Caltech and the Human Genome Project

PASADENA- Two of the key inventions that made possible the monumental task of sequencing the human genome came from the California Institute of Technology. These were especially important in the sequencing of the 3 billion DNA base pairs composing the human genome because the inventions speeded up progress on the task.

The first landmark invention was a method for the automated sequencing of DNA by Leroy Hood, then a professor of biology at Caltech, and his colleagues, Mike Hunkapiller, Tim Hunkapiller, Charles Connell, and Lloyd Smith. Before their discovery, figuring out the sequence of a segment of DNA had been exceedingly difficult and laborious. Because the process was so slow and required the work of highly skilled technicians, it was clear to most scientists in the mid '80s that it would not be possible to sequence entire genomes by manual methods.

The method devised by Hood and his colleagues changed that. They developed a novel chemistry that permitted a machine to detect DNA molecules, using fluorescent light. This method revolutionized DNA sequencing, ultimately making it possible to launch the Human Genome Project. Coupled with some recent advances, the method remained the core for the just-completed phase of sequencing the human genome.

A second key invention for the genome project was developed at Caltech by Professor Melvin Simon, chair of Caltech's biology division, and his coworker Hiroaki Shizuya. They recognized that a critical part of sequencing would be preparing large DNA segments for the process. To accomplish this, they invented "bacterial artificial chromosomes" (BACs), which permit scientists to use bacteria as micromachines to accurately replicate pieces of human DNA that are over 100,000 base pairs in length. These BACs provided the major input DNA for both the public genome project and Celera.

The Simon research group was also a major contributor to the mapping and sequencing of chromosome 22-a substantial segment of the human genome, which was completed in 1999. These researchers are presently using genomic information to create an "onco-chip," which will give researchers convenient experimental access to a miniature array containing hundreds of BACs, each carrying a gene whose mutation can cause human cancer.

Caltech researchers, both current and past, have also been important in promoting the Human Genome Project itself-a project that originally met with scientific skepticism when it was born 12 years ago, particularly when the goal of a fully sequenced human genome by the year 2003 was announced.

That skepticism has long since been replaced by wholesale enthusiasm from the scientific community. David Baltimore, president of Caltech and a Nobel laureate for his work on the genes of viruses, was a highly influential supporter of the Human Genome Project at its inception. Baltimore, then a professor of biology at MIT, was one of an international cadre of farsighted biologists that also included Hood and Simon. They shared a vision of the future in which knowledge of every gene that composes the human genome would be available to any scientist in the world at the click of a computer key.

To shape this unprecedented and complex project, Caltech professors Norman Davidson, Barbara Wold, and Steve Koonin have served in national scientific advisory roles to the genome project in the intervening years. Also, Baltimore chaired the National Institutes of Health (NIH) meeting where the human genome project was launched.

Koonin, who is Caltech's provost, was chair of the JASON study of 1997, which noted to the scientific community that quality standards could be relaxed so that a "rough draft" of the human genome could be made years earlier and still be of great utility. This, in fact, was the approach that prevailed.

The Human Genome Project is unique among scientific projects for having set aside, from the beginning, research support for studies of the ethical, legal, and social implications of the new knowledge of human genes that would result. In Caltech's Division of the Humanities and Social Sciences, Professor Daniel Kevles has examined these ethical issues in his book The Code of Codes: Scientific and Social Issues in the Human Genome Project, which he coedited in 1992 with Leroy Hood.

Caltech scientists are also actively engaged in the future of genomics, which is the use of the newly obtained DNA sequences to discover and understand the function of genes in normal biology and in disease and disease susceptibility. This includes devising new ways to extract and manipulate information from the human genome sequence and from recently completed genome sequences of important experimental organisms used by scientists in the laboratory, such as the fruit fly, mustard weed, and yeast.

In one new project, Caltech recently became the home site for the international genome database for a key experimental organism called C. elegans, under the direction of Caltech Professor Paul Sternberg. This tiny worm has about 19,000 different genes, many of which correspond to related genes in humans. The shared origin and functional relationships between the genes of worm and man (and fruit fly and all other animals) let scientists learn much about how human genes work, by studying these small creatures in the laboratory.

The Worm Genome Database, called Wormbase, is undertaking the major task of collecting and making computer-accessible key information about every worm gene, its DNA sequence, and what its function is in the animal. This will require that new methods in automated data-mining and computing be brought together and fused with expert knowledge in biology, and then made accessible by computer to anyone interested.

Because of the relatedness of many genes and their functions among all animals, this information about the worm and its genome will be important for understanding human genes, and vice versa.

Another major genomics effort at Caltech is aimed at understanding how groups of genes work to direct development from a fertilized egg to an adult organism, and how these groups of genes change their action or fail in aging, cancer, or degenerative disease. The genomics approach to these problems involves the application of new computational methods and automated experimental technologies.

To do this, Barbara Wold, together with Mel Simon, Professor Stephen Quake from Caltech's Division of Engineering and Applied Science, and Dr. Eric Mjolsness of the NASA's Jet Propulsion Laboratory, have established the L. K. Whittier/Caltech Gene Expression Center, funded by the Whittier Foundation. The new work in genomics is also fueling new interdisciplinary programs at Caltech in the computational modeling of cells and organisms.

Robert Tindol

Caltech appoints Elliot Meyerowitz to head Division of Biology

PASADENA—Elliot Meyerowitz, a specialist in the genetics of flowering plants, has been named chair of the Division of Biology at the California Institute of Technology. The announcement was made by Steven Koonin, vice president and provost.

Meyerowitz replaces Mel Simon, who is returning to full-time faculty and research duties after serving five years in the office. The appointment becomes effective July 1, and has been approved by the Caltech Board of Trustees.

"A faculty search committee strongly recommended that Elliot Meyerowitz succeed Mel Simon," Koonin said on announcing the appointment. "Elliot is widely respected for his intellect and scientific accomplishments and his demonstrated administrative ability as Executive Officer for Biology.

"The Institute is very fortunate that someone of his caliber has agreed to assume administrative responsibilities," Koonin said.

Meyerowitz, a professor of and current executive officer for biology, has been a member of the Caltech faculty since 1980. His primary research interest is the genes that control the formation of flowers, and how altering these genes will affect flower development. He has identified mutations that cause petal cells to develop into stamens instead, and another mutation that causes these same embryonic petals to become sepals.

Meyerowitz earned his bachelor's degree in biology, summa cum laude, at Columbia University in 1973, and his doctorate at Yale University in 1977. He received the John S. Nicholas Award for Outstanding Biology Dissertation from Yale for his doctoral research. Following a postdoctoral appointment at Stanford, he joined the Caltech faculty as an assistant professor, and was appointed full professor in 1989.

Among his awards is the 1996 "Science pour l'Art" Science Prize, for which he was corecipient, and which was presented in Paris by the firm LVMH—Moët HennessyoLouis Vuitton. The award is presented annually to researchers whose science is of aesthetic and artistic merit.

Meyerowitz also won the Genetics Society of America Medal in 1996, the Gibbs Medal from the American Society of Plant Physiologists in 1995, and the Pelton Award from the Botanical Society of America and the Conservation Research Foundation in 1994.

He was elected to membership in the National Academy of Sciences in 1995, the American Academy of Arts and Sciences in 1991, and the American Philosophical Society in 1998. He was winner of the Richard Lounsbery Award of the National Academy of Sciences in 1999, and received a Sloan Foundation Research Fellowship in 1981.

Robert Tindol

Parsons Foundation Grants Caltech $2 Million

For Immediate Release

The Ralph M. Parsons Foundation has awarded the California Institute of Technology a $2 million grant to be used over three years to purchase scientific computer equipment for the Biomolecular Structures Laboratory at Caltech.

"This equipment is absolutely essential to put Caltech in a position to lead the field of protein design, which has great promise for applications to medical research," said Caltech president David Baltimore.

The computational biology hardware will be used by scientists like Stephen Mayo, associate professor of biology and Howard Hughes Medical Institute assistant investigator. They will use it to study protein structure, function, and design. "It's phenomenal," said Mayo. "Computational biology is a new and rapidly emerging area and this will be very high end, high performance computer hardware. It will be one of the most significant computing facilities at Caltech."

The equipment will provide a means for studying biotechnology materials that could be used in human therapeutics, industrial biotechnology, and agriculture. It will be housed in the Broad Center for Biological Sciences, a structure that, when completed in 2002, will provide space for 10 new Caltech research groups that will work at the cutting edge of the biological sciences.

Caltech kicked off the Biological Sciences Initiative in 1998, to raise $100 million for new faculty and resources. The Parsons Foundation gift is the first to address one of the key objectives of the Initiative, providing equipment for state-of-the-art instrumentation facilities that scientists in the Broad Center will share with others on campus.

Caltech has a history of discovery in the biological sciences, with six Nobel Prizes in medically related fields. Thomas Hunt Morgan, who founded the Division of Biology at Caltech in 1928, won the Nobel Prize for identifying the gene as a specific entity with a fixed location on a chromosome. His Nobel was followed by prizes for George Beadle, Max Delbrück, Renato Dulbecco, Roger Sperry, and Edward Lewis, who, in 1995, received the Nobel for his decades of work on how genes control development. Baltimore received a Nobel Prize at the age of 37 for his work in virology.

The Ralph M. Parsons Foundation was established in 1961 by the late Ralph M. Parsons, founder of the international engineering and construction firm that bears his name. The foundation, since 1974 a separate, free-standing, charitable organization independent of the corporation, awards grants focusing on the areas of higher education, social-impact programs, health, and civic and cultural endeavors.

Contact: Jill Perry (626) 395-3226

Visit the Caltech Media Relations Web site at:


Caltech president David Baltimore named winner of 1999 National Medal of Science

PASADENA-David Baltimore, president of the California Institute of Technology, has been named by President Clinton as a recipient of the 1999 National Medal of Science. The award was announced today (Monday, January 31) at the White House.

One of the world's leading scientists, Baltimore was cited for his Nobel Prize-winning work showing that the flow of biological information is reversed, allowing cancer-inducing viruses to become genes in cells. Baltimore was also recognized for his leadership in academic and public policy. He joins 11 others this year as winners of America's most prestigious science honor.

Prior to his appointment as Caltech president in 1997, Baltimore was a faculty member at MIT and was founding director of MIT's Whitehead Institute for Biomedical Research. He served as director from the institute's creation in 1982, to 1990, when he became president of Rockefeller University.

He played a pivotal role with Paul Berg, Maxine Singer, and several other eminent biologists in the mid-1970s in creating a consensus on national science policy regarding recombinant DNA research. This nationwide effort helped allay reservations about genetics research, and also established research standards that are followed by the genetics community to this day.

Baltimore has also been a major figure in Washington as head of the National Institutes of Health AIDS Vaccine Research Committee, and in 1986 he was co-chair of the National Academy of Sciences and Institute of Medicine's committee on a National Strategy for AIDS.

Born in New York City in 1938, Baltimore earned his undergraduate degree at Swarthmore College and his doctorate at Rockefeller University. He did postdoctoral work at MIT, and later worked as a research associate at the Salk Institute for Biological Studies in La Jolla, California, from 1965 to 1968.

He was a professor at Rockefeller University from 1990 to 1994, and Rockefeller's president in 1990 and 1991. He resigned the Rockefeller presidency in 1991 during a heated controversy that stemmed from his support of a collaborator who had been accused of scientific misconduct but whose scientific honesty he had resolutely defended. Years later, the collaborator was found to be innocent of all charges raised against her.

His honors include the 1970 Gustave Stern Award in Virology; the 1971 Eli Lilly and Co. Award in Microbiology and Immunology; the 1974 National Academy of Sciences' United States Steel Award in Molecular Biology; and the 1975 Nobel Prize in physiology or medicine.

He was named to the National Academy of Sciences in 1974, and in 1978 was elected a member of the Pontifical Academy of Sciences. He is also a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science, a foreign member of the Royal Society in England, and a fellow of the American Academy of Microbiology.

He is married to Dr. Alice Huang, former dean for science at New York University, senior councilor for external relations at Caltech, and also an eminent biologist. The Baltimores have a daughter, Lauren, a Yale University graduate who lives and works in New York City.





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The potential of stem cells to be the focus of 2000 Biology Forum

PASADENA-Stem cells and their promise for novel treatments of human disease will be the focus of the 2000 Biology Forum at the California Institute of Technology.

"Stem Cells: The Science of Regeneration" will be held at 8 p.m. Thursday, February 24, in Caltech's Beckman Auditorium. Free and open to the public, the forum is sponsored by Caltech and cosponsored by the San Gabriel Newspaper Group and Huntington Memorial Hospital. The event will focus particularly on breakthroughs of the last year in stem cell research.

Voted as the No. 1 science story of the year by the journal Science, stem cell research is thought to be especially promising because the cells themselves are immature and undifferentiated and can become specific kinds of cells in different kinds of tissue. Thus, the hope is that stem cells can be harvested and coerced to form differentiated cells to replace defective or absent cells in a variety of human organs, from the brain to the heart.

Stem cell research has been controversial in the past because the most obvious source of cells was harvested fetal tissue. But according to Science, research of the past year has shown that "stem cells from adults retain the youthful ability to become several different kinds of tissues."

"Brain cells can become blood cells, and cells from bone marrow can become liver," according to the journal. "Thus, 1999 marks a turning point for this young field, as both science and society recognized-and wrestled with-our newfound power to manipulate a cell's destiny."

The Caltech forum speakers will address the various kinds of stem cells that have been used to generate heart, bone, fat, liver, muscle, and brain cell types, as well as possible future protocols for the testing of new drugs. Also, the speakers will address how stem cell research can shed light on one of the great puzzles of biology: how a single cell, the egg, gives rise to the thousands of different cell types in the adult organism.

The forum will be moderated by Robert Lee Hotz, award-winning science writer at the Los Angeles Times and author of several books on biological topics.

Panelists will be David Anderson, a Caltech professor of biology and an investigator with the Howard Hughes Medical Institute; Jeremy Brockes, a professor of biology at University College, London; Alexander M. Capron, a law professor at the University of Southern California; and Barbara Wold, a professor of biology at Caltech.

For more information, please call (626) 395-4652 or (800) 423-8849. Persons with disabilities may make arrangements by calling (626) 395-4688 (voice) or (626) 395-3700 (TDD).

Robert Tindol

David Baltimore and Seymour Benzer awarded honorary degrees from Cold Spring Harbor Laboratory

PASADENA—David Baltimore, president of the California Institute of Technology, and Seymour Benzer, James G. Boswell Professor of Neuroscience, Emeritus, were awarded honorary degrees by the Cold Spring Harbor Laboratory's Watson School of Biological Sciences on November 5 at the school's inaugural convocation.

Since his initial contact with CSHL as a member of the first class of the lab's Undergraduate Research Program, Baltimore has maintained close ties with the lab. "I returned at least once every year for the next 20 years, either for a seminar, a symposium, or a course. In fact, I got my start in virology at the CSHL Animal Virus Course in 1961, and my start in immunology at the CSHL Symposium in 1976." Baltimore has been president of Caltech since October 1997. Before coming to Caltech, he was an Institute Professor at the Massachusetts Institute of Technology. He was founding director of MIT's Whitehead Institute for Biomedical Research, and served from 1982, the year of the institute's creation, to 1990, when he became president of Rockefeller University. His career has been distinguished by his dual contribution to biological research and to national science policy.

Baltimore helped pioneer the molecular study of animal viruses, and his research in this field had profound implications for understanding cancer and, later, AIDS. In 1975, he shared the Nobel Prize in physiology or medicine with Howard Temin and Renato Dulbecco.

Baltimore has been a major figure in Washington as head of the National Institutes of Health AIDS Vaccine Research Committee, and also in 1986 as co-chair of the National Academy of Sciences and Institute of Medicine's committee on a National Strategy for AIDS. He is a member of the National Academy of Sciences, the Pontifical Academy of Sciences, the American Academy of Arts and Sciences, and the Royal Society of London.

After attending a course on bacteriophage genetics at CSHL in the summer of 1948, Benzer, whose early interest was in physics, subsequently changed fields and became a preeminent molecular biologist. He initially worked in phage genetics and, since 1960, has worked in nervous system development and behavioral genetics of the fruit fly Drosophila.

Benzer received his BA in 1942 from Brooklyn College and a PhD from Purdue University in 1947. 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.

Cold Spring Harbor Laboratory is a private, nonprofit research and educational institution with programs focusing on cancer, neurobiology, and plant biology. Its other areas of research expertise include molecular and cellular biology, genetics, structural biology, and bioinformatics. CSHL is located in Cold Spring Harbor, New York.

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, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni, including the Nobel Prize in chemistry awarded to Professor Ahmed Zewail in October. 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 77 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 69 members of the National Academy of Sciences and 48 members of the National Academy of Engineering.

Sue Pitts McHugh
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Caltech Receives $10 Million to Establish Bren Professors Endowment

PASADENA-The Donald Bren Foundation of Newport Beach has awarded the California Institute of Technology a $10 million grant to establish named professorships to support Caltech's ambitious Biological Sciences Initiative.

The Bren Professors Endowment will provide support for scholarly activities in biology and related disciplines, which are focused on solving some of the toughest problems of the life sciences. This gift brings the Biological Sciences Initiative total to over $80 million. A three-year fundraising effort announced in May 1998, the Initiative aims to provide essential resources and people to explore new territory in the biological sciences through the kind of interdisciplinary approach at which Caltech excels.

"Caltech's focus on biological sciences will open a new area for its scholarly inquiry and research that promises endless possibilities to profoundly touch and improve our lives," said Bren, the chairman of The Irvine Company. "It pleases me to be able to encourage this initiative and the distinguished scholars who will carry it out."

The named professorship is the highest honor a university can confer upon a faculty member. It is a tool to recognize and reward achievements and for recruiting senior faculty to join a new institution. Ultimately, five senior faculty will be named new Bren Professors, joining Peter Dervan who holds the first Bren Professorship established at Caltech in 1988.

Initially, a portion of the $10 million grant will be used to establish the Bren Scholars Program, which will support new faculty identified by Caltech as scientific stars before they are recognized in the scientific community at large. The Bren Scholars Program will fund the expenses associated with initiating their research programs for a period of six years, thus launching them on a lifelong career, and maximizing their contributions to science and engineering. After six years, the endowment for the Bren Scholars Program will be added to the Bren Professors Endowment.

The Bren Foundation grant is being made in memory of Earle Jorgensen, Bren's stepfather, who died this August at the age of 101. He was a self-made Southern California steel pioneer, whose products fortified the area's economic boom and whose commitment to community included support for Ronald Reagan's campaigns for governor of California and president. He also served as a member of Reagan's "kitchen cabinet." Jorgensen was a Caltech trustee from 1957 to 1999.

"Earle's life spanned the 20th Century, and for 42 years, he brought his special energy, optimism, curiosity, and interest in science and engineering to the Caltech board - attending his last meeting as a Life Trustee after he had turned 100," said Bren who has been a Caltech trustee since 1983.

Caltech President David Baltimore said the grant will help Caltech reach its goals. "I think Don has focused his giving on the most important aspect of Caltech, which is the quality of our faculty," Baltimore said. "Bringing the very best people here is at the heart of Caltech's mission."

The Bren Foundation is a private philanthropic organization chartered by Donald Bren, the chairman of The Irvine Company, to further his lifetime interests in public and private education, scientific research, conservation, and the visual arts.

Since 1988, Bren's higher education philanthropy is making possible, over time, the creation of at least 20 endowed chairs that are being filled at U.C. Irvine, U.C. Santa Barbara, Caltech and Chapman University.

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, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni, including the Nobel Prize in chemistry awarded to Professor Ahmed Zewail earlier this month. 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 77 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 69 members of the National Academy of Sciences and 49 members of the National Academy of Engineering.


Mutations in the mitochondrial DNA of cells dramatically increase with aging, Caltech study shows

PASADENA-Certain effects of aging could be caused by mutations in the DNA molecules of the energy-producing engines of cells known as mitochondria, according to new research from the California Institute of Technology and the University of Milan.

The study, published in the October 22 issue of the journal "Science", describes the results of skin-cell biopsies of about 30 individuals in a variety of age groups. The study concludes that damage to mitochondrial DNA dramatically increases around the age of 65.

"It's not a magic number, but we see a clear trend," says Giuseppe Attardi, who is Grace C. Steele Professor of Molecular Biology at Caltech and leader of the team authoring the paper.

Attardi and his colleagues focused their efforts on the small structures in cells known as mitochondria. Every cell can have tens to hundreds of these structures, which play an important metabolic role in the energy production that allows the cell to do its work.

Each of the mitochondria has about 10 to 20 molecules of DNA, which means that a single cell can have hundreds or thousands of mitochondrial DNA molecules.

But mitochondrial DNA is known to be susceptible to mutations over the course of a lifetime. These mutations can be due to oxidative damage, some enzyme malfunction, or even the cell's own efforts to repair itself. But prior to the new study, molecular biologists had difficulty in detecting aging-related mutations.

Over a period of about five years, Attardi and his colleagues developed a technique for detecting aging-related mutations in the main control region of mitochondrial DNA. This provided a very reliable method for determining the percentage of mitochondrial DNA molecules in a cell that had actually undergone mutations.

With this technique, they then studied tissue samples provided by the National Institutes of Health (NIH) and the University of Milan from skin biopsies. These biopsies came from individuals ranging from a 20-week-old fetus to a 101-year-old subject, which allowed the researchers to determine the prevalence of mutations in different age groups.

The results showed virtually no aging-related mutations for any of the subjects under the age of 65. But a dozen or so individuals above the age of 65 showed a dramatic increase in mutations. And not only did the rate of mutations sharply increase with age, but individuals also showed a sharp increase in mutations if they passed the age of 65 between biopsies.

Overall, the researchers found that up to 50 percent of the mitochondrial DNA molecules had been mutated in subjects 65 or over.

Attardi says future study will be needed to ascertain the precise effects of the mutations and the relationship to the known characteristics of aging. In addition, the researchers would like to know how the original mutation "amplifies," or is established in thousands of other molecules.

Also, the precise mechanism of the mutations is not known at this time. And finally, the study was done only on skin cells, although Attardi says the effect may possibly be seen in other cells of the human body.

In addition to Attardi, the other authors are Yuichi Michikawa, a senior research fellow in biology at Caltech; and Franca Mazzucchelli, Nereo Bresolin, and Guglielmo Scarlato, all of the University of Milan.

Robert Tindol

A heart medication is found effectivein treating skin cancer, Caltech researchers discover

PASADENA-Researchers have discovered that one type of drug used for human heart disease can inhibit the growth of skin cancer cells.

The drug, known as BQ788, is proving effective in suppressing skin cancer in mice, and drugs of this type could have potential for ovarian and prostate tumors as well. In the September 28, 1999, issue of the Proceedings of the National Academy of Sciences, California Institute of Technology biology professor Paul Patterson and researchers Ronit Lahav and Garrett Heffner report that the drug can stop melanoma tumor growth and even reduce tumors in some cases.

Further, the drug seems to be effective both as a direct treatment of the tumor and when injected systemically into the animal. The latter result is particularly promising as it has the potential for also suppressing metastasis, or the spread of tumors to other organs, says Patterson.

"If you went to the doctor with a tumor on the skin, he would take it out immediately," says Patterson, who is executive officer for the Division of Biology at Caltech. "So the first line of treatment is to surgically excise the tumor, and if it's a superficial tumor, you essentially have a complete cure.

"But the worry is when the tumor has penetrated more deeply and already metastasized," he says. "We think this drug could turn out to be an effective way to stop cancer cells from spreading, or at least stop their growth if they have already spread."

The strategy is based on the targeting of "growth factors," or proteins that cells use to stimulate their growth. The cancerous state represents a reversal of healthy, mature cells to a state similar to that of embryonic cells. In other words, cancerous cells tend to multiply rapidly, just as cells do in a developing embryo.

Lahav, the lead author on the paper, reasoned that melanoma cancer cells perhaps use a growth factor similar to that employed by their precursor cells in the embryo. She showed that such a growth factor, called endothelin, acts on the embryonic cells, and is also made by the cancer cells. By serendipity, the heart drug BQ788 is an antagonist for the endothelin receptor B. Thus, BQ788 is a substance that disrupts the receptor from performing its function in the cell.

Lahav found that this drug can stop human melanoma cell growth when introduced into cell cultures. In fact, the drug not only makes the cells stop dividing, but it can also kill such cells.

When the drug was given to mice with tumors, tumor growth slowed dramatically, and in some cases even regressed.

"It works whether you inject it into the tumor or into the body cavity," Patterson says. "In about half the mice, the tumors actually shrank."

Patterson says there is reason to think this type of drug could also work on certain other cancers (ovarian, prostate) where runaway cell growth may also be controlled by the same growth factor, endothelin.

Ronit Lahav is a postdoctoral scholar from Israel, and Garrett Heffner is a Caltech sophomore who participated in this research the summer after graduating from high school.

Robert Tindol

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.

Robert Tindol


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