From The Quarterly, Summer 2013
An important new phase of research on the brain has begun and the Brain & Behavior Research Foundation is playing a critical role, funding NARSAD Grants for investigators with innovative ideas for developing new technologies.
What are these new technologies and what will they enable doctors and scientists to do?
The answers are so remarkable it almost makes them seem like science fiction. But these projects are already under way, with the potential to transform knowledge about the brain and treatments for brain and behavior disorders. In this feature, we highlight a few examples.
Stem Cell Technology: New Window Into Diseased Cells, Cell Therapy and Regenerative Medicine
Zhiping Pang, Ph.D., a two-time NARSAD Young Investigator Grantee, and others, are developing a technology that enables ordinary skin cells to be genetically reprogrammed to an earlier stage of cellular development, or transformed into other cell types, including brain cells, for scientific research and potential therapeutic purposes.
Dr. Pang, on the faculty of the Robert Wood Johnson Medical School in New Brunswick, New Jersey was awarded the Foundation’s Freedman Prize in 2012. With the support of his first NARSAD Young Investigator Grant in 2008 he figured out how to genetically induce mouse and human skin cells to change into cells functionally similar to an authentic neuron. The converted “iN” (induced neuronal) cell forms communication junctions called synapses with other nerve cells. It can generate the electrical impulses (action potentials) that “real” neurons use to do their communicating.
What can be done with such a technology? Dr. Pang is excited about several possibilities, each of which could be transformative. In one scenario, patients with a serious illness such as depression or schizophrenia might donate a few harmless skin cells that would then be “induced” to become neural-like cells. Dr. Pang hopes that such a converted cell would manifest all or at least some of the defects found in neurons native to that patient’s own brain. This could work similarly to how a biopsy works with physical diseases of the body in living patients and might provide otherwise unobtainable insights into brain disease pathology (where biopsies are too dangerous to perform).
Another approach is to use iNs, or another “induced” cell type called iPS cells, to perform cell therapy. iPS cells (induced pluripotent stem cells), often skin cells, are reprogrammed to the pluripotent state, a primitive developmental state in which they can be coaxed to mature into any one of a number of different cell types, including brain cell types. Diseased cells or neurons might be replaced with newly manufactured cells of the same type, made from these reprogram-med skin cells. This could slow or halt progression of the disease and might even have promise in reversing damage caused by illness. Dr. Pang stresses that this work is in its early stages and clinical applications aren’t ethical in people until more is understood about the biological properties of reprogrammed cells.
NARSAD Independent Investigator Grantee Hongjun Song, Ph.D., meanwhile, is studying stem cells in the brain to determine how they generate different kinds of brain cells in adulthood. These include neurons as well as “helper” cells (glia), which provide essential support for neurons.
Dr. Song is intrigued about niches in a brain structure called the hippocampus where stem cells live and can give rise to new neurons, a process called neurogenesis.
With the support of a 2008 NARSAD Independent Investigator Grant, he and colleagues discovered that any single stem cell is capable of both replacing itself and of giving rise to both neurons and glia. They also discovered that a lone stem cell can generate two new stem cells; that is, stem cells don’t just maintain the numerical status quo, or deplete in number, they can amplify their number. This was an unexpected finding, about which Dr. Song says: “If we can somehow cash in on this newly discovered property of stem cells in the brain, and find ways to intervene so they divide more, then we might actually increase their numbers instead of losing them over time, which is what normally happens, perhaps due to aging or diseases.”
These findings have significance for understanding processes involved in depression and schizophrenia, among other illnesses. The hippocampus is one area of the adult brain where neurogenesis is known to occur, and it’s also intimately involved in learning, memory and mood regulation. Research on stem cells opens a new window to understand how these illnesses may affect the development of new neurons in the adult brain. And this emerging technology and capacity may also lead to the development of regenerative medicine opportunities for patients with these illnesses.
Photon Lasers and Calcium Imaging
NARSAD Distinguished Investigator Grantee Rafael Yuste, M.D., Ph.D., has begun a highly innovative project that seeks to manipulate the activity of a rare class of brain cells whose malfunction is thought to generate pathologies seen in schizophrenia.
The cells in question, called chandelier cells, look very much like old-fashioned candelabras whose ‘branches’ connect with numerous excitatory neurons called pyramidal cells. These excitatory cells are the main type of neuron throughout the cortex, and mediate essentially all neuronal signals and commands involved in perception, memory and language. One chandelier cell connects with up to 500 excitatory neurons, and has the capacity to powerfully inhibit each one of them, in whole or in part. This could make them crucial switches in the cortex.
There is evidence suggesting chandelier cells are dysfunctional in schizophrenia, and Dr. Yuste is using a technology his team developed to modulate the activity of these cells in living animals. The technique employs a light-sensitive chemical derived from the metal ruthenium and ultrafast two-photon lasers to activate chandelier cells. The group combines this ruthenium photo-activation with calcium imaging, a technique, also developed by Dr. Yuste, which enables the team to monitor the activity of all cortical neurons simultaneously. “We’ve been working on these technologies for years,” says Dr. Yuste, “and now we’re using them together in this important project. By changing the firing pattern of chandelier cells, we hope to see if indeed they can control cortical activity. Their dysfunction could be the cause of the pathophysiology in schizophrenia.”
Some advanced technologies seem downright magical, including several in the research prospectus of NARSAD Distinguished Investigator Grantee Brian Litt, Ph.D. Dr. Litt’s interests range across the disciplines, from neuroscience, biology and chemistry to physics, computer science and materials science.
Dr. Litt is pioneering a new field called electroceuticals. These are medicines devices that use electrical impulses to modulate the body’s neural circuits. Unlike pacemakers and defibrillators, electroceuticals will be devices on the nanoscale, far too small to be visible to the naked eye. As now conceptualized, they would be ingested and would come into being as functional therapeutic units only after self-assembling once inside the body.
Dr. Litt’s lab “translates neuro-engineering research directly into patient care.” His current NARSAD Grant-supported project of creating an implantable nanoscale device is no pipe dream. He intends for the implanted device to deliver therapy for neurological illness. The device under development will be coated with antibodies, enabling it to find and bind to surface receptors in a specific type of nerve cell. Dr. Litt intends to preprogram the first generation of such devices to activate upon receiving a light or radio signal from outside the body.
According to Dr. Litt, such an approach could one day make feasible a unique class of non-invasive treatments for brain disorders. Nanodevices could be used to control or induce electrical signals in specific neuronal types or in specific spots in brain circuits, to correct or compensate for existing pathologies.