New research shows that brain is involvedin visual afterimages

If you stare at a bright red disk for a time and then glance away, you'll soon see a green disk of the same size appear and then disappear. The perceived disk is known as an afterimage, and has long been thought to be an effect of the "bleaching" of photochemical pigments or adaptation of neurons in the retina and merely a part of the ocular machinery that makes vision possible.

But a novel new experimental procedure by psychophysicists shows that the brain and its adaptive change are involved in the formation of afterimages.

Reporting in the August 31 issue of the journal Science, a joint team from the California Institute of Technology and NTT Communication Science Laboratories, led by Caltech professor Shinsuke Shimojo, demonstrates that adaptation to a specific visual pattern which induces perception of "color filling-in" later leads to a negative afterimage of the filled-in surface. The research further demonstrates that this global type of afterimage requires adaptation not at the retinal, but rather at the cortical, level of visual neural representation.

The Shimojo team employed a specific type of image (see image A below) in which a red semi-transparent square is perceived on top of the four white disks. Only the wedge parts of the disks are colored, and there is no local stimulus or indication of redness in the central portion of the display, yet the color filling-in mechanism operates to give an impression of filled-in red surface.

If an observer were staring only at the red square for at least 30 seconds, then he or she would see a reverse-color green square for a few seconds after refixating on a blank screen (as in the image at the top of C).

However, an observer who fixates on the image at left (in A) and then refixates on a blank screen will usually see four black disks such as the ones at the bottom of C, followed by a global afterimage in which a green square appears to be solid.

The fact that no light from the center of the original square was red during adaptation demonstrates that the effect was not merely caused by a leaking-over or fuzziness of neural adaptation, because the four white disks are at first clearly distinct as black afterimages. Thus, the global afterimage is distinct from a conventional afterimage.

One possibility is that local afterimages of the disks and wedges—but only these—are induced first, and then the color filling-in occurs to give an impression of the global square, just as in the case of red filling-in during adaptation. The researchers considered this element-adaptation hypothesis, but eventually turned it down.

The other hypothesis is that, since neural circuits employing cortical neurons are known to cause the filling-in of the center of the red square, then perhaps it is this cortical circuit that undergoes adaptation to directly create the global negative green afterimage. This is called the surface-adaptation hypothesis, which was eventually supported by their results.

The researchers came up with experiments to provide three lines of evidence to reject the first and support the second hypothesis. First, the local and the global afterimages were visible with different timing, and tended to be exclusive of each other. This argued against the first hypothesis that the local afterimages are necessary to see the global afterimage.

Second, when the strength of color filling-in during adaptation was manipulated by changing the timing of the presentation of disks and colored wedges, the strength of the global afterimage was positively correlated with it, as predicted by the surface-adaptation hypothesis but not by the element adaptation hypothesis.

For the last piece of evidence, the researchers prepared a dynamic adapting stimulus designed specifically to minimize the local afterimages, yet to maximize the impression of color filling-in during adaptation. If the element-adaptation hypothesis is correct, then test subjects would not observe the global afterimage. If, on the other hand, the surface-adaptation hypothesis is correct, the observers would see a vivid global afterimage only. The result turned out to be the latter.

The study has no immediate applications, but furthers the understanding of perception and the human brain, says Shimojo, a professor of computation and neural systems at Caltech and lead author of the study.

"This has profound implications with regard to how brain activity is responsible for our conscious perception," he says.

According to Shimojo, the brain is the ultimate organ for humans to adapt to the environment, so it would make more sense if the brain, as well as the retina, can modify their activity—and perception as a result—due to experience and adaptation.

The other authors of the paper are Yukiyasu Kamitani, a Caltech graduate student in computation and neural systems, and Shin'ya Nishida of the NTT Communication Science Laboratories in Atsugi, Kanagawa, Japan.

Contact: Robert Tindol (626) 395-3631

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Caltech biologist David Chan selectedas Rita Allen Foundation Scholar

David C. Chan, an assistant professor of biology at the California Institute of Technology, has been named a Rita Allen Foundation Scholar. The award carries a $50,000 stipend for up to three years.

Chan specializes in research on mitochondria, components of the cell important in energy metabolism and also in programmed cell death. Specifically, he investigates the manner in which cells coordinate mitochondrial functions with the development of tissues and organs.

A graduate of Harvard Medical School and MIT, Chan joined the Caltech faculty in January 2000. From 1996 to 1999 he was a postdoctoral researcher at MIT's Whitehead Institute, where he succeeded in determining the crystal structure of the core of the HIV protein gp41. He also did structural analysis of the HIV envelope proteins in cell fusion and infection, and looked at ways the gp41 protein could be disabled to inhibit viral infection.

The Rita Allen Foundation was incorporated in 1953 in New York. The foundation supports medical research in the fields of cancer, cerebral palsy, multiple sclerosis, and the treatment of terminal illness, with special emphasis on the development of effective euphoric and analgesic agents.

The Rita Allen Foundation Scholarships program is designed to provide financial support for researchers in the early stages of their careers who show promise of becoming leaders in one of the areas of special interest to the foundation.

Founded in 1891, Caltech has an enrollment of some 2,000 students, and a faculty of about 285 professorial members. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 2,400 on campus and 4,800 at JPL.

Over the years, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-seven 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 78 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 70 members of the National Academy of Sciences and 46 members of the National Academy of Engineering.

Contact: Robert Tindol (626) 395-3631

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Survival of the Fittest . . . Or the Flattest?

Darwinian dogma states that in the marathon race of evolution, the genotype that replicates the fastest, wins. But now scientists at the California Institute of Technology say that's true, but when you factor in another basic process of evolution, that of mutations, it's often the tortoise that defeats the hare.

It turns out that mutations, the random changes that can take place in a gene, are the wild cards in the great race. The researchers found that at high mutation rates, genotypes with a slower replication rate can displace faster replicators if the former has a higher "robustness"—or fitness—against mutations; that is, if a mutation is, on average, less harmful to the slower replicator than to the faster one. The research, to appear in the July 19th issue of the journal Nature, was conducted by several investigators, including Claus Wilke, a postdoctoral scholar, Chris Adami, who holds joint appointments at Caltech and the Jet Propulsion Lab, Jia Lan Wang, an undergraduate student, Charles Ofria, a former Caltech graduate student now at Michigan State University; and Richard Lenski, a professor at Michigan State.

In a takeoff of a common Darwinian phrase, they coin their work "survival of the flattest" rather than the survival of the fittest. The idea is this: If a group of similar genotypes with a faster replication rate occupies a "high and narrow peak" in the landscape of evolutionary fitness, while a different group of genotypes that replicates more slowly occupies a lower and flatter, or broader, peak, then, when mutation rates are high, the broadness of the lower peak can offset the height of the higher peak. That means the slower replicator wins. " In a way, organisms can trade replication speed for robustness against mutations and vice versa," says Wilke. "Ultimately, the organisms with the most advantageous combination of both will win."

Discerning such evolutionary nuances, though, is no easy task. To test an evolutionary theory requires generations and generations of an organism to pass. To make matters worse, the simplest living system, namely that which has been a precursor to all living systems on Earth, has been replaced by much more complicated systems over the last four billion years.

Wilke and his collaborators found the solution in the growing power of computers by constructing, via a software program, an artificial living system that behaves in remarkably lifelike ways. Such digital creatures evolve in the same way biological life forms do; they live in, and adapt to, a virtual world created for them inside a computer. Doing so offers an opportunity to test generalizations about living systems that may extend beyond the organic life that biologists usually study. Though this research did not involve actual living organisms, one of the authors, Richard Lenski, is a leading expert on the evolution of Escherichia Coli bacteria. Lenski believes that digital organisms are sufficiently realistic to yield biological insights, and he continues his research on both E. coli and digital organisms.

In their digital world, the organisms are self-replicating computer programs that compete with one another for CPU (central processing units) cycles, which are their limiting resource. Digital organisms have genomes in the form of a series of instructions, and phenotypes that are obtained by execution of their genomic program. The creatures physically inhabit a reserved space in the computer's memory—an "artificial Petri dish"—and they must copy their own genomes. Moreover, their evolution does not proceed toward a target specified in advance, but rather proceeds in an open-ended manner to produce phenotypes that are more successful in a particular environment.

Digital creatures lend themselves to evolutionary experiments because their environment can be readily manipulated to examine the importance of various selective pressures. In this study, though, the only environmental factor varied was the mutation rate. Whereas in nature, mutations are random changes that can take place in DNA, a digital organism's mutations occur in the random changes of its particular computer program. A command may be switched, for example, or a sequence of instructions copied twice.

For this study, the scientists derived 40 pairs of digital organisms that were derived from 40 different ancestors in identical selective environments. The only difference was that one of each pair was subjected to a four-fold higher mutation rate. In 12 cases out of the 40, the dominant genotype that evolved at the lower mutation rate replicated at a pace that was 1.5-fold faster than its counterpart at the higher mutation rate.

Next, the scientists allowed each of these 12 disparate pairs to compete across a range of mutation rates. In each case, as the mutation rate was increased, the outcome of competition switched to favor the genotype that had the lower replication rate. The researchers believe that these slower genotypes, although they occupied a lower fitness peak and were located in flatter regions of the fitness surface, were, as a result, more robust with respect to mutations.

The digital organisms have the advantage that many generations can be studied in a brief period of time. But the researchers believe a colony of asexual bacteria, subjected to the same stresses as the digital organisms, would probably face similar consequences.

The concept of "survival of the flattest" seems to imply, the authors say, that, at least for populations subject to a high mutation rate, selection acts upon a group of mutants rather than the individual. Thus, under such circumstances, genotypes that unselfishly produce mutant genotypes of high fitness are selected for, and supported in turn, by other mutants in that group. The study therefore reveals that "selfish genes," while being the successful strategy at low mutation rates, may be outcompeted by unselfish ones when the mutation rate is high.

Factors causing high mutations could have led to origin of sexual reproduction, study shows

Biologists have long known the advantages of sexual reproduction to the evolution and survival of species. With a little sex, a fledgling creature is more likely to pass on the good mutations it may have, and more able to deal with the sort of environmental adversity that would send its asexual neighbors floundering into the shallow end of the gene pool.

The only problem is that it's hard to figure out how sex got started in the first place. Not only do many primitive single-celled organisms do just fine with asexual reproduction, but mathematical models show that a sexual mutant in an asexual population is most likely not favored to compete successfully and pass on its genes.

Now, researchers from the California Institute of Technology and the Jet Propulsion Laboratory, using "digital organisms" and RNA, have concluded that established asexual bacteria could be nudged to evolve into sexual reproduction if there are certain forms of stress on the environment, such as radiation or catastrophic meteor or comet impacts that give rise to a high rate of mutations.

In an article that has significant implications for understanding the origin of sexual reproduction in the early world, Claus Wilke of Caltech and Chris Adami, who holds joint appointments at Caltech and JPL, report that a change in conditions causing higher rates of mutations can lead an asexual population to an adaptation that may be sufficient to give mutant individuals a greater advantage if those mutants reproduce sexually.

The paper, published in the July 22 issue of the Royal Society journal Proceedings: Biological Sciences B, builds on earlier work by Adami and his collaborators, showing that digital organisms—that is, self-replicating computer programs designed to closely resemble the life cycles of living bacteria—can actually adapt to become more robust.

"What we showed in the other paper," says Adami, "is that if you transfer a fragile organism that evolved with a small mutation rate into a high-mutation-rate environment, it will adapt to this environment by becoming more robust."

One of the reasons the origin of sexual reproduction has been a mystery is because of an effect known as "mutation accumulation." Organisms tend to adapt so as to decrease the effects of mutations in order to become less vulnerable.

But this kind of robustness is poisonous, because with sexual recombination, deleterious mutations would simply accumulate in the organism and thus lead to a gradual loss of genes. This handicap of sexual creatures would be enough to guarantee their extinction when competing against asexual ones.

This can be avoided if the effects of mutations are compounding—that is, if the effect of two or more simultaneous deleterious mutations is worse than the combined effect of each of the mutations. In this manner, an organism may be robust to a few mutations, but incapable of surviving a large number of mutations, so that mutations cannot accumulate.

The new revelation by Wilke and Adami is that there is a conservation law at work in the relationship between the compounding of mutations and the fitness decay due to single mutations. This law says that robustness to a few mutations implies vulnerability to a large number, while robustness to many mutations must go hand in hand with vulnerability to single mutations.

Thus, increasing robustness to single mutations automatically makes multiple mutations intolerable, which removes organisms with multiple deleterious mutations from the population and allows sexual recombination to reap the rewards from sharing beneficial mutations.

Because stressful environments with high mutation rates push organisms to become robust to single mutations, the conservation law guarantees that this evolutionary pressure also pushes asexual organisms on to the road toward sexual recombination.

The researchers studied the evolution of digital organisms and RNA secondary structure, because accurate data on the decay of fitness and the effect of multiple mutations (whether they are compounding or mitigating) for living organisms is quite rare. For the RNA study, the researchers used known sequences with well-understood folds and then tried various mutations to see which mutations mattered and which didn't, in a system that computationally predicts RNA secondary structure. The results supported the conservation law.

Though the study did not involve actual living organisms, Adami has collaborated in the past with experts on bacteria to demonstrate that the digital organisms are indeed realistic. In an earlier 1999 study, for example, Adami's collaborator was a leading expert on the evolution of the E. coli bacteria.

The digital organisms have the advantage that many generations can be studied in a brief period of time, but Adami thinks a colony of asexual bacteria subjected to the stress imposed on the digital organisms in the experiment would probably face similar consequences.

"If you took a population of E. coli and subjected it to high mutation rates for many years—for example by irradiation or introducing mutagenic factors—at some point you might observe that exchange of genetic material, a precursor to sexual recombination, would become favorable to the organisms and thus selected for, if at the same time the environment changes fast enough that enough mutations are beneficial," he says.

"But that's a very difficult experiment with living organisms because of the time involved, and because it is difficult to construct constantly changing environments in a petri dish. This is easier with digital organisms, and will probably be first observed there.

"The reason the origin of sexual reproduction has been such a big mystery is that we look at the world as it is now," Adami says. "But the early world was a much more stressful place, sometimes changing very rapidly.

"We can't say how or when sexual reproduction came to take a hold in nature, but we can now say that high mutation rates can, under the right conditions, force an asexual organism to become sexual."

Adami earned his doctorate in theoretical physics at SUNY Stony Brook. He is a faculty associate in the computation and neural systems department at Caltech, and a research scientist at JPL. He is the author of the 1998 book Introduction to Artificial Life. Wilke, also a physicist, is a postdoctoral fellow in Adami's Digital Life Laboratory.

The article appears in Proceedings: Biological Sciences B, volume 268, number 1475, page 1469. The cover date is 22 July 2001, but the article is available on-line at http://www.pubs.royalsoc.ac.uk/proc_bio/proc_bio.html

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Hensen's node in chicken embryos governs movement of neural cells, study shows

For us living creatures with backbones, existence begins as a single fertilized cell that then subdivides and grows into a fetus with many, many cells. But the details of how those cells end up as discrete organs instead of undifferentiated heaps of cells is only now being understood in microscopic detail.

Why, for example, should some of the cells migrate to the region that will become the brain, while others travel netherward to make a spinal cord? Although some details are known about which cells contribute to particular regions of the nervous system and which signals help to establish the organization of the brain, much less is known about factors that guide the development of the spinal cord.

In a new study, researchers from the California Institute of Technology have gained unprecedented information about the molecular signals and cell movements that coordinate to form the spinal cord. The study takes advantage of recently developed bioimaging and cell labeling techniques to follow individual cell movements in a developing chick embryo through a clear "window" cut into a fertilized egg. The results, reported in the June issue of the journal Nature Cell Biology, suggest that a proliferative stem zone at the tail end of the growing embryo contributes descendants to the growing neuraxis.

"The basic idea is that descendants of cells from Hensen's node, the structure that lays down the trunk, are sequentially distributed along the elongating spinal cord" says Luc Mathis, a former researcher in the lab of Caltech biology professor Scott Fraser, and lead author of the paper. "In the past, we did not have the ability to follow individual cells in living vertebrate embryos and could not determine how neural precursor cells could remain within Hensen's node, while some descendants leave it to form the spinal cord. "

In the paper, the researchers explain that neural precursor cells get displaced into the neural axis by the proliferation in Hensen's node. The researchers labeled cells near Hensen's node in 40-hour old chick embryos by using an external electric field to deliver an expression vector encoding green fluorescent protein (GFP) into cells, a process called electroporation. Using state-of-the-art imaging techniques developed by postdoctoral researcher Paul Kulesa, the group recorded the motion of fluorescent cells in ovo using a confocal microscope set up for time-lapse imaging and surrounded by a heated chamber to maintain embryo development.

"As the cells proliferate, some progenitors are displaced from the stem zone to become part of the neural plate and spinal cord," Mathis says. "Our analyses show that the Hensen's node produces daughter cells that are eventually displaced out of the node zone on the basis of their position in relation to other proliferating cells, and not on the basis of asymmetric cell divisions."

The paper also addresses the molecular signaling involved in the spreading of the cells. Previous work has shown that fibroblast growth factor (FGF) is somehow involved in formation of the posterior nervous system. To test the possibility that FGF could act by maintaining the stem zone of cell proliferation, the researchers disrupted FGF signaling within Hensen's node. Indeed, the result was a seriously shortened spinal cord and premature exit of cells from the node, indicating that FGF is required for the proliferation of neural precursor cells in the stem zone that generates the spinal cord.

A structure similar to Hensen's node—called simply a "node"—is found in mammals, and analogous zones are found in other vertebrates as well. The cell behavior and genetic control discovered in the chick might also be responsible for the development of the spinal cord in mammals, including humans.

"This new understanding of the formation of the spinal cord is the result of a fusion between hypotheses that arose during previous studies that I had conducted in France, the great embryological background and imaging facilities provided by Scott Fraser, and the original experimental systems of cell tracking developed by Paul Kulesa" concludes Mathis."

Scott Fraser is the Anna L Rosen Professor of Biology and the director of the Biological Imaging Center of Caltech's Beckman Institute. Luc Mathis is a former researcher at the Biological Imaging Center who is currently at the Pasteur Institute in Paris. Paul Kulesa is a senior research fellow supported by the computational molecular biology progam and associated with the Biological Imaging Center.

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Caltech Uses Fluorescent Protein to Visualize the Work of Living Neurons

Neuroscientists have long suspected that dendrites—the fine fibers that extend from neurons—can synthesize proteins. Now, using a molecule they constructed that "lights up" when synthesis occurs, a biologist and her colleagues from the California Institute of Technology have proven just that.

Erin M. Schuman, an associate professor of biology at Caltech and an assistant investigator with the Howard Hughes Medical Institute, along with colleagues Girish Aakalu, Bryan Smith, Nhien Nguyen, and Changan Jiang, published their findings last month in the journal Neuron. Proving that protein synthesis does indeed occur in intact dendrites suggests the dendrites may also have the capacity to adjust the strength of connections between neurons. That in turn implies they may influence vital neural activities such as learning and memory.

Schuman and colleagues constructed a so-called "reporter" molecule that, when introduced into neurons, emits a telltale glow if protein synthesis is occurring. "There was early evidence that protein-synthesis machinery was present in dendrites," says Schuman. "Those findings were intriguing because they implied that dendrites had the capacity to make their own proteins."

The idea that dendrites should be able to synthesize proteins made sense to Schuman and others because it was more economical and efficient. "It's like the difference between centralized and distributed freight shipping," she says. "With central shipping, you need a huge number of trucks that drive all over town, moving freight from a central factory. But with distributed shipping, you have multiple distribution centers that serve local populations, with far less transport involved."

Previous studies had indicated that, in test tubes, tiny fragments of dendrites still had the capacity to synthesize proteins. Schuman and her colleagues believed that visualizing local protein synthesis in living neurons would provide a more compelling picture than was currently available.

The scientists began their efforts to create a reporter molecule by flanking a gene for a green fluorescent protein with two segments of another gene for a particular enzyme. Doing this ensured that the researchers would target the messenger RNA (mRNA) for their reporter molecule to dendrites.

Next, in a series of experiments, the group inserted the reporter molecule into rat neurons in culture, and then triggered protein synthesis using a growth factor called BDNF. By imaging the neurons over time, the investigators showed that the green fluorescent protein was expressed in the dendrites following BDNF treatment—proof that protein synthesis was taking place. Going a step further, the researchers showed they could cause the fluorescence to disappear by treating the neurons with a drug that blocked protein synthesis.

Schuman and her colleagues also addressed whether proteins synthesized in the main cell body, called the soma, could have diffused to the dendrites, rather than the dendrites themselves performing the protein synthesis. The researchers proved the proteins weren't coming from the soma by simply snipping the dendrites from the neurons, while maintaining their connection to their synaptic partners. Sure enough, the isolated dendrites still exhibited protein synthesis.

Intriguingly, says Schuman, hot spots of protein synthesis were observed within the dendrites. By tracking the location of the fluorescent signal over time, the researchers could see that these hotspots waxed and waned consistently in the same place. "The main attraction of local protein synthesis is that it could endow synapses with the capacity to make synapse-specific changes, which is a key property of information-storing systems," says Schuman. "The observation of such hot spots suggests there are localized areas of protein synthesis near synapses that may provide new proteins to synapses nearby."

Schuman and her colleagues are now applying their reporter molecule system to more complex brain slices and whole mice. "In the whole animals, we're exploring the role of dendritic protein synthesis in information processing and animal learning and behavior," says Schuman.

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Caltech Professor Pamela Bjorkman Elected To National Academy of Sciences

Pamela Bjorkman, professor of and executive officer for biology at the California Institute of Technology, is one of 72 American scientists elected this year to membership in the National Academy of Sciences (NAS). The announcement was made earlier this month in Washington at the 138th annual meeting of the academy.

Bjorkman, who has been on the Caltech faculty since 1989, focuses much of her research on molecules involved in cell-surface recognition, particularly molecules of the immune system. Investigators in her lab use a combined approach, including X-ray crystallography to determine three-dimensional structures, molecular biological techniques to produce proteins and to modify them, and biochemistry to study the properties of the proteins.

Much of the Bjorkman lab's efforts has involved proteins known as class I MHC, as well as very similar proteins—or homologues—that have a number of functions aside from an immunological role. In a 1999 study, for example, Bjorkman and her colleagues determined the three-dimensional structure of a protein that causes cachexia, a wasting syndrome in cancer and AIDS patients. The discovery provided the scientific basis for possible future strategies for controlling cachexia and/or treatment of obesity.

A native of Portland, Oregon, Bjorkman earned her bachelor's degree from the University of Oregon in 1978 and her doctorate from Harvard University in 1984. Afterward, she held postdoctoral positions at Harvard and the Stanford University School of Medicine.

She is an investigator of the Howard Hughes Medical Institute and has been a Pew Scholar in the biomedical sciences, an American Cancer Society Postdoctoral Fellow, and an American Society of Histocompatibility and Immunogenetics Young Investigator.

She has been the recipient of the William B. Coley Award for Distinguished Research in Fundamental Immunology, the Gairdner Foundation International Award for achievements in medical science, and the Paul Ehrlich and Ludwig Darmstaedter Award.

Bjorkman's election to the National Academy of Sciences brings to 67 the number of living Caltech professors and professors emeritus who have earned the prestigious honor. The National Academy, established in 1863 by President Lincoln, acts as an advisory body for the federal government on scientific matters.

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Caltech President Honored for Pioneering Work Leading to Cancer Therapy

PASADENA, Calif. — David Baltimore, the president of the California Institute of Technology, was one of five scientists to receive the 13th annual Warren Alpert Foundation Scientific Prize today, May 1, for research that ultimately led to a new groundbreaking cancer therapy.

The prize, awarded at a ceremony at Boston's Four Seasons Hotel, recognizes the significance of STI571, a new cancer therapy that has shown remarkable effectiveness against chronic myelogenous leukemia (CML) in clinical trials.

Created by understanding the fundamental mechanisms by which CML occurs, STI571 was cited by Dr. Francis Collins, director of the National Human Genome Research Institute, as an early example of the kind of rational drug design that will stem from human genome studies. At a recent lecture at Harvard Medical School he stated that the STI571 clinical trials have shown "pretty dramatic results and ones which we hope will be repeated in other disorders as we get this kind of molecular understanding of what's gone awry in disease."

Phase I clinical trials of STI571 have produced encouraging results for patients with CML, a form of cancer characterized by rising white blood cell counts. Currently approved treatments are aggressive and difficult for patients to tolerate. A person with CML, which affects an estimated 5,000 Americans each year, typically dies within five years. With STI571, however, clinical investigators report that so far, 51 of 53 patients who received the highest dose in one study have gone into remission with few and modest side effects.

In addition to serving as president of Caltech, Baltimore continues his work as a biology professor with an active research lab on campus. Baltimore and Owen N. Witte, MD, Howard Hughes Medical Institute investigator, and professor of microbiology, immunology and molecular genetics at UCLA and the Jonsson Cancer Center, were honored by the Alpert Foundation for the basic science investigations that characterized the genetic pathway to CML.

For their preclinical work that led to the creation of STI571, the Alpert Foundation presented the award to Alex Matter, MD, head of oncology research, Novartis Pharma AG, and Nicholas B. Lydon, PhD, formerly of Novartis and now vice president for small molecule drug discovery at Amgen, Inc. Brian J. Druker, MD, professor of medicine at Oregon Health Sciences University, was recognized for both his preclinical work and clinical trial investigations. The foundation will divide a $150,000 award among the winners.

CML is caused by a genetic anomaly triggered by the rearrangement of chromosomes nine and 22, forming what is called the Philadelphia chromosome. A molecular consequence of this anomalous chromosome is the Bcr-Abl gene, whose product is a member of the tyrosine kinase family of proteins, which play a central role in a variety of cellular processes. Bcr-Abl's cancer-causing properties were identified and characterized by Drs. Baltimore and Witte.

The presence of Bcr-Abl in 95 percent of CML patients made this molecule a particularly attractive target for the design of a selective kinase inhibitor. Matter, an early champion of kinase inhibitor research at Novartis, recruited Lydon to take on the effort of identifying Bcr-Abl inhibitors. Lydon, while working on this effort, began collaborating with Druker, whom he had met years earlier when Druker was an oncology fellow studying kinases in the 1980s at the Dana Farber Cancer Institute, a Harvard Medical School teaching affiliate. They ultimately identified STI571, and in 1998, after curing mice, the drug was taken into clinical trials, and today Druker continues to take a lead role in the development of STI571 for CML. The drug works by blocking Bcr-Abl's ability to transfer phosphate groups to acceptor proteins, a key process in signaling the continued growth of the tumor cells.

Recently, STI571 has also shown effectiveness against gastrointestinal stromal tumors (GISTs), which occur in an estimated 2,000 Americans each year. GISTs originate in the stomach or small intestine in cells that form the organs' connective tissue. Patients with malignant GISTs that cannot be removed by surgery generally die within a year or two of diagnosis. Researchers found that STI571 blocked another tyrosine kinase, KIT, the flawed protein found in GISTs, and one patient has shown significant shrinkage in tumor size.

The foundation's Scientific Advisory Committee comprises physicians and scientists from Harvard Medical School and the Massachusetts Institute of Technology and is chaired by Harvard Medical School dean Joseph B. Martin, MD, PhD. Each year the committee recognizes creative research that has dramatically affected the human condition.

Chelsea, Massachusetts, native Warren Alpert, chairman of Warren Equities, established the Alpert Prize in 1987 after reading an article about the University of Edinburgh's Kenneth Murray, who had developed a vaccine for hepatitis B. Alpert decided he would like to reward such far-reaching breakthroughs. He called Murray to tell him he had won a prize, then set about creating the foundation. To choose subsequent recipients, he asked Dr. Daniel Tosteson, then dean of Harvard Medical School, to convene a panel of experts to select and honor renowned scientists from around the world. Nominations are invited from scientific leaders nationwide.

In 1950, Warren Alpert, a first generation American, started his business with, as he tells it, $1,000 and a used car. Today Warren Equities and its subsidiaries, which market petroleum, food, and spirits and engage in transportation and real estate investments, generate approximately $900 million in annual volume and have more than 2,100 employees in 11 states. Forbes listed Warren Equities number 225 on its most recent list of the nation's largest privately held companies. Alpert is Warren Equities' sole owner and the foundation's sole benefactor.

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Owls perform a type of multiplicationin locating ground prey in dark, study shows

Owls have long been known for their stunning ability to swoop down in total darkness and grab unsuspecting prey for a midnight snack.

In the April 13 issue of the journal Science, neuroscientists from the California Institute of Technology report that an owl locates prey in the dark by processing two auditory signal cues to "compute" the position of the prey. This computation takes place in the midbrain and involves about a thousand specialized neurons.

"An owl can catch stuff in the dark because its brain determines the location of sound sources by using differences in arrival time and intensity between its two ears," says Mark Konishi, who is Bing Professor of Behavioral Biology at Caltech and coauthor of the Science paper.

For example, if a mouse on the ground is slightly to the right of a flying owl, the owl first hears the sound the mouse makes in its right ear, and a fraction of a second later, in its left ear. This information is transmitted to the specialized neurons in the midbrain.

Simultaneously, the owl's ears also pick up slight differences in the intensity of the sound. This information is transmitted to the same neurons of the midbrain, where the two cues are multiplied to provide a precise two-dimensional location of the prey.

"What we did not know was how the neural signals for time and intensity differences were combined in single neurons in the map of auditory space in the midbrain," Konishi says. "These neurons respond to specific combination of time and intensity differences. The question our paper answers is how this combination sensitivity is established."

"The answer is that these neurons multiply the time and intensity signals," he says.

Thus, the neurons act like switches. The neurons do not respond to time or intensity alone, but to particular combinations of them.

The reason the neural signals are multiplied rather than added is that, in an addition, a big input from the time pathway alone might drive the neuron to the firing level. In a multiplication, however, this possibility is less likely because a multiplication reduces the effects of a big input on one side.

It's not clear how the owl perceives the location of the mouse in the third dimension, Konishi says, but it could be that the owl simply remembers how far it is to the ground or how much noise a mouse generally makes, and somehow adds this information into the computation.

The lead author of the Science paper is José Luis Peña, a senior research fellow in biology at Caltech.

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Baxter Awards Caltech Professor $250,000

PASADENA, Calif.— The BioScience business of Baxter Healthcare Corporation, Hyland Immuno, has awarded $250,000 to a California Institute of Technology faculty member to continue his protein design research.

Glendale-based Baxter Hyland Immuno awarded the unrestricted grant to Dr. David Tirrell, the Ross McCollum - William H. Corcoran Professor of Chemistry and Chemical Engineering. Tirrell is also division chair for the Chemistry and Chemical Engineering Division at Caltech.

Tirrell's research addresses the design and synthesis of novel proteins and protein-like materials for applications in biology, biotechnology and medicine. He and his coworkers use biological cells to make proteins, just as nature does, but the cells are reprogrammed to produce specific materials that are targeted toward important biomedical technologies.

"I am delighted by this award, which will allow us to move our research forward much more rapidly," said Tirrell. "The link to Baxter will also help us connect our programs more directly to important clinical problems."

Said Norbert Riedel, PhD, president of Hyland Immuno's recombinant business, "One of our keys to growth is the collaboration with world-class academic research centers like Caltech. We are pleased to provide this grant to Dr. Tirrell to further his important work in protein design."

Founded in 1891, Caltech has an enrollment of some 2,000 students, and an academic staff of about 275 professorial faculty and 130 research faculty. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 2,100 on campus and 4,800 at JPL. Over the years, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-seven 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 78 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 70 members of the National Academy of Sciences and 48 members of the National Academy of Engineering.

Baxter Healthcare Corporation is the principal U.S. subsidiary of Baxter International Inc. (NYSE:BAX), a global medical products and services company that focuses on critical therapies for people with life-threatening conditions. Baxter's medical products and services include blood therapies, medication delivery and renal therapy, and are used by healthcare providers and their patients in more than 100 countries. The Hyland Immuno business of Baxter Healthcare Corporation develops and produces therapeutic proteins from plasma and through recombinant methods to treat hemophilia, immune deficiencies, and other blood-related disorders. Hyland Immuno's portfolio of therapies includes coagulation factors, immune globulins, albumin, wound management products and vaccines.

Contact: Deborah Williams-Hedges (626) 395-3227 debwms@caltech.edu

Visit the Caltech Media Relations Web site at: http://www.caltech.edu/~media

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