Caltech Professor Receives Ellison Award

PASADENA, Calif.—Giuseppe Attardi, the California Institute of Technology's Grace C. Steele Professor of Molecular Biology, has received the Ellison Medical Foundation Senior Scholar Award. The award is for $935,584 over four years.

Attardi's work encompasses research in the area of aging and in the detection of DNA that affects the aging processes. He is responsible for the discovery and development of new genetic research techniques that are used by laboratories internationally.

Attardi's career spans nearly a half century, including 35 years at Caltech. Prior to joining the Caltech faculty in 1963, Attardi was an assistant professor in histology and general embryology at the University of Padua, Italy. He received his MD from the University of Padua in 1947.

Throughout his career, Attardi has received numerous distinguished honors and awards.

The Ellison Medical Foundation is a nonprofit corporation that was established by a gift from Mr. Lawrence J. Ellison to support basic biomedical research on aging, relevant to understanding aging processes and age-related diseases and disabilities. The Ellison Medical Foundation stimulates basic biomedical research in multiple disciplines including molecular genetics, cell cycle regulation, cellular differentiation, genetic epidemiology, immunology, gene/environment and gene/gene interactions, metabolism, endocrinology, signal transduction, and integrative physiology. Through various award mechanisms, including the Senior Scholar and New Scholar Awards programs, the foundation fosters research by means of grants-in-aid to investigators at universities and laboratories within the United States.

Contact: Deborah Williams-Hedges (626) 395-3227

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Odor recognition is a patterned, time-dependent process, research shows

PASADENA, Calif.-When Hamlet told the courtiers they would eventually "nose out" the hidden corpse of Polonius, he was perhaps a better neurobiologist than he realized. According to research by neuroscientists at the California Institute of Technology, the brain creates and uses subtle temporal codes to identify odors.

This research shows that the signals carried by certain neuron populations change over the duration of a sniff such that one first gets a general notion of the type of odor. Then, the wiring between these neurons performs work that leads to a more subtle discrimination, and thus, a precise recognition of the smell.

In the February 2 issue of the journal Science, Caltech biology and computation and neural systems professor Gilles Laurent and his colleague, postdoctoral scholar Rainer W. Friedrich, now at the Max Planck Institute in Heidelberg, Germany, report that the neurons of the olfactory bulb respond to an odor through a complicated process that evolves over a brief period of time. These neurons, called mitral cells because they resemble miters, thepointed hats worn by bishops, are found by the thousands in the olfactory bulb of humans.

"We're interested in how ensembles of neurons encode sensory information," explains Laurent, lead author of the study. "So we're less interested in where the relevant neurons lie, as revealed by brain mapping studies, than in the patterns of firing these neurons produce and in figuring out from these patterns how recognition, or decoding, works."

The researchers chose to use zebrafish in the study because these animals have comparatively few mitral cells and because much is already known about the types of odors that are behaviorally relevant to them. The Science study likely applies to other animals, including humans, because the olfactory systems of most living creatures appear to follow the same basic principles.

After placing electrodes in the brain of individual fish, the researchers subjected them sequentially to 16 amino-acid odors. Amino acids, the components of proteins, are found in the foods these fish normally go after in their natural environments.

By analyzing the signals produced by a population of mitral cells in response to each one of these odors, the researchers found that the information they could extract about the stimulus became more precise as time went by. The finding was surprising because the signals extracted from the neurons located upstream of the mitral cells, the receptors, showed no such temporal evolution.

"It looks as if the brain actively transforms static patterns into dynamic ones and in so doing, manages to amplify the subtle differences that are hard to perceive between static patterns," Laurent says.

"Music may provide a useful analogy. Imagine that the olfactory system is a chain of choruses-a receptor chorus, feeding onto a mitral-cell chorus and so on-and that each odor causes the receptor chorus to produce a chord.

"Two similar odors evoke two very similar chords from this chorus, making discrimination difficult to a listener," Laurent says. "What the mitral-cell chorus does is to transform each chord it hears into a musical phrase, in such a way that the difference between these phrases becomes greater over time. In this way, odors that, in this analogy, sounded alike, can progressively become more unique and more easily identified."

Applied to our own experience, this result could be described as follows: When we detect a citrus smell in a garden, for example, the odor is first conveyed by the receptors and the mitral cells. The initial firing of the cells allows for little more than the generic detection of the citrus nature of the smell.

Within a few tenths of a second, however, this initial activity causes new mitral cells to be recruited, leading the pattern of activity to change rapidly and become more unique. This quickly allows us to determine whether the citrus smell is actually a lemon or an orange.

However, the individual tuning of the mitral cells first stimulated by the citrus odor do not themselves become more specific. Instead, the manner in which the firing patterns unfold through the lateral circuitry of the olfactory bulb is ultimately responsible for the fine discrimination of the odor.

"Hence, as the system evolves, it loses information about the class of odors, but becomes able to convey information about precise identity," says Laurent. This study furthers progress toward understanding the logic of the olfactory coding.

Robert Tindol

New research shows that the ears can sometimes trick the eyes

Though it seems to follow common sense that vision is the most dominant of the human senses, a new study by California Institute of Technology researchers shows that auditory signals can sometimes trick test subjects into misinterpreting what they have seen.

In a new study appearing in the Dec. 14 issue of the journal Nature, Caltech psychophysicists Ladan Shams, Yukiyasu Kamitani, and Shinsuke Shimojo report that auditory information can alter the perception of accompanying visual information, even when the visual input is otherwise unambiguous.

"We have discovered a visual illusion that is induced by sound," the authors write in the paper. Using a computer program that runs very short blips of light accompanied by beeps, the researchers asked test subjects to determine whether there was one or two flashes.

However, unknown to the subjects, the number of flashes mismatch that of beeps in some trials. When the subjects were shown the flash accompanied by one beep, everyone correctly stated that they had seen one flash. But when they were shown the flash with two very quick beeps spaced about 50 milliseconds apart, the subjects all erroneously reported that they had seen two flashes.

What's more, test subjects who were told that there was actually only one flash still continued to perceive two flashes when they heard two beeps.

According to Shimojo, a professor of biology at Caltech, the effect works only if the beeps are very rapid. When they are, "there's no way within the time window for vision to tell whether there's a single or double flash," he says.

According to Shams, a postdoctoral scholar working in Shimojo's lab and lead author of the paper, the results contribute to a shift in our view of visual processing from one "that is independent of other modalities, toward one that is more intertwined with other modalities, and can get as profoundly influenced by signals of other modalities as it influences them."

Contact: Robert Tindol (626) 395-3631


Sequencing of Arabidopsis genome will havehuge payoffs, Caltech plant geneticist says

Whether or not the man was right when he said a mustard seed can move mountains, a poorer cousin of mustard named Arabidopsis has just been certified one of the heavy lifters of 21st-century biology.

With today's announcement that the international effort to sequence the Arabidopsis genome has been completed, plant biologists now have a powerful tool that is a triumph for biology as well as world agriculture, says Caltech plant geneticist Elliot Meyerowitz.

"Anything you learn in Arabidopsis is easily applied to crop plants," says Meyerowitz, in whose Caltech lab the first cloning and sequencing of an Arabidopsis gene took place.

"With knowledge from the genome sequencing, you might be able to make crops more resistant to disease and other plant problems," he said. "Fifty percent of all pre- and postharvest losses are due to pests, so if you could solve these problems, you could double the efficiency of world agriculture."

Arabidopsis is a nondescript weed of the mustard family that has a thin 6-inch-long stem, small green leaves, and tiny white blooms when it flowers. With no commercial, medicinal, decorative, or other practical uses, the plant is hardly even worth grubbing out of the flower bed when it springs up in its various habitats around the world.

But for geneticists, Arabidopsis is the powerhouse of the plant world. It is easy to plant and grow, maturing in a couple of weeks; it is small and thus requires little precious lab space; it is easy to clone and sequence its genes; and it produces plenty of seeds very quickly so that future generations—mutants and otherwise—can be studied. And now, Arabidopsis is the only plant species whose genome has been totally sequenced.

"Arabidopsis took off in the 1980s after it was demonstrated it has a very small genome, which makes it easier to clone genes," said Meyerowitz, a longtime supporter of and adviser to the international Arabidopsis genome project.

"One reason the plant was chosen was because it doesn't have that much DNA," he said. "Arabidopsis has about 125 million base pairs in the entire genome—and that's 20 times smaller than the human genome, and thus about 20 times less expensive to sequence. It's been a bargain."

The sequencing of the plant genome was originally proposed in 1994 for a 2004 completion, but experts later realized the project could be completed four years early—and under budget.

"Everybody shared the cost, and everybody will share the benefits—all the information is in the public domain," Meyerowitz says. "Taxpayers got a big bargain."

Sequencing Arabidopsis has benefits for the understanding of basic biological mechanisms, in much the same way that sequencing the roundworm or fruit fly has benefits. As a consequence of evolution, all organisms on Earth share a huge number of genes.

Thus, the information obtained from sequencing Arabidopsis as well as fruit flies and roundworms will contribute to advances in understanding how the genes of all living organisms are related. These underlying genetic interactions, in turn, will eventually lead to new treatments of human disease as well as the genetic engineering of agricultural products.

In addition to making crops more disease- and pest-resistant, genetic engineering could also change the time of flowering so that crops could be fitted to new environments; make plants more resistant to temperature changes; and possibly lengthen the roots so that plants could make more efficient use of nutrients.

Also, approximately one-fourth of all medicines were originally derived from plants, Meyerowitz says. So better understanding of the enzymes that create these pharmaceutical products could be used for creating new drugs as well as making existing drugs better and more efficient.

Contact: Robert Tindol (626) 395-3631


Human brain employs the same neurons in seeing an objectand later imagining it

In a study of nine epilepsy patients awaiting brain surgery, researchers have discovered that humans use the same neurons to conjure up mental images that they use when they see the real object with their eyes.

In the November 16 issue of the journal Nature, UCLA neurosurgeon and neuroscientist Itzhak Fried and Caltech neuroscientists Christof Koch and Gabriel Kreiman report on results obtained by questioning nine patients who had been fitted with brain sensors. The patients, all suffering from severe epilepsy uncontrolled with drugs, were being observed for a period of 1-2 weeks so that the regions of their brains responsible for their seizures could be identified and later surgically removed.

During their extended hospital stay, the patients were asked to look at photos of famous people such as President Clinton, pictures of animals, abstract drawings, and other images. While they were looking at the images, the researchers noted the precise neurons that were active.

Then, the subjects were instructed to close their eyes and vividly imagine the images. Again, the researchers took note of the neurons active at the time of visual imagery.

Analysis of the data showed that a subset of neurons in the hippocampus, amygdala, entorhinal cortex, and parahippocampal gyrus would fire both when the patient looked at the image, as well as when he or she imagined the image.

The results build upon previous work by Fried's group showing that single neurons in the human brain are involved in memory and can respond selectively to a wide variety of visual stimuli and stimulus features such as facial expression and gender.

According to Koch, a professor of computation and neural systems at Caltech, the study helps settle long-standing questions about the nature of human imagery. Particularly, the research sheds light on the process at work when humans see things with the "mind's eye."

"If you try to recall how many sunflowers there are in the Van Gogh painting, there is something that goes on in your head that gives rise to this visual image," Koch says. "There has been an ongoing debate about whether the brain areas involved in perception during 'vision with your eyes' are the same ones used during visual imagery."

The problem has been difficult to address because the techniques that yield very precise results in animals are generally not suitable for humans, and because the brain imaging techniques suitable for humans are not very precise, Koch says. Such techniques can image only large portions of the brain, each containing on the order of one million very diverse nerve cells.

"Recording the activity of single cells allows us to investigate the neuronal correlates of visual awareness at a detailed level of temporal and spatial resolution," says Kreiman.

The work was supported by the National Institutes of Health, the National Science Foundation, and the Center for Consciousness Studies at the University of Arizona.

Contact: Robert Tindol (626) 395-3631


Caltech researcher wins Lasker Award

Alexander Varshavsky, who is Smits Professor of Cell Biology at the California Institute of Technology, has been named a recipient of the 2000 Albert Lasker Award in Basic Medical Research for his groundbreaking work on the ubiquitin system that targets proteins for destruction.

The Lasker Awards are given each year by the Albert and Mary Lasker Foundation for basic and clinical medical research. This year's award winners were announced Sunday, September 17, in New York City. He shares the Lasker Award with Avram Hershko and Aaron Ciechanover of the Technion (Israel) Institute of Technology in Haifa, Israel.

Varshavsky was cited by the foundation "for the discovery and the recognition of the broad significance of the ubiquitin system of regulated protein degradation, a fundamental process that influences vital cellular events, including the cell cycle, malignant transformation, and responses to inflammation and immunity."

"Alex's record of scientific originality is extraordinary," wrote Caltech Biology Division Chair Elliot Meyerowitz earlier this year.

"His earlier work included the invention and first use of several of the most important and most widely used methods of modern molecular genetics. His work from the late 1970s to the present has centered on understanding the cellular regulation of protein stability: in this crucial area he and his laboratory are the world leaders.

"As Alex's work has progressed, it has become evident that control of protein stability is one of the fundamental properties of living cells, and that it plays a role in many cellular processes, and in health and disease," Meyerowitz said.

Varshavsky, a native of Moscow, has been a member of the Caltech biology faculty since 1992. After finishing his doctorate in biochemistry at the Institute of Molecular Biology in the former Soviet Union in 1973, he headed the institute's research group for four years before joining the biology faculty at MIT, where he worked from 1977 to 1992.

Varshavsky is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. His other honors include the 1998 Merit Award from the National Institutes of Health, the 1998 Novartis-Drew Award, the 1999 Gairdner International Award from the Gairdner Foundation of Canada, the 2000 Shubitz Prize in Cancer Research from the University of Chicago, the 2000 Sloan Prize from the General Motors Cancer Research Foundation, and the 2000 Hoppe-Seyler Award from the German Biochemical Society.

Robert Tindol
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New visual test devised by Caltech, USC researchers

A new five-minute vision test using a desktop computer and touch-sensitive screen is showing promise as a diagnostic tool for a variety of eye diseases and even certain brain tumors.

Invented by California Institute of Technology physicist Wolfgang Fink and University of Southern California professor of ophthalmology and neurosurgery Alfredo A. Sadun, the 3-D Computer-Based Threshold Amsler Grid Test offers a novel method for medical personnel to evaluate the central visual field. The test is sensitive and specific enough to allow an ophthalmologist to diagnose visual disorders such as macular degeneration, and to discriminate between visual disorders with subtly different symptoms, such as macular edema and optic neuritis.

In order to take the test, the patient sits in front of a touch-sensitive computer screen displaying a grid pattern and a central bright spot. Staring at the central spot with one eye closed, the patient traces a finger around the portions of the grid he or she can see, and the computer records the information.

After the computer records the patient's tracings, the operator changes the contrast of the grid slightly and the patient again traces the visible portions of the grid. This process is repeated and information is gathered for the computer to process a three-dimensional profile of the patient's visual field for that eye. Then, the process is repeated for the other eye.

Patients suffering from macular degeneration, for example, experience a loss of vision at the central focus and thus will have trouble seeing the grid pattern near the center. Since macular degeneration sufferers have peripheral vision, they would likely trace a central hole on the screen, and if they also had a relative field defect, they might trace an ever-smaller circle as the brightness of the grid pattern intensified. Once the information was processed, the 3-D graph would provide doctors with a complete description of what the patient sees under various conditions.

The test will also be useful for diseases and conditions such as optic neuritis, detached retina, glaucoma, anterior ischemic optic neuropathy (AION), macular edema, central or branch retinal artery occlusions, and several genetic impairments. Also, the test can be used to detect, characterize, and even locate several types of brain tumors.

Thus, the new test is not only more revealing than standard visual field tests, but it is also much quicker and simpler than existing methods of characterizing the visual field, says Sadun. Likening the test to a recreational video game, Sadun says the new technology will be cheap and easily marketable, and also will be a powerful means of processing patient data.

"The patient is playing the game while the machine is digesting the information," Sadun says.

Fink created a program that permits the computer acquisition and analysis of the psychophysical techniques developed by Sadun. The computer processes patient responses into a computer profile.

Fink says the test is "a completely noninvasive way to understand and diagnose certain eye diseases."

"We can gain more information from this test than any other visual field test," Sadun says. "The test creates a greater sensitivity for detecting problems, it provides quantitative measures for monitoring, and it characterizes the 3-D visual field, which makes a big contribution to diagnosis."

The test has already been used since April on about 40 patients suffering from macular degeneration, AION, and optic neuritis. In the coming months, the researchers will begin testing the program on patients with glaucoma.

The 3-D Computer-Based Threshold Amsler Grid Test has been approved by USC's institutional review board. Fink and Sadun have applied for a U.S. patent.

Fink was supported by a grant from the National Science Foundation during the course of his work.


Caltech Breaks Ground for Broad Center for Biological Sciences

PASADENA—The California Institute of Technology broke ground for the Broad Center for Biological Sciences at noon, September 12, at the site of the future building, at the southeast corner of Wilson Avenue and Lura Street in Pasadena.

Expected to be completed in the year 2002, the Broad Center will be the site of up to a dozen key research groups that will expand Caltech's existing strengths and position the Institute for leadership in a number of critical areas of investigation. Principal funding for the building was provided by a gift of more than $20 million from Edythe and Eli Broad. Eli Broad is chairman and CEO of SunAmerica Inc. and has been a Caltech trustee since 1993.

The Broads' gift is part of a $100 million fund-raising effort for the biological sciences at Caltech.

Speakers at the groundbreaking included David Baltimore, president of Caltech; Broad; Los Angeles Mayor Richard Riordan; Pasadena Mayor Bill Bogaard; Gordon Moore, chair of the Caltech Board of Trustees; James Freed, senior partner with Pei Cobb Freed & Partners Architects; John Rudolph, principal with Rudolph and Sletten, the construction company; and Mel Simon and John Abelson, biology faculty.

Pei Cobb Freed & Partners is known for its work on the U.S. Holocaust Memorial Museum in Washington, D.C.; the Museum of Modern Art in Athens; the Miho Museum of Shiga, Japan; the Rock and Roll Hall of Fame and Museum in Cleveland; the Grand Louvre in Paris; and the Morton H. Meyerson Symphony Center in Dallas.

Caltech's Broad Center will be located on the northwest corner of campus, near the Beckman Institute. Measuring 120,000 square feet, with three floors above ground and two below, the building will include laboratories and offices for 10 to 12 research teams, as well as conference rooms, compact libraries, a lecture hall, and a seminar room. The latest modular design elements will be used to allow the greatest flexibility for rearranging labs and offices to accommodate future needs at minimum cost. The square modern design is intended to maximize scientific interaction within.

The building will contain several major research facilities including an imaging center and a biomolecular structures laboratory.

A mall covered by red Chinese pistache trees will line one side of the building. The exterior walls of the building will be travertine on the south-facing wall adjacent to the Beckman Institute, and etched stainless steel on the other walls.

Founded in 1891, Caltech has an enrollment of some 2,000 students, and a faculty of about 275 professorial members and 130 research members. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 2,100 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-five 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 77 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 48 members of the National Academy of Engineering.


Caltech Faculty Member Receives McKnight Award

Pasadena, Calif.--Gilles Laurent, associate professor of biology and computational and neural systems at the California Institute of Technology, has received the McKnight Investigator Award for his work in "Memory in Olfactory Network Dynamics." This award, granted by the McKnight Endowment Fund for Neuroscience, is given to stimulate research in neuroscience as it pertains to memory and, ultimately, to a clearer understanding of diseases affecting memory. Laurent is one of five scientists to have received the award nationally. Each McKnight recipient will receive a grant of $150,000 over the next three years to further his or her work in neuroscience.

Laurent is renowned for his work on the "sense of smell," or olfactory processing in the brain. This work may have extensive medical and commercial applications. Laurent earned a PhD from the University of Toulouse (France), and a DVM from the National School of Veterinary Medicine of Toulouse. He has been a member of the faculty at Caltech since 1990.

The McKnight Foundation was established in 1953 by William L. and Maude L. McKnight. Supported through the McKnight Endowment Fund for Neuroscience, the McKnight Awards programs in neuroscience were established in 1976 to stimulate research in neuroscience, especially as it pertains to memory. The specific purpose of the McKnight Awards program is to identify investigative programs of outstanding quality involving established neuroscientists and to encourage these seasoned investigators to develop new approaches to an understanding of the basic mechanisms of memory and diseases affecting it.

Founded in 1891, Caltech is now ranked as one of the top universities in the country. Over the years, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-five 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 77 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 48 members of the National Academy of Engineering.

Contact: Deborah Williams-Hedges (626) 395-3227

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Caltech receives $1 million grant for Worm Genome Database

PASADENA—In a major follow-up to the sequencing of the human genome, the National Institutes of Health has awarded $1 million to the California Institute of Technology for a genome database to aid in biomedical research as well as basic biology.

Known as the Worm Genome Database, or simply "WormBase," the project will link the already-completed genome sequence of the experimental organism C. elegans to the functions that the genes perform, says Caltech biology professor Paul Sternberg, leader of the project. Also, the information in WormBase will contribute to advances in understanding how genes of all animals are related so that underlying genetic interactions can perhaps be exploited for future treatments of human disease.

More commonly known as a roundworm or nematode, C. elegans has a genome that comprises about 19,000 genes. As a consequence of evolution, the roundworm shares a huge number of genes with human beings—as do all other organisms on Earth, including plants.

The reason this fundamental relationship will be important to 21st-century medicine is that these commonly shared genes, or homologs, often have the same functions in their respective organisms. In Sternberg's own lab, for example, researchers found that several genes that control what cells do during the development of the worm are worm versions of human genes that mutate to cause cancer.

This finding had two implications, Sternberg says. Genes that work together in the worm are likely to work together in the human, and the normal function of "oncogenes" is to control normal cell behavior, not to cause disease.

Thus, improved knowledge of the roundworm at the molecular level could lead to new and improved approaches for dealing with human disease, or even result in a cure.

And as a side benefit, Sternberg says, knowing the differences between ourselves and a roundworm could lead to new approaches to eradicate the creature, which is an agricultural nuisance.

"I think one of the important things about WormBase is that it will lead to new ways to study basic mechanisms," says Sternberg, adding that the sequencing of several other experimental organisms will be important for the same reason. Among the other organisms are the laboratory mouse, the mustardlike flowering plant Arabidopsis, the fruit fly, and the yeast cell.

"We could see patterns emerge from information in different organisms," Sternberg says. "Now that we have the human genome, we can start asking what a certain gene does in humans, what the homolog does in yeast, or fruit flies, or worms, and what's the common denominator."

WormBase's more immediate goals will be to make the genetic information more computer-accessible to anyone interested, Sternberg says. "The standard of success would be that the bench researcher could get within a minute or two the relevant data for his or her own research, rather than go to the library and pore for hours or days through reading materials."

WormBase will continue an existing database developed by Richard Durbin of the Sanger Centre in the United Kingdom, one of two centers that sequenced the worm genome; Jean Theirry-Mieg, now at the National Center for Biological Information; and Lincoln Stein of the Cold Spring Harbor Laboratory. These researchers will remain involved, Sternberg says, as will John Spieth of the Genome Sequencing Center at Washington University in St. Louis, the other sequencing center.

The new phase of the work will involve biologists in curating new data, including cell function in development, behavior, and physiology; gene expression at a cellular level, and gene interactions—in much the same manner that the Human Genome Project will continue now that the genome itself has been completely sequenced. The National Human Genome Research Institute, which is funding this project, also supports databases of other intensively studied laboratory organisms.

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