Sight Recovery After Blindness Offers New Insights on Brain Reorganization

PASADENA, Calif.--Studies of the brains of blind persons whose sight was partially restored later in life have produced a compelling example of the brain's ability to adapt to new circumstances and rewire and reconfigure itself.

The research, conducted by postdoctoral researcher Melissa Saenz of the California Institute of Technology along with Christof Koch, the Lois and Victor Troendle Professor of Cognitive and Behavioral Biology and professor of computation and neural systems, and their colleagues, shows that the part of the brain that processes visual information in normal individuals can be co-opted to respond to both visual and auditory information. That brain reorganization persists even if the blind subjects later regain their vision--for example, through technologies such as corneal stem-cell transplants, retinal prosthetics, and gene therapy.

"Sight-recovery patients can face many challenges in using restored vision because of brain reorganization that occurs during prolonged blindness. Understanding this brain adaptation will be useful for helping patients make the best use of their restored vision," says Saenz.

Researchers scanned the brains of two individuals whose sight had been recovered decades after having been lost. One volunteer, Michael May, was blinded in a chemical accident at the age of three, and then he had his vision partially restored in his left eye at age 46 through a corneal stem-cell transplant. The second subject, a 53-year-old woman, had been blind since birth because of damage to the retina and cataracts. At age 43, sight in her right eye was partially restored by cataract removal.

Each subject listened through headphones to several types of sounds including speech, frequency sweeps (simple tones whose frequency changes), and sounds that appeared to be "moving" horizontally from one side of the head to the other (the illusion was created by increasing the volume or timing of sounds delivered to either the left or the right speaker) while lying in a magnetic scanner.

This allowed Saenz to monitor changes in blood flow that are closely linked to the underlying neuronal activity in a region of the brain called MT+/V5, which is specifically involved in visual motion processing. Ten test subjects with normal vision were similarly studied.

Only in the two individuals with recovered sight did the MT+/V5 region light up in response to sound. No response was seen in the control subjects.

"Previous studies had shown that a variety of new sensory functions move into the visual cortex when a person loses their vision, especially when vision is lost as a young child, when the brain is very adaptable," says Saenz. "Our data show for the first time what happens to the new sensory responses if a blind person has the chance to see again. The sound responses didn't go away. They persisted together with the restored visual responses, even after many years with regained sight."

Most interestingly, the MT+/V5 region reacted only to auditory motion, but not to other types of auditory stimuli. In other words, moving sound activated a part of the brain that is normally reserved for processing moving visual images.

"This wasn't a random takeover. We didn't find responses to all types of sounds, but specifically to moving sounds. This brain reorganization was efficient and took advantage of this region's specialized role in motion processing," she says.

"Our volunteers with sight recovery gave us the unique opportunity to answer the question of whether the different sensory response in a blind person activates a specific visual area (MT+/V5). Normally, the location of this area is variable and is identified in sighted people by how it responds to visual stimulation, not based on anatomical landmarks alone. So we couldn't convince a critic that we identified this area in someone who was still blind."

In fact, According to Saenz, such multitasking may contribute to the strong ability to perceive motion--as opposed to the poor visual acuity--that has been seen before among patients who have recovered their sight after a lifetime of blindness.

"This study demonstrates the plasticity inherent in even adult brains and the very tight linkage between neural activity in particular pieces of gray matter and the subject's perception in the privacy of his and her mind," Koch says.

"When my vision was restored after 43 years of being totally blind, I had no idea of the complexity of how our brain sees," says test subject Michael May. "It is through vision scientists that I have had a front-row seat in learning about how I perceive the world with my new vision. Turns out that the integration of all my senses, tools, and techniques has been the key to a maximum life experience."

The paper, "Visual motion area MT+/V5 responds to auditory motion in human sight-recovery subjects," was published in the May 14 issue of the Journal of Neuroscience.

Go to http://www.klab.caltech.edu/~saenz/soundstimuli.html for samples of the auditory stimuli.

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Kathy Svitil
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Illusions of the Present

PASADENA, Calif.--Have you ever noticed that signposts and trees on the side of the road seem to whoosh by faster right as you drive past them, or that a door frame seems to curve outward as you approach it? These are just two examples of real-life movements that underlie more than 50 types of illusions, now systematically organized and explained by scientists at the California Institute of Technology.

The systematization also lends a glimpse into how illusions are not simply tricks your brain likes to play on you; they are manifestations of how the visual system evolved to keep up with real-life motion. These illusions now fall into 28 predictable categories defined by Mark Changizi during a fellowship in the Sloan-Swartz Center for Theoretical Neurobiology at Caltech and appearing May 28 in the journal Cognitive Science.

"I had been reflecting on the classical geometrical illusions always shown in Psychology 101 classes--the ones involving lines and vanishing points--and it struck me that I can explain them," Changizi says.

To picture a geometrical illusion, imagine a spoked bike wheel with two squares superimposed on it in different places. The square closer to the center, where the spokes meet--called the vanishing point--will always seem larger than the square toward the rim of the wheel. In other words, the closer an object is to the vanishing point, the larger it appears.

Your brain thinks that you are physically moving forward. In real life, forward motion would generate "spokes" on the eye's retina, "like in Star Trek, when they go into warp speed," Changizi describes. It would also bring you closer to that square near the wheel's center, naturally making it seem larger than the other object. "Your brain generates a perception of what the world will be like in the next moment because by the time that perception finally occurs--it takes about a tenth of a second--that object will be larger," explains Changizi.

"Later I realized that my same old idea could be radically generalized, so that it made predictions not just about geometrical illusions, but about 27 other illusion classes as well," Changizi says. "I realized that I could make a massive pattern of predictions about the kinds of illusions humans are subject to."

Changizi built a table, a matrix that distributes the different kinds of illusions into four columns distinguishing what visual feature is misperceived (size, speed, luminance, and distance), and seven rows indicating the different kinds of optical features that occur when an observer is moving forward. "Each spot in this table makes a prediction about perception," he says.

From there, Changizi culled a century's worth of papers reporting what people see when they look at different kinds of illusions. "There are hundreds of illusions collected like butterflies over the years," he notes, "with no real systematics behind them. Just a massive heap of illusions." He wanted to see if each individual case would fall into one of the 28 classes he had designated. "I found that the disordered pile of illusions followed the predicted pattern, and I was able to arrange the illusions in an orderly fashion inside the unifying matrix."

Changizi believes these illusions arise from the way the visual system evolved to process and react to visual cues. Called "perceiving the present," the theory explains, for example, why your hand is ready to hit the ball in a game of tennis: your brain translates the ball's motion into where it will be when you hit it.

"Motion is crucial to the story of illusions. What you perceive is a premonition, not present reality!" Changizi notes. Shinsuke Shimojo, a biology professor at Caltech and a coauthor on the report, explains, "We have evidence from other studies showing that when you perceive a moving object, you localize it in the current position because your brain normalizes it. The brain has been trained via genetic and learning processes to compensate in dynamic situations. This paper says even more--that the brain applies the same algorithm to perceive a static image. Nobody had come up with this theory to explain all illusions in this framework."

The potential applications that the new organization of illusions presents are dizzying. Movies or video games, for example, could incorporate illusions to "make someone perceive motion when the object is actually motionless," Changizi suggests. Another possibility: street signs or other visual warnings could incorporate visual tricks to grab attention, by having a pattern that seems to bulge, spiral, or turn redder as the viewer approaches.

Changizi is now an assistant professor of cognitive science at Rensselaer Polytechnic Institute. Other authors on the study are Andrew Hsieh, a former Caltech undergraduate student now at the University of Southern California; Romi Nijhawan, a psychologist at the University of Sussex in England; and Ryota Kanai, a former postdoc in Shimojo's lab now at the Institute of Cognitive Neuroscience in London. 

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Elisabeth Nadin
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Unraveling the Genomic Code for Development

PASADENA, Calif.-- Scientists at the California Institute of Technology have produced the first complete description of the complex network of genes that create a particular type of cell in an organism.

Scientists have known for decades that the program for development is encoded in the genome, the total genetic complement of any living thing. "Cats beget cats and frogs beget frogs, so how you develop depends on what genome you've inherited," says Eric H. Davidson, the Norman Chandler Professor of Cell Biology at Caltech.

Just knowing the sequence of the genome, however, won't get you far. To actually make a cat or a frog, you need to understand the relationships between genes--what genes control other genes, turning them on or off at specific times during the development of the organism to produce an organism's skeletal system, or leaves, or skin. Biologists call the complex network of gene interactions involved in this process a gene regulatory network.

In 2006, the Baylor College of Medicine Human Genome Sequencing Center, along with Davidson and Andy Cameron of Caltech, and an international team of researchers from more than 70 institutions, revealed the entire 814 million base-pair sequence of the genome of the California purple sea urchin (Strongylocentrotus purpuratus). The genome is about one-fourth the size of the human genome, and contains some 23,300 genes.

Using these data and other techniques to determine the regulatory genes expressed at each point during embryonic development and how their interrelationships influence the architecture of the sea urchin's skeletal system, Davidson and his colleagues created a complete blueprint for the development of a lineage of cells whose particular function is to build a series of biomineral skeletal rods inside the embryo.

The work, coauthored by Qiang Tu, a postdoctoral research fellow at Caltech, and Paola Oliveri, now of University College London, appears in the April 22 issue of the Proceedings of the National Academy of Sciences.

Unlike a regular blueprint, which describes how to simultaneously construct all of the various parts of a structure, the gene regulatory network represents a dynamically changing plan, with the relationships between genes at one stage providing the program for the next stage of development.

According to Davidson, the research marks the first time that all of the "moving parts"--the regulatory genes specifically expressed in a particular developmental process that recognize target DNA sequences, bind them, and control the expression of other genes--have been included in a gene regulatory network.

"We've reached the point where all of the biology that you see in a microscope for this cell lineage can be interpreted in terms of what we know about this control program. The network concerns only one day in the life cycle of an animal that lives for 50 or a hundred years, and only one cell lineage of the embryo, but it is a step forward to be able to relate the biology to the regulatory DNA sequence in this way."

In a commentary accompanying the published paper, biologist Leroy Hood of the Institute for Systems Biology describes the study as a "tour de force." The research, he says, "represents a brilliant integration of biology, technology, computational approaches, and powerful logic." The paper, he adds, "will be the model for many more that will undoubtedly follow, transforming the landscape of developmental biology and ultimately elucidating the molecular systems that drive development."

The major effort in the Davidson lab is to decipher the gene regulatory networks that control the rest of the embryonic development of the California purple sea urchin.

That information will reveal for the first time the code for a whole embryo, a small but complex creature. At that point, scientists can begin to tinker with and re-engineer the network--a process that simulates the genetic changes that accompany the evolution of organisms in real life. "The evolution of animals is due to changes in the structure of these gene regulatory networks, so this work provides us with an opportunity to study evolution in a new and decisive way," he says.

Indeed, in a second paper in the same issue of the journal, Davidson and his colleague Feng Gao report that the gene regulatory network for the sea urchin's embryonic skeletal development evolved from another network present in adult animals, and probably was co-opted into the embryonic network by hijacking a big piece of the regulatory apparatus that controls the construction of the adult skeletal system. 

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Two Faculty Members Join American Academy of Arts and Sciences

PASADENA, Calif.--Caltech professors Michael Dickinson and Thomas Palfrey are among the 190 new fellows elected to the American Academy of Arts and Sciences this year. They join an assembly that was founded in 1780 by John Adams, James Bowdoin, John Hancock, and other scholars to provide practical solutions to pressing issues.

Their election brings the Caltech total membership to 86.

Thomas Palfrey, Caltech's Flintridge Foundation Professor of Economics and Political Science and also a Caltech grad (PhD '81), specializes in the study of voting and elections, economic and political theory, public and experimental economics, and game theory.

A central focus of Palfrey's research is how people devise strategies when faced with incomplete information. He has applied game theory to examine voting behavior in committees and elections, and bidding in auctions. He founded or cofounded several experimental labs, including the California Social Science Experimental Laboratory at UCLA, the Social Science Experimental Laboratory at Caltech, and the Princeton Social Science Experimental Laboratory, and used observations from experiments to help develop a general theory of strategic behavior with human error. Called Quantal Response Equilibrium, it has been successfully applied to study a broad range of political and economic behavior.

Michael Dickinson, the Zarem Professor of Bioengineering at Caltech, studies animal physiology and behavior. He has become well known for Robofly, a mechanical fly that sprang from his work on the neurobiology and biomechanics of fly locomotion. Throughout his career, Dickinson has used a variety of tools, such as wind tunnels, virtual reality simulators, high-speed video, and giant robotic models, to determine how the poppy seed-sized brains of these tiny insects can rapidly control aerodynamic forces.

More than a simple understanding of the material basis for insect flight, Dickinson's studies provide insight into complex systems operating on biological and physical principles: neuronal signaling within brains, the dynamics of unsteady fluid flow, the structural mechanics of composite materials, and the behavior of nonlinear systems are all linked when a fly takes wing.

"The Academy honors excellence by electing to membership remarkable men and women who have made preeminent contributions to their fields, and to the world," says Academy president Emilio Bizzi. "We are pleased to welcome into the Academy these new members to help advance our founders' goal of 'cherishing knowledge and shaping the future.'" An independent policy research center, the Academy currently focuses on science, technology, and global security; social policy and American institutions; the humanities and culture; and education.

Dickinson and Palfrey will be inducted into the Academy at a ceremony on October 11, at the organization's headquarters in Cambridge, Massachusetts.

Other new members include legendary blues guitarist B. B. King, two-time cabinet secretary and former White House Chief of Staff James Baker III, and former eBay CEO Margaret Whitman, as well as foreign honorary member Pedro Almodóvar, a Spanish film director. 

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Elisabeth Nadin
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Decoupling through Synchrony

PASADENA, Calif-In the brain, as in sports, sex, and life, timing--and teamwork--are everything. Such is the message of a series of studies by researchers at the California Institute of Technology that offer insight into the processes by which memories are stored in the brain and that may someday guide the development of new therapies to prevent epileptic seizures.

Using computer models of neuronal circuits and experiments on live rats, Athanassios Siapas, assistant professor of computation and neural systems at Caltech, and his postdoctoral researcher Evgueniy Lubenov are revealing the curious mechanism by which the brain spontaneously tips itself toward a state balanced between order and chaos. The driving factor in the brain's self-regulation, they say, is the timing of neural pulses.

The researchers looked at how the timing of pulses fired by neurons in a simulated network (and, later, within the brains of freely roaming rats) interact with the plasticity in the synaptic connections between those neurons to influence the system as a whole. The studies revealed that when neurons fire in synchronized bursts, their harmony is fleeting; over time, the very act of synchrony tends to decouple the neurons, so that they become less organized, and their subsequent firing patterns more random.

Conversely, when neurons initially fire in a more random pattern, the randomness leads to strengthening of connections that drive the system toward a more synchronized firing pattern.

"Networks self-organize to an intermediate state, in between the two extremes," Siapas says.

Beyond its relevance to a basic understanding of neuronal circuits, the study may also prove significant for other, more clinically important, research. For example, overly synchronized neuronal firing is a characteristic of seizures in patients with epilepsy. Researchers have recently begun studying the effectiveness of deep brain stimulation in epilepsy patients. In the procedure, a device called a brain pacemaker is inserted into the brain, where it delivers electrical pulses to targeted regions.

"If this stimulation translates into the generation of synchronous events, it could decouple a possible locus for synchronous activity, while guiding the selection of targets for deep brain stimulation," thus reducing seizures, says Siapas. "One can fight synchrony with synchrony," he says, although he stresses that this is merely a conjecture and not based in experimental evidence.

The research also points to a mechanism by which short-term memories could be transferred from the hippocampus, a brain region involved in memory formation, to the neocortex, the area where long-term memories are held.

Neuroscientists have long known that during slow-wave sleep, the hippocampus exhibits a surge in synchronized neural firing directed to the neocortex. "This simultaneous activity is very effective at driving cortical neurons and strengthening the interactions between them," Lubenov says, and thus consolidating that information in the neocortex. In essence, a permanent memory is formed.

"We believe those same synchronous bursts also have a consequence for the memory trace in the hippocampus itself," Lubenov says, which is related to the self-organization that he and Siapas found in the system.

Their idea is that because synchronized neural firing in the hippocampus during this information transfer acts to desynchronize the system, it would reduce the strength "and lead to the gradual weakening of the hippocampal memory trace," Siapas says. Indeed, in experiments on rats implanted with electrodes, the researchers found a reduction in the simultaneous firing of neurons over the course of slow-wave sleep, indicating a move from synchrony to asynchrony. Eventually, through this process, a memory trace--unless reinforced through experience--would be erased from the hippocampus, freeing up neural resources there that could then be used to store new memories.

The paper, "Decoupling through synchrony in neuronal circuits with propagation delays," appears in the April issue of the journal Neuron.

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Kathy Svitil
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Geneticist Giuseppe Attardi Dies

PASADENA, Calif.--Giuseppe Attardi, whose work linked degenerative diseases and aging to genetic mutations, died at his home in Altadena on Saturday, April 5. He was 84 years old.

Attardi, the California Institute of Technology's Steele Professor of Molecular Biology, was among the first scientists to delve into the processes through which DNA's information is transferred. He identified all the genes of the DNA in human mitochondria--often called the powerhouses of biological cells. He then developed techniques for investigating genetic diseases, including Alzheimer's, and aging in general, which he discovered is associated with changes in mitochondrial DNA (mtDNA).

Born in 1923 in Vicari, Italy, a town of less than 3,000 people in the Province of Palermo, Attardi earned an MD from the University of Padua in 1947. He remained there for almost 10 years as an assistant professor in the Institute for Histology and General Embryology. During those years, he also visited the Karolinska Institute in Stockholm, Sweden, as a research fellow in cell research and genetics, and the Washington University in St. Louis School of Medicine as a Fulbright Fellow.

Still on the Fulbright Fellowship, Attardi arrived at Caltech in 1959. He was appointed associate professor of molecular biology four years later. It was at Caltech that Attardi turned his interests to mitochondria, establishing that mtDNA is an active, working genome. This spurred research into the organelle's genetic machinery.

David Chan, an associate professor of biology and Attardi's colleague and friend, credits Attardi with being a leading figure in identifying the products and functions of the mitochondrial genome. Attardi and a student developed a technique in which they replaced the mtDNA of a human cell line with the mtDNA from diseased cells. This allowed them to distinguish the roles of mtDNA and the genome of the nucleus--where the rest of a cell's DNA resides--in causing the disease. With this technique, they could also examine the relationship between changes in mtDNA and changes in cell function caused by the disease. "Many labs have used his approach to understand how mutations in mtDNA diseases affect mitochondrial function," Chan says.

"Giuseppe was one of the founders of what is now a central and still-expanding area of molecular cell biology," adds Attardi's colleague and friend Gottfried Schatz, emeritus professor of biochemistry at the University of Basel's Biozentrum, in Switzerland. "His unique insights bore magnificent fruits with the landmark description of the transcription map of mammalian mtDNA, as well as the precise characterization of the mechanism of mitochondrial diseases and the dynamics of human mitochondrial genomes."

In recent years, researchers in Attardi's lab at Caltech have focused on how mtDNA replicates, and on detecting mutations that result from aging, and what effects those mutations have. The team discovered that older people carry a significantly greater number of genetic defects in a specific region of their mtDNA, suggesting that cell aging begins in the mitochondria.

"He has been a central figure in mitochondrial research for several decades. One of the things I will always remember about him is his constant excitement for all types of biological questions," Chan says. "I think his intense curiosity is one reason he accomplished so much as a scientist."

Schatz adds, "To him, science was everything and he never tired of discussing the latest experiments. Yet he also embodied a vanishing breed of scientists whom I would define as 'gentlemen intellectuals.' He had a superb grasp of European history and world culture, had mastered French and German at a very high level of proficiency, and even in his most spirited discussions refrained from personal invective or overt aggression. To me, he was an example of how science can keep us young in spirit, and ennoble us."

During his career, Attardi garnered several distinctions. They include two Guggenheim Fellowships; election to the National Academy of Sciences; the Antonio Feltrinelli International Prize for Medicine from the Accademia Nazionale dei Lincei; a degree of doctor honoris causa from the University of Zaragoza, Spain; the Passano Foundation Award; and the Gairdner Foundation International Prize.

Attardi is survived by his wife and fellow researcher, Anne Chomyn, a senior research associate, emeritus, at Caltech; a son, Luigi Attardi, of Rome; a daughter, Laura Attardi, of Palo Alto, who is a professor of cancer biology at Stanford University; and a grandson, Marcello Attardi, of Palo Alto.

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Elisabeth Nadin
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New Rosen Bioengineering Center Funded

PASADENA, Calif.- Seeing a burgeoning new research field at the interface of biology and engineering, the Benjamin M. Rosen Family Foundation of New York has donated $18 million to the California Institute of Technology to establish the Donna and Benjamin M. Rosen Bioengineering Center.

"Ben and Donna Rosen are recognizing how critical bioengineering is to the future of Caltech, science, and society, and they also appreciate the power an endowment can have in sustaining such an initiative," said Caltech President Jean-Lou Chameau. "The Institute is fortunate to have them as friends."

The Rosen Center will advance both basic scientific exploration and development of engineering analysis and synthetic approaches. Innovations in these areas are resulting in rugged and inexpensive diagnostic devices, in new insights into the functioning of the heart, and in the engineering of molecular devices capable of recognizing and responding to disease processes in individual cells.

Bioengineering developed at Caltech in recognition of the fact that biology is becoming more accessible to approaches that are commonly used in engineering, including mathematical modeling, systems theory, computation, and abstraction-based synthesis. At each level of organization, from the molecule to the cell to the organ, the accelerating pace of discovery in the biological sciences reveals new design principles that are of fundamental importance in understanding living organisms, and that will have important practical applications in future synthetic biological and biomedical systems and devices.

"Bioengineering arose at Caltech from the grassroots efforts of a handful of committed faculty coming together to establish a graduate option with great enthusiasm," said Scott Fraser, the Anna L. Rosen Professor of Biology and professor of bioengineering, who will lead the new center. "This gift will endow the program allowing it to foster the most innovative collaborative research. Such funding fuels innovation by offering support to venturesome efforts far earlier than would be possible through conventional granting agencies."

"There are a few times in history when diverse sciences, technologies and researchers fortuitously come together at the same time and at the same place to make possible great achievements for mankind," said Rosen. "This is one of those times, and Caltech is one of those places. We're honored to be able to play a small part in helping start this exciting new Caltech Bioengineering Initiative."

According to Ed Stolper, Caltech's provost, "Our current challenge is to provide an intellectual and programmatic focus for our growing teaching and research programs in bioengineering, spanning synthetic, systems, and computational biology; biomechanics and bio-inspired design; and development of novel biotechnologies. The Rosen Center will provide such a focus and critical support for these activities, which span many of the Institute's existing programs."

"Caltech's Bioengineering Center will foster the foundational work that will blossom into the next generation of tissue regeneration and diagnostic instrumentation," said Fraser. "The results of these innovations will make tools once considered too futuristic for anything but science fiction films into practical devices that can be carried in a physician's rear pocket."

Ben Rosen was founding chairman of Compaq Computer Corp. and a founding partner of Sevin Rosen Funds, a venture capital firm that has provided initial financing for more than 100 technology companies. Previously, he was vice president and senior electronics analyst at Morgan Stanley & Co., and before that he was an electronics engineer at Raytheon and Sperry Gyroscope. In 1992, Computerworld chose Rosen as one of 25 people in the computer industry "who changed the world." Rosen joined Caltech's board of trustees in 1986 and became chairman in 2001. He is also a member of the board of overseers and managers of Memorial Sloan-Kettering Cancer Center, a member of the board of overseers of Columbia Business School, and a director of the New York Philharmonic. Rosen earned a bachelor's degree in electrical engineering at Caltech in 1954. He also earned a master's in electrical engineering from Stanford and an MBA from Columbia University.

Donna Rosen was the former owner/director of Galerie Simonne Stern in New Orleans for 23 years until she moved to New York in 2002. She pioneered the New Orleans Warehouse District as the "Art District of New Orleans." She is a national trustee of the New Orleans Museum of Art; vice chairman of the board of American Friends of the British Museum; board member of The Society of Memorial Sloan-Kettering Cancer Hospital; and trustee of Second Stage Theater.

 

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Jill Perry
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Fly Flight Simulators Reveal Secrets of Decision Making

PASADENA, Calif.-- Even flies like video games--and it's not just child's play, say scientists at the California Institute of Technology. With the help of a unique bug-sized flight simulator, Caltech researchers are deciphering the secrets of behavior and decision making in the fly brain, and, ultimately, in our own.

Using the simulator, Michael Dickinson, the Zarem Professor of Bioengineering at Caltech, along with postdoctoral students Gaby Maimon and Andrew Straw, has discovered an algorithm that guides decision making during the flight of Drosophila melanogaster, the common fruit fly. The algorithm is basically a set of rules that determine how flies will behave when confronted with one of two simple stimuli: long vertical stripes or small spots. A paper describing the work appears in the March 25 issue of the journal Current Biology.

Their experiments were conducted on both free-flying flies and on flies tethered within a virtual-reality flight simulator. In the flight simulator, flies could steer toward or away from images displayed on an electronic panorama.

"We can present the fly with different scenes and the fly reacts to them, like a 12-year-old boy playing a video game," says Dickinson.

Although the insects couldn't actually fly anywhere, they were free to beat their wings, and that motion was recorded with optical sensors, providing a measure of the direction in which the flies intended to fly. For example, a fly wanting to turn left would beat its right wing harder and vice versa.

The experiment revealed that flies are attracted to, and will fly toward, the vertical line, but are repelled by the small spots.

"One way to interpret this is that the fly's brain is programmed to fly toward big vertical edges, because it evolved in a world where big vertical edges indicate vegetation," says Dickinson. A simplistic example would be a tree--although Dickinson points out that the fly, with its tiny brain, need not have any concept of "tree."

"A vertical edge could be something to eat, or it could be a landmark of something to land on," says Maimon. "With a fly's low-resolution eyes, each equivalent to a 700-pixel camera, the world is literally a blur, so edges are a good landmark. Fly toward it and you know you're flying straight, and by following these landmarks, from vertical edge to vertical edge, you can search through space, and eventually find something good to eat."

Small blobs, however, could represent just about anything in a fly's environment that it would not want to either land on, such as a falling leaf or other debris, or to collide with--say, a spider in a suspended web, or another benign insect. If you're a flying Drosophila and you see a little blob? "You'd do well to turn away," Dickinson says.

The results are significant, Dickinson says, because they represent "an important step toward understanding processes like decision making, which we think from our own perspective should be complicated, but which in the fly emerge from a simple set of principles."

"Humans make decisions all the time, about whom to marry, where to go to school. We hope that understanding how a smaller brain makes decisions will let us understand how a primate brain works, and understand it faster. It's a jumping-off point," says Maimon.

The results also offer important insight into the origin and nature of complexity. "The mission of our lab is to understand where complexity comes from," says Dickinson. "Fly behavioral activity is relatively uncomplicated, yet flies achieve amazing aerodynamic feats with a level of complexity that is astonishing if we think about them as an engineering entity. By understanding that, we can understand where complexity comes from."

That knowledge opens other doors, Dickinson says.

"Engineers would like to be able to build simple things that behave in complex ways, like a power grid or a robot, and one of the best ways to figure out how to get complex behavior from simple things is by studying biological organisms. It's Model Biological Systems 101: study an animal that's easy to study, and then extrapolate.

"If we knew enough, could we build a fly? The answer is yes, but it will take a while."

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Kathy Svitil
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Pupil Dilation Marks Decision Making

PASADENA, Calif.-- The eyes may be the windows to the soul, but the simple pupil--the circular opening at the center of the eye that contracts and dilates to regulate the amount of light the eye receives--offers a remarkable portal to the inner workings of the brain. Such is the conclusion of neurobiologist Christof Koch of the California Institute of Technology and his colleagues, who have found that changes in pupil diameter correspond to the moment when a simple decision is made.

Koch, the Troendle Professor of Cognitive and Behavioral Biology and professor of computation and neural systems and the author of The Quest for Consciousness: A Neurobiological Approach, working with former postdoc Wolfgang Einhäuser of the Swiss Federal Institute of Technology and Olivia Carter of Harvard University, discovered the phenomenon in volunteers viewing ambiguous stimuli. These stimuli, or "percepts," consist of images or sounds that can be correctly interpreted in either of two forms, such as the famous optical illusion of a young girl wearing a feathered hat. The image morphs into a picture of an old crone, and vice versa.

Another, more straightforward example, used in the current study, is the so-called "Necker cube," a simple line drawing consisting of two connected but offset squares that form an interlocking cube. The cube can appear to either jut out from the page, or to be inverted into the page.

Either interpretation is correct, but because both cannot be seen simultaneously, our brains will flip back and forth repeatedly between the two. "Essentially, the switch occurs so that our brain can check out the other one," says Koch. "Bistable percepts are fascinating because nothing changes in the real world. Everything changes in your head."

In their experiment, the researchers presented six volunteers with four types of ambiguous stimuli. Three were visual--including the Necker cube--and one was auditory (a sound that could be interpreted as either a single tone or two separate ones). The volunteers viewed or listened to the stimuli--and pressed a key on a keyboard when a perceptual shift occurred-- when the Necker cube flipped from inverted to outward, for example, or back again. At the same time, infrared eye-tracking software measured the diameter of the subjects' pupils.

The scientists found a significant increase in the diameter of the pupil at the instant preceding the perceptual switch. The pupil, which is about 2 mm wide in bright light, dilated by as much as 1 mm at that moment--a change that, in theory, could be noticeable to a casual observer. Koch and his colleagues also found that the more the pupil dilated, the longer the period of time before the switch from one interpretation to the other

Pupils dilate and contract not just in response to light levels, but also depending on the chemical state of the brain. For example, drugs such as opiates cause the pupil to constrict to pinhole size, while the drug MDMA, or "ecstasy," causes it to dilate. In the normal body, the pupils dilate largely in response to norepinephrine (or noradrenaline), the neurotransmitter responsible for our "flight or fight" response to dangerous situations. Because the subjects' pupils dilated at the moment their brains decided between one form of the ambiguous stimuli and the alternative, the scientists say, norepinephrine may also be important in rapid, unconscious, low-level decisions--including what we see from one moment to the next. The pupil-dilating effect also may explain the ability of some professional poker players to detect "tells"--information about their opponents' cards--by looking at the other players' eyes.

"The pupil is not only there to regulate light, but is linked to our emotional state. This may have evolved for us to monitor the emotional state of others, and may offer a very simple way to track decision-making in general," says Koch.

The paper, "Pupil dilation reflects perceptual selection and predicts subsequent stability in perceptual rivalry," was published in the early online edition of the Proceedings of the National Academy of Sciences.

Writer: 
Kathy Svitil
Writer: 

Neurogenetics Pioneer Seymour Benzer Dies

PASADENA, Calif.--Seymour Benzer, a founder of the field of modern genetics, died from a stroke on Friday, November 30, at Huntington Hospital in Pasadena. He was 86.

An emeritus professor at the California Institute of Technology, Benzer's lasting impact on modern-day genetics can be seen in continuing work whose foundations he helped lay. Studies in gene mutations and regulation and in the genetic underpinnings of behavior can all be attributed to his groundbreaking research.

A native of New York City, Benzer attended Brooklyn College, earning a bachelor's degree in physics in 1942. After getting his PhD in physics at Purdue University in 1947, he stayed on to teach the subject. A visit to Cold Spring Harbor Lab in 1948, followed by a two-year stint as a postdoctoral scholar at Caltech in the lab of Nobel Laureate Max Delbrück, introduced Benzer to the field of bacteriophage genetics, the study of viruses that infect bacteria. He immersed himself in it.

At Purdue, Benzer pioneered a technique of recombination in mutant bacteriophages, providing the first evidence that a single gene can be divided. He proved that mutations are distributed throughout many parts of a single gene through experiments that are widely regarded as among the most elegant in modern genetics. They are also thought to have laid the foundation for the later understanding of the fine structure and regulation of the gene.

Benzer returned to Caltech as a biology professor in 1967. His work with bacteriophages led him to experiments with Drosophila melanogaster. He used mutants of this fruit fly to pioneer the field of neurogenetics, and his lab discovered the first circadian-rhythm mutants in a series of studies of how genes affect behavior. These experiments were replicated for other animal models and formed the foundation for the field of molecular biology of behavior. In his recent work, Benzer studied neurodegeneration in fruit flies in an attempt to find an approach for suppressing human diseases by modeling them, and for uncovering the genetics of aging.

Throughout a career that spanned physics, biophysics, molecular biology, and behavioral genetics, Benzer garnered many honors. His memberships included the National Academy of Sciences, the Royal Society, and the American Academy of Arts and Sciences. He was awarded the National Medal of Science, the Wolf Prize in Medicine from Israel, the Crafoord Prize of the Royal Swedish Academy of Sciences, the International Prize for Biology from Japan, the Albert Lasker Award for Basic Medical Research, and the Albany Medical Center Prize. He was also one of few two-time winners of the Gairdner International Award.

In 2000, Benzer was the subject of the book Time, Love, Memory: A Great Biologist and His Quest for the Origins of Behavior, by Pulitzer Prize-winning author Jonathan Weiner. Of the widely acclaimed book, reviewer Lewis Wolpert in his review for the New York Times wrote, "Benzer has many gifts beyond cleverness. He has that special imagination and view of the world that makes a great scientist."

Benzer was active in his lab at Caltech until his death. Last year he spoke at the centennial celebration of his former mentor Delbrück, fondly recounting the lab shenanigans from more than five decades ago.

"Seymour was one of the great scientists of our era and made fundamental contributions in several areas," says Elliot Meyerowitz, the Beadle Professor of Biology and chair of Caltech's Division of Biology. "He was an amazing person, a truly original scientific thinker, and an adventurous character both in and out of his scientific work. Everybody knew him, and enjoyed his legendary wit. He was a central part of the life of the biology division and we will all miss him."

"It was a great privilege to be able to work with him," adds David Anderson, Caltech's Sperry Professor of Biology and investigator with the Howard Hughes Medical Institute. Anderson was recruited by Benzer in 1986 and switched fields to begin working on behavior in flies in 2002. "I'm very proud that I was able to publish with him. He was a revered colleague and mentor and I'm going to miss him. He was a giant in science. He started an entire field, and few people can claim to have done that."

Benzer is survived by his wife, Carol Miller; two daughters, Barbara Freidin and Martha Goldberg; a son, Alexander Benzer; two stepsons, Renny and Douglas Feldman; and four grandchildren. Services are pending.

Writer: 
Elisabeth Nadin
Writer: 

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