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.

Contact: Robert Tindol (626) 395-3631

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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.

Contact: Robert Tindol (626) 395-3631

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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.

Contact: Robert Tindol (626) 395-3631

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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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Caltech Professor Awarded Wolf Foundation Prize for Insights Into the Life Cycle of Cells

PASADENA, Ca.-For his discovery of a critical protein system that regulates normal cell division and many other biological processes, the California Institute of Technology's Alexander Varshavsky has been named the co-recipient of the 2001 Wolf Foundation Prize in Medicine.

Varshavsky, the Smits Professor of Cell Biology at Caltech, will share the award with Avram Hershko of the Technion-Israel Institute of Technology. The Wolf Prize was established in 1978, and is designed to promote science and art for the benefit of mankind. Specifically, the pair is being honored for the discovery of the "ubiquitin system of intracellular protein degradation and the crucial functions of this system in cellular regulation." The prize includes an honorarium of $100,000 that will be split between the two awardees.

Proteins are biology's blue-collar workers. They are the catalysts that jump-start the various reactions of cellular life, telling cells when it's time to divide, change into other cell types, or die, and monitoring the timing of such events. When its specific job is done, it's often critical that a particular protein should be destroyed and thereby cease functioning.

Ubiquitin is a small protein that attaches itself to other proteins within a cell, marking them for degradation (or destruction) by proteases, still another kind of specialized protein. Ubiquitin is, well, ubiquitous in all organisms other than bacteria; hence its name. Using both mouse cells and baker's yeast as model organisms, Varshavsky proved that ubiquitin is essential for protein degradation in living cells. His laboratory also showed that the ubiquitin system plays major roles in a number of biological processes, including cell growth and division, DNA repair, and responses to stress. Subsequent work by numerous laboratories uncovered many other functions of this remarkable system, including its multiple roles in the functioning of the brain (for example, memory formation), in the development of most organs in the body, and in the regulation of general metabolism.

Conversely, malfunctions of the ubiquitin system often allow the cell's mechanisms to run amok. Therefore, these malfunctions play major roles in many human diseases, including cancer, bacterial and viral infections, and neurodegenerative syndromes like Parkinson's and Alzheimer's diseases. Varshavsky's work on the ubiquitin system was instrumental in making possible the current efforts to devise new classes of drugs to attack such diseases.

Varshavsky is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Academy of Microbiology. His other honors include the 1998 Merit Award from the National Institutes of Health; the 1998 Novartis-Drew Award in Biomedical Science; the 1999 Gairdner International Award from Canada's Gairdner Foundation; the 2000 Sloan Prize from the General Motors Cancer Research Foundation; the 2000 Albert Lasker Award in Basic Medical Research from the Lasker Foundation; and the 2001 Merck Award, from the American Society for Biochemistry and Molecular Biology.

 

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Baxter Awards Caltech Professor $250,000

PASADENA, Calif.— The Hyland Immuno division of Baxter Healthcare Corporation 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 the reasons Baxter is in Southern California is the opportunity to collaborate 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."

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.

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CONTACT: Jill Perry, Media Relations Director (626) 395-3226 jperry@caltech.edu

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Researchers progress toward mutating a mousefor studying Parkinson's disease

Some inventors hope to build a better mousetrap, but California Institute of professor of biology Henry Lester's grand goal is to build a better mouse.

Not that the everyday laboratory mouse is inappropriate for a vast variety of biological and biomedical research. But for Parkinson's disease research, it has become clear that a strain of mutant mice with "slight" alterations would be a benefit in future medical studies. And not only would the mutant mice be useful for Parkinson's, but also for studies of anxiety and nicotine addiction.

Though Lester and his colleagues Johannes Schwarz and Cesar Labarca have not yet produced the mouse they envision, they have already achieved encouraging results by altering the molecules that form the receptors for nicotine in the mouse's brain. If they can just make these receptors overly sensitive in the right amount, they reason, the mice will develop Parkinson's disease after a few months of life.

Two earlier strains of mice were not ideal, but nonetheless convinced the Lester team members they were on the right track. One strain of mice suffered from nerve-cell degeneration too quickly, developing ion channels that opened literally before birth. These overly sensitive receptors essentially short-circuited some nerve cells. These mice usually do not survive birth, and never live long enough to reproduce.

Another strain developed modest nerve-cell degeneration in about a year, which is a long time in a mouse's life as well as a long time for a research project to wait for its test subjects. Lester wants the "Goldilocks mouse," with neurons that die "not before birth—that's too fast. Not at a year—that's too slow and incomplete. With a mouse strain that degenerates in three months, we could generate and test hypotheses several times per year."

Though they haven't achieved the "Goldilocks mouse" yet, the strain of mice developing modest degeneration after a year is particularly interesting. Tests showed that they were quite anxious, but tended to be calmed down by minuscule doses of nicotine. For reasons not entirely understood, humans who smoke are less likely to develop Parkinson's disease later in life, pointing to the likelihood that a mouse with hypersensitive nicotine receptors will be a good model for studying the disease.

In fact, the Lester team originally set out to build the strain of mice in order to study nicotine addiction and certain psychiatric diseases that might involve acetylcholine, a natural brain neurotransmitter that is mimicked by nicotine. The work in the past has been funded by the California Tobacco-Related Disease Research Program, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (NINDS).

Once they had some altered mice, Schwarz (a neurologist who works with many Parkinson's patients) realized that the dopamine-containing nerve cells were dying fastest. The death of these cells is also a cause of Parkinson's disease. Because present mouse models for Parkinson's research are unsatisfactory, the researchers applied for and soon received funding from the National Parkinson Foundation, Inc. (NPF). Not only did the researchers receive the funding from the NPF, but they also were named recipients of the Richard E. Heikkila Research Scholar Award, which is presented for new directions in Parkinson's research.

"The Heikkila award is gratifying recognition for our new attempts to develop research at the intersection of clinical neuroscience and molecular neuroscience here at Caltech," says Lester.

Dr. Yuan Liu, program director at NINDS, says the Lester team's research is important not only because it is the first genetic manipulation of an ion channel that might lead to a mammalian model for Parkinson's disease, but also because the research is a pioneering effort in an emerging field called "channelopathy."

"Channelopathy addresses defects in ion channel function that causes diseases," Liu says. "Dr. Lester is one of the pioneers working in this field.

"We're excited about this development," she says, "because Parkinson's is a disease that affects such a large number of people—500,000 in the US. The research on Parkinson's is one of the research highlights that the NINDS is addressing."

The first results of the Lester team's research are reported in the current issue of the journal Proceedings of the National Academy of Sciences (PNAS).

In addition to Labarca, a member of the professional staff in the Caltech Department of Biology, and Schwarz, a visiting associate, the collaborators include groups led by professors James Boulter of UCLA and Jeanne Wehner of the University of Colorado.

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