Reflections on race,ethnicity, and NIH research awards

It has been a decade since “Race, Ethnicity, and NIH Research Awards” was published. Receiving the American Society for Cell Biology Public Service Award allows me to reflect on this research and its impact. In this essay, I share the story of how my research interests and professional networks provided the opportunity to do this important work. I also make the case for improved data and mentoring to address race and ethnic disparities in NIH funding.     

The case of philanthropy: bringing scientists and philanthropic donors together,for good

Summary: Philanthropists and scientists share many common interests, and yet they are not familiar with each other''s ways of thinking. This Editorial highlights how to improve their mutual understanding to advance research and life sciences.

“Wealth is not new. Neither is charity. But the idea of using private wealth imaginatively, constructively, and systematically to attack the fundamental problems of mankind is new.” – John Gardner

Philanthropy, derived from private wealth, stands unique as a vital source of scientific funding. Yet many scientists don''t truly understand the workings of this form of charitable giving. Some are even wary of it, and believe that a divide between the worlds of science and business is a normal state of affairs. My experience has exposed striking similarities between the two specialties: both dedicate their resources to innovation and the sincere desire to do good for their fellow man.I''ve been lucky to work on both sides of the fence. I conducted research for my PhD at the Wistar Institute in Philadelphia, PA, and at Sloan Kettering Institute in New York City, NY, where I worked on the Id1 gene and its role in the molecular mechanism of mammalian cell differentiation. I later moved to the Pershing Square Foundation. In 2013, to support young investigators with bold and risky ideas in cancer research in the New York area, the Pershing Square Foundation partnered with the Sohn Conference Foundation to create the Pershing Square Sohn Research Alliance (PSSCRA). Since the organization''s founding, I have served as its Executive Director. As a result of my career experience, I understand firsthand the role of philanthropic support of medical research. I am always excited to work with new, young and innovative talent, and to introduce that talent into the social mainstream.     

A Tale of Mother and Daughter

Loving science and nature and being a scientist can be very different, yet the two are so intertwined in a scientist''s life that you will certainly experience both aspects. This essay presents my perspective on how, as one who loves science and nature, I came to fall in love with centrosome behavior in stem cells and how I came to run a lab as a scientist. When I started, there was a big gap between my love for science and my experience as a scientist. I filled this gap by learning a “laid-back confidence.”Before the beauty of cell biology (or whatever you love), who you are (i.e., your age, gender, or race) is immaterial. Yet history shows that the ease with which you can pursue science is influenced by who you are. This has certainly been my experience. The key is to find a way to fill in the gap between who you are and what you are (i.e., a scientist), a goal in which we must all support each other. It is my hope that this essay will convey something helpful to those who are at early stages of their career and might be encountering obstacles because of who they are.     

By the scientists, for the scientists

My association with the JCB began very early in my scientific career. In fact, it predated my understanding that there would even be a scientific career. In the mid-1970s while still an undergraduate, the JCB published my very first paper, a contribution noted perhaps less so for its reporting the characterization of the first known protein in plant cell walls than for a footnote that called attention to the evolutionary conservation of a relationship between “sex and slime” throughout the plant and animal kingdoms.     

Mismatched expectations

Public funding for basic research rests on a delicate balance between scientists, governments and the public. COVID could further shift this equilibrium towards translation and application.

Keeping a research laboratory well‐funded to pay for salaries, reagents, infrastructure, travel, and publications is surely a challenging task that can consume most of a PI’s time. The risk is that if the funding decreases, the laboratory will have to shrink, which means less publications and a decreased probability of getting new grants. This downward spiral is hard to reverse and can end up with a token research activity and increased teaching instead. Some would see this is as an unwelcome career change. Apart from the personal challenge for PIs to keep the income flowing, there is no guarantee that the overall funding wallet for research will continue to grow and no certainty that the covenant between the funder and the funded will remain unchanged. The COVID‐19 pandemic could in fact accelerate ongoing changes in the way public funding for research is justified and distributed.There are three legs that support the delicate stool of competitive funding. The first is the scientists or, more precisely, the primary investigators. To get to that position, they had be high achievers as they moved from primary degree to PhD to post doc to the Valhalla of their own laboratory. Along the way they showed to be hard‐working, intelligent, competitive, innovative, lucky, and something between a team player and a team leader. The judgment to grant independence is largely based on publications—and given their track record of great papers to get there, most young PIs assume they will continue to get funding. This is not a narcissistic sense of entitlement; it is a logical conclusion of their career progression.They will get started by recruiting a few PhD or higher degree students. Although this is about educating students, a PI of course hopes that their students generate the results needed for the next grant application. The minimum time for a PhD is about three years, which explains that many grants are structured around a 3‐ to 5‐year research project. The endpoints are rarely the finishing line for a group’s overall research program: Hence, the comments in reviews along the line that “this paper raises more questions than it answers and more work will be required…” Work is carried on with a relay of grants edging asymptotically to answer a question raised decades before. I recall a lecturer from my PhD days who said that he would not do an obvious experiment that would prove or disprove his hypothesis, because “If I did that experiment, it would be the end of my career”. Others are less brazen but still continue to search for the mirage of truth when they know deep in their hearts that they are in a barren desert.The funding from the competitive grants is rarely enough to feed the ever‐growing demand for more people and resources and to make provisions for a hiatus in grant income. Eventually, an additional income stream comes from industry attracted by the knowledge and skills in the laboratory. The PI signs a contract for a one‐year period and allocates some resources to deliver the answers required when due. Similarly, some other resources are shepherded to fulfill the demands of a private donor who wants rapid progress on a disease that afflicts a loved one. The research group is doing a marathon run working on their core challenges with occasional sprints to generate deliverables and satisfy funders who require rapid success—a juggling act that demands much intellectual flexibility.State funding is the second leg and governments have multiple reasons for supporting academic research, even if these are not always presented clearly. Idealistically, the public supports research to add to the pool of knowledge and to understand the world in which we live but this is not how public funding started. The first universities began as theological seminars that expanded to include the arts, law, philosophy and medicine. Naturalists and natural scientists found them a serene and welcoming place to ponder important questions, conduct experiments, and discuss with their colleagues. The influence of Wilhelm von Humboldt who championed the concept of combining teaching and research at universities was immense: both became more professional with codified ways of generating and sharing knowledge. Government funding was an inevitable consequence: initially to pay for the education of students, it expanded to provide for research activities.While that rationale for supporting teaching and research remains, additional reasons for funding research emerged, mostly in the wake of World War 2: the military, national economies, and medicine required new products and services enabled by knowledge. It also required new structures and bodies to control and distribute public resources: hence the establishment of research funding agencies to decide which projects deserve public money. The US National Science Foundation was founded in 1950 following the analysis of Vannevar Bush that the country’s economic well‐being and security relied on research. The NIH extramural program started tentatively in the late 1930s. The Deutsche Forschungsgemeinschaft (DFG) was established in 1951. The EU Framework Programmes started in 1984 with the explicit goal to strengthen the economy of the community. It was only in 2007 that the European Research Council (ERC) was established to support excellence in research rather than to look at practical benefits.But the tide is inevitably moving toward linking state research funding with return on investment measured in jobs, economic growth, or improved health. Increasingly, the rationale for government investment is not just generation of knowledge or publications, but more products and services. As science is seen as the driver of innovation and future economic growth, the goal has been to invest 3% or more of a country’s GDP into research—although almost two‐thirds of this money comes from industry in advanced economies. Even nations without a strong industrial base strive to strengthen their economies by investing in brains. This message about government’s economic expectations is not lost on the funding agencies and softly trickles down to selection committees, analysts, and program officers. The idealistic image of the independent scientist pursuing knowledge for knowledge’s sake no longer fits into this bigger picture. They are now cajoled into research collaborations and partnerships and, hooked to the laboratories’ funding habit, willingly promise that the outcome of the work will somehow have practical applications: “This work will help efforts to cure cancer”.The third leg that influences research directions is the public who pay for research through their taxes. Mostly, they do not get overly excited or concerned about those few percentages of the national budget that go to laboratories. However, the COVID‐19 crisis could change that: Now, the people in the white coats are expected to provide rapid solutions to pressing and complex problems. The scientists have so far performed extremely well: understanding SARS‐CoV‐2 pathology, genetics, and impact on the immune system along with diagnostic tests and vaccine candidates came in record time. Vaccine development moved with lightning speed from discovery of the crucial receptor proteins to mass‐producing jabs, employing many new technologies for the first time. 2020 has been a breath‐taking and successful year for scientists who delivered a great return on investment.The public have also seen what a galvanized and cooperative scientific community across disciplines can achieve. “Aha,” they may say, “why don’t you now move on to tackle triple‐negative breast cancer, Alzheimer’s or Parkinson’s?” This is a fair and challenging question. And the increasing involvement of consumers and patients in research, at the behest of funding agencies, will further this expectation until the researchers respond. And respond they will, as they have always done to every hint of what might be needed to obtain funding.The old order is changing. The days of the independent academics getting funding for life to do what they like in the manner they chose will not survive the pressures from government to show a return on investment and from society to provide solutions to their problems. The danger is that early‐stage research—I did not say “basic” as it has joined “academic” as a pejorative term—will be suffocated. Governments appoint the heads of funding agencies, and it is not surprising if the appointees share the dominant philosophy of their employer. Peer‐review committees are being discouraged, subtly, from supporting early‐stage research. Elsewhere, the guidelines for decisions on grant applications give an increasing score for implementation, translation, IP generation, and so on. Those on the panels get the message and bring it back to their institutions that slowly move away from working to understand what we are ignorant about to using our (partial) understanding to develop cures and drugs.As in all areas, balance is needed. Those at the forefront of translating knowledge into outcomes for society have to remind the public as well as the government that the practical today is only possible because of the “impractical” research of yesterday. Industry is well aware of this and has become a strong champion for excellent early‐stage research to lay the groundwork for solving the next set of hard problems in the future. The ERC and its national counterparts have a special role to play in highlighting the benefits of supporting research with excellence as the sole criterion. In the meantime, scientists have to embrace the new task of developing solutions to societal problems without abandoning the hard slog of innovative research that opens up new understanding from which flows translation into practical applications.     

Behavioral neuroendocrinology in nontraditional species of mammals: things the 'knockout' mouse CAN'T tell us

The exploration of many of the fundamental features of mammalian behavioral neuroendocrinology has benefited greatly throughout the short history of the discipline from the study of highly inbred, genetically characterized rodents and several other "traditional" exemplars. More recently, the impact of genomic variation in the determination of complex neuroendocrine and behavioral systems has advanced through the use of single and multiple gene knockouts or knockins. In our essay, we argue that the study of nontraditional mammals is an essential approach that complements these methodologies by taking advantage of allelic variation produced by natural selection. Current and future research will continue to exploit these systems to great advantage and will bring new techniques developed in more traditional laboratory animals to bear on problems that can only be addressed with nontraditional species. We highlight our points by discussing advances in our understanding of neuroendocrine and behavioral systems in phenomena of widely differing time scales. These examples include neuroendocrine variation in the regulation of reproduction across seasons in Peromyscus, variation in parental care by biparental male rodents and primates within a single infant rearing attempt, and circadian variation in the regulation of the substrates underlying mating in diurnal vs. nocturnal rodents. Our essay reveals both important divergences in neuroendocrine systems in our nontraditional model species, and important commonalities in these systems.     

Divining the Essence of Symbiosis: Insights from the Squid-Vibrio Model

Biology has a big elephant in the room. Researchers are learning that microorganisms are critical for every aspect of the biosphere''s health. Even at the scale of our own bodies, we are discovering the unexpected necessity and daunting complexity of our microbial partners. How can we gain an understanding of the form and function of these “ecosystems” that are an individual animal? This essay explores how development of experimental model systems reveals basic principles that underpin the essence of symbiosis and, more specifically, how one symbiosis, the squid-vibrio association, provides insight into the persistent microbial colonization of animal epithelial surfaces.     

A sustained passion for intracellular trafficking

I am honored to be the first recipient of the Women in Cell Biology Sustained Excellence in Research Award. Since my graduate school days, I have enjoyed being part of a stimulating scientific community the American Society for Cell Biology embodies. Having found myself largely by accident in a career that I find deeply enjoyable and fulfilling, I hope here to convey a sense that one need not have a “grand plan” to have a successful life in science. Simply following one''s interests and passions can sustain a career, even though it may involve some migration.     

Hongyuan Yang: Tracking lipids,one droplet at a time

Hongyuan Yang investigates lipid trafficking and lipid droplet biogenesis.

Hongyuan Yang grew up in a small city east of Beijing, China. From his childhood, Hongyuan recalls that “food was not abundant, so I was hungry at times, but education was free and good.” Driven by his curiosity for science, after completing his undergraduate studies at Peking University Health Science Center, China, he enrolled at Columbia University, NY, for his doctoral training. Under the guidance of his advisor, Dr. Stephen Sturley, Hongyuan studied lipids in budding yeast. The laboratory’s research department fostered a strong interest in lipids and atherosclerosis, and after earning his PhD, Hongyuan obtained a faculty position at the National University of Singapore (NUS) in 1999. In 2007, he moved to the University of New South Wales (UNSW) in Sydney, Australia, to continue his scientific journey exploring lipids. We contacted Hongyuan to learn more about his career and interests.Hongyuan Robert Yang. Photo courtesy of UNSW.What interested you about lipids?My five-year doctoral study focused entirely on the enzymes Sterol O-Acyltransferases (SOAT, also known as ACAT, Acyl-CoA Cholesterol Acyltransferases), which catalyze the formation of sterol esters from sterols/cholesterol and fatty acyl CoAs (1). SOATs, integral membrane proteins of the ER, are potential therapeutic targets for heart disease and Alzheimer’s disease. Since then, I have been fascinated by two things related to SOAT: first, what happens upstream of SOAT, i.e., how exogenous cholesterol reaches SOAT/ER; and second, what happens downstream of SOAT, i.e., how its product—cholesterol esters—is stored in cells in the form of lipid droplets (LDs).These are fundamental questions in cell biology. While reading on how cholesterol arrives at the ER for esterification by SOAT/ACAT in the late 1990s, I realized that the trafficking of most lipids was poorly characterized with little molecular insight. Significant progress has been made in the last 20 years, but the lack of tools that track the movement of lipids has hampered our understanding of the selectivity, efficacy, and kinetics of lipid trafficking. Few cell biologists cared about LDs ∼20 years ago, even though LDs are prominent cellular structures in many disease conditions. Each LD comprises a hydrophobic core of storage lipids (triglycerides and sterol esters) wrapped by a monolayer of phospholipids. Largely considered inert lipid granules, LDs originate from the ER and are relatively simple cellular structures as compared with other organelles (see image). Now, we know that LDs are not that simple: their biogenesis is tightly regulated, they actively interact with other organelles, and they regulate many aspects of cellular function as well as disease progression. Astonishingly, we still have little understanding of how LDs originate from the ER. I am very much intrigued by the complexity of these two seemingly simple cellular processes, i.e., lipid trafficking and LD biogenesis.What are some of the scientific questions currently of interest in your laboratory?We are currently focusing on how LDs originate from the ER. The first significant paper from my own laboratory was the discovery of seipin as a key regulator of LD formation (2). Results from many groups have demonstrated that seipin can organize the formation of LDs; however, the exact molecular function of seipin remains mysterious. Our data suggest that seipin may directly impact the level and/or distribution of lipids such as phosphatidic acid near sites of LD biogenesis, and the effect of seipin deficiency on LD formation is secondary to changes in local lipids. We are now working hard to test this hypothesis. Moreover, data from my laboratory and others indicated that nonbilayer lipids may have a greater impact on the biogenesis of LDs than that of other ER-derived structures, such as COPII vesicles. This may result from the monolayer nature of the LD surface. We hope to dissect the dynamic changes of lipids at ER domains where LDs are born. More broadly, the ER is a fascinating organelle to me. The simple division of ER into sheets and tubules does not reflect the dynamic nature of this organelle. Dissecting the composition and organization of lipids and proteins of the ER would help answer key questions relating to LD biogenesis, and it is therefore one of our future directions.Another major focus is to understand how cholesterol and phosphatidylserine are moved between organelles. We have been working on how low-density lipoprotein (LDL)–derived cholesterol (LDL-C) reaches the ER for two decades. The release of LDL-C from lysosomes requires the Niemann Pick C1&2 proteins, whose malfunction causes lysosomal cholesterol accumulation and a lethal genetic disorder affecting young children. The Ara Parseghian Medical Research Foundation has led the way in supporting research into cholesterol trafficking, and I take this opportunity to thank their generous support. Once released from lysosomes, LDL-C is believed to reach the plasma membrane first and then the ER. We identified ORP2 as a possible carrier of LDL-C to the plasma membrane using a PI(4,5)P₂ gradient (3). There must be other carriers and/or pathways because ORP2 deficiency only causes a minor accumulation of cholesterol in lysosomes. Another interesting question is what prevents LDL-C from reaching the ER directly from lysosomes, given the close contact between lysosomes and the ER. We reported that ORP5 may bring LDL-C directly to the ER (4). However, it was later found that ORP5 binds and transfers phosphatidylserine, not cholesterol. Thus, our observed link between ORP5 and cholesterol is through some indirect yet unknown mechanism. We have been perplexed by these observations for many years, but a recent study demonstrated that phosphatidylserine is required for the trafficking of LDL-C, establishing a close link between cholesterol and phosphatidylserine (5). We are now trying to understand how the trafficking and distribution of cholesterol, phosphatidylserine, and PI(4,5)P₂ are interconnected. For a long time, I felt that it was impossible to figure out the molecular details governing the cellular trafficking of lipids due to redundant pathways and a lack of tools to track lipids. Recent progress in this field has given me hope.Lipid droplets in a HeLa cell are shown in red (BODIPY), with their surface in green. DAPI (blue) labels DNA. Image courtesy of Hongyuan Yang.What kind of approach do you bring to your work?Besides honesty and open-mindedness, we emphasize rigor and comprehensiveness. We often make our initial discoveries in cell-based screens. This approach has many advantages, but it also gives rise to artifacts and cell-line specific observations. We aim to complement our initial findings with biochemical and structural analyses in vitro as well as animal studies in vivo. To further establish the reproducibility of our data, I often ask my close friends and collaborators to independently repeat the key findings of a study before submission. It generally takes a long time for us to complete a study, but I believe the effort will pay off in the long run.What did you learn during your training that helped prepare you for being a group leader? What were you unprepared for?During my PhD at Columbia, I was most impressed with the general attitude of my mentors toward research. No matter how much they have achieved, they take every new experiment and every poster presentation seriously.As I did not have postdoctoral training, I was somewhat unprepared at the beginning of my independent career. One difficult challenge was knowing when to finish a paper and project. We often kept working and working. I have now gotten a lot better.You’ve done research on three continents throughout your career. Can you tell us about some of these transitions?During the last year of my doctoral studies at Columbia, I was offered a lecturer position by the Department of Biochemistry at NUS. It was a very hard decision to leave the United States, but I was excited by the prospect of starting my own laboratory at a top institution. Life at NUS was very good overall, despite some struggles. I had to make ∼700 slides for teaching during the first year and my start-up fund was 10,000 Singapore dollars (~6,000 USD). But the graduate students were fully supported by the university, and most of them are hard working and talented. The crucial screen that led to the discovery of seipin as a key regulator of LD formation was performed at NUS (2). I enjoyed my time at NUS, where I was promoted and tenured. However, my family and I could not get used to the heat and humidity. We looked for a place with better climate, and it happened that my current employer, UNSW, had an opening in 2006. Moving continents with two kids was very disruptive, and I had zero publications in 2007. Our work on seipin was delayed and almost got scooped. I was also very worried about funding in Australia since I hardly knew anyone and the funding system. It turned out that the Australian community was very supportive of our research from day one. I have also been very fortunate to receive generous support from the Ara Parseghian Medical Research Foundation, based in the United States, after my move to Sydney.Hongyuan’s “metabolism team” after a basketball game. Photo courtesy of Hongyuan Yang.What has been the biggest accomplishment in your career so far?While I am mostly recognized for discovering seipin’s role in lipid droplet formation, I am prouder of the work we have done on lipid trafficking and the oxysterol binding proteins. We struggled mightily for the first 15 years. At one point in 2015, I seriously considered abandoning this line of research. But we persisted and discovered their roles in regulating plasma membrane PI(4,5)P₂ and cholesterol, as well as in lipid droplet formation (3, 6).What has been the biggest challenge in your career so far?The biggest challenge has to do with the subject of my research topic: the fundamental cell biology of lipids. The sorting, distribution, and storage of cellular lipids are clearly very important topics in biology, but they are sometimes too fundamental to explain to funding agencies and new students. These days, lipid research is not as “sexy” as other topics. But there are so many unanswered questions in lipidology. I strongly believe that lipid research is going to be the next “big thing” as new techniques such as cryoEM now allow us to appreciate lipids and membrane proteins with unprecedented clarity.Who were your key influences early in your career?Besides mentors and teachers at Columbia, I really enjoyed reading and studying the works by Drs. Mike Brown and Joseph Goldstein, Ta-Yuan Chang, and Scott Emr. While they were not my teachers, their work inspired and impacted many young scientists, including me.What is the best advice you have been given?I have been given many pieces of great advice during my career. The best one in my view is “Less is more.” I was once told, “You would be better off with a lab of six than twelve.” Initially, I did not get it because I thought that a bigger group would allow me to explore more directions and be more productive. The reality is that, as a little-known junior researcher, few experienced people would join my laboratory. Funding is also a major limiting factor. Supervising a large number of students is fulfilling, but it also takes away some of my own time to think critically about the projects. I have largely kept my group under six, and this allows me to better supervise and guide the trainees. People say, “Once your team has more than 15 members, you become a manager instead of a scientist.” My own experience corroborates that statement because I struggled quite a bit when my group reached 12 at one point.What hobbies do you have?I am heavily into sports, especially basketball and tennis. I follow the NBA closely, and Jeremy Lin is my hero. I still play basketball at least twice a week. I am the captain of a basketball team comprised of scientists working on metabolism (see image). We play real, refereed basketball games against local teams during conferences. As I am getting older, I have also picked up tennis. I watch coaching videos on YouTube but still need a lot of work on my forehand. Through sports, I learned teamwork and the spirit of fighting to the last second. If I were not a scientist, I would probably run a sports-related business.What has been your biggest accomplishment outside of the laboratory?I got married and had children relatively early. Both of my kids are now in college and they appear to be decent human beings. I have been extremely lucky because my wife did most of the heavy lifting in looking after the kids. It was still a struggle for me to balance work and parental duties during the early days of my independent career. I am very proud and happy with where we are as a family right now.Any tips for a successful research career?Everyone is unique. Knowing your strengths and especially your weaknesses can be crucial to your success. My undergraduate training was in medicine and health management, and my PhD work focused on genetics and cell biology, so my understanding of physical chemistry is rather inadequate. I am also very bad at developing new methods. To alleviate these deficiencies, I constantly monitor new methods in my field and I purposefully look for collaborators with strong chemistry backgrounds. I have benefited immensely from such efforts.     

A passion for the science of the human genome

The complete sequencing of the human genome introduced a new knowledge base for decoding information structured in DNA sequence variation. My research is predicated on the supposition that the genome is the most sophisticated knowledge system known, as evidenced by the exquisite information it encodes on biochemical pathways and molecular processes underlying the biology of health and disease. Also, as a living legacy of human origins, migrations, adaptations, and identity, the genome communicates through the complexity of sequence variation expressed in population diversity. As a biomedical research scientist and academician, a question I am often asked is: “How is it that a black woman like you went to the University of Michigan for a PhD in Human Genetics?” As the ASCB 2012 E. E. Just Lecturer, I am honored and privileged to respond to this question in this essay on the science of the human genome and my career perspectives.

“Knowledge is power, but wisdom is supreme.”

     

Fruit Flies in Biomedical Research

Many scientists complain that the current funding situation is dire. Indeed, there has been an overall decline in support in funding for research from the National Institutes of Health and the National Science Foundation. Within the Drosophila field, some of us question how long this funding crunch will last as it demotivates principal investigators and perhaps more importantly affects the long-term career choice of many young scientists. Yet numerous very interesting biological processes and avenues remain to be investigated in Drosophila, and probing questions can be answered fast and efficiently in flies to reveal new biological phenomena. Moreover, Drosophila is an excellent model organism for studies that have translational impact for genetic disease and for other medical implications such as vector-borne illnesses. We would like to promote a better collaboration between Drosophila geneticists/biologists and human geneticists/bioinformaticians/clinicians, as it would benefit both fields and significantly impact the research on human diseases.     

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.     

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.     

‘Keeping silent’: the problem of citizenship for Lilian Thuram

Abstract

Drawing upon translations of the football player Lilian Thuram's critiques of French racism and immigration, as well as other English language sources on the condition of banlieue life in France, this essay explores the relationship between citizenship and representation. Rather than merely reading Thuram as an athlete, I situate him as a political figure. The essay reads Thuram philosophically: as a figure who is familiar with and thinks the French and European political through its philosophical history. It is argued that Thuram's critiques are inexplicable unless they are understood as a redress to the very philosophical core of European modernity. Instead of presuming an inevitable relationship between citizenship and representation, this essay seeks to understand how representation works in relation to questions of citizenship and the limits of citizenship in contemporary Europe for those who are defined as Berber, black or Arab.     

Developing the genotype-to-phenotype relationship in evolutionary theory: A primer of developmental features

For decades, there have been repeated calls for more integration across evolutionary and developmental biology. However, critiques in the literature and recent funding initiatives suggest this integration remains incomplete. We suggest one way forward is to consider how we elaborate the most basic concept of development, the relationship between genotype and phenotype, in traditional models of evolutionary processes. For some questions, when more complex features of development are accounted for, predictions of evolutionary processes shift. We present a primer on concepts of development to clarify confusion in the literature and fuel new questions and approaches. The basic features of development involve expanding a base model of genotype-to-phenotype to include the genome, space, and time. A layer of complexity is added by incorporating developmental systems, including signal-response systems and networks of interactions. The developmental emergence of function, which captures developmental feedbacks and phenotypic performance, offers further model elaborations that explicitly link fitness with developmental systems. Finally, developmental features such as plasticity and developmental niche construction conceptualize the link between a developing phenotype and the external environment, allowing for a fuller inclusion of ecology in evolutionary models. Incorporating aspects of developmental complexity into evolutionary models also accommodates a more pluralistic focus on the causal importance of developmental systems, individual organisms, or agents in generating evolutionary patterns. Thus, by laying out existing concepts of development, and considering how they are used across different fields, we can gain clarity in existing debates around the extended evolutionary synthesis and pursue new directions in evolutionary developmental biology. Finally, we consider how nesting developmental features in traditional models of evolution can highlight areas of evolutionary biology that need more theoretical attention.     

It's a Wonderful Life: A Career as an Academic Scientist

Many years of training are required to obtain a job as an academic scientist. Is this investment of time and effort worthwhile? My answer is a resounding “yes.” Academic scientists enjoy tremendous freedom in choosing their research and career path, experience unusual camaraderie in their lab, school, and international community, and can contribute to and enjoy being part of this historical era of biological discovery. In this essay, I further elaborate by listing my top ten reasons why an academic job is a desirable career for young people who are interested in the life sciences.Students are attracted to careers in academic science because of their interest in the subject rather than for financial reward. But then they hear messages that make them think twice about this career choice. It is difficult to find a job: “Hear about Joe? Three publications as a postdoc and still no job offers.” The NIH pay line is low: “Poor Patricia, she is now on her third submission of her first NIH grant.” Publishing is painful: “Felix''s grad school thesis work has been rejected by three journals!” Academic jobs are demanding: “Cathy has spent her last three weekends writing grants rather than being with her family.”Such scenarios do take place, but if you think that this is what a career in academic science is about, then you need to hear the other side of the story. And this is the purpose of this article—a chance to reflect on the many good things about the academic profession. In the classic movie It''s a Wonderful Life, George Bailey is at the point of despair but regains his confidence through the wisdom and perspective of a guardian angel, Clarence. Doubt and setbacks also are bound to happen in science (as is true of other careers), but pessimism should not rule the day. It is a great profession and there are many happy endings. I would like to share my top ten reasons of why being an academic professor is a “wonderful life,” one that bright and motivated young people should continue to aspire to pursue.     

Uncovering the biodiversity of genetic and reproductive systems: time for a more open approach. American Society of Naturalists E. O. Wilson Award winner address

Important scientific findings frequently arise from serendipitous findings. Unfortunately, many scientists are not prepared to take advantage of unexpected results and to question established paradigms, and this prevents them from capitalizing on their good fortune. In this essay, I first explain how pure serendipity led us to discover unusual modes of reproduction such as clonal reproduction by males and a green-beard gene. Next, I argue that the reproductive systems of ants and other organisms are probably much more diverse than is generally appreciated. This leads me to advocate for a new "molecular naturalist" approach to reproductive systems and a more "naturalistic" approach in population and evolutionary genetics. Finally, I make two further points. The first is that our current funding and education systems tend to hinder originality and curiosity. The other is that the field of ecology and evolution, and more generally all of science, would benefit from a shift in values from scientific productivity to scientific creativity. A few suggestions are made to this effect.