DanStem plans to recruit outstanding scientists for independent research group leader positions at the senior and junior levels in the near future.
We are seeking potential candidates with an impressive track record and a compelling vision for independent research in the broad area of stem cell and developmental biology. DanStem’s current mission is to achieve a quantitative understanding of cell behavior during development, homeostasis and disease, and we particularly encourage letter of interests from scientists who have quantitative or computational facets to their future plans.
The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) addresses fundamental research questions in stem cell and developmental biology and has activities focused on the translation of promising basic research results into new therapeutic strategies for cancer and chronic diseases. While opportunities exist for translation, the primary criteria for membership in DanStem is excellence in fundamental basic research. DanStem is a vibrant, internationally diverse and ambitious research center with state-of-the-art facilities located at the Faculty of Health and Medical Sciences, University of Copenhagen. The setting is ideally suited for seamless collaboration and exchange with other centers and departments of the Faculty and Copenhagen science community. Learn more about DanStem at https://danstem.ku.dk/.
As a group leader, you will initiate a new independent research program within the field of stem cell and developmental biology. DanStem provides a generous support package for the group leader, which includes salary of the group leader, support to other personnel, consumables and modern laboratory and office facilities. The group leader is expected to complement this budget through other national or international grants and/or industrial collaborations. In addition, the group leader is expected to engage in multidisciplinary research collaborations with other DanStem research groups other research groups within the Copenhagen area.
Your background includes a PhD or equivalent degree, postdoctoral training and an experience-appropriate track-record of publications in top journals. International mobility, such as training in high-quality institutions and universities globally will be valued.
We offer
A generous package, including salary, support to other personnel, consumables.
Access to cutting edge technologies through shared-resource platforms and staffed expertise in flow cytometry, genomics, imaging, stem cell culture and data analytics.
A vibrant scientific community, with strong internal synergy, situated for easy collaboration and exchange with other centers and departments at the University of Copenhagen and the greater Danish scientific and clinical communities.
Opportunities for the development of basic research discoveries into translational research
Affiliation to the Copenhagen Bioscience PhD Program for international PhD student recruitment and training
Support from management and DanStem fora with regard to career path and development.
A local Administration and Research Support unit to support with economy, HR, Research and Innovation.
Inquiries are welcome to Henrik Semb (semb@sund.ku.dk).
Letter of interest
Letters of interest should include a cover letter summarizing the applicant’s career, past research accomplishments (max 1 page) and future plans (max 5 pages), a CV and a list of publications (with up to five of the most significant publications indicated), and names of three references.
The University of Copenhagen International Staff Mobility Office offers assistance and guidance with regard to relocation, e.g., housing, spouse program, pension, taxes, etc. For more information, visit the ISM website: https://ism.ku.dk/.
DanStem highly values diversity and encourages people of all backgrounds to submit letter of interest, in English to GL-2019@sund.ku.dk.
The closing date for letters of interest is August 1, 2019
Founded in 1479, the University of Copenhagen is the oldest university in Denmark. It is among the largest universities in Scandinavia and is one of the highest ranking in Europe. The University´s six faculties include Health Sciences, Humanities, Law, Science, Social Sciences and Theology.www.ku.dk
A postdoctoral position is available in the Bush lab bush.ucsf.edu at the University of California, San Francisco to study the cellular basis of morphogenesis using live imaging, mouse genetic, and iPSC and ESC approaches. Our dynamic team focuses on understanding basic mechanisms of signaling control of morphogenesis particularly as related to human structural birth defects. The position is in the collaborative UCSF Department of Cell and Tissue Biology and Program in Craniofacial Biology, located at the UCSF Parnassus Heights campus, in the center of San Francisco. UCSF offers an outstanding developmental biology community, access to cutting edge technologies and a supportive working environment. Candidates with a Ph.D. degree in a biological science and research experience in molecular biology, genetics, biochemistry, or live cell or live embryo imaging should submit a C.V. and names of at least 2 references via email to: jeffrey.bush@ucsf.edu
The Sun lab at Yale University is currently seeking a postdoctoral candidate. We study the function of the cilium in vertebrate development and diseases, with a particular focus on polycystic kidney disease and primary ciliary dyskinesia. More detailed information about lab research can be found at https://medicine.yale.edu/genetics/people/zhaoxia_sun-2.profile.
We use multidisciplinary approaches ranging from genetics to live imaging in our research. A solid foundation in molecular biology and/or development is a prerequisite. Although the candidate is expected to work with both zebrafish and mouse models, experience in both is not required. In addition to technical proficiency, the ability to drive an independent project and collaborate with scientists within and outside of our group is essential. The successful candidate is also expected to participate multiple joint group meetings by presenting and offering feed backs.
Interested? Please send a cover letter, CV and names and contact information of three references to professor Zhaoxia Sun (Zhaoxia.Sun@Yale.edu)
The University of Texas Southwestern Medical Center, Department of Urology invites applications for an Instructor (without track, non-tenured) faculty position. Position entails research in genetics and development of the lower urinary tract in normal development and congenital disease.
Experience and Education:
M.D./Ph.D. or Ph.D. in Molecular Biology, Genetics, Biochemistry, Developmental Biology or equivalent field in basic science required. Two to five years of postdoctoral training; minimum two publications from Grad School; one every two years during Postdoc. Appointment rank will be commensurate with academic accomplishments and experience.
Job Duties:
Plans, organizes, coordinates, directs, and personally participates in assigned scientific or medical research projects, including development and implementation of research protocols. Selects or assists in selection of key research personnel. Determines specific goals or objectives to be attained; assigns, and reviews work of subordinates. Plans experimental protocols.
Reviews and analyzes resulting research data. Revises techniques or approaches to work problems as indicated necessary by research data.
Compiles, writes, and submits research results to principal investigator. Prepares or assists in preparation of research papers, reports, and abstracts for publication as one of co-authors.
Designs, develops, or adapts equipment used in experiments or research to obtain desired results.
Plans and supervises training of technicians and other laboratory personnel with respect to proper laboratory techniques, use of laboratory equipment, and safety procedures.
Participation in preparation of manuscripts and research funding applications will be required, as well as participation in lab group activities as appropriate.
Confers with industrial, governmental or other groups concerning progress or results of research project.
Performs other duties as assigned.
UT Southwestern Medical Center is an Affirmative Action/Equal Opportunity Employer. Women, minorities, veterans and individuals with disabilities are encouraged to apply.
This summer, Development will be publishing a special issue showcasing the best research in stem cell and developmental biology, building on the rapidly evolving tools of single cell analysis. Some papers in the issue have already been published as part of our continuous publication system (see the latest articles here), while other research articles and front section content are still in production.
A special issue deserves a special cover, and that’s why we are running a cover competition. We are looking for beautiful images that capture the theme of development at the single cell level – be they immunofluorescence, computational visualisations or artwork. You don’t have to be an author of a paper in the issue to submit.
The competition deadline is May 06, and the images will be judged by Allon Klein and Barbara Treutlein, guest editors of the issue. To enter, simply send your images via email to aidan.maartens@biologists.com with the subject ‘Cover competition’. The winner will be announced in when the issue is finalised, and will get a complimentary print copy of the special issue.
The Faculty of Science and the Mathematical Institute invites applications for a
four-year
PhD Student on Mathematical Modeling of Cell-ECM Interactions During Angiogenesis (1.0 fte) Project description
The opening is for a research position, within the field of mathematical or theoretical biology, computational physics, applied mathematics or computational science.
The outgrowth of new blood vessels from pre-existing vessels, called angiogenesis, is a crucial step in wound healing and tumor growth. Cell-based simulation models help to analyze how cells assemble into blood vessels and other tissue structures. Recently our group has developed novel techniques for modeling one of the key controlling factors of angiogenesis, the extracellular matrix (ECM). The ECM is a diverse class of jelly or hard materials providing structural support to the tissue and that acts as a medium for cell-cell communication.
The work will be embedded in the Multiscale Mathematical Biology team at the Mathematical Institute and the Institute of Biology Leiden. The team carries out mathematical biology research in close collaboration with experimental researchers. The team focuses on modelling pattern formation and morphogenesis in multicellular organisms and bacterial ecosystems. More information about the group can be found on biomodel.project.cwi.nl.
Key responsibilities
The project will be part of an NWO-funded Vici-project that will unravel how the extracellular matrix (ECM) coordinates the interactions between endothelial cells and other cells contributing to angiogenesis, and how modifications of the ECM, as they can occur for example near tumors, can modify the structure of new blood vessel networks. In this project you will work closely together with experimental researchers, that will test the mathematical models in the wetlab by imaging of cell cultures and zebrafish experiments. Your task will be to develop novel mathematical models, which will be informed by literature data and the insights coming from the wetlab. Your models will be experimentally validated by your direct colleagues in the wetlab, based on which you will correct and update your models. Based on cycles of iterative model refinement and experimental validation, you will unravel aspects of angiogenic sprouting, and prepare your insights for publication in the biological, biophysical, and/or biomathematical literature.
The mathematical models will be based on hybrid cellular Potts model, in which stochastic models of cell motility interact with continuum and discrete models of the ECM. You will contribute to the development of novel and efficient numerical methods for simulating the biomechanics of the ECM, that will interface naturally with pre-existing, stochastic models of endothelial cell behavior. You will integrate the novel methodology into our lab’s modeling framework Tissue Simulation Toolkit, and prepare the new developments for public release alongside our scientific publications.
Selection criteria
Master’s degree in applied mathematics, computational/theoretical physics, theoretical biology, computer science or a related discipline;
Excellent written and oral proficiency in English;
Ability to work independently in a multidisciplinary environment;
Fluent interdisciplinary communication skills with scientists in cell biology and mathematics;
Research at our faculty
The Faculty of Science is a world-class faculty where staff and students work together in a dynamic international environment. It is a faculty where personal and academic development are top priorities. Our people are driven by curiosity to expand fundamental knowledge and to look beyond the borders of their own discipline; their aim is to benefit science, and to make a contribution to addressing the major societal challenges of the future.
The research carried out at the Faculty of Science is very diverse, ranging from mathematics, information science, astronomy, physics, chemistry and bio-pharmaceutical sciences to biology and environmental sciences. The research activities are organized in eight institutes. These institutes offer eight bachelor’s and twelve master’s programmes. The faculty has grown strongly in recent years and now has more than 2,200 staff and almost 4,200 students. We are located at the heart of Leiden’s Bio Science Park, one of Europe’s biggest science parks, where university and business life come together. For more information, see http://www.science.leidenuniv.nl.
The Mathematical Institute (MI) is responsible for the research and education in mathematics and statistics at Leiden University. The institute has a strong international orientation. Its mission is to perform high quality research at the frontiers of mathematical knowledge, and to educate future generations of mathematicians and statisticians in a friendly but challenging environment. For more information see https://www.universiteitleiden.nl/en/science/mathematics.
The Institute of Biology Leiden (IBL) is an internationally oriented institute for research and education in biology. IBL performs top quality innovative fundamental and strategic research that will lead to scientific progress, contribute to solutions for societal challenges, and generate industrial opportunities, reflected in the general theme ‘Healthy Lives in a Changing World’. The Institute is organized in three multidisciplinary clusters: Animal Sciences & Health, Plant Sciences & Natural Products and Microbial Biotechnology & Health. For more information see: https://www.universiteitleiden.nl/en/science/biology. There is a large research community in The Netherlands (in particular, in Leiden), including many PhD students. There is close collaborating nationwide.
Terms and conditions
We offer a full-time position for initially one year. After a positive evaluation of the progress of the thesis, personal capabilities and compatibility the appointment will be extended by a further three years. Salary range from € 2,325.- to € 2,972.- gross per month (pay scale P, in accordance with the Collective Labour Agreement for Dutch Universities).
Leiden University offers an attractive benefits package with additional holiday (8%) and end-of-year bonuses(8.3 %), training and career development and sabbatical leave. Our individual choices model gives you some freedom to assemble your own set of terms and conditions. Candidates from outside the Netherlands may be eligible for a substantial tax break. Additional budget allows for research visits abroad and attendance of international conferences. More at http://www.workingat.leiden.edu/.
All our PhD students are embedded in the Leiden University Graduate School of Science www.graduateschools.leidenuniv.nl. Our graduate school offers several PhD training courses at three levels: professional courses, skills training and personal effectiveness. In addition, advanced courses to deepen scientific knowledge are offered by the research school.
Diversity
Leiden University is strongly committed to diversity within its community and especially welcomes applications from members of underrepresented groups.
Information
Enquiries about the position can be made to Prof. dr. Roeland Merks, merksrmh (on server:) math.leidenuniv.nl. Also see the group website at http://biomodel.project.cwi.nl.
Applications
To apply for this vacancy, please send an email to merksrmh (on server: ) math.leidenuniv.nl. Please ensure that you join to your application the vacancy number and the following additional documents:
• A letter of motivation
• An updated CV
• The letters of recommendation by 1 or 2 former supervisors
• The transcripts of your MSc studies
• Examples of previously written code
Only applications received before April 15th, 2019 will be considered.
The Faculty of Science and Institute of Biology are looking for a
Senior Research Technician in Cell and Developmental Biology and Imaging
Key responsibilities
The opening is for a research technician position within the field of cell and developmental biology and imaging. The position is in an interdisciplinary team of mathematical and experimental biologists. Our team specializes in the mathematical and computational modeling of angiogenesis. We are currently setting up an experimental research line, which will directly test the mathematical models in the lab. Discrepancies between the lab observations and the mathematical models identify the gaps in our understanding, based on which the mathematical models will be updated or rejected. Our team focuses in particular on the coordination of collective endothelial cell behavior by the extracellular matrix (ECM). We will use cell cultures, followed by in vivo studies in the zebrafish.
As senior technician you will actively participate in the interdisciplinary research of our group. You will be responsible for setting up and running experimental work to test our mathematical models in collaboration with an experimental PhD student and with a number of PhD students in mathematical modeling.
Your key tasks include:
Setting up and maintaining experimental systems such as cell cultures, lab-on-a-chip, zebrafish, in vitro and in vivo imaging using time-lapse microscopy, quantitative reflection microscopy, TIRF, and 4D imaging using a VAST system;
Fluorescent imaging of dynamic cell behavior, cell morphology and ECM characteristics in vitro and in vivo under the influence of a range of pharmacological and genetic experimental interventions, including ECM characteristics such as stiffness, matrix orientation and acidity using imaging techniques, which will lead to insight in conjunction with the model;
Active participation in image analysis and digital annotation of the results;
Practical assistance of the PhD student, including teaching of experimental skills;
Active participation in the research projects, including interpretation and reporting.
Selection criteria
Master’s or Bachelor’s degree in cell biology, biophysics, imaging or a related discipline, with minimally 2 years of relevant work experience. Applications from postdocs will also be considered;
Outstanding experimental skills in cell and developmental biology and imaging;
Keen interest or experience with image analysis and/or mathematical modeling approaches;
Fluent interdisciplinary communication skills with scientists in cell biology and mathematics;
Excellent written and oral proficiency in English;
Ability and enthusiasm for working in a multidisciplinary environment;
You are a team player, but also able to work independently;
You take initiative and have a strong interest in academic research.
Research at our Faculty
The Faculty of Science is a world-class faculty where staff and students work together in a dynamic international environment. It is a faculty where personal and academic development are top priorities. Our people are driven by curiosity to expand fundamental knowledge and to look beyond the borders of their own discipline; their aim is to benefit science, and to make a contribution to addressing the major societal challenges of the future.
The research carried out at the Faculty is very diverse, ranging from mathematics, information science, astronomy, physics, chemistry and bio-pharmaceutical sciences to biology and environmental sciences. The research activities are organised in eight institutes. These institutes offer eight bachelor’s and twelve master’s programmes. The faculty has grown strongly in recent years and now has more than 1,300 staff and almost 4,000 students. We are located at the heart of Leiden’s Bio Science Park, one of Europe’s biggest science parks, where university and business life come together.
The Institute of Biology (IBL) is positioned in the Faculty of Sciences. The core business of IBL is to perform top quality innovative fundamental and strategic research that will lead to scientific progress, contribute to solutions for societal challenges, and generate industrial opportunities. The Institute is organised in three multidisciplinary clusters: Animal Sciences & Health, Plant Sciences & Natural Products and Microbial Biotechnology & Health. Presently, over 120 fte (including postdocs and PhDs) are employed at IBL.
The Mathematical Institute (MI) is responsible for the research and education in mathematics and statistics at Leiden University. The institute has a strong international orientation. Its mission is to perform high quality research at the frontiers of mathematical knowledge, and to educate future generations of mathematicians and statisticians in a friendly but challenging environment.
Terms and conditions
We offer a one year term position with the possibility of renewal based on need, funding and performance. The salary range is from €2.835 to €3.895 gross per month (pay scale 9 in accordance with the Collective Labour Agreement for Dutch Universities).
Leiden University offers an attractive benefits package with additional holiday (8%) and end-of-year bonuses (8.3 %), training and career development and sabbatical leave. Our individual choices model gives you some freedom to assemble your own set of terms and conditions. For international spouses we have set up a dual career programme. Candidates from outside the Netherlands may be eligible for a substantial tax break. More at: https://www.universiteitleiden.nl/en/working-at/job-application-procedure-and-employment-conditions.
Diversity
Leiden University is strongly committed to diversity within its community and especially welcomes applications from members of underrepresented groups.
Enquiries can be made to Prof. dr. Roeland Merks, telephone 071-5277106, email r.m.h.merks (on server) biology.leidenuniv.nl. More information about the research group is at http://biomodel.project.cwi.nl.
Applications
To apply for this vacancy, please send an email to sylvius (on server) biology.leidenuniv.nl with a motivation letter, cv and the names and phone numbers of two referees, no later than April 26. Interviews will take place in week 19. You are kindly requested to be available during this time
The Giraldez laboratory at Yale University is seeking to recruit a highly qualified Associate Research Scientist as a long-term scientist in the laboratory (www.giraldezlab.org). Prerequisites for appointment on the research scientist track include a doctoral degree and relevant postdoctoral experience.
The successful candidate will bea highly-motived scientist with excellent organizational, mentoring and leadership skills. They will be responsible for coordinating the overall scientific operations of the Giraldez lab and will provide critical training and mentoring to individual lab members. In addition, the successful candidate will have the opportunity to participate in multiple research projects and drive a scientific project aligned with the major interests of the laboratory. The successful candidate will have the following attributes:
• A doctoral degree and relevant postdoctoral experience
• Excellent interpersonal and communication skills
• Excellent organizational skills and attention to detail
• Solid publication record and the ability to drive long-term, successful research projects
• Expertise in one or more of the following: molecular biology, chromatin biology, developmental biology, genomics, and/or imaging
This appointment can be renewed indefinitely provided the need for the position continues, the funding for the position is available, and the expectations for performance are met.
To apply to this position please submit the following using the Interfolio Link: https://apply.interfolio.com/50482:
1) A one-page cover letter describing your motivation for the position, research experience, and relevant mentoring/organizational experience,
2) biosketch or CV,
3) three letters of references
4) PDFs of three publications .
For inquiries please contact hiba.codore@yale.edu. Please include “Associate Research Scientist” in the subject of the email.
Applications are now open and will be considered on a rolling basis. Salary will be commensurate with experience and the appointment includes an attractive benefits package in line with an appointment in the research track within the Yale School of Medicine
Yale University is an Affirmative Action/Equal Opportunity employer. Yale values diversity among its students, staff, and faculty and strongly welcomes applications from women, persons with disabilities, protected veterans, and underrepresented minorities.
At the end of 2014, a friend asked me “What is your story”? I had just started my postdoc in the laboratory of Karla Neugebauer and was a bit perplexed by the direct question. I started talking about some loose project ideas of mine involving words like development, metabolism, and RNA – after all, I joined an RNA lab after doing my PhD on fly development, growth control, and lipid metabolism. But the story behind our paper did not start for another few months.
Historically, metabolism and developmental biology are deeply connected. This was emphasized in Joseph Needham’s mammoth three-volume work “Chemical Embryology” published in 1931 on the subject of physico-chemical embryology. This research faded away since the molecularization of experimental embryology, but over the last few years has reemerged as a quantitative field of study in developmental biology. Two consecutive meetings, the 2016 Company of Biologist Workshop ‘Metabolism in Development and Disease’ and the 2017 EMBO Symposium ‘Metabolism in Time and Space’ (Krejci & Tennessen 2017), highlighted that developmental biologists are once again investigating the role of cellular metabolism in growth, differentiation, and maturation during development. This resurgence of metabolisms role in development sets the stage for our story.
Developing embryos, like all living systems, are open systems exchanging energy and matter with their environment. They function out of equilibrium and require a continuous supply of energy to remain alive. From a thermodynamic perspective, metabolism can be regarded as an energy converter that directs energy from nutrients through an interconnected web of chemical reactions to meet the energetic and biosynthetic demands of growth, proliferation, and development. An emerging view is that this bioenergetic function of metabolism is tightly regulated in time and space in order to fulfill the changing energetic and biosynthetic demands of animal development (See Miyazawa & Aulehla 2018 and Gándara & Wappner 2018 for reviews). One particular example is that highly proliferative cells exploit increased glycolytic activity even in the presence of oxygen – a metabolic state known as aerobic glycolysis or the Warburg effect (Ward & Thompson 2012). How and why cells adopt this metabolic state has been the focus of intense research in the last decade and is not entirely understood. It has been recognized that this metabolic wiring supports the increased energetic and biosynthetic demands necessary for rapid cell growth and proliferation during development and disease. Indeed, implanted mammalian embryos seem to utilize Warburg metabolism with high levels of glucose uptake, glycolytic activity, and lactate production. Interestingly, early embryos undergoing rapid reductive cleavage divisions do not rely on glucose but rather use pyruvate, lactate and amino acids as energy sources (Gardner 1998). This indicates that early embryos rely on respiration to proliferate and switch their metabolic state during the transition from the cleavage to the blastocyst stage. This metabolic switch seems to coincide with the transition from maternal to zygotic instructions of developmental control known as maternal-to-zygotic transition (MZT) when maternally deposited RNA is degraded and zygotic gene expression is initiated.
Karla Neugebauer’s laboratory at Yale University focuses on the regulation of transcription and splicing in a variety of biological contexts, including MZT. When I joined the lab, RNA-interactome studies had just identified many ‘classical’ metabolic enzymes of intermediary metabolism as RNA-binding proteins and I was intrigued by the idea of combining expertise with the Neugebauer lab to study the dynamic interplay between transcription, RNA-binding proteins and metabolism during early zebrafish embryogenesis, particularly during MZT. Although this was the original idea for my project in her lab if you’ve read our paper you know that we ended up elsewhere… using calorimetry to measure the heat flow between a developing embryo and its surroundings. How did the project change so drastically? Stay with me, as I will explain in the next few paragraphs.
The change in a metabolic state is usually associated with a change in the energetic and biosynthetic requirements of the system under investigation. In the case of embryonic cleavage stage development, cells lack growth phases and thus become smaller as they divide. One could hypothesize that they use oxidative phosphorylation because of the absence of volumetric growth. However, increasing embryonic cell number demands precursors (e.g. nucleotides, fatty acids, and amino acids) for DNA replication, an increase in plasma membranes, and protein synthesis. Thus, the embryo must produce and/or polymerize the precursors necessary for cleavage stage development. Each cell of the embryo must also expend energy to assemble and disassemble cellular machinery (e.g. chromatin, mitotic spindles), generate forces needed to segregate the chromosomes and divide the cell, and change the activity of signaling pathways that enforce cell cycle phasing, even in the absence of volumetric growth. As development proceeds and the embryonic cell cycle gains G1 and G2 phases, the embryo faces the additional energetic demands of volumetric growth and might switch to aerobic glycolysis as a metabolic strategy to fulfill those. But what are those energetic demands? I realized that we lack a quantitative understanding of how the metabolic energy converted by different metabolic states is partitioned among the complex array of cellular processes that take place during cell growth, proliferation, and development. What if we could put numbers on energetic requirements of making a new cell or an embryo? Maybe then we will be able to understand why metabolism functions the way it does. I became fascinated by the thought of studying the energy budget of early embryogenesis and my focus shifted away from the regulation and interplay of RNA biology and metabolism during MZT. This is where our story truly started – with the question of how to measure the energy required for embryonic development.
The amount of energy dissipated by an animal per unit of time is defined as metabolic rate and is reported in energy units per unit time in Watt (joule/second) or Watt per kg body mass (W/kg). An average human at rest consumes ~2000 kcal per day and dissipates energy in the form of heat at a rate of about 100 W or 1 W/kg (Joules/s*kg). These estimates are conceptually based on the first law of thermodynamics. The change in energy (2000 kcal /day) equals heat dissipated (100W) minus work. The average human is at rest – not growing or conserving any energy – and does not perform any net chemical synthesis or anabolic reactions. All the 2000 kcal/day is converted by catabolic reactions and immediately used by various cellular processes defined as maintenance reactions to keep the individual alive or away from thermodynamic equilibrium. Now let’s consider a growing organism which must perform anabolic reactions and invests energy into chemical synthesis of new biomass in order to grow. In this case, the organism conserves energy and performs net chemical synthesis. Measurements of heat dissipation now reflect the difference between energy consumption in the form of nutrients and energy conservation by biosynthesis, which is equal to the net change in enthalpy of all the reactions taking place in the system. This is how heat dissipation differs from respiratory metabolic rate measurements such as O2 consumption or CO2 production. They reflect rates of catabolic reactions and are inherently blind towards energy conservation in the system by anabolic reactions.
Heat dissipation is directly connected to the laws of thermodynamics. When approaching this question, I thought, “maybe we can measure the heat flow between developing embryos and their environment using calorimetry.” It’s also possible that I always wanted to stick a developing organism in a calorimeter to see what I could measure… Isothermal titration calorimetry (ITC) is traditionally used to measure the heat transfer associated with a biomolecular interaction to determine the binding constant, stoichiometry, enthalpy and entropy of the binding event in solution, without the need of labels. After spending a few weeks of optimizing a 17 years old ITC machine housed in the biophysical core facility into measuring heat flow for prolonged periods of time without titrations, we were ready to try to measure the heat flow associated with early development. It worked incredibly well – and I was thrilled when I saw the first heat flow data from early zebrafish embryos undergoing cleavage stage development (see picture).
Isothermal calorimetry set up used to measure the heat flow between zebrafish embryos undergoing cleavage stage development and their environment. Not the actual first experiment. #mymachinewithoutme.
The initial finding was that the heat flow between embryo’s undergoing cleavage stage development and their environment increased over time. Surprisingly, however, I discovered that there was a small (~2% of the mean) but reproducible heat flow oscillation superimposed on the steady increase. The period and number of oscillations matched the division cycles taking place during this phase of embryogenesis. The oscillations suggested the presence of cyclic energetic events associated with embryonic cell proliferation, leading us to wonder if the oscillations are associated with the embryonic cell cycle.
After the initial discovery, I started a collaboration with Joe Howard, a biophysicist, to tackle the theory and thermodynamic aspects of heat flow during embryonic development. In the summer of 2015, Joe was invited faculty for the physiology course at the Marine Biology Laboratory (MBL) in Woods Hole, Massachusetts. We decided to take the project to the MBL for two weeks and I had the pleasure to work with two amazing students on the energetic costs of embryonic development. Manuel Razo was interested in the temperature scaling of the heat flow and Mathijs Vleugel started to investigate the underlying metabolic state and mitochondrial biology of embryos undergoing cleavage stage development. The two weeks at the physiology course and the MBL deeply influenced my thinking about the energetics of development and science in general. The course brings together scientists from diverse backgrounds and provides a truly collaborative and open environment. We started to throw ideas around and discussed what these heat flow oscillations could be? As the early embryonic cell cycle is solely composed of DNA replication, mitosis and cytokinesis, a prediction was that these heat flow oscillations could represent the energy used by either of those processes. My personal bet was on mitosis – but it turned out we were all wrong.
The experiment which pointed us in a new direction was when I blocked both DNA replication and mitosis by inhibitors. To our surprise, the heat flow oscillations persisted with a similar period and amplitude as control treated embryos. What followed was a series of quantitative heat flow measurements combined with perturbation experiments, theoretical modeling, and order of magnitude estimates for energetic costs of oscillatory cellular processes to investigate the underlying principle of the heat flow oscillations. We were able to show that they were driven by the phosphorylation and dephosphorylation reactions catalyzed by the cell cycle oscillator, the biochemical network controlling mitotic entry and exit, and thus revealed the energetic costs of cell cycle signaling.
In summary, the story started with an unconventional idea and a discovery. It evolved to show that quantitative heat flow measurements combined with perturbation experiments, theoretical modeling, and order-of-magnitude estimates can be a powerful approach to dissect the energetic costs of various cellular processes driving embryogenesis. In our work, we postulated that the energetic cost of cell cycle signaling likely reflects the thermodynamic burden of imposing accurate and robust timing on cell proliferation during development, as predicted by a theoretical tradeoff between energy dissipation and precision of biomolecular oscillators. I am currently working on establishing systems to measure the accuracy of the embryonic cell cycle and modulate the oscillatory heat flow amplitude and phase to test these in-silico predictions in-vivo and in-vitro. Furthermore, we have been able to allocate the oscillatory component to the energetic cost of the cell cycle signaling representing 2% of embryos total energy expenditure. What about the other 98%? Why does it increase during cleavage stage development – even absence of volumetric growth?
Searching for a post-doc who is passionate about both teaching and research. We are studying the interplay between division and inductive signaling. In particular, we are exploring how signaling receptors are trafficked in dividing cells to generate asymmetric induction of a cardiac progenitor lineage. We are also using comparative genomics to explore the evolutionary constraints that shape gene regulatory networks. We study these questions in the invertebrate chordate, Ciona robusta. Ciona embryos consists of extremely low cell numbers allowing high resolution analysis of intra-cellular dynamics in intact embryos. The ease of generating transgenic Ciona embryos make this an excellent model organism for undergraduate research. We have recently initiated a collaboration with Danelle Devenport at Princeton focused on similar processes in cultured mouse epithelial cells. This is a great opportunity for a post-doc with an interest in undergraduate teaching and research. My former post-doc is moving on to a tenure-track position at a small liberal arts college and it was clear that the combination of a strong research record along with a demonstrated commitment to undergraduate mentoring and teaching made her a strong candidate for these very competitive positions.
Applicants should have a PhD (or be close to completing one) in a relevant subject area. Excellent communication skills and a commitment to undergraduate mentoring are essential.
To apply or if you have questions about the position – please send your CV and a cover letter describing your interest to Bradley Davidson at bdavids1@swarthmore.edu. I will be in touch with instructions for submitting a formal application.
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