The mounting evidence that mental disorders are neurodevelopmental disorders does not make our job of finding causes and cures any easier. Clinical neuroscientists have always been challenged by not having direct access to the organ of interest. But if the key events for schizophrenia or autism are occurring during brain development, years before symptoms emerge, how can we possibly detect these events, let alone preempt them?
An answer may be emerging from the technology of induced pluripotent stem (iPS) cells . First reported in 2007 by Yamanaka and colleagues, iPS cells accomplish two remarkable feats. First, they convert adult skin cells into stem cells, that is, cells capable of growing into many cell types. Then, by varying the chemical environment, these “de-differentiated” cells are differentiated into neurons or other mature cell types in a dish. This would be the stuff of neuroscience fiction — if it weren’t real. This is nothing less than a way to reprogram a patient’s easily-obtained skin cells into his or her own neurons, theoretically allowing us to fathom the secrets of that specific individual’s disorder. And, perhaps someday, to use the information to inform that patient’s treatment — or maybe even engineer a one-on personalized treatment.
Notwithstanding the more ambitious potential applications in personalized medicine, this tool might make it possible to study the molecular and cellular workings of neurodevelopment, even in an adult with a brain disorder. While most applications of this groundbreaking technology have focused on disorders caused by a single gene mutation, could this approach work for schizophrenia or bipolar disorder?
Brennand and colleagues from the Gage lab at the Salk Institute reported 1 last month that iPS cell-derived neurons from schizophrenia patients developed fewer connections, or synapses, with each other than those from healthy controls. Patients’ neurons also had fewer projections. The researchers traced this to altered expression of some 600 mostly synaptic genes, a fourth of them previously implicated in schizophrenia. Among several antipsychotic medications introduced into the cultured neurons, one stand-out, loxapine, normalized all patients’ synapses — and each of the other meds benefited synapses from at least one of the four patients studied.
Just a month earlier, Chiang and colleagues from the labs of Margolis and Ming at Johns Hopkins University reported 2 similarly deriving neurons from iPS cells from two related patients harboring mutations in a gene involved in schizophrenia, DISC1, and a healthy control. They are in the process of studying how the DISC1 mutation affects neuronal function, with an eye to identifying molecules that might serve as drug targets. They are also working on creating more iPS cell-derived neurons from other members of the DISC1-affected family.
Some of the most dramatic progress, to date, using iPS cells has been emerging from studies of autism spectrum disorders (ASD). Marchetto and colleagues from the Muotri lab at the University of California San Diego last November announced 3 that they had not only identified several abnormalities in iPS cell derived neurons from Rett Syndrome patients, but also reversed them by treating with insulin growth factor 1, which had corrected symptoms in mice with the same mutation. Like the schizophrenia-related neurons, those from Rett patients had fewer synapses.
Ricardo Dolmetsch of Stanford University, and colleagues, have discovered an abnormal proliferation of neurons that produce dopamine and norepinephrine in children with some classes of ASDs. Using iPS cell and automation technologies, the researchers are compiling such cell biological defects into a “phenotypic fingerprint” of individuals with ASDs that can be related to their genetic profiles.
As Dolmetsch points out4, for complex disorders like schizophrenia and autism, which likely stem from multiple rare genetic variations, experimental animals such as knockout mice can’t capture the genetic diversity of humans. Nor can postmortem brain tissue provide the same kind of developmental window into the illness process — or serve as the basis for screening assays – as live neurons from a patient. Nor can they trace the functional consequences of a particular gene variant.5
To nurture such advances, NIMH last fall convened a meeting of NIH-supported investigators using iPS and other stem cell approaches to model psychiatric disorders. As with any new technology, there are still a number of wrinkles to iron out. For example, a virus is often used to deliver the reprogramming cocktail, with the risk of introducing genes foreign to the cell. And it is now clear that iPS cells are not equivalent to embryonic stem cells in that they retain some traits of their cell of origin. To work out many of these technical issues, the NIH Common Fund last year launched an intramural iPS Cell Center on the Bethesda campus.
From astronomy to microbiology, new technology has often been the portal to new understanding. For neurodevelopmental disorders, iPS cells could be a transformative technology that allows us finally to study how and when brain development goes off track. But these are still early days in the iPS era. These recent papers are just a first glimpse into what may be a new way of understanding normal and abnormal neurodevelopment.
- Modelling schizophrenia using human induced pluripotent stem cells . Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage FH. Nature. 2011 Apr 13. [Epub ahead of print] PMID: 21490598
- Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation . Chiang CH, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL, Song H, Ming GL. Mol Psychiatry. 2011 Apr;16(4):358-60. Epub 2011 Feb 22. No abstract available. PMID: 21339753
- A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells . Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. Cell. 2010 Nov 12;143(4):527-39. PMID: 21074045
- Induced pluripotent stem cells: A new tool to confront the challenge of neuropsychiatric disorders . Vaccarino FM, Stevens HE, Kocabas A, Palejev D, Szekely A, Grigorenko EL, Weissman S. Neuropharmacology. 2011 Jun;60(7-8):1355-63. Epub 2011 Mar 1. PMID: 21371482