Single-Cell Recognition: A Halle Berry Brain Cell

Embargoed for release at 10 a.m., PDT, June 22, 2005

PASADENA, Calif. - World travelers can instantly identify the architectural sails of the Sydney Opera House, while movie aficionados can immediately I.D. Oscar-winning actress Halle Berry beneath her Catwoman costume or even in an artist's caricature. But how does the human brain instantly translate varied and abstract visual images into a single and consistently recognizable concept?

Now a research team of neuroscientists from the California Institute of Technology and UCLA has found that a single neuron can recognize people, landmarks, and objects--even letter strings of names ("H-A-L-L-E-B-E-R-R-Y"). The findings, reported in the current issue of the journal Nature, suggest that a consistent, sparse, and explicit code may play a role in transforming complex visual representations into long-term and more abstract memories.

"This new understanding of individual neurons as 'thinking cells' is an important step toward cracking the brain's cognition code," says co-senior investigator Itzhak Fried, a professor of neurosurgery at the David Geffen School of Medicine at UCLA, and a professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior, also at UCLA. "As our understanding grows, we one day may be able to build cognitive prostheses to replace functions lost due to brain injury or disease, perhaps even for memory."

"Our findings fly in the face of conventional thinking about how brain cells function," adds Christof Koch, the Lois and Victor Troendle Professor of Cognitive and Behavioral Biology and professor of computation and neural systems at Caltech, and the other co-senior investigator. "Conventional wisdom views individual brain cells as simple switches or relays. In fact, we are finding that neurons are able to function more like a sophisticated computer."

The study is an example of the power of neurobiological research using data drawn directly from inside a living human brain. Most neurobiological research involves animals, postmortem tissue, or functional brain imaging in magnetic scanners. In contrast, these researchers draw data directly from the brains of eight consenting clinical patients with epilepsy at the UCLA Medical Center, wiring them with intracranial electrodes to identify the seizure origin for potential surgical treatment.

The team recorded responses from the medial temporal lobe, which plays a major role in human memory and is one of the first regions affected in patients with Alzheimer's disease. Responses by individual neurons appeared on a computer screen as spikes on a graph.

In the initial recording session, subjects viewed a large number of images of famous people, landmark buildings, animals, objects, and other images chosen after an interview. To keep the subjects focused, researchers asked them to push a computer key to indicate whether the image was a person. After determining which images prompted a significant response in at least one neuron, additional sessions tested response to three to eight variations of each of those images.

Responses varied with the person and stimulus. For example, a single neuron in the left posterior hippocampus of one subject responded to 30 out of 87 images. It fired in response to all pictures of actress Jennifer Aniston, but not at all, or only very weakly, to other famous and non-famous faces, landmarks, animals, or objects. The neuron also (and wisely, it turns out) did not respond to pictures of Jennifer Aniston together with actor Brad Pitt.

In another patient, pictures of Halle Berry activated a neuron in the right anterior hippocampus, as did a caricature of the actress, images of her in the lead role of the film Catwoman, and a letter sequence spelling her name. In a third subject, a neuron in the left anterior hippocampus responded to pictures of the landmark Sydney Opera House and Baha'í Temple, and also to the letter string "Sydney Opera," but not to other letter strings, such as "Eiffel Tower."

In addition to Koch and Fried, the research team included Rodrigo Quian-Quiroga of Caltech and UCLA, Leila Reddy of Caltech, and Gabriel Kreiman of the Massachusetts Institute of Technology.

The research was funded by grants from the National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, the National Science Foundation, the Defense Advanced Research Projects Agency, the Office of Naval Research, the W. M. Keck Foundation Fund for Discovery in Basic Medical Research, a Whiteman fellowship, the Gordon Moore Foundation, the Sloan Foundation, and the Swartz Foundation for Computational Neuroscience.

MEDIA CONTACTS: Mark Wheeler, Caltech (626) 395-8733 wheel@caltech.edu

Dan Page, UCLA (310) 794-2265 dpage@mednet.ucla.edu

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Norman Horowitz Dies; Conducted Experiment with Viking Lander to Search for Life on Mars

PASADENA, Calif.--Norman Horowitz, a geneticist best known for his work on the "one-gene, one-enzyme" hypothesis and the experiments aboard the Viking lander to search for life on Mars in 1976, died on Wednesday, June 1, at his home in Pasadena. He was 90.

A pioneer of the study of evolution through biochemical synthesis, Horowitz was a professor of biology at the California Institute of Technology for many years. After a distinguished career studying the genetics of the red bread-mold Neurospora crassa, he began collaborating with the Jet Propulsion Laboratory in 1965 after becoming interested in the biochemical evolution of life and its possible applications to the search for life on other worlds. He spent five years as chief of JPL's bioscience section.

Horowitz was a member of the scientific teams for both the Mariner and Viking missions to Mars. On the Viking mission, he and two collaborators designed an instrument capable of detecting any biochemical evidence of life on the planet. The results of the experiment were negative at the two Viking sites, but this information in itself was a robust scientific result that continues to inform current efforts in astrobiology to this day.

Horowitz is most renowned in the field of biochemistry for his 1945 thought experiment on biochemical evolution. The paper, published in the Proceedings of the National Academy of Sciences, is today considered the origin of the study of evolution at the molecular level. Horowitz also performed a seminal experiment that led to the widespread acceptance of the one-gene, one-enzyme hypothesis that, until the early 1950s, was considered a radical theory of the way that life carries on its chemistry. Horowitz and a colleague used mutations to disprove an alternative interpretation that was gaining credence at the time, thereby indirectly strengthening the one-gene, one-enzyme hypothesis.

A native of Pittsburgh, Horowitz earned his bachelor's degree at the University of Pittsburgh, and then came to Caltech in 1936 for graduate study in the comparatively new division of biology, founded by famed geneticist Thomas Hunt Morgan. After completing his doctorate in 1939 under embryologist Albert Tyler, Horowitz became a postdoctoral researcher at Stanford University, in the laboratory of George W. Beadle.

When Beadle became chair of the Caltech biology division in 1946, Horowitz returned to his alma mater as a faculty member, and stayed at the Institute for the remainder of his career. He was the biology division chair from 1977 to 1980, and became a professor emeritus in 1982. His contributions to the division also included the endowment of the Horowitz Lecture Series.

He was a member of the National Academy of Sciences and the American Academy of Arts and Sciences. His honors included a 1998 medal from the Genetics Society of America. He was also the author of a 1986 book titled To Utopia and Back: The Search for Life in the Solar System.

Horowitz is survived by a daughter, Elizabeth Horowitz of Berkeley, and a son, Joel Horowitz of Iowa City, Iowa and Evanston, Illinois. He has two grandchildren, Katharine of Minneapolis, Minnesota, and Daniel of Davis, California. He was married to Pearl (née Shykin) Horowitz, who died in 1985. Horowitz funded the Pearl S. Horowitz Book Fund at Caltech in her honor.

 

 

 

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Caltech Neuroscientists Unlock Secrets of How the Brain Is Wired for Sex

PASADENA--There are two brain structures that a mouse just can't do without when it comes to hooking up with the mate of its dreams--and trying to stay off the lunch menu of the neighborhood cat. These are the amygdala, which is involved in the initial response to cues that signal love or war, and the hypothalamus, which coordinates the innate reproductive or defensive behaviors triggered by these cues.

Now, neuroscientists have traced out the wiring between the amygdala and hypothalamus, and think they may have identified the genes involved in laying down the wiring itself. The researchers have also made inroads in understanding how the circuitry works to make behavioral decisions, such as when a mouse is confronted simultaneously with an opportunity to reproduce and an imminent threat.

Reporting in the May 19 issue of the journal Neuron, David Anderson, Caltech's Roger W. Sperry Professor of Biology and a Howard Hughes Medical Institute investigator, his graduate student Gloria Choi, and their colleagues describe their discovery that the neural pathway between the amygdala and hypothalamus thought to govern reproductive behaviors is marked by a gene with the rather unromantic name of Lhx6.

For a confirmation that their work was on track, the researchers checked to see what the suspected neurons were doing when the mice were sexually aroused. In male mice, the smell of female mouse urine containing pheromones was already known to be a sexual stimulus, evoking such behaviors as ultrasonic vocalization, a sort of "courtship song." Therefore, the detection of neural activity in the pathway when the mouse smelled the pheromones was the giveaway.

The idea that Lhx6 actually specifies the wiring of the pathway is still based on inference, because when the researchers knocked out the gene, the mutation caused mouse embryos to die of other causes too early to detect an effect on brain wiring. But the Lhx6 gene encodes a transcription factor in a family of genes whose members are known to control the pathfinding of axons, which are tiny wires that jut out from neurons and send messages to other neurons.

The pathway between the amygdala and hypothalamus that is involved in danger avoidance appears to be marked by other genes in the same family, called Lhx9 and Lhx5. However, the function of the circuits marked by these factors is not as clear, because a test involving smells to confirm the pathways was more ambiguous than the one involving sexual attraction. The smell of a cat did not clearly light up Lhx9- or Lhx5-positive cells. Nevertheless, the fact that those cells are found in brain regions implicated in defensive behaviors suggests they might be involved in other forms of behaviors, such as aggression between male mice.

The researchers also succeeded in locating the part of the mouse brain where a circuit-overriding mechanism exists when a mouse is both exposed to a potential mate and perceives danger. This wiring is a place in the hypothalamus where the pathways involved in reproduction and danger avoidance converge. The details of the way the axons are laid down shows that a mouse is clearly hard-wired to get out of harm's way, even though a mating opportunity simultaneously presents itself.

"We also have a behavioral confirmation, because it is known that male mice 'sing' in an ultrasonic frequency when they're sexually attracted," Anderson explains. "But when they're exposed to danger signals like predator odors, they freeze or hide.

"When we exposed the mice to both cat odor and female urine simultaneously, the male mice stopped their singing, as we predicted from the wiring diagram," he says. "So the asymmetry in the cross-talk suggests that the system is prioritized for survival first, mating second."

The inevitable question is whether this applies to humans as well. Anderson's answer is that similarities are likely, and that the same genes may even be involved.

"The brains of mice and humans have both of these structures, and we, like mice, are likely to have some hard-wired circuits for reproductive behavior and for defense," he says. "So it's not unreasonable to assume that some of the genes involved in these behaviors in mice are also involved in humans."

However, humans can also make conscious decisions and override the hard-wired circuitry. For example, two teenagers locked in an amorous embrace in a theater can ignore a horrid monster on the screen and continue with the activity at hand. In real-life circumstances, they would be more inclined to postpone the groping until they were out of danger.

"We obviously have the conscious ability to interrupt the circuit-overriding mechanism, to see if the threat is really important," Anderson says.

Gloria Choi, a doctoral student in biology, did most of the lab work involved in the study. The other collaborators are Hongwei Dong and Larry Swanson, a professor at USC who in the past has comprehensively mapped the neural wiring of the rat brain, and Andrew Murphy, David Valenzuela, and George Yancopoulos at Regeneron Pharmaceuticals, in Tarrytown, New York, who generated the genetically modified mice using a new high-throughput system that they developed, called Velocigene.

 

 

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Four from Caltech Named to National Academy of Sciences

PASADENA-Three members at the California Institute of Technology faculty and one former faculty who is now a visiting associate are among the 72 new members and 18 foreign associates being named to the National Academy of Sciences today. The election was announced during the 142nd annual meeting of the Academy in Washington, D.C.

Caltech's newest members are Richard Andersen, the Boswell Professor of Neuroscience; James Eisenstein, the Roshek Professor of Physics; and Wallace Sargent, the Bowen Professor of Astronomy. Roger Blandford, a former Caltech faculty member and current visiting associate in physics, is also among the electees.

Membership in the National Academy of Sciences is considered one of the most important honors that a scientist can achieve. In addition to the 1,976 active members of the academy following today's election, 360 foreign associates are also listed in the organization's roster as nonvoting members.

The National Academy of Sciences is a private organization of scientists and engineers dedicated to the furtherance of science and its use for the general welfare. It was established in 1863 by a congressional act of incorporation signed by Abraham Lincoln that calls on the Academy to act as an official adviser to the federal government, upon request, in any matter of science or technology.

Andersen is a neuroscientist who has garnered considerable attention in recent years for his progress toward the goal of controlling prosthetic devices with brain signals. Much of his current work focuses on severely paralyzed human patients who can think about making movements, but due to brain lesions from trauma, stroke, or peripheral neuropathies, can no longer make movements. His approach is to create brain-implant technology that will act as an interface between a patient's thoughts for movement and artificial limbs, computers, or other devices, that would "read out" the patient's desires.

Eisenstein is a specialist in condensed-matter physics, which involves the exploration of the fundamental laws of nature as they apply to atoms and molecules that comprise solid matter. His most significant research accomplishment in the last year has been his demonstration that unusual particles known as "excitons" can inhabit solid semiconductor materials in such a way that each exciton loses its individual identity and, in certain ways, a large collection of excitons becomes a single quantum entity.

Sargent is particularly well-known in the astrophysical community for his work in spectroscopy. His research in extragalactic spectroscopy provided the first evidence for a black hole in galaxy M87, and his work on intergalactic gas has led to new insights on the primeval materials of the early universe. His work in the stellar spectroscopy of A-type stars led to the discovery of the He3 isotope in the star 3 Centauri.

Blandford is a former faculty member in the Division of Physics, Mathematics and Astronomy at Caltech. He is currently a visiting associate in physics at Caltech and the Pehong and Adele Chen Professor of Physics and Stanford Linear Accelerator Center at Stanford University, where he is also director of the Kavli Institute for Astrophysics and Cosmology.

Today's election brings the total number of Caltech faculty members of the National Academy of Sciences to 70.

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Five from Caltech Faculty Elected to American Academy of Arts and Sciences

PASADENA, Calif.-Five faculty members at the California Institute of Technology are among this year's newly elected fellows of the American Academy of Arts and Sciences. They join 191 other Americans and 17 foreign honorees as the 225th class of fellows of the prestigious institution that was cofounded in 1780 by John Adams.

This year's new Caltech inductees are Barry Barish, the Linde Professor of Physics and director of the Laser Interferometer Gravitational-Wave Observatory (LIGO); Andrew Lange, the Goldberger Professor of Physics; Barry Simon, the IBM Professor of Mathematics and Theoretical Physics; David Tirrell, chair of the Division of Chemistry and Chemical Engineering and McCollum-Corcoran Professor and professor of chemistry and chemical engineering; and William Bridges, the Braun Professor of Engineering, Emeritus.

The five from Caltech join an illustrious list of fellows, both past and present. Other inductees in the 225th class include Supreme Court Chief Justice William Rehnquist, Angels in America author Tony Kushner, Academy Award-winning actor Sidney Poitier, former NBC Nightly News anchor Tom Brokaw, Washington Post CEO Donald Graham, and Pulitzer Prize-winning cartoonist Art Spiegelman. Past fellows have included George Washington, Benjamin Franklin, Ralph Waldo Emerson, Albert Einstein, and Winston Churchill.

According to the academy's president, Patricia Meyer Spacks, the fellows were chosen "through a highly competitive process that recognizes individuals who have made preeminent contributions to their disciplines and to society at large."

"Throughout its history, the Academy has convened the leading thinkers of the day, from diverse perspectives, to participate in projects and studies that advance the public good," said Executive Officer Leslie Berlowitz.

The academy is an independent policy research center that focuses on complex and emerging problems such as scientific issues, global security, social policy, the humanities and culture, and education.

The new fellows and foreign honorary members will be formally recognized at the annual induction ceremony on October 8 at the academy's headquarters in Cambridge, Massachusetts.

 

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HHMI Investigator's Approach Could Lead to Novel Drug Design, New Way to Generate Energy

PASADENA, Calif.--For anyone suffering from cystic fibrosis or AIDS, the bacterium Pseudomonas aeruginosa is bad news. While the organism is found everywhere--including in sediment on the ocean floor--it can cause lung infections in those with weak immune systems.

California Institute of Technology researcher Dianne Newman thinks her laboratory work could lead to ways of neutering the organism's threat to patients--and, at the same time, perhaps even hijack the microbe's internal chemistry for a novel method of energy generation.

This unlikely marriage of medical application and environmental engineering has won Newman one of this year's prestigious funding awards from the Howard Hughes Medical Institute. Newman, who is Caltech's Luce Assistant Professor of Geobiology and Environmental Science and Engineering, joins 42 other leading American researchers as this year's new crop of HHMI Investigators.

One of the most prestigious honors in the country for scientists involved in biomedicine, the grant is designed to provide a select group of individuals "with the freedom and flexibility they need in order to make lasting contributions to mankind," says Thomas R. Cech, the HHMI president.

Newman's approach toward the microbe is to exploit the manner in which it must generate energy through electron transfer reactions in order to survive. Scientists know the fine details of electron transfer about a few proteins involved in cellular energy generation, but not about the processing of redox-active small molecules produced by organisms such as Pseudomonas aeruginosa, Newman says. Progress could lead toward new insights about the function of these molecules in biofilms.

For the biomedical application, the work could determine if other discoveries in Newman's lab can be applied to understanding how electrons shuttle about in the course of the microbe's carrying on its life functions, and how these processes could be interfered with for novel treatments. With the new HHMI funding, Newman says she will be able to take full advantage of her collaborative work at the Jet Propulsion Laboratory--work that has already led to her codesigning a special apparatus for studying electron shuttling in biofilms.

A possible outcome of the research would be the demonstration that electron shuttles work in such a way that the human pathogen Pseudomonas aeruginosa could be attacked through rational drug design. In other words, new drugs might be specifically created to interfere with the way that electrons move around in the course of the bacterium's doing what it needs to do to remain alive. Such a drug would be a new type of antibiotic.

"It's hard to treat these bacterial infections with conventional antibiotics," Newman says. "Hopefully we can learn something about what these organisms need to live, and can develop a new way to interfere with it."

A fuller understanding of the bacterium's electron shuttling mechanism could also perhaps lead to a new type of energy production with a novel device called a "sediment fuel cell." These are devices that are planted in ocean sediment, with the anode side (the side from which electrons flow) buried beneath the surface, and the cathode side (to which electrons flow) above the sediment surface.

Because the Pseudomonas aeruginosa bacterium has been found in significant numbers in biofilms developing on marine cathodes, the fuel cell could possibly be designed in such a way that the organism's life functions could be tapped to catch the energy from the current flow. This research is already receiving DARPA funding, and Newman says that the additional HHMI funding should provide her with greater flexibility to understand the basic biology needed to make the fuel cells work.

Such a fuel cell would work like an underwater battery, with the bacteria ultimately providing a source of current by carrying on their life processes.

A nonprofit medical research organization, HHMI was established in 1953 by the aviator-industrialist Howard Hughes. The Institute, headquartered in Chevy Chase, Maryland, is one of the largest philanthropies in the world with an endowment of $12.8 billion at the close of its 2004 fiscal year. HHMI spent $573 million in support of biomedical research and $80 million for support of a variety of science education and other grants programs in fiscal 2004.

 

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McKnight Awards Go to Two from Caltech

PASADENA, Calif.--Richard Andersen, Boswell Professor of Neuroscience, and Kai Zinn, professor of biology, both of the California Institute of Technology, have each received a 2005 McKnight Neuroscience of Brain Disorder Award.

Andersen's work focuses on severely paralyzed human patients. These patients can think about making movements, but due to brain lesions from trauma, stroke, or peripheral neuropathies, can no longer make movements. The McKnight funding will allow Andersen's group to further their research in creating brain-implant technology that will interface between a patient's thoughts for movement and artificial limbs, computers, and other devices that will "read out" the patient's desires.

Zinn's work on prions, which are commonly known to the public as the cause of mad cow disease, addresses the mechanisms involved in the accumulation of these proteins. Aggregates composed of prion proteins are known to cause fatal human brain diseases. Through his study of prion propagation, in Drosophila and yeast, Zinn hopes to uncover how prions are formed and whether prions might have functions in the normal brain.

The Research Projects Award from the McKnight Foundation, established in 1977, and its Endowment Fund for Neuroscience, established in 1986, will provide $300,000 each to the Caltech professors over three years to further their work in neuroscience.

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Toward a Longer, Healthier Life

PASADENA, Calif. - The Spanish explorer Ponce de Leon spent a fair amount of his time in 1513 looking for the fountain of youth. The upside was that he discovered Florida. The downside was that the fountain was a myth. Now in two separate awards from the Ellison Medical Foundation, two scientists from the California Institute of Technology are taking a much more scholarly approach to the ravages of aging. Harry Gray, a chemist, has been awarded $970,000 to reveal the structure of a protein and a peptide that underlie two age-related diseases, Alzheimer's and Parkinson's, while biologist Alexander Varshavsky has been awarded $972,000 to conduct a systematic investigation of the genetics and biochemistry of aging.

Gray, the Arnold O. Beckman Professor of Chemistry, notes that approximately one million Americans suffer from Parkinson's, while 4.5 million have Alzheimer's. In order to design a drug to combat these two diseases, a key step is to understand the critical structural differences between normal proteins and the malignant proteins that comprise these diseases.

Both Alzheimer's and Parkinson's are associated with the accumulation in the brain of aggregates of proteins known as fibrils. In Parkinson's, the fibrils are composed of the protein alpha-synuclein, while in Alzheimer's, the fibrils or plaques are composed of the AB amyloid peptide. Alpha-synuclein and AB amyloid peptide are known as "disordered biopolymers," meaning that they do not have well-defined structures. Because of this lack of structure, the traditional tools used by chemists, such as x-ray crystallography and nuclear magnetic resonance spectroscopy, are virtually useless. They are only effective if the peptides and proteins being studied have well-defined structures in crystals or solutions.

Instead, Gray and his colleagues plan to use laser spectroscopic methods developed in Caltech's Beckman Institute to gain new insights into the structures, dynamics, and misfolding of malignant proteins and peptides. One of the most powerful methods they will use will employ an ultrafast camera to obtain distances between atoms in disordered structures that are constantly changing.

"We're very excited about the possibility of applying our laser methods to study proteins and peptides that are involved in disease in older people," says Gray. "We have a chance to identify toxic species that lead to these diseases, and point the way to successful interventions."

For Alexander Varshavsky, the Howard and Gwen Laurie Smits Professor of Cell Biology, it is the causes and alterations of the aging process that interest him. Every cell contains within it a molecular machine to eventually destroy its own proteins, he notes. The mechanisms and functions of this so-called regulated protein degradation became (mostly) understood over the last 25 years, in large part through discoveries in Varshavsky's lab. When a protein called ubiquitin is linked to another protein in a cell, that protein is marked for destruction. The molecular machines inside a cell that link ubiquitin to other proteins, and the intracellular machinery that "recognizes" ubiquitin-linked proteins and destroys them, are elaborate and complex. "Detailed understanding of these protein-destruction pathways will have a profound impact on the practice of medicine," says Varshavsky, "because all kinds of things that go wrong with us, from cancer and infectious diseases, to neurodegenerative syndromes and even normal aging, have a lot to do with either inherent imperfections of the ubiquitin system, or with an overt damage to it in a specific disease." Many clinical drugs of the future, he notes, will be designed to suppress, enhance, or otherwise modify various aspects of the ubiquitin system.

In this research Varshavsky will overexpress, selectively and in a controlled manner, specific components of the mouse ubiquitin system in intact mice, in order to determine the effects of such alterations on the rate of aging. He also plans to use analogous approaches with a much simpler organism, S. cerevisiae, common baker's yeast. His aim is to discover the molecular circuits that contribute to normal aging, and also to see whether some of the alterations that he plans to introduce could slow down the aging process.

The Ellison Medical Foundation is a nonprofit corporation that was established by a gift from Mr. Lawrence J. Ellison to support basic biomedical research to understand aging processes and age-related diseases and disabilities. Through various award mechanisms, including the Senior Scholar and New Scholar award programs, the foundation fosters research by means of grants-in-aid to investigators at universities and laboratories within the United States.

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Scientists Discover What You Are Thinking

PASADENA, Calif. - By decoding signals coming from neurons, scientists at the California Institute of Technology have confirmed that an area of the brain known as the ventrolateral prefrontal cortex (vPF) is involved in the planning stages of movement, that instantaneous flicker of time when we contemplate moving a hand or other limb. The work has implications for the development of a neural prosthesis, a brain-machine interface that will give paralyzed people the ability to move and communicate simply by thinking.

By piggybacking on therapeutic work being conducted on epileptic patients, Daniel Rizzuto, a postdoctoral scholar in the lab of Richard Andersen, the Boswell Professor of Neuroscience, was able to predict where a target the patient was looking at was located, and also where the patient was going to move his hand. The work currently appears in the online version of Nature Neuroscience.

Most research in this field involves tapping into the areas of the brain that directly control motor actions, hoping that this will give patients the rudimentary ability to move a cursor, say, or a robotic arm with just their thoughts. Andersen, though, is taking a different tack. Instead of the primary motor areas, he taps into the planning stages of the brain, the posterior parietal and premotor areas.

Rizzuto looked at another area of the brain to see if planning could take place there as well. Until this work, the idea that spatial processing or movement planning took place in the ventrolateral prefrontal cortex has been a highly contested one. "Just the fact that these spatial signals are there is important," he says. "Based upon previous work in monkeys, people were saying this was not the case." Rizzuto's work is the first to show these spatial signals exist in humans.

Rizzuto took advantage of clinical work being performed by Adam Mamelak, a neurosurgeon at Huntington Memorial Hospital in Pasadena. Mamelak was treating three patients who suffered from severe epilepsy, trying to identify the brain areas where the seizures occurred and then surgically removing that area of the brain. Mamelak implanted electrodes into the vPF as part of this process.

"So for a couple of weeks these patients are lying there, bored, waiting for a seizure," says Rizzuto, "and I was able to get their permission to do my study, taking advantage of the electrodes that were already there." The patients watched a computer screen for a flashing target, remembered the target location through a short delay, then reached to that location. "Obviously a very basic task," he says.

"We were looking for the brain regions that may be contributing to planned movements. And what I was able to show is that a part of the brain called the ventrolateral prefrontal cortex is indeed involved in planning these movements." Just by analyzing the brain activity from the implanted electrodes using software algorithms that he wrote, Rizzuto was able to tell with very high accuracy where the target was located while it was on the screen, and also what direction the patient was going to reach to when the target wasn't even there.

Unlike most labs doing this type of research, Andersen's lab is looking at the planning areas of the brain rather than the primary motor area of the brain, because they believe the planning areas are less susceptible to damage. "In the case of a spinal cord injury," says Rizzuto, "communication to and from the primary motor cortex is cut off." But the brain still performs the computations associated with planning to move. "So if we can tap into the planning computations and decode where a person is thinking of moving," he says, then it just becomes an engineering problem--the person can be hooked up to a computer where he can move a cursor by thinking, or can even be attached to a robotic arm.

Andersen notes, "Dan's results are remarkable in showing that the human ventral prefrontal cortex, an area previously implicated in processing information about objects, also processes the intentions of subjects to make movements. This research adds ventral prefrontal cortex to the list of candidate brain areas for extracting signals for neural prosthetics applications."

In Andersen's lab, Rizzuto's goal is to take the technology they've perfected in animal studies to human clinical trials. "I've already met with our first paralyzed patient, and graduate student Hilary Glidden and I are now doing noninvasive studies to see how the brain reorganizes after paralysis," he says. If it does reorganize, he notes, all the technology that has been developed in non-paralyzed humans may not work. "This is why we think our approach may be better, because we already know that the primary motor area shows pathological reorganization and degeneration after paralysis. We think our area of the brain is going to reorganize less, if at all. After this we hope to implant paralyzed patients with electrodes so that they may better communicate with others and control their environment."

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Potential New Approach to Fighting Cancer

PASADENA, Calif. - The immune system is a remarkable defense mechanism, able to defend the body against a lifetime's worth of pathogens and pathogen attractors--bacteria and viruses, toxins and parasites, splinters and cuts--everything, that is, except cancer. Although the immune system handles most of these disease-causing organisms and insults well, it does a poor job of suppressing the growth of tumors.

A major goal of cancer immunotherapy has been to bolster the immune system by generating large numbers of white blood cells (T cells) that could specifically seek and destroy cancer cells. Now, two scientists from the California Institute of Technology have come up with a novel and promising approach to antitumor immunotherapy. Reporting in the online edition of the Proceedings of the National Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), Lili Yang, a postdoctoral scholar, and David Baltimore, professor of biology, Caltech president, and Nobel Prize recipient, have developed a new methodology they are calling "instructive immunotherapy" that someday may fight human cancer.

In mice and humans, hematopoietic stem cells (HSC) form both red blood cells and immune system cells. In mice, Yang and Baltimore succeeded in altering some HSCs so that they would generate specific kinds of T cells that aggressively attack and destroy specific cancer cells. Once the mouse immune system received this enhancement, it became able to generate its own cancer-specific T cells on a long-term basis. When helped by dendritic cells (another type of immune system cell) carrying a piece of the tumor's marker protein, the methodology achieved the complete elimination of large, established tumors. While the work is preliminary and was done with mice, says Baltimore, instructive immunotherapy could eventually be used for controlling the growth of tumors in humans.

"We've achieved something that could one day prove important," says Baltimore, who was awarded the 1975 Nobel Prize in Physiology or Medicine, "but the first caveat is that this is all with mice, and mice are often not predictive of behavior in humans." Still, he notes, "everything we have done is in principle possible to do in humans, so we plan to try to develop a system for optimizing the ability to program human stem cells."

Yang, a former graduate student of Dr. Baltimore, says current cancer strategies fall into two categories: developing a cancer vaccine, or developing a drug that can be given when cancer is diagnosed. "Our strategy is threefold," she says, "a combination of gene therapy, stem cell therapy, and immunotherapy. When these three methodologies work together, it is possible to provide life-long immunity."

In addition to making billions of new blood cells each day, HSCs are responsible for providing immune protection of every cell type in the body. In fact, HSC transplants are routinely used to treat patients with cancers. In their case, Yang and Baltimore chose to manipulate HSCs for three reasons--because HSCs normally make T cells, they make them by the billions, and they exist in humans through their lifetime.

The first step was to design a retrovirus vector that could deliver genes for both chains of the T cell receptor to HSCs. This was actually the key to the whole study. For this work, two vectors delivering two sets of genes were developed. The HSCs then gave rise to both of the major types of T cells known as CD4 helper cells and CD8 killer cells. Together, these two cell types can recognize the foreign nature of the test cancer cells used in the study and can kill them. The researchers were successful in programming up to a quarter of the mouse's T cells to react to the model tumor. Even better, once modified, the mouse's immune system continued to produce these antigen-specific T cells on its own. However, with this method alone, Yang and Baltimore found that mice were only partially resistant to the tumor cells.

To achieve complete protection required boosting the animal's immune system with dendritic cells carrying a fragment of the tumor cell's marker protein. These dendritic cells are thought to use their long tentacle-like branches (called dendrites) to stimulate the T cells and make them more active. With this combination, Yang and Baltimore were able to achieve the complete shrinkage and suppression of even large, well-established tumors.

Dr. Yang recalled her reaction to the first positive results: "It was a great surprise that the method worked so well. This level of efficacy makes us believe that the method may have real therapeutic potential."

The next step, says Yang, will be to repeat the experiment, this time using conditions that more closely approximate human tumors. After that, if things hold up, the next step will be to start thinking about human trials.

"Producing a state of antitumor immunity has been a dream of immunologists for years, but has been unrealized in humans," says Baltimore. "Here we've developed a methodology that provides a new opportunity to realize this goal. We certainly hope that it will prove to be effective in humans."

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