Spotlight Cite This: ACS Chem. Biol. 2018, 13, 1700−1704
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ABSTRACT: The discovery of green fluorescent protein (GFP) and its development into a genetic tag for monitoring cell fate was transformative for bioscience, and in 2008 the Nobel Prize in Chemistry was awarded to Osamu Shimomura, Martin Chalfie, and Roger Tsien for their discoveries. Roger Tsien’s development of GFP into an expansive color palette of fluorescent protein tags allowed for the revolutionary ability to monitor different biological processes simultaneously and paved the way for chemical biologists to see into cells like never before. ACS Chemical Biology collected memories from his colleagues, trainees, friends, and family that portray a creative, incisive, and endlessly curious scientist who is deeply missed. This special issue on biological sensing and imaging would not have been possible without his discoveries and is dedicated to his memory.
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INTRODUCTION BY JIN ZHANG, UNIVERSITY OF CALIFORNIA, SAN DIEGO I have learned a lot from my interactions with Roger. One particular moment stands out in my memory. It happened a few months after I joined Roger’s lab as a postdoctoral fellow. One day when I was busy doing imaging experiments, Roger caught me outside the imaging room between my experiments and asked how the experiments were going. I told him that I was not finished with the experiments and had not gotten a chance to analyze the data. What Roger said at that very moment left a strong impression on me, one that will stick with me throughout my entire career. He told me not to close my eyes and cover my ears during the experiments and wait until the next day to analyze the data, instead enjoy and take advantage of the live-cell experiments where two-way communications are happening between the cells and the experimenters. He said it in the best way, “I much prefer experiments where there are pretty colors, and real activity, where the cells can talk back to you while they are alive. It makes it possible to design the experiments based on the conversation you’re having with them.” To enable such conversations, Roger created and developed a series of ingenious molecular tools that revolutionized neurobiology and cell biology. Another lesson was taught to me by examples. In a world where everything becomes more complicated and running a lab becomes more like running a business, Roger showed me the value of focusing on science itself. With his forward-looking vision, profound knowledge, and ingenious creativity, Roger laid out the conceptual framework and impacted our thinking in many areas, including chemical biology. Roger had such a profound influence on science, the scientific community, as well as many of us personally.
ROBERT CAMPBELL, UNIVERSITY OF ALBERTA Warm memories of my time in Roger’s lab have never been far from my mind. However, since his passing, I find myself thinking about those times, and Roger’s many scientific contributions, even more often than when he was alive. As I flip through the pages of any issue of any journal in the area of chemical or cell biology, I see his influence in article after article.
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RICHARD TING, WEILL CORNELL MEDICINE In 2009, Prof. Tsien and I were drafting a manuscript for Bioconjugate Chemistry on the topic of fluorescence guided surgery. I had named my molecule the “[18F]-boron/optical multimodality beacon” and had slipped this reference a single time into a 4000-word article that Prof. Tsien and I were preparing for submission. I had thought that this reference would go unnoticed by Prof. Tsien. 2009 was the year following Dr. Tsien’s receipt of a Nobel, and I figured that he would be too busy giving Nobel lectures, coauthoring multiple papers, and touring the world as the plenary lecturer to notice that I had slipped the acronym “F-BOMB” into the submitted manuscript. Not only had Prof. Tsien noticed the acronym, but in the very next group meeting, in front of the entire research group, told me that, “...on the other side of the Atlantic, we used F-BOMB(s) to describe only negative results.” Ultimately, Prof. Tsien let me keep the nomenclature and, surprisingly, encouraged me to use the acronym throughout the manuscript. To me, this anecdote quickly summarizes many of Prof. Tsien’s unique personality traits, including an acute attention to detail, an ability as a tactful communicator, a sense of humor, and infinite patience. He is, and will continue to be, missed.
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GEOFFREY BAIRD, UNIVERSITY OF WASHINGTON, SEATTLE I was an unusual graduate student in Roger Tsien’s Lab, primarily for the reason that before I asked him if I could work in his lab in 1997, I’d never heard of him. I was looking for a place to learn chemistry, but not just for chemistry’s sake. I wanted to learn how to be an applied biochemist, and I lucked out, because Roger’s lab was the best place on earth to learn how to do that. Roger’s style in leading a research lab, affording substantial Special Issue: Sensors Image courtesy of Paul Steinbach.
© 2018 American Chemical Society
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I also found it super cool that he really liked the outreach work we did with Science Bridge at the time. He even included it in his laureate address.
independence to lab members but requiring high productivity in return, yielded great returns throughout his career. Just as Virginia Woolf talked about how a woman must be afforded “...a room of one’s own” to write good fiction, so it seems that Roger understood that the best way to get science done was to assemble a dynamic and diverse group of intelligent hard workers; to give those scientists the time, money, and space they need to succeed; and then to get the hell out of their way. Aside from that pearl of scientific leadership, the other career lesson I learned from Roger is that it is the PI’s role to tell the graduate student that their dumb ideas will not work. This is mostly to keep the graduate students from wasting their time, but also to incentivize the graduate students to prove their boss wrong. I thank Roger for every time he told me I was wrong, mostly because he was almost always right, but also because the few times he was wrong ignited in me the excitement that lives at the heart of scientific exploration and the passion that motivates one to work so hard in the pursuit of knowledge. Roger was my inspiration: a brilliant scientist, an artist, a thinker, a historian, and a pretty funny guy. He was taken from us far too early, and if there is an afterlife, I hope Roger is still doing science and running group meetings in the great beyond. It’d give me comfort to know that every Friday afternoon, Roger’s out there somewhere, eating his two-banana lunch, asking why his postdocs keep ordering chemicals from Sigma, scratching his left ear with his right arm bent over his head or slapping his head on both sides simultaneously in a display of astonishment, and posing the most incisive questions about scientific experiments that any human has ever asked.
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LESLEY ELLIES, UNIVERSITY OF CALIFORNIA, SAN DIEGO Roger loved to work on his own research project over the end of year holidays when the lab was quiet. I found him working away one afternoon and asked him whether he was preparing some data for a group meeting. He laughed and said that his experiments were not working quite the way he expected, and he was not sure what he would be able to present. We both laughed. This is a cherished memory, as one of Roger’s greatest sorrows following his stroke was that he did not have the dexterity to be able to continue with his own research projects.
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HIROTATSU KOJIMA, THE UNIVERSITY OF TOKYO I was working on the development of fluorescent chemical probes for detecting protein−protein interactions using singlet oxygen as a postdoc in his lab. During the work, he let me know that a similar method, AlphaScreen, had been successfully developed by another team, which is now widely used for drug discovery. I learned a lot from his foreseeing what would be useful and his directing research rationally.
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CSILLA LIPPERT, STANFORD UNIVERSITY When the UCSD campus closed for winter holidays each year and he was less encumbered by administrative tasks, Roger conducted a hands-on research project as a gift to himself. One of my strongest lab memories is of seeing on him on Christmas Eve sitting on the floor while fervently digging through a cabinet for just the right beaker. I was eager to complete my tasks and get home, but I stopped and stared. He looked happy there in his lab, using his lab equipment.
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TIMOTHY RINK, CAMBRIDGE, UK Roger Tsien was a career-long colleague and friend, whose oncein-a-generation brilliance gave a huge contribution to two very different stages of my professional life. While working together as young scientists at Cambridge in the 1970s, Roger demonstrated an unparalleled ability to innovate in organic and physical chemistry relevant to biology, and to devise and create rapidly the requisite equipment that underpinned our success in pioneering key developments in voltage sensing and intracellular calcium as well as pH and sodium and measurement. In the mid 1990s, in San Diego, he asked me to be CEO at Aurora Biosciences, a biotech company he had cofounded based on commercializing a suite of his latest fluorescence probes for drug discovery, including green fluorescent proteins, a novel gene reporter, and fast-response voltage reporters. From the latter technology, Aurora scientists (now part of Vertex, Inc.) developed important medicines for cystic fibrosis. Like so many who knew him, I still miss his astonishingly incisive and creative mind, his ability to bring it to bear on pretty much any scientific problem we wrestled with, and his wry sense of humor. Roger was generous to other scientists with his time and his reagents. He was surprisingly self-deprecating and had great difficulty in believing that colleagues might not be able easily to turn their hands to such tasks as complex integral calculus, circuit board design, or image analysis in the facile way he could.
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KAZUYA KIKUCHI, OSAKA UNIVERSITY What Roger taught me was, “Try the most difficult project and stick to it. An easier project must be undertaken by somebody else, already.” He added that this is what his piano teacher taught him. He also said that, “True biological application is extremely difficult, so it is worth working on it.” I appreciate these words, and when I am struggling for a new project, these words call back to me.
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MARGARET BUTKO, BIODESY, INC. One of my most vivid memories of Roger is how elated and excited he was to report his Christmas project findings to the group the first lab meeting after winter break, whether it was a success (and often became a new project in the lab) or an utter failure. His enthusiasm for creating new technology and for collecting and sharing data was contagious! Of course, his journey into the lab came at a cost. Every year after returning from winter break, I would find my bench (probably the cleanest in the lab upon leaving for vacation) full of piles of unlabeled glassware often containing very brightly colored substances. I would always ask Roger if he wanted me to clean it up, and every year he would reluctantly come out of his office to my bench, assess the situation, turn around, and walk away without saying anything, and about 5 min later Stephen or another chemist in the lab would be cleaning up the glassware in the chemical hood. One of my fondest memories with Roger is going to an intimate Janelia Farm conference with him months after I became
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JEREMY BABENDURE, ARIZONA SCITECH FESTIVAL I remember Roger used to use the quote from Pauling: “Change favors the prepared mind.” 1701
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peak represented the right compound. Having identified the fura-2/AM peak, Roger and I set out on a new synthesis of fura2/AM. When we came up with synthesis of the AM ester that gave us mainly one product (the right one), we were in business suddenly the door was open to doing a lot of biology. In another episode, Greg Grynkiewicz came to me and told me that he was secretly making a set of model fluorophores. He did not want Roger to know about it until after it was done because he thought Roger might disapprove. He asked me if I would secretly determine the extinction coefficient and quantum yield for each model compound. So, for accuracy, I dissolved the compounds in relatively large amounts of solvent using almost all the volumetric flasks we had in the lab. I remember Roger walking past these boxes of volumetric flasks, full of colored liquids, that were sitting on the floor. He seemed to be puzzled but never asked what was going on (to my relief). Anyway, eventually we were done, and I cannot tell you how many times Roger asked for the notebook pages with all the fluorophore data on them.
engaged to my now husband. This trip came with the expected conference shenanigans with Roger, including showing him data I had collected earlier in the week in the corner of the social hall so that he could add it to his talk that evening. However, to my surprise, when he introduced me to colleagues at the social hour, he often told them to congratulate me on my recent engagement. Later, he told me that finding a life partner was the most important decision I would make, and that he was so happy to see that I was fulfilling that part of my life. He spoke fondly about “courting” Wendy and told me that he hopes more than anything else that every person in his lab could find such a fitting life partner. It was very sweet, especially because this encounter came right before my advancement exam, which at the time felt like the most important thing in my life.
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ERIK RODRIGUEZ, GEORGE WASHINGTON UNIVERSITY While most people remember Professor Roger Y. Tsien for his mind and contributions to science, his wife, Wendy Tsien, and I often remember all the things that made him an amazing human. Roger had a unique personality that was formed by being the youngest child. When angered or annoyed, Roger would often smack his head or stick out his tongue. The group often took pictures with these gestures as jokes. Professor Tsien had a passion for life that spanned all facets of art, including writing, playing the piano, and taking photographs. Roger loved to travel with Wendy and would take hundreds of pictures on his trips, which he would show the entire group at meetings. His guilty pleasure was sweets, and he would often snag cookies at group meetings and chastised anyone who held onto the package too long. Professor Tsien had an incredibly dry and sarcastic sense of humor, which was often inappropriate when taken out of context. One example is “Look at what my grant money is being used for, chemical incompetence.” He liked joke acronyms, such as F-BOMB and smURFP, and everyone laughed to hear a Nobel laureate say the acronyms. Throughout his life, Roger was curious and always wanted to know why we were laughing and the joke. Professor Tsien always pointed out when I could not stop laughing and would say “Look, Erik is about to pee himself!” Roger had a deep passion for science, and he longed to perform his winter holiday science project. Usually my bench was taken because I was neat, and I would return to a bench covered in hairs because Roger had scratched if off while working and thinking. Semantics were extremely important to Roger to illuminate science. One of my favorite examples is, “Just as no one type of fruit in a grocery store supplants all others, so there is no single best fluorescent protein within the cornucopia derived from DsRed via mRFP1 and dimer2.” While this was true for the fluorescent proteins, unfortunately there was only one Professor Roger Y. Tsien.
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TIM BARDER, ARTHUR D. LITTLE It was during a regular Tsien lab meeting one afternoon where I witnessed the most impressive display of creativity, intellect, and scientific rigor in my career. Roger stood up toward the end of the meeting in order to share an idea he had for a new research project. Over the span of 15 min, Roger eloquently and unwaveringly discussed his idea from molecular orbital theory (the ideal HOMO−LUMO gap) to synthetic chemistry (precise retrosynthetic analyses) to in vitro biology (detailed discussion of relevant receptors and pathways) to in vivo pharmacology (optimal target engagement and expected physiological outcome). To this day, I cannot precisely recall the research idea but I still continue to be amazed and invigorated by both the breadth and depth of Roger’s knowledge and passion for everything in his life. Just another day for Roger but a life changing experience for me. R.I.P., Roger.
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BRIAN BACSKAI, HARVARD Roger Tsien was a genius. But more than that, he inspired everyone around him to think big. He recruited some of the smartest people I’ve ever worked with and pushed us to accomplish something great. His expectations were generally unrealistic but, on many occasions, became reality out of sheer determination. His dream was to improve human health, and the optical tools he developed have led to major advances to that end. He will be missed as one of the most impactful scientists of our generation.
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MARTA GIACOMELLO, UNIVERSITY OF PADOVA In 2005, I had the chance and honor to work in the laboratory of R. Y. Tsien. At that time, I was a second year Ph.D. student, and the time spent in his lab (although short) really marked my scientific path. Not only was he able to transmit to his younger trainees his enthusiasm for, what I like to define as, “the colors of research” (i.e., fluorescent proteins) but he was inspirational in many research fields in general. Starting from chemistry, thorough biology and pathology, his discoveries certainly lie at the basis of modern biotechnology.
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MARTIN POENIE, UNIVERSITY OF TEXAS AT AUSTIN I remember Roger complaining that his chemists wanted to do biology and that his biologist(s) (me at the beginning) wanted to do chemistry. But I got the chance. When I came to the lab, fura-2 was sitting on the shelf and not being used. Basically, it was not working. I looked at the acetoxymethy (AM) ester derivative which had been made by the traditional synthesis used for quin-2 and found that it was a mixture of more than a dozen peaks by HPLC. I collected these peaks drop by drop, hydrolyzed the ester, and titrated the samples in order to find which
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BRENT MARTIN, UNIVERSITY OF MICHIGAN When I heard Roger lecture in my first-year cell biology course, it was like nothing I’d ever seen. He introduced the idea of using fluorescent dyes to detect voltage and calcium in cells with all of 1702
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questions at scientific seminars. While it appeared that he might not be paying attention to the speaker (he often was observed scratching his leg or gazing at the audience), when he told the speaker, “I’m confused,” on a certain point, it always meant that the speaker was confused. Finally, Roger was both nice and fun to work for as a postdoc.
his quirky enthusiasm. During my rotation in his lab, I started a new project to develop cell-based retroviral screens. Roger thought this project would take just a few months, but things were not so simple. Fortunately, Roger’s Christmas projects always reminded him the challenges of getting experiments to work just right. Through my years in the Tsien lab, I tried a number of wild ideas, from trying to design tools to reprogram mRNAs, to testing out different labeling reagents for electron microscopy. When projects did not work out as planned, after bumping his head on his desk a few times, he always had the most insightful suggestions. I am still in awe of his breadth of knowledge across fields. He will always be an inspiration and an example of how to think about problems from many different perspectives.
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ANTOINE ROYANT, EUROPEAN SYNCHROTRON RADIATION FACILITY Prof. Tsien gave me the opportunity to spend a 1-year sabbatical in his lab in 2007. While I had hoped to know one of the classically studied fluorescent proteins of the GFP family, I got to witness how his constant reading of scientific literature and his way of thinking out of the box made him envisage developing fluorescent proteins from different types of light-absorbing proteins, including some absorbing in the far-red part of the light spectrum, which resulted in the design of authentic infrared fluorescent proteins. In addition, his encyclopedic knowledge in chemistry easily surpassed his expertise in protein engineering, and he taught me how various small molecules and proteins could either detect or generate reactive specific oxygen species, which would eventually pave the way to the development of various imaging and biotechnological applications. In brief, I lived a short, yet truly mind-boggling experience in Prof. Tsien’s lab, which decisively affected my scientific career, and I will always be thankful for this.
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BEN GIEPMANS, UNIVERSITY OF GRONINGEN Roger is renowned for his extraordinary achievements worldwide. Here, I share one of my memories of how phenomenal Roger was during group meetings. Typically, we had an easy start as Roger always brought cookies and other treats during the general announcements. When the scientific discussions started, he was eager to grasp everything, going back to slides for further discussion when needed, but also often hitting the “next slide” button due to the slow pace of the presenter, which sometimes led to a hilarious going back and forth in slides and a battle for the control button. One of the most remarkable elements that directly struck me was Roger’s use of his arms and legs, still seated in his chair, sometimes as if he was trying to transform into a beta barreled fluorescent protein to explain to us what important changes in the protein could be made. For me that body language is still the basis for the mFruit development.
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SUJATA R. EMANI, PH.D “You are persistent,” he curtly said to me, followed hastily by, “That is good for science.” Roger’s words have been etched in my brain ever since that day. I can imagine his face looking somewhere between bemused and annoyed, with the slightest smile. His curiously light-filled eyes behind his specs sort of glared at my first-year grad student face, and all I could feel was my pulse pounding in my head. All I could think was, “Did he just say that I could join his lab?” I was a junior in college when I read the FlAsH biarsenical dye papers, and that is when I swore I would work on this brilliant person’s team someday. Fast-forward two years later, and I was staring at the brilliant person, in his office, while his head hovered over stacks of research papers. I had no idea what I was in for, and I’m sure I disappointed him a hundred times, but he still gave me chance after chance to prove myself. I am forever indebted to Roger because he taught me how to keep going even when everything you are doing seems like it is going nowhere. My grad work was only so-so, but since then, I’ve started companies and taken on challenges that I never would have dared to try before. Roger told me I was persistent, and I feel every day that I cannot let him down.
ELAMPRAKASH N. SAVARIAR, VERTEX PHARMACEUTICALS When I joined the Tsien lab as a postdoctoral researcher, I was characterizing some lipid nanoparticles, and Roger was more interested to know the number of such nanoparticles per unit volume, rather than the typical hydrodynamic radius and polydispersity index. He stated that fluorescence correlation spectroscopy is famous for being able to measure the absolute concentration of dilute fluorophores without even requiring external standards. He wondered, why not use light scattering techniques to measure the number of nanoparticles? That resulted in a discussion with Drs. Sigrid Kuebler and Michael Larkin at Wyatt Technology. They verified that his intuition was true, and later I measured the absolute number of nanoparticles using static light scattering techniques. He was relieved when my measured values matched his back-of-the-envelope calculation. In the following year, we were invited to attend Wyatt’s light scattering conference, and Roger presented these findings as a part of his plenary seminar. As a scientist, Roger was unique and asked deep scientific questions in seminars. He was a big advocate for doing the right control experiments and never liked the simpler approach of, “It works, but we don’t know how.” He emphasized that if you know how, you can do it again and again. We have often seen him bringing learnings from diverse scientific disciplines to solve a problem in a nontraditional way. His loss was unexpected and deeply painful. He had very strong influence on my scientific career and was a great mentor.
ALEC HAROOTUNIAN, PH.D., AVELAS BIOSCIENCES, INC. Roger Tsien was the greatest polymath I have met. He had a broad and deep knowledge of chemistry and biology. He could also program the PDP-11 computer for image processing and reconfigure a circuit in the imaging camera for better linearity at low light levels. Roger also was known for his insightful
JESUS “TITO” GONZALEZ, AVELAS BIOSCIENCES I was a postdoctoral fellow in Roger’s lab from March of 1993 to January 1997, where I worked one-on-one with Roger to develop improved fluorescence indicators of cellular membrane potential using energy transfer between a fluorescent “gating charge” and a fixed fluorophore on the outer surface of the cell membrane. This was also the time period where the seminal
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One reason there were so many dead ends was due to the limited tools available to Roger to purify and isolate compounds. Many entries ended with a complex mixture, no product recovered, or product that would not recrystallize. He did not have available the chromatography tools we have today where we can isolate a minor product from a complex mixture. It must have been very frustrating to see his dream of physiological indicators being limited by the capricious behavior of synthetic chemistry and crude isolation methods. Yet there was no hint of frustration in his notes but rather a seemingly endless parade of creative ideas and energy to pursue them. Perhaps his deep appreciation of chemical experimentation and the lab scientist came, in part, from the challenges he faced in the lab to get chemistry to yield and enable his ideas to progress.
work on GFP occurred, and I was fortunate to have a front row seat. After moving into the corporate biotechnology scene to apply our invention to help find new drugs, Roger and I stayed in touch discussing mutual scientific and corporate interests. For many years, up to the time of his death, we regularly discussed many topics including those related to Avelas Biosciences, the company we helped found. I applied for a postdoctoral position with Roger after attending a seminar he gave about fluorescent indicators of cellular calcium. I was pleasantly surprised when he took a serious interest in my research on synthetic membrane probes and research proposals on membrane-spanning optical probes that could orient in bilayer membranes. Our discussions rapidly progressed to an offer letter to work on a new type of fluorescent membrane probe to enable imaging of rapid changes in cellular membrane potential. Only later did I fully understand the basis of his interest. My interaction with Roger the first few months at UC San Diego was a wonderful learning and scientific experience. I quickly became exposed to his incredibly broad scientific knowledge, insight, and creativity. But more than that, I realized that I was working on an extension of work he deeply cared about and had started during his Ph.D. work at Cambridge some two decades earlier. Roger’s thesis is an amazing piece of work. I felt fortunate to use his thesis as a key reference. There are four chapters, and two of them involved fluorescent indicators of cellular membrane potential. The first involved tetrodotoxin probes of sodium channels, and the last one was on optical indicators of physiological calcium. The last chapter was the scientific seed that Roger grew into the tremendously productive and impactful work that spurred so many areas of cell biology and medicine. Much later in 2008, when I heard that Roger had won the Nobel Prize, my first reaction was wondering which work was being recognized. I honestly thought, and still do, that the impact of the cellular calcium indicators was on par with GFP. In the case of Roger’s membrane potential probes work, there had been no new molecules since the 1970s. I was working on a new molecular approach to a problem that had been simmering on a back burner of his brain. This was extremely exciting; I was transported back in time to Cambridge through his thesis and back further via conversations with Roger about conversations he had with various scientific luminaries that inhabited the various university laboratories and offices. On my first day/ week, I remember following him around the lab as he excitedly scurried around collecting papers, introducing me to people who could help me get started, and finally ending at a cabinet in a back lab. He opened the door, knelt down, and extracted a 100count tray of scintillation vials full of various synthesized compounds. After a couple of missed attempts, he located his target and pulled out a vial of a red-colored compound labeled with a neatly drawn structure and a date from the 1970s. He squinted at the vial and said something to the effect of, “This should be good,” and handed me the vial. First, I was shocked that he had retained material for so long (and several moves) and, second, I was immensely impressed that he knew where it was located. While Roger’s brilliance and creativity are well-known, his love of experimental work, the lab, and the lab scientist may not be as well publicized. Pouring through his lab notebooks from his Cambridge days (yes, his actual lab notebooks), I could not help but get some insight into the young scientist. His chemistry notebooks were filled from top to bottom with usually between 3 and 7 experiments going on simultaneously. What first struck me was how often experiments failed or led to dead ends.
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WENDY TSIEN, WIFE OF ROGER TSIEN Everyone who knew Roger, or knows his work, agrees on his brilliance, but they will not know that allied to his great inborn gift of light and brilliance was a darker, fatal, inborn gift: a ferocious work ethic. Roger never took time off that was not paid for, done by doubling and trebling his efforts until he felt he’d almostnever fully!made up for the lost time, even when that time was supposed to be a vacation. Honesty, precision, and clarity of thought and expression were of paramount importance to him. He had the highest regard for language, both spoken and written. Writing did not come easily to him; he loathed it, but his finished writing was always beautiful: precise use of words; simple, clear, coherent, concise. He abhorred sloppy thinking; sloppy data; sloppy writing; sloppy attention to the requirements of journals, prize committees, and grant agencies. Before sending it out into the world, everything that was to bear his name had to be as close to perfection as he could make it. As Roger’s wife and close companion of 40 years (minus 4 months), I had intimate knowledge of the relentless effort Roger expended in all his work, and I knew that no one, not even Roger, who possessed immense stores of energy, could long live at the level of intensity and at the pace he demanded of himself. Roger had for many years a very fine doctor who tried, for all those years, as did I, to get Roger to reduce his traveling and his work load, but Roger was a driven man, and no doctor, no wife, not anyone could change him. Roger accomplished an extraordinary amount in his too-brief life, and there is no one in the world prouder of him and of his achievements than I. He was magnificent. He left a wonderful body of work, and intriguing ideas, for those who follow him to build upon. There is a very high price to be paid for brilliance, and we both paid it, Roger paying the highest price of all, but he and his beautiful work live onneither will be forgotten, both will always be loved.
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