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Director’s Blog: Wanted: A Few Good Brains

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Donated organs have saved the lives of many; most of us would gratefully receive a heart or kidney, and many of us willingly identify ourselves as potential donors for organs that can be used to restore health and life. It does not seem to be widely known, however, that there is a pressing need for donated postmortem brains—not for transplantation, which exists only in the realm of science fiction, but for research.

Even assuming an awareness of the need for human brain tissue, the notion of donating the brain after death gives many pause. This is perhaps because identity, our sense of self, resides in our brains, not our kidneys. But this squeamishness is unfortunate. Compared to what we know about the heart or the kidney, it’s humbling to realize how little we know about our brains. Basic facts, like the number of cell types, the wiring diagram, and the mechanisms of memory or mood remain mysteries with too many clues that so far are eluding our ability to put them all together into an overall understanding of brain function.

The mysteries of the brain are profound when we focus on disorders. When we talk about cardiac arrhythmias, we have a clear idea of the circuit involved and the source of the irregular heartbeat. It’s easy enough to talk about mental disorders as brain disorders or brain circuit problems. But do we really understand the circuitry for depression or psychosis or autism? Not by a long shot.

This lack of knowledge is especially remarkable because the last decade has been a golden age for neuroscience. The brains of invertebrates and some vertebrates have been carefully mapped and tools like optogenetics (which can be used to manipulate circuits) have given us a deeper understanding of the link between brain anatomy and brain function. Studies of genetically engineered mice have provided a precise molecular neuroanatomy that can be linked to function. We can learn a lot from studying mice, but what makes us human includes the parts of the brain that mice lack.

In fact, recent studies have revealed that the human brain is unique even at the most molecular level. For example, we know that experience is processed in the brain via epigenetics: with experience or learning, proteins bind to the genome in such a way that they turn on or turn off specific genes. Lister and colleagues recently reported that the mechanisms for epigenetics in the human brain appear to be different from those in any other organ.1 “Exceptionalism” is showing up more and more in brain studies: more of the genome is expressed in the brain than in any other organ, the brain develops faster than any other organ, the brain consumes more energy than any other organ. But much of what makes the human brain exceptional remains a mystery.

New tools like CLARITY, which allows study of 3-dimensional neuroanatomy, and the Human Connectome , which reveals the functional connections, promise to give us a new picture of the human brain, both in health and disease.2 The problem now is that we don’t have the brains to study. Yes, we have volunteers for “in vivo” studies using imaging techniques like functional MRI, but we lack donations of post-mortem brain for “ex vivo” studies which provide the most detailed anatomy. Relative to the many thousands of healthy and diseased hearts and kidneys that have been studied, there are a tiny number of brains donated from people who died with depression, psychosis, or autism. To make progress on brain disorders, we need brains.

This week, NIMH, along with the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke, announced the NIH NeuroBioBank  initiative, creating a new framework to collect, process, and store human brain tissue. Brains have been collected in the past, but by individual labs for individual disorders. The NIH NeuroBioBank is a strategy to collect tissue for many disorders and create a registry that will allow any scientist with a pressing question to have access to the tissue needed to find an answer. Data and tissue sharing have already transformed genomics. Sharing brain tissue is more complicated because, unlike DNA which can be replicated, the brain resource is not renewable. That’s why we need numbers.

We know this will not be easy. No one is lining up to donate brains the way they donate other organs or blood. But there is no other way. Blood cells are a wholly inadequate surrogate for learning about brain cell function, stem cells are promising but have not yet given us the complex connectivity of brain circuits, and brain imaging lacks the resolution we need to fully understand the biology of brain disorders. Brain donation is unpopular but it is critically important for scientists to understand autism, schizophrenia, depression, and other brain disorders. If we think these are brain disorders, it’s time to study the brain.

References

 1 Lister R, et al. Global epigenomic reconfiguration during mammalian brain development . Science 2013 Aug 9;341(6146):1237905. doi: 10.1126/science.1237905. Epub 2013 Jul 4.

 2 Chung K, et al. Structural and molecular interrogation of intact biological systems . Nature 2013 May 16;497(7449):332-7. doi: 10.1038/nature12107. Epub 2013 Apr 10.