Gene linked to human kidney disease is also responsible for mating in roundworms

PASADENA-For a male nematode, the LOV-1 gene couldn't be more aptly named. The millimeter-long roundworm, if its LOV-1 gene is functioning properly, has the eagerness to mate and the instincts to perform successfully.

But if the LOV-1 gene is disabled, the male nematode is truly clueless. The fact that "LOV" is an acronym for "location of vulva" pretty much says it all.

While there is no such single gene controlling sexual interest and instinct in humans, California Institute of Technology researchers who recently identified the LOV-1 gene say there is a similar human gene involved in a type of kidney disease.

In the Sept. 23 issue of the British journal Nature, Caltech researchers Paul Sternberg and Maureen Barr write of their discovery that the LOV-1 gene has a sensory role in nematodes. The human homolog (or counterpart) is PKD1, or polycystic kidney disease gene 1.

In other words, a male nematode that has this particular gene intact is able and willing to mate, while a human with the gene intact is disease-free. But if the genes are respectively knocked out, the nematode is sexually dysfunctional and the human is prone to autosomal dominant polycystic kidney disease, a serious disease that afflicts about one in 1,000 people and may ultimately result in renal failure.

"This is a surprise," says Sternberg, a biology professor at Caltech. "We can only speculate on what the connection might be."

PKD1 and a second gene, PKD2, account for about 95 percent of all cases of autosomal dominant polycystic kidney disease. These genes cause the human body to produce polycystin 1 and polycystin 2, which are thought to work somehow in concert at the molecular level.

In an analogous manner, the LOV-1 gene also seems to work in concert with the PKD-2 gene, which in nematodes is the counterpart of the PKD2 gene in humans. The fact that the genes in both humans and nematodes seem to work in pairs actually strengthens the likelihood that there is some underlying molecular relationship, Sternberg says.

Much of the lab work leading to this discovery was done by Maureen Barr, a postdoctoral scholar in Sternberg's lab who painstakingly watched in a microscope for male nematodes who were not successfully mating.

Barr then singled out the dysfunctional males and used standard genetic screening techniques and DNA sequencing analysis to identify the LOV-1 gene, which when mutated, is responsible for the lack of mating behavior.

While the researchers are not clear on why a gene involved in mating behavior in one species would be involved in disease in another, they say there could be a couple of possible explanations.

For one thing, the connection between the human gene and the worm gene might be very basic. Perhaps the gene is involved in setting up polarity of human kidney cells and polarity of worm neurons that govern sexual behavior.

In the case of the worm, the LOV-1 might actually act as part of a sensory signaling pathway responding to the presence of a mating partner by altering the electrical properties of the specific nerve cell that senses the mate.

Or perhaps the underlying relationship has to do with cell structure, Sternberg says. In this case, the LOV-1 protein might function as a molecular scaffold for other molecules, or promote the assembly of many molecules to create structures such as the sensory neuronal cilia.

Sternberg and Barr say the scientific goal of the study was to investigate ways in which genes influence behavior. But the findings could also serendipitously point to new avenues for research on autosomal dominant polycystic kidney disease.

"This is a mystery disease, so it could be that renal failure is just the first defect in a disease with broader manifestations," Sternberg says. In that case, improved knowledge at the molecular level could lead to different approaches in identifying treatments or even a cure.

"Here's a new way to study the basic mechanism," Sternberg says.

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Robert Tindol
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A unique class of neurons in humans and apes that may participate in cognition, volition, and self-awareness discovered by researchers

PASADENA-Clusters of large neurons found exclusively in the brains of humans and other primates closely related to humans may provide these species with enhanced capacities for solving hard problems, as well as for self-control and self-awareness.

In the April 27 issue of Proceedings of the National Academy of Science, neurobiologists Patrick Hof from Mount Sinai and John Allman from Caltech and their colleagues have found an unusual type of neuron, that is likely to be a recent evolutionary acquisition.

The neurons in question are spindle-shaped cells, which are almost large enough to be seen with the naked eye. Their location in the brain is in the frontal lobe near the corpus callosum, which connects the two halves of the brain.

Allman, the Hixon Professor of Psychobiology and professor of biology; Hof; and their team studied 28 different species of primates and found the spindle neurons only in humans and very closely related apes. The concentration of spindle neurons was greatest in humans, somewhat less in chimpanzees, still less in gorillas, and rare in orangutans.

According to Allman, "This declining concentration matches the degree of relatedness of these apes to humans." There were no spindle cells in gibbons, which are small apes, or in of any of the other 22 species of monkey or prosimian primates they examined. The spindle cells were also absent in 20 nonprimate species examined including various marsupials, bats, carnivores and whales.

The cells in question are found in an area of the brain already linked to psychiatric diseases. According to Allman, "In brain imaging studies of depressed patients, there is less neuronal activity in the region and the volume of the area is smaller. The activity of the area is increased in obsessive compulsive patients."

The activity of the area has been shown to increase with the difficulty of the cognitive task being performed. This suggests that the area enhances the capacity to do hard thinking. Activity is also increased when a subject withholds a response or focuses its attention, suggesting the area is involved in self-control.

Furthermore, the spindle neurons themselves are especially vulnerable to degeneration in Alzheimer's disease, which is characterized by diminished self-awareness. From this Allman suggests, "Part of the neuronal susceptibility that occurs in the brain in the course of age-related dementing illnesses may have appeared only recently during primate evolution."

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Robert Tindol
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Caltech biologists reveal structure of protein responsible for weight loss in cancer and AIDS patients

PASADENA-Caltech biologists have determined the three-dimensional structure of a protein that causes wasting in cancer and AIDS patients. The discovery could lead to new strategies for controlling weight loss in patients with devastating illnesses-and conversely, perhaps new strategies for fighting obesity.

The protein is commonly known as ZAG and is found in most bodily fluids. But researchers have been aware for some time that the protein is particularly abundant in patients who have cancer.

More recently, researchers have discovered that the protein is involved in the wasting syndrome known as cachexia, which is associated with both cancer and AIDS.

"This protein has something to do with fat metabolism," says Pamela Bjorkman, a professor of biology at Caltech and associate investigator of the Howard Hughes Medical Institute. Bjorkman and her team recently published a paper in the journal Science showing ZAG's structure.

One of the most noteworthy features of the structure is the resemblance between ZAG and a family of proteins known as class I major histocompatibility complex molecules, or MHC.

"MHC proteins have a large groove that binds a peptide derived from a pathogen," says Bjorkman, explaining that their new picture of the ZAG crystal shows an unexpected blob in the ZAG counterpart of the MHC peptide binding grove.

"It's not a peptide, but some organic molecule," she says. "We suspect that it is involved in the function of ZAG. If this compound is involved in breaking down lipids, then maybe you could design a drug that replaces it and interfere with lipid breakdown."

According to Bjorkman, other research shows that tumor cells themselves seem to stimulate the body to overproduce ZAG somehow, which in turn leads to the breakdown of body fat.

Thus, people suffering from cachexia don't lose body weight because they don't eat, but because the fat in their bodies is ultimately destroyed by an interaction involving ZAG.

An intervention to stop the wasting, then, might be to disrupt the overexpression of ZAG, and this might be accomplished with monoclonal antibodies or small molecules that bind to ZAG, she says.

The research appeared in the March 19 issue of Science, and was also the subject of an article in HHMI news, published by the Howard Hughes Medical Institute.

The other authors of the paper are Luis Sanchez and Arthur Chirino, both senior research fellows in Bjorkman's lab.

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Alice Huang Receives Achievement Award

PASADENA—Alice S. Huang, senior councilor for external relations and faculty associate in biology at the California Institute of Technology, has been awarded the 1999 Achievement Award from the Chinese-American Faculty Association of Southern California for her outstanding contribution to microbiology research and for her dedicated leadership in higher education.

Huang was recognized at the association's 28th annual convention on February 27, at which she presented a keynote address titled "New Challenges for Chinese-American Activism."

Huang sits on the boards of AAAS, Johns Hopkins University, and the Health Effects Institute. She is also chair of the Foundation for Microbiology and chair of the Scientific Board of the Institute for Molecular and Cell Biology in Singapore. She is a member of the Food and Drug Administration Advisory Committee on Vaccines and Related Biological Products. She was previously dean for science at New York University and prior to that professor of microbiology and molecular genetics at Harvard Medical School.

Born in China, she grew up in the United States attending St. Mary's Hall, Burlington, New Jersey; the National Cathedral School, Washington, D.C.; and Wellesley College. She received BA, MA, and PhD degrees (microbiology, 1966) from Johns Hopkins University.

Dr. Huang has been recognized by the American Society for Microbiology with the Eli Lilly Award in Immunology and Microbiology (1977), followed by election as that society's president in 1988–1989. She has honorary doctorates of science from Wheaton College, Mt. Holyoke College, and the Medical College of Pennsylvania. She has served on the board of trustees of UMass and Shady Hill School. She is a fellow of the Academia Sinica in Taiwan (1991).

As an administrator Dr. Huang is particularly interested in education, in career mentoring, and in policy issues related to science and technology. Since coming to Caltech, where her husband David Baltimore is the president, Dr. Huang has joined the board of the Keck Graduate Institute of Applied Life Sciences, the Pacific Council on International Policy, and the Blue Ribbon Committee of the Los Angeles Music Center.

Dr. Huang resides in Pasadena, California, and has one daughter in New York City.

The Chinese-American Faculty Association was established 28 years ago with the purpose of promoting closer cultural and social ties among Chinese-American scholars in colleges and universities in Southern California. Today it has over 100 members. Previous annual convention speakers and achievement awardees include Caltech alumnus David Ho, former Caltech trustee Yuan Lee, and Caltech's Hoag Professor of Biophysical Chemistry Sunney Chan.

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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.

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Robert Tindol
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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.

 

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Robert Tindol
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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 www.hhmi.org/undergrad98].

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