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2005 Pioneer Award Recipients Progress Reports,
June 2006
- Vicki L. Chandler, Ph.D.
- Hollis T. Cline, Ph.D.
- Leda Cosmides, Ph.D.
- Titia de Lange, Ph.D.
- Karl Deisseroth, M.D., Ph.D.
- Pehr A.B. Harbury, Ph.D.
- Erich D. Jarvis, Ph.D.
- Thomas A. Rando, M.D., Ph.D.
- Derek J. Smith, Ph.D.
- Giulio Tononi, M.D., Ph.D.
- Clare M. Waterman-Storer, Ph.D.
- Nathan D. Wolfe, D.Sc.
- Junying Yuan, Ph.D.
Vicki L. Chandler, Ph.D.
University of Arizona
Tucson, AZ
Vicki Chandler’s lab studies paramutation, a process in which a gene from one parent communicates a change to the corresponding gene from the other parent. This change is remembered in the progeny, even those that do not inherit the parental copy originally directing the change. The group has demonstrated that communication between genes is mediated by unique tandem repeats (identical or nearly identical adjacent copies of a short DNA sequence) through an RNA-directed mechanism that reduces gene expression but does not involve changes in the gene’s DNA sequence. Parental gene interactions that affect gene function in progeny could contribute to unexpected inheritance patterns that would complicate efforts to identify the genes involved in complex human diseases. The Chandler lab used a bioinformatics approach to look for candidate genes that might be undergoing paramutation in humans and located roughly 2,000 unique tandem repeats within or near these genes. The lab will next examine variation within these repeats and potential changes in the expression of associated genes.
Hollis T. Cline, Ph.D.
Cold Spring Harbor Laboratory
Cold Spring Harbor, NY
Hollis Cline's lab has made progress along two lines toward the goal of understanding the architecture, development, and plasticity of brain circuits. One is generating the constructs and improving the methods for making transgenic Xenopus in which specific proteins can be induced in specific subsets of cells in the brain. The second is testing candidate reagents that may cross synapses.
Leda Cosmides, Ph.D.
University of California
Santa Barbara, CA
Leda Cosmides and her colleague, John Tooby, are using her Pioneer Award to reconceptualize human motivation using an evolutionary and computational approach. Their team has discovered a previously unsuspected class of evolved programs that register and compute levels of socially important variables like the degree of genetic relatedness (kinship), the formidability of antagonists, and welfare trade-off ratios (how much to sacrifice one’s own welfare for that of another). Such information was necessary for adaptively regulating social behavior among the ancestral hunter-gatherers from whom we evolved. The team has made progress in identifying computational variables that regulate anger, altruism, and sexual attraction, and they have shown how some of these are nonconsciously computed. In addition to illuminating risk factors for violence and sexual abuse, the results may have therapeutic implications. Some mental health conditions are certainly disorders of these adaptive computational systems that regulate motivation. But other mental health conditions may not be disorders at all — they may instead represent the proper functioning of a motivational system as it adaptively recomputes and recalibrates the matrix of computational variables that regulate its operations.
Titia de Lange, Ph.D.
The Rockefeller University
New York, NY
Titia de Lange’s lab is developing a new system to study how cells detect and repair damage in their DNA. The DNA damage response is crucial for the integrity of the genome and prevents the development of cancerous cells. The group’s goal is to create a new experimental system that will allow the study of the earliest events in DNA damage signaling and repair at molecularly defined sites of DNA damage.
Karl Deisseroth, M.D., Ph.D.
Stanford University
Stanford, CA
Karl Deisseroth’s group is employing and further developing optical neuroengineering technologies for the noninvasive imaging and control of brain circuits as they operate in real time within living, intact tissue. The lab hopes that using these tools to probe neural circuit dynamics with millisecond temporal resolution will lead to basic neuroscience insights, fundamental new conceptualizations of neurological and psychiatric disorders, and treatment interventions. As a psychiatry department clinician, Deisseroth also employs novel, interventional high-speed (action potential-based) brain stimulation techniques for therapeutic purposes in human patients. A large-scale, systematic effort to map key neural circuit dynamics on the millisecond timescale will enable testing of the hypothesis that impairments in high-speed circuit dynamics are the source of severe psychiatric symptoms such as anxiety and hopelessness.
Pehr A.B. Harbury, Ph.D.
Stanford University School of Medicine
Stanford, CA
Erich D. Jarvis, Ph.D.
Duke University Medical Center
Durham, NC
Erich Jarvis’ goal is to decipher the molecular basis of vocal learning, which is the behavioral substrate for spoken language. Ultimately, he hopes to manipulate brain circuits that control vocal learning to provide greater insight into the mechanisms involved, which could pave the way for repairing vocalization disorders in humans. He uses avian vocal learning species as model systems to test a hypothesis on the genetic machinery underlying vocal learning. His approach involves screening for molecular differences between vocal learning and vocal non-learning species, developing tools that manipulate neural connectivity, and characterizing the neuroanatomical source of brain pathways for vocal learning. Preliminary findings indicate that vocal learning brain pathways may have evolved out of existing pathways that control movement.
Thomas A. Rando, M.D., Ph.D.
Stanford University School of Medicine
Stanford, CA
Thomas Rando and his group focus on the effects of aging on stem cells. Previously, they showed that stem cells in aged animals can be “rejuvenated” by exposure to factors in the blood of young animals. The lab has completed some initial studies to try to identify what it is about the “youthful” environment that enhances stem cell function and what it is about the “aged” environment that suppresses stem cell function. Using different technologies to test individual proteins that are secreted into the blood and that can affect all tissues of the body, Rando and his team have begun to establish which proteins change with age and can affect stem cell function.
Derek J. Smith, Ph.D.
University of Cambridge
Cambridge, England
Erasmus Medical Center
Rotterdam, The Netherlands
Derek Smith and colleagues have been analyzing the immune response to influenza infection and vaccination, developing methods to quantify the selection pressures on the virus, and comparing the evolution of influenza viruses in different species. The team is applying its method of “antigenic cartography” to map evolutionary patterns and evaluate vaccines for the H5N1 strain of avian influenza as well as to studies of the malaria parasite. Smith and colleagues are also building an antigenic cartography software toolkit for free release to the public health, academic, and industrial communities. In addition, they are developing an antigenic database and curation methods for storing, combining, and sharing antigenic data and antigenic maps.
Giulio Tononi, M.D., Ph.D.
University of Wisconsin-Madison Medical School
Madison, WI
Giulio Tononi’s project is focused on a longstanding biological puzzle: the function of sleep. He is testing a comprehensive, novel hypothesis about what sleep is for. This so-called synaptic homeostasis hypothesis accounts for many aspects of sleep and its regulation and has fundamental implications for health and disease. Tononi and colleagues used large-scale computer simulations to construct detailed predictions based on the hypothesis, then tested the predictions in rats and humans. Their results support the hypothesis by showing that predicted changes in oscillating brain patterns occur during sleep and suggesting that a decrease in slow wave activity during sleep is caused by a progressive decrease in synaptic strength.
Clare M. Waterman-Storer, Ph.D.
The Scripps Research Institute
La Jolla, CA
Clare Waterman-Storer’s goal is to understand how subcellular parts work together as systems to contribute to cell physical behaviors, such as the pushing and pulling forces critical to the cell shape changes and motions underlying the immune response, wound repair, and development. Waterman-Storer’s group has begun to develop technology to correlate the dynamics of multiple subcellular parts with physical cell outputs during dynamic cell behaviors. The approach combines multicolor, high-resolution light microscopy of living cells with optical trapping, magnetic trapping, and traction force microscopy.
Nathan D. Wolfe, D.Sc.
Johns Hopkins University
Bloomberg School of Public Health
Baltimore, MD
Nathan Wolfe is establishing the first global network to monitor the transmission of viruses including Ebola, SARS, AIDS, Nipah, and monkeypox from animals into human populations. By creating surveillance systems among people who are highly exposed to wildlife, such as subsistence hunters in Africa and wet market workers in Asia, Wolfe and his colleagues are discovering previously unknown viral threats to humanity and identifying the factors that influence how new viruses emerge. Through this research, the group works to identify ways to control potentially catastrophic pathogens before they develop into pandemics.
Junying Yuan, Ph.D.
Harvard Medical School
Boston, MA
Junying Yuan’s lab seeks to understand the mechanisms by which the accumulation of mutant proteins lead to the onset of neurodegeneration in human diseases such as Huntington’s disease and Alzheimer’s disease. The group has developed a high-throughput screen for identifying small molecule compounds that selectively reduce the accumulation of cytotoxic proteins. Using the screen, the lab identified 239 primary hits that it will subject to a series of secondary tests to identify compounds that can enhance the removal of toxic proteins with minimal side effects. Such compounds may be promising new drug leads for the prevention and treatment of neurodegenerative diseases.
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