Better Models for Brain Disease NEWS FEATURE Traditional Animal Models Have Had Limited Success Mimicking Mental Illnesses

NEWS FEATURE Better models for brain disease NEWS FEATURE Traditional animal models have had limited success mimicking mental illnesses. Emerging technologies offer the potential for a major model upgrade. Helen H. Shen, Science Writer Starting with just a tiny chunk of skin, neuroscientist Flora Vaccarino tries to unlock mysteries hidden inside the brains of people with autism. By introducing certain genes to the skin cells, the Yale University School of Medicine researcher reprograms them to an embryo-like state, turning them into induced pluripotent stem cells (iPSCs); and with two more months of nurturing and tinkering, Vaccarino can guide the cells to develop into small balls of neural tissue akin to miniature human brains. Less than two millimeters across, these “cerebral organoids” don’t look or work exactly like full brains. But they contain many of the same cell types and un- dergo some of the same key developmental pro- cesses as fetal brains. Also key, the cells perfectly match the genetic makeup of the adults and children with autism who donated the original skin samples, allowing Vaccarino’s team to track the very beginnings of their disorder. Human brain tissue usually can’t be collected and studied until after death, and by then, it can be too late to glean important insights. “You don’t get to see the same person’s cells progressing through a series of steps and time points, like we do with these organoids,” Vaccarino explains. “The organoids are a very powerful system. You can actually change things and see what the outcome is going to be.” Neurons such as these, derived from the induced pluripotent stem cells of a Parkinson’s Predicting outcomes and, crucially, developing disease patient, are on the forefront of efforts to improve models for brain disease. psychiatric drugs has proven exceedingly difficult in Image courtesy of Cedric Bardy and Fred H. Gage (The Salk Institute, La Jolla, CA). recent decades. Inadequate animal models have been a major stumbling block, researchers say. First de- is the first time that we’ve been able to begin digging veloped in 2013 (1), cerebral organoids grown from deep into the causes and neurobiology of these human iPSCs—affectionately called minibrains by ” some—are one of several emerging technologies that disorders. are finally allowing researchers to make more sophis- ticated models of neuropsychiatric disorders. Ad- The Mouse Problem — vances in genomics are also helping to shed new For decades, traditional animal models commonly, — light on mental illnesses by pointing researchers to genetically engineered mice have allowed scientists ’ new gene targets. These, in turn, can be combined to manipulate the brain s cells, genes, and molecules, with recent precision gene-editing techniques to revealing some basic but important insights. Modi- make animal models that many researchers hope will fied mice, for example, have helped reveal how mis- more faithfully reproduce aspects of human diseases, folded versions of the α-synuclein protein gunk up such as Alzheimer’s, autism, and schizophrenia. the Parkinson’s-diseased brain and possibly injure “It’s a very exciting time,” says Guoping Feng, a neurons. Mice with mutations linked to Alzheimer’s neuroscientist at the Massachusetts Institute of Technol- disease have helped scientists examine how mis- ogy (MIT) in Cambridge, Massachusetts. “Between the folded amyloid-β protein collects into sticky plaques technology development and the genetic findings, this in the brain. www.pnas.org/cgi/doi/10.1073/pnas.1605358113 PNAS | May 17, 2016 | vol. 113 | no. 20 | 5461–5464 Downloaded by guest on September 25, 2021 electrical properties or abnormal numbers of cell-to- cell connections (synapses) are thought to be involved in several psychiatric disorders, and synapse formation and function appear very similar between mice and humans. “There’s no such thing as schizophrenic behavior in mice, but if I can prove a particular gene causes the same synaptic defect in humans and in mice, and I can correct it in my model, then that has hope as a treatment,” says Feng. Creating Better Copies Even with greater focus on basic biological mechanisms, researchers must know which genes and mutations to incorporate into models. This alone has proven challenging. But large-scale genomic studies of humans, facilitated by cheap DNA sequencing, are beginning to reveal new candidates, including some To study brain disorders in living human tissue, researchers grew this cerebral for schizophrenia, a disease whose genetic contribu- ’ organoid from stem cells derived from a healthy donor s skin sample. In this cross- tors have long perplexed scientists. section, the neurons are green, progenitors are red, and nuclei are blue. Image courtesy of Madeline A. Lancaster and Juergen A. Knoblich. Reproduced from ref. No single genetic abnormality accounts for a large 1, with permission from Macmillan Publishers: Nature, copyright (2013). number of cases of the disease. Instead, researchers have found many potential hits across different people, each with a relatively small effect on schizophre- But most current mouse models simply can’t cap- nia risk, says Pamela Sklar, chief of the psychiatric ture the genetic, cellular, or behavioral complexity of genomics division at Mount Sinai Hospital in New human psychiatric conditions, researchers argue. In York City. “The sample sizes are only now just getting many cases, researchers have struggled to clarify the large enough in schizophrenia to be able to do some genes and mutations required to replicate brain dis- fine mapping and localizing of genetic risk factors,” orders in mice. In others, scientists have been ham- says Sklar. pered by fundamental differences between mice and In 2014, the Psychiatric Genomics Consortium, an humans in brain structure and function. international research collaboration, announced their Without knowing precisely which molecular or ge- genome-wide scans of more than 150,000 people had netic defects to copy, researchers have tried to make found 108 regions associated with risk for schizo- animal models that at least mimic human psychiatric phrenia (3). And within the chromosomal region with symptoms. In one common test for depression-like the strongest links to schizophrenia risk identified so behaviors, for example, they measure how long mice struggle against being held upside down by the tail. far, a team led by researchers at Harvard Medical (Animals that give up sooner are typically judged as School reported in January that they had pinpointed a showing greater “despair.”) But such strategies have gene that could be a major contributor to the signal met with increasing skepticism, especially in light of coming from this area (4). The C4 (complement com- the lack of therapeutic breakthroughs. ponent 4) gene encodes a set of immune system “We can make models by challenging mice in dif- proteins, and the team found that the more people ferent ways and looking at their behavior, but it’snotat expressed one particular form of C4 protein, the all clear that these animals have the same disease that greater their risk of developing schizophrenia. In the we do,” says Fred H. Gage, a neuroscientist at the Salk neurons of newborn mice, researchers found that C4 Institute for Biological Studies in La Jolla, California. expression ramped up during the period when cell- Feng echoed these concerns in a 2015 commen- to-cell connections normally get pruned and refined. tary (2) in Nature Medicine, criticizing the over- When the researchers made mice with a disabled C4 interpretation of many current mouse models of gene, they saw decreased pruning, leading them to brain disorders, in particular those based primarily on speculate that overproduction of C4 could lead to early matching behavioral signs rather than known or sus- hyperactive pruning in people with schizophrenia. pected mechanisms. Among his caveats: mice lack a Beyond finding new genes to tweak, identifying well-developed prefrontal cortex, an area that in hu- the precise mutations in those genes that affect peo- mans is thought to mediate higher cognitive functions ple, and replicating them in mice will be equally im- and appears to play a role in disorders such as autism portant, says Feng. Many past studies have used and schizophrenia. “knockout” mice, which are designed to fully disable “I’m not saying mice are not useful for schizo- one or both copies of the gene of interest, to un- phrenia studies, but it’s important to understand the derstand a gene’s effect. But in reality, human patients limitations,” says Feng. Instead of relying on hard-to- often exhibit more subtle mutations that alter gene interpret mouse behaviors, Feng and others have ar- function rather than eliminate it entirely. “If you don’t gued in favor of modeling disease-related changes make the precise human mutation, you might be in basic neuronal properties. For example, aberrant studying the wrong disorder,” says Feng. 5462 | www.pnas.org/cgi/doi/10.1073/pnas.1605358113 Shen Downloaded by guest on September 25, 2021 Feng has been investigating how different muta- contact to communicate rather than to convey ag- tions in the Shank3 gene contribute to certain forms of gression. From a practical perspective, they also cost either schizophrenia or autism. In a paper published in less than macaques to maintain because of their January, Feng’s group created two lines of mice, each smaller size and the fact that entire families live to- carrying a human mutation associated with one of the gether in a single cage (9). conditions (5). Although the models showed some In February, scientists published the first behavioral neural deficits in common, mice with an autism-asso- descriptions of marmosets engineered to overexpress ciated mutation developed problems earlier in life, the methyl CpG binding protein 2 (MeCP2) gene (10); including weakened neuronal signaling in the stria- people with mutations in MeCP2 or extra gene copies tum, which is involved in certain repetitive or compul- develop syndromes that include autism symptoms.

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