A couple of weeks ago I read the blog of one of my favorite writers Matt Carey of Left Brain Right Brain fame. This particular blog related Matt’s experience while attending an IMFAR congress from which his take home message was the importance of postmortem research in autism. I have to imagine that Matt attended the presentation of Eric London. At that time Eric was being honored for his long-standing efforts on behalf of autistic individuals.
Some twenty plus years ago Eric was distraught at the lack of credible scientific research in autism. He was deeply concerned as both the parent of an autistic boy and as a psychiatrist taking care of many of these children. In order to make a difference, Eric called upon his friends to create an organization that could make a difference. That was the beginning of the National Alliance for Autism Research (NAAR) for which I was honored in being a founding member.
NAAR was a mom and pop type of operation. Our first meetings in New Jersey were “come at your own expense”. I still remember Eric picking us up at the airport in his old station wagon and serving as our host bringing boxes with cookies from the supermarket. Eric and his wife Karen did all of the paperwork and coordinating of NAAR from their home. While I was a member of the Scientific Advisory Board our overhead was only about 5%. This changed drastically as the organization merged with Autism Speaks and the overhead quickly shot over 90%. At Autism Speaks most of the money went to pay for employees and travel (36 employees earned over $100,00 and Gerri Dawson whose salary was $644,272) (http://bit.ly/1mZX9DX).
Eric always worked on behalf of autistic individuals. He never looked for glory or acclaim. When other autism organizations started proliferating, he decided that the best way to proceed was to join forces, to merge the different organizations. In this way NAAR, and later on CAN, soon merged with the newer organization: Autism Speaks. Mind you the idea for the merger came from outside Autism Speaks. In the end Eric parted ways with Autism Speaks, in disagreement as to what research initiatives were being selected for funding. He and other members that similarly resigned from Autism Speaks went on to establish the Autism Science Foundation (http://bit.ly/1sAA5ih).
Eric also was a major player in establishing INSAR/IMFAR. Having had the idea for an international congress regarding autism research he looked for federal financial help. He soon found out that Joe Piven was interested and had a similar idea. After at least a year of deliberation and while getting ready to proceed the MIND institute also entered the picture with a similar proposal. In the end the MIND institute, NAAR and CAN established the new autism organization (INSAR). (Oh, if I could only post the whole story…but can’t.)
I am very proud to say that Eric has been my good friend for over 20 years. In a recent book that I edited (Imaging the Brain in Autism) I asked Eric to join me with a commentary to one of our chapters. The few paragraphs below provide a short excerpt from the book.I readily agree with Eric. The big money in autism research has heavily leaned towards genetics and animal models. Although this will sustain the work of the powerful academic institutions, what they have been able to do for autism has been meager by comparison.
The Importance of Postmortem Research in Autism
By Eric London, M.D.
In the past 20 or so years that I have been involved with autism, as a parent, a researcher, a clinician, and a funder, I have seen the field take off from a backwater of the medical and research field to a place of prominence. Parents often ask “ is there anything new and exciting coming out of the research”. By that, I believe they mean is there anything emerging from the research that is useful and could improve the lives of their children. During these 20 years, the progress made in treating autism has been rather meager. In 1989 the year I became interested in autism, the treatment of choice was Applied Behavior Analysis (ABA) as outlined by Lovass along with some evidence that some medications were beneficial, most specifically haloperidol. In 2012 the treatment of choice remains ABA with some modifications and improvements, along with the medications risperidone or aripiprazol both of which are similar to haloperidol. Many treatments and strategies have been attempted; however, research evidence for their benefit is lacking. Many widely used treatments have not even been researched, while others which seem to be promising show no benefit when careful research methods are used in an attempt to document the benefit.
Autism is not alone in being stuck in terms of progress, and the issue appears to pervade psychiatric disorders. Akil et al. (1995) directly address this question noting that there have been no major breakthroughs in schizophrenia in the last 50 years and no breakthroughs in the treatment of depression in the past 20 years. Klein (2010) notes that the pace of psychotropic drug discoveries in the 1950’s and 1960’s was dizzying, whereas progress came to a halt over the past 40 years. Despite this lack of success there has be great strides made by the more basic scientists. Our progress in genetics and molecular biology has been dizzying.
I would like to suggest that one of the major factors holding back progress is a lack of high quality “translational” science, and by that I mean the ability to relate the basic science findings directly to the disease state. There are three major strategies for translational research, one is genetics, the second is animal models and the third is the research on human tissue. To be sure, in some diseases such as Rett’s syndrome, great strides have been made mostly due to the discovery of the centrality of the MECP2 gene. Genetics however, despite dominating the funding of the NIH over the past few decades has contributed little to the understanding of the more complex brain disorders such as autism. While the search goes on, autism’s apparent phenotypic and etiologic heterogeneity is causing many to become dubious about the prospects of success. Animal models also present some serious and perhaps insurmountable difficulties. Many question the suitability of using the lower primates such as mice or rats to model diseases focused on functions which are only present in higher species such as language development. Research on great apes is difficult and expensive thereby losing many of the advantages that monkeys afford. Human tissue on the other hand offers a direct look at the disease processes themselves. For reasons not clear at all, there has been a pernicious neglect of support and funding this type of research.
The only NIH spending on human tissue banks for developmental disabilities is the Maryland Brain Bank, which is funded by the NICHD. They have a contract for funding at the rate of 7.15 million dollars for 5 years or about 1.4 Million dollars per year. According to the NIH Report file which categorizes spending by categories, the NIH is estimated to spend in 2012 approximately 1.18 billion dollars on categories related to developmental disorders. The developmental disabilities list includes autism, CP, Battens’s, conditions affecting the unborn, Down’s, muscular dystrophy, epilepsy, fetal alcohol syndrome, fragile X, infant mortality and perinatal problems related to low birth weight , intellectual and developmental disabilities, Rett’s, and SIDS. Therefore the investment in tissue banking for these diseases is 0.07% of the portfolio. Similarly the amount spend by the NIH on tissue banking for DD, is 0.02% of the budget spent on genetics research.
It is exceedingly difficult for an individual scientist to provide his own tissue for research. While animal modelers can buy mice commercially, from agencies set up to provide these animals, no such system exists for human tissue. In addition, the tissue is worth little without the clinical data associated with that tissue. A careful system of brain collection, characterization, treatment, neuropathology and distribution must be in place for the tissue to be utilized commensurate with its potential value. I am sorry to say that such a system is not in place to any significant extent.
Society has made several decisions over the years that have hurt research on human tissue. The first of which is the dramatic decrease in the numbers of autopsies done. From a clinical perspective this has hurt the ability of doctors to learn about pathology especially in the cases where information is not forthcoming from premorbid testing. This is especially true for organs such as the brain or the heart which are not amenable for biopsy.
The primary factor in the decline in hospital autopsy rates is due to clinicians not wanting them. However the discrepancy rate between the cause of death offered by clinicians and that shown on autopsy is 10%–30%. Increasing amounts of litigation however place a damper on the enthusiasm for the autopsy; at the cost of physicians not learning from their mistakes. The lack of enthusiasm for autopsies has been compounded by the adverse media attention to the retention of organs for illegal economic gain. All sorts of legal protections have been instituted, most of which has little to do with brain collection not used for transplant. Nevertheless, most governmental jurisdictions would rather make blanket laws and pay little attention to the research sacrifice being made.
While some point to resistance of the donor families, I have not seen this as a major issue. My experience with the families of autism cases who died is that the families feel that the tissue is a necessary step to reach an understanding of the disease that they had struggled with.
Although postmortem techniques, have been used for hundreds of years, a new generation of systematic quantitative tools is still in its infancy. Tissue work remains the only way to study microscopic anatomy and cellular characteristics such as cell number and quantifying the length of dendritic processes. Microanatomic detail and brain region organization can give important information about developmental anomalies. Scanning technology allows the visualization of only grosser structures. A voxel resolution is about 1 mm, compared to a pyramidal neuron which is about 10 μm–50 μm. Molecular studies can identify, measure and localize proteins, neurotransmitter receptors, or genes expressed in cells in a given region of the brain. Gene products and epigenetic studies cannot be done in peripheral tissue or animal models.
The very few postmortem tissue studies of autism published are very frequently cited papers. Animal models are based on postmortem reports of only a few cases, often using tissue of dubious quality or even equivocal diagnosis. Why funding is available for the models of autism and not for similar work on the autism cases themselves speaks to skewed priorities of our funding systems. If there is not a remedy to this problem in the near future, it is likely that we will have a generation of researchers who have no knowledge of how to handle or use human tissue, I believe delaying progress in understanding these diseases by years or decades.