Bruce Alberts - US grants

Two of the three major objectives of the research program supported by this grant remain unchanged from the original proposal. The first of these involves the use of a combination of biochemical and genetic approaches to decipher the biological role of histone acetylation in higher eukaryotes. The second objective is to uncover some of the molecular details of the process whereby positional information is imparted to cells during embryogenesis, using as a model system the specification of anterio-posterior position by the "zone of polarizing activity" (ZPA) in the early chick limb bud. A newer objective concerns determining the biological role of mammalian type II DNA topoisomerases, new enzymes recently discovered in this laboratory which we suspect are intimately involved in the initiation of eukaryotic DNA replication.

The T4 bacteriophage DNA polymerase (the product of gene 43), the T4 helixdestabilizing protein (the gene 32-protein), and five other T4- induced proteins (the products of genes 41, 44, 45, 61, and 62) are the fundamental components of the protein complex that moves a replication fork. The 44/62 and 45 proteins are part of the DNA polymerase "holoenzyme" and are termed "polymerase accessory proteins". The gene 41 protein is a DNA helicase that uses GTP hydrolysis energy to move rapidly along the DNA; it forms a moving complex known as the "primosome" with the gene 61 protein, which is the primase that synthesizes the pentaribonucleotide primers that start each Okazaki fragment on the lagging strand of a replication fork. In an in vitro reaction requiring all seven of these purified proteins (plus deoxyribo- and ribonucleoside triphosphates), replication forks move through purified double-stranded DNA templates with near in vivo rates and fidelities. Our experiments have revealed that there is a continuous recycling of the DNA polymerase molecule on the lagging strand at the fork. This recycling is believed to involve a direct connection between the DNA polymerase holoenzyme complexes present on the leading and lagging strands, as well as a close interaction with the DNA helicase. The entire complex works as a unit; for example, RNA primer synthesis appears to be delayed until the lagging strand DNA polymerase molecule in the complex finishes each Okazaki fragment and is released from the DNA. The first major aim in this proposal is to develop a more detailed understanding of the concerted fork movement reaction just described. We believe that the accessory proteins form a sliding clamp with a timed release mechanism, so that the polymerase holoenzyme converts from a non-dissociating form to a rapidly dissociating form after a minimum stall time is exceeded. Mutant accessory proteins will be sought that keep the polymerase holoenzyme bound at all times. The DNA complexes formed by this holoenzyme will be used for DNA footprinting and crystallization studies, with the long-range aim of determining the complete three-dimensional structure of the replication protein complex. The second major aim of this proposal is to identify, purify, and characterize all of the T4 proteins required to reconstruct the process of translesion DNA synthesis in vitro. A temporary, recombination- mediated switch to conservative DNA synthesis on a second DNA template is believed to occur, in a reaction that is likely to require (in addition to replication proteins) the T4 uvsX (recA-like), uvsY, dda and gene 59 proteins thus far characterized in this laboratory, plus at least one missing component.

The University of California, San Francisco Science Institute for Elementary Teachers (UCSF City Science Project) is an integral component of the San Francisco Unified School District's comprehensive plan for K-5 Science Program Improvement. The Project will be responsible for the inservice education of 100 teachers over four years. Through three years of month long education sessions, where the content of elementary science will be presented through sessions modeling excellent hands-on science teaching, these teachers will become the UCSF Science Partners. Working in conjunction with an experienced leader in their school, these newly trained teachers will be responsible for making significant changes in their school's science program. The 100 UCSF Science Partners will exhibit leadership by supporting their fellow classroom teachers as they initiate the city's new hands-on curriculum. In partnership with K-5 Science Support Teachers and the City's Science Specialists, the UCSF Science Partners will be released to provide presentations, demonstrations and/or team-teaching with colleagues during the Site-Institute at their own school. In addition, the 100 UCSF Science Partners will be teamed by grade levels to provide workshops on specific grade level Model Science Units to teachers throughout the system. The cost sharing for the project will be 47%.

It has been 40 years since the discovery of the double helix structure of DNA and it is appropriate for the 58th Cold Spring Harbor Symposium of Quantitative Biology to have as its theme "DNA and Chromosomes. The meeting will be held at Cold Spring Harbor Laboratories from June 2,-June 9, 1993, bringing together approximately 350-450 scientists from around the world. The meeting will bring together many of the leading investigators as well as a significant number of younger scientists in a setting conducive to intense discussion and interactions. %%% The research discussed at this meeting will have an impact on all areas of biology in many different organisms and experimental systems. Understanding the role of chromosome structure on DNA metabolism is at a critical stage and this meeting should help to catalyze further advances.

9355774 Alberts The National Academy of Sciences' National Research Council's "Partnership for Leadership" project will provide support for: o coordination of all NAS/NRC education activities through the Coordinating Council on Eucation; o activities of the Mathematical Sciences Education Board to continue studies and disseminations efforts on implementing the National Council of Teachers of Mathematics standards; o completion of the national science teaching and assessment standards; o reform of undergradiate education through support of the Board of Engineering Education and the Committee on Undergaduate Science Education; and o continued identification of appropriate new directions for NAS/NRC. ***

Two equally critical dimensions of the work of scientists remain absent from undergraduate classrooms: a) how scientists ground their research in the questions, approaches, and context of other discoveries; and b) how scientists communicate within and beyond their community what they themselves are learning from their own explorations. Both of these skill sets can be honed by reading scientific literature. Science, the publication of the American Association for the Advancement of Science, is in a prime position to lead an effort to integrate this approach into the classroom. This award supports the research and development of educational resources capitalizing on recently published papers in Science. Our initiative, called "Science in the Classroom," introduces undergraduates to the scientific process by using contemporary scientific papers, taken from Science and translated into tools for learning by an expert team of scientists and educators, with the goal of exposing students to primary data sets. The project encourages students to assume the persona of the scientist by guiding them through the process of posing questions, designing experiments to answer these questions, analyzing the data resulting from the experiments, and working toward new conclusions in response to the analysis. It also engages students in understanding, first-hand, the process of scientific communication, through which scientists explain their progression from question to experiments to data to conclusions, while also generating the next set of questions for themselves and their peers. This award,will result in a refined and pilot-tested resource, as well as a guide with useful and effective pedagogy.

Since the High School Intern Program (HIP) began in 1989, nearly 250 students from San Francisco's public schools have spent their summers conducting scientific research under the direction of a University of California, San Francisco scientist mentor while simultaneously learning how to maneuver the critical and difficult transition from high school to college. Since 2001, 158 students have participated in HIP; 47% of these students are from underrepresented minority backgrounds (i.e., African American, Hispanic, or American Indian/Alaska Native), 68% are women, and 74% come from families where neither parent has graduated from a two- or four-year college. Through HIP, students become comfortable working in a laboratory environment, begin to conduct experiments independently, learn to present scientific research in oral and written formats, and, critically, begin to see the opportunities available to them should they continue their education. A longitudinal survey of alumni from the 2000-2003 program years found that 76% of the respondents had completed undergraduate degrees in the sciences and 87% were pursuing education beyond a bachelor's degree.

Science education reforms are focusing on active learning strategies that engage students in the process of science. Science (the journal) is offering a unique approach to transforming the undergraduate STEM learning environment, one that introduces undergraduates to important elements of science: reading primary research articles, communicating science, and engaging in a peer review system. Through reading and deconstructing carefully selected scientific papers, students gain an understanding of how scientists design their experiments and present their results, allowing students to actively experience the logic of getting from a set of data to a new conclusion. In addition, in their publications scientists discuss how they have incorporated and confirmed the results of other scientists, as well as where they disagree with prior conclusions. They also mention what steps might be taken next, showing students that there are still many unanswered questions. The PIs are working with a team of expert scientists and educational researchers to develop these resources, with the goal of providing students a deep understanding of how scientists design experiments, gather and analyze data, and present their conclusions. Science is thereby translating scientific papers into tools for learning, essentially helping students assume the persona of the scientist. The goal is to enable students to truly understand the scientific enterprise: science as a powerful "way of knowing" about the world. The PI team is accomplishing this goal through the use of online annotations, detailed explanations of scientific figures and methods, and additional activities allowing students to work with actual scientific data.