Mark Ams, Ph.D.
Associate Professor, Department of Chemistry, Allegheny College
Toward creating alien life: a genetic self-replicating system using chalcogen bonds
Can life be created? At the heart of this proposal is the fundamental question of whether life can exist beyond the confines of DNA – the only blueprint for life that humans know. However, the invention of an alternative to DNA, one that is radically different and not based on biotic chemicals (i.e., exobiotic), would represent a seismic shift of our own understanding of DNA’s uniqueness and origins, as well as open the door for entirely new advances in biotechnology. We propose an alternative architecture to DNA, based on the little-known but highly versatile benzochalcogenadiazole (BCD) building block. Our blueprint is designed to carry out the two basic functions of self-replication and genetic encoding, a combination that is unprecedented in current exobiotic designs. Unlike DNA, our design does not require help from enzymes to operate, and thus is engineered to function in the early stages of its evolutionary development. To achieve our goal, we will demonstrate the “proof of concept” that our BCD template can undergo autocatalytic self-replication. Once achieved, our long-term goal is to create an expanded BCD chemical network that allows for competition and natural selection to take hold. Thus, the “big picture” of this proposal is to stimulate molecular evolution, moving us a step closer to realizing a synthetic cell of alien origins. All experiments will be conducted by undergraduate students under the close mentorship of the primary investigator, directly impacting up to 16 undergraduates and ensuring high-quality training for the next generation of research scientists.
ADDITIONAL GRANTS AWARDED BY THE PITTSBURGH FOUNDATION (2020)
The two grantees below applied to the Integrated-Research and Education Grants program through the Kaufman Foundation and were ranked highly by the Scientific Advisory Board. Due to the availability of additional scientific research funds through The Pittsburgh Foundation and the highly competitive nature of the proposal, these proposals were consequently reviewed by The Pittsburgh Foundation board and approved for funding at the Nov. 18, 2020 Program and Policy Committee meeting.
Lisa A. Fredin, Ph.D.
Assistant Professor, Department of Chemistry (Co-PI), Lehigh University
Elizabeth R. Young, Ph.D.
Assistant Professor, Department of Chemistry (Co-PI), Lehigh University.
A new chemical intuition of excited-state reactivity
In order to build a clean energy economy, new photochemically-driven reactions are important for efficient solar energy capture and conversion. While driving reactions with light is less conventional than the typical heating of a beaker, it provides unique opportunities to initiate and control chemical reactions. For the past 50 years, physical chemists, especially spectroscopists and theorists, have built our so-called “chemical intuition” or understanding of how electron and proton transfer reactions occur primarily in the lowest energy states of molecules. However, when driving reactions with light, molecules necessarily become excited. The complex nature of excited states makes them more difficult to predict and understand, and thus we must develop a new chemical intuition for their reactivity. This integrated research-education grant will establish a program for undergraduates to build chemical intuition of light-initiated electron and proton transfer in model azo dyes by combining spectroscopy and quantum mechanics.
Daniela Fera, Ph.D.
Assistant Professor, Department of Chemistry and Biochemistry (PI), Swarthmore College
Dissecting interactions of protein kinases critical to antibody production
Protein kinases act as molecular on/off switches in cells. Their functions vary from controlling cell growth to controlling immune responses. The proposed research will focus on protein kinases that are critical regulators of B cell activation. B cells are the specialized cells that produce antibodies in the human body to protect against foreign antigens, such as viruses or bacteria. The message of a B cell binding to an antigen gets transmitted into the cell, which triggers kinases to turn on other macromolecules, eventually resulting in the proliferation of B cells and the production of antibodies. A detailed atomic picture of the complete molecular pathway involved in this process is not yet available and would be important for understanding how the development of antibodies is regulated. The proposed research will involve performing a molecular “dissection” at one juncture of the pathway using approaches from structural biology, biochemistry, and molecular biology, to understand important kinase interactions and effects on activity. These studies will provide a proof-of-concept for studying other kinase complexes and help us better understand the fundamental principles of antibody production. Such information has implications in understanding how B cells behave in the face of viruses and other pathogens and could pave the way for learning what causes autoimmune disease, i.e. through the production of antibodies that target host macromolecules. Through this work, research and course students will engage in authentic research experiences, gain skills that will help them in future scientific endeavors, and make important contributions to science.
Roberto Ramos, Ph.D.
Associate Professor, Department of Physics, University of the Sciences
Undergraduates Investigating Quantum Effects In Multi-Gap Superconductivity In Novel Superconductors
The goal of this proposal is to enable undergraduate physics students to investigate the superconducting energy gap structure of quantum materials, particularly the recently- discovered iron-based superconductors and their resulting quantum properties, as measured using high- resolution tunneling spectroscopy at low to very low temperatures. Iron-based superconductors provide a new and natural platform where multi-band superconductivity can be studied. Multiple energy gaps in these samples can be measured, depending on the way the crystal has been grown and how the tunneling directions are accessed through fabrication and the way electrical contacts are made. These energy gaps exhibit anisotropy relative to the crystal lattice, with gaps sensitive to tunneling that is parallel or perpendicular to the c-axis of the lattice. The PI and his all-undergraduate research team have access to crystal samples from some of the world’s leading groups that fabricate high-quality samples of K-doped Ba(1-x)KxFe2As2, Co-doped and P-doped BaFe2As2. Physics majors in his group have developed a method of soft-point-contact spectroscopy that builds on crystals contacted using gold wires and silver paint – making these measurements accessible to undergraduates. By reducing thermal broadening and thermal noise using a cryo-cooler with a base temperature of 2 Kelvin and a wet helium cryostat with a based temperature of 0.3K, an all-undergraduate research team with access to world-class samples will perform some of the highest resolution measurements of the energy gap of these quantum materials. These measurements differ from prior measurements of the group made on conventional BCS superconductors such as MgB2 (magnesium diboride) which has demonstrated multi-gap behavior. Beyond energy gap measurements, the undergraduate team will perform new low-temperature, microwave studies designed to probe the quantum nature of these materials. The method is known as microwave resonant activation which is a way of exploring superconducting Josephson effects in these materials – an area which has not yet been well studied for multi-gap materials. Th is of great interest to the community because it can shed light on the potential of using pnictides for quantum measurements. Furthermore, because of the presence of multiple energy gaps in the material, the team can compare their results with pnictides with prior results using MgB2. In these prior measurements, the PI and collaborating students had performed the first measurements of microwave resonant activation, saw signatures of macroscopic quantum tunneling and escapes from the superconducting state with a quality factor Q comparable to the first qubits.
Because the physics program at USciences is purely undergraduate, this proposal promises to impact in a profound way the research and education of physics majors at the institution by providing undergraduates access to frontier research using world-class samples, training in ultra-low temperature physics and high- vacuum systems, microwave engineering, low-noise conductance measurements, data acquisition and analysis, modeling density of states of multi-gap materials and escapes from the superconducting state, and scientific communication of their results. Students will participate in research conferences to present their research. Undergraduates will be trained and integrated to an all-undergraduate cohort system with a meaningful research and education program. Students will have the chance to travel to collaborator laboratories to take part in fabrication experiences. This program will emphasize several components, including (a) a system of maintaining and updating a daily research notebook; (b) a mentoring system that includes a daily briefing at the beginning and at the end of the day and centered about the research notebook; (c) junior mentorship of younger undergraduates with built-in-accountability; (d) giving regular research seminars and (e) training workshops in scientific communication – in particular, training undergraduates to give compelling elevator talks in both specialist and non-specialist language, crafting effective abstracts and research posters, and acquiring skills in extended research-storytelling. Using these skills, they will help organize an annual mini-research workshop centered on these “best-practices”, and which will be open to STEM undergraduates from both USciences and area colleges, for maximum impact. They will be required to participate in existing research activities organized by USciences’ Center for Undergraduate Research. Finally, the program will be assessed through yearly interviews and mid-year blind surveys.
ADDITIONAL GRANTS AWARDED BY THE PITTSBURGH FOUNDATION (2018)
The two grantees below applied to the Integrated-Research and Education Grants program through the Kaufman foundation and were ranked highly by the Scientific Advisory Board. Due to the availability of additional scientific research funds through The Pittsburgh Foundation and the highly competitive nature of the proposal, this proposal was consequently reviewed by The Pittsburgh Foundation board.
Margaret M.P. Pearce, Ph.D.
Assistant Professor of Biology and Neuroscience, University of the Sciences
Elucidating phagocytic glial responses to protein aggregation in neurons
Phagocytosis is a fundamental cellular process required for survival of many single-celled eukaryotes, and in multicellular organisms, is responsible for clearing extracellular pathogens or debris. Professional phagocytes in the immune system (e.g., macrophages and neutrophils) and the nervous system (e.g., astrocytes and microglia) eliminate invading microorganisms, dead or dying cells, or other harmful particles by first recognizing and migrating toward chemical “eat me” signals, upregulating expression of phagocytic genes, and then engulfing the debris and sending it to the lysosome for degradation. Phagocytic engulfment is initiated by cell surface receptors that trigger cytoskeletal arrangement and internalization of extracellular material within an intracellular vesicle known as a phagosome. Nascent phagosomes mature through a series of fusion events with endosomes and lysosomes, culminating with degradation of the vesicle contents in the lysosome. However, many bacterial and viral pathogens have evolved mechanisms for co-opting the phagolysosomal pathway to gain access to a host cell’s cytoplasm. Likewise, various disease states are characterized by defective phagocytosis, leading to accumulation of noxious debris inside and outside cells. Various pieces of evidence suggest that leakage of phagosomal contents might also occur under physiological conditions. We have recently developed a Drosophila melanogaster (fruit fly) model of neurodegenerative disease that shows that pathogenic protein aggregates within neurons are recognized and engulfed by phagocytic glia. Surprisingly, a portion of these neuronal aggregates escape from the phagolysosomal system and reach the glial cytoplasm. This experimental model provides a powerful tool for identifying new components of the glial phagocytic pathway, for determining which steps that are susceptible to phagosomal leakage, and for assessing changes in glial gene expression profiles when protein aggregates are present in neurons. The studies described here will engage undergraduate students in a candidate-based screen for phagocytic genes and cell type-specific global changes in protein-coding genes using sophisticated tools available in Drosophila. The students will be exposed to classic fly genetic techniques and cutting-edge high resolution imaging and sequencing techniques (RNAseq) to identify new mechanisms that regulate membrane integrity during phagocytosis and glial transcriptional responses to protein aggregation in neurons.
Véronique A. Delesalle, Ph.D.
Professor of Biology Department of Biology, Gettysburg College
What genetic and ecological factors determine the evolutionary path of viral pathogens as they adapt to their bacterial hosts?
The interactions between bacteriophages (phages for short), viruses that “eat” bacteria, and their bacterial hosts are both interesting in their own right and provide model systems to study host- pathogen interactions. Phages are the most numerous entities in the biosphere with an estimated population size of 1031. They have been implicated in the evolution of bacteria, including their acquisition of virulence, the control of bacterial population densities, the structuring of bacterial communities, as well as in biogeochemical cycling. In the face of increasing antibiotic resistance in bacteria, phage therapy has been proposed as an alternative to control bacterial pathogens (as in the enemy of my enemy is my friend). However, while phage-based solutions to control bacteria in food processing settings have reached the commercial stage, regulatory concerns and uncertainties about treatments using live viruses with unknown evolutionary potential complicate extending phage therapy to human medicine (unless you live in parts of the old Soviet Union).
For practical and theoretical reasons, we need a better understanding of how phages adapt to both “known” and novel hosts. Phages vary in the collection of bacterial strains they can infect; some phages are generalists, others are specialists. Building upon current work in our lab, we will address the following questions: Do specialists and generalists differ in their ability to adapt to their hosts? Does it matter whether the host is susceptible to phages (attacked by more phages) or resistant (attacked by fewer phages)? Does it matter if the bacterial host has adapted to the homogeneous conditions of a lab environment or not? Do lab-adapted phages differ in their ability to adapt compared to “wild” phages? Ultimately, we want to gain an understanding of the condition that allows phages to jump to new hosts. Can genetic or ecological factors predict when host jumps are more likely? These questions require multidisciplinary tools to be answered but can be addressed by undergraduates in the context of summer and/or course-based research experiences and are attractive to students with interests ranging from biochemistry, ecology to human health.