Roger Y. Tsien


Roger Y. Tsien

Q: What do elementary school pupils and Nobel Laureates have in common? A: They both have to write autobiographical essays on command.

Ancestors and family
My father, Hsue Chu Tsien (1915–1997), came from the “scholar-gentry” class in Hangzhou, China, where “Tsien” (now more commonly transliterated as Qian) is quite a common surname. Apparently in 907 A.D., Qian Liu, my paternal ancestor 34 generations ago, established a kingdom around Hangzhou and fostered its growth through many civil engineering projects. This fiefdom prospered peacefully under the rule of Qian Liu and his successors until 978, when they surrendered to the Sung dynasty to avoid bloodshed*. I had thought that descent from Qian Liu was an obscure secret of our family, but this factlet somehow found its way onto Wikipedia through no fault of mine. Furthermore, this genealogy is hardly much of a distinction given that everyone in principle has 234 ancestors from 34 generations ago. 234 (about 17 billion) vastly exceeds the earth’s population in the 10th century, so practically everyone, at least from that part of China, probably has Qian Liu as an ancestor, even if not so strictly through the Y chromosome. By far the most famous Tsien in modern times is Hsue Shen Tsien or Qian Xuesen, the aeronautical engineer who was deported from the U.S. during the McCarthy era and then became father of the ballistic missile program of the People’s Republic1. He and my father were first cousins. Several other Chinese-American bioscientists, including Robert Tjian, now President of the Howard Hughes Medical Institute, and Shu Chien, a prominent bioengineer at UCSD, also have the same Chinese surname as mine and are likewise descended from Qian Liu, so we are distant relatives.

Dad too was excited by flight and airplanes, which were the cutting-edge technology of his day. In the 1930s he won a national scholarship (Tsinghua) to study in America. He went to MIT’s mechanical engineering department, where he obtained a Master’s degree for research on aircraft engines, including a proposal to boost the thrust during takeoff by injecting water into the exhaust to become steam. Before he could pursue any further studies in America, he had to return to China to serve in the Nationalist (Kuomingtang) Air Force. One of his best friends and fellow engineers, Yao Tzu Li, had an attractive and intelligent sister, Yi Ying Li, who had trained as a nurse at Peking Union Medical College, the most prestigious of Chinese medical institutions. My father courted her eagerly by letters even before they had ever met in person. When they finally did meet, she found him socially awkward and overly impressed with his own academic prowess2. Despite her lack of romantic feelings for him, she agreed to marry him, perhaps because she doubted her own prospects in wartime China. Their first son, Yongyou, was born in March 1945. Soon thereafter, Dad was ordered to go to the U.S. as a liaison officer to try to extract more military aid for the Chinese Air Force. He had to travel over the Himalayas to India and then by ship, zigzagging to avoid enemy submarines, so he did not arrive in the U.S. until the day that Japan’s surrender was announced2. His mission was therefore futile, but he knew that China would be racked by postwar civil war. Somehow he used contacts in the Defense Department to arrange for Mom and Yongyou to come to the U.S. Such permission was not trivial, because the Chinese Exclusion Act forbidding immigration from China to the U.S. had been repealed only in 1943, at which time the national quota was set at just 105 immigrants per year and thousands were ahead on the waiting list.

After Mom and Yongyou arrived in America in January 1947, life was quite a struggle because Dad could not find a professional job as an aircraft engineer. Such employment at the major firms required a security clearance, which a Chinese citizen could not get. So he started a tiny export-import business in New York City and later an engineering consultancy firm in Westchester County, which yielded enough to live on but not to become prosperous. Nevertheless their next son, Yonglo or Louis, was born in October 1949. Around then, Yongyou started school and needed to pick an American name. He wanted to be “Dick”, so the school officials explained to my parents that this was a nickname for “Richard”. “Yongyou” was somehow transliterated as “Winyu” to become Richard’s middle name in English.

According to Mom, she always planned to have three children, though this statement came many years after the fact. After two sons, even Dad was looking forward to a girl2, but in February 1952 they got me instead. Dad picked my Chinese name, Yongjian (transliterated Yonchien to become my middle name in English), but Dick insisted that my American name should be Roger. My mother later told me this was because Dick had a playmate at the time named Roger. Much later, perhaps when I was in college, I quizzed Dick about this mysterious namesake. Dick confessed that he actually named me after Roy Rogers, the famous cowboy actor. I mention all this to clarify the origins of the similarity between the names “Richard W. Tsien” and “Roger Y. Tsien”, which has continually confused many scientists and their secretaries even up to now. I don’t know why my parents chose two different transliterations for “Yong”, but if they had not, Richard and I would be completely indistinguishable (“Tsien RY”) in bibliographical databases.

Growing up: Home chemistry experiments
One of my earliest memories, probably from age 3 or 4, is of building a sand path at the beach across a strip of coarse pebbles that hurt my feet to cross. I loved to draw maps of imaginary cities with freeways vaulting over or tunneling under the surface streets. Perhaps these were the first signs of my future obsessions with bridge-building and activity-mapping. Some time in elementary school my parents bought a Gilbert chemistry set, but I didn’t find it very interesting because the experiments seemed so tame. Then I discovered a book in the school library that had much better experiments and illustrations. Regrettably, I cannot now remember the book’s name or author, though I hand-copied many sketches of its experiments into a notebook dated around 1960, now deposited in the Nobel Museum. Two experiments I remember best: 1) silica gardens, in which crystals of metal salts (e.g. CoCl2, NiSO4, CuSO4) dropped into a solution of sodium silicate would develop bright magenta, green, or blue gelatinous coatings from which vertically rising dendrites would sprout; 2) preparation of a strongly alkaline (0.5M NaOH or KOH) aqueous solution of dilute (~ 0.5 mM) potassium permanganate, which colored the liquid an intense purple. As this solution passed through a folded cone of filter paper, its color changed to a beautiful green, reflecting reduction of MnO4 to MnO42–, presumably by the cellulose. In November 2008, I reproduced this surprisingly little-known demonstration for Swedish television and Nobel Media as an example of what got me interested in chemistry. Both experiments reflect an early and long-lasting obsession with pretty colors.

Our family in 1960, just before moving to Livingston.

Figure 1. Our family in 1960, just before moving to Livingston. From left: Richard (15), Louis (11), H.C. (my father), me (8), Yi Ying (my mother).

In 1959, Dad closed his consulting firm and started working for RCA’s vacuum tube division in Harrison, NJ. Mom and Dad looked for a town with affordable homes, within convenient commuting distance, and with good public schools for the three of us. A photo from around then is Figure 1. They chose a new housing development in Livingston, NJ, but the developer refused to sell to us, saying that they could not permit Livingston to become a Chinatown, nor could they afford the likelihood that other customers would refuse to buy houses next to a Chinese family. My parents appealed to the Governor of New Jersey, Robert Meyner. His office sent a letter to the developers warning them that racial discrimination was illegal. Finally a compromise was reached: the developers sold us a house completely surrounded by houses that had already been sold. The problem for us kids was that Livingston has lots of rocks in its soil, left from the glaciers. My parents were determined to have a respectable American-style grassy lawn, which required removal of the rocks. We had to cart away not only our own stones but many from our neighbors, who had used the unoccupied leftover lot as a dumping ground, or so we believed. The many weeds in the lawn revealed a deep personality difference: Dad, as an impatient mechanical engineer, liked the instant solution of digging them up one by one from close enough to extirpate all the roots. I was an occasionally asthmatic hay fever sufferer, deeply afraid of pollen, so I advocated a chemical approach, sprinkling herbicide on the weeds from a safe distance. We tried my way once. The weeds slowly turned brown but eventually recovered. Dad declared the experiment a failure and went back to hand weeding. I still think about this result in relation to our current research on cancer therapy.

In 1960, RCA closed its vacuum tube division, presumably because semiconductors were replacing tubes, so Dad moved to Esso (later renamed Exxon) Research and Engineering. Esso provided much better projects and pay, so he stayed until his retirement in 1983. I believe some of the chemicals and glassware that enabled me to do the more interesting chemistry experiments were diverted from the company stockroom. Other supplies could be bought by mail order in those days with a parent’s signature. Over the next 5 or 6 years I gradually did many of the classic experiments of inorganic chemistry in the basement of our house: preparing and burning H2 gas, preparing O2 and burning steel wool in it, preparing NH3 in a flask and watching it suck water up as a fountain inside the flask. I distilled HF from CaF2 + H2SO4 in plastic apparatus and was delighted to see its ability to etch glass. I electrolyzed molten NaOH using a step-down transformer and rectifier from a model train set, the nickel crucible as cathode, and a carbon rod salvaged from a dead flashlight battery as anode. I managed to get a few granules of very impure metallic sodium, which gave off a satisfying hiss when dropped into water. Pyrotechnics were naturally of great interest: I made and ignited gunpowder, ammonium dichromate volcanoes, and even a spectacular thermite reaction with powdered aluminum and chromium oxide. My most ambitious attempt was a multistep sequence aimed at synthesizing aspirin, for which I needed acetic anhydride, which had to be made from acetyl chloride, for which I needed phosphorus trichloride, for which I needed to burn red phosphorus in a stream of chlorine gas. I tried to do this reaction sequence in flasks with rubber stoppers (Figure 2), because I had no glassware with ground glass joints. The corrosive chemicals largely chewed up the rubber, so I did not get beyond acetyl chloride. Because I had no fume hood, I did the more dangerous experiments outdoors on a picnic table on the backyard patio. Looking back, I am appalled at how dangerous all this was for an unsupervised boy of 8 to 15, but it was also very good training in how to improvise equipment, plan and execute experiments, interpret confusing results, and decide how to do things better. These experiments made me confident enough that when I had to earn my first merit badge as a Boy Scout and was advised to pick something really easy, I chose Chemistry. Tougher merit badges like Hiking, with its requirement for a twenty-mile hike in one day, I got later.

Setup for preparing Cl2 and reacting it with red phosphorus

Figure 2. Setup for preparing Cl2 and reacting it with red phosphorus, sometime in 1966– 1967, in our screened backyard patio. The leftmost flask contained KMnO4 to react with aqueous HCl added through the funnel controlled by a pinch clamp. The Cl2 was dried by passage through CaCl2 then directed onto P4 in the flask on the ring stand. Because no running water was available, the water to cool the PCl3 condenser was siphoned from the recycled milk jug and deposited into the waste can labeled “Hawaiian Punch”. The receiver for PCl3 was immersed in ice in the thermos bottle. The alcohol lamp allowed auxiliary heating for the phosphorus. Note rubber stoppers everywhere.

Elementary school to high school;
Westinghouse science talent search

School was usually bearable but frequently boring. I really looked forward to days in winter when heavy snow would close school, so that I could spend the day sledding. I was terrible at ball games at school, such as football, soccer, basketball, and softball, because I was small, nonathletic, and two years younger than my classmates at an age when this makes a huge difference. But I was popular enough in high school to be elected student council treasurer by an overwhelming majority.

Mom tried hard to teach us Chinese after school, but as I got older I found these lessons increasingly tedious. I well understood spoken Chinese at a child’s level (e.g. the Chinese for “Tidy your room!” is permanently etched into my brain) but was reluctant to speak it myself, due to the wish (all too common among children of immigrants) to distance myself from my parents’ accents and intense pride in their ethnicity and traditions. Likewise they despaired over my refusal (like a “foreign devil”) to eat most Chinese food, especially the most authentic dishes with the strongest tastes or smells, or prepared from exotic creatures.

My first exposure to a research environment was in a National Science Foundation-sponsored summer research program at Ohio University in 1967, where I was assigned to work in the laboratory of Prof. Robert Kline on the ambident coordination of thiocyanate (SCN). The Pearson theory of hard and soft ligands and metals was new and fashionable at the time, so Prof. Kline wanted me to find out if thiocyanate could simultaneously bind with its “soft” sulfur to a soft metal and its “hard” nitrogen to a hard metal, e.g. PhHg–SCN–Cr(III). He hoped that the infrared absorbances of thiocyanate would tell us whether such bridging was taking place. I prepared a lot of amorphous precipitates of rather ill-defined composition and measured their infrared spectra. In the winter of 1967, my senior year at Livingston High School, I entered the Westinghouse Science Talent Search, the nationwide “science fair” competition. (This annual event still exists, though sponsorship was taken over by Intel in 1998.) For lack of any alternatives, I wrote up my Ohio University project, trying my best to draw some conclusions from a mess of dubious data. Prof. Kline largely disowned those conclusions, pointing out that my preparations had not given correct carbon, hydrogen, and nitrogen microanalyses. The 40 finalists were summoned to Washington DC in March 1968 for interviews and a public poster session. I remember being envious of my fellow finalists, who were much more adult and sophisticated. Also their projects and exhibits seemed much more exciting and explainable than mine. I felt intimidated by the senior judge, Glenn Seaborg, partly because of his commanding height, partly because he was chairman of the U.S. Atomic Energy Commission, partly because of his 1951 Nobel Prize for work in inorganic chemistry. The awards ceremony was very tense for us because the ten scholarship winners were announced in reverse order, forcing everyone to hope their name was called but as late as possible. I am still mystified how I won first prize despite the unsoundness of my project, and I retain a dislike for scientific competitions. Dad did his bit to keep me grounded: when I phoned home, his first comment was that it was a good thing I now had a $10,000 scholarship, because he had recently lost that amount on the stock market. One of the most satisfying compliments I received was that the developer who had not wanted to sell a house to Mom and Dad in 1960 now used my photo in one of their advertisements as evidence of the quality of the local school system.

In April 1968 I had to choose between four colleges: Columbia, MIT, Caltech, and Harvard. Dad vetoed Columbia because of the student unrest that spring, and I did not mind because I wanted to get further away from New Jersey. I rejected MIT because Dick and Louis had both gone there and I was tired of being compared to them. The small size of Caltech’s undergraduate class sounded attractive, but I finally decided against Caltech because Richard Feynman was no longer teaching introductory physics and because the music department was tiny and of negligible fame compared to Harvard’s. Indeed Harvard did turn out to be a salutary experience on the whole. Friendships with classmates were crucial in helping me grow up. The student protests of spring 1969 and 1970 provided my first exposures to cannabis, police brutality, and participatory politics. The diversity of courses let me sample art history, visual design, economics, Colonial history, constitutional law, psychology, both music theory and chamber music performance, etc. Ironically, the worst courses were those intended to lead Harvard’s elite chemistry majors into research careers. These required courses were so distasteful I abandoned chemistry. Looking for alternatives, I dabbled in molecular biology (taught by Walter Gilbert, who later shared a Nobel Prize for DNA sequencing), oceanography, relativistic quantum mechanics, and astrophysics. But what I finally chose was neurobiology, partly because the relationship between brain and mind seemed philosophically the most important problem in science, partly because David Hubel, John Nicholls, and Torsten Wiesel ran a course charismatically proselytizing undergraduates to become neuroscientists. Hubel and Wiesel were still doing the research on visual cortex that eventually won them the 1981 Nobel Prize in Medicine or Physiology. I asked Prof. Hubel if I could do a summer internship in their lab, but he told me they had no space for undergraduates and suggested that I apply to Nelson Kiang at the Massachusetts Eye and Ear Infirmary instead. In summer 1971, Kiang gave me intensive tutorials in auditory neurophysiology and an interesting project analyzing spike trains from the cochlear nucleus. I am still plugging away at neurobiological problems almost four decades later.

When I asked Hubel and Kiang for advice on where to apply to graduate school in neuroscience, their only point of agreement was that the top places were Cambridge, MA and Cambridge, UK. I felt it was time to leave Cambridge, MA to broaden my horizons, so I applied for a Marshall Scholarship to go to the other Cambridge. In early 1972, while still a senior at Harvard, I learned my application was successful, and that my Ph.D. supervisor would be a Dr. R. H. Adrian, whom I had never heard of. I phoned my brother Dick, who had just become an Assistant Professor at Yale after finishing his D. Phil. from Oxford on cardiac electrophysiology. Dick informed me that R. H. Adrian was one of Britain’s most eminent skeletal muscle electrophysiologists, and son of E. D. Adrian, a Nobel Laureate in neurophysiology. Moreover R. H. Adrian had been the external examiner on Dick’s D. Phil. degree. “But muscle is a backwater,” I exclaimed. “I want to work on the brain.” Dick assured me that Richard Adrian was a true British gentleman, who would let me work on a topic of my own choosing. So I decided to wait and see. After a summer intensively studying music at Fontainebleau, near Paris, I arrived in Cambridge in October 1972. At my first lunch in Churchill College, an aristocratic-looking don sat down opposite me and asked if I was Roger Tsien. I immediately realized he was Richard Adrian, because only someone who knew a member of my family could pronounce our surname correctly, as he just had. Within the first few minutes of our conversation, he asked “Is it true you think muscle is a backwater?” I had to admit the accuracy of the quotation. (I later found out that Dick had mischievously teased Adrian about this at a conference they had both attended that summer.) Adrian looked a bit pained at my confession, but immediately said that he would not object whenever I wanted to transfer to one of the real neurophysiologists in the department.

Thus began my Ph.D. training. I never did switch to another official supervisor, because I soon realized I did not enjoy doing conventional electrophysiology of the central nervous system. The traditional thesis project, basically following the paradigm so successfully employed by Hubel and Wiesel, was to drop an extracellular microelectrode into the brain of an anesthetized animal and record the activity of individual neurons while providing sensory stimuli. After several hundred such recordings, one could classify the different response patterns and write up a thesis and several publications. To me this seemed too much like ice fishing, i.e. cutting a hole in the ice covering a lake, dropping a fishing line into the opaque water beneath, and patiently waiting for a bite. The brain derives its power from trillions of neurons working in parallel, so I wanted to see lots of neurons simultaneously signaling to each other and processing information. Ideally one would stain the neurons with a dye that would visibly light up or change color whenever and wherever a neuron fired an action potential. A few commercially available dyes had indeed been found that responded to neuronal action potentials, but the optical responses were extremely tiny, e.g. a 10–4 or 10–5 change in fluorescence.

They were detectable only if thousands of action potentials driven by the investigator were averaged under highly simplified conditions3. Many orders of magnitude improvement would be necessary to detect endogenous signals in a complex brain. I rashly decided in winter 1972 that I would try to design and synthesize new dyes for the specific purpose of imaging neuronal activity. One strategy was to target the dye to the vicinity of sodium channels, which were believed to undergo large conformational changes as they generated action potentials. Another strategy was to create “electrochromic dyes” with large changes in dipole moment between ground and excited state, so that a change in neuronal membrane potential could shift the peak wavelengths of absorbance or fluorescence4. In either case I would have to learn organic synthesis, which I had hated in those Harvard chemistry courses and which nobody in the Physiological Laboratory could teach me. Fortunately, Dr. Ian Baxter, a junior faculty member in the Chemistry Department and a friend of a friend of Richard Adrian’s, was intrigued by my idea for targeting sodium channels and agreed to supervise me unofficially. Baxter had no other students and had the time, kindness, and patience to look over my shoulder several times a day and show me the necessary techniques. I found to my own surprise that I could do and enjoy organic synthesis once it was for a biological purpose of my own choosing. I remained hooked on this type of research even though the molecule I synthesized proved incapable of binding sodium channels, even though Baxter soon left to become a careers counselor in the north of England, and even after other generations of my synthetic voltage sensors proved inferior to those found by other labs screening large numbers of commercially available dyes and their close analogs5.

My first glimmer of success required shifting to another biological target. Action potentials almost always generate large increases in intracellular calcium to exert any biological effect such as the release of neurotransmitters to excite or inhibit the next neuron in the pathway. In 1975 there was great excitement over the discovery that arsenazo III, a dye invented to measure heavy metals in nuclear waste, could also be used to monitor calcium in giant axons from squid neurons, though the signals from this dye were very small and somewhat ambiguous6. I felt that designing a dye to measure Ca2+ should be a far easier problem than designing a dye to track fast changes in neuronal membrane potential. Hundreds of dyes were already known in the chemical literature to respond to Ca2+, e.g. for determination of water hardness. The real problem was that inside cells, the free Mg2+ concentration is about four orders of magnitude higher than that of Ca2+, so that an intracellular Ca2+ indicator needs yet higher selectivity for Ca2+ over its sister ion Mg2+. No chemist had yet recognized the biological need for such a selective indicator. A colorless buffer called EGTA was the only synthetic molecule known to have the necessary Ca2+:Mg2+ selectivity7, but it had never been made into any sort of dye molecule. By doodling on paper and playing with molecular models, I saw a way to make EGTA into a very rudimentary dye molecule. I started on this brand new project without telling Richard Adrian, because any prudent supervisor would have told me I should be bringing older projects to closure rather than starting radically new ones. Fortunately, within a few weeks I managed to make a small, impure sample of the target molecule (much later given the acronym “BAPTA”) and found that it had the expected optical response to Ca2+ combined with high Ca2+:Mg2+ selectivity8. After many more years and discoveries, better dyes descended from BAPTA** became the most popular way of seeing endogenous intracellular Ca2+ signals, screening for ligands and receptors linked to Ca2+ signaling, and imaging neuronal activity microscopically.10

After my Ph.D., I stayed in Cambridge as a postdoctoral Research Fellow at Gonville & Caius College. My change in focus towards Ca2+ signaling led me into collaboration with Dr. Timothy Rink, a new faculty member in the Physiological Laboratory, because Tim wanted to make Ca2+-selective electrodes from materials sent from Switzerland11. The directions for assembly were in German, which Tim could not read. I had learned to read chemistry papers in German, so I translated the instructions. Our collaboration started with these Ca2+-selective electrodes and continued with the biological testing and exploitation of my fluorescent indicators for Ca2+. Even more importantly, Tim and his wife Norma invited me to their Christmas party in 1976, where I first met their sister-in-law, Wendy. Soon I was spending every weekend visiting Wendy at her house in North London. When Tim and Norma found out several months later, they were quite astonished at the effectiveness of their entirely unintentional matchmaking. Wendy (Figures 3–4) is still the love of my life.

My fellowship at Gonville & Caius College was to end in late 1981, so in 1979–1980 I started looking for an independent position. Because of Wendy’s residence in London, I applied to the National Institute of Medical Research in Mill Hill, but was rejected without an interview. This was not a good time to search for a research job in Britain, because of the austerity program of the new Thatcher administration. It was time to return to the U.S., yet I had almost no contacts and few publications. Almost all my applications were unsuccessful. Biological departments considered me a chemist, while chemistry departments rejected me as a biologist. Nowadays the application of chemistry to solve biological problems is a very fashionable subdiscipline dubbed “chemical biology”, but in 1980 the only venue for such interdisciplinary efforts was in the pharmaceutical industry. Even there, individual scientists were typically either chemists or biologists, not both simultaneously.

Wendy with our dog, Kiri, in 2004

Figure 3. Wendy with our dog, Kiri, in 2004.

Luck intervened. The Department of Physiology-Anatomy, University of California, Berkeley, had a vacant assistant professorship, for which the chair of the search committee was Terry Machen, whom I had gotten to know while he was on sabbatical in Cambridge. Also Berkeley had two faculty members, Richard Steinhardt and Robert Zucker, who were interested in Ca2+ signaling. These connections enabled me to get an interview at Berkeley. Fortunately, the fluorescent indicators for Ca2+ had finally progressed enough to enable the first direct measurements of cytosolic Ca2+ in lymphocytes, including the elevation due to mitogenic stimulation12,13. Now one could investigate Ca2+ signals in populations of small mammalian cells, whereas previous techniques required single cells large and robust enough to withstand microinjection. This prospect, together with the fact that my Ph.D. was in Physiology, convinced the Department to offer me the Assistant Professorship, which I accepted before I found out that Berkeley was suffering a financial crisis. The startup package to get my laboratory going in early 1982 was cut to just a few thousand dollars, and each item had to be justified as a replacement for obsolete instructional equipment. For example, to get me a UV lamp for viewing thin layer chromatography plates, an old microscope illuminator from the teaching lab had to be junked. More importantly, the Department had no resources to provide a fume hood, which I needed to continue synthesizing the Ca2+ indicators. Prof. Robert Macey, whose lab was next to mine, kindly donated an old fume hood including its irreplaceable ductwork extending to the roof of the building. For the remainder of my seven years at Berkeley, all our synthetic reactions took place in this single wooden fume hood, less than 4 feet wide, with wire netting embedded in the glass of the front window. The entire lab stank from chemicals in unvented storage cabinets, and became lachrymatory when reactions using excess ethyl bromoacetate had to be worked up outside the hood. I mention these austerities only to remind young scientists that some good research can be accomplished without lavish facilities and startup funds.

Despite these troubles, my time at Berkeley was scientifically quite productive, including collaborations with Machen14, Steinhardt15, Zucker16, and others. I recruited Drs. Grzegorz Grynkiewicz and Akwasi Minta, who synthesized much improved Ca2+ indicators (fura-2, indo-1, fluo-3)17,18 and a Na+ indicator (SBFI)19, all of which are still in use today. After the budget crisis eased, the Berkeley administration helped me buy a primitive image processor, which I painfully programmed20 to calculate images of the ratio of fluorescences at two alternating excitation wavelengths. Such real-time ratioing revealed Ca2+, Na+, and pH signals14 inside single living cells, often with unprecedented spatiotemporal resolution.

Moving to UCSD
However, I began to worry about being trapped in a career of imaging inorganic ions. I wanted to explore signals transmitted through more complex biochemicals such as cAMP (cyclic 3′,5-adenosine monophosphate) and the wider, more fashionable world of macromolecular interactions. As my bargaining power grew, I also came to want a lab with enough fume hoods, vented storage cabinets, and small darkrooms for fluorescence microscopy to support my unusual combination of chemistry and biology, as well as a joint appointment in a Chemistry department and support from the Howard Hughes Medical Institute. None of these were possible in Berkeley, so in 1989 we moved south to the University of California, San Diego, where we still are. UCSD satisfied the above desires and was much younger, roomier, faster-growing, and less tradition-bound than Berkeley, which I felt more than compensated for its lesser fame. The highlights of the science started at UCSD are recounted in my Nobel lecture.

Dressed up for the Nobel Ceremony

Figure 4. Wendy and I, dressed up for the Nobel Ceremony.

Writing this autobiography has reminded me how my career has been shaped by a strange mixture of chance and fateful predisposition. The use of chemistry to build biologically useful molecules is a form of engineering, so I did not escape the tradition set up by my father, uncles, and brothers. However, I avoided the mechanical, aeronautical, electrical, and computer specialties they chose, probably because like many youngest siblings21, I had to seek a distinct niche. But if I had not found Ian Baxter to re-instill my enjoyment of chemistry, perhaps I would have chosen yet another direction. My interest in imaging with multiple glowing colors also reflects visual interests from early childhood, which I have been lucky enough to align with a professional career. From a strictly biological point of view, our contributions have mainly been in the development of techniques. Man-made techniques do have a habit of becoming obsolete, whereas basic discoveries about how nature works should last forever. But truly fundamental insights such as those of Darwin or Watson & Crick are rare and often subject to intense competition, whereas development of successful techniques to address important problems allows lesser mortals to exert a widespread beneficial impact for at least a few years. Moreover, the same engineering approach is what creates new therapeutic strategies to alleviate disease, not just tools for our fellow researchers.

* The benevolent reign of these kings is commemorated in at least two immaculately maintained shrines, one in Lin’an, a medium-sized city in Zhejiang Province, the other constructed in 2002 on prime real estate on the famous West Lake at the center of Hangzhou. My mother, my wife, and I visited both shrines in 2004. My mother interpreted the prominence of these shrines as an attempt by the current Chinese regime to advertise a historical precedent for reunification with Taiwan.

** The invention of a generalizable structure that sensed Ca2+ with unprecedented selectivity was duly reported to the National Research Development Corporation, as required for work funded by the UK Science Research Council. Initially NRDC was enthusiastic enough to file a patent application, 42927/78, but the administrators soon decided that measuring intracellular Ca2+ was of negligible commercial value. They felt that the only possible use for biological Ca2+ measurements was in clinical assays in blood serum, an application with completely different performance criteria, so they abandoned the patent application. In principle I could have taken over the patent costs out of my own pocket, but the NRDC’s estimate of the fees equaled about 20 years of a postdoctoral salary, so I did not try. Eventually, follow-up patent applications by the University of California covering narrower variations in molecular structure proved quite lucrative. A much more important example of the NRDC’s conservatism9 was their failure to patent Milstein and Köhler‘s monoclonal antibodies, another Cambridge invention of the mid-1970’s.

1. Chang, I. Thread of the Silkworm. Basic Books (1995).
2. Tsien, Y. Y. Unpublished memoirs. 2007.
3. Conti, F. & Tasaki, I., “Changes in extrinsic fluorescence in squid axons during voltage-clamp,” Science 169, 1322–1324 (1970).
4. Platt, J. R. “Electrochromism, A Possible Change of Color Producible in Dyes by An Electric Field,” J. Chemical Physics 34, 862–863 (1961).
5. Cohen, L. B. & Salzberg, B. M., “Optical measurement of membrane potential,” Rev. Physiol. Biochem. Pharmacol. 83, 35–88 (1978).
6. Brown, J. E. et al., “Rapid changes of intracellular free calcium concentration: detection by metallochromic indicator dyes in squid giant axon,” Biophys. J. 15, 1155–1160 (1975).
7. Schwarzenbach, G., Senn, H. & Anderegg, G., “Komplexone XXIX. Ein Grosser Chelateffekt Besonderer Art,” Helv. Chim. Acta 40, 1886–1900 (1957).
8. Tsien, R. Y., “New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures,” Biochemistry 19, 2396–2404 (1980).
9. Milstein, C., “With the benefit of hindsight,” Immunol. Today 21, 359–364 (2000).
10. Tsien, R. Y., “Monitoring Cell Calcium,” chapter 2 in Calcium as a Cellular Regulator, Carafoli, E. & Klee, C. (eds.), pp. 28–54 (Oxford University Press, New York, 1999).
11. Ammann, D., Güggi, M., Pretsch, E. & Simon, W., “Improved calcium ion-selective electrode based on a neutral carrier,” Analytical Letters 8, 709–720 (1975).
12. Tsien, R. Y., Pozzan, T. & Rink, T. J., “T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes,” Nature 295, 68–71 (1982).
13. Tsien, R. Y., Pozzan, T. & Rink, T. J., “Calcium homeostasis in intact lymphocytes: cytoplasmic free Ca2+ monitored with a new, intracellularly trapped fluorescent indicator,” J. Cell Biol. 94, 325–334 (1982).
14. Paradiso, A. M., Tsien, R. Y. & Machen, T. E., “Digital image processing of intracellular pH in gastric oxyntic and chief cells,” Nature 325, 447–450 (1987).
15. Poenie, M., Alderton, J., Tsien, R. Y. & Steinhardt, R. A., “Changes in free calcium levels with stages of the cell division cycle,” Nature 315, 147–149 (1985).
16.  Tsien, R. Y. & Zucker, R. S., “Control of cytoplasmic calcium with photolabile tetracarboxylate 2-nitrobenzhydrol chelators,” Biophys. J. 50, 843–853 (1986).
17. Grynkiewicz, G., Poenie, M. & Tsien, R. Y., “A new generation of Ca2+ indicators with greatly improved fluorescence properties,” J. Biol. Chem. 260, 3440–3450 (1985).
18. Minta, A., Kao, J. P. Y. & Tsien, R. Y., “Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores,” J. Biol. Chem. 264, 8171–8178 (1989).
19. Minta, A. & Tsien, R. Y., “Fluorescent indicators for cytosolic sodium,” J. Biol. Chem. 264, 19449–19457 (1989).
20. Tsien, R. Y. & Harootunian, A. T., “Practical design criteria for a dynamic ratio imaging system,” Cell Calcium 11, 93–109 (1990).
21. Sulloway, F. J., Born to Rebel: Birth order, family dynamics, and creative lives, Pantheon Books, New York (1996).

From Les Prix Nobel. The Nobel Prizes 2008, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2009

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.

Copyright © The Nobel Foundation 2008

Roger Tsien died on 24 August 2016.

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