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Undergraduate Summer Research InternshipsThe Systems Biology community at Harvard invites interested undergraduates who will not have graduated by June 2008 to apply for research internships in the summer of 2008. Starting on Monday June 16 the internship will last for ten weeks, or longer by mutual agreement. Interns will work on research projects in the labs of the Bauer Fellows and Systems Biology faculty whose work spans many fields of science, from biology (including genetics, cell biology, neuroscience, animal behavior and evolution) to applied mathematics and computation. Each intern will have the opportunity to learn a range of cutting-edge genomics or bioinformatics techniques in the exciting, dynamic environment at the FAS Center for Systems Biology and the Department for Systems Biology at Harvard Medical School. The internships will be offered to Harvard students and students from other universities. We will help students, particularly non-Harvard students, to find housing near the Cambridge campus.Harvard students are encouraged to apply for PRISE and HCRP fellowships. The salary for a ten-week internship will be $4500. Underrepresented minority students are particularly encouraged to apply. Unfortunately we cannot consider international students unless they are enrolled at US universities and have valid student or work visas. Internship research projects are listed below. A few additional projects may be added by Jan 14. in your application, please specify for which project(s) you are applying and why you are particularly interested in that project. You can apply for several projects. After submitting your application form please send or deliver your resumé, transcript (unofficial is OK), and two recommendation letters (sealed or sent separately by recommender), to Caitlin O'Leary, FAS Center for Systems Biology, Harvard University, Bauer Laboratory, 7 Divinity Avenue, Cambridge MA 02138. If you want you can print out the application form, before you hit the submit button, and attach it to the other documents. You can also send the complete application by email with documents attached as Pdf files to coleary@cgr.harvard.edu with the recommendation letters sent separately by your referees. The deadline for applications to be delivered to Caitlin O'Leary is Sunday February 10, 2008. Intern Experiences in past years Projects 1 and 2, Kevin Verstrepen Project 3,
Kevin Foster Project 4, Kobi Benenson 5.Examining patterns of candidate gene expression during wing pattern development 6.Examining patterns of DNA sequence variation in wing patterning candidate genes 7. Breaking through the mucus barrier
8.A yeast model for amyotrophic lateral sclerosis 9.Origin of life: RNA vs. DNA 10.Origin of life: the survival of replicators 11. Phage therapy: evolving the host specificity of viruses. Projects 12-16, Suckjoon Jun 14. What is the force of growth of bacteria? And for "gliding" bacteria? 15.Kinetics of “hibernation and waking up” of bacteria – will they “communicate”? 16. How does a small molecule detect and solve a global, topology problem of the cell? 17.Optimality of the temporal gene expression response to antibiotic treatment 18.Rationalizing antibiotic interactions using a theoretical model of the bacterial cell 19. Sex or Stress in Yeast
Project 21, Ron Milo and Mike Springer 21. BioNumbers - the database of useful biological numbers Kevin
Verstrepen Tandem repeats, also known as satellite regions, often make up more than 50% of a genome. Repeats have long been considered to be uninteresting, non-functional, ‘junk’ DNA. However, it is hard to believe that Mother Nature would foster such a wasteful system, where half of a genome does not have any function. Project 2. A “green beard gene” turns microbes into multicellular organisms? The classic perception of microbes as individual cells is based on the routine practice of growing pure cultures of domesticated microorganisms in rich medium and under constant shaking. However, in the “real world”, microbes tend to aggregate and form multicellular communities that may be critical for survival and proliferation in adverse conditions. We have re-introduced cellular aggregation into a laboratory strain of the brewer’s yeast Saccharomyces cerevisiae by activating one particular gene, FLO1, that became silent during the domestication of this laboratory workhorse. Induction of FLO1 makes cells stick to each other, resulting in clumps or “flocs” consisting of thousands of yeast cells. We have shown that cells embedded within flocs are protected from multiple stresses, including antimicrobials, oxidative stress and ethanol. Hence, by forming a multicellular social community (a “floc”), the yeast cells experience a mutual benefit. However, this benefit does not come without a cost, because the cells need to express FLO1 at high levels, which requires a relatively high energy input, making the cells grow slower than cells that do not express the gene. This brings up a central question in social biology: how can cooperative traits such as flocculation develop? Simply put, the conundrum boils down to two related problems: If one cell first develops a social trait, it will not find any other cell that also invests in the system. Second, even when most cells in a population show the social phenotype and invests into the community, the community is still very vulnerable for so-called “cheaters”, i.e. cells that do not invest in the system, but manage to profit from the investment of the other cells. Since these cheaters will experience the benefits without the costs of the cooperation, they will be able to outgrow the non-cheaters, ultimately resulting in the loss of cooperation. Evolution theory predicts that some genes (called “green beard genes”) involved in cooperation might therefore have a built-in mechanism to protect the community from cheaters by only directing the social benefit to non-cheaters. However, there currently are only two somewhat spurious examples of green beard genes. In this project, we will investigate if FLO1 is indeed a bona fide example of such an elusive green beard gene. So far, the preliminary results look promising… Ideal candidates for both projects will have a sound knowledge of basic genetics and biology, and will have some relevant lab experience.
Project 3. Social evolution and cheating in
microbes
Applicants will benefit from knowledge of microbiology, microscopy and an interest in evolutionary questions.
Project 4. Biological Computers in Human Cells We are looking for exceptional candidates with laboratory experience in mammalian cell culture and genetic engineering to build biological computers inside live human and mouse cells. We will use them to integrate and process multiple endogenous signals and make decisions about the state of a cell, for example if a cell is cancerous or not. Basic knowledge of computer science and simulation/modeling tools such as Matlab is an advantage.
Warning coloration and mimicry serve as classic examples of adaptive morphological evolution. Research in our lab focuses on understanding the evolution and genetics of wing color patterns in the butterfly genus Heliconius, a group of distasteful, warningly-colored and mimetic butterflies from the New World tropics. As part of this work we are hunting down the genomic locations of the genes that control the bold wing patterns Heliconius butterflies use to warn predators of their distastefulness. The goals of this research are to characterize the molecular identities of these color patterning genes, identify the DNA sequence variation responsible for wing pattern variation, and elucidate the developmental mechanisms by which this nucleotide variation influences wing pattern phenotype. As part of this research we are seeking undergraduate interns to participate in projects aimed at exploring the genetic basis of color patterning in Heliconius butterflies.
Project 6. Examining patterns of DNA sequence variation in wing patterning candidate genes Project 7. Breaking through the mucus barrier
Mucus is an important biogel that has critical roles in preserving our health. It lines many epithelial surfaces in our bodies and forms a barrier, which shields us from infectious agents and toxins. Unfortunately, the mucus barrier is not perfect - certain viruses break through and cause damage ranging from a mild flu to serious cancer formation. The aim of this project is to understand how viruses break through the mucus barrier. We will use a combination of biochemistry, live microscopy and modeling to address this question. This project will shed light on functional principles of biological barriers, but it is also potentially important for medicine, since it may lead to new approaches for preventing prevalent infectious diseases. We are interested in how protein misfolding disrupts proper cellular function. In humans, misfolding of the protein superoxide dismutase 1 (SOD1) is associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS); a mouse model of the disease also involves SOD1 misfolding. Although the disease is well-studied and has a complicated etiology, we believe that some of the basic cellular changes involved should appear in any eukaryotic cell. For example, protein misfolding exposes buried hydrophobic residues which stick to cell membranes and can open channels in them, disrupting ionic balances and causing cell death. Using the yeast S. cerevisiae, in which human SOD1 can be efficiently expressed, you will determine how wild-type SOD1 and various destabilized mutants associated with ALS interact with the cell membrane. You will use osmotic shock and staining techniques, coupled with direct visualization by microscopy as well as growth assays, to probe the relationship between the cellular burden of misfolded protein and membrane integrity. We study evolution at a molecular level using simple, stripped-down systems. Our goal is to understand how chemical changes in biomolecules translate into functional changes. Let’s do something medically useful with directed evolution in simple systems. Bacteriophages are viruses that attack bacteria. Given the looming crisis of bacteria that are resistant to the antibiotics of ‘last resort’, can we evolve phages to infect these pathogens? The intern will evolve a small viral genome to infect different bacterial host species. This project requires a background in molecular biology. Our lab is interested in understanding fundamental processes in biological systems. Our approach is not restricted to any specific disciplines; we employ a wide range of theoretical and experimental tools to answer significant questions at the interface of physics and biology. Two main themes of our research revolve around bacteria, especially chromosomes (organization/dynamics/segregation) and “bacteria as individuals.” For this, (1) we have developed a micro-piston system to study physical properties of chromosomes in an artificial cell environment. This work was motivated by our wish to understand the extent to which the general, fundamental behavior and functioning of chromosomes is governed by their physical and mechanical properties, and (2) we have also constructed a micro chemostat system to link the individuality of bacteria and their behavior as population. We have a number of projects available for undergraduate students, which can lead to a publication. The projects listed below are designed for students to learn and use a variety of biophysical techniques including, but not limited to: molecular tweezers, single molecule microscopy, microfluidic device fabrication and soft lithography, electrophoresis, and molecular dynamics simulations. Undergraduate students from either the physical and biological sciences are encouraged to apply.
Project 13. Hydrodynamic trapping of bacteria & Do E.coli love funnels? Also, we have designed chips with funneled walls. We are wondering whether the bacteria will move from one place another faster because of the funnels, and we (you!) will watch and quantitatively characterize their motion at individual level in the chips. One particular type of chip is a loop with funnel walls in which the bacteria should go around in one direction.
(a) E.coli keeps growing (elongating) as long as they are given nutrients at the right temperature. But how strong is this force of growth? When they face a counter-force against their growth, what will bacteria do? (b) Mycoplasma mobile is one of the simplest living organisms on earth. It forms membrane projections at the one cell end, attaches to the host cell or glass, and begins to glide! The gliding is performed with special leg-like protein machineries. They grab the material, pull and release it. But how strong is this force of gliding? What is the effect of the difference of grabbing materials? When they face a counter-force against their gliding such as water flow (M. mobile has reotaxis), what will they do? While the very first step of either of these projects is typical of single-molecule force measurement, there is a deeper motivation in the context of evolution to understand how bacteria will respond (if any) when they are in a situation where they cannot do what they are normally supposed to do. Project 15. Kinetics of “hibernation and waking up” of bacteria – will they “communicate”? Project16. How does a small molecule detect and solve a global, topology problem of the cell? Note. While our lab is always open and happy to discuss, in case you intent to use some of our original ideas, please do contact us first.
Antibiotics are of crucial importance in the treatment of bacterial infections. In order to improve the efficiency of antibiotic treatment and to develop strategies for avoiding the emergence of resistance, it is important to understand how the bacterial cell reacts to antibiotics. Modern experimental techniques now allow us a detailed system-level picture of the way bacteria regulate the expression of their genes in response to antibiotic treatment. In this project, you will investigate the temporal patterns of gene expression changes in Escherichia coli upon exposure to different antibiotics. Of particular interest are certain antibiotics for which the culture growth rate continuously decreases over a period of several hours before settling to a new steady state of slow exponential growth. You will use a state-of-the-art robotic system and a recently developed library of bacteria engineered to report for regulation of gene expression by level of the Green Fluorescence Protein (GFP) to quantitatively measure the expression of E. Coli genes. This will be done at very high time resolution. The acquired data will reveal the temporal order of gene regulation in the genetic program initiated by different antibiotics. A key question is whether this order can be rationalized using optimality considerations. During the project, you will gain experience with modern high throughput methods including robotics, flow cytometry, and possibly microscopy and quantitative image analysis. Previous knowledge of basic lab techniques, basic microbiology, a programming language, or some knowledge of nonlinear dynamics would be beneficial but is not a requirement. Project 18. Rationalizing antibiotic interactions using a theoretical model of the bacterial cell Multi-component drug therapies are crucial in the treatment of various illnesses and conditions like HIV and tuberculosis. Drugs, such as antibiotics, can interact to increase (synergize) or decrease (antagonize) their individual effects. Despite their importance, drug interactions are often hard to understand and predict. Different antibiotics target different key essential components in the bacterial cell: transcription, translation, DNA synthesis, cell wall biosynthesis, as well as critical metabolic pathways. We refer to the inhibited pathway in the cell as the Mode of Action (MOA) of the antibiotic. We have recently shown that in many cases, antibiotics with a MOA interact with all antibiotics of a different MOA in the same way. Further, there is evidence that antibiotics cause physiological changes in the cell that depend strongly on the MOA. For example, the relative abundance of DNA, RNA, or proteins in the cell may change upon antibiotic treatment. The reasons for this are not understood quantitatively. In this project, you will develop an effective theoretical description of key cell constituents like DNA, RNA, ribosomes, proteins, and ATP (energy) the synthesis and degradation of which is interdependent. In this framework, you will then investigate the effects of different antibiotics and characterize the types of dynamical behavior (like multi-stability, bifurcations) that this system is capable of. Using optimality criteria, you will further address if the effects of antibiotics with different MOA and their combinations can be understood from this theoretical framework.
Project 19. Sex or stress in yeast? The pathways that allow yeast cells to have sex or activate stress response genes have evolved to share many components at the molecular level. However, these responses are thought to be mutually exclusive and the influence of stress on sex is poorly understood. Using traditional genetic approaches, live-cell microscopy, and analysis of mating behavior in the model system budding yeast, we will explore the evolutionary rationale of the signaling pathways that regulate both the response to mating and stress cues. Andrew Murray Project 20. Self-Organization and Non-Equilibrium Fluctuations in Metaphase Spindles: Quantitative Experiments, Analysis, and Theory Project 21. BioNumbers – the database of useful biological numbers Systems biology is aiming to deepen our quantitative understanding of biology but the ability to find concrete values in molecular biology is very limited. BioNumbers is an exciting community effort that aims to create a repository of useful biological numbers from the literature and make it easily accessible and informative. We are looking for students with at least a year or two of college biology courses. Computer science and physics background will be useful but not mandatory.
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