Neuroscience has come a long way since the staining and identification of the neuron by Camillo Golgi and Ramón y Cajal over a century ago. Now the field has joined forces with other disciplines such as chemistry, computer science, engineering, and psychology, creating areas of focus that range from individual cells to social communities. Combining specialties has helped progress the understanding of social behavior as well as various psychological disorders, which some say are the final frontiers in biological science. By Jacqueline Ruttimann Oberst
“By turning on or off specific neurons, one can identify their place in particular neurocircuits and how these circuits function in normal behavior or go haywire in disease. We can use this technology to identify molecular targets and develop better drugs.” —Feng Zhang
Ask neuroscientists to define the area that they are studying and one is bound to get a different answer every time. No longer fitting into one niche, the field can delve into the microcosm of molecules and cells but also expand out into the macrocosm of mankind itself.
“The complexity of issues we’re addressing now is at a completely different level than what we did 15 years ago,” says Nora Volkow, director of the U.S. National Institute on Drug Abuse at the National Institutes of Health (NIH). “In the past, it used to be one receptor in one area of the brain. Now we have the tools to monitor the complete system at any given point in time—that is, the entire brain and how it changes at short- and long-term intervals. We now can start to study all the proteins in the cell and their interactions, how cells communicate with one another to create networks, and how these relate to behaviors.”
Within the past 10–20 years, three areas have come on the scene: transdifferentiation, optogenetics, and social neuroscience. From the Lilliputian to the large-scale, these subfields all aid in puzzling together the various pieces that comprise the brain.
Cell Fate Realized: Transdifferentiation
Stem cells and regenerative medicine have worked their way into the field of neuroscience in the form of transdifferentiation. In this process, either a tissue-specific stem or precursor cell begets cells that it normally was not destined to produce. Transdifferentiation occurs in nature, albeit rarely. For example, when the lens of the eye is removed in salamanders, iris cells fashion themselves into lens cells.
Fifty years ago, cell fate conversion consisted of a cloning technique called somatic cell nuclear transfer, which allows somatic cell DNA to be inserted into an enucleated egg cell. The technology has spawned such animals as Dolly the sheep but has fallen short of cloning non-human primates. In 2005, the field became checkered when a South Korean research team, led by Woo Suk Hwang, claimed to have derived human embryonic stem cells using this technology, only to subsequently admit that they fabricated the data.
However, the field was redeemed one year later when Shinya Yamanaka’s group at Kyoto University in Japan utilized four embryonic stem cell genes—Oct3⁄4, Sox2, c-Myc, and Klf4—to convert mouse and human skin fibroblasts into embryonic stem cell–like cells called induced pluripotent stem (iPS) cells. Since then other researchers have used different gene or chemical concoctions to turn fibroblasts into iPS cells.
“One uses recipes kind of like in ‘The Joy of Cooking,’” explains Story Landis, director of the U.S. National Institute of Neurological Disorders and Stroke at the NIH. “Now you don’t have to start at an embryonic stem cell or induce a pluripotent stem cell. Instead, you can take a fibroblast and treat it in a special way to directly turn it into various cell types.”
The technique has various applications in neuroscience.
“Transdifferentiation gives you an unprecedented opportunity to study neurological diseases such as autism, schizophrenia, Alzheimer’s disease, and Parkinson’s disease,” explains Sheng Ding, senior investigator of the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco. “We hope to readily reprogram easily accessible somatic cells from a patient with one of these neurological diseases into iPS cells or directly into neurons to model the disease and develop personalized treatments.”
Postdoctoral researchers and graduate students interested in the field should enter now, according to Ding. He proposes that new therapeutics developed through iPS cell technology will be available in 10 years.
Shedding Light: Optogenetics
The brain consists of approximately 100 billion neurons—about the same number as stars in a galaxy. Each neuron can also have anywhere from 1,000 to 10,000 synapses. Depending on the type of information that a neuron is sending, the signaling speeds can vary from 0.6 m⁄s (in the case of transmitting pain) to upwards of 120 m⁄s (in the case of muscle stimulation). Hence neuronal mass and speed make studying brain functions daunting.
Scientists have used a variety of techniques to elucidate neuronal function, but each has its own shortcomings. Electrophysiological techniques that physically delve electrodes into brain tissue are restricted by the depth to which probes can be placed and have limited ability to distinguish a single cell type amongst the myriad of cells interspersed throughout the brain. Pharmacological or genetic manipulations can help isolate signals from specific cell types; however, the results are often slow to take effect, from hours or days to months.
Enter optogenetics or “the merging of optics and genetics to allow control of very well-defined events within a particular cell,” explains Karl Deisseroth, associate professor of psychiatry and bioengineering at Stanford University, who coined the term.
Gero Miesenböck, a physiology professor at the University of Oxford describes the technique as using “two flavors of light-responsive proteins: sensors that light up when a neuron becomes active and actuators that absorb light and turn activity on or off.”
Deemed “Method of the Year” by Nature Methods in 2010 and highlighted in the “Insights of the Decade” special section by Science that same year, optogenetics is a newcomer in the neuroscience realm, emerging less than 10 years ago.
This field however, borrows from observations and discoveries made 30–40 years ago. In 1979, Francis Crick pointed out the difficulty of using electrodes to pinpoint specific neurons in the brain and later speculated that light might be able to hone in on one type of cell and leave others unaltered. At the time though, no neuroscientist knew how to make neurons responsive to light. Over the years, biologists discovered many different kinds of light-responsive proteins, or opsins. Among these, ion channels that open when a chemical co-factor, all-trans-retinal, absorbs photons were found in algae.
However, the genes encoding these opsins were not identified until 2003, and neurobiologists focused rather on cell-directed tools that used combinations of custom-made chemicals and genes to alter neuronal function. Until 2005, when Deisseroth’s group discovered that these microbial opsins could precisely control neurons in response to light and, in 2006, showed that even adult vertebral tissues, including the brain, express natural all-trans-retinal.
Prior to these studies, Miesenböck’s lab had developed other strategies for optogenetic control of nerve cells by reassembling fruit fly (Drosophila) opsin signaling pathways in neurons or combining light-activated chemicals with introduced genes. In 2005, they “remote-controlled” fly behavior with light. His group also developed a genetic means to visualize nerve cell activity by creating synapto-pHluorin, a pH-sensitive form of green fluorescent protein.
Deisseroth’s group subsequently demonstrated the use of microbial opsins for neuronal control in freely moving mammals. They described fiberoptic interfaces that can be implanted in the brain to provide the light needed to activate these channels and target specific neurons in the recesses of the brain. Now, optogenetics is ubiquitous in neuroscience, and a variety of tools can be used to either activate or inhibit a neuron.
“It offers the best of all worlds: You can manipulate a specific cell type within a specific brain region, and you can do so with millisecond precision. This means that we can start to tease apart the functions of different cell types, activating or inactivating them to causally test their roles in brain function and behavior,” comments Joanna Mattis, a graduate student in Deisseroth’s lab.
Feng Zhang, a former graduate student of Deisseroth who is now an assistant professor of neuroscience at the Massachusetts Institute of Technology, adds: “By turning on or off specific neurons, one can identify their place in particular neurocircuits and how these circuits function in normal behavior or go haywire in disease. We can use this technology to identify molecular targets and develop better drugs.”
Optogenetics studies from Miesenböck and Deisseroth’s groups, as well as others, have literally and metaphorically shed light on neural codes relevant to Parkinson’s disease, autism, schizophrenia, drug abuse, anxiety, and depression. For future and current graduate students in neuroscience, Deisseroth advises that they follow their passion. “Students should pursue the things that interest them,” comments Deisseroth. “The history of optogenetics is a parable for maintenance of basic science research. These days everybody is trying to justify their biology work in terms of disease relevance. Whereas deep insights into neurology and psychological diseases have been provided using optogenetics, the essential tools for this work were taken from algae and archaebacteria, remote and odd forms of life that were studied for many decades by people who had no consciousness of disease relevance and studied them just for their beauty.”
Because of the breadth and depth of data that is now coming into the field, Zhang advises students to get multidisciplinary training. “Things are becoming high throughput and experiments are done on a shorter timescale. Before, it took a year to test a hypothesis, now one can do it in a couple of months,” he says. “Don’t just get training in biology, but also in computational biology and physics. The more versatile a person is, the more contributions this person will be able to make.”
Strength in Numbers: Social Neuroscience
The brain does not work in isolation and neither do humans. We are, after all, social creatures.
A new field has arisen from this idea—social neuroscience—the study of the neural, hormonal, cellular, and genetic mechanisms that define social species.
For 40 years, traditional neuroscience considered the nervous system as an isolated entity devoid of any significant influences from the social environment.
“Biology and social sciences, at best, were at odds,” explains John Cacioppo, who is one of the founders of the field and is now director of the Center for Cognitive and Social Neuroscience at the University of Chicago. “Biologists thought social processes had little relevance to the basic structure and function of human biology. Social scientists thought we were centuries away from biology being able to contribute to solutions to world wars, great depressions, and social injustices. There have been a lot of changes since then.”
These changes came from the convergence of data from psychology and biology studies using traditional animal models. For example, knowledge about social bonding (attachment, altruism, trust) advanced from the discovery that oxytocin and vasopressin receptors are localized in different brains regions of the more social prairie vole compared to the more solitary montane and meadow voles. Because of this research, clinical studies are emerging investigating intranasal oxytocin as a treatment for autism. “Social neuroscience has an application for various mental disorders, for example, depression and autism, since these all have a social component,” states Cacioppo.
The field draws upon numerous neurobiological techniques such as functional magnetic resonance imaging (fMRI), transcranial magnetic stimulation, electrocardiograms, and studies of patients with focal brain lesions.
“Social neuroscience is becoming more of a heavyweight in science now that we have tools, theories, and a common language to communicate with one another,” says Greg Norman, a postdoc in Cacioppo’s lab. “This is the science of the mind—not just psychology, not just biology—but the integration of the human condition. It encompasses many fields. You can be a geneticist or a sociologist and still be a social neuroscientist.”
This multidisciplinary approach can be both a strength and a weakness. Although more data is generated from collaboration, each discipline has its own jargon, often obfuscating each level of analysis.
“There is a challenge in trying to get people to use a common language instead of just talking past each other. And trying to understand how all the pieces fit into a whole is really difficult,” adds Norman. “Our field encompasses genetics all the way to the study of societies. You can be in this field for 100 years and still not comprehend its breadth.”
To avoid competition among the disciplines and bring them together, the Society for Social Neuroscience, for which Cacioppo is president, has separate awards—one for animal science and one for human science. But he hopes that in time, “we won’t have this distinction.”
State of (Neuro)Science
These additional facets of neuroscience—transdifferentiation, optogenetics, social neuroscience—reflect the overall state of science.
“Fifty years ago a solitary genius was doing the work, now the geniuses are working in teams,” says Cacioppo. It’s not only how science is performed that has changed, but also budgets.
“It’s the best of times and it’s the worst of times,” says Landis. “There are wonderful opportunities to use all of this technology but not enough funding for all of the possible projects. Choosing the most promising areas to pursue will require difficult choices.”
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This article was published as an advertising feature in the November 4, 2011 issue of Science.
Jacqueline Ruttimann Oberst is a freelance writer living in Chevy Chase, Maryland.