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.

Factors causing high mutations could have led to origin of sexual reproduction, study shows

Biologists have long known the advantages of sexual reproduction to the evolution and survival of species. With a little sex, a fledgling creature is more likely to pass on the good mutations it may have, and more able to deal with the sort of environmental adversity that would send its asexual neighbors floundering into the shallow end of the gene pool.

The only problem is that it's hard to figure out how sex got started in the first place. Not only do many primitive single-celled organisms do just fine with asexual reproduction, but mathematical models show that a sexual mutant in an asexual population is most likely not favored to compete successfully and pass on its genes.

Now, researchers from the California Institute of Technology and the Jet Propulsion Laboratory, using "digital organisms" and RNA, have concluded that established asexual bacteria could be nudged to evolve into sexual reproduction if there are certain forms of stress on the environment, such as radiation or catastrophic meteor or comet impacts that give rise to a high rate of mutations.

In an article that has significant implications for understanding the origin of sexual reproduction in the early world, Claus Wilke of Caltech and Chris Adami, who holds joint appointments at Caltech and JPL, report that a change in conditions causing higher rates of mutations can lead an asexual population to an adaptation that may be sufficient to give mutant individuals a greater advantage if those mutants reproduce sexually.

The paper, published in the July 22 issue of the Royal Society journal Proceedings: Biological Sciences B, builds on earlier work by Adami and his collaborators, showing that digital organisms—that is, self-replicating computer programs designed to closely resemble the life cycles of living bacteria—can actually adapt to become more robust.

"What we showed in the other paper," says Adami, "is that if you transfer a fragile organism that evolved with a small mutation rate into a high-mutation-rate environment, it will adapt to this environment by becoming more robust."

One of the reasons the origin of sexual reproduction has been a mystery is because of an effect known as "mutation accumulation." Organisms tend to adapt so as to decrease the effects of mutations in order to become less vulnerable.

But this kind of robustness is poisonous, because with sexual recombination, deleterious mutations would simply accumulate in the organism and thus lead to a gradual loss of genes. This handicap of sexual creatures would be enough to guarantee their extinction when competing against asexual ones.

This can be avoided if the effects of mutations are compounding—that is, if the effect of two or more simultaneous deleterious mutations is worse than the combined effect of each of the mutations. In this manner, an organism may be robust to a few mutations, but incapable of surviving a large number of mutations, so that mutations cannot accumulate.

The new revelation by Wilke and Adami is that there is a conservation law at work in the relationship between the compounding of mutations and the fitness decay due to single mutations. This law says that robustness to a few mutations implies vulnerability to a large number, while robustness to many mutations must go hand in hand with vulnerability to single mutations.

Thus, increasing robustness to single mutations automatically makes multiple mutations intolerable, which removes organisms with multiple deleterious mutations from the population and allows sexual recombination to reap the rewards from sharing beneficial mutations.

Because stressful environments with high mutation rates push organisms to become robust to single mutations, the conservation law guarantees that this evolutionary pressure also pushes asexual organisms on to the road toward sexual recombination.

The researchers studied the evolution of digital organisms and RNA secondary structure, because accurate data on the decay of fitness and the effect of multiple mutations (whether they are compounding or mitigating) for living organisms is quite rare. For the RNA study, the researchers used known sequences with well-understood folds and then tried various mutations to see which mutations mattered and which didn't, in a system that computationally predicts RNA secondary structure. The results supported the conservation law.

Though the study did not involve actual living organisms, Adami has collaborated in the past with experts on bacteria to demonstrate that the digital organisms are indeed realistic. In an earlier 1999 study, for example, Adami's collaborator was a leading expert on the evolution of the E. coli bacteria.

The digital organisms have the advantage that many generations can be studied in a brief period of time, but Adami thinks a colony of asexual bacteria subjected to the stress imposed on the digital organisms in the experiment would probably face similar consequences.

"If you took a population of E. coli and subjected it to high mutation rates for many years—for example by irradiation or introducing mutagenic factors—at some point you might observe that exchange of genetic material, a precursor to sexual recombination, would become favorable to the organisms and thus selected for, if at the same time the environment changes fast enough that enough mutations are beneficial," he says.

"But that's a very difficult experiment with living organisms because of the time involved, and because it is difficult to construct constantly changing environments in a petri dish. This is easier with digital organisms, and will probably be first observed there.

"The reason the origin of sexual reproduction has been such a big mystery is that we look at the world as it is now," Adami says. "But the early world was a much more stressful place, sometimes changing very rapidly.

"We can't say how or when sexual reproduction came to take a hold in nature, but we can now say that high mutation rates can, under the right conditions, force an asexual organism to become sexual."

Adami earned his doctorate in theoretical physics at SUNY Stony Brook. He is a faculty associate in the computation and neural systems department at Caltech, and a research scientist at JPL. He is the author of the 1998 book Introduction to Artificial Life. Wilke, also a physicist, is a postdoctoral fellow in Adami's Digital Life Laboratory.

The article appears in Proceedings: Biological Sciences B, volume 268, number 1475, page 1469. The cover date is 22 July 2001, but the article is available on-line at http://www.pubs.royalsoc.ac.uk/proc_bio/proc_bio.html

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Hensen's node in chicken embryos governs movement of neural cells, study shows

For us living creatures with backbones, existence begins as a single fertilized cell that then subdivides and grows into a fetus with many, many cells. But the details of how those cells end up as discrete organs instead of undifferentiated heaps of cells is only now being understood in microscopic detail.

Why, for example, should some of the cells migrate to the region that will become the brain, while others travel netherward to make a spinal cord? Although some details are known about which cells contribute to particular regions of the nervous system and which signals help to establish the organization of the brain, much less is known about factors that guide the development of the spinal cord.

In a new study, researchers from the California Institute of Technology have gained unprecedented information about the molecular signals and cell movements that coordinate to form the spinal cord. The study takes advantage of recently developed bioimaging and cell labeling techniques to follow individual cell movements in a developing chick embryo through a clear "window" cut into a fertilized egg. The results, reported in the June issue of the journal Nature Cell Biology, suggest that a proliferative stem zone at the tail end of the growing embryo contributes descendants to the growing neuraxis.

"The basic idea is that descendants of cells from Hensen's node, the structure that lays down the trunk, are sequentially distributed along the elongating spinal cord" says Luc Mathis, a former researcher in the lab of Caltech biology professor Scott Fraser, and lead author of the paper. "In the past, we did not have the ability to follow individual cells in living vertebrate embryos and could not determine how neural precursor cells could remain within Hensen's node, while some descendants leave it to form the spinal cord. "

In the paper, the researchers explain that neural precursor cells get displaced into the neural axis by the proliferation in Hensen's node. The researchers labeled cells near Hensen's node in 40-hour old chick embryos by using an external electric field to deliver an expression vector encoding green fluorescent protein (GFP) into cells, a process called electroporation. Using state-of-the-art imaging techniques developed by postdoctoral researcher Paul Kulesa, the group recorded the motion of fluorescent cells in ovo using a confocal microscope set up for time-lapse imaging and surrounded by a heated chamber to maintain embryo development.

"As the cells proliferate, some progenitors are displaced from the stem zone to become part of the neural plate and spinal cord," Mathis says. "Our analyses show that the Hensen's node produces daughter cells that are eventually displaced out of the node zone on the basis of their position in relation to other proliferating cells, and not on the basis of asymmetric cell divisions."

The paper also addresses the molecular signaling involved in the spreading of the cells. Previous work has shown that fibroblast growth factor (FGF) is somehow involved in formation of the posterior nervous system. To test the possibility that FGF could act by maintaining the stem zone of cell proliferation, the researchers disrupted FGF signaling within Hensen's node. Indeed, the result was a seriously shortened spinal cord and premature exit of cells from the node, indicating that FGF is required for the proliferation of neural precursor cells in the stem zone that generates the spinal cord.

A structure similar to Hensen's node—called simply a "node"—is found in mammals, and analogous zones are found in other vertebrates as well. The cell behavior and genetic control discovered in the chick might also be responsible for the development of the spinal cord in mammals, including humans.

"This new understanding of the formation of the spinal cord is the result of a fusion between hypotheses that arose during previous studies that I had conducted in France, the great embryological background and imaging facilities provided by Scott Fraser, and the original experimental systems of cell tracking developed by Paul Kulesa" concludes Mathis."

Scott Fraser is the Anna L Rosen Professor of Biology and the director of the Biological Imaging Center of Caltech's Beckman Institute. Luc Mathis is a former researcher at the Biological Imaging Center who is currently at the Pasteur Institute in Paris. Paul Kulesa is a senior research fellow supported by the computational molecular biology progam and associated with the Biological Imaging Center.

Contact: Robert Tindol (626) 395-3631

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Caltech Uses Fluorescent Protein to Visualize the Work of Living Neurons

Neuroscientists have long suspected that dendrites—the fine fibers that extend from neurons—can synthesize proteins. Now, using a molecule they constructed that "lights up" when synthesis occurs, a biologist and her colleagues from the California Institute of Technology have proven just that.

Erin M. Schuman, an associate professor of biology at Caltech and an assistant investigator with the Howard Hughes Medical Institute, along with colleagues Girish Aakalu, Bryan Smith, Nhien Nguyen, and Changan Jiang, published their findings last month in the journal Neuron. Proving that protein synthesis does indeed occur in intact dendrites suggests the dendrites may also have the capacity to adjust the strength of connections between neurons. That in turn implies they may influence vital neural activities such as learning and memory.

Schuman and colleagues constructed a so-called "reporter" molecule that, when introduced into neurons, emits a telltale glow if protein synthesis is occurring. "There was early evidence that protein-synthesis machinery was present in dendrites," says Schuman. "Those findings were intriguing because they implied that dendrites had the capacity to make their own proteins."

The idea that dendrites should be able to synthesize proteins made sense to Schuman and others because it was more economical and efficient. "It's like the difference between centralized and distributed freight shipping," she says. "With central shipping, you need a huge number of trucks that drive all over town, moving freight from a central factory. But with distributed shipping, you have multiple distribution centers that serve local populations, with far less transport involved."

Previous studies had indicated that, in test tubes, tiny fragments of dendrites still had the capacity to synthesize proteins. Schuman and her colleagues believed that visualizing local protein synthesis in living neurons would provide a more compelling picture than was currently available.

The scientists began their efforts to create a reporter molecule by flanking a gene for a green fluorescent protein with two segments of another gene for a particular enzyme. Doing this ensured that the researchers would target the messenger RNA (mRNA) for their reporter molecule to dendrites.

Next, in a series of experiments, the group inserted the reporter molecule into rat neurons in culture, and then triggered protein synthesis using a growth factor called BDNF. By imaging the neurons over time, the investigators showed that the green fluorescent protein was expressed in the dendrites following BDNF treatment—proof that protein synthesis was taking place. Going a step further, the researchers showed they could cause the fluorescence to disappear by treating the neurons with a drug that blocked protein synthesis.

Schuman and her colleagues also addressed whether proteins synthesized in the main cell body, called the soma, could have diffused to the dendrites, rather than the dendrites themselves performing the protein synthesis. The researchers proved the proteins weren't coming from the soma by simply snipping the dendrites from the neurons, while maintaining their connection to their synaptic partners. Sure enough, the isolated dendrites still exhibited protein synthesis.

Intriguingly, says Schuman, hot spots of protein synthesis were observed within the dendrites. By tracking the location of the fluorescent signal over time, the researchers could see that these hotspots waxed and waned consistently in the same place. "The main attraction of local protein synthesis is that it could endow synapses with the capacity to make synapse-specific changes, which is a key property of information-storing systems," says Schuman. "The observation of such hot spots suggests there are localized areas of protein synthesis near synapses that may provide new proteins to synapses nearby."

Schuman and her colleagues are now applying their reporter molecule system to more complex brain slices and whole mice. "In the whole animals, we're exploring the role of dendritic protein synthesis in information processing and animal learning and behavior," says Schuman.

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Caltech Professor Pamela Bjorkman Elected To National Academy of Sciences

Pamela Bjorkman, professor of and executive officer for biology at the California Institute of Technology, is one of 72 American scientists elected this year to membership in the National Academy of Sciences (NAS). The announcement was made earlier this month in Washington at the 138th annual meeting of the academy.

Bjorkman, who has been on the Caltech faculty since 1989, focuses much of her research on molecules involved in cell-surface recognition, particularly molecules of the immune system. Investigators in her lab use a combined approach, including X-ray crystallography to determine three-dimensional structures, molecular biological techniques to produce proteins and to modify them, and biochemistry to study the properties of the proteins.

Much of the Bjorkman lab's efforts has involved proteins known as class I MHC, as well as very similar proteins—or homologues—that have a number of functions aside from an immunological role. In a 1999 study, for example, Bjorkman and her colleagues determined the three-dimensional structure of a protein that causes cachexia, a wasting syndrome in cancer and AIDS patients. The discovery provided the scientific basis for possible future strategies for controlling cachexia and/or treatment of obesity.

A native of Portland, Oregon, Bjorkman earned her bachelor's degree from the University of Oregon in 1978 and her doctorate from Harvard University in 1984. Afterward, she held postdoctoral positions at Harvard and the Stanford University School of Medicine.

She is an investigator of the Howard Hughes Medical Institute and has been a Pew Scholar in the biomedical sciences, an American Cancer Society Postdoctoral Fellow, and an American Society of Histocompatibility and Immunogenetics Young Investigator.

She has been the recipient of the William B. Coley Award for Distinguished Research in Fundamental Immunology, the Gairdner Foundation International Award for achievements in medical science, and the Paul Ehrlich and Ludwig Darmstaedter Award.

Bjorkman's election to the National Academy of Sciences brings to 67 the number of living Caltech professors and professors emeritus who have earned the prestigious honor. The National Academy, established in 1863 by President Lincoln, acts as an advisory body for the federal government on scientific matters.

Contact: Robert Tindol (626) 395-3631

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