Caltech Scientists Gain Fundamental Insight into How Cells Protect Genetic Blueprints

PASADENA, Calif.—Molecular biologists have known for some time that there is a so-called checkpoint control mechanism that keeps our cells from dividing until they have copied all the DNA in their genetic code. Similar mechanisms prevent cells from dividing with damaged DNA, which forms, for example, in one's skin after a sunburn. Without such genetic fidelity mechanisms, cells would divide with missing or defective genes.

Now, a California Institute of Technology team has uncovered new details of how these checkpoints work at the molecular level.

Reporting in the March 10 issue of the journal Cell, Caltech senior research associate Akiko Kumagai and her colleagues show that a protein with the unusual name "TopBP1" is responsible for activating the cascade of reactions that prohibit cells from dividing with corrupted genetic blueprints. The researchers say that their result is a key molecular insight, and could possibly lead to molecular breakthroughs in cancer therapy someday.

"The function of the checkpoint control mechanisms is to preserve the integrity of the genome," says William Dunphy, the corresponding author of the paper and a professor of biology at Caltech. "When these genetic fidelity mechanisms do not function properly, it can lead to cancer and ultimately death."

The research began with a study of a protein called ATR that was known to be a key regulator of checkpoint responses. This protein is a vital component of every eukaryotic cell (in other words, the cells of most organisms on Earth excluding bacteria). ATR is a "kinase," an enzyme that controls other proteins by modifying them with phosphate groups.

However, no one knew how the cell turns on this enzymatic activity of ATR when needed. To figure out how ATR gets activated in protecting against mutations has been one of the most urgent questions of the field for the past decade.

Acting on a hunch, the researchers decided to look at the TopBP1 protein, whose molecular function was hitherto mysterious. Strikingly, the team found that purified TopBP1 could bind directly to ATR and activate it. The activation was so quick and robust that the researchers knew immediately that they had found the long-sought activator of ATR and deciphered how cells mobilize their efforts to prevent mutations. Interestingly, the researchers found that only a small part of TopBP1 is necessary for activating ATR.

The researchers suspect that the remaining parts of TopBP1 hold additional secrets about checkpoint control mechanisms. Dunphy says that this molecular insight shows how a cancer-repressive mechanism works in a healthy cell. "Knowing how the normal system works might also help lead to insight on how to fix the system when it gets broken," he adds.

In addition to Kumagai and Dunphy, the other authors of the Cell paper are Joon Lee and Hae Yong Yoo, both senior research fellows at Caltech.

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Robert Tindol
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Old-World Primates Evolved Color Vision to Better See Each Other Blush, Study Reveals

PASADENA, Calif.—Your emotions can easily be read by others when you blush—at least by others familiar with your skin color. What's more, the blood rushing out of your face when you're terrified is just as telling. And when it comes to our evolutionary cousins the chimpanzees, they not only can see color changes in each other's faces, but in each other's rumps as well.

Now, a team of California Institute of Technology researchers has published a paper suggesting that we primates evolved our particular brand of color vision so that we could subtly discriminate slight changes in skin tone due to blushing and blanching. The work may answer a long-standing question about why trichromat vision (that is, color via three cone receptors) evolved in the first place in primates.

"For a hundred years, we've thought that color vision was for finding the right fruit to eat when it was ripe," says Mark Changizi, a theoretical neurobiologist and postdoctoral researcher at Caltech. "But if you look at the variety of diets of all the primates having trichromat vision, the evidence is not overwhelming."

Reporting in the current issue of the journal Biology Letters, Changizi and his coauthors show that our color cones are optimized to be sensitive to subtle changes in skin tone due to varying amounts of oxygenated hemoglobin in the blood.

The spectral sensitivity of the color cones is somewhat odd, Changizi says. Bees, for example, have four color cones that are evenly spread across the visible spectrum, with the high-frequency end extending into the ultraviolet. Birds have three color cones that are also evenly distributed in the visible spectrum.

The old-world primates, by contrast, have an "S" cone at about 440 nanometers (the wavelength of visible light roughly corresponding to blue light), an "M" cone sensitive at slightly less than 550 nanometers, and an "L" cone sensitive at slightly above 550 nanometers.

"This seems like a bad idea to have two cones so close together," Changizi says. "But it turns out that the closeness of the M and L cone sensitivities allows for an additional dimension of sensitivity to spectral modulation. Also, their spacing maximizes sensitivity for discriminating variations in blood oxygen saturation." As a result, a very slight lowering or rising of the oxygen in the blood is easily discriminated by any primate with this type of cone arrangement.

In fact, trichromat vision is sensitive not only for the perception of these subtle changes in color, but also for the perception of the absence or presence of blood. As a result, primates with trichromat vision are not only able to tell if a potential partner is having a rush of emotion due to the anticipation of mating, but also if an enemy's blood has drained out of his face due to fear.

"Also, ecologically, when you're more oxygenated, you're in better shape," Changizi adds, explaining that a naturally rosy complexion might be a positive thing for purposes of courtship.

Adding to the confidence of the hypothesis is the fact that the old-world trichromats tend to be bare-faced and bare-butted as well. "There's no sense in being able to see the slight color variations in skin if you can't see the skin," Changizi says. "And what we find is that the trichromats have bare spots on their faces, while the dichromats have furry faces."

"This could connect up with why we're the 'naked ape,'" he concludes. The few human spots that are not capable of signaling, because they are in secluded regions, tend to be hairy-such as the top of the head, the armpits, and the crotch. And when the groin occasionally does tend to exhibit bare skin, it occurs in circumstances in which a potential mate may be able to see that region.

"Our speculation is that the newly bare spots are for color signaling."

The other authors of the paper are Shinsuke Shimojo, a professor of biology at Caltech who specializes in psychophysics; and Qiong Zhang, an undergraduate at Caltech.

 

 

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Robert Tindol
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Caltech Launches Brain Study Program with $8.9 Million Gift from Eli Broad to Fund 24 Researchers and Six New Labs

PASADENA, Calif.—For years, scientists have worked to study each of the 100 billion neurons in the human brain. But while they understand individual neurons, they've been stumped by how neurons work together, how they encode information, and how they generate thoughts, emotions, and actions.

That pioneering area of study is behind the Broad Fellows Program in Brain Circuitry at the California Institute of Technology, announced today and made possible through an $8.9 million grant from the Broad Foundations and philanthropist Eli Broad.

The funding will enable the program to establish six new neuroscience labs at Caltech and hire 24 researchers over the next five years.

"Caltech is one of the country's greatest research institutions, and this program will encourage some of the brightest young minds in science to devote their research to unlocking the mysteries of the brain," said Eli Broad, founder of the Broad Foundations.

While scientists have made tremendous progress in recent years in understanding the brain's overall activity, the interactions between neurons--which hold the clues to mental diseases such as Alzheimer's, autism, and schizophrenia--are still a mystery.

"We have no idea how these neurons are assembled in groups of 50 to 100,000 to generate conscious thoughts," said Christof Koch, Troendle Professor of Cognitive and Behavioral Biology and Professor of Computation and Neural Systems at Caltech, who will serve as director of the Broad Fellows Program. "We truly believe that the best way to learn about small neuronal networks is to find a few brilliant young neurobiologists, engineers, or physicists with innovative ideas on how to record and manipulate networks of nerve cells. Then, if we provide them with the funding for research assistants and equipment to develop the relevant technologies, all we need to do is get out of their way."

"Neuroscience is becoming an increasingly multidisciplinary exercise," said Michael Dickinson, Zarem Professor of Bioengineering at Caltech, who will serve on the selection committee for the Broad Fellows Program. "Future progress will depend on a creative mixture of expertise in biology, engineering, and mathematics. An exciting feature of this program is that it will provide talented young researchers with a borderless research environment from which to pursue programs from different perspectives."

Koch and his colleagues will hire the first two Broad Fellows in Brain Circuitry later this year, and will hire two more in 2007 and an additional two in 2008. Each of the six Broad Fellows will receive funding to hire up to three assistants, for a total of 24 researchers in the program, which will be housed in Caltech's Division of Biology.

"Each of the fellows will be able to devote up to five years to their projects, without having to worry about finding another postdoctoral appointment in a year or two or limiting themselves only to research that will lead to tenure," Koch said. "These researchers will be at a level between postdoctoral fellow and assistant professor, which means that they will be very independent and won't have to worry about the tenure clock."

"The freedom that comes with these fellowships should foster quite productive interactions among fellows and members of the Caltech community," added Dickinson. "An important role of the selection committee will be to recruit a diverse array of young researchers with complementary skills."

The program is designed to give researchers the freedom and flexibility to advance their work in whatever way is most productive, and may include the development of specific technologies or the invention of new instruments. The Broad Fellows will be given individual space to do their work in the Beckman Laboratories of Behavioral Biology on the Caltech campus.

The program will be under the direction of Koch and a committee of other Caltech faculty members, including Dickinson; Gilles Laurent, the Hanson Jr. Professor of Biology and Computation and Neural Systems; David Anderson, the Sperry Professor of Biology; Barbara Wold, director of the Beckman Institute at Caltech and Bren Professor of Molecular Biology; and Mark Konishi, the Bing Professor of Behavioral Biology.

Founded in 1891, Caltech is located on a 124-acre campus in Pasadena. The Institute also manages the nearby Jet Propulsion Laboratory and operates several other off-campus astronomical, seismological, and marine biology facilities. Caltech has an enrollment of some 2,100 students, more than half of whom are in graduate studies, a faculty of about 280 professorial members and 62 research members, and some 570 postdoctoral scholars. Caltech employs a staff of more than 2,500 on campus and 5,000 at JPL.

U.S. News &World Report consistently ranks Caltech's undergraduate and graduate programs as being among the nation's best. The average SAT scores of members of recent incoming freshman classes have consistently been among the highest in the country. Over the years, 32 Nobel Prizes and five Crafoord Prizes have been awarded to faculty members and alumni.

The Broad Foundations were founded by Eli and Edythe L. Broad as a Los Angeles-based venture philanthropy focused on entrepreneurship for the public good in education, science, and the arts. The Broad Foundations Internet address is www.broadfoundations.org.

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Baltimore Is President-Elect of the American Association for the Advancement of Science

PASADENA, Calif.—David Baltimore, president of the California Institute of Technology since 1997, has been chosen to serve as president-elect of the American Association for the Advancement of Science. Baltimore will begin his term as president-elect on February 21, at the close of the 2006 annual AAAS meeting, and will begin his one-year term as president in February 2007.

"I am gratified to be given the honor and responsibility of the presidency of the AAAS by its membership," Baltimore said. "I look forward to leading this very important organization and particularly to interacting with the community of scientific leadership in the U.S. and the rest of the world."

Baltimore, who late last year announced his retirement from Caltech's presidency pending the appointment of a successor, will remain at the Institute as a professor of biology. One of America's leading scientists, he has maintained an intense research program in his lab throughout his presidency, and is currently embarking on the $13.9-million grant-funded initiative "Engineering Immunity Against HIV and Other Dangerous Pathogens," which promises to address the challenge of creating immunological methods to deal with chronic diseases. This grant was awarded by the Bill and Melinda Gates Foundation.

Baltimore received the Nobel Prize in Physiology or Medicine in 1975 for his work on the genetic mechanisms of viruses. This research has contributed widely to the understanding of cancer, AIDS, and the molecular basis of the immune response.

Baltimore's lab in recent years has announced many important findings while at Caltech, including establishing a new methodology to help fight cancer, developing a new gene therapy that is highly effective in preventing HIV from infecting individual cells in the immune system, and creating a methodology for producing transgenic mice. He has also joined with others in proposing a global effort to create an HIV vaccine. He received the National Medal of Science in 1999 from President Bill Clinton, and the Warren Alpert Foundation Scientific Prize in 2001 for pioneering work leading to cancer therapy.

"David Baltimore will go down in history as not only a great scientist, but also as one of the great presidents of Caltech," said Eli Broad, when Baltimore announced his retirement. Broad is a Caltech trustee and major donor. "It is rare to find someone of his intelligence, integrity, and leadership who can relate so well to people both within and outside the world of science. It was David who inspired Edye and me to become interested in science. We had no background in the field, but he made us feel comfortable. We are fortunate that he will continue his research at Caltech."

Not only has Baltimore been prolific in writing about his findings in scientific journals, but has also been a strong advocate for scientific research by contributing opinion pieces to general-interest media on such subjects as the value of stem cell research, the unnecessary public panic that arose during the SARS epidemic, science research under the Bush administration, and maintaining the scientific workforce in the United States.

Baltimore has several outstanding administrative and public policy achievements to his credit. In the mid-1970s, he played an important role in creating a consensus on national science policy regarding recombinant DNA research. He served as founding director of the Whitehead Institute for Biomedical Research at MIT from 1982 until 1990, and was president of Rockefeller University in 1990-91. An early advocate of federal AIDS research, he cochaired the 1986 National Academy of Sciences Committee on a National Strategy for AIDS, and was appointed in 1996 to head the National Institutes of Health AIDS Vaccine Research Committee.

The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science around the world by serving as an educator, leader, spokesperson, and professional association. In addition to organizing membership activities, AAAS publishes the journal Science, as well as many scientific newsletters, books, and reports, and spearheads programs that promote the understanding of science worldwide.

Founded in 1848, AAAS serves some 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of one million. The non-profit AAAS is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy, international programs, and science education.

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Deciphering the Mystery of Bee Flight

PASADENA, Calif.- One of the most elusive questions in science has finally been answered: How do bees fly?

Although the issue is not as profound as how the universe began or what kick-started life on earth, the physics of bee flight has perplexed scientists for more than 70 years. In 1934, in fact, French entomologist August Magnan and his assistant André Sainte-Lague calculated that bee flight was aerodynamically impossible. The haphazard flapping of their wings simply shouldn't keep the hefty bugs aloft.

And yet, bees most certainly fly, and the dichotomy between prediction and reality has been used for decades to needle scientists and engineers about their inability to explain complex biological processes.

Now, Michael H. Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering, and his postdoctoral student Douglas L. Altshuler and their colleagues at Caltech and the University of Nevada at Las Vegas, have figured out honeybee flight using a combination of high-speed digital photography, to snap freeze-frame images of bees in motion, and a giant robotic mock-up of a bee wing. The results of their analysis appear in the November 28 issue of the Proceedings of the National Academy of Sciences.

"We're no longer allowed to use this story about not understanding bee flight as an example of where science has failed, because it is just not true," Dickinson says.

The secret of honeybee flight, the researchers say, is the unconventional combination of short, choppy wing strokes, a rapid rotation of the wing as it flops over and reverses direction, and a very fast wing-beat frequency.

"These animals are exploiting some of the most exotic flight mechanisms that are available to insects," says Dickinson.

Their furious flapping speed is surprising, Dickinson says, because "generally the smaller the insect the faster it flaps. This is because aerodynamic performance decreases with size, and so to compensate small animals have to flap their wings faster. Mosquitoes flap at a frequency of over 400 beats per second. Birds are more of a whump, because they beat their wings so slowly."

Being relatively large insects, bees would be expected to beat their wings rather slowly, and to sweep them across the same wide arc as other flying bugs (whose wings cover nearly half a circle). They do neither. Their wings beat over a short arc of about 90 degrees, but ridiculously fast, at around 230 beats per second. Fruit flies, in comparison, are 80 times smaller than honeybees, but flap their wings only 200 times a second.

When bees want to generate more power--for example, when they are carting around a load of nectar or pollen--they increase the arc of their wing strokes, but keep flapping at the same rate. That is also odd, Dickinson says, because "it would be much more aerodynamically efficient if they regulated not how far they flap their wings but how fast "

Honeybees' peculiar strategy may have to do with the design of their flight muscles.

"Bees have evolved flight muscles that are physiologically very different from those of other insects. One consequence is that the wings have to operate fast and at a constant frequency or the muscle doesn't generate enough power," Dickinson says.

"This is one of those cases where you can make a mistake by looking at an animal and assuming that it is perfectly adapted. An alternate hypothesis is that bee ancestors inherited this kind of muscle and now present-day bees must live with its peculiarities," Dickinson says.

How honeybees make the best of it may help engineers in the design of flying insect-sized robots: "You can't shrink a 747 wing down to this size and expect it to work, because the aerodynamics are different," he says. "But the way in which bee wings generate forces is directly applicable to these devices."

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Contact: Kathy Svitil (626) 395-8022 ksvitil@caltech.edu

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Modified Mice Test Alzheimer's Disease Drugs

PASADENA, Calif.- Alzheimer's disease is a progressive brain disorder that afflicts an estimated 4.5 million Americans and that is characterized by the presence of dense clumps of a small peptide called amyloid-beta in the spaces between neurons.

Developing therapeutic drugs to stop the formation of the lesions, called amyloid plaques, and to remove them from the brain has become the focus of intense research efforts by pharmaceutical companies. Unfortunately, methods to test the efficacy of the drugs are limited as is the access to test results given to outside researchers.

Now neuroscientist Joanna L. Jankowsky, a senior research fellow in the laboratory of Henry A. Lester, Bren Professor of Biology at the California Institute of Technology, in collaboration with David R. Borchelt at the University of Florida, Gainesville, and colleagues at Johns Hopkins School of Medicine, Mayo Clinic Jacksonville, and the National Cancer Institute, have created a strain of genetically engineered mice that offers an unprecedented opportunity to test these new drugs and provides striking insight into possible future treatment for the disease.

A paper about the mouse model was published November 15 in the international open-access medical journal PLoS Medicine (www.plosmedicine.org).

The amyloid-beta peptide is something of an enigma. It is known to be produced normally in the brain and to be churned out in excess in Alzheimer's disease. But researchers don't know exactly what purpose the molecule usually serves--or, indeed, what happens to dramatically raise its concentration in the Alzheimer's brain.

The peptide is created when a molecule called amyloid precursor protein (APP) is snipped in two places, at the front end by an enzyme called beta-APP cleaving enzyme, and at the back end by an enzyme called gamma-secretase. If either of those two cuts is blocked, the amyloid-beta protein won't be released--and plaque won't build up in the brain.

To prevent plaques from accumulating, drug companies have been experimenting with compounds that inhibit one or the other of the enzymes, thereby blocking the release of amyloid-beta. Jankowsky and her colleagues decided to test how well this approach to treating Alzheimer's disease will work. Because they lacked access to the drugs themselves, they instead engineered a laboratory mouse with two added genes that would mimic the effect of secretase inhibitor treatment. One gene triggered the continuous production of APP in the brain (and thus also the amyloid-beta peptide) leading to substantial plaque deposits in mice as young as six months old. The second gene served as an off-switch to amyloid-beta. The researchers were able to flip the switch at will by adding the antibiotic tetracycline into the mice's food--and when they did so, they also halted all plaque formation.

"The key point here is that we've completely arrested the progression of the pathology," says Jankowsky.

Plaque deposits that had already formed, however, weren't cleared out.

"We can stop the disease from getting worse in these mice, but we can't reverse it," says study co-author David Borchelt, Jankowsky's former postdoctoral research advisor at Johns Hopkins University. "Although it is possible that human brains repair damage better than mouse brains, the study suggests that it may be difficult to repair lesions once they have formed."

One implication of the research is that it suggests that treatment with drugs to stop plaque formation should begin as soon as possible after the disease is diagnosed. "It looks like early intervention would be the most effective way of treating disease," Jankowsky says.

"It was surprising to many people that the plaques didn't go away, but they are really very stable structures," says Jankowsky. It is also possible, some researchers believe, that the plaques themselves aren't damaging. Rather, they may be a sign of the overproduction of amyloid-beta and of the small, free-floating clumps of the peptide that actually cause cognitive problems. "The plaques may simply act as trash cans for what has already been produced," she says. If that is indeed the case, Jankowsky says, then "shutting down the production of amyloid-beta itself would be adequate to reverse cognitive decline."

On the other hand, removal of the plaques could improve cognitive function by allowing neurons that had previously been displaced by the protein deposits to reform and form new neural connections. That is why, the researchers say, an ideal therapy would be one that both prevented the overproduction of new amyloid-beta and cleared out existing deposits.

Drug companies are currently investigating treatment protocols for Alzheimer's disease in which antibodies against the amyloid-beta peptide are directly injected into the body. The antibodies latch onto the molecule and quickly clear it from the brain, along with any plaque deposits that have already formed. However, Jankowsky says, these drugs therapies may not be appropriate for long-term use because of possible side effects. One clinical trial of the antibodies had to be stopped because some patients developed a serious brain inflammation known as encephalitis.

"The upshot of this research is that a combination of approaches may be the best way to tackle Alzheimer's disease," Jankowsky says. "The idea would be to use immunotherapy to acutely reverse the damage, followed by chronic secretase inhibition to prevent it from ever recurring."

For a copy of the paper, go to http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1...

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Contact: Dr. Joanna L. Jankowsky (626) 395-6884 jlj2@caltech.edu

Kathy Svitil (626) 395-8022 ksvitil@caltech.edu

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Caltech Researchers Join Global GEM4 Initiative

PASADENA, Calif.—Researchers at the California Institute of Technology have joined a global medical effort to address a number of diseases through innovative, multi-institutional, multidisciplinary approaches. The initiative, the Global Enterprise for Micromechanics and Molecular Medicine (GEM4), is centered at MIT's Department of Materials Science and Engineering, and was officially launched October 12 at an MIT campus ceremony.

According to Mory Gharib, who is the Liepmann Professor of Aeronautics and Bioengineering at Caltech, the participation of Caltech researchers will concentrate on the micromechanics of cells and tissues related to certain diseases.

"In the past, researchers have always looked at the biological and chemical aspects of diseases like malaria," says Gharib. "So this is a novel approach. The idea is that, by looking at the ways certain mechanical properties of the cell change with the disease, you could have new and ideally faster technical devices for doing diagnoses."

An end result might be a microfluidic device, for example, that would use a hairpin needle for doing in situ examinations of cells passing by. The sensor, by utilizing the laws of physics, would be able to tell the percentage of infected cells.

Such a device could also be used for screening, Gharib says. "Millions and millions of cells could be screened, with no need for determining their chemical or spectral behavior."

Another Caltech researcher who will be closely involved in the GEM4 effort is Ares Rosakis, who is director of the Graduate Aeronautical Laboratories (GALCIT) and the von Kármán Professor of Aeronautics and Mechanical Engineering. According to Rosakis, a $750,000 gift from Joe and Edwina Charyk to GALCIT will go to facilitating Caltech's participation in GEM4. Specifically, the Charyk gift will be used for the creation of the Charyk Biomechanics Laboratory, which will be part of the existing GALCIT complex.

According to MIT's announcement, GEM4 is "a new paradigm in global interactions among leading institutions to work together seamlessly across the boundaries of science, engineering, technology, medicine, and public health, with an emphasis on biomechanics at the microscopic and molecular levels."

Among GEM4's goals are the bringing together of institutions globally, the creation of new models for interdisciplinary partnerships, and the fostering of a global forum to address and explore huge challenges for the future. The diseases and conditions to be addressed include metastatic cancer, cardiovascular diseases, inflammatory diseases, and infectious diseases such as malaria.

"The initial emphasis will include (but will not be limited to) molecular, subcellular, and cellular mechanics applied to major problems in biomedicine," the MIT announcement continues, "where a single investigator or institution is not likely to have the full spectrum of expertise, infrastructure, or resources available to span fundamental molecular science all the way to clinical practice and societal implications."

Professor Subra Suresh, who is the GEM4 director, is the Ford Professor of Engineering and head of the Department of Materials Science and Engineering at MIT. At Caltech he held the Clark Millikan Visiting Professor Chair in Aeronautics and was also a Moore Visiting Scholar.

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Baltimore to Retire as Caltech President; Will Remain at Institute as Biology Professor

PASADENA, Calif.- David Baltimore, the seventh president of the California Institute of Technology, will retire on June 30, 2006, after nearly nine years in the post. He will remain at the Institute, where he intends to focus on his scientific work and teaching.

"This is not a decision that I have made easily," Baltimore announced to the Caltech trustees, faculty, staff, and students, "but I am convinced that the interests of the Institute will be best served by a presidential transition at this particular time in its history. By next summer we will be well along in the process of implementing our plans to strengthen the financial foundation of the Institute. Although our $1.4 billion campaign is not scheduled for completion until the end of 2007, we have made remarkable progress, and successful attainment of its audacious goals will remain my highest priority. As these important endeavors near their final stages, it will be time for the Institute to once again turn to the future, guided most effectively by the revitalizing vision and leadership of a new president."

He has agreed to remain in the position until a successor is named.

"David Baltimore's articulate advocacy of the Institute's mission has played a huge role in raising the public's awareness of Caltech as a unique national treasure. Our task ahead is to find our next president to carry this vision of excellence into the future," said Kent Kresa, the chairman of the Caltech Board of Trustees.

Baltimore, 67, assumed the presidency on October 15, 1997. His tenure saw many significant events at Caltech. Early on, he oversaw the completion of a fund-raising initiative for the biological sciences, marked by the construction and dedication of the Broad Center for the Biological Sciences. He launched the current $1.4 billion capital campaign, which has included receipt of the largest gift to higher education, $600 million from Gordon and Betty Moore and the Gordon and Betty Moore Foundation. The campaign still has two years to run, but has already raised almost $1.1 billion. An important aspect of Caltech is its stewardship of the Jet Propulsion Laboratory, supported by NASA. Baltimore's presidency has seen many spectacular JPL successes, notably the Mars Exploration Rovers, as well as the appointment of a new director, Dr. Charles Elachi.

"David Baltimore will go down in history as not only a great scientist, but also as one of the great presidents of Caltech," said Eli Broad, a trustee of, and major donor to, the Institute. "It is rare to find someone of his intelligence, integrity, and leadership who can relate so well to people both within and outside the world of science. It was David who inspired Edye and me to become interested in science. We had no background in the field, but he made us feel comfortable. We are fortunate that he will continue his research at Caltech."

Other events during his term have been Caltech's acquisition of the former St. Luke Medical Center in northeast Pasadena; the funding of the design-development phase of the Thirty Meter Telescope; and the establishment of the Information Science and Technology (IST) initiative. Baltimore championed contemporary architecture, chosing James Freed of Pei, Cobb, Freed for the Broad Center, Thom Mayne of Morphosis for the new Cahill Center for Astronomy and Astrophysics, and Rem Koolhaas for the new Walter and Leonore Annenberg Center for Information Science and Technology. The latter two buildings are still in the design phase. Baltimore worked toward increasing diversity at Caltech, particularly by bringing more women into administrative roles. He also was concerned about the quality of undergraduate life, appointing the first full-time vice president for student affairs and starting a $3 million fund for enhancing student life. During the last year, an important activity for him has been his membership on the Independent Citizens Oversight Committee for the California stem cell initiative.

"David Baltimore is an incisive and articulate leader who has strengthened Caltech's core commitments to excellence in research and teaching and has led several initiatives that have ensured promising avenues of research can be pursued at the Institute," said Paul Jennings, Caltech's provost. In a written announcement to the campus and its trustees, Baltimore said, "It has been a privilege to serve as president of Caltech and a pleasure to work with the dedicated and remarkable Caltech faculty, staff, students, trustees, and alumni. The administration in place at Caltech is an extraordinary group, and I will retire with full confidence in their abilities to effect a smooth transition. During my time in the president's office, I have worked to keep Caltech the unique and highly effective university that was imagined into existence by George Ellery Hale almost 100 years ago. Its dedication to excellence has been undiminished, requiring that it continually be in flux, reaching for the altering frontiers of knowledge. The great gift from Gordon and Betty Moore has provided the resources for maintaining our momentum and was truly a defining event of my time as Caltech's president."

Baltimore will remain at Caltech as a professor of biology. In June he was awarded a grant of $13.9 million by the Grand Challenges in Global Health initiative for his proposal "Engineering Immunity Against HIV and Other Dangerous Pathogens," which promises to address the challenge of creating immunological methods to deal with chronic diseases. This grant was awarded by the Bill & Melinda Gates Foundation.

"David has been a wonderful Caltech president," said Caltech faculty chair Henry Lester, the Bren Professor of Biology. "His energy, articulate intelligence, and vision have resulted in a stronger, more interesting, and more diverse Caltech. Speaking also as a Caltech biologist, I'm delighted that he will remain on campus to contribute to our research and teaching programs."

Baltimore, who received a Nobel Prize for his work on the genetic mechanisms of viruses in 1975 at the age of 37, has contributed widely to the understanding of cancer, AIDS, and the molecular basis of the immune response. He has continued to operate his research lab while president and has announced many important findings while at Caltech, including establishing a new methodology to help fight cancer, developing a new gene therapy that is highly effective in preventing HIV from infecting individual cells in the immune system, and creating a new methodology for producing transgenic mice. He has also joined with others in proposing a new global effort to create an HIV vaccine. He received the National Medal of Science in 1999 from President Bill Clinton and the Warren Alpert Foundation Scientific Prize in 2001 for pioneering work leading to cancer therapy.

Not only has Baltimore been prolific in writing about his findings in scientific journals, but he also raised Caltech's visibility by contributing opinion pieces to general interest media on such subjects as the value of stem cell research, the unnecessary public panic that arose during the SARS epidemic, science research under the Bush administration, and maintaining the scientific workforce in the U.S.

"Throughout my years as a Caltech trustee, I have been repeatedly impressed by David's skill at communicating the importance of Caltech to a wide range of constituencies, from the scientific community to potential donors to readers of daily newspapers," said Kresa, the chairman of the Caltech Board of Trustees.

Baltimore has several outstanding administrative and public policy achievements to his credit. In the mid-1970s, he played an important role in creating a consensus on national science policy regarding recombinant DNA research. He served as founding director of the Whitehead Institute for Biomedical Research at MIT from 1982 until 1990, and was president of Rockefeller University in 1990-91. An early advocate of federal AIDS research, he cochaired the 1986 National Academy of Sciences Committee on a National Strategy for AIDS and was appointed in 1996 to head the National Institutes of Health AIDS Vaccine Research Committee.

Feynman Professor and Professor of Theoretical Physics Kip Thorne, who chaired the faculty search committee that selected Baltimore, feels Baltimore has accomplished what the search committee hoped he would. "We attracted David to Caltech to provide leadership in a period of change-changing relations to the federal government, changing ties to the private sector, and a growth in biological sciences at Caltech-while maintaining our traditional strengths. He has led us through this superbly well, and has been a remarkable intellectual force on campus. His presidential shoes will be hard to fill, but I'm tremendously pleased he will remain as a professor, liberated to contribute more strongly to the intellectual life of the Caltech community," Thorne said.

Walter Weisman, trustee chairman of the Caltech capital campaign, has worked closely with Baltimore since its kickoff in 2002, and is pleased with the impact Baltimore has had. "David Baltimore has made an enormous contribution to our campaign success. I am delighted that he will continue to assist the Institute with the campaign as he moves to full-time research. His legacy at Caltech will be felt for years to come, thanks in no small part to his fund-raising achievements as president of the Institute."

Gordon Moore-a Caltech alumnus who was trustee chairman when Baltimore was hired-said, "David's leadership over the last nine years has significantly strengthened Caltech in many important ways. His impact will be felt for decades."

Ben Rosen, also an alumnus and former trustee chairman, said, "During his years of leadership at Caltech, David Baltimore elevated the already considerable reputation and strengths of the Institute. The faculty is stronger than it has ever been. The students are smarter, more diverse, and better rounded. The facilities have been substantially augmented to meet the growing needs of leading-edge research. JPL has achieved triumph after triumph. And the ambitious capital campaign that began during his period in office, and led by his energetic fund-raising skills, will assure that future Caltech needs are met and our goals achieved. Sometime next year, David will begin doing research full time in his biology lab, and a new president will lead Caltech. But because David will remain on campus, we'll still be lucky enough to share with him his myriad interests outside of science, a small sample of which would include art, fly-fishing, music, architecture, travel, literature, and politics."

Caltech's Board of Trustees will immediately initiate the search process for a new president.

Baltimore is the seventh person to lead "modern day" Caltech, his predecessors being James A. B. Scherer, Robert A. Millikan, Lee A. DuBridge, Harold Brown, Marvin L. Goldberger, and Thomas E. Everhart.

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JP
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Caltech Stem Cell Biology Training Program Awarded $2.3 Million

PASADENA, Calif. - At a historic meeting today in Sacramento, a three-year, $2.3 million grant was earmarked for the creation of the Caltech Stem-Cell Training Program at the California Institute of Technology. The grant is part of the first round of funding resulting from the passage by California voters of Proposition 71, the California Stem Cell Research and Cures Initiative, in November 2004. The controversial bond measure provides $3 billion over the next ten years to support human embryonic stem-cell research at California universities and research institutions.

The new program, an independently funded collaboration with the Keck School of Medicine at the University of Southern California and Children's Hospital Los Angeles, will provide cross-disciplinary education to postdoctoral scholars on the potential medical uses for stem-cell research, as well as training in the social, ethical, and legal issues surrounding such research. It will be directed by Paul H. Patterson, Anne P. and Benjamin F. Biaggini Professor of Biological Sciences, who currently studies stem cells in the adult brains of mice and their potential usefulness in the treatment of Alzheimer's disease.

The program will support ten postdoctoral students, drawn from different disciplines on campus, for three years.

"This will allow us to bring people into stem-cell research that might otherwise have gone in different directions, providing new expertise and research ideas to the field," Patterson says. "A physicist will look at a problem in a way that a biologist might not have."

A key feature of the program will be newly developed courses in bioethics, and a unique tri-institutional stem-cell biology lecture course, taught in conjunction with the USC Keck School of Medicine and Children's Hospital, that will train students in cutting-edge gene-transfer technology applications in the clinic, medical applications, and current stem-cell research.

The collaboration with the Keck School of Medicine and Children's Hospital "will bring a new medical, preclinical, and clinical outlook to Caltech's work," says Patterson. The university is a world leader in basic stem-cell research. Recently, Caltech researchers uncovered crucial mechanisms regulating the fate of stem cells, and provided unprecedented views of the movement of stem cells through living embryos. Other work has demonstrated the ability to manipulate the genes of stem cells.

The allocation of funds was recommended at a meeting of the Independent Citizens' Oversight Committee of the California Institute for Regenerative Medicine (CIRM). In subsequent awards, CIRM will provide the funds to construct new research facilities and to support individual research programs.

"This is the first fruit of Proposition 71, an initiative that was overwhelmingly voted in by the people of California to support stem-cell research. Caltech will luckily be part of that effort," said Caltech president and Nobel laureate David Baltimore. "This training grant will allow us to use our expertise to develop a pool of new talent to conduct stem-cell research," he adds. Baltimore is on the 29-member CIRM oversight committee. Committee members do not vote on applications in which they have a conflict of interest.

"This is just the beginning," Patterson says. "It's part of a comprehensive approach that is unique to California, and we hope to participate in all aspects of this at Caltech."

Caltech Media Relations contacts: Kathy Svitil (626) 395-8022 ksvitil@caltech.edu

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KS
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Authority on the Brains and Behavior of Owls and Songbirds Wins Neuroscience Prize

PASADENA, Calif.-Masakazu "Mark" Konishi, a California Institute of Technology neuroscientist renowned for his work on the neural wiring that allows owls to swoop in on their prey in darkness and songbirds to sing, and his former postdoctoral researcher Eric Knudsen, who is now chair of the neurobiology department at Stanford University, have been awarded this year's Peter Gruber Foundation Neuroscience Prize.

Konishi, who is the Bing Professor of Behavioral Biology at Caltech, and Knudsen received the prize for their work on the brain mechanisms of sound localization in barn owls, which Konishi has worked on since the mid-1970s. The two will receive an unrestricted cash prize of $200,000, a gold medal, and a citation for their contributions to neuroscience. The award was established in 2004 and is given each year to "to honor the most distinguished work in the field of the brain, nervous system and the spinal cord."

Konishi has worked extensively for two decades on the auditory systems of barn owls, which can use their acute hearing to home in on mice on the ground, even in total darkness. The research has led to a good understanding of how the owl's brain manages to "compute" precise locations in two dimensions, and how the neural pathways and circuits are involved.

One of their noteworthy collaborative accomplishments was their work on the auditory physiology of owls in which they used "free-field" speakers that could be moved around the owls' heads. This method allowed them to find the "space-specific" neurons that respond to sounds coming from particular directions. As they plotted the directions and the brain-recording sites, it became clear to them that the neurons involved formed a map of auditory space.

The neurobiology of birdsongs is also of interest to Konishi because several areas of the bird's brain are involved, and because the interaction between the neural wiring and the birds' behavior is of interest to those who strive to better understand the vertebrate brain. Young birds select the song of their own species out of many alien songs in their environment, and they do so because of the way they memorize a "tutor song" at an early stage of development and then produce a copy of it at maturity.

Konishi's work has implications for better understanding the human brain and perhaps even for future interventions in certain neurological disorders.

For example, his group in the past has focused on the death of a special group of nerve cells during a particular developmental period in songbirds, and on the hormonal means of preventing cell death. The problem of the biologically programmed death of nerve cells may have long-term implications for understanding human disorders such as Alzheimer's and Parkinson's diseases.

The Peter Gruber Foundation was founded in 1993 and established a record of charitable giving principally in the U.S. Virgin Islands, where it is located. In recent years the foundation has expanded its focus to a series of international awards recognizing discoveries and achievements that produce fundamental shifts in human knowledge and culture. In addition to the Neuroscience Prize, the foundation presents awards in the fields of cosmology, genetics, justice, and women's rights. Further information about the Peter Gruber Foundation and its awards is available from www.petergruberfoundation.org.

Last year, Seymour Benzer, who is Caltech's Boswell Professor of Neuroscience, Emeritus, became the first recipient of the Neuroscience Prize.

 

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Robert Tindol
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