On July 22, Dr. Alan Guttmacher was named Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This interview with Dr. Guttmacher and Dr. Alice Kau. Extramural Program Staff Officer for the Intellectual and Developmental Disabilities (IDD) branch of NICHD was conducted by Autism Science Foundation intern Emily Hotez, a senior at George Washington University.
How does autism research play into the major goals of NICHD?
A.G. For many years we were simply the National Institute of Child Health and Human Development (NICHD). The reason Eunice Kennedy’s name was added is that she was instrumental in working with her brother, then President Kennedy, to found an institute at the NIH that was particularly focused on the health and well being of people with intellectual and developmental disabilities. Historically, it is at the very core of the mission of our institute to support research, in terms of understanding various kinds of intellectual and developmental disabilities, and also in terms of improving the lives of the people who have those kinds of conditions. We know much more about autism than we did back when the institute was founded, now almost 50 years ago, and it is a significant part of intellectual and developmental disabilities. Autism research is very important to us, but we are certainly not the only institute at NIH for whom it is important. Particularly, the National Institute of Mental Health is also in the vanguard of NIH work on autism. We work closely with them, along with National Institute of Deafness and other Communication Disorders National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, the National Institute of Nursing Research, and the National Center for Complementary and Alternative Medicine, all of which support autism research.
NICHD has an autism conference coming up focused on improving diagnosis across different populations. In what ways will this conference benefit autism research at NICHD?
A.G. I think it has been apparent for some time that there are particular challenges in diagnosis and interventions for folks with autism in special populations, for example, those who do not have access to good medical care. Also, people who come from minority populations have even more challenges, for various reasons, than do others who have autism. The idea of this conference is to look at some of these extra challenges, to look at the ways that research can move forward our understanding of them, to overcome some of those challenges, and to even remove some of them.
A.K. As you know, autism is diagnosed behaviorally, so it could be influenced by culture and the perception of the parents, and even the language we use. NIH program staff wanted to hold the conference to get the sense of what we know so far and what we need to do to bring the disparities down.
How has the focus of autism research in general evolved at NICHD since you have come to be acting director?
A.G. Well, I have only been acting director for 7 months so I don’t think it’s changed a whole lot since then. In some ways the focus is that we really try to coordinate with the other institutes in how we do the NIH’s research involving autism. We have the NIH Autism Coordinating Committee, which helps to coordinate research among the various institutes and centers, and also program staff such as Alice work closely across the institutes to try to do that. I don’t think an emphasis has really changed since I’ve been here, but I think I have tried to encourage working with the other institutes to make sure that we are doing things that coordinate in a productive fashion. We are not worried about who gets particular credit for a particular finding, but that we really identify the scientific questions that we can be answering through research.
A.K. We are in the middle of our funding for the Autism Centers of Excellence. Dr. Guttmacher came into the Institute when the initiative was really in high gear. We are into the second and third years of funding. There are autism research centers and autism research networks and we also work with the autism communities.
A.G. We coordinate not only within NIH but we also try to coordinate with the wider world, both in terms of various advocacy organizations and also in terms of working very closely with extramural scientists that we support. We really see this as a multiple player partnership and we try to play our role in that.
A.K. The advocacy groups are funding a substantial amount of autism research so it is very important that we coordinate with each other to avoid overlaps.
A.G. We have had specific conversations with some groups looking at various kinds of research and initiatives. We are constantly having new conversations and we have had some new ones about a public-private partnership. There are some things that obviously government agencies with funding can do best, but there are also things nongovernmental groups can do best. In general, the best situation is when both get together so we are not worrying about who gets the credit but how we can move our understanding forward.
Your predecessor, Dr. Duane Alexander, suggested that that a smaller part of the population could have a genetic variation that predisposed them, after vaccine exposure, to ASD. Can you elaborate on this idea?
A.G. I don’t know that we have an official agency view of that, although my own view is that the research we have so far has shown no convincing tie between immunization and autism. If there are new reasons to pursue that, we should, but at this point we know there are environmental factors (we use the term “environmental” quite broadly) that have to do with autism. We also know that there are genetic and other biological factors that have to do with it. We haven’t identified all of them, so it is hard to prove if something is not involved, but there is no evidence at this point whatsoever that vaccination plays a role. We have seen the agent in vaccines that many people thought might have a role pulled out of vaccines, yet we haven’t seen any decline in the incidence of autism. If anything, we have seen an increase in the incidence of autism, so that, again, would be even more evidence to suggest that vaccination does not play a role.
A.K. The NIH with NIAID’s leadership has an open program announcement to support research that will contribute to the overall understanding of vaccine safety in general, not just in relation to autism. NIH is open to good ideas, good proposals and research of vaccine safety in general. NIH as a whole is always welcoming good ideas and good opportunities.
In a New York Times interview with you in April, you were quoted saying “many of the different types of autism are either genetic or triggered by environmental factors and a genetic predisposition”. This implies that environmental factors in isolation cannot cause autism. Can you elaborate on this?
A.G. I don’t think we know for sure whether they can. I think that, when I say purely genetic, we know that there are certain inherited conditions, such as Fragile X syndrome, in which we see a high frequency of autism. Of course, not everyone with Fragile X has autism- but many people do. So even there, the environment might play a role in modifying the effect of the Fragile X gene, so that someone with Fragile X also develops autism. Most things in health are a combination of genes and environment but whether everything is, is still an open question. Is it conceivable that there is some environmental trigger that can cause autism no matter what the biology of the individual? It is conceivable but my guess is it would be exceedingly rare if it exists, and in the vast majority of people with autism, it would be a combination of their individual genetic makeup and various kinds of environmental exposures and influences. Whether that turns out to be everybody or just the vast majority, I don’t think we have enough knowledge to really know yet.
A.K. It is a complex genetic interplay. It is typically not a single gene; it is how the genes interact.
A.G. Particularly when you look at the environment, it may be that exposure to “factor A” is important in terms of causing autism. My guess is there could be certain genetic variants, which are somewhat protective. Even if they are exposed to a fair bit of whatever it was, they seem to be immune to it, whereas there are other genetic variants that may make one more sensitive. So even if we removed that environmental cause and that portion of autism disappeared, it would still be the environmental- genetic interaction.
In the previously mentioned New York Times interview, you said, “the jury was still out” as to whether autism is actually increasing or if we are becoming better at recognizing it. How would the answer to this question improve our knowledge on autism, if at all? What kind of research has NICHD recently done on this subject, if any?
A.G. I think it is very clear that our ability to recognize autism across the autism spectrum is much better than it used to be, so there is no question that some of the increase in what we see in the rate of incidence and prevalence of autism is clearly because of better diagnosis, and I imagine we are going to continue to see better diagnosis. We still don’t have perfect diagnosis; so as that gets better and better we may continue to see some rise in incidence. Whether or not there is an increase for other reasons, I don’t think we know for sure. Designing studies to find out would be very difficult, because ideally you would need to go back in time and you cannot go back in time very effectively. It would be important because if we did for sure say there was increase in incidence, that would be some suggestion that there is some environmental influence that is increasing, because we know genes do not change very quickly across our species. If we are seeing an increase over several centuries, that could be because of variance in genes changing in frequency. However, if you see an increase over a few decades, that would suggest there is some environmental factor or very possibly factors that for some reason we are having more exposure to, and that they are responsible. It would be useful data because this would help us figure out exactly what are the environmental triggers for autism.
On the NICHD website you are quoted saying “I truly believe that, for children born today, knowing their genomics will have a significant impact on their health into adulthood. Possibly in ways we have yet to imagine.” Can you describe how the progress NICHD has made on mapping the human genome can contribute to what we know about autism and how this will have an impact on individuals with autism?
A.G. Having the human genome sequence in hand, which we have basically had since 2003, is very helpful if we are going to understand if all autism is due to some interaction between various genetic factors and various environmental factors. Now that we know much more about our genomic makeup, we know much more about variation, both from the sequencing of the genome that was done back in 2003 and since then, improving our understanding of the role of copy number variants in the genome, which is something we have only known about in the past few years. In autism, there is a suggestion that copy number variants could be one of those genetic variations that is important to understanding autism. Our knowledge of the genome continues to unfold and get more sophisticated, and we are coming to understand epigenetic phenomenon. Those kinds of things will be very important in terms of finally beginning to understand what are the specific causes of autism. The great news is we are beginning to acquire those genomic tools. The bad news is we are still early in that age. We are still developing some of those tools but it is a very promising area in the near future
Can genomics provide not only insight into the biological basis for autism, but also insight into how individuals with autism may respond to certain treatments or medications?
A.G. Absolutely, very good question. Certainly in terms of medications, whether we are talking about medications for autism or any other condition, if you give somebody a medicine, it has 1 of 3 effects. The medication either has the desired, therapeutic effect, it has no effect, or it has a toxic side effect. Sometimes, it may have the desired effect and the toxic effect. And why is that variation? It is for lots of reasons but a lot of it has to do with how a body metabolizes the drug once we take it. What determines how we metabolize drugs or enzymes we have in our body (enzymes are nothing more than proteins that are coded by genes) is that we have genetic variants. There is no reason to think drugs we use for autism would be very much different from all other drugs. It is also possible that for some of the nonmedical treatments that are used today or will be in the future for autism, genes could play a role. There are probably genetic variants that we very well don’t much understand today that affect how responsive one is. Someday, and that day is still far away, we may use one’s genetic makeup, or their genome, to help individualize the various kinds of therapies we use, particularly medical therapies but even non-medical therapies and interventions that may give us some guide. A lot of other things will help guide too but that is one of the pieces of information that will someday be helpful.
My younger sister has PDD-NOS and this has allowed me to truly understand some of the difficulties that exist in families of individuals with autism. It has also helped me to understand the struggles that these individuals have in society as a whole. What are some specific ways in which identifying genetic markers in autism can help individuals with autism and their families? What kind of social impact can this bring about?
A.G. Well this is a good question, a very complicated one in some ways. Obviously if we can understand genetic factors that are largely but not only inherited and how genetic factors play a role in autism, families can get a better understanding of what are the inherited factors in their families and could change one’s risk for developing autism. Eventually the hope would be that by understanding genetic mechanisms involved, we can both guide most folks with autism more accurately and earlier in their lives but also, really tailor therapies, whether they be medical or other, specifically for who they are as individuals. For many diseases or conditions, not just true of autism, but conditions like asthma, etc., we treat them like they are one disorder. Biologically, whether it’s asthma or autism, we are probably talking about a number of different conditions, which simply have the same symptoms. We historically tend to label conditions by symptoms, rather than by cause, but if you want to treat something and prevent it from getting worse, you really want to understand the biology. If you try to treat the symptom you won’t be as effective as if you treat the underlying biological causation. Our hope is that genetics and other kinds of scientific advances will give us a more sophisticated view of autism so we can begin to tease out autism. Right now we have identified autism primarily by where on the spectrum someone fits. That can be very useful obviously, but even more useful in some ways would be not just where on the spectrum and what are the effects, but what are the actual causes involved. Someone who has autism for one biological reason may respond very differently to a given therapy than someone who has autism from a completely different biological basis, but simply has the same behaviors.
Can you elaborate on the progress that has been made at the NICHD’s “Brain and Tissue Bank for Developmental Disabilities” in regards to autism research?
A.K. The bank was reconvened last year. We are in a new phase of the banking contract for NICHD. One thing that we are very interested in is developing a protocol for post- mortem diagnosis for autism. It is challenging to diagnose someone with autism when the person is alive, let alone to do so when the person is gone. It is very important we devise a systematic way of doing this so that all of the brains recruited from the various banks, nationally or internationally, will undergo the same diagnostic procedures so we can compare them accurately. We continue to engage the community and listen and work with various organizations outside of NIH and within NIH. The challenge is great, and it can be overwhelming, but we want to take all of the little steps we can take and eventually reach the final goal of having as many brains available with good tissue quality, and good clinical phenotyping for researchers to use.
A.G. There has been a lot of progress with this and we have been having conversations with a number of various interested parties about how we can leverage the resources that we have in the NICHD Brain and Tissue Bank and about how we can leverage that with other efforts to try to create a richer resource that will be of even more use to the research community. That is one of those things that we try to leverage what we are doing by working with others to have even more impact. We are pretty optimistic that we can figure out how exactly we can do that in the not too distant future.
What are some of the other developments in autism research that NICHD has been working on since you were appointed as acting director? What is the current status on these projects and what do you hope will come of them in the future?
A.K. We are working with NIMH and NIDCD on a project focusing on nonverbal, or non-speaking, individuals with autism. The NIH with NIDCD’s leadership recently held a workshop on nonverbal school-aged children with autism. I think we at NIH all agree that this is a population, a subgroup, which has not been given enough attention. We are looking into a number of research gaps and opportunities to see how we can better diagnose and treat. So that is one effort that NIH as a whole is working on.
As a geneticist, what do the complexities of autism research mean to you?
A.G. I am not sure if I answer that primarily as a geneticist or primarily as a pediatrician or primarily as a human being. Genetics is one tool, and an important one, but not the only one. It is just one of the newer ones we have to try to figure out what is the cause of this condition so that we can give people information they can use to improve the lives of people who have autism. I think it is a very promising era. I understand fully the frustration of families who have members with autism. At the same time, this is an era with a real promise that we will see a fairly steep increase in our level of understanding and knowledge and that can really make a difference and have an impact on the lives of individuals with autism. I haven’t had family members with autism but I have certainly had both friends and patients with autism and I have some sense of what that means for peoples’ lives. I think the reason why most of us who work at NIH work here, is the fact that we get to go to work and do something that we think can improve people’s lives. We are pretty optimistic that a lot of the work we are going to be doing will do that. One of the contexts that I always keep in mind is that a doctor named Leo Kanner first described autism in 1943. Leo Kanner happened to be the guy who introduced my parents to each other. When I was a child I used to go over and visit him. My mother came to the United States from Argentina to work with Leo Kanner, so I knew him as a little kid. It is not the reason for doing this but it does give me a certain particular excitement or delight or something to think he would have been very happy to have me–who wouldn’t exist if he hadn’t introduced my parents to each other– play a role in advancing understanding of a condition he was the first to recognize. I think I’m moved more by this connection than by specific individuals with autism that I know fairly well. Of course, I don’t mean to discount the experiences of individuals with autism and their families and I’m sure your life has probably been shaped by your sister’s existence. However, Dr. Kanner’s descriptive work and his role in forming my own family is something that continues to move me in terms of why we need to continue to get this work done.
Can you describe some of NICHD’s short and long-term goals for autism research?
A.G. I cannot really single out one, although we haven’t really talked about the cognitive process which is so variable in individuals with autism. The goal is getting a better understanding of what are the factors that are responsible for both cognitive and behavioral features of autism. This is obviously going to be very important to understand more fully if we are going to find ways to benefit the lives of people with autism. That is not going to come easily but there is no reason to think we can’t do it eventually with research and can’t understand it much better than we do today.
A.K. The challenge is so great. Addressing the biology of autism’s causes will help us to really interpret the picture better.
A.G. Some of the new imaging techniques will also allow us to look at brain function in people with autism and allow us to separate it out into various different types. Maybe there will be some correlations between one genetic factor and one kind of brain imaging finding. Maybe it won’t be linked, but it can help us really figure out the different strands that make up the tapestry of autism.
Emily Hotez is an intern with the Autism Science Foundation. She is a senior at the George Washington University, working towards a major in psychology with a concentration in developmental psychology and a minor in Spanish. Her 17 year old sister Rachel has Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and continues to inspire her interest in autism spectrum disorders. Emily is currently working towards applying to Ph.D. programs in clinical/community psychology.
This interview was conducted on July 20, 2010.