Two from Caltech Faculty Elected to the American Academy of Arts and Sciences

PASADENA, Calif.—Two faculty members at the California Institute of Technology are among this year's newly elected fellows of the American Academy of Arts and Sciences. They join 173 other Americans and 20 foreign honorees as the 2006 class of fellows of the prestigious institution that was cofounded in 1780 by John Adams.

This year's new Caltech inductees are Anneila Sargent, the Rosen Professor of Astronomy and director of the Combined Array for Research in Millimeter-Wave Astronomy (CARMA), and Henry Lester, the Bren Professor of Biology. Their election brings the total number of fellows from Caltech to 83.

Sargent and Lester join an illustrious list of fellows, both past and present. Other inductees in the 2006 class include former presidents George H. W. Bush and William Jefferson Clinton; Supreme Court Chief Justice John Roberts; Nobel Prize-winning biochemist and Rockefeller University President Sir Paul Nurse; the chairman and vice chairman of the 9/11 commission, Thomas Kean and Lee Hamilton; actor and director Martin Scorsese; choreographer Meredith Monk; conductor Michael Tilson Thomas; and New York Stock Exchange chairman Marshall Carter. Past fellows have included George Washington, Benjamin Franklin, Ralph Waldo Emerson, Albert Einstein, and Winston Churchill.

Sargent, a native of Scotland, is an authority on star formation. Most recently she has been investigating the way in which stars like the sun are created and evolve to become planetary systems. She uses various radio and submillimeter telescopes to search for and study other potential planetary systems.

Her interests range from the earliest stages of star formation, when dense cores in interstellar clouds collapse to form stars, to the epochs when individual planets may be born. This field has garnered considerable interest within the scientific community, as well as from the news media and the general public, because of the possibility of locating other worlds beyond the solar system.

She is a former president of the American Astronomical Society, incoming chair of the National Research Council's board of physics and astronomy, cochair of the 1996 "Search for Origins" workshop sponsored by the White House Office of Science and Technology Policy, a former chair of NASA's space science advisory committee, and a member of the 2000 National Research Council's survey committee on astronomy and astrophysics.

Her major honors include the 2002 University of Edinburgh Alumnus of the Year award and the 1998 NASA Public Service Medal.

Lester is a New York City native who has been a Caltech faculty member since 1973. His lab is currently involved in several avenues of research, but he is probably best known for his research on the neuroscience of nicotine addiction. A recipient of research funding from the California-based Tobacco-Related Disease Research Program (TRDRP) and the National Institutes of Health, Lester has published numerous papers showing the underlying mechanisms of nicotine addiction.

In 2004, he and collaborators from Caltech and other institutions announced their discovery that activating the receptor known as alpha4 involved in the release of the neurotransmitter dopamine is sufficient for reward behavior, sensitization, and tolerance to repeated doses of nicotine. The discovery was important, experts said, because knowing precisely the cells and cell receptors that are involved could provide useful targets for addiction therapies.

Lester, Caltech chemist Dennis Dougherty, and a group from the University of Cambridge last year announced their success in finding the "switch" part of receptors like those for nicotine and serotonin.

His other current research interests include ion channels, synaptic transmission, light-flash physiology, and signal transduction. Within the past year he has also published papers on the creation of mouse models for epilepsy, tardive dyskinesia, Alzheimer's disease, and Parkinson's disease. The academy is an independent policy research center that focuses on complex and emerging problems such as scientific issues, global security, social policy, the humanities and culture, and education.

The new fellows and foreign honorary members will be formally recognized at the annual induction ceremony on October 7 at the academy's headquarters in Cambridge, Massachusetts.

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Benzer Receives $500,000 Albany Medical Center Prize

PASADENA, Calif.--Seymour Benzer, a California Institute of Technology neuroscientist, molecular biologist, and physicist who uncovered genetic links to behavior in fruit flies that today serve as the foundation for the study and treatment of human neurological diseases, has been named the recipient of the $500,000 Albany Medical Center Prize in Medicine and Biomedical Research.

In the 1960s, Benzer and his students demonstrated how mutations in single genes could have a radical effect on behavior in the fruit fly, Drosophila. The fly would later prove to be a model organism for the study of neurological disease, due to the remarkable degree of similarity between the fly and human genomes.

Benzer's seminal discoveries, which ran counter to the prevailing theory that environment was the primary factor in shaping human behavior, profoundly influenced a generation of scientists who, along with Benzer, identified the genetic basis for differences in circadian rhythm, courtship, learning, and memory in fruit flies. Heralded by the scientific community as the "father of neurogenetics," Benzer's pioneering work opened the field to exploration of models for specific neurodegenerative diseases of the human brain such as Alzheimer's, Huntington's chorea, Parkinson's, and amyotrophic lateral sclerosis (Lou Gehrig's disease).

Benzer is the James Griffin Boswell Professor of Neuroscience, Emeritus (Active), at Caltech. An octogenarian whose unconventional circadian rhythm has fueled all-night laboratory research sessions for more than half a century, Benzer is credited with founding the discipline of neurogenetics, defined broadly as the science of how genes control development and function of the nervous system and the brain, and influence behavior. Prior to pioneering this field, Benzer made his mark with monumental discoveries in molecular biology that bridged the gap between DNA and the fine structure of the gene, which helped to pave the way for the Human Genome Project, an effort to map and sequence every one of the three billion letters in the human genome.

In addition to honoring Benzer and his work, this year's prize ceremony paid tribute to Morris "Marty" Silverman, founder of the Albany Medical Center Prize, who died in January 2006 at the age of 93. Silverman founded the Albany Prize in November 2000 with a $50 million gift commitment to Albany Medical Center. A New York City businessman and philanthropist, born in Troy, N.Y., and educated in nearby Albany, Silverman succeeded in realizing his dream to have the prize widely recognized as "America's Nobel."

"This year we honor two outstanding visionaries, Seymour Benzer and Marty Silverman--one a great scientist, the other a world-class philanthropist--each of whom has made an immortal contribution to mankind and to whom the world owes an infinite debt of gratitude," said James J. Barba, chairman of the board, president and chief executive officer of Albany Medical Center, who also chairs the national selection committee for the Albany Medical Center Prize.

The Albany Medical Center Prize is the largest prize in medicine in the United States and worldwide is second only to the Nobel Prize in Physiology and Medicine. The annual prize--announced each spring--was created to encourage and recognize extraordinary and sustained contributions to improving health care and promoting biomedical research with translational benefits applied to improved patient care.

Benzer was selected for the Albany Medical Center Prize for his entire body of scientific work, which spans more than half a century and has incorporated the disciplines of solid-state physics, molecular biology, and neurogenetics. In the 1950s, using mutations in a virus that devours bacteria, Benzer made the seminal discovery that a single gene could be cut and dissected into many parts, which would help lay the groundwork for the explosion of genetic mapping and genetic engineering that now dominate biology.

Albany Medical Center is one of only 125 academic health sciences centers in the nation and the only such health care institution in northeastern New York.

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Contact: Jill Perry
(626) 395-3226
jperry@caltech.edu

Greg McGarry
(518) 262-3421
McGarrG@mail.amc.edu

Mark Bardack
(518) 383-6183
mbardack@edlewi.com

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

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McDonnell Foundation Grant Will Be Used to Study Neurons Involved in Snap Decisions

PASADENA, Calif.-Where do you get your "gut feelings," that intuition that leads you to distrust someone who appears trustworthy? It could be your Von Economo brain cells in action, and a neurobiologist at the California Institute of Technology intends to find out for sure.

John Allman, the Hixon Professor of Neurobiology, has received a $1.8 million grant from the James S. McDonnell Foundation to study the Von Economo neuron. The funding will allow Allman and his colleagues to perform a wide variety of research on the specialized neurons. The work could lead to new insights into the nature and treatment of various psychiatric disorders.

According to Allman, the Von Economo neurons (or VENs) are large bipolar cells located in the anterior cingulate and fronto-insular cortex. Also referred to as spindle neurons because of their shape, the neurons have been the focus of intense attention by Allman and his team for several years.

"We think that the VENs may have an important role in intuition," Allman says. "By intuition, we mean a form of cognition in which many variables are rapidly evaluated in parallel and compressed into a single dimension for fast decision-making." It is essential for making fast decisions in complex, rapidly changing social contexts.

"We experience the intuitive process at the visceral level," Allman explains. "Intuitive decision-making enables us to react quickly in situations that involve a high degree of uncertainty, which commonly involve social interactions."

In fact, the term "gut reaction" is not accidental, Allman says, because the mechanism may share some wiring with the controlling of the digestive system. One possibility is that the very primitive system originally may have been helpful in keeping animals away from poisonous plants. A rapid reaction, thus, may have evolved so that an animal would know instantly to spit out a noxious berry or risk being poisoned. Allman believes that this system for regulating the consumption of nutritious foods and rejecting those that are toxic was the basis for the neural circuitry governing complex social feelings such as love and hate, empathy and guilt.

Allman says the work is important because VENs may be particularly vulnerable to dysfunction in certain cases in which early development is disturbed. Related brain structures are known to be associated with obsessive-compulsive disorder, psychopathy, fronto-temporal lobe dementia, autism, Asperger's syndrome, and maybe even schizophrenia.

The researchers will use the grant money to work on several related questions, including how the VENs arise during infant development, whether the gut indeed sends direct signals to the VENs, how the VENs in humans compare to those of apes, and whether the VENs are somehow abnormal in the brains of autistic patients.

The James S. McDonnell Foundation grant that Allman has received is formally titled the 21st Century Science Initiative in Bridging Brain, Mind, and Behavior-Collaborative Award.

Founded in 1950 by aerospace pioneer James S. McDonnell, the foundation was established to "improve the quality of life," and does so by contributing to the generation of new knowledge through its support of research and scholarship.

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Contact: Jill Perry (626) 395-3226 jperry@caltech.edu

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Caltech Receives $2.3 Million for Stem Cell Research

PASADENA, Calif.- The California Institute of Technology has been awarded $2.3 million from the California Institute for Regenerative Medicine to support 10 postdoctoral scholars in the Caltech Stem Cell Biology Training Program.

The grant is one of 16 that were awarded by CIRM to non-profit institutions in California. The grants total $12.1 million and are intended to train the next generation of stem cell researchers. They are the first grants awarded by the California stem cell agency.

"This is an exhilarating day for the scientists, patients and the millions of Californians who support stem cell research," said Robert Klein, chairman of the Independent Citizens' Oversight Committee, the agency's governing board. "CIRM was created to fund science in the service of therapies, and today we're making our first grants. These grants are an investment in human capital. They will train the next generation of scientists. Patients can celebrate today because the flow of funds has started to the physicians and scientists who have dedicated their lives to this pioneering field that holds such promise for reducing human suffering."

The Caltech program will educate postdoctoral scholars in stem cell biology, its various potential medical applications, as well as the social, ethical and legal issues in this field.

"Caltech is already undertaking many stem cell research projects, and I think this will stimulate considerable additional interest," said Paul Patterson, training program director and Biaggini Professor of Biological Sciences. "The is the first step in expanding our efforts in this area."

In addition to Caltech's current stem cell course offerings, the Institute will offer a new bioethics course that emphasizes issues raised by stem cell research and applications.

Caltech will also collaborate with the Keck School of Medicine at the University of Southern California and the Children's Hospital of Los Angeles to offer a new tri-campus lecture course in stem cell biology.

The major strengths of the training program at Caltech will be the extremely high quality of the trainee population, the strength and cross-disciplinary nature of research offerings, the research facilities, and the available and new courses.

Relevant areas of current research at Caltech include embryonic and adult stem cell plasticity, stem cells and cancer, embryonic development, imaging technology, tissue engineering and macromolecular fabrication, computational biology, nanoscale biology and chemistry, and the basic science of hematopoietic, muscle, endothelial and neural stem cells. The cells and organisms being studied in this context include yeast, C. Elegans, Drosophila, Xenopus, zebrafish, mice and humans, including a variety of animal models of human diseases.

The new, collaborative part of this training program utilizes the expertise at Keck/USC and Children's Hospital in the areas of human embryonic stem cell growth and differentiation, cutting-edge gene transfer technology application in the clinic, stem cell research in a variety of organs, as well as medical ethics. Together, these institutions can provide a broad, in-depth curriculum for trainees. This collaboration also offers the opportunity and stimulus for basic scientists to become familiar with related clinical issues and the potential application of their findings to disease.

To enhance interaction among the CIRM trainees and to keep them up to date in this field, the Caltech program will include new stem cell seminar and journal club programs, as well as an annual scientific symposium.

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Contact: Jill Perry (626) 395-3226 jperry@caltech.edu

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Researchers Determine How Plants Decide Where to Position Their Leaves and Flowers

PASADENA, Calif.—One of the quests of modern biologists is to understand how cells talk to each other in order to determine where to form major organs. An international team of biologists has solved a part of this puzzle by combining state-of-the-art imaging and mathematical modeling to reveal how plants go about positioning their leaves and flowers.

In the January 31 issue of the Proceedings of the National Academy of Sciences (PNAS), researchers from the California Institute of Technology, the University of California at Irvine, and Lund University in Sweden reported their success in determining how a plant hormone known as auxin affects plant organ positioning. Experts already knew that auxin played some role in the development of plant organs, but the new study employs imaging techniques and computer modeling to propose a new theory about how the mechanism works.

The research involves the growing tip of the shoot of the plant Arabidopsis thaliana, a relative of the mustard plant that has been studied intensely by modern biologists. With its simple and very well understood genome, Arabidopsis lends itself to a wide variety of experiments.

The achievement of the researchers is their demonstration of how plant cells, with purely local information about their nearest neighbors' internal concentration of auxin, can communicate to determine the position of new flowers or leaves, which form in a regular pattern, with many cells separating the newly formed primordia (the first traces of an organ or structure). The authors theorize that the template the plant uses to make the larger parts comes from two mechanisms: a polarized transport of auxin into a feedback loop and a dynamic geometry arising from the growth and division of cells.

To capture the development, Beadle Professor of Biology Elliot Meyerowitz, division chair of the biology division at Caltech, and his team used green fluorescent proteins to mark specific cell types in the plant's meristem, the plant tissue in which regulated cell division, pattern formation, and differentiation give rise to plant parts like leaves and flowers.

The marked proteins allowed the group to image the cell's lineages through meristem development and differentiation leading to specific arrangement of leaves and reproductive growth, and also to follow changes in the concentration and movement of auxin.

Although the study applies specifically to the Arabidopsis plant, Meyerowitz says the mechanism is probably similar for other plants and even other biological systems in which patterning occurs in the course of development.

In addition to Meyerowitz, the paper's authors are Henrik Jönsson of Lund University, Marcus G. Heisler of Caltech's Division of Biology, Bruce E. Shapiro of Caltech's Biological Network Modeling Center, and Eric Mjolsness of UC Irvine's Institute of Genomics and Bioinformatics and department of computer science.

 

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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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Robert Tindol
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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.

 

 

Writer: 
Robert Tindol
Writer: 

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