The Chemical Synthesis of DNA/RNA: Our Gift to Science

It is a great privilege to contribute to the Reflections essays. In my particular case, this essay has allowed me to weave some of my major scientific contributions into a tapestry held together by what I have learned from three colleagues (Robert Letsinger, Gobind Khorana, and George Rathmann) who molded my career at every important junction. To these individuals, I remain eternally grateful, as they always led by example and showed many of us how to break new ground in both science and biotechnology. Relative to my scientific career, I have focused primarily on two related areas. The first is methodologies we developed for chemically synthesizing DNA and RNA. Synthetic DNA and RNA continue to be an essential research tool for biologists, biochemists, and molecular biologists. The second is developing new approaches for solving important biological problems using synthetic DNA, RNA, and their analogs.     

A career pathway in protein folding: from model peptides to postreductionist protein science

This review discusses the inherent challenge of linking "reductionist" approaches to decipher the information encoded in protein sequences with burgeoning efforts to explore protein folding in native environments-"postreductionist" approaches. Because the invitation to write this article came as a result of my selection to receive the 2010 Dorothy Hodgkin Award of the Protein Society, I use examples from my own work to illustrate the evolution from the reductionist to the postreductionist perspective. I am incredibly honored to receive the Hodgkin Award, but I want to emphasize that it is the combined effort, creativity, and talent of many students, postdoctoral fellows, and collaborators over several years that has led to any accomplishments on which this selection is based. Moreover, I do not claim to have unique insight into the topics discussed here; but this writing opportunity allows me to illustrate some threads in the evolution of protein folding research with my own experiences and to point out to those embarking on careers how the twists and turns in anyone's scientific path are influenced and enriched by the scientific context of our research. The path my own career has taken thus far has been shaped by the timing of discoveries in the field of protein science; together with our contemporaries, we become part of a knowledge evolution. In my own case, this has been an epoch of great discovery in protein folding and I feel very fortunate to have participated in it.     

My path to primatology: some stories from the field

Primates - In this paper, I summarize the major facets of my 50-year career as a primatologist. I briefly describe the aspects of my upbringing and early education that led me to the study of...     

Being at the right place at the right time

I am tremendously honored to receive the 2012 Women in Cell Biology Junior Award. In this essay, I recount my career path over the past 15 years. Although many details are specific to my own experiences, I hope that some generalizations can be made to encourage more women to pursue independent scientific careers. Mine is a story of choosing a captivating question, making the most of your opportunities, and finding a balance with life outside the lab.It is a great honor to have been awarded the 2012 Women in Cell Biology Junior Award from the ASCB. Looking back at the 15 years I have spent doing research in cell biology, my overwhelming feeling is that it has been and still is a lot of fun. I am extremely fortunate to have a job that I truly enjoy and that gives me complete intellectual freedom. My lab choices over the years were motivated by scientific curiosity and enthusiasm for new environments and topics, rather than by career building. It is thus truly amazing to be rewarded for (rather a lot of) work enjoyed.     

Balancing teaching and research experiences in doctoral training programs: lessons for the future educator

While a variety of alternative careers has emerged for Ph.D. life scientists in industry, business, law, and education in the past two decades, the structure of doctoral training programs in many cases does not provide the flexibility necessary to pursue career experiences not directly related to a research emphasis. Here I describe my efforts to supplement my traditional doctoral research training with independent teaching experiences that have allowed me to prepare myself for a career that combines both into a combined educational program. I describe the issues I have come across in finding and taking part in these endeavors, how these issues have affected my work in pursuing my Ph.D., and how my experiences translate into my hopes for a future education-based career in molecular and cell biology.     

Fifty-eight years in science--a commentary

After 58 years in science, mostly in pharmacology, one gains perspective. Mine is that there have been important changes over this time, some good and some questionable. In this commentary, I try to reveal how I got to this stage, partially explaining my biases, and possibly helping others learn from my experiences including mistakes. Changing from seeking an M.D. to cellular biology and then to pharmacology early in my career were the best moves I made. The next best move was migration to Canada, away from the McCarthy-McCarran hysteria. Arriving at a time after the end of World War II when science in Canada was expanding was very good luck. I had an excellent opportunity to enjoy both the administration (as Chair of the first independent Department of Pharmacology at the University of Alberta) and the practice of pharmacology (as a practitioner of research on smooth muscle in health and disease). For me, the practice of research has always won over administration when a choice had to be made. Early on, I began to ask questions about educational practices and tried to evaluate them. This led me to initiate changes in laboratories and to seek nondidactic educational approaches such as problem-based learning. I also developed questions about the practice of anonymous peer review. After moving to McMaster in 1975, I was compelled to find a solution for a failed "Pharmacology Program" and eventually developed the first "Smooth Muscle Research Program". Although that was a good solution for the research component, it did not solve the educational needs. This led to the development of "therapeutic problems", which were used to help McMaster medical students educate themselves about applied pharmacology. Now these problems are being used to educate pharmacology honours and graduate students at the University of Alberta. The best part of all these activities is the colleagues and friends that I have interacted with and learned from over the years, and the realization that many of them have collaborated with me again in this volume.     

A career at the interface of cell and developmental biology: a view from the crest

Just as neural crest cells migrate great distances through the embryo, my journey has taken me from a childhood in a distant land to a career as a biologist. My mentoring relationships have shaped not only the careers of my trainees, but also the trajectory of my own science. One of the most satisfying aspects of mentoring comes from helping to empower the next generation of scientists to do more tomorrow than is possible today. This, together with a passion for discovery and learning new things, motivates me and makes science such a rewarding career.First, let me say how honored I am to receive the Women in Cell Biology Senior Award. I am particularly thankful to my former postdoctoral fellows and students. I have learned as much, or more, from them as they have from me and take great pride and vicarious pleasure from their successes. My goal as a mentor has been to impart an enthusiasm for science and for the satisfaction it can bring at both a professional and personal level. It is the pleasure of discovery and the bonds of collegiality that make being a scientist not only a worthwhile and interesting but also a very fulfilling career.When looking back upon my life as a biologist, many of the “choices” made along my career path were more of a random walk than a premeditated trajectory. Perhaps the most important and constant influences come from my family background, wonderful friends and colleagues, and an inherent interest in the natural world. For me, these were mixed with a good deal of luck and the generous mentorship of valued colleagues.     

(M,R)-systems, (P,M,C)-nets, hierarchical decay, and biological aging: reminiscences of Robert Rosen

I have the pleasure to present a number of personal experiences that I had with Robert Rosen, both as his student and as a research colleague, and I will describe how this affected my academic career over the past decades. As a matter of fact, Rosen's work with (M,R)-systems as well as his continuing mentorship guided me into my own research in gerontology and geriatrics. Amazingly, this still continues to affect my work in complexity theory after 30 years.     

A quest to understand molecular mechanisms for genetic stability

In the midst of the post-war turmoil in Japan, I fortunately followed a path to become a scientist. Sometime at an early stage of my career, I encountered the problem of the cellular response to DNA damage and had the chance to discover a DNA repair enzyme. This event greatly influenced the subsequent course of my research, and I extended my studies toward elucidating the molecular mechanisms of mutagenesis as well as of carcinogenesis. Through these studies I came to understand the importance of mechanisms for dealing with the actions of reactive oxygen species to the living systems. These recollections deal with these endeavors with emphasis on the early part of my scientific career.     

Plans of mice and men: from bench science to science policy

The transition from bench science to science policy is not always a smooth one, and my journey stretched as far as the unemployment line to the hallowed halls of the U.S. Capitol. While earning my doctorate in microbiology, I found myself more interested in my political activities than my experiments. Thus, my science policy career aspirations were born from merging my love of science with my interest in policy and politics. After receiving my doctorate, I accepted the Henry Luce Scholarship, which allowed me to live in South Korea for 1 year and delve into the field of science policy research. This introduction into science policy occurred at the South Korean think tank called the Science and Technology Policy Institute (STEPI). During that year, I used textbooks, colleagues, and hands-on research projects as my educational introduction into the social science of science and technology decision-making. However, upon returning to the United States during one of the worst job markets in nearly 80 years, securing a position in science policy proved to be very difficult, and I was unemployed for five months. Ultimately, it took more than a year from the end of the Luce Scholarship to obtain my next science policy position with the American Society for Microbiology Congressional Fellowship. This fellowship gave me the opportunity to work as the science and public health advisor to U.S. Senator Harry Reid. While there were significant challenges during my transition from the laboratory to science policy, those challenges made me tougher, more appreciative, and more prepared to move from working at the bench to working in the field of science policy.     

Seven transmembrane receptors—A brief personal retrospective

Receptors have fascinated biologists for more than a century and they have fascinated me for the entirety of my own research career. The seven transmembrane receptors, also known as G protein coupled receptors, represent the largest of the several families of plasma membrane receptors, comprising more than a thousand genes and regulating virtually all known physiological processes in mammals. Moreover, they represent one of the commonest targets of currently used drugs. I have spent the entirety of my research career working on these receptors. Here I set down some personal reflections on the evolution of the field during the past 35 years, hanging the thread of the story on some of the work from my own laboratory.     

Seven transmembrane receptors: a brief personal retrospective

Receptors have fascinated biologists for more than a century and they have fascinated me for the entirety of my own research career. The seven transmembrane receptors, also known as G protein coupled receptors, represent the largest of the several families of plasma membrane receptors, comprising more than a thousand genes and regulating virtually all known physiological processes in mammals. Moreover, they represent one of the commonest targets of currently used drugs. I have spent the entirety of my research career working on these receptors. Here I set down some personal reflections on the evolution of the field during the past 35 years, hanging the thread of the story on some of the work from my own laboratory.     

Sociobiology and the Comparative Approach: One Way to Study Ourselves

This paper is based on my lecture in a macroevolution course I team-teach with Profs. Daniel Brooks and David Evans at the University of Toronto. The lecture has undergone many revisions over the years as I grappled with problems discussing certain areas (e.g., rape as an adaptive strategy, gender “roles”). Eventually, I realized that the problem areas said more about my personal conflicts than they did about the science. This was one of those epiphany moments, a time when I recognized that I was less likely to accept hypotheses that contradicted the way I wanted the world to be and more likely to uncritically accept hypotheses that confirmed my world view. That epiphany, in turn, led me to realize that science is never separate from the personal biases/demons of its practitioners, especially when we are asking questions about the evolution of human behavior. That realization was not novel within the vast literature of sociology and philosophy. But it was novel for me. I was aware of discussions about personal biases clouding scientific interpretation; I just didn’t think it applied to me (I absorbed the philosophical discussions without making the connection to “my world”). So, on the heels of that epiphany, the following is a very personal take on the question of teaching sociobiology, based on where my journey, aided by my experience as an ethologist and phylogeneticist and colored by my own history, has taken me.     

Biophysical Reviews ‘Meet the editor series’—Addmore Shonhai

It gives me great pleasure to have the opportunity to introduce myself to the readers of Biophysical Reviews as part of the ‘meet the editors’ series. What follows is a mini-autobiography of my life as it relates to my scientific career and research.

     

Genome-enabled exploration of microbial ecology and evolution in the sea: a rising tide lifts all boats

As a young bacteriologist just launching my career during the early days of the ‘microbial revolution’ in the 1980s, I was fortunate to participate in some early discoveries, and collaborate in the development of cross-disciplinary methods now commonly referred to as "metagenomics". My early scientific career focused on applying phylogenetic and genomic approaches to characterize ‘wild’ bacteria, archaea and viruses in their natural habitats, with an emphasis on marine systems. These central interests have not changed very much for me over the past three decades, but knowledge, methodological advances and new theoretical perspectives about the microbial world certainly have. In this invited ‘How we did it’ perspective, I trace some of the trajectories of my lab's collective efforts over the years, including phylogenetic surveys of microbial assemblages in marine plankton and sediments, development of microbial community gene- and genome-enabled surveys, and application of genome-guided, cultivation-independent functional characterization of novel enzymes, pathways and their relationships to in situ biogeochemistry. Throughout this short review, I attempt to acknowledge, all the mentors, students, postdocs and collaborators who enabled this research. Inevitably, a brief autobiographical review like this cannot be fully comprehensive, so sincere apologies to any of my great colleagues who are not explicitly mentioned herein. I salute you all as well!     

Ye Tian: Surveilling stress to live longer

Ye Tian investigates how mitochondrial stress signaling pathways regulate longevity using C. elegans as a model system.

An avid reader, Ye Tian used to save up her child allowance with the sole purpose of buying science fiction books. Reading and solving mathematical problems were her favorite hobbies; indeed, she liked mathematics so much that she was about to enroll herself as an architecture major but finally chose biotechnology. Ye moved from her hometown in the Northwest of China, Baoji—famous for housing the Zhou dynasty’s bronzeware and being close to the Terracotta Army—to Beijing for her college and graduate studies.Ye is proud of being among the earliest researchers working on Caenorhabditis elegans in her country; for her PhD studies, she joined the lab of Hong Zhang, who at that time has just established the first C. elegans lab in China at the National Institute of Biological Sciences in Beijing. Ye identified epg-2 as an adaptor for cargo recognition during autophagy. In 2010, she crossed the Pacific toward the U.S. West Coast for her postdoctoral training in the aging field with Andrew Dillin, first at the Salk Institute in San Diego and then at the University of California, Berkeley. There, she discovered that mild mitochondrial stress during development in worms rewires their chromatin landscape to establish specific gene expression patterns throughout the lifespan and promote longevity.Ye Tian. Photo courtesy of Ye Tian.Ye came back to China at the end of 2016 to start her own lab at the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences. Her research team studies mitochondrial stress signaling pathways and their interplay with aging. We chatted with her to learn more about her next scientific plans.What interested you about the interplay between mitochondria and aging?I became interested in mitochondrial biology during my postdoc in Andrew Dillin’s lab. Since the origin of eukaryotic cells, mitochondria have been a driving force of evolution. During reproduction, mitochondria are passed from the mother to the offspring through egg cells and they exhibit a unique inheritance pattern. As essential hubs that dictate cellular metabolism, it is clear now that mitochondria and the nucleus maintain a bidirectional communication. Early life “stressed” mitochondria communicate with the nucleus to induce gene expression changes that are beneficial on longevity and persist throughout the lifespan. The fact that mitochondrial function is crucial to aging fascinated me; I wanted to continue exploring that topic further, and that’s why I established my lab around the question of how mitochondrial surveillance mechanisms regulate the aging process.What are you currently working on? What is up next for you?My research team focuses on the interplay between mitochondrial stress signaling pathways and aging. The first work that my lab published was a project that I started during my postdoc. The Dillin lab reported a phenomenon in which perturbations of mitochondria in neurons induced a mitochondrial stress response in the peripheral tissues and hypothesized that a secreted signal molecule, named after mitokine, is required for the cell non-autonomous regulation (1). The identity of this molecular signal remained elusive for almost ten years until we found that a secreted Wnt ligand, EGL-20, functions as the mitokine to coordinate mitochondrial stress signaling across tissues and promote longevity of the organism (2). We are also interested in how the crosstalk between mitochondria and the nucleus influences lifespan. We found that mitochondrial perturbations alter the nuclear epigenome to induce longevity via the histone deacetylation complex NuRD in response to cellular acetyl-CoA levels, the key metabolite at the entry point of the Krebs cycle (3).Lab group picture; current lab members (2021). Photo courtesy of Ye Tian.Our latest work stemmed from a serendipitous observation that neuronal mitochondrial stress is sensed by and transmitted through the mitochondria in the germline. Intergenerational, maternal inheritance of elevated levels of mitochondrial DNA via the mitokine Wnt/EGL-20, which causes the activation of the mitochondrial unfolded protein response (UPR^mt), provides descendants with a greater tolerance to environmental stress. This makes the offspring live longer (4).Among our short-term scientific plans, we’re determining how mitochondria functions during the aging process at both the genetic and biochemical levels and searching for ways to apply our findings from C. elegans to neurodegenerative disease models in mammals.What kind of approach do you bring to your work?The curiosity about how things work drives me; what I enjoy the most is when I see things happening in front of my eyes and when I figure out why they occur that way. That enthusiasm is what I try to spread to my team every day. In the lab, we rely on C. elegans as our model system and on genetics to dissect complex biological processes like aging. We have also adapted modern biochemical and imaging techniques as well as bioinformatics to complement our genetic studies. I’m a geneticist at heart, and I like to initiate a project with a well-designed genetic screen. The best part is that the screen often leads me to answers I was not expecting, and that’s genuinely inspiring!What did you learn during your PhD and postdoc that helped prepare you for being a group leader? What were you unprepared for?Like most scientists, my research career has gone through ups and downs. I had to change my research project in the last year of my graduate school; that was nerve-racking, but I eventually managed to redirect my thesis and get exciting results under time pressure, thanks in large to the support of my parents, mentors, and lab mates. That helped me prepare to become a principal investigator; I gained confidence in problem solving, and since I’ve experienced the stress of dealing with last-minute scope changes firsthand, I connect better with my students.I guess, as many other non-native English speakers, I wasn’t prepared for writing grants and papers fluently in English. This issue wasn’t obvious during my graduate and postdoctoral studies, as my mentors were always there for me and proofread and edited my writing. Now I have to stand up for myself. I spend most of my time writing; I’ve improved my writing skills but it’s still an ongoing process.Reconstruction of the nerve system of C. elegans by confocal microscopy. Green corresponds to YFP-labeled neuronal specific marker Q40, and red labels germline specific mitochondrial outer membrane protein TOMM-20::mkate2. Image courtesy of Ye Tian’s lab.What has been the biggest accomplishment in your career so far?My very first PhD student, Qian Zhang, graduated with two first-author papers and decided to pursue a research career in academia. Being responsible for someone else’s career is challenging but also rewarding.What has been the biggest challenge in your career so far?I use the model organism C. elegans for my research in aging, so from time to time, peers criticize the relevance of my work to human health. I’m used to justifying my scientific approach to funding agencies and peers in other fields, but sometimes it’s exhausting or not pleasant.Who were your key influences early in your career?My PhD mentor, Hong Zhang. He is very passionate about the science he does, and he is courageous to shift his research directions to answer new biological questions.What is the best advice you have been given?I think the best advice I’ve gotten is that “tomorrow is another day.” It reminds me to keep going and be optimistic.What hobbies do you have?I love art and music. When I was in San Diego, I used to play in the Chinese Music Band; I miss my musician friends over there. In my teens, I used to hike mountainside trails along the river with my parents. Now, running has become my new favorite hobby. I enjoy the tranquility and peace of mind while running; it’s soothing.     

Travels in a world of small science*

As a boy, I read Sinclair Lewis's Arrowsmithand dreamed of doing research of potential benefit to society. I describe the paths of my scientific career that followed. Several distinguished scientists served as my mentors and I present their profiles. Much of my career was in a small department at a small institution where independent researchers collaborated informally. I describe the unique method of carrying on research there. My curiosity about glycolate metabolism led to unraveling the enzymatic mechanism of the glycolate oxidase reaction and showing the importance of H₂O₂ as a byproduct. I discovered enzymes catalyzing the reduction of glyoxylate and hydroxypyruvate. I found α-hydroxysulfonates were useful competitive inhibitors of glycolate oxidase. In a moment of revelation, I realized that glycolate metabolism was an essential part of photorespiration, a process that lowers net photosynthesis in C₃ plants. I added inhibitors of glycolate oxidase to leaves and showed: (1) glycolate was synthesized only in light as an early product of photosynthetic CO₂ assimilation, (2) the rate of glycolate oxidation consumed a sizable fraction of net photosynthesis in C₃ but not in C₄ plants, and (3) that glycolate metabolism increased greatly at higher temperatures. For a while I studied the control of stomatal opening in leaves, and this led to the finding that potassium ions are a key solute in guard cells. I describe experiments that show that when photorespiration rates are high, as occurs at higher temperatures, genetically increasing leaf catalase activity reduces photorespiration and increases net photosythetic CO₂ assimilation. This revised version was published online in June 2006 with corrections to the Cover Date.     

Gaia Pigino: Inside the cell

Gaia Pigino studies the molecular mechanisms and principles of self-organization in cilia using 3D cryo-EM.

Gaia Pigino was only 3 yr old when she became fascinated with nature in the beautiful countryside of Siena, Italy, where she grew up. The neighbor’s daughter showed her a hen in the chicken coop, and they caught it in the act of laying an egg. Gaia remembers, “This was for me almost a shock, as my experience about eggs was that they come directly out of paper boxes!” Her father was also an important part of awakening Gaia’s curiosity for the amazing things in nature. He used to bring home the award-winning magazine Airone, the Italian equivalent of National Geographic. Gaia never missed an issue; even before learning to read, she could spend hours looking at the captivating photos of the wildlife. She wanted to understand what she was seeing, and maybe because of that, she was determined to do science.Gaia Pigino. Photo courtesy of Human Technopole.Gaia took her first “scientific” steps with Professor Fabio Bernini and Professor Claudio Leonzio at the University of Siena, where she studied bioindicators of soil contamination and detoxification strategies of soil arthropods as part of her PhD project. But it was later, when she joined the laboratory of Professor Pietro Lupetti and met Professor Joel Rosenbaum, a pioneer of cilia research, that Gaia discovered the world of 3D EM and felt her place was “inside a single cell.” She solidified her interest in the structure of protein complexes of cilia and flagella and boosted her passion for cryo-electron tomography (ET) in the laboratory of Professor Takashi Ishikawa, first at the ETH Zurich and then at the Paul Scherrer Institut in Switzerland. In 2012, Gaia started her own laboratory at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, with the vision of creating a truly interdisciplinary laboratory. Her team combines techniques from different fields such as biophysics, cell biology, and structural biology to answer open questions in the cilia field. Gaia recently moved countries again—this time to take over the position of Associate Head of the Structural Biology Research Centre, at the Human Technopole, Milan, Italy.We reached out to Gaia to learn more about her scientific journey and future research directions.What interested you about cilia?The first thing that attracted me toward cilia and flagella were some EM micrographs, by Professor Romano Dallai in Siena, that showed the beautiful geometrical microtubular structures of sperm flagella. I was intrigued by the apparent perfection of these organelles that clearly showed me that a cell is a coordinated system of complex molecular machines, the mechanism of many of which we do not understand. Soon after, Professor Joel Rosenbaum introduced me to the bidirectional transport of components inside cilia, which, he explained to me, is required for both assembly and function of virtually all cilia and flagella, from the motile cilia in our lungs to the primary cilium in our kidneys. He called it intraflagellar transport (IFT) and compared it to a Paternoster elevator, where the individual cabins were what we now call IFT trains. I was completely fascinated by the IFT system, the structure, the function, the dynamics, and the mechanism of which were still largely unknown. Quickly, I realized that in addition to IFT, cilia represent a virtually infinite source of open biological questions waiting to be solved, from the mechanics and regulation of the beating to the sensory function of primary cilia, and their importance for human health.What are some of the scientific questions currently of interest in your laboratory?In the past few years, we have made substantial contributions to the current understanding of the structure and the mechanism of the IFT (1, 2, 3). Currently, we are investigating how the structure of IFT trains relates to their functions by looking, in cryo-electron tomography, at how anterograde trains transform into retrograde trains and at how different ciliary cargoes are loaded on the trains. Beside this more classical line of research, we are exploring other approaches to study IFT, for instance we have developed a method to reactivate IFT trains in vitro on reconstituted microtubules. We want to use this approach to investigate the behavior of IFT trains, and their motors, in experimentally controllable conditions, e.g., in the presence of only certain tubulin posttranslational modifications. We have also made interesting discoveries about the distribution of tubulin posttranslational modifications on the microtubule doublets of the axoneme and how this spatially defined tubulin code affects the function of different ciliary components. We hope we will be able to share these new “stories” with the structural and cell biology community very soon!What kind of approach do you bring to your work?I believe that the main reason for why science became an integral, and dominant, part of my life is because it provides infinite riddles and continuous challenges. I have always been curious about how things work in nature, but I quickly realized that learning from books didn’t satisfy me. My desire was to be at the frontline, to be among the ones that see things happening in front of their eyes, at the microscope, for the first time. I wanted to be among the ones that make the discoveries that students read about in textbooks. Thus, what I bring to my work is an endless desire of solving biological riddles, curiosity, creativity, determination, and energy, with which I hope to inspire the members of my team. My laboratory uses an interdisciplinary approach; we use whatever method, technique or technology is needed to reach our goal, from the most basic tool to the most sophisticated cryo-electron microscope. And if the method we need does not yet exist, we try to invent it.A young Gaia Pigino (3 yr old) the day she discovered how eggs are made. Photo courtesy of Giancarlo Pigino.Could you tell us a bit about the Structural Biology Research Centre at the Human Technopole (HT)?At the HT Structural Biology Centre, we are working to create a vibrant and interdisciplinary scientific environment that will attract molecular, structural, cell, and computational biologists from all over the world. We are creating fantastic facilities, including one of the most well equipped and advanced electron microscopy facilities in Europe—and likely the world—headed by Paolo Swuec. My team, together with the teams of my colleague Alessandro Vannini and the research group leaders Ana Casañal, Francesca Coscia, and Philipp Erdmann, already cover a vast range of competences and know-how from classical molecular and structural biology approaches, such as crystallography and protein biophysics, to cryo-CLEM, cryo-FIB SEM and cryo-ET, all of which allow us to address questions in cell biology. Our goal is to create a scientific infrastructure and culture that will enable biologists to obtain a continuum of structural and functional information across scales.What did you learn during your PhD and postdoc that helped prepare you for being a group leader? What were you unprepared for?I learned that everyday research is mostly made of failures, but that with the right amount of obsession, persistence, curiosity, and creativity, it is always possible to succeed and discover new things. Being given the freedom to develop your own ideas and your own project very early in your career is a treat; science is not only about having good ideas! One needs to follow up on these ideas with intense work and troubleshooting to make them reality. In addition, I realized that being fearless and attempting what is considered too difficult by others, despite challenges, can turn into a worthy learning experience. Also, how you present your work to the scientific community matters for swinging the odds of success in your favor. Different places might work in very different ways, and conducting good science does not only depend on you, but also on the possibilities given to you by your environment.What was I unprepared for?—I guess several things, but one comes immediately to mind: I underestimated how much being responsible not only for my own life and career, but also the career of students, postdocs, and others in the laboratory, would affect me personally.Structure of the 96-nm axonemal repeat reconstructed by cryo-ET and subtomogram averaging. Image courtesy of Gonzalo Alvarez Viar, Pigino Lab.What has been the biggest accomplishment in your career so far?This is a tricky question for me... I tend to look into the future more than celebrating the past. I fight to succeed in something, but as soon as I conquer it, I find it less of an achievement than the thing I could conquer next. Nevertheless, I am happy about the discoveries and the papers published together with my students and postdocs (1, 2, 3, 4, 5). I am extremely excited about the fact that after many years of work I am now leading an interdisciplinary laboratory, where we combine techniques from different fields. I am also happy that three times my husband and I were able to move from one world class academic institution to the another to start exciting and fitting jobs and could still live together in the same place. We worked hard for this, but we also got lucky.What has been the biggest challenge in your career so far?I studied French in school; I had almost no exposure to spoken English until the end of my PhD. To avoid having to show my English insufficiencies, I did hide beside the board of my poster at the first international conference I attended in 2004! It took me a while to overcome this barrier and feel confident to express my thoughts and ideas in English.What do you think you would be if you were not a scientist?I had been a good fencer during my youth. I was a member of the Italian National Team between ages 14 and 19 and saw quite a bit of the world, which was cool! When my sporting career failed, due to diabetes, I was torn between art and science. I guess that in a parallel universe, I am a wildlife photographer and a potter specialized in wood kiln firing. [Gaia confesses that she misses “the amazing and addictive adrenaline rush of a good fencing match!”]Any tips for a successful research career?Do not compare your performances to the ones of the people at your career stage; compare yourself with people that are already successful one level higher than you currently are at. For example, if you are a PhD student, ask yourself what in your current performance separates you from being a good postdoc—once a postdoc, what is missing to be a good PI.