Neuroscientists Discover the Neurons That Act As Novelty Detectors in the Human Brain

PASADENA, Calif.—By studying epileptic patients awaiting brain surgery, neuroscientists for the first time have located single neurons that are involved in recognizing whether a stimulus is new or old. The discovery demonstrates that the human brain not only has neurons for processing new information never seen before, but also neurons to recognize old information that has been seen just once.

In the March 16 issue of the journal Neuron, researchers from the California Institute of Technology, the Howard Hughes Medical Institute, and the Huntington Memorial Hospital report their success in distinguishing single-trial learning events from novel stimuli in six patients awaiting surgery for drug-resistant epileptic seizures. As part of the preparation for surgery, the patients have had electrodes implanted in their medial temporal lobes. Inserting small additional wires inside the clinical electrodes provides a way for researchers to observe the firing of individual human brain cells.

According to lead author Ueli Rutishauser, a graduate student in the computation and neural systems program at Caltech, the neurons are located in the hippocampus and amygdala, two limbic brain structures located deeply in the brain. Both regions are known to be important for learning and memory, but neuroscientists had never been able to establish the role of individual brain cells during single-trial learning until now.

"This is an unprecedented look at single-trial learning," explains Rutishauser, who works in the lab of Erin Schuman, a Caltech professor of biology and senior author of the paper. "It shows that single-trial learning is observable at the single-cell level. We've suspected it for a long time, but it has proven difficult to conduct these experiments with laboratory animals because you can't ask the animal whether it has seen something only once—500 times, yes, but not once."

With the patients volunteering to do perceptual studies while their brain activity is being recorded, however, such experiments are entirely possible. For the study, the researchers showed the six volunteers 12 different visual images, each presented once and randomly in one of four quadrants on a computer screen. Each subject was instructed to remember both the identity and position of the image or images presented.

After a 30-minute or 24-hour delay, each subject was shown previously viewed images or new images presented at the center of the screen, and asked whether each image was new or old. For each image identified as familiar, the subject was also asked to identify the quadrant in which the stimulus was originally presented.

The six subjects correctly recognized nearly 90 percent of the images they had already seen, but were less able to correctly recall the quadrant location in which the images had originally appeared. The researchers identified individual neurons that increased their firing rate either for novel stimuli or for familiar stimuli, but not both. These neurons thus responded differently to the same stimulus, depending on whether it was seen the first or the second time.

The fact that certain individual neurons of patients can be shown to fire only for recognition of something seen before, in fact, demonstrates that there is a "familiarity detector" neuron that explains why a person can have a feeling he or she has seen a face sometime in the past. Further, these neurons continue to fire and signal the familiarity of a stimulus, even when the subject mistakenly reports that the stimulus is new.

This type of neuron can account for subconscious recollections. "Even if the patients think they haven't seen the stimulus, their neurons still indicate that they have," Rutishauser says.

The third author of the paper is Adam Mamelak, who is a neurosurgeon at the Huntington Memorial Hospital and the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center.

Schuman is professor of biology and executive officer for neurobiology at Caltech and an investigator with the Howard Hughes Medical Institute.

 

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Caltech Scientists Discover the Part of the Brain That Causes Some People to Be Lousy in Math

PASADENA, Calif.—Most everyone knows that the term "dyslexia" refers to people who can't keep words and letters straight. A rarer term is "dyscalculia," which describes someone who is virtually unable to deal with numbers, much less do complicated math.

Scientists now have discovered the area of the brain linked to dyscalculia, demonstrating that there is a specific part of the brain essential for counting properly. In a report published in the March 13 issue of the Proceedings of the National Academy of Sciences (PNAS), researchers explain that the area of the brain known as the intraparietal sulcus (IPS), located toward the top and back of the brain and across both lobes, is crucial for the proper processing of numerical information.

According to Fulvia Castelli, a postdoctoral researcher at the California Institute of Technology and lead author of the paper, the IPS has been known for years as the brain area that allows humans to conceive of numbers. But she and her coauthors from University College London demonstrate that the IPS specifically determines how many things are perceived, as opposed to how much.

To explain how intimately the two different modes of thinking are connected, Castelli says to think about what happens when a person is approaching the checkout lines at the local Trader Joe's. Most of us are impatient sorts, so we typically head for the shortest line.

"Imagine how you really pick the shortest checkout line," says Castelli. "You could count the number of shoppers in each line, in which case you'd be thinking discretely in terms of numerosity.

"But if you're a hurried shopper, you probably take a quick glance at each line and pick the one that seems the shortest. In this case you're thinking in terms of continuous quantity."

The two modes of thinking are so similar, in fact, that scientists have had trouble isolating specific networks within the IPS because it is very difficult to distinguish between responses of how many and how much. To get at the difference between the two forms of quantity processing, Castelli and her colleagues devised a test in which subjects performed quick estimations of quantity while under functional MRI scans.

Specifically, the researchers showed subjects a series of blue and green flashes of light or a chessboard with blue and green rectangles. The subjects were asked to judge whether they saw more green or more blue, and their brain activity was monitored while they did so.

The results show that while subjects are exposed to the separate colors, the brain automatically counts how many objects are present. However, when subjects are presented with either a continuous blue and green light or a blurred chessboard on which the single squares are no longer visible, the brain does not count the objects, but instead estimates how much blue and green is visible.

"We think this identifies the brain activity specific to estimating the number of things," Castelli says. "This is probably also a brain network that underlies arithmetic, and when it's abnormal, may be responsible for dyscalculia."

In other words, dyscalculia arises because a person cannot develop adequate representations of how many things there are.

"Of course, dyscalculics can learn to count," Castelli explains. "But where most people can immediately tell that nine is bigger than seven, anyone with dcyscalculia may have to count the objects to be sure.

"Similarly, dyscalculics are much slower than people in general when they have to say how many objects there are in a set," she adds. "This affects everyday life, from the time when a child is struggling to keep up with arithmetic lessons in school to the time when an adult is trying to deal with money."

The good news is that the work of Castelli and her colleagues could lead to better tools for assessing whether a learning technique for people with dyscalculia is actually working. "Now that we have identified the brain system that carries out this function, we are in a position to see how dyscalculic brain activities differ from a normal brain," Castelli says.

"We should be in a position to measure whether an intervention is changing the brain function so that it becomes more like the normal pattern."

The article is titled "Discrete and analogue quantity processing in the parietal lobe: A functional MRI study." Castelli's coauthors are Daniel E. Glaser and Brian Butterworth, both researchers at the Institute of Cognitive Neuroscience at University College London.

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Researchers Create New "Matchmaking Service" Computer System to Study Gene Interactions

PASADENA, Calif.—Biologists in recent years have identified every individual gene in the genomes of several organisms. While this has been quite an accomplishment in itself, the further goal of figuring out how these genes interact is truly daunting.

The difficulty lies in the fact that two genes can pair up in a gigantic number of ways. If an organism has a genome of 20,000 genes, for example, the total number of pairwise combinations is a staggering total of 200 million possible interactions.

Researchers can indeed perform experiments to see what happens when the two genes interact, but 200 million is an enormous number of experiments, says Weiwei Zhong, a postdoctoral scholar at the California Institute of Technology. "The question is whether we can prioritize which experiments we should do in order to save a lot of time."

To get at this issue, Zhong and her supervising professor, Paul Sternberg, have derived a method of database-mining to make predictions about genetic interactions. In the current issue of the journal Science, they report on a procedure for computationally integrating several sources of data from several organisms to study the tiny worm C. elegans, or nematode, an animal commonly used in biological experiments.

This is possible because various organisms have a large number of genes in common. Humans and nematodes, for example, are similar in 40 percent of their genes. Therefore, a genetic-interaction network provides a faster and better way at determining how certain genes interact. Such a network also provides information about whether anyone has ever done an experiment to determine the interaction of two particular genes in one of several species.

"This process works like a matchmaking service for the genes," says Zhong. "It provides you with candidate matches that most likely will be interacting genes, based upon a number of specified features."

The benefit, she adds, is that biologists do not need to do a huge number of random experiments to verify if two genes indeed interact. Therefore, instead of the experimenter having to run 20,000 experiments to see if two genes randomly chosen from the genome of a 20,000-gene organism interact, they might get by with 10 to 50 experiments.

"The beneft is that you can be through in a month instead of years," says Sternberg. "Also, you can do experiments that are careful and detailed, which may take a day, and still be finished in a month."

To build the computational system, the researchers constructed a "training set" for pairs of nematode gene interactions. The "positives" for genetic interactions were taken from 4,775 known pairwise interactions from nematodes.

By "training" the system, Zhong and Sternberg arrived at a way to rapidly arrive at predictions of whether two genes would interact or not.

According to Sternberg, who is the Morgan Professor of Biology at Caltech, the results show that the data-mining procedure works. Also, the results demonstrate that the federal money spent on sequencing genomes-and the comparatively modest expenditures that have gone toward the improvement of biological data processing-have been dollars well spent.

"This is one of a suite of tools and methods people are coming up with to get more bang for the buck," he says.

In particular, Sternberg and Zhong cite the ongoing WormBase project, now in its sixth year as a database funded by the National Institutes of Health for understanding gene interactions of nematodes. WormBase received $12 million in new funding in 2003, and the project is already leading to new database tools ultimately aimed at promoting knowledge of how genes interrelate.

The new study by Zhong and Sternberg is not directly a product of WormBase, but nevertheless mines data from that and other sources. In fact, the study compiles data from several model organisms to reconstruct a gene-interaction network for the nematode.

Zhong says that the system is not perfect yet, because "false negatives" can still arise if the information is simply not in the database, or if the computer fails to recognize two genes as orthologs (i.e., essentially the same gene). "But it will get better," she adds.

"Choosing how to combine these data is the big deal, not the computational ability of the hardware," says Sternberg. "You can also see how the computer made the call of whether two genes should interact. So it's not a black box, but all transparent; and to biologists, that's really valuable. And finally, it's in the public domain."

Finally, the system provides a good window into the manner in which the biology of the future is emerging, Sternberg says. Zhong, for example, has a doctorate in biology and a master's in computer science: she spends about as much time working on computer databases as she does in the lab with the organisms themselves.

"This is the new generation of biologists," Sternberg says.

The study is titled "Genome-wide Prediction of C. elegans Genetic Interactions," and is published in the March 10 issue of Science.

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Caltech Scientists Gain Fundamental Insight into How Cells Protect Genetic Blueprints

PASADENA, Calif.—Molecular biologists have known for some time that there is a so-called checkpoint control mechanism that keeps our cells from dividing until they have copied all the DNA in their genetic code. Similar mechanisms prevent cells from dividing with damaged DNA, which forms, for example, in one's skin after a sunburn. Without such genetic fidelity mechanisms, cells would divide with missing or defective genes.

Now, a California Institute of Technology team has uncovered new details of how these checkpoints work at the molecular level.

Reporting in the March 10 issue of the journal Cell, Caltech senior research associate Akiko Kumagai and her colleagues show that a protein with the unusual name "TopBP1" is responsible for activating the cascade of reactions that prohibit cells from dividing with corrupted genetic blueprints. The researchers say that their result is a key molecular insight, and could possibly lead to molecular breakthroughs in cancer therapy someday.

"The function of the checkpoint control mechanisms is to preserve the integrity of the genome," says William Dunphy, the corresponding author of the paper and a professor of biology at Caltech. "When these genetic fidelity mechanisms do not function properly, it can lead to cancer and ultimately death."

The research began with a study of a protein called ATR that was known to be a key regulator of checkpoint responses. This protein is a vital component of every eukaryotic cell (in other words, the cells of most organisms on Earth excluding bacteria). ATR is a "kinase," an enzyme that controls other proteins by modifying them with phosphate groups.

However, no one knew how the cell turns on this enzymatic activity of ATR when needed. To figure out how ATR gets activated in protecting against mutations has been one of the most urgent questions of the field for the past decade.

Acting on a hunch, the researchers decided to look at the TopBP1 protein, whose molecular function was hitherto mysterious. Strikingly, the team found that purified TopBP1 could bind directly to ATR and activate it. The activation was so quick and robust that the researchers knew immediately that they had found the long-sought activator of ATR and deciphered how cells mobilize their efforts to prevent mutations. Interestingly, the researchers found that only a small part of TopBP1 is necessary for activating ATR.

The researchers suspect that the remaining parts of TopBP1 hold additional secrets about checkpoint control mechanisms. Dunphy says that this molecular insight shows how a cancer-repressive mechanism works in a healthy cell. "Knowing how the normal system works might also help lead to insight on how to fix the system when it gets broken," he adds.

In addition to Kumagai and Dunphy, the other authors of the Cell paper are Joon Lee and Hae Yong Yoo, both senior research fellows at Caltech.

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Old-World Primates Evolved Color Vision to Better See Each Other Blush, Study Reveals

PASADENA, Calif.—Your emotions can easily be read by others when you blush—at least by others familiar with your skin color. What's more, the blood rushing out of your face when you're terrified is just as telling. And when it comes to our evolutionary cousins the chimpanzees, they not only can see color changes in each other's faces, but in each other's rumps as well.

Now, a team of California Institute of Technology researchers has published a paper suggesting that we primates evolved our particular brand of color vision so that we could subtly discriminate slight changes in skin tone due to blushing and blanching. The work may answer a long-standing question about why trichromat vision (that is, color via three cone receptors) evolved in the first place in primates.

"For a hundred years, we've thought that color vision was for finding the right fruit to eat when it was ripe," says Mark Changizi, a theoretical neurobiologist and postdoctoral researcher at Caltech. "But if you look at the variety of diets of all the primates having trichromat vision, the evidence is not overwhelming."

Reporting in the current issue of the journal Biology Letters, Changizi and his coauthors show that our color cones are optimized to be sensitive to subtle changes in skin tone due to varying amounts of oxygenated hemoglobin in the blood.

The spectral sensitivity of the color cones is somewhat odd, Changizi says. Bees, for example, have four color cones that are evenly spread across the visible spectrum, with the high-frequency end extending into the ultraviolet. Birds have three color cones that are also evenly distributed in the visible spectrum.

The old-world primates, by contrast, have an "S" cone at about 440 nanometers (the wavelength of visible light roughly corresponding to blue light), an "M" cone sensitive at slightly less than 550 nanometers, and an "L" cone sensitive at slightly above 550 nanometers.

"This seems like a bad idea to have two cones so close together," Changizi says. "But it turns out that the closeness of the M and L cone sensitivities allows for an additional dimension of sensitivity to spectral modulation. Also, their spacing maximizes sensitivity for discriminating variations in blood oxygen saturation." As a result, a very slight lowering or rising of the oxygen in the blood is easily discriminated by any primate with this type of cone arrangement.

In fact, trichromat vision is sensitive not only for the perception of these subtle changes in color, but also for the perception of the absence or presence of blood. As a result, primates with trichromat vision are not only able to tell if a potential partner is having a rush of emotion due to the anticipation of mating, but also if an enemy's blood has drained out of his face due to fear.

"Also, ecologically, when you're more oxygenated, you're in better shape," Changizi adds, explaining that a naturally rosy complexion might be a positive thing for purposes of courtship.

Adding to the confidence of the hypothesis is the fact that the old-world trichromats tend to be bare-faced and bare-butted as well. "There's no sense in being able to see the slight color variations in skin if you can't see the skin," Changizi says. "And what we find is that the trichromats have bare spots on their faces, while the dichromats have furry faces."

"This could connect up with why we're the 'naked ape,'" he concludes. The few human spots that are not capable of signaling, because they are in secluded regions, tend to be hairy-such as the top of the head, the armpits, and the crotch. And when the groin occasionally does tend to exhibit bare skin, it occurs in circumstances in which a potential mate may be able to see that region.

"Our speculation is that the newly bare spots are for color signaling."

The other authors of the paper are Shinsuke Shimojo, a professor of biology at Caltech who specializes in psychophysics; and Qiong Zhang, an undergraduate at Caltech.

 

 

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Caltech Launches Brain Study Program with $8.9 Million Gift from Eli Broad to Fund 24 Researchers and Six New Labs

PASADENA, Calif.—For years, scientists have worked to study each of the 100 billion neurons in the human brain. But while they understand individual neurons, they've been stumped by how neurons work together, how they encode information, and how they generate thoughts, emotions, and actions.

That pioneering area of study is behind the Broad Fellows Program in Brain Circuitry at the California Institute of Technology, announced today and made possible through an $8.9 million grant from the Broad Foundations and philanthropist Eli Broad.

The funding will enable the program to establish six new neuroscience labs at Caltech and hire 24 researchers over the next five years.

"Caltech is one of the country's greatest research institutions, and this program will encourage some of the brightest young minds in science to devote their research to unlocking the mysteries of the brain," said Eli Broad, founder of the Broad Foundations.

While scientists have made tremendous progress in recent years in understanding the brain's overall activity, the interactions between neurons--which hold the clues to mental diseases such as Alzheimer's, autism, and schizophrenia--are still a mystery.

"We have no idea how these neurons are assembled in groups of 50 to 100,000 to generate conscious thoughts," said Christof Koch, Troendle Professor of Cognitive and Behavioral Biology and Professor of Computation and Neural Systems at Caltech, who will serve as director of the Broad Fellows Program. "We truly believe that the best way to learn about small neuronal networks is to find a few brilliant young neurobiologists, engineers, or physicists with innovative ideas on how to record and manipulate networks of nerve cells. Then, if we provide them with the funding for research assistants and equipment to develop the relevant technologies, all we need to do is get out of their way."

"Neuroscience is becoming an increasingly multidisciplinary exercise," said Michael Dickinson, Zarem Professor of Bioengineering at Caltech, who will serve on the selection committee for the Broad Fellows Program. "Future progress will depend on a creative mixture of expertise in biology, engineering, and mathematics. An exciting feature of this program is that it will provide talented young researchers with a borderless research environment from which to pursue programs from different perspectives."

Koch and his colleagues will hire the first two Broad Fellows in Brain Circuitry later this year, and will hire two more in 2007 and an additional two in 2008. Each of the six Broad Fellows will receive funding to hire up to three assistants, for a total of 24 researchers in the program, which will be housed in Caltech's Division of Biology.

"Each of the fellows will be able to devote up to five years to their projects, without having to worry about finding another postdoctoral appointment in a year or two or limiting themselves only to research that will lead to tenure," Koch said. "These researchers will be at a level between postdoctoral fellow and assistant professor, which means that they will be very independent and won't have to worry about the tenure clock."

"The freedom that comes with these fellowships should foster quite productive interactions among fellows and members of the Caltech community," added Dickinson. "An important role of the selection committee will be to recruit a diverse array of young researchers with complementary skills."

The program is designed to give researchers the freedom and flexibility to advance their work in whatever way is most productive, and may include the development of specific technologies or the invention of new instruments. The Broad Fellows will be given individual space to do their work in the Beckman Laboratories of Behavioral Biology on the Caltech campus.

The program will be under the direction of Koch and a committee of other Caltech faculty members, including Dickinson; Gilles Laurent, the Hanson Jr. Professor of Biology and Computation and Neural Systems; David Anderson, the Sperry Professor of Biology; Barbara Wold, director of the Beckman Institute at Caltech and Bren Professor of Molecular Biology; and Mark Konishi, the Bing Professor of Behavioral Biology.

Founded in 1891, Caltech is located on a 124-acre campus in Pasadena. The Institute also manages the nearby Jet Propulsion Laboratory and operates several other off-campus astronomical, seismological, and marine biology facilities. Caltech has an enrollment of some 2,100 students, more than half of whom are in graduate studies, a faculty of about 280 professorial members and 62 research members, and some 570 postdoctoral scholars. Caltech employs a staff of more than 2,500 on campus and 5,000 at JPL.

U.S. News &World Report consistently ranks Caltech's undergraduate and graduate programs as being among the nation's best. The average SAT scores of members of recent incoming freshman classes have consistently been among the highest in the country. Over the years, 32 Nobel Prizes and five Crafoord Prizes have been awarded to faculty members and alumni.

The Broad Foundations were founded by Eli and Edythe L. Broad as a Los Angeles-based venture philanthropy focused on entrepreneurship for the public good in education, science, and the arts. The Broad Foundations Internet address is www.broadfoundations.org.

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Baltimore Is President-Elect of the American Association for the Advancement of Science

PASADENA, Calif.—David Baltimore, president of the California Institute of Technology since 1997, has been chosen to serve as president-elect of the American Association for the Advancement of Science. Baltimore will begin his term as president-elect on February 21, at the close of the 2006 annual AAAS meeting, and will begin his one-year term as president in February 2007.

"I am gratified to be given the honor and responsibility of the presidency of the AAAS by its membership," Baltimore said. "I look forward to leading this very important organization and particularly to interacting with the community of scientific leadership in the U.S. and the rest of the world."

Baltimore, who late last year announced his retirement from Caltech's presidency pending the appointment of a successor, will remain at the Institute as a professor of biology. One of America's leading scientists, he has maintained an intense research program in his lab throughout his presidency, and is currently embarking on the $13.9-million grant-funded initiative "Engineering Immunity Against HIV and Other Dangerous Pathogens," which promises to address the challenge of creating immunological methods to deal with chronic diseases. This grant was awarded by the Bill and Melinda Gates Foundation.

Baltimore received the Nobel Prize in Physiology or Medicine in 1975 for his work on the genetic mechanisms of viruses. This research has contributed widely to the understanding of cancer, AIDS, and the molecular basis of the immune response.

Baltimore's lab in recent years has announced many important findings while at Caltech, including establishing a new methodology to help fight cancer, developing a new gene therapy that is highly effective in preventing HIV from infecting individual cells in the immune system, and creating a methodology for producing transgenic mice. He has also joined with others in proposing a global effort to create an HIV vaccine. He received the National Medal of Science in 1999 from President Bill Clinton, and the Warren Alpert Foundation Scientific Prize in 2001 for pioneering work leading to cancer therapy.

"David Baltimore will go down in history as not only a great scientist, but also as one of the great presidents of Caltech," said Eli Broad, when Baltimore announced his retirement. Broad is a Caltech trustee and major donor. "It is rare to find someone of his intelligence, integrity, and leadership who can relate so well to people both within and outside the world of science. It was David who inspired Edye and me to become interested in science. We had no background in the field, but he made us feel comfortable. We are fortunate that he will continue his research at Caltech."

Not only has Baltimore been prolific in writing about his findings in scientific journals, but has also been a strong advocate for scientific research by contributing opinion pieces to general-interest media on such subjects as the value of stem cell research, the unnecessary public panic that arose during the SARS epidemic, science research under the Bush administration, and maintaining the scientific workforce in the United States.

Baltimore has several outstanding administrative and public policy achievements to his credit. In the mid-1970s, he played an important role in creating a consensus on national science policy regarding recombinant DNA research. He served as founding director of the Whitehead Institute for Biomedical Research at MIT from 1982 until 1990, and was president of Rockefeller University in 1990-91. An early advocate of federal AIDS research, he cochaired the 1986 National Academy of Sciences Committee on a National Strategy for AIDS, and was appointed in 1996 to head the National Institutes of Health AIDS Vaccine Research Committee.

The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science around the world by serving as an educator, leader, spokesperson, and professional association. In addition to organizing membership activities, AAAS publishes the journal Science, as well as many scientific newsletters, books, and reports, and spearheads programs that promote the understanding of science worldwide.

Founded in 1848, AAAS serves some 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of one million. The non-profit AAAS is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy, international programs, and science education.

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Deciphering the Mystery of Bee Flight

PASADENA, Calif.- One of the most elusive questions in science has finally been answered: How do bees fly?

Although the issue is not as profound as how the universe began or what kick-started life on earth, the physics of bee flight has perplexed scientists for more than 70 years. In 1934, in fact, French entomologist August Magnan and his assistant André Sainte-Lague calculated that bee flight was aerodynamically impossible. The haphazard flapping of their wings simply shouldn't keep the hefty bugs aloft.

And yet, bees most certainly fly, and the dichotomy between prediction and reality has been used for decades to needle scientists and engineers about their inability to explain complex biological processes.

Now, Michael H. Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering, and his postdoctoral student Douglas L. Altshuler and their colleagues at Caltech and the University of Nevada at Las Vegas, have figured out honeybee flight using a combination of high-speed digital photography, to snap freeze-frame images of bees in motion, and a giant robotic mock-up of a bee wing. The results of their analysis appear in the November 28 issue of the Proceedings of the National Academy of Sciences.

"We're no longer allowed to use this story about not understanding bee flight as an example of where science has failed, because it is just not true," Dickinson says.

The secret of honeybee flight, the researchers say, is the unconventional combination of short, choppy wing strokes, a rapid rotation of the wing as it flops over and reverses direction, and a very fast wing-beat frequency.

"These animals are exploiting some of the most exotic flight mechanisms that are available to insects," says Dickinson.

Their furious flapping speed is surprising, Dickinson says, because "generally the smaller the insect the faster it flaps. This is because aerodynamic performance decreases with size, and so to compensate small animals have to flap their wings faster. Mosquitoes flap at a frequency of over 400 beats per second. Birds are more of a whump, because they beat their wings so slowly."

Being relatively large insects, bees would be expected to beat their wings rather slowly, and to sweep them across the same wide arc as other flying bugs (whose wings cover nearly half a circle). They do neither. Their wings beat over a short arc of about 90 degrees, but ridiculously fast, at around 230 beats per second. Fruit flies, in comparison, are 80 times smaller than honeybees, but flap their wings only 200 times a second.

When bees want to generate more power--for example, when they are carting around a load of nectar or pollen--they increase the arc of their wing strokes, but keep flapping at the same rate. That is also odd, Dickinson says, because "it would be much more aerodynamically efficient if they regulated not how far they flap their wings but how fast "

Honeybees' peculiar strategy may have to do with the design of their flight muscles.

"Bees have evolved flight muscles that are physiologically very different from those of other insects. One consequence is that the wings have to operate fast and at a constant frequency or the muscle doesn't generate enough power," Dickinson says.

"This is one of those cases where you can make a mistake by looking at an animal and assuming that it is perfectly adapted. An alternate hypothesis is that bee ancestors inherited this kind of muscle and now present-day bees must live with its peculiarities," Dickinson says.

How honeybees make the best of it may help engineers in the design of flying insect-sized robots: "You can't shrink a 747 wing down to this size and expect it to work, because the aerodynamics are different," he says. "But the way in which bee wings generate forces is directly applicable to these devices."

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Modified Mice Test Alzheimer's Disease Drugs

PASADENA, Calif.- Alzheimer's disease is a progressive brain disorder that afflicts an estimated 4.5 million Americans and that is characterized by the presence of dense clumps of a small peptide called amyloid-beta in the spaces between neurons.

Developing therapeutic drugs to stop the formation of the lesions, called amyloid plaques, and to remove them from the brain has become the focus of intense research efforts by pharmaceutical companies. Unfortunately, methods to test the efficacy of the drugs are limited as is the access to test results given to outside researchers.

Now neuroscientist Joanna L. Jankowsky, a senior research fellow in the laboratory of Henry A. Lester, Bren Professor of Biology at the California Institute of Technology, in collaboration with David R. Borchelt at the University of Florida, Gainesville, and colleagues at Johns Hopkins School of Medicine, Mayo Clinic Jacksonville, and the National Cancer Institute, have created a strain of genetically engineered mice that offers an unprecedented opportunity to test these new drugs and provides striking insight into possible future treatment for the disease.

A paper about the mouse model was published November 15 in the international open-access medical journal PLoS Medicine (www.plosmedicine.org).

The amyloid-beta peptide is something of an enigma. It is known to be produced normally in the brain and to be churned out in excess in Alzheimer's disease. But researchers don't know exactly what purpose the molecule usually serves--or, indeed, what happens to dramatically raise its concentration in the Alzheimer's brain.

The peptide is created when a molecule called amyloid precursor protein (APP) is snipped in two places, at the front end by an enzyme called beta-APP cleaving enzyme, and at the back end by an enzyme called gamma-secretase. If either of those two cuts is blocked, the amyloid-beta protein won't be released--and plaque won't build up in the brain.

To prevent plaques from accumulating, drug companies have been experimenting with compounds that inhibit one or the other of the enzymes, thereby blocking the release of amyloid-beta. Jankowsky and her colleagues decided to test how well this approach to treating Alzheimer's disease will work. Because they lacked access to the drugs themselves, they instead engineered a laboratory mouse with two added genes that would mimic the effect of secretase inhibitor treatment. One gene triggered the continuous production of APP in the brain (and thus also the amyloid-beta peptide) leading to substantial plaque deposits in mice as young as six months old. The second gene served as an off-switch to amyloid-beta. The researchers were able to flip the switch at will by adding the antibiotic tetracycline into the mice's food--and when they did so, they also halted all plaque formation.

"The key point here is that we've completely arrested the progression of the pathology," says Jankowsky.

Plaque deposits that had already formed, however, weren't cleared out.

"We can stop the disease from getting worse in these mice, but we can't reverse it," says study co-author David Borchelt, Jankowsky's former postdoctoral research advisor at Johns Hopkins University. "Although it is possible that human brains repair damage better than mouse brains, the study suggests that it may be difficult to repair lesions once they have formed."

One implication of the research is that it suggests that treatment with drugs to stop plaque formation should begin as soon as possible after the disease is diagnosed. "It looks like early intervention would be the most effective way of treating disease," Jankowsky says.

"It was surprising to many people that the plaques didn't go away, but they are really very stable structures," says Jankowsky. It is also possible, some researchers believe, that the plaques themselves aren't damaging. Rather, they may be a sign of the overproduction of amyloid-beta and of the small, free-floating clumps of the peptide that actually cause cognitive problems. "The plaques may simply act as trash cans for what has already been produced," she says. If that is indeed the case, Jankowsky says, then "shutting down the production of amyloid-beta itself would be adequate to reverse cognitive decline."

On the other hand, removal of the plaques could improve cognitive function by allowing neurons that had previously been displaced by the protein deposits to reform and form new neural connections. That is why, the researchers say, an ideal therapy would be one that both prevented the overproduction of new amyloid-beta and cleared out existing deposits.

Drug companies are currently investigating treatment protocols for Alzheimer's disease in which antibodies against the amyloid-beta peptide are directly injected into the body. The antibodies latch onto the molecule and quickly clear it from the brain, along with any plaque deposits that have already formed. However, Jankowsky says, these drugs therapies may not be appropriate for long-term use because of possible side effects. One clinical trial of the antibodies had to be stopped because some patients developed a serious brain inflammation known as encephalitis.

"The upshot of this research is that a combination of approaches may be the best way to tackle Alzheimer's disease," Jankowsky says. "The idea would be to use immunotherapy to acutely reverse the damage, followed by chronic secretase inhibition to prevent it from ever recurring."

For a copy of the paper, go to http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1...

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Contact: Dr. Joanna L. Jankowsky (626) 395-6884 jlj2@caltech.edu

Kathy Svitil (626) 395-8022 ksvitil@caltech.edu

Visit the Caltech Media Relations Web site at: http://pr.caltech.edu/media

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KS
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Caltech Researchers Join Global GEM4 Initiative

PASADENA, Calif.—Researchers at the California Institute of Technology have joined a global medical effort to address a number of diseases through innovative, multi-institutional, multidisciplinary approaches. The initiative, the Global Enterprise for Micromechanics and Molecular Medicine (GEM4), is centered at MIT's Department of Materials Science and Engineering, and was officially launched October 12 at an MIT campus ceremony.

According to Mory Gharib, who is the Liepmann Professor of Aeronautics and Bioengineering at Caltech, the participation of Caltech researchers will concentrate on the micromechanics of cells and tissues related to certain diseases.

"In the past, researchers have always looked at the biological and chemical aspects of diseases like malaria," says Gharib. "So this is a novel approach. The idea is that, by looking at the ways certain mechanical properties of the cell change with the disease, you could have new and ideally faster technical devices for doing diagnoses."

An end result might be a microfluidic device, for example, that would use a hairpin needle for doing in situ examinations of cells passing by. The sensor, by utilizing the laws of physics, would be able to tell the percentage of infected cells.

Such a device could also be used for screening, Gharib says. "Millions and millions of cells could be screened, with no need for determining their chemical or spectral behavior."

Another Caltech researcher who will be closely involved in the GEM4 effort is Ares Rosakis, who is director of the Graduate Aeronautical Laboratories (GALCIT) and the von Kármán Professor of Aeronautics and Mechanical Engineering. According to Rosakis, a $750,000 gift from Joe and Edwina Charyk to GALCIT will go to facilitating Caltech's participation in GEM4. Specifically, the Charyk gift will be used for the creation of the Charyk Biomechanics Laboratory, which will be part of the existing GALCIT complex.

According to MIT's announcement, GEM4 is "a new paradigm in global interactions among leading institutions to work together seamlessly across the boundaries of science, engineering, technology, medicine, and public health, with an emphasis on biomechanics at the microscopic and molecular levels."

Among GEM4's goals are the bringing together of institutions globally, the creation of new models for interdisciplinary partnerships, and the fostering of a global forum to address and explore huge challenges for the future. The diseases and conditions to be addressed include metastatic cancer, cardiovascular diseases, inflammatory diseases, and infectious diseases such as malaria.

"The initial emphasis will include (but will not be limited to) molecular, subcellular, and cellular mechanics applied to major problems in biomedicine," the MIT announcement continues, "where a single investigator or institution is not likely to have the full spectrum of expertise, infrastructure, or resources available to span fundamental molecular science all the way to clinical practice and societal implications."

Professor Subra Suresh, who is the GEM4 director, is the Ford Professor of Engineering and head of the Department of Materials Science and Engineering at MIT. At Caltech he held the Clark Millikan Visiting Professor Chair in Aeronautics and was also a Moore Visiting Scholar.

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Robert Tindol
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