Caltech Receives $1.4 Million for L. K. Whittier Gene Expression Center

PASADENA-The California Institute of Technology has received a $1,444,000 grant from the L. K. Whittier Foundation. The award is for support of the L. K. Whittier Gene Expression Center.

Led by Professor of Biology Barbara Wold, the L. K. Whittier Gene Expression Center will utilize unique resources already available at Caltech to initiate a large-scale human gene expression analysis. This breakthrough will be made in the growing field of "functional genomics," a field whose entire purpose is to make new medical and biological discoveries based on the DNA sequence of the human genome.

Mel Simon, chair of the Caltech Division of Biology and the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences, has produced probes for all 40,000 known human genes. By combining this information with what scientists have already learned from the Human Genome Project, the center is expected to produce wide-ranging discoveries in both the medical and biological sciences.

"We hope to make the center a useful tool for all of the biologists on campus, and ultimately for scientists around the world, through our accumulated database of gene expression information," says Stephen Quake, assistant professor of applied physics and another collaborating scientist at the L. K. Whittier Gene Expression Center. "The interesting thing about the gene arrays is that they provide more data than any one person can analyze, and the aggregate sum of the data provides a powerful resource to answer a number of questions about gene function."

The L. K. Whittier Foundation, located in South Pasadena, was incorporated in 1955 by the late Leland Whittier and other members of the Whittier family. The Whittiers are descendants of Mericos H. Whittier, who was one of the first independent oil producers in California.

Founded in 1891, Caltech has an enrollment of some 2,000 students, and an academic staff of about 280 professorial faculty and 130 research faculty. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 1,700 on campus and 5,300 at JPL.

Over the years, 27 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-four 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 75 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 68 members of the National Academy of Sciences and 49 members of the National Academy of Engineering.

Caltech discovers genetic process for controlling plant characteristics

PASADENA-Caltech biologists have harnessed a gene communication network that controls the size and shape of a flowering land plant.

The discovery is a fundamental advancement in understanding the processes that make plants what they are. The knowledge could also lead to greater control over certain characteristics of plants such as fruit size and stem durability.

In the March 19 issue of the journal Science, Professor of Biology Elliot Meyerowitz and his colleagues explain how they have managed to control three genes found in the "shoot apical meristem." This structure is the source of all cells creating a plant's leaves, stems, and flowers, and is somewhat analogous to the stem cells in animals.

The shoot apical meristem-also known as SAM-begins as a portion of the seed comprising just a few hundred cells. Like stem cells, they are undifferentiated at first, but as the young organism develops, they diversify to create the cells that make up all the recognizable features. "These divide in highly specific patterns to make leaves and stems and flowers," says Meyerowitz, who specializes in the molecular biology of plants. "Everything you see above ground arises from these cells."

Working with the nondescript flowering plant known as Arabidopsis thaliana, the Meyerowitz team first cloned the genes that gave appearance to the plant. These genes, known as CLV1 and CLV3, turned out to reveal a communication network that the plant uses to make its various parts.

Meyerowitz and his team discovered that the Arabidopsis plant tends to grow differently when the genes are disrupted. For example, the normal plant is about six inches in height with a thin, fragile stem and a few white flowers at the top.

But when the genes are knocked out, the plant grows a much thicker stem and mutant flowers with extra organs of all types, especially stamens and carpels.

In effect, this means that the researchers are in control of the genetic mechanism that governs various characteristics of a plant. And since the effect is genetic, the mutated characteristics are passed along to future generations.

Meyerowitz says the discovery could be used to mutate certain plants of human benefit so that they would have more favorable traits. For example, wheat might be altered so that the stem would be stouter and more resistant to being blown over.

But many of these effects have been accomplished for centuries with selective breeding, he says.

"The difference between a cherry tomato and a big beefsteak tomato is just like the difference between a normal Arabidopsis plant and those mutant for CLV1 or CLV3," he says. "We're not sure if it's exactly the same gene because we haven't yet looked.

"So there are ways to make fruit bigger, for example, without understanding the process," he says. "But what we're trying to do is understand the process."

Also involved in the research are Jennifer Fletcher, a research fellow in biology at Caltech; Mark Running, a graduate of Caltech who is now at UC Berkeley; Rüdiger Simon of the Institut für Entwicklungsbiologie in Cologne, Germany; and Ulrike Brand, a grad student in Simon's lab.

Robert Tindol

U.S. Holocaust Memorial Museum architect to design Caltech's new Broad Center for Biological Sciences

PASADENA—James Freed, the architect who designed the United States Holocaust Memorial Museum, has been chosen to design the new Broad Center for the Biological Sciences on the Caltech campus.

Freed, a senior partner of the firm Pei Cobb Freed & Partners, was selected from four finalists to design the building, which is the cornerstone of a $100-million initiative to strengthen Caltech's research efforts in the biological sciences.

The building is named for Eli Broad, chairman and CEO of SunAmerica Inc. and a Los Angeles civic leader and philanthropist. Broad provided $18 million for the building's construction.

David Baltimore, president of Caltech and a member of the committee that selected Freed, said the Holocaust Museum especially shows the architect's genius in designing a magnificent building to benefit society within a well-established neighborhood of other buildings.

"We were impressed by his flexibility and his ability to design a structure that is at once modern and appropriate to a settled architectural style in its surrounding," Baltimore said. "We were also impressed that he could take our very sketchy program and turn it into a fascinating model."

"The work he has done shows a remarkable ability to translate a set of needs into a structure of elegance and clear functionality." Eli Broad said he is "very pleased with the selection of James Freed."

"His functional yet highly creative designs have greatly enhanced many of America's most important metropolitan areas," Broad said. "I have no doubt his design for the Broad Center for Biological Sciences will both reflect and enhance Caltech's heritage of academic excellence, innovation and creativity."

The Broad Center will be located on the northwest quadrant of the campus. Measuring 100,000 square feet, the building will include laboratories and offices for 10 to 12 new research teams, as well as conference rooms, 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 building will house several major new research facilities, including an Imaging Center and a Biomolecular Structures Lab. The Imaging Center will feature powerful new magnetic resonance imagers that, for the first time, will give Caltech scientists the capability to view noninvasively the brains of large mammals and humans while they carry out normal activities such as viewing objects and paying attention. The result will be a deeper understanding of the complex relationship between brain-cell activity and behavior, including the causes of mental illness.

The Biomolecular Structures Laboratory will house state-of-the-art electron microscopes and powerful computational tools for visualizing and analyzing the structures of the multimolecular assemblies critical to the functioning of the immune response and other important biological processes.

The selection committee asked that each finalist discuss his/her approach for making the building blend into the surroundings while at the same time "capturing the essence of modern-day technology," developing a design that would comport with Southern California's seismic code requirements, maintain an open modular concept of laboratory space while incorporating specialized facilities, enhance student and faculty life, and address community concerns for public space.

As design architect, Freed will work closely with the executive architectural firm SMP-SHG, which will be represented by Susan O'Connell as project manager and William Diefenbach as lead architect. The lab programming architectural firm will be Kornberg Associates, with Ken Kornberg as lead architect.


Robert Tindol

Professor Seymour Benzer Receives Ellison Medical Senior Foundation Scholar Award

PASADENA-The California Institute of Technology is pleased to announce that Seymour Benzer, the James G. Boswell Professor of Neuroscience, Emeritus, has been named a 1998 Ellison Medical Foundation Senior Scholar as part of the Ellison Medical Foundation Senior Scholars in Aging Program. The $993,000 award will support Benzer's research over the next four years.

Benzer's recent research has centered around the discovery of the "Methuselah" gene in fruit flies. This gene, when mutated, increases the life span of the fruit fly by one-third. The discovery of this gene has interesting implications for future research in that an analogous gene might also be found in humans.

"Very often indeed, fruit fly genes have human homologues," Benzer said in discussing his current research. "The basic idea is to use the fruit fly as a model system and look for human equivalents."

Benzer received his BA in 1942 from Brooklyn College and a PhD from Purdue University in 1974. Before joining the Caltech faculty in 1965, he had been the Stuart Distinguished Professor of Biophysics at Purdue University. Benzer has won numerous other awards while on the faculty at Caltech, including the National Medal of Science and the Crafoord Prize.

The Ellison Medical Foundation has been established by a gift from Mr. Laurence J. Ellison to support biomedical research (including basic biology, epidemiology, and clinical investigation) on aging. The Ellison Medical Foundation Senior Scholars in Aging Program is designed to support established investigators in their conduct of research in the basic biological and clinical sciences relevant to understanding aging processes and age-related diseases and disabilities. The award is intended to provide the significant support to established investigators in order to allow this development of new, creative research programs by investigators who may not currently be conducting aging research or who may wish to develop new research programs in aging.

Founded in 1891, Caltech has an enrollment of some 2,000 students, and a faculty of about 280 professorial members and 130 research members. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 1,700 on campus and 5,300 at JPL.

Over the years, 27 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-three 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 75 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 68 members of the National Academy of Sciences and 46 members of the National Academy of Engineering. 

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Caltech neuroscience ranked No. 1 in impact

PASADENA—The California Institute of Technology has been recognized as the No. 1 institution in the nation for the impact of its neuroscience research. The results are reported in the September/October issue of Science Watch.

In a survey of papers published in hundreds of scientific journals between 1993 and 1997, Science Watch noted that Caltech neuroscientists published 395 papers during the period. Based on the number of times the papers were cited in other scientific papers, the Philadelphia-based publication concluded that Caltech papers were the most influential.

According to editor Chris King, Science Watch determines the number of times each paper in a scientific field is cited by other papers in that field, and then compares these scores to a world average for papers in the same field for a quantification of "relative impact."

In all, Caltech's 395 neuroscience papers earned 6,074 citations during the period. This was an average of 15.38 citations per paper, as compared to the world average of 6.54 for neuroscience papers. Thus, Caltech papers were 135 percent above the worldwide average. Because this was the highest average of any institution, Caltech was ranked as having the highest relative impact.

The calculation "represents what scientists think is important in their field when they write papers," says King.

Science Watch is published by the Institute for Scientific Information, which is headquartered in Philadelphia.

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Caltech gets $2 million from HHMI for undergraduate biological sciences

PASADENA—The Howard Hughes Medical Institute has awarded $2 million to the California Institute of Technology for support of undergraduate programs in the biological sciences.

The four-year grant is earmarked for support of student research, development of teaching laboratories and computer-based curricula, and outreach activities for students and teachers from the Pasadena school district. The award was announced today at HHMI headquarters in Chevy Chase, Maryland.

Among the existing programs Caltech will support with the grant money are the Summer Undergraduate Research Fellowships (SURF), which has operated for a number of years to provide undergraduates with a chance to work on real research programs. The HHMI funds will be used for SURF stipends in the biological and chemical sciences, particularly for women and minority students.

Also, HHMI funds will be used for the Minority Undergraduate Research Fellowships (MURF), which was created in 1991 and has been supported by HHMI since 1992. This program is directed toward giving gifted underrepresented minority undergraduate students from other universities a summer of research on the Caltech campus.

Another program to be supported by the new funding is the Teaching and Interdisciplinary Education (TIDE) program, which brings faculty and students together to develop innovative teaching tools for coursework. The HHMI funds will provide support for five students to work directly with faculty.

Caltech's $2 million award this year is one of 58 HHMI awards going to American colleges and universities for undergraduate programs in the biological sciences. Begun in 1988, the program's total awards this year will total $91.1 million.

According to Purnell W. Chippin, president of the Howard Hughes Medical Institute, the grants program "is having a major impact on how biology and related disciplines are taught at the college level."

Caltech, founded in 1891, has an enrollment of some 2,000 students, and a faculty of about 280 professorial faculty and 130 research faculty. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 1,700 on campus and 5,300 at JPL.

Over the years, 26 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-three 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 75 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 68 members of the National Academy of Sciences and 46 members of the National Academy of Engineering.

[Note to editors: More information can be downloaded from the Howard Hughes Medical Institute Web site at].

Robert Tindol

Caltech Launches Major Bioscience Initiative with $18 Million Donation from Eli Broad

PASADENA--Eli Broad, one of Southern California's most prominent civic and business leaders, has teamed with the California Institute of Technology to create a center for the biological sciences which will drive technological and scientific innovation and solidify Southern California's role as a leader in the biotechnology industry.

Broad has donated $18 million to create the Broad Center for the Biological Sciences, which will provide 100,000 square feet of space for 10 new Caltech research groups to work at the cutting edge of the biological sciences. The contribution is part of a $100 million campaign by Caltech to increase its historical strength in the biological sciences. The gift was announced on Tuesday, September 15 at a press conference held at Caltech's Athenaeum.

"Advances in the biological sciences will have the single greatest impact on human experience in the coming century," said Broad. "I want Southern California to be a leader in this critically important field, and Caltech is uniquely qualified to spearhead this remarkable new initiative."

Broad's gift is the largest donation so far in Caltech's new Biological Sciences Initiative, which aims at raising $100 million for new faculty and resources. A total of $56 million has been raised since the initiative was announced in May of this year.

The Initiative comes at a time when the scientific community is clearly directing greater resources to fundamental discovery in the biological sciences. With many new and promising biological and medical advances on the horizon, Caltech officials feel that augmenting the resources available to biological research will have a direct impact on high-tech ventures in the Los Angeles/Pasadena area as well as breakthroughs in the health field.

"Eli's gift will insure that Caltech remains at the biological forefront as we enter the new century," said David Baltimore, president of Caltech and a Nobel Prize-winning biologist.

"I see great strides ahead in the manipulation of genes in myriad areas from medicine to information technology to agriculture," Baltimore added. "We are entering the post-genomic age."

The new building will be located in the northwest quadrant of campus near the Beckman Institute. As the cornerstone capital project of the Biological Sciences Initiative, the building will provide crucial infrastructure in the Institute's new capabilities for magnetic imaging, structural chemistry, and mammalian genetics.

"The biological sciences are being touted as the economic engine of the 21st century," said Mel Simon, chair of the Caltech Division of Biology. "This gift is going to lead to significant contributions toward our country's economic well-being as well as our physical well-being."

In addition to the new building, the initiative also sets as its goal the hiring of a dozen new professors, the creation of new disciplines and new approaches within existing disciplines, the support of new graduate fellowships and postdoctoral positions, and the creation of new MD/PhD programs. The Biological Sciences Initiative is being co-chaired by Caltech trustees Camilla Chandler Frost and Benjamin M. Rosen.

Robert Tindol

Mechanism of cell suicide determined by Caltech, MIT researchers

PASADENA—Biologists at MIT and Caltech have uncovered the chemical details of a mechanism that cells use to commit suicide. The work appears in the August 28 issue of the journal Science.

According to David Baltimore, president of Caltech and a Nobel Prize-winning biologist, his lab at MIT has succeeded in describing how roundworms known as nematodes kill off unwanted cells. The work is especially interesting, Baltimore says, because human beings have very similar proteins to those causing cell suicide in nematodes and, in fact, his lab can often substitute human proteins for the same results.

"All cells contain the machinery to commit suicide," Baltimore said prior to publication of the paper. "You can see this in a wide variety of events, such as a tadpole's resorption of its tail, local ischemia in a stroke victim's brain, and tissue destruction after a heart attack.

"Cell suicide is also one of the great protections against cancer." According to the current paper in Science, a common type of apoptosis, or cell suicide, involves three stable proteins found in nematode cells. These proteins are normally quiet, but can be readily triggered by death signals in such a way that the cell digests itself.

The three proteins are known as CED-3, CED-4, and CED-9. None of these proteins alone will kill cells, the research shows, but the three interact in such a way that CED-4 can signal CED-3 to begin the destruction process, while CED-9 acts as an inhibitor to CED-4.

The general outline of this particular pathway of apoptosis was discovered by MIT professor Robert Horvitz some years ago, but the details have never been understood until now, Baltimore says.

"We did all of this with proteins from a nematode where the pathway was first found, but the proteins all have human homologs," Baltimore says. These are Apaf-1, which is very similar to CED-4; Bcl-2, which is a homolog of CED-9; and mammalian cysteine protease zymogens that are analogous to CED-3.

Therefore, the cascade of reactions in nematode cells could very well resemble the manner in which the human body can cause cancerous cells to self-destruct. The work was supported by the National Institutes of Health. In addition to Baltimore, the authors are Xiaolu Yang and Howard Y. Chang. Yang is currently at the University of Pennsylvania.

Robert Tindol

New Study Shows How Axons Find Their Way Home

Pasadena--Like a commuter trying to get to work during rush hour, a growing axon must thread its way through a throng of other axons that are headed in many different directions in the developing brain. Axons are the wire like extensions of nerve cells that carry electrical signals from one place to another in the brain, and during development they must navigate across long distances (many centimeters) to reach their correct address within the brain. If the axon gets lost, brain circuits cannot form normally, and, like the commuter showing up at the wrong office, the axon may not be able to do its job. So how do axons find their way? A report published in the July 24 issue of the journal Science. by Drs. Susan Catalano and Carla Shatz of the University of California at Berkeley, sheds light on how axons home in on their correct targets.

Traditionally, scientists studying the mechanisms of axon navigation thought in terms of molecular guidance cues. Molecules located in specific places in the brain can tell a growing axon "grow here," "don't grow there," or "make a left turn here." The collective distribution of these molecules in the developing brain forms a pathway that the axon can follow to get to the right place. But Catalano and Shatz suspected that the situation might be more complicated than that. The brain is too complicated, and the genome too small, for there to be a molecular address at every possible target location in the brain. They suspected that there might be another potential source of guidance cues for the growing axons: electrical activity itself. They decided to block electrical activity within the developing brain with a neurotoxin made by the Japanese puffer fish, and their suspicions were confirmed: in the absence of activity many axons fail to find their way to the correct address. Instead they become confused and wander into other regions they normally bypass. Dr. Susan Catalano, now at the California Institute of Technology, offers this analogy: "If the growing axon is like a car, then the highway pavement and traffic signals would be like the guidance molecules. Demonstrating that neural activity is critical for axon navigation is like adding a Global Positioning System into the mix; its a whole new level of information that the axon can potentially use to guide its way toward the appropriate target."

Catalano and Shatz studied axons that grow out from nerve cells located in a brain structure called the thalamus. During development these axons must navigate toward their correct target, the neocortex. The thalamus is a vital way station within the brain; all of the information coming from the sensory organs (such as the eyes, ears, and skin surface) passes through the thalamus on its way to the neocortex. The neocortex is the highly folded layer of neurons on the surface of the brain that is responsible for such functions as language processing; in other words, it is the brain structure that makes us uniquely human. The connections from the thalamus to the cortex are not randomly organized: specific groups of nerve cells within the thalamus (called nuclei) connect up to specific areas of the neocortex. This precise organization, or "map", is critical for proper brain function. In order to form this circuit correctly during development, groups of axons coming from specific places within the thalamus must navigate across the vast expanse of neocortex. They must bypass incorrect areas of the neocortex and choose just the right area to connect with, but without electrical activity, the axons become lost.

How might electrical activity produce this effect? While that is not currently known, clues can be found in studies of other regions in the brain. Previous work from Dr. Shatz's lab has shown that very early in development when the axons from the eye are still navigating toward their targets in the brain, waves of electrical activity sweep across the retina. This means that axons that are nearest neighbors are electrically active at the same time. Simultaneous activity could alter the molecular environment of the pathway through which the axons grow and allow cohorts of axons to keep together during navigation.

Ever since the pioneering work of Nobel laureates David Hubel and Torsten Wiesel, it has been known that the pattern of electrical activity carried by different sets of axons can influence the physical shape of the axons themselves. During the last phases of development, axons from the thalamus form many branches as they spread out through the neocortex to make their final sets of connections. These branches are literally shaped like the branches of a tree, and hence are called the "terminal arbor." Changes in the axon's pattern of electrical activity can change the shape of the tree that forms; less activity results in a shrunken, knarled axon tree. Surrounding axons with normal levels of activity form many more branches that grow into the shrunken tree's territory, just like their counterparts in nature that grow into the sunlit space created when a neighbor falls.

While the role of electrical activity in the final stages of thalamic axon branch formation had been well established, the possibility that the same process might be crucial in early development during axon navigation remained uninvestigated until now. The clinical implications of this are potentially alarming: drugs such as nicotine, which can affect electrical activity within the brain, have the potential to disrupt circuit formation in a developing infant's brain at very early stages, when the major circuits of the brain are being formed. The possibility that developing brains are vulnerable to disruption by activity-altering agents at such early times suggests important areas for future research.

Brain cells attuned to visual nearness and farness interact to allow judgments of size, research shows

PASADENA—Evolution has been benevolent to humans and other primates in providing us with eyes that can judge the size of nearby objects.

With a visual feature known as "size constancy," we can pretty accurately judge whether the furry thing walking across our field of view is the size of a mouse or the size of a lion, regardless of its distance and whether we recognize the object. Where survival of the species is concerned, the advantage of having size constancy is pretty obvious: it helps us identify dinner, but at the same time helps us stay off someone else's menu.

But the precise neurological nature of size constancy has never been well understood. If we are seeing our very first lion and the lion is walking away from us, then his image in our field of vision is getting smaller and smaller. Distance cues and stereoscopic vision are at play, but what is really happening in our brains? Is the third dimension added on at a late stage in visual processing, or are the images of lions at varying distances actually analyzed at the very first stage of visual perception?

New research from the California Institute of Technology shows that the latter is the case. Our brains need information for object and three-dimensional scaling, and this information is common to all visual cortical areas of the brain.

In the July 24 issue of Science, Caltech biology professor John Allman and his colleagues write that brain cells involved in vision tend to be apportioned to picking up farness or nearness. In working with rhesus monkeys trained to follow dots of varying size on a moving TV monitor, the researchers have found that the monkeys use their nearness and farness cells in tandem.

"The perception of depth is the product of the interaction of the two opposed tendencies, near and far," says Allman. "There are many systems in the body, and several in the visual system, which work by the precise counterbalancing of two opposed tendencies.

"For color perception, for example, you have opposition between black and white, red and green, and blue and yellow," he adds. "So our results show that depth perception is also a fundamental opposition."

Thus, the basic idea is that ability to judge the size of objects is embedded in the primary visual center as a code of opposed interaction of "nearness" and "farness" cells. Therefore, the neurons are pooled for depth perception; lab work with monkeys earning rewards for correct depth identification bears this out.

In addition to Allman, the authors are Jozsef Fiser of the University of Southern California; and Allan C. Dobbins and Richard M. Jeo of the Caltech Division of Biology.

Robert Tindol


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