Gaining a Better Understanding of the Brain

PASADENA, Calif. — A panel of experts who conduct a wide range of brain research will come together for California Institute of Technology's annual Biology Forum, "Gray Matters: Perception, Intention, Memory, and Dysfunction in the Brain," April 25 at 8 p.m. in Beckman Auditorium, 332 S. Michigan Ave, Pasadena. The event is free and open to the public.

The speakers for the program, which is sponsored by Caltech and Huntington Memorial Hospital and co-sponsored by the San Gabriel Valley Newspaper Group, will discuss topics as diverse as the dynamics of smell, moving robotic limbs using brain signals, and pinpointing and excising the spot in the brain where epilepsy seizures occur.

"Our speakers exemplify the world-class work that is being done on the brain right here in Pasadena," says Paul Patterson, biology professor and Biology Forum coordinator. Three of the four speakers are Caltech faculty and one is a Huntington Hospital neurosurgeon.

The speakers are:

Richard Andersen, James G. Boswell Professor of Neuroscience at Caltech. Andersen and his colleagues are beginning to decipher neuron firing patterns in the visuomotor part of the brain preceding arm movement. Using this code they can now predict where the arm will be moved. The eventual goal of this research is to develop a neural prosthesis that records this intended-movement signal from paralyzed patients, enabling them to operate a robot limb or other external devices.

Gilles Laurent, professor of biology and computation and neural systems at Caltech. Laurent studies neural coding in the brain. He focuses on the dynamics of neuronal circuits, brain oscillations, and the sense of smell, in insects, fish, and rodents. His laboratory studies the general problem of olfactory representations: how is an odor represented by brain circuits? What are the neuronal elements of the memory of a smell? What do brain circuits do to optimize those representations?

Adam Mamelak, neurosurgical director of the Epilepsy and Brain Mapping Program at Huntington Memorial Hospital, and associate professor of neurosurgery at City of Hope Cancer Center. The Huntington Brain Mapping Program is one of a handful of comprehensive epilepsy centers in the country. Through the program, patients' seizures and normal brain functions are mapped, the source of seizures is pinpointed, and the damaged portion of the brain is excised. It provides the most advanced and successful seizure evaluation and treatment available today.

Steven Quartz, assistant professor of philosophy at Caltech. Quartz uses experimental and theoretical methods from neuroscience to study traditional problems of mind, ranging from the formal learning properties of neurally constrained developing systems to the nature of moral decision-making.

The moderator of the program will be Robert Lee Hotz, a Pulitzer Prize-winning science writer with the Los Angeles Times.

For more information, call (626) 395-4652 or toll-free 1-888-222-5832. Persons with disabilities can call (626) 395-4688 (voice) or (626) 395-3700 (TDD) weekdays, 9 a.m. to 4 p.m.

CONTACT: Jill Perry, Media Relations Director (626) 395-3226 jperry@caltech.edu

Visit the Caltech media relations web site: http://pr.caltech.edu/media

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Caltech and Purdue scientists determinestructure of the Dengue fever virus

Scientists at the California Institute of Technology and Purdue University have determined the fine-detail structure of the virus that causes dengue fever. This advance could lead to newer and more focused strategies for devising a vaccine to protect the world against a viral illness that causes 20,000 deaths each year.

Reporting in the March 8 issue of the journal Cell, Caltech biology professor James H. Strauss, lead author Richard J. Kuhn of Purdue (a former postdoctoral scholar in Strauss's lab), and Michael G. Rossman and Timothy S. Baker, both of Purdue, describe the structure of the virus they obtained with a cryoelectron microscope. The detailed electron-density map shows the inner RNA core of the virus as well as the other spherical layers that cover it. At the surface is the glycoprotein scaffolding thought to allow the virus to interact with the receptor and invade a host cell.

This is the first time the structure of one of the flaviviruses has been described, Strauss says. The flaviviruses are a class of viruses that include the yellow fever, West Nile, tick-borne encephalitis, and Japanese encephalitis viruses. All are enclosed with a glycoprotein outer layer that includes minor projections out of the lipid layer due to the geometry of the scaffolding.

"Most viruses that cause serious illness are enveloped, including influenza, hantaviruses, West Nile virus, smallpox, and herpes—though not polio," Strauss says.

The surprise for the researchers was the unusual manner in which the glycoproteins are arranged. Details from the Caltech and Purdue computer-generated images show a highly variegated structure of glycoprotein molecules that are evenly dispersed, but with a surprisingly complicated pattern.

"It's symmetrical, but not with the obvious symmetry of most symmetric viruses," Strauss explains. "This was not an expected result."

Strauss says it's still unclear what the odd symmetry will ultimately mean for future research aimed at controlling the disease, because the precise function of the different structural domains of the glycoproteins are still not known. Those that have been false-colored blue in the image are the domain of glycoproteins thought to be involved in receptor binding—and thus responsible for the virus's entry into a cell. The glycoprotein structures coded yellow are an elongated domain thought to be responsible for holding the scaffolding together; and the ones coded red have a function that is not yet known.

But a more detailed view of these structures is the beginning of a more informed strategy for a focused medical or pharmaceutical attack, Strauss says. "You can think of the protease inhibitors for HIV. Those in large part came from knowing the structure of the HIV enzymes you were trying to interfere with."

Thus, the new work could lead to drugs that will bind to the virus to prevent it from entering the cell, or perhaps from reassembling once it is already inside the cell.

Dengue fever is a mosquito-spread disease that has been known for centuries, but was first isolated in the 1940s after it became a significant health concern for American forces in the Pacific theater. A worldwide problem, the disease is found throughout Latin America, the Caribbeans, Southeast Asia, and India, and is currently at epidemic levels in Hawaii.

Especially virulent is the closely related dengue hemorrhagic fever, which is responsible for most of the deaths. The disease is a leading cause of infant mortality in Thailand, where there is an especially vigorous program to find an effective vaccine.

More information can be found on the Center for Disease Control Web site at http://www.cdc.gov/ncidod/dvbid/dengue/index.htm.

Contact: Robert Tindol (626) 395-3631

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Caltech Scientists Block Effect of Huntington Disease Protein in Cultured Cells

PASADENA, Calif.— Huntington's disease is a cruel disorder, destroying nerve cells in the brain that, over time, rob an individual of the ability to walk, talk, and eat. As yet, there is no cure or effective treatment for this hereditary disorder. The end result, then, is death, caused by such complications as infection or heart failure.

Now scientists at the California Institute of Technology have come one step closer to understanding how Huntington's disease develops and how it can be stopped. In a paper to be published in the January 22 issue of the Proceedings of the National Academy of Sciences, Paul H. Patterson, a Caltech professor of biology, postdoctoral scholar Ali Khoshnan, and research assistant Jan Ko have blocked the effects of the disease in cultured cells using antibodies.

Huntington's disease (HD) is caused by a mutation in the protein huntingtin (htt), specifically by the expansion of a site on the protein called polyQ. Such sites induce the production of antibodies that bind with a particular site, normally to kill the antigen. Khoshnan and his colleagues made an antibody that binds to the polyQ site, along with another antibody that binds to a different site, called polyP. The idea was to block either of these sites and see whether the toxic effects of mutant htt, which kills nerve cells in the brain, could be blocked.

"We knew that the polyQ site was critical because when it is expanded by mutation it causes HD," says Patterson." "It was also known that the polyP site on htt might be important for interfering with the functions of other proteins." The investigators produced a modified version of the antibodies that would allow them to be produced inside cells that also carry the toxic mutant htt. They found a key result: when the antibody against the polyP site is produced by cells carrying the mutant htt, the cells are rescued. That is, they are unaffected by the toxic HD protein. In striking contrast, when cells carrying the toxic htt are induced to produce the antibody against the polyQ site, the toxicity of htt is enhanced and the cells die even faster.

Khoshnan and coworkers suggest that the surprising result with the polyQ antibody may be due to the antibody stabilizing a shape of the mutant htt protein in its most deadly form. Most important, though, says Patterson, is that the rescue of the cells that produce the polyP antibody may indicate this is the site of the toxic htt in which the actual killing of cells takes place, and that covering it up with an antibody saves the cell. "Or, an alternative interpretation is that the binding of the antibody preserves the protein in a non-toxic shape," he says.

The researchers have two goals in mind with their work: elucidating the mechanism of neuronal death caused by mutant htt, and devising molecular strategies for blocking its toxic effects.

To arrive at their results, the scientists first developed eight monoclonal antibodies (mAbs), finding the three that either inhibited or exacerbated the toxicity of the mutant Htt protein. They next cloned the antigen-binding "domains" of the three; that is, the portion of the mAbs that does the actual binding. Finally, they caused these domains to be produced inside cells that were also making the mutant htt.

"Potentially, this knowledge could be useful in designing a therapeutic drug, one that covers up that part of the mutant protein that kills healthy cells," says Patterson. "The next stage of the work will be to deliver this antibody into the brains of mice that carry the human mutant gene and that have developed motor symptoms that are related to the disease. We want to see if this antibody can rescue these mice, even after they show signs of the disease. These experiments are, however, just beginning."

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Caltech biologists invent newer, better methodfor making transgenic animals

Using specially prepared HIV-derived viruses stripped of their disease-causing potential, California Institute of Technology biologist David Baltimore and his team have invented a new method of introducing foreign DNA into animals that could have wide-ranging applications in biotechnology and experimental biology.

The Baltimore team reports, on today's Science Express Web site, on their study of single-cell mouse embryos that have been virally infected in a manner that leaves a new gene from a jellyfish permanently deposited into their genomes. The mice, after they have been carried to term, carry at least one copy of the gene in 80 percent of the cases, and 90 percent of these show high levels of the jellyfish protein. Further, the study shows that the offspring of the mice inherit the genes and make the new protein. Thus the method makes transgenic mice that have new genetic potential.

According to Baltimore, who is president of Caltech, the use of the HIV-like viruses could prove far superior to the current method of producing transgenic animals by pronuclear injection.

"It's surprising how well it works," says Baltimore, whose Nobel Prize-winning research on the genetic mechanisms of viruses 30 years ago is central to the new technique. "This technique is much easier and more efficient than the procedure now commonly in use, and the results suggest that it can be used to generate other transgenic animal species."

The technique exploits features of HIV-like viruses known as lentiviruses, which can infect both dividing and non-dividing cells, as gene delivery vehicles. Unlike HIV, the lentivirus is rendered incapable of causing AIDS. The lentivirus carries new genes into the cell's existing genome. In this case, newly fertilized mouse eggs were engineered to carry the green fluorescent protein (GFP) derived from jellyfish.

Baltimore and his team developed two ways of introducing the lentivirus into cells: microinjection of virus under the layer that protects recently fertilized eggs, or incubation of denuded fertilized eggs in a concentrated solution of the virus. The latter method is easier, although less efficient.

The transgenic mice, once they are born, carry a protein marker in all body tissues that make them glow green under a fluorescent light. This trait is genetic because the trait is a permanent feature of the animal's genome, and thus is carried throughout life and is inheritable by offspring. The term "transgene" refers to the fact that the new gene has been transferred.

Transgenics holds promise to biotechnology and experimental biology because the techniques can be used to "engineer" new, desirable traits in plants and animals, provided the trait can be identified and localized in another organism's genome. A transgenic cow, for example, might be engineered to produce milk containing therapeutic human proteins, or a transgenic chicken might produce eggs low in cholesterol.

In experimental biology, transgenics are valuable laboratory animals for fundamental research. A cat with an altered visual system, for example, might better accommodate fundamental studies of the nature of vision.

According to Baltimore, the procedure works on rats as well as mice. This is a huge advantage to experimentalists because of the number of laboratory applications in which rats are preferable, he says.

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Sound alters the activity of visual areas in the human brain,Caltech research reveals

Scientists at the California Institute of Technology have discovered that hearing can significantly change visual perception, and that the influence of hearing on visual perception occurs at an early perceptual level rather than at a higher cognitive level.

Ladan Shams, a Caltech postdoctoral researcher, and Shinsuke Shimojo, a professor of computation and neural systems at Caltech report that visual signals are influenced significantly by sounds at early cortical levels that have been believed to be "vision specific."

The team's initial behavioral finding was that when an observer is shown one flash of light accompanied by two beeps, the visual system is tricked so that the observer sees two flashes instead of one. In the new study, 13 healthy volunteers were asked to observe the stimuli on a computer screen and judge the number of flashes they saw on the screen.

While the participants performed the task, their brains' electric potentials were recorded from three electrodes positioned in the back of the scalp, where the early visual areas are located.

The researchers found that when the participants perceived the illusion—in other words, when sound changed the visual perception—the activity in the visual areas was modified. Furthermore, the change in activity was similar to that induced by an additional physical flash.

This suggests that the second flash, which is nothing but an illusion and is not due to a visual stimulus but rather caused by sound, invokes activity in the visual areas very similar to that which would be caused by a physical second flash. In short, sound induces a similar effect in this area of the brain to a visual stimulus.

The goal of this study was to get an understanding of how this alteration of vision by sound occurs in the brain. More specifically, the researchers asked whether the change in visual perception is caused by a change in the higher-level areas of the brain that are known to combine information from multiple senses, or whether it is a change that directly affects the activity of the areas that are believed to be exclusively involved in processing visual information.

The main result of the study was that the early visual cortical responses were modulated by accompanied sounds under conditions where the observers experienced the double-flash illusion. This suggests that the activity of the "visual" areas in the brain is affected by sound.

These findings challenge two traditional perspectives on how the brain processes sensory information. The first assumption is that humans are visual animals; vision is the dominant modality and hence not malleable by information from other modalities. Another general belief is that the information from different modalities is processed in the brain in parallel and separate paths.

The findings show that the visual information is affected by the auditory signals while being processed in the "modality-specific" visual pathway. These findings, together with earlier results in other modalities, suggest a paradigm of sensory processing that is more intertwined than segregated.

"The findings have an important implication for the new studies of human perception," says Shimojo. The overwhelming majority of studies in the field of perception have concerned themselves with one modality alone (based on the assumption of modality segregation).

This study, together with other studies indicating vigorous early plasticity and interactions across sensory modalities, is also very encouraging for applications such as sensory aids for children suffering from blindness or dyslexia, for educational applications, for man-made interfaces, and for media and information technology.

A report on this study will appear in the December issue of the journal NeuroReport. Ladan Shams is lead author of the paper.

Contact: Robert Tindol (626) 395-3631

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Caltech biologist Barbara Woldnamed Beckman Institute director

Caltech biology professor Barbara Wold has been appointed director of the Beckman Institute, President David Baltimore announced today. She succeeds founding director Harry Gray, who will return to full-time professorial duties after 15 years at the institute's helm.

Wold, who specializes in embryonic development and regeneration in vertebrates, will lead the Beckman Institute in its continuing goal of building a research interface between chemistry and biology, Baltimore said.

"Professor Wold was chosen to be the second leader of this unique Caltech institution after careful consideration of the pool of candidates," Baltimore said. "We would also like to take this opportunity to thank Harry Gray, who over the past 15 years has provided his talents and energy in formulating and implementing the vision of the Beckman Institute and its exciting program of science and technology."

The Beckman Institute was opened in 1989 in a 160,000-square-foot building on the west end of campus. Made possible with an initial $50-million commitment and challenge from the Arnold and Mabel Beckman Foundation in 1986, the institute provides space for interdisciplinary work in endeavors such as advanced imaging, methods for synthesizing and sequencing genes and proteins, laser spectroscopy and X-ray diffraction, synthesis and characterization of novel organic and inorganic materials, and advanced mass spectroscopic methods for characterization of large biomolecules.

Wold has been a professor of biology at Caltech since 1981. She earned her bachelor's degree in 1973 from Arizona State, her doctorate from Caltech in molecular developmental biology, and did postdoctoral research at Columbia College of Physicians and Surgeons.

Wold has been active in national and international science policy concerned with the Human Genome Project, advising the National Institutes of Health and the Department of Energy programs in genomics.

She is the author of some 60 papers in professional journals.

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Caltech completes $111 million fundraising effort for the biological sciences

The California Institute of Technology has successfully completed a $111 million fundraising effort begun in 1998 to expand the biological sciences. The $111 million exceeds the original $100 million goal.

Funds raised during the Biological Sciences Initiative (BSI) will make possible a new building on the Pasadena campus, new professorships and fellowships, new faculty appointments, and a wide range of new research programs.

In commenting on the successful conclusion of the BSI, Caltech President David Baltimore said, "Caltech's biological heritage and traditional interdisciplinary strength give us a powerful advantage when addressing fundamental biological questions. The Institute's faculty have already made creative use of early BSI planning and gifts to create unique research and teaching opportunities that bring the perspective of fields such as geology, chemistry, computation, physics, philosophy, and engineering to bear on complex biological questions.

"The announcement this summer of the mapping of the human genome provided unequivocal evidence that modern biology has evolved into a science of information," Baltimore continued. "As noteworthy a milestone as that accomplishment will be in the annals of scientific history, the completion of the Human Genome Project really just provides scientists with a new tool—not with solutions. The gifts our donors made to the BSI will provide our talented scientists, engineers, and social scientists with critical resources to move beyond the genomic information to explore the basic questions of life and disease.

"The phenomenal success of the BSI reflects the foresight of many individuals in supporting Caltech's important work in the biological sciences," Baltimore added. "On behalf of the entire Caltech community, I wish to express my appreciation to the donors to the campaign for enabling this work to move forward and to the dedicated and enthusiastic members of the BSI Gift Committee who guaranteed the success of the Biological Sciences Initiative."

This research will result in new drugs and therapies to address diseases such as cancer and AIDS, and will also lead to a deeper understanding of how organisms develop and why they sometimes develop anomalies, as well as an understanding of the biological basis of higher-level brain functions such as consciousness and cognition.

Cochairs for the BSI were Caltech alumnus Ben Rosen (who has since been named chairman of the board of trustees) and senior trustee Camilla Frost. The campaign was planned and led by a special committee comprising trustees, alumni, faculty, and other friends of the Institute.

"Speaking for the committee, we are extremely pleased with the result of the campaign, and we want to thank all of Caltech's friends for supporting this great effort," said Frost, who contributed $5 million toward construction of the Broad Center, the building that will be made possible by the campaign.

"Caltech's supporters have always been extremely generous," added Rosen, who contributed $5 million and thereby single-handedly met the campaign's goal for endowed graduate fellowships.

"In the case of the BSI, I think our friends realized that it was particularly important to support the Institute's programs in the biological sciences, given the opportunity to make important discoveries that will improve the human condition," Rosen said.

The physical centerpiece of the new research efforts will be the Broad Center for the Biological Sciences, named for Caltech trustee and Los Angeles business and civic leader Eli Broad and his wife, Edythe. The Broads provided $23 million—the lead gift—for the building, which is currently under construction and is projected to open for research occupancy next summer. The building is designed by world-renowned architect James Freed, who also designed the acclaimed U.S. Holocaust Memorial Museum in Washington, D.C.

The Broad Center will house about a dozen research groups working in such areas as structural, behavioral, and computational biology, and will also contain shared facilities for electron microscopy and magnetic resonance imaging. Additional funding for the building's construction and equipment has come from the estate of William Hacker, Caltech class of 1931, which provided $8 million in capital funds as well as $1.4 million in discretionary funds for the chair of the Division of Biology.

Eight new professorships were endowed through the campaign. Trustee Donald Bren contributed $10 million through the Donald L. Bren Foundation to support new faculty as Bren Scholars and eventually endow five Bren Professorships.

More than 5,500 Caltech alumni participated in the BSI by responding to a challenge from Ron and Maxine Linde, in which the Lindes agreed to match new and increased gifts toward the naming of the Ronald and Maxine Linde/Caltech Alumni Laboratories on the ground floor of the Broad Center.

Also, Caltech received $5 million from the late William and Georgina Gimbel, to be designated for the William T. Gimbel Discovery Fund in Neuroscience. The Keck Foundation, too, provided a $5 million Discovery Fund.

Through the BSI, Caltech has already made several new appointments of young faculty members whose interests are indicative of the interdisciplinary nature of the initiative. For example, David Chan, assistant professor of biology, uses cell biological, biophysical, and genetic approaches to study how membrane-bound systems like organelles and viruses fuse under certain circumstances.

In particular, Chan is interested in understanding the fusion mechanism of mitochondria, organelles important for energy production and cell death. In addition, he studies how the human immunodeficiency virus (HIV), the agent of the disease AIDS, enters human cells by fusing with the cell membrane.

Dianne Newman, the Clare Boothe Luce Assistant Professor of Geobiology and Environmental Engineering Science, is leading a project to investigate how microorganisms and Earth's near-surface environments have interacted over billions of years. Her project integrates molecular microbiology with geochemistry and field geology to try to identify chemical signatures of early life in the geological record.

"The biological sciences today present an intellectual challenge that is changing the environment at Caltech," said Mel Simon, the former chair of the Caltech Division of Biology, who played a pivotal role in the BSI. "So the resources are here, the vision is here, and some of the people are here. Now all we have to do is great science."

Contact: Robert Tindol (626) 395-3631

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New research shows that brain is involvedin visual afterimages

If you stare at a bright red disk for a time and then glance away, you'll soon see a green disk of the same size appear and then disappear. The perceived disk is known as an afterimage, and has long been thought to be an effect of the "bleaching" of photochemical pigments or adaptation of neurons in the retina and merely a part of the ocular machinery that makes vision possible.

But a novel new experimental procedure by psychophysicists shows that the brain and its adaptive change are involved in the formation of afterimages.

Reporting in the August 31 issue of the journal Science, a joint team from the California Institute of Technology and NTT Communication Science Laboratories, led by Caltech professor Shinsuke Shimojo, demonstrates that adaptation to a specific visual pattern which induces perception of "color filling-in" later leads to a negative afterimage of the filled-in surface. The research further demonstrates that this global type of afterimage requires adaptation not at the retinal, but rather at the cortical, level of visual neural representation.

The Shimojo team employed a specific type of image (see image A below) in which a red semi-transparent square is perceived on top of the four white disks. Only the wedge parts of the disks are colored, and there is no local stimulus or indication of redness in the central portion of the display, yet the color filling-in mechanism operates to give an impression of filled-in red surface.

If an observer were staring only at the red square for at least 30 seconds, then he or she would see a reverse-color green square for a few seconds after refixating on a blank screen (as in the image at the top of C).

However, an observer who fixates on the image at left (in A) and then refixates on a blank screen will usually see four black disks such as the ones at the bottom of C, followed by a global afterimage in which a green square appears to be solid.

The fact that no light from the center of the original square was red during adaptation demonstrates that the effect was not merely caused by a leaking-over or fuzziness of neural adaptation, because the four white disks are at first clearly distinct as black afterimages. Thus, the global afterimage is distinct from a conventional afterimage.

One possibility is that local afterimages of the disks and wedges—but only these—are induced first, and then the color filling-in occurs to give an impression of the global square, just as in the case of red filling-in during adaptation. The researchers considered this element-adaptation hypothesis, but eventually turned it down.

The other hypothesis is that, since neural circuits employing cortical neurons are known to cause the filling-in of the center of the red square, then perhaps it is this cortical circuit that undergoes adaptation to directly create the global negative green afterimage. This is called the surface-adaptation hypothesis, which was eventually supported by their results.

The researchers came up with experiments to provide three lines of evidence to reject the first and support the second hypothesis. First, the local and the global afterimages were visible with different timing, and tended to be exclusive of each other. This argued against the first hypothesis that the local afterimages are necessary to see the global afterimage.

Second, when the strength of color filling-in during adaptation was manipulated by changing the timing of the presentation of disks and colored wedges, the strength of the global afterimage was positively correlated with it, as predicted by the surface-adaptation hypothesis but not by the element adaptation hypothesis.

For the last piece of evidence, the researchers prepared a dynamic adapting stimulus designed specifically to minimize the local afterimages, yet to maximize the impression of color filling-in during adaptation. If the element-adaptation hypothesis is correct, then test subjects would not observe the global afterimage. If, on the other hand, the surface-adaptation hypothesis is correct, the observers would see a vivid global afterimage only. The result turned out to be the latter.

The study has no immediate applications, but furthers the understanding of perception and the human brain, says Shimojo, a professor of computation and neural systems at Caltech and lead author of the study.

"This has profound implications with regard to how brain activity is responsible for our conscious perception," he says.

According to Shimojo, the brain is the ultimate organ for humans to adapt to the environment, so it would make more sense if the brain, as well as the retina, can modify their activity—and perception as a result—due to experience and adaptation.

The other authors of the paper are Yukiyasu Kamitani, a Caltech graduate student in computation and neural systems, and Shin'ya Nishida of the NTT Communication Science Laboratories in Atsugi, Kanagawa, Japan.

Contact: Robert Tindol (626) 395-3631

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Caltech biologist David Chan selectedas Rita Allen Foundation Scholar

David C. Chan, an assistant professor of biology at the California Institute of Technology, has been named a Rita Allen Foundation Scholar. The award carries a $50,000 stipend for up to three years.

Chan specializes in research on mitochondria, components of the cell important in energy metabolism and also in programmed cell death. Specifically, he investigates the manner in which cells coordinate mitochondrial functions with the development of tissues and organs.

A graduate of Harvard Medical School and MIT, Chan joined the Caltech faculty in January 2000. From 1996 to 1999 he was a postdoctoral researcher at MIT's Whitehead Institute, where he succeeded in determining the crystal structure of the core of the HIV protein gp41. He also did structural analysis of the HIV envelope proteins in cell fusion and infection, and looked at ways the gp41 protein could be disabled to inhibit viral infection.

The Rita Allen Foundation was incorporated in 1953 in New York. The foundation supports medical research in the fields of cancer, cerebral palsy, multiple sclerosis, and the treatment of terminal illness, with special emphasis on the development of effective euphoric and analgesic agents.

The Rita Allen Foundation Scholarships program is designed to provide financial support for researchers in the early stages of their careers who show promise of becoming leaders in one of the areas of special interest to the foundation.

Founded in 1891, Caltech has an enrollment of some 2,000 students, and a faculty of about 285 professorial members. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 2,400 on campus and 4,800 at JPL.

Over the years, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-seven Caltech faculty members and alumni have received the National Medal of Science; and eight alumni (two of whom are also trustees), two additional trustees, and one faculty member have won the National Medal of Technology. Since 1958, 13 faculty members have received the annual California Scientist of the Year award. On the Caltech faculty there are 78 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 70 members of the National Academy of Sciences and 46 members of the National Academy of Engineering.

Contact: Robert Tindol (626) 395-3631

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Survival of the Fittest . . . Or the Flattest?

Darwinian dogma states that in the marathon race of evolution, the genotype that replicates the fastest, wins. But now scientists at the California Institute of Technology say that's true, but when you factor in another basic process of evolution, that of mutations, it's often the tortoise that defeats the hare.

It turns out that mutations, the random changes that can take place in a gene, are the wild cards in the great race. The researchers found that at high mutation rates, genotypes with a slower replication rate can displace faster replicators if the former has a higher "robustness"—or fitness—against mutations; that is, if a mutation is, on average, less harmful to the slower replicator than to the faster one. The research, to appear in the July 19th issue of the journal Nature, was conducted by several investigators, including Claus Wilke, a postdoctoral scholar, Chris Adami, who holds joint appointments at Caltech and the Jet Propulsion Lab, Jia Lan Wang, an undergraduate student, Charles Ofria, a former Caltech graduate student now at Michigan State University; and Richard Lenski, a professor at Michigan State.

In a takeoff of a common Darwinian phrase, they coin their work "survival of the flattest" rather than the survival of the fittest. The idea is this: If a group of similar genotypes with a faster replication rate occupies a "high and narrow peak" in the landscape of evolutionary fitness, while a different group of genotypes that replicates more slowly occupies a lower and flatter, or broader, peak, then, when mutation rates are high, the broadness of the lower peak can offset the height of the higher peak. That means the slower replicator wins. " In a way, organisms can trade replication speed for robustness against mutations and vice versa," says Wilke. "Ultimately, the organisms with the most advantageous combination of both will win."

Discerning such evolutionary nuances, though, is no easy task. To test an evolutionary theory requires generations and generations of an organism to pass. To make matters worse, the simplest living system, namely that which has been a precursor to all living systems on Earth, has been replaced by much more complicated systems over the last four billion years.

Wilke and his collaborators found the solution in the growing power of computers by constructing, via a software program, an artificial living system that behaves in remarkably lifelike ways. Such digital creatures evolve in the same way biological life forms do; they live in, and adapt to, a virtual world created for them inside a computer. Doing so offers an opportunity to test generalizations about living systems that may extend beyond the organic life that biologists usually study. Though this research did not involve actual living organisms, one of the authors, Richard Lenski, is a leading expert on the evolution of Escherichia Coli bacteria. Lenski believes that digital organisms are sufficiently realistic to yield biological insights, and he continues his research on both E. coli and digital organisms.

In their digital world, the organisms are self-replicating computer programs that compete with one another for CPU (central processing units) cycles, which are their limiting resource. Digital organisms have genomes in the form of a series of instructions, and phenotypes that are obtained by execution of their genomic program. The creatures physically inhabit a reserved space in the computer's memory—an "artificial Petri dish"—and they must copy their own genomes. Moreover, their evolution does not proceed toward a target specified in advance, but rather proceeds in an open-ended manner to produce phenotypes that are more successful in a particular environment.

Digital creatures lend themselves to evolutionary experiments because their environment can be readily manipulated to examine the importance of various selective pressures. In this study, though, the only environmental factor varied was the mutation rate. Whereas in nature, mutations are random changes that can take place in DNA, a digital organism's mutations occur in the random changes of its particular computer program. A command may be switched, for example, or a sequence of instructions copied twice.

For this study, the scientists derived 40 pairs of digital organisms that were derived from 40 different ancestors in identical selective environments. The only difference was that one of each pair was subjected to a four-fold higher mutation rate. In 12 cases out of the 40, the dominant genotype that evolved at the lower mutation rate replicated at a pace that was 1.5-fold faster than its counterpart at the higher mutation rate.

Next, the scientists allowed each of these 12 disparate pairs to compete across a range of mutation rates. In each case, as the mutation rate was increased, the outcome of competition switched to favor the genotype that had the lower replication rate. The researchers believe that these slower genotypes, although they occupied a lower fitness peak and were located in flatter regions of the fitness surface, were, as a result, more robust with respect to mutations.

The digital organisms have the advantage that many generations can be studied in a brief period of time. But the researchers believe a colony of asexual bacteria, subjected to the same stresses as the digital organisms, would probably face similar consequences.

The concept of "survival of the flattest" seems to imply, the authors say, that, at least for populations subject to a high mutation rate, selection acts upon a group of mutants rather than the individual. Thus, under such circumstances, genotypes that unselfishly produce mutant genotypes of high fitness are selected for, and supported in turn, by other mutants in that group. The study therefore reveals that "selfish genes," while being the successful strategy at low mutation rates, may be outcompeted by unselfish ones when the mutation rate is high.

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