. Otherwise the activation energy to make it start happening isn’t going to happen. Dr. Beaudet: It seems to me that it would be interesting to know if the two camps could come together around a truly blind chelation trial, in which certain patients got infusions of placebo, and this went on for a year. Some parents would have to take the risk that their child might or might not be on placebo chelation for a year. But I think this would take considerable investment of both sides to agree to something like that. I would be pretty impressed if such a study could show something is going on. Dr. Swedo: I just wanted to say that such a trial has been developed in collaboration with the DAN practitioners. We are using their protocol and breaking those elements down. The gluten-free, casein-free diet is already under investigation at one of the START centers as well. So I think the individual components, the hard question and the thing we really have to grapple with is this issue of—it appears that one of the successes of the DAN approach is that it is very broad and deep. There are a lot of things going on with those kids all at the same time, so trying to figure out which components of it are useful is something that is going to take some more work.
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155 PROCEEDINGS Dr. Oberdorfer: Just to follow up on Martha Herbert’s point, when you have observational studies that you are going to be undertaking that you haven’t planned yet, if you do what you suggest, you are going to see what sort of samples that you can take from a number of different studies in a much more global sense. That way you would have some commonality in a tool kit. Right now, my impression is that they are going in cross purposes. They are not collected in the same ways, they are not in the same times, but they are moving in that direction. It seems to me that even if the studies go in different directions, you will have samples that you can compare homogeneously. I think that is very important, these kinds of toolboxes. We can do that now. Dr. Lipkin: Alan, this is not a comment. Maybe if Sue Swedo could summarize for us what is going on, we might save some questions. We are continually going back to asking what is being done at NIMH. If you could just summarize what is being done in terms of treatment, then maybe some of these questions would already be addressed. Dr. Swedo: All right. The new intramural research program is about a year old. We started with two major types of studies. One is an in-depth phenotyping effort, making use of the anecdotal literature and the clinical experience from clinicians across the country, but also the CHARGE, CADDRE, and other data that had been collected. It is everything from family history of medical illness and environmental exposures to neuroimaging, genetics, and other evaluations. Within that, we have a regressions substudy that looks at children specifically with regression for additional factors, such as microbial triggers or inflammatory responses. We also have a treatment compo- nent. Intramural does best novel treatments. Tom Insel called us a SWAT team. We go where we see a lead. For example, we are using meno- cycline for its effects on NF kappa B to try and see if that would decrease neuro inflammation. We have a trial in antiglutamate agents, seeing what effect that would have not only in repetitive behaviors, but overall autistic behaviors. The chelation study is currently on hold because of some recent reports of a rat study that reported cognitive deficits in DMSA- alone treated animals. We are going back to the IRB (Institutional Review Board) on May 1 to look at that question. That is what we are doing in-house. My colleagues from extramural can talk about the new A centers. But I think that many of the things that
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156 AUTISM AND THE ENVIRONMENT are happening, some of them are underway. Probably the most important is this issue of common measures and trying to get as much richness of clinical data as we can from every subject that is studied with NIH funding. That includes, as I mentioned, standardized diagnostic assessments, behavioral assessments, neuroimaging if it is being done on a common platform, as well as obtaining genetic material and biological samples. Dr. Lipkin: A constellation of toolboxes. Dr. Swedo: Right. I think we have already heard about some of the ongoing efforts in which supplements are being done to get the same kind of biological data. Now one of the questions is how do we organize it and go after the hypotheses. Participant: My name is Becky Peters. I have worked in the autism community for the last 5 years. I missed the very beginning, but I don’t think until Sue Swedo just mentioned it that I have heard anything about the possibility of food allergies. I read a lot about and heard lectures on things like the gluten- and casein-free diet, the specific carbohydrate diet, and how for some children with autism, it has not only improved some, but even caused recovery in some. So I was just wondering if anyone in the research community is looking into the possibility that food allergies or certain foods that maybe children are genetically predisposed to be more sensitive to could be environmental factors in causing autism. Dr. Leshner: Does somebody have a very brief answer? Participant: A brief answer is the recent data on microflora associated with obesity, for instance. It is something that occurs in response to a specific diet. We are finding that there is increasing research that tells us that you can change metabolism and adipose cytokines and adipose tissue can change in response to the diet in conjunction with the microflora. We have the opportunity now with the tools that exist to begin to explore those types of issues. It may not be the standard allergies. It could also be other models that we need to also think about. Participant: Claudia Miller from U.T. (University of Texas) Health Sciences Center in San Antonio. We have worked extensively with adults with food intolerances and environmental intolerances. Until you eliminate all of the things that bother that particular person, you don’t see the problems reversed.
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157 PROCEEDINGS Now we have started doing the same things in autism. The caution is that if you start doing a few things and just gluten and just casein, you may get some reversal but you may not get all of it. You may get other intolerances that develop, which is why you have to have a very comorbidity protocol. Participant: My question is about it being part of the etiology. I know that diet is out there and it is helping people, but I don’t feel like anybody here has addressed the possibility of the food allergies causing that problem. I was just wondering if anyone is considering that, or if that is not on the table for research. Participant: I am Dr. Richard Deth from Northeastern University in Boston. There is something missing here from this discussion that unifies many of the observations and the questions that have come up during this afternoon’s discussion. That is reflecting some of the work that we did and we continue to do on the dopamine D4 receptor. The D4 dopamine receptor is involved in methylating membranes of neurons. It uses methyl groups from the folate pathway through the enzyme methionine synthase. We discovered that a certain number of years ago. The D4 dopamine receptor is linked to ADHD, and is now recog- nized as the most important genetic risk factor for ADHD. The D4 dopamine receptor is linked to lead toxicity and the role of lead in contributing to ADHD. The D4 receptor is linked to IQ. It is a risk factor for IQ reductions. So it has all the characteristics of a candidate receptor, dopamine included. This is the only receptor that utilizes sulfur pathways. It uses the enzyme methionine synthase that is turned off by oxidative stress. When oxidative stress occurs, be it mercury or be it pollutants or be it pesticides, that enzyme turns off to make more glutathione and robs that system of its methylation ability. The role of the D4 receptor is to synchronize that gamma synchrony that is gamma-frequency synchronized, synchronization of the brain during attention, a system that is deficient during autism as well as ADHD. As we have pursued this line of investigation, we have recently found that there is alternative splicing of the gene from the mRNA from methionine synthase in the human cortex. We have found that this alternative splicing is related to aging; it is complete in 80-year-olds, and it is incomplete in 20-year-olds.
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158 AUTISM AND THE ENVIRONMENT As a result of recognizing the central role of this process, I think you can find mechanisms to explore. The enzyme methionine synthase utilizes methyl B12, which is a treatment that approximately 30 percent of people respond to. So I would say that there are all the elements here to start building from, even though it might not be a complete story. I just recommend that area of science to the panel members, because it can unify many of the things that they are concerned about. Dr. Leshner: Have you published it? Participant: I published several papers. The first paper about the D4 receptor was published in Molecular Psychiatry. The second paper was about methionine synthase being inhibited by ethanol, mercury, lead, thimerosal, because glutathione levels are low and methyl B12 synthesis is impaired. There is a lot to know about this. You just have to look into it. Dr. Leshner: Thank you. We will put that onto the list. Very helpful. Participant: I am from CDC. I want to make three points and try to make them quickly. The first is, I hope that everyone will be here tomorrow morning, because there will be several epidemiologic studies that will be presented, and they can be built upon in terms of specific environmental questions that are not being addressed. The CHARGE study will be presented and the CDC CADDRE study will be presented. It sounds like a lot of the questions that people are asking about studies and cohorts might be answered tomorrow morning. The second point is, Dr. Schwartz was asking about large cohorts that are available for study. I wanted to mention one in China. These are children of mothers that received folic acid. These children are about 12 years old now. There are about 200,000 children that are going to be characterized for autism. So I just wanted to go on the record to say that is a cohort that could be studied. The third point is to talk about the National Children’s Study a little bit more. Dr. Landrigan did mention that study, but there are a lot of environmental agents that are going to be studied as part of that study in terms of levels in the children, and autism is an outcome. There will be a research protocol that will be available for public comment. If that study is not addressing some of the questions that people have, if we don’t have the right chemicals identified, if we don’t have the right confounders, mediators, and modifiers described in the
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159 PROCEEDINGS study, then I would encourage people who are here today to comment upon that. That study was designed to answer a lot of these questions about specific environmental exposures. So I just wanted to remind people that there are some studies in addition to the ones that Sue Swedo had mentioned within NIH. There are some studies underway that might be able to shed some light on some of these questions. Dr. Leshner: I’ll just reiterate your point about tomorrow morning. A lot of very important talks are going to touch on an array of these issues that we have been talking about already. But we allow free talking. Thank you. Participant: My name is Harold Grahams. I am a private practi- tioner in Pennsylvania. To address Dr. Insel’s issue about the urgency of a biomarker, there is a tool that has come across my radar a few years ago that has been used in chemistry labs and hospitals and university settings all across the world that has been underutilized in autism. It is a high-performance liquid chromatography. There is a gentleman, Wayne Madsen, from PSA Labs who did work with lead studies 20, 30 years ago. Wayne Madsen did some unpublished studies with a controversial group up in the Philadelphia area probably about 10 years ago. I think it is a tool that might answer a lot of questions that all of us as practitioners and anybody could use as a reliable biomarker. What Wayne Madsen found with a group of kids is that we could give him bloodwork, and he could tell us—if we give him the blood tubes, he could run it through his chromatography, look at all these metabolites. What he could then spit back was that this was a cerebral palsy kid, this was a Down syndrome kid, or this was an autistic kid, just from those metabolites. The nice thing about it—yes, pretty impressive, right? But it was unpublished. Participant: How do we see it? How do we see the data? Dr. Leshner: People have to get the data into the system. Participant: I understand that. Dr. Leshner: I questioned unknowingly before about publication. Particularly in this field I think we have to be extremely careful that we not lead families astray, lead the scientific enterprise astray. So if you could tell Sue Swedo or somebody, people who are actively involved about this, maybe they can get access to the data.
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160 AUTISM AND THE ENVIRONMENT I am a journal publisher, so I am obsessed with peer review and publication and making sure that whatever it is that we communicate is going to be as scientifically rigorous and credible as possible, lest we lead people astray. Participant: Oh, I understand that. I hate to stand up here and say there is this fabulous tool that has not been worked. But just to throw it out, that it is a tool that has been preliminarily looked at with maybe 100 or so kids. I think it also allows us—the tool also has the fingerprint for the individual child. So what Martha Herbert was talking about, as having a way to track our treatments, I think we should as physicians be allowed the freedom to do whatever we do, because each doctor may be fixing a certain subset of children, but if we don’t know, that is the frustrating world of the clinician. Dr. Leshner: I agree with that. I would just urge you to somehow get the individual attached to these networks that are developing, because we don’t want to lose the opportunity if there is something particularly in this. So perhaps you could refer the physician to the networks that are developing. Participant: That is my frustration as a clinician. How do we know whether what we are doing is valuable and have the time to collect the data that the scientific community—when I went to UC–Davis (Univer- sity of California–Davis) too many years ago, I know the rigors that science wants, and we just don’t have it available, but we are doing something. So while we are doing something, we might as well be collecting a yardstick so we can measure what anybody is doing, and we don’t have that kind of biomarker. But I think this is a potential tool. Participant: One model that might apply here, and maybe we can talk about it more tomorrow, is the cystic fibrosis (CF) model, in which they started with a few very focused research centers, encouraged them to begin the training. That very rapidly got out to regional centers, and the regional centers began to work with the private physicians, and they markedly improved survival rates for individuals with CF. So I would be very thrilled to try to help spearhead that effort. Obviously it is going to be a major undertaking, but I think working together we can probably get that done. Participant: The bloods are already being collected so you don’t need a whole lot of blood. Participant: Right. We would need to make sure that the diagnoses were accurate and blinding was done. So I think the testing of that
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161 PROCEEDINGS particular hypothesis, absolutely, that can happen very quickly. The larger question is how physicians can be providing feedback and families can be providing information. It is something I think we need to organize both sides in at the same time. Participant: I am a grandparent of two autistic grandsons. I thank you for inviting the public. I hope to be one of the taxpayers and voters who gets you the funding to go on with your research. I must say, when I saw the advertisement for this on the Internet, I was distressed to see that mercury was not going to be discussed in the context of vaccines. I thought there was going to be a white elephant roaming around in the middle there, and everybody would avert their gaze. But I see that there is frank discussion on that, and I am very encouraged. I think the pursuit of science, obviously you have to go where the truth leads you. Also, as a taxpayer funding this research, I think it is very important for you to understand that the people who are going to be out there getting political want some basic questions answered. They want you to look at the mercury hypothesis and tell them why it is not mercury, why it is not repeated environmental insults, and the number of shots they get. It is mercury and it is an immune assault to get these inoculations, and there are so many of them. So they need an explanation for why that is not the cause. I think we can’t move beyond and do good research until we answer that question, put that one to bed. So let’s not ignore it. Let’s address it head on, and tell parents why they needn’t feel guilty. There are so many emotional issues involved here. Another thing is, people don’t really trust their government all that much anymore, CDC, FDA, and beyond. They need to trust their government more in their research by knowing that certain areas are not off limits. If we do not allow an explanation for mercury and vaccines, it will be like doing lung cancer research and saying, but let’s not say ciga- rettes. Nobody would believe it, and they would know their money was wasted. So that needs to be on the table. I have another tack altogether. Psychology doesn’t seem to be represented here. I know that is perhaps not a good fit with environ- mental issues, but it is something that should participate in any funding for autism. In our situation we have gotten a lot more bang for the buck with the
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162 AUTISM AND THE ENVIRONMENT biomedical. We have pretty much given up a lot of the behavioral therapies. They have been good, but they haven’t been as good as the other. So we need guidance. Then one more thing. I have a natural experiment to suggest. Rho- negative mothers are subjected to a standard of care that calls for a RhoGAM injection at 5 months of gestation, so we give them a little extra environmental assault and a little extra mercury there. I understand that Rho-negative mothers have a higher percentage of autistic children than others, so what is the explanation for that? Is it Rho-negative mothers? I don’t know. These are some questions we would like answered. Thank you very much. Participant: I would like to comment on the RhoGAM issue. There is a small study which is not very well done, and it shows this kind of finding. Since then there has been a more systematic study which I hope is in press. I can’t give more details, but it is from somewhere very respected in the United States, which has done a large sample in a study of that kind, and it showed there was no association between RhoGAM and being the mother of an autistic child. It is in press. Participant: Just going back to something both Mark Blaxill and Mark Noble said before, we are looking at first of all a very complex set of circumstances here. I don’t think there is going to be one thing that is found. I think it is going to be multifactorial, and I think this group is saying that. But I think as we address that from a clinical point of view, we have to look at not just one treatment modality, but also what the child is experiencing overall. When we look at what Jill James was showing us between the gut and the immune system and the brain, looking at all of those factors before we say, how does chelation affect a child? I think as we set up the studies that Sue Swedo is doing, for instance, if we set it up in such a way that we are just looking at the effects of DMSA on a child without looking at whether that child has had and still has gut or immunologic abnormalities, we would have very different outcomes than if we look at a child that is otherwise healthy and then looking at how chelation does it. So it is a very messy set of data and we have to look at all those parameters going in and coming out, or else we are going to have data that show us nothing. Participant: My name is Heather Elias. There is a subgroup of
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163 PROCEEDINGS children with autism, and a critical factor in treating them is regulating their hormone levels, particularly their testosterone levels. We know that boys are more likely to have autism than girls, but the girls tend to be more severely affected by the autism. That also makes me think that testosterone plays a big effect on how these children’s treatment should go. We know that Risparitol, Lepran, Spironolactone, all pharmaceutical drugs, are effective treatments for certain behaviors associated with hormone levels. I am curious if any of the scientists here are doing any kind of research on the hormones and how it affects the behaviors of people with autism and regulating those, how it helps them, if there is any kind of study going on about that. Participant: The study that we will be describing tomorrow, one of the domains of research that we are investigating, is related to hormone abnormalities. Dr. Leshner: Good, that will make you come back tomorrow. Participant: It will be including also immune dysfunction, which will address a lot of the other issues that have been raised today. Participant: There is someone in the United Kingdom whose name is Simon Cohen, who has been doing studies in relation to autistic symptoms or traits in the children who are born from these pregnancies. He has shown some relationship. It is very preliminary. It is not looking at autism as a disorder, as an outcome. Participant: I just also wanted to mention, I have a daughter who has autism, and we have followed the DAN protocol, and I am so grateful for these doctors doing all of this research. But we now are looking at the data. Just keep in mind that the parents have basically spent thousands of dollars to get these tests done, and they have really sacrificed a lot to get that information. So just remember the children when you are looking at the data. Thank you. Dr. Leshner: That is what this is about. You can be the last word. Participant: My name is Scott Bono. I live in Durham, North Carolina. I thank the panel for convening and taking up this topic. It is deeply personal. Last month I filed to retain guardianship of my 18-year- old son. I have two other children in college, and I never expected that when my son was born I would have to do this at age 18. It is very personal. I know what happened to my son was inexplicable, but you all are looking into it, and I appreciate that.
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164 AUTISM AND THE ENVIRONMENT The most relevant question that has been asked today was asked by Dr. Choi. That is, for 15 years nobody has been looking at the urine and the blood of the children that we are talking about right now. Most parents, when they go to a pediatrician and they are told that their child is autistic, they are dismissed. That child’s illness is dismissed on the basis of behavior. I am so grateful that each of you is looking into some of the systems that have gone wrong in my son and so many other children. Treatment should always be what is in your mind as you proceed here, because I want my son back. Everybody wants their child back. I really want to thank all of you for coming. And Jackson thanks you. Dr. Leshner: Thank you, sir, and thank you for reminding us. We are going to stop for the day. This has been from my perspective a wonderful day. I want to thank the speakers, I want to thank the audience. This was for me a very—I guess the right word is dramatic, but it was a wonderful example of how the patient and family community and the scientific community can work together. You have to come back tomorrow. I am really tough, so if you don’t come back tomorrow I am going to chase you. But I didn’t want to leave without making the comment that I am not sure that I have seen as good an interaction between the scientific community and the patient and family community, and I really appreci- ate it greatly. I am very grateful to the family members for coming and sharing your experience and your insight with us.