As a graduate student in the 1980s, Bruce Yankner wondered what if cancer-causing genes switched on in non-dividing neurons of the brain. Rather than form a tumor, would those genes cause neurons to degenerate? To explore such what-ifs, Yankner spent his days tinkering with neural cells, using viruses to insert various mutant genes and study their effects. In a stroke of luck, one of Yankner’s insertions encoded a precursor to a protein called amyloid. Those experiments and later ones from Yankner’s own lab showed definitively that high concentrations of amyloid, as found in the brains of people with Alzheimer’s disease, are toxic to neural cells .
The discovery set Yankner on a career path to study normal changes in the aging human brain and their connection to neurodegenerative diseases. At Harvard Medical School, Boston, Yankner and his colleague George Church are now recipients of an NIH Director’s 2016 Transformative Research Award to apply what they’ve learned about the aging brain to study changes in the brains of younger people with schizophrenia and bipolar disorder, two poorly understood psychiatric disorders.
Yankner showed a few years ago that Alzheimer’s disease is associated with abnormally low levels of a protein called REST. It’s a transcription factor that represses neural genes from activating outside of the brain and nervous system .
REST was known primarily as a possible master switch that regulates early brain development. But his studies found the gene that encodes REST comes back on in the brains of older people. This boost of REST, associated with longevity and healthy aging, activates an anti-stress response that protects old brain cells from destructive molecules called free radicals and toxic misfolded proteins, such as amyloid, that cause them to degenerate and die.
Yankner now suspects that altered regulation of REST and its related networks of transcription factors, either due to particular mutations or stress early in life and even in the womb, might alter the brain’s circuitry, potentially predisposing people to schizophrenia or bipolar disorder. The team’s initial studies indeed suggest there are changes in REST activity in particular brain regions of people with either condition. They also have early evidence that the drug lithium, commonly used in treating bipolar disorder but for which the mechanism of action remains unclear, might work in part by boosting brain levels of REST.
To further explore these leads, Yankner and Church are producing induced pluripotent stem cells (iPSCs) from the adult skin cells of people diagnosed with schizophrenia and bipolar disorder. They then induce these patient-derived iPSCs to produce neurons that they can study in the lab.
The researchers will look for evidence that the function of REST and related transcription factors are altered in those neurons and in others edited to carry mutations linked to schizophrenia. In studies of mice lacking normal REST function, they’ll also examine the brain in search of changes associated with the two disorders.
But, for Yankner and Church, it’s not enough to know that REST levels in the brain are altered in these conditions. They also want to map the changes in gene activity and the function of REST with much greater spatial precision. To do that, they’re applying a groundbreaking technology called fluorescence in situ sequencing of RNA (FISSEQ). Developed in the Church lab, FISSEQ makes it possible to explore changes in transcription at the level of single neurons fixed within intact brain tissue, so that their spatial relationships are maintained.
With FISSEQ, Yankner and Church can observe genome-wide differences in transcriptional activity in individual cells without disrupting the brain’s complex biocircuitry. The FISSEQ technique can be applied to any organ in the body, but Yankner says that such a fine detail might be especially important for understanding the brain. That’s because the brain’s spatial organization is so essential to its proper function.
Despite decades of study, understanding the brain and the changes that come with psychiatric disorders and normal aging remains a major challenge. As Yankner, Church, and their teams continue to make great technological and research strides, clinical progress is expected to follow—and we need that as soon as possible.
 Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Yankner BA, Duffy LK, Kirschner DA. Science. 1990 Oct 12;250(4978):279-82.
 REST and stress resistance in ageing and Alzheimer’s disease. Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiácovo MP, Yankner BA. Nature. 2014 Mar 27;507(7493):448-54.
Bipolar Disorder (National Institute of Mental Health/NIH)
FISSEQ (Harvard Medical School, Boston)
Church Lab (Harvard Medical School, Boston)
Yankner Lab (Harvard Medical School, Boston)
Yankner/Church Project Information (NIH RePORTER)
NIH Director’s Transformative Research Program (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health