Max Rolison: How did you become involved in the autism tissue program?
Eric London: I founded it back in about 1996. At that time, there was very little in the literature about autism tissue research. The most prominent articles were by Bauman and Kemper, and it was only on a few cases. They had a few more brains in the freezer, but they didn’t have money at that time to study them. So there was in effect no tissue available to any other investigator in the country. When NAAR was first starting out, we took it upon ourselves to create the Autism Tissue Program. That program functioned to do outreach to the advocacy community to generate brain donations, which is pretty much the role it still plays.
MR: Why is it important to collect brain tissue?
EL: Even at the present time, we actually know very little about what’s going on in the brain in autism. The only way we can know much about brain functioning is through various scanning techniques, including electrophysiology. By that I mean MRI scans, functional MRI scans, PET scans, and EEGs and MEGs. And these all yield us information, but the information is very limited. The information is on a very gross level, so we see large sections of the brain functioning, but on a microscopic level we learn almost nothing from these scanning techniques. So to understand the anatomy and to some extent the physiology of the brain on a more microscopic level we need to actually have tissue.
MR: What regions of the brain are studied in autism?
EL: Probably the most studied area is the amygdala, which is a structure that is involved with emotion and fear. Proper functioning of the amygdala helps people to determine correctly what is a danger, what is a threat, and what is not. The amygdala is found to be poorly functioning in autism. Other areas of the brain that have been relatively well studied include the cerebellum; the cerebellum has also been shown to be quite impaired in autism. The cerebellum probably has the function of coordinating many other centers of the brain; it functions to some extent like an orchestra conductor, bringing in the different parts of the brain at the time when they are needed to function. The cortex has been studied, and for a long time the cortex was thought to not be impaired; however, at this point, especially through tissue work, we know a little bit more about some abnormalities in the cortex.
MR: What can we learn from brain tissue in the study of autism?
EL: It’s very likely that what causes the brain in autism to malfunction involves aberrant connections. So, again, with scanning we can see at the gross level, but we cannot see this on a microscopic level. And so we can learn a lot more about connectivity of the brain by studying brain tissue.We’ve been somewhat disappointed by our inability to find a prominent gene or many genes that are abnormal in autism. It’s more than likely, at this point, that the genes themselves may not be the problem, but it could be epigenetics, or basically the modifying of gene behavior and the turning on and turning off of genes. You can study the genes in peripheral tissue, but it’s not at all clear that the epigenetic phenomenon inside the brain and outside the brain is the same. So to actually study various structures in the brain and how the genes are functioning will actually need tissue.
MR: Where is this research being performed?
EL: There is brain tissue research being performed on a small level in many sites. There are only a handful of labs that study brain tissue as a full time job. One of these places, here where I am, the Institute for Basic Research in New York , Dr. Jerzy Wegiel. Another investigator working full time in tissue work is Dr. Gene Blatt at Boston University. And also Dr. Cynthia Schumann at the MIND institute. But actually very few investigators are doing it. Part of the problem is the lack of brain tissue. Because to actually plan projects when there is a relative inability to get tissue is very risky and so if you do get a grant and you don’t get the tissue you can’t perform your grant. As opposed to studying mice, where there is virtually an unlimited supply of mice, human brain tissue is very hard to come by. Also, it is very hard to come by high quality brain tissue. The longer it takes for us to take the tissue after death, the more deterioration of the tissue. It’s called a post mortem interval and because of various laws and regulations needing to get consent and where the bodies are placed and getting medical examiners to take the brains, getting medical examiners to treat the tissue in a method that’s suitable. Very often, even if we do get the tissue, it’s in many hours and the tissue has deteriorated. This is dangerous for the research because sometimes investigators might confuse deterioration with the pathology of autism. And so for example, for other diseases where people die more predictably like Alzheimer’s disease or Parkinson’s disease, people very often die in hospitals, they take the brain and the brain can be taken within minutes of death and can be taken down to the brain bank in the hospital. Many of the deaths that we deal with are accidental death, drowning, and things like that, where it’s very hard to get the brain tissue in a timely fashion. So to actually get a system in place to get high quality tissue has been very difficult.
MR: Why is the study of human brain tissue better than the mouse models?
EL: That’s a very important question, and the answer is actually quite simplistic. There is no such thing as an autistic mouse. Autism is a phenotype that’s described by social deficits, language deficits, and a rigid adherence to sameness. Clearly mice don’t have language or communication deficits. Their social deficits are quite different than what you might see in a human. And so the question of whether a mouse’s social deficit is analogous is a very difficult question. So when we model the mice, there are basically three ways. One is behavioral, which has problems that I just outlined. Another is neuro-anatomically, and again the mouse has a very different neuroanatomic brain than a human, we have these gigantic cortex and mice don’t. Whether what we see in the mouse is analogous to the development in humans we don’t know. And the third way would be genetically. If there is a gene that is conserved, meaning the same gene is operative in the mouse and human, then we could study those genetic issues. However, we have really not found major genes that contribute to autism yet.We do animal modeling for lots of reasons, including to learn about genes, to develop pharmaceutical treatments, you want to model it after the autism brain, but we really don’t know that much about the autism brain, so a lot of the mouse models are actually faulty. They are actually modeling it after poorly done brain tissue work.
MR: What new, encouraging research has been performed with brain tissue?
EL: Some of the work that we’re doing at IBR, what we’ve found is that in some places sub-cortically we’re finding very small cells, especially in the younger samples. In other words, in the post mortem tissue of children between the ages of 4-8, we are finding some very small cells. In the adolescents that we’ve studied, the cells are larger, and in the adults we’ve studied the cells are about equal to the size of the cells of the control. These are in very important areas such as the amygdala and the basal ganglia, including the nucleus accumbens. These areas could be very important in thinking, acting, and it could be that these cells, which are very small, are cells that have not fully developed and it’s interesting that in the older samples it appears that the cells normalize, perhaps indicating late development. Clearly if we could study this phenomenon in greater detail with more samples, and understand the phenomenon, this could potentially lead to very significant treatment to try to help develop these cells much earlier in life.
MR: What are some areas that need to be researched more?
EL: The gene product or the genetic functioning of the cells really is extremely important and could also lead to treatments, for example pharmaceutical treatments. Knowing the neuroanatomy of autism, which we still don’t really know, there are many structures that still have not been really looked at carefully, that can help us understand more about what’s going on in the brain.
MR: What would you like to see researched with brain tissue, personally?
EL: The structure called the nucleus accumbens, if our findings hold up, that’s an area that’s very involved in reward mechanisms. And one of my hypotheses is that one of the major functions that autistic children do not do is get adequate reward for naturalistically exploring their environment. If you give a typical two year old a new, novel toy, they are completely enthralled. They feel ecstatic. Their eyes light up. They literally devour that toy, learning everything they can about it. If you give that toy to an autistic child, very often they ignore it, put it down, and may not even touch it, and they go back to their repetitive behaviors and movements. My theory might be that they’re not getting the intrinsic reward for exploring novel things, which inhibits learning, which inhibits their cognitive and language development. So I believe if the hypothesis of how these reward structures don’t develop, this could lead to a very significant treatment for autism.
MR: Are there any bottlenecks in the brain tissue research?
EL: The number one bottleneck is getting adequate amounts of high quality tissue. The second bottleneck is getting more investigators interested in the field. Unfortunately, the message being sent out to young scientists is that it’s not a fertile place to create a career. There is very little funding in it, partly because the NIH has not invested in the infrastructure to get, store, and treat the tissue. I believe that if we could get a flow of tissue that more people would go into the field, and I believe the funding would go up because they would be writing more grants.
MR: How is it determined which scientists and studies receive the tissue?
EL: For anyone who wants to study tissue, there is a two-step process. Process step number one, you have to get the tissue. Very few scientists are able to get their own tissue. There have been one or two scientists who have been able to get tissue donations for their own lab. But the vast majority of scientists who study tissue have to apply to a brain bank. At this point, there are two major pathways for getting brain bank tissue. One is through the Maryland Brain Bank, which is a developmental disease brain bank, and people could apply directly to them and ask for tissue. The second way is to apply to the Autism Tissue Program, and they have a scientific advisory board. That scientific advisory board decides whether your project is meritorious because the tissue is very scarce so it’s precious and the feeling is not to frivolously give away tissue to people whose projects might not be good. So you first have to pass the scientific review of your project, then of course you have to get grant money to do the work. SO usually people apply to the tissue program, get accepted, and they usually don’t even get the tissue until they get grant funding.
MR: What would you tell the parents of a child with autism who are considering donating their child’s brain post mortem?
EL: What we’ve been telling them for the last fifteen years is the extreme importance of brain donation and the extreme importance of using brain tissue for learning about autism, for developing treatments of autism, for understanding the genetic functioning of autism. And obviously nobody wants to minimize the trauma of losing a child and when people lose their child, of course, it’s always very painful. Nevertheless, over the years we’ve received over 100 donations, the parents who have donated the tissue, in my experience, universally, feel good about having done it. It’s as if that child’s death or that adult’s death was not in vain, and the death might lead to the curing of the illness. So we have parents who can speak to that, who feel that the gift of their child’s brain was actually a cathartic experience for them.
MR: Are the donations usually prepared in advance? Do families usually decide before the child passes away that in the case of death the child’s brain will be donated?
EL: What we’ve done at ATP, we’ve asked people to sign up for brain donations, not related to anybody’s death. But that has no legal standing, and it’s sort of symbolic. You have to get the consent after the death, so even if a parent signs up and the child dies five years later, we still have to go back and get a legal consent.
MR: Those are all the questions I have. Is there anything else you would like to add?
EL: I want to emphasize the point of the story that I do think that the lack of tissue study has held up the field and right now I believe that getting the tissue in place is actually more important than genetic work, and more important than scanning work, and will lead to the development of treatments faster than these other types of research.