Cerebrum Winter 2020

These models offer us a way to study things we have never had access to before.

“We’ve now cured Alzheimer’s disease a dozen times over in mice, but we haven’t cured it in human patients,” said Matthew Blurton-James, Ph.D., a neurobiologist at the University of California, Irvine. “There’s clearly a big species difference in how this disease develops, which means our current animal models can’t get us the answers we’re searching for.” In the past few years, however, advances in technology have led to the development of innovative models to study the activity of human neurons— and how they communicate with one another. Such models, which include ex vivo tissue harvested from living human donors, organoids, and chimeric models (animal tissue modified with human genes or cells), are enabling scientists to investigate processes in ways that were previously unthinkable. “These new technologies, including those that use induced pluripotent stem cells (iPSCs), are really quite striking,” said Walter Koroshetz, M.D., director of the National Institute of Neurological Disorders and Stroke. “And the real advantage of these is that they offer us a new way to study human brain cells, particularly when it comes to developmental processes, that is incredibly valuable.” Despite that value, there are numerous concerns, both practical and ethical, surrounding the use of such models—concerns that experts say should be addressed now before the technologies that support the development of models dramatically outpace scientific policy and oversight regarding their use. Understanding the Models What do you imagine when you hear the term, “brain in a dish?” Or “human brain experimental model”? It may conjure an image straight out

of a science fiction movie—a full-size, pulsating brain in a jar of fluid that can think and feel, even without a body. At first glance, said Jonathan Ting, Ph.D., a researcher at the Allen Institute, most people wouldn’t even realize that most of these new experimental models are made of human brain tissue. His own laboratory is using sugar cube- sized samples of ex vivo tissue—actual brain tissue harvested from consenting patients undergoing brain surgery—to better catalogue the variety of cell types found in the human cortex. “We now have the ability to collect tissue from the operating room and then transport it to our lab by ambulance and keep it alive with oxygen for a few days,” he explained. “That allows us to gain a deep understanding of the composition of the brain in different regions, including how many different cell types reside there, and what their defining molecular, morphological, and anatomical properties are. It gives us a strong foundation to understand the component parts of the brain – and use that as a jumping off point to understand what may go wrong in disease.” Yet Ting’s tissue models, taken from adults, can tell us little about the developing brain. Hence researchers like Paola Arlotta, Ph.D., chair of the Department of Stem Cell and Regenerative Biology at Harvard University, are using organoids, or so- called “mini-brains,” three-dimensional, self-organizing tissue cultures derived from human iPSCs, to study how brain cells come together as the brain grows. Arlotta said most people have no idea what organoids look like—instead of life-sized, fully functioning brains, they are actually 4-to-5-millimeter pieces of tissue that resemble potato gnocchi rather than any bodily organ. But despite their small stature, Arlotta

said, these assemblages of cells allow scientists like her to investigate both brain development and the genetic aspects of disease in a very precise manner. “You don’t have to be a neuroscientist to know that an animal model is different than a human,” she said. “While animal models have been essential, there’s only so much we can learn. And as we have no access to actual human brain development and how different genes contribute to that, since so much occurs in utero, we have not been able to experimentally study it. Organoids, as primitive as they are, offer us the opportunity to ask new questions and do some of those experiments.”


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