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.

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Kathy Svitil
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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.

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Elisabeth Nadin
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Southern California Institutions to Collaborate on Stem Cell Research

New partnership to maximize discovery potential through shared facilities, resources and programs

PASADENA, Calif.-- Research institutions across Southern California have joined forces to advance stem cell research by establishing the Southern California Stem Cell Scientific Collaboration (SC3). Members of the collaboration include the California Institute of Technology; University of Southern California; Childrens Hospital Los Angeles; City of Hope; the University of California, Santa Barbara; and the House Ear Institute.

"The potential applications for stem cell research in medicine are enormous," says Martin Pera, PhD, director of USC's Center for Stem Cell and Regenerative Medicine. "Tackling these complex problems requires scientists with diverse expertise. We are delighted to have an opportunity to work with such an outstanding collection of scientists to really accelerate the pace of discovery and translational research in regenerative medicine."

Through grants from organizations such as the California Institute for Regenerative Medicine (CIRM) and the National Institutes of Health, SC3 members have a long history of partnering on various research projects. The new agreement is a major step forward in supporting potential significant stem cell findings by allowing members to share training programs, scientific core facilities, and expertise, and to team up on a wide range of research programs.

"For patients and their families, cures for cancer, HIV/AIDS, and other diseases cannot come soon enough," says Michael A. Friedman, MD, president and chief executive officer, City of Hope. "As an institution, City of Hope is working to speed advances in medical science to improve and save lives. We believe the SC3 collaboration provides a critical mass of expertise that will create new knowledge and significantly accelerate treatments for diseases that impact so many."

"Stem cell research is vibrant at Childrens Hospital Los Angeles because of the long-term commitment of our hospital to support high-quality research in general, and stem cell research in particular," says Gay M. Crooks, MD, director of the Stem Cell Program at Childrens Hospital Los Angeles and professor of pediatrics at the Keck School of Medicine of the University of Southern California. "We believe that such innovative research should be available to the children of California."

Each institution will appoint a faculty member to serve on a joint scientific advisory committee, which will serve as a forum to develop collaborative research ventures, facilitate access to scientific resources, and provide expertise across the collaboration. Regional seminar programs and courses, such as the ongoing CIRM-funded stem cell biology course offered jointly by USC, Caltech, and Childrens Hospital Los Angeles, will be expanded to allow additional participation. The agreement also ensures that each member will give investigators access to resources for training or for conducting short-term research projects.

"The SC3 collaboration is already engendering new ideas for collaborative projects between scientists at the participating institutions. UC Santa Barbara will benefit from shared resources and synergistic collaborations in stem cell research as part of a proposed Center for Stem Cell Biology and Engineering," says Dennis Clegg, chair of molecular biology and director of the Stem Cell Program at UC Santa Barbara.

UC Santa Barbara has a CIRM-funded stem cell training program and a shared lab facility. Research in the proposed center will focus on two areas of basic and discovery stem cell research: molecular mechanisms and bioengineering. The long-term goal will be the application of results to the development of stem cell-based therapeutics for human disease, particularly macular degeneration.

"The ultimate goal of the collaborative stem cell research at the House Ear Institute is the regeneration or transplantation and successful functioning of sensory cells and other cell types in the inner ear to restore hearing," says David Lim, MD, executive vice president of research, House Ear Institute (HEI).

Scientists at HEI have discovered that sensory cell progenitors (stem cells) in the inner ear (cochlea) are supporting cells that may help manipulate hair cell regeneration to restore hearing. Future work seeks to more fully understand the biology of these two pathways, while at the same time examining their potential in therapeutic approaches to hair cell regeneration.

"We look forward to the establishment of this new stem cell collaboration. The shared facilities should move this important science along considerably faster," says Paul H. Patterson, the Biaggini Professor of Biological Sciences and director of the stem cell training program at Caltech.

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Kathy Svitil
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Neuroscientists Uncover Brain Region Involved in Voluntary Behavior

PASADENA, Calif.-Scientists at the California Institute of Technology have deciphered the activity of an area of the brain that could one day prove vital in the development of neural prostheses--within-the-brain implants that would translate thought into movement in paralyzed patients. The results of this study were published as the featured article in the November 8 issue of Neuron.

Richard A. Andersen, the James G. Boswell Professor of Neuroscience at Caltech, and his postdoctoral fellow, He Cui, looked in particular at the posterior parietal cortex (PPC), a higher brain region where sensory stimuli are transformed into movement.

To tease out the functions of two subregions of the PPC, the parietal reach region (PRR) and the lateral intraparietal area (LIP), Cui and Andersen designed an experiment in which rhesus monkeys were allowed to freely chose one of two actions, an eye movement or an arm movement, to acquire a visual target. Prior to the monkeys' selection, a computer program "guessed" which of those two actions would be performed by the monkeys, and picked the opposite movement as the choice to be rewarded. (The monkeys were essentially playing a matching game.) The computer's choices were biased by the previous choices made by the monkeys, which gave the monkeys an incentive to mix up their choices. Without it, they would invariably opt for the eye movement, which is the less energetically taxing of the two.

When the monkeys chose the arm movement, the PRR showed the most activity; when the monkeys opted for the eye movement, the LIP was most active.

The experiment shows that it is "the monkey's own choice that activates these areas," says Cui, and not the sensory stimuli provided by the visual target it sees on the computer screen. This finding is significant, Andersen says, because "this is the earliest stage in the brain found so far that is actively related to movement plans."

The research in Andersen's laboratory is focused on understanding the neurobiological underpinnings of brain processes, including the senses of sight, hearing, balance, and touch, and the neural mechanisms of action. The lab is working toward the development of implanted neural prosthetic devices that would serve as an interface between severely paralyzed individuals' brain signals and their artificial limbs--allowing thoughts to control movement. To assist in designing a more optimal prosthetic, they are now examining whether the decision to make a reaching motion is first made in PRR, or is made in another area of the brain and then transferred to PRR to form the movement plan.

"These areas are prime targets for neural prosthetics. The better we understand these areas, the better we can design prosthetics to decide the subjects' intent," Andersen says.

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Kathy Svitil
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Brain Imaging Aids in Defense against Genetic Disease

Pasadena, Calif.--Children born with a rare genetic disorder that can lead to debilitating and irreversible brain injury may find protection with the aid of brain imaging and a modified diet.

Caltech researchers joined scientists at Penn State College of Medicine to study the signs of glutaric aciduria type I (GA-I), a disorder arising from a gene defect that blocks a child's ability to break down the amino acids lysine and tryptophan. Lysine in the blood stream goes straight to the brain, where acids concentrate and damage the mitochondria, the brain's energy producers. The team made two significant discoveries: all the mice fed a tailored diet survived the disorder symptom-free, and signs of impending brain injury could be detected with brain imaging techniques.

The findings are available online this week in the latest issue of Journal of Clinical Investigation.

A rare disorder in the general population, GA-I affects around 1 in 35,000 children in the United States. However, 1 in 400 Amish children are born with GA-I-sometimes called "Amish cerebral palsy"-because in their small communities, chances are higher that two carriers of the recessive gene will marry. Not all children with the disorder will develop symptoms, but when a GA-I-affected child gets an inflammation from a mainstream illness like the flu, they can suffer a stroke. Despite current treatments, GA-I can lead to severe brain damage, painful crippling, or death in 25 to 30 percent of children who have it.

Jelena Lazovic, a postdoctoral scholar in biology, specializes in imaging brain injuries. She had spent the six months prior to her 2004 arrival at Caltech working in a clinic specializing in genetic disorders like GA-I. So when Penn State biologists Keith Chang and William Zinnanti--her husband and the study's lead author--asked her to lend her expertise to studying the disease in mice, she was happy to get on board.

Lazovic and Russell Jacobs, a researcher at Caltech's Biological Imaging Resource Center, began with magnetic resonance imaging (MRI) of mice that Zinnanti fed with a high-lysine diet, in order to pinpoint the regions of the brain affected by GA-I. Zinnanti used a "knockout" mouse model that lacked the functional gene that is disrupted in children with the disease. He discovered that increasing the level of lysine in the mouse diet could trigger a brain injury that was strikingly similar to those caused by GA-I in human patients.

The disease affects a region of the brain called the striatum in a manner similar to Huntington's disease. "We first thought we need to image the mice to see what areas of the brain will get damaged when we give them a lysine diet," says Lazovic. Other approaches to the problem are invasive, she says, but "imaging seemed to be the most convenient; it's in vivo and the findings can translate to humans." At the imaging center, Lazovic and Jacobs put the mice in an MRI machine first to get a brain image, and then to run proton nuclear magnetic resonance spectroscopy. The peaks of the spectroscopic reading reveal different compounds, called metabolites, which aid in growth and development. "Each peak is like a fingerprint with its own frequency," says Lazovic, and the area under a peak shows how much of the metabolite is present. The team found that one of the brain's more important metabolites, a neural transmitter called glutamate, is actually reduced just before brain injury occurs

One aspect of the disease that puzzled the scientists was the appearance of symptoms primarily in children younger than age three. Zinnanti found the same age-dependent brain-damage susceptibility in his mice. The scientists think that young mice are more susceptible to GA-I because their immature brains metabolize and accumulate more lysine than an adult brain does. The young mice were also seen to develop hypoglycemia just as patients with GA-I do.

Using a dietary intervention strategy, Zinnanti and colleagues showed that a combination of homoarginine, which limits lysine accumulation in the brain, and glucose, which prevents hypoglycemia and reduces lysine breakdown in the brain, can prevent brain injury in 100 percent of susceptible young mice. Lazovic's and Jacobs's spectroscopic analyses may also provide a means to monitor children with GA-I for impending brain injury, something that has previously been impossible. Children who test positive for the genetic deficiency at birth could be monitored on a monthly basis.

"We had no pointers as to what was happening with these kids," says Lazovic. "Now we think we have a method where you can do spectroscopy on the children, and you can measure decreased glutamates, and you can tell that energy production in the brain is suppressed." The technique may also help with other genetic disorders that inhibit amino-acid metabolism, like maple syrup urine disease (so called because of the sweet smell it gives infants' urine), propionic acidemia, and methylmalonic academia. Each of these affects children at about the same rate as GA-I, and is more prevalent in tight-knit communities.

"This disease is certainly a major concern in the Amish community, so it's something they know to be on the lookout for," Zinnanti says. "But it also affects children around the world, and it's ten times worse when you're not expecting it and don't know what to look for. We hope our work begins to offer tools for these patients and their caregivers to diagnose and treat this disorder before it causes irreversible damage."

Other authors of the paper are Cathy Housman, Kathryn LaNoue, Ian Simpson, James Connor, and Keith Cheng of Penn State; James O'Callaghan of the Centers for Disease Control and Prevention; and Michael Woontner and Stephen Goodman of the University of Colorado at Denver.

Writer: 
Elisabeth Nadin
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Caltech Neuroscientist Named to Institute of Medicine

PASADENA, Calif.-- Richard A. Andersen, the James G. Boswell Professor of Neuroscience at the California Institute of Technology, has been elected as a member of the Institute of Medicine (IOM). Andersen is one of 65 new individuals to be admitted to the elite organization, which was established in 1970 by the National Academy of Sciences and now has 1,538 active members. It is recognized as a national resource for independent, scientifically informed analysis and recommendations on human health issues. By their membership, inductees agree to volunteer their time on IOM committees examining health policy issues.

Andersen studies the neurobiological underpinnings of brain processes, including the senses of sight, hearing, balance, and touch, and the neural mechanisms of action and is a pioneer in the development of implanted neural prosthetic devices that would serve as an interface between severely paralyzed individuals' brain signals and their artificial limbs--allowing thoughts to control movement. Andersen says, "It's a very exciting time in neuroscience. After decades of study, our basic research is finally yielding findings we are able to translate into clinical advancements to help paralyzed people. Caltech has provided a unique environment for such study, as we in our lab have enjoyed close collaboration with bioengineers, electrical engineers, economists, and physicists as well as clinicians toward developing a neural prosthesis. The next step is to move our studies into clinical trials with human patients, an endeavor we will enter jointly with the medical community."

Andersen received his PhD from the University of California, San Francisco, in 1979, and was a postdoctoral fellow at Johns Hopkins Medical School. He was on the faculties of the Salk Institute and MIT before joining Caltech in 1993. He is a member of the National Academy of Sciences, and a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science. He is the recipient of a McKnight Foundation Scholars Award, a Sloan Foundation Fellowship, the Spencer Award from Columbia University, a McKnight Technical Innovation in Neuroscience Award, and a McKnight Neuroscience Brain Disorders Award. The new members of the IOM will be formally inducted during the annual meeting, which is scheduled for October 12-13, 2008.

Writer: 
Kathy Svitil
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