A Theoretical Aside
I saw a press release yesterday from the NIH that the Neurobiobank initiative was moving forward Here. This initiative intends to drum up public interest and knowledge of tissue donations for science, and particularly brain donations for use in the study of genetic disease. I commend this effort, but I feel there are some insights the larger public and scientific community may not know that I may provide from having access to and working with these tissues over the past 6 years or so.
We Desperately Need Brains!
This holds for all diseases. Simply stated, there are currently not enough brain or organ tissues available for the study of any neurodevelopmental or neurodegenerative disease. This is better described by Dr. Insel in the press release, so I will defer to him on this topic.
What we as scientists are not doing a particularly good job of doing is describing our work to the public in a way that makes them want to even consider donating their tissues to research after their death. We fail in delivering our message in a number of ways:
1) We try to simplify the science so badly that it sounds like we are food network dropouts trying to explain cooking. For example, I have heard the process described as follows: when you die someone will come and take your brain out of your head. They will then freeze half of it and put the other half in a bucket to preserve it. Later, chunks of the brain will be sent to researchers who will cut it into thin slices and study it. Hmm, I know that does not make me excited to donate my brain. Sounds like I’m giving it to someone who isn’t taking it at all seriously.
From experience in my family, I can tell you with full confidence that speaking in a condescending way to families just pisses them off. It is extremely disrespectful and engenders nothing less than a charged and hostile environment. As families we are usually polite to you during our meeting, but afterward we talk about you and your behavior in a very unflattering light, and choose not to help you out. Also, personally, I don’t trust anyone who speaks to me like I’m a child. Don’t quote me an encyclopedia, but don’t try to Dr. Seuss it up either. Just tell me what you are doing and why. Then answer my questions as patiently as you can. Believe me, it works, and we appreciate it.
2) We try to act like brain donation is no big deal because the person the tissue is coming from is dead. Talking to the public like we as scientists are unfeeling robots is definitely not the right way to approach this.
Now this one is harder to get a handle on. We all understand the loved one or ourselves will be dead and won’t care what happens to our organs-they are removed at the morgue anyway. But diminishing or hiding the fact that the family is making a sacrifice is not only insulting, but very creepy. I am not even going to cover the fact that a very large proportion of people, even if not religious, do carry an innate sense that there is some sanctity of the human body-even extending after death. We must respect this and have a patient, honest dialogue with the families about why this sacrifice on their part is worth it in the larger context of scientific discovery.
I know these sound small, but they matter. They matter a lot. I will explain later in this piece when I describe my family’s and my struggle with the decision to donate my late brother’s brain.
A Broken, but Fixable, Laboratory Culture
As I stated earlier, I have worked with post mortem human tissue, primarily brain tissue, for the last 6 years. I have learned some lessons since then that bear repeating.
My introduction to working with human tissue was in the context of my work studying the Fragile X-Associated Tremor/Ataxia Syndrome. I was fortunate enough to have a skilled mentor for all things histology: Jürgen Wenzel. I mention Jürgen not only for his German love of precision and doing things exactly right (which will come into play in a moment), but also his experience as head of anatomy at a medical university in Berlin-and with extensive experience with handling brain and organ donations. My second mentor(s) were David Amaral, with whom I did a research rotation studying brain tissue from autistic individuals, and his lab manager, Jeff-with whom I worked directly.
Jürgen and David/Jeff taught me two lessons: 1) Someone had to die for me to get this tissue. If I mess it up or treat it without respect, then someone else has to die for me to get more. I know this is overly dramatic, but it is a great motivator to never halfass or treat lightly an experiment with human tissue. It was made crystal clear to me that arrogance and hubris do not come into it, either I do it right or I ask help from someone who can.
And 2) you owe it to the family of the person that made the donation to be as thorough and precise as possible in your work. There are no shortcuts, protocols are not suggestions; they are to be explicitly followed. Complete and comprehensive reports need to be written, and every finding has to be independently verified. I keep these lessons in mind every time I begin an experiment using human tissues.
The other great experience I had that taught me the importance of human tissue research was working with Paul and Randi Hagerman at UC Davis. Because they really are authorities on Fragile X-Associated Disorders (namely FXTAS), they were able to specifically acquire donated brain tissue from families that they studied during life. As such, whenever Jürgen and I undertook an experiments on post mortem tissues, our results were actually reported directly back to the families of the individual that made the donation. Importantly, there was never any pressure on me to find one thing or another, just that I be thorough and provide a clear, easy to understand analysis of my findings that could be given to the family. I was given the time to do things right and allowed to have a trained neuropathologist take the time sanity check my findings. In my opinion, this kind of openness with the families is commendable, and should be aspired to by all brain banks.
Unfortunately, I have also seen the bad sides of research using donated human tissues. I have watched as collaborators contact the Maryland or Harvard brain banks and ask for “just a small chunk from the frontal cortex” or request large blocks of tissue from “all the brains from [the population]”. I have also heard researchers request human tissue because they needed it to generate preliminary data for a grant-a grant that did not even contain human tissue research. This calloused approach, in my opinion, is highly disrespectful to the families and the individual that struggled with the decision to donate their brain-and did so on good faith that it would be used wisely.
Additionally, the imprecision I have observed in handling human tissues troubles me. In the cases I described above in my work, we had a standardized set of brain gyri from which 5mm squares of tissue were taken for molecular analysis. I have, on the other hand, seen brains that looked like a small spatula was used to wedge out chunks of brain tissue in random locations. I consider this type of behavior disrespectful to the individual that donated the brain, but also disrespectful for anyone who studies that brain later, since they lose a lot of ability to have complete, standardized section sets as random chunks of cortex have been removed.
Similarly, I have been in situations in labs when someone reaches into their -80C (or worse in one case, a -20C) freezer and finds a block of human tissue they had requested, received, and subsequently forgotten about. Usually this is laughed off as funny, but it always stung a bit to me that someone else could perhaps have made an important discovery using that tissue. But now they couldn’t if they wanted to because someone else didn’t show the requisite care and respect for the tissue they were given.
Now, these are clearly not indicative of how the whole of science treats human tissue. I only raise these points because I have observed these behaviors in a relatively short career working in the field. Most scientists treat tissue with respect and would not think of trying out use human tissue with anything less than their full attention.
This will be short, but situations like what happened at Harvard when there was a freezer failure Read more here. What gets my goat about this was the fact that a lot of tissue samples were moved from the various freezers they were in and accumulated into a single freezer so hugely could be showed off for PR. Greater than 150 samples were compromised, including 54 autism samples that took more than 14 years to collect. This was nothing short of catastrophic to the field of autism research because nearly 25% of autism samples in the world were compromised.
Needless to say, this provides an example of a situation where valuable human tissue was improperly used. They moved everything into one place and never moved it back. I find this despicable. Especially since my family had already donated my brothers brain-fortunately to the MIND Institute through the MIND Institute Brain Endowment for Autism Research Sciences (BEARS) Link.
My Story…Donating Kyle’s Brain to Science
My family and I have always known, since the 1980s that we were going to have Kyle’s brain donated to science. My parents had signed all the forms and everything. But 20+ years elapsed.
Kyle was in the hospital and I was confident he was not going to recover. Because I knew the researchers involved and trusted them, I sent an email and a text to the head of the MIND Institute BEARS to ask her how to proceed with a potential donation. This was extra tough since usually the donations are set up beforehand, not on the fly in the last days like I was requesting. As I was going to begin postdoctoral work in their research lab, they called around to verify the ethics involved with them taking the donation. Once it was determined there was no ethical issues, she forwarded me all the forms and instructions have my parents sign and the give to the nurses.
I still have the emails saved, in an 8 day period I have 47 emails back and forth coordinating the donation. In every single one of the emails you can read the compassion from the coordinators. They made me feel Kyle was not just another tissue opportunity for them.
Even though we had already decided to donate Kyle’s brain, signing forms is infinitely harder to do when a loved one is slowly dying in front of you. You invent a lot of hope, a lot of reasons why you should hold back and not give up. Maybe they will pull through. Maybe our doubt will negatively impact their progress…and so on. It always feels like the wrong time, like you are disrespecting your loved one…
It took a few days until the family was okay with signing the forms, because it was one more step explicitly forcing us to let Kyle go. To let Kyle die. For me, to lose a part of myself.
Within 24 hours, Kyle died, and the nurses whisked him away after my mother said her final goodbyes and the donation (his brain and eyes were donated to science) was taken care of very professionally. The donation was performed in such a way as to allow an open casket funeral, in other words, discretely. My family did not have to do anything. They did not have to explain their decision, or let anyone know they had made it…
Afterward, my mother and I had to “endure” what felt like constant phone calls from a social worker affiliated with the BEARS program trying to ascertain how we were doing. I appreciate this, and her for dealing with my half answers for six months. You do not think of the psychological health of the family after a brain donation, but I do still randomly break down crying when I think of Kyle for too long. I tear up in another way entirely when I allow myself to think that his brain might be used to uncover a deep mystery of autism. He might have the opportunity to contribute to science after his death in a way he never could during his life. In an odd sort of way, it gives me one more thing I can be proud of Kyle for.
My Proposal for moving Forward
Personally, I find all of the movement with the Neurobiobank intriguing and exhilarating. Perhaps we may be able to unlock secrets of developmental disorders, all we need are brains… However, upon reading the press releases further I note that Dr. Insel was citing innovative techniques like CLARITY as rationale for needing more tissue. In my eyes, such a justification is just plain wrong.
Honestly, if I found out a researcher as using Kyle’s brain as a means toward getting that elusive Nature paper and not to study a fundamental question related to autism, I would be livid. Thinking about the possibility infuriates me. Honestly, I would seriously consider hunting them down and punishing them. I’m not sure how, but mind you it would be unpleasant.
I have no problem with avante garde research, but I have yet to see how these new, “innovative” techniques could provide more data than the infinity of basic science methods that have not yet been performed in use tissue. Where is the cell counting? Where is the characterization of proposed disease states, microglial activation levels, glial abnormalities, neuronal architecture differences, etc? Are we going to bypass these studies and give tissue to those with cooler sounding techniques? I certainly hope not.
To prevent this, here is a somewhat Swiftian modest proposal I expect to be ignored, but in my opinion is needed now more than ever.
In order to get access to human brain or organ tissue, one needs to do the following:
Researchers would be required to submit an application similar to the background and aims in an RO1. This would be considered a grant and judged on scientific merit. As an appendix to the application, submit a specific justification for why human tissue is needed and how much is needed.
Broadly speaking, this means that instead of a simple request for tissue with a broad justification, the specific experiments being proposed along with the scientific rationale and proposed outcomes would be part of the application process. Similarly, progress reports would be submitted outlining where the scientists are in the project(s) they proposed. A secondary effect of a process like this is that the bar for human tissue research would be raised, such that tissue would not be given for pilot experiments or optimization of some new method without having the request pass muster with a scientific committee.
My parting thoughts are simple. We all see the need human brain and organ tissue to learn more about human disease. However, I feel that, as scientists, we need to raise the bar for the use of these precious tissues such that they are used only to answer specific questions about the disorder.
Despite any misgivings I stated above, I do plan on donating as much of my body to science as I will be allowed, including my brain to the MIND Institute BEARS. Are you? If so, I recommend filling out as much paperwork as you can early. It takes the burden off your family and loved ones.