For the past few months I have had a hectic travel schedule that has made me spend a significant amount of time at the airport or in an airplane. Occasionally I sit across a stranger and I will be asked what is it that I do for a living. I usually answer that I am a Neurologist and a Neuropathologist and almost immediately I can see their eyes roll. As a medical professional I have had many interesting experiences that I could develop into stories, and although of interest to me, they could possibly repel more sensitive individuals. So, I will keep those “interesting” stories to myself and tell them as an add-on that I do research on autism. As a matter of fact my laboratory has probably led the field in regards to postmortem research in autism spectrum disorders.
I like doing research into the workings of the brain but needed to prepare myself by pursuing many years of training. I first became board certified in neurology and then pursued back-to-back fellowships in neuropathology at Johns Hopkins first as a clinician and then as a researcher. I eventually practiced as a consultant neuropathologist at several hospitals/institutions and finally as a medical examiner at both Maryland and Washington, DC. After all of these years the brain remains for me an organ of remarkable interest.
The brain defines your personality as well as all of your higher cognitive functions (e.g., speech, memory). Your ability to move, talk and experience emotions all depend on how your brain functions. Although Nature has tried to protect the brain by giving it a bony enclosure (skull) and isolating it from the blood (a blood brain barrier) many things can damage the brain. Think of tumors, trauma, stroke and infections just to name a few. Contrary to other systemic conditions, treatments for brain conditions are rather limited. Once damage has occurred to a part of the brain your options for treatment are limited. Dialysis can act as an artificial kidney when that organ is damage. Although advances are being made in the field of neuroprosthetics, there is no such thing as an artificial brain (for those interested read the interesting discussion and growing controversy as to the European flagship for neurosciences research based on modeling the brain with a computer http://t.co/ku6J3bnoSK .
If there is a problem in autism, the origin must be in the brain. Establishing the mechanisms involved is of the utmost importance. Postmortem studies are not simply about examining the brain and looking for cellular abnormalities. Postmortem findings allow us to establish clinical correlations. They give patients and clinicians the ability to explain salient or core symptoms but more importantly they may allow us to predict findings that are as yet unknown about the condition. After I described our initial findings of certain abnormalities within the cerebral cortex of autistic individuals, so-called minicolumnopathies, I published a couple of articles describing the significance of the same. In the first article, I described how our findings could help explain sensory problems and seizures in ASD (correlation to known findings) but also the fact that patients so affected would also have an abnormality in their blueprint of corticocortical connectivity and in their ability to connect different areas of the cortex with high frequency signals (correlation to unknown findings). I later expanded our explanation of sensory phenomena in order to introduce the concept of an excitatory/inhibitory imbalance in the brains of autistic individuals. In subsequent years many studies have proven our predictions as being correct (see previous blog: http://bit.ly/1nvnJq0).
There is a fair amount of postmortem research being done in autism. The main problem, as I see it, is that the quality of the same is suboptimal and the vast array of findings provides for a confusing literature with findings heading in every direction. Researchers work in silos and are apparently bent on defending their own turfs. The problem in postmortem research is not that there are not enough brains to do proper research; rather, it is that proper research is not being done.
To claim that there are not enough brains to do research is to only see the tip of the iceberg.Focusing on this won;t change the state of chaos in regards to postmortem research. It is true that, unfortunately, there is a severe shortage of brains available for research in autism. However, there are multiple problems that confound the issue. Those in a position of power could try to tackle the problem in several different ways. We could try to alleviate the problem by increasing the number of brains being donated, by limiting the number of researchers that are able to use the samples to those researchers that are truly qualified, better handling of available tissue (see the McLean Brain Bank Fiasco: http://bit.ly/1tFh2EM) (see Note at the of blog) and/or by increasing the quality of the samples.
At present, the unfortunate circumstance is that most postmortem research in autism is conducted by people ill prepared to do the same. Many researchers have, at most, a degree in anatomy but no experience in the field of neuropathology. The same thing happens for those collecting brains and in-charge of establishing our national initiative. They have never had their hands dirty in an autopsy room and in some cases they have never even worked with human material. In this regard many of those conducting postmortem research as well as those assigned to administrate brain banks are similarly ill prepared or qualified.
A major gaffe of the interagency autism coordinating committee is their lack of expertise in postmortem research and insistence in relying on an old boys network for which the administration is well-known. Indeed in their original proposal, when stipulating short and long term aims in regards to neuropathology, these emphasized work in the diverging field of neuroimaging. For most neuropathologists the lack of expertise and audacity in publicizing their lack of knowledge by the Interagency Coordinating Committee was, and still is, a cause for concern.
Given the lack of expertise in the area of postmortem research, I expected the role for the Interagency Committee to be one of collecting information from knowledgeable sources. A proper avenue would have been to survey the opinion of those trained in neuropathology and having hands-on experience in brain banking. Call this doing first a market research or a needs assessment survey. Thus far, unfortunately, they have limited themselves to providing opinions based on their own biases and limitations. The “experts” of the Interagency Committee know only a piece of the truth and proceed in their deliberations by only following their pre-existing consensus.
I think that there is an overt bias in the NIH on how to conduct research in regards to autism. This bias comes from the higher echelons of administration who themselves did their training with animal models on either rodents or primates (see http://bit.ly/1oxKhRY) . Unfortunately their way of thinking has trickled into autism research. Now as part of postmortem research in autism we have animal models based on fish, worms and flies.
Tissue availability needs to be restricted to people with adequate expertise. I recently visited a poster presentation at IMFAR 2014 where a researcher had done vast amount of work involving immunocytochemistry. When examining the photomicrographs I asked about the large amount of ice crystal artifacts in her sample caused by slow freezing. The researcher was oblivious to the nature of this artifact or how it could have confounded her results. That research could have probably been re-titled, “Tissue gone to waste”. More recently Courchesne’s group publicized their results regarding patches of disorganized cortex in autism spectrum disorders (see previous blog: http://bit.ly/1iPTQiw). The study was published in the New England Journal of Medicine. Several people with experience within the field amply criticized the results as possible artifacts (http://bit.ly/1jiqWVT). Robert Hevner, a renowned developmental neuropathologist, thought the results were due to tissue degradation. In effect, notes from the Autism Tissue Program (the source for some of the tissue) stated:
“…it was very disappointing to discover that the majority of the brain samples showed extensive degradation and that no meaningful conclusions could be drawn from the experiments. If we had not decided to perform the autoradiography and the hemalum staining after the Western blot experiments, we would have not been aware that we were working with degraded tissue samples. Several research groups received the same brain samples that we got and because they did not perform brain sections, they did not realize the problem with the tissue quality and went on to publish their findings.” Catalina Betancur and Salah El Mestikawy, Universite Pierre et Marie Curie, Paris France, ATP Report, 2010.
At present we find ourselves drowning in a sea of questionable postmortem results (http://bit.ly/1kTc2TJ). Indeed to say that more brains are needed for research in autism is to take a myopic view on the subject. Having more brains available for research is likely to compound the problems rather than help solve the same. I foresee with this approach an exponential growth of irreproducible results. We need to do much, much, much more than to collect brains. I would end by saying that the band aid orientation towards simply collecting more brains, is silly, distasteful and even unethical when considering our responsibility to those making donations.
Note: The brain bank responsible for losing a significant portion of collected postmortem tissue and who refused to assume personal responsibility for the loss, is now a prime partner in the brain banking efforts to collect still more autism tissue. Some things never change.