Where was Roger Tsien’s lab?

Will it be you or your science to be remembered?

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In the spring of 2019, I visited my collaborator in University of California San Diego (UCSD) for organizing a project. There I have experienced the three must in San Diego: beach, party, and taco. I had good time mixing with graduate students, feeling like back to my school days.

However, I had a personal agenda: visiting Roger Tsien’s lab.

My first project as a postdoc was to build a mouse model of metastasis with labeled cells that allowed disease monitoring. It was supposed to be simple: labeling the cancer cells with the green fluorescence protein (GFP) gene, transplanting them into mice, and then watching them. Unexpectedly, I encountered lots of difficulties. To solve all these issues, I had to invent new labeling vectors [1] and even a genetically engineered mice [2] able to maintain GFP expression in the labeled cells. These two items became my “trade mark”, and literally GFP initiated my academic career.

[1] https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1755-148X.2009.00545.x

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219677/

Later I tried to create a red-leaning fluorescence protein equipped with its own excitation light, so I searched the literature for “orange” fluorescence protein. Amazingly, Dr. Roger Tsien (http://www.tsienlab.ucsd.edu/) had already created a series of fluorescence proteins that exhibit a wide spectrum of colors, almost like a box of assorted paint. I emailed Dr. Tsien; his lab was obviously well prepared for intensive requests from all over the world. All it took was to log on to their website, fill an online form for material transfer agreement, and the DNA vector would be sent out. Everyone can get such generous gift in such an efficient manner.

Dr. Tsien received Nobel Prize in Chemistry in 2008 for his contribution in fluorescence proteins. I found he was originated from Tsien Family in Lower Yangtze Region (surrounding greater Shanghai metropolitan), the most prestigious Chinese academic powerhouse. The founder of the family was a legendary king in 10th century, when China was fragmented by many local military forces. King Tsien (錢鏐) drove out warlords from Yangtze Delta region but did not attempt to expand his domain. Instead, he focused on agriculture and economic development. To avoid bloodshed of people, his descents voluntarily merged their kingdom to the rising power Sung Empire, which sought for reunification of China. The policy of King Tsien made the Lower Yangtze Region the most prosperous economic center of China, a legacy that lasts a thousand years and continues even today.

Tsien Family flourishes over centuries in the old place of their kingdom. They dedicate in education of liberal art, producing lots of talents and scholars in each generation. In modern era, the Family has produced the greatest contemporary historian (錢穆), authors (錢鍾書),archaeologist (錢玄同), nuclear physicists (錢三強、錢偉長), Director of Chinese Academy (錢思亮), and many more intellectuals. Roger's father was a renowned engineering expert. His father's first cousin, Qian Xuesen (or Hsue-Shen Tsien), was a prominent aerodynamicist. He retuned China from US, thank for McCarthyism, and then single-handedly changed the balance of world powers during the early stage of cold war.

In a twist, however, Roger’s academic achievements were partially attributed to the bad luck of an anonymous scientist.

In 1960, a young man Osamu Shimomura moved to Princeton for postdoctoral study right after receiving his Ph.D. in Japan. He worked in the Department of Biology at Princeton for Professor Johnson. They collected jellyfish Aequorea victoria during many summers at the Friday Harbor Laboratories of the University of Washington and wondered why this animal was glowing. Eventually, they isolated aequorin and green fluorescence protein(GFP), which emitted green fluorescence as shined by blue light. The results were published in Science in 1962. Shimomura stayed with Princeton until 1980 when he moved to Woods Hole Oceanographic Institution, Massachusetts, where he continued his research in fluorescence proteins.

In 1980s, a young Ph.D. Douglas Prasher joined Woods Hole to study bioluminescence and fluorescence proteins. Previously, he had successfully identified the gene sequence for aequorin. In 1988, he received a two-year grant from the American Cancer Society to clone the gene for GFP. Prasher succeeded in this project and published the results in 1992. This study had attracted lots of attention; many people requested the gene vector from him. Among these requesters, two of them- Roger Tsien and Martin Chalfie- profoundly understood the potential of this gene. Chalfie thought it could be used to track cells in developmental biology, and he already had a model organism in mind: the tiny worm, nematode C. elegans. Chalfie collaborated with Prasher to express GFP in the bacterium E. coli and the C. elegans, and later in the plant Arabidopsis thaliana. They co-authored several papers to publish these results in high-profile journals. Tsien, on the other hand, focused on the engineering of GFP, creating a series of fluorescence proteins that gave the whole spectrum of colors. These proteins allowed multi-task tracking, revolutionizing the fields of cell labeling, sorting, and imaging. GFP opened a whole new world of biotechnology and lifted the careers of Chalfie and Tsien to the spotlight.

Ironically, Prasher’s career hit rock bottom since finishing collaboration with Chalfie.

His application for NIH funding had been turned down as he was undergoing review for promotion from assistant to untenured associate. Feeling stuck in a dead end, he decided to leave academia. Subsequently, Prasher worked as a population geneticist for U.S. Department of Agriculture at its Otis Plant Protection Center in Cape Cod, Massachusetts, and was later transferred to the Plant Germplasm Quarantine & Biotechnology Laboratory in Beltsville, Maryland. After working conditions deteriorated there, he changed to NASA subcontractor AZ Technology in Huntsville, Alabama, working on an existing project to develop lab-on-a-chip devices of human diagnostics during long-term spaceflight. However, he lost his job after 1.5 years when NASA reorganized and canceled the project. He had nowhere to go but took the job of driving customer courtesy van for local Toyota dealership.

One day he found from the news that Nobel Prize in Chemistry were awarded to Shimomura, Chalfie, and Tsien because of their breakthrough works applying fluorescence proteins in biology. Chalfie said of Prasher's work “was critical and essential for the work we did in our lab. They could've easily given the prize to Douglas and the other two and left me out.” Tsien also agreed that they couldn't have done it without Prasher and "Doug Prasher had a very important role."

Prasher wanted to cry. Even though, he called the local TV station to correct the journalist’s pronunciation of “Tsien”, without mentioning who he was.

Chalfie and Tsien not only invited Prasher and his wife to attend the Nobel Prize ceremonies in Stockholm, but also paid for their airfare and hotel. Prasher took a week off from his van-driving job. It was the first vacation he and his wife had taken in years. On the day of the awards, he donned a rented copy of the penguin suit that all male Nobel attendees are required to wear, along with a pair of leather shoes that a Huntsville store had let him borrow.

When he returned Alabama, his story was revealed to the world and resonated to many scientific workers.

Both Chalfie and Tsien thought owing Prasher. Tsien especially felt staggering for him and even offered him a research associate position in lab. However, Prasher did not accept it immediately. He wanted this job offering was based on merit, not mercy. He still went back to drive the courtesy van.

In 2010, Prasher left car dealership to work for Streamline Automation in Huntsville, the first step returning to science. In 2012, finally, he accepted Tsien’s job offer and moved to UCSD. A successful scientific figure was grateful and helped the unfortunate person who lifted his career. This was supposed to be a happy ending.

However, life took another turn again. Tsien died suddenly in his Oregon home in 2016. His group would be most likely dissolved. Where would Prasher end up with?

I need to know that. This is my personal task in my trip to UCSD.

As soon as I arrived UCSD campus, I asked my host professor where Roger Tsien’s lab was. She did not know the name. It might not be a surprise, considering her background- electronic engineering- was not really overlapped with biochemistry/molecular biology. I kept asking but found this was not a well-known name in the campus. What was going on here?

After a few days, the graduate student who worked with me and her boyfriend invited me for a dinner. We went to a restaurant owned by a local brewer, having great time to taste fancy beers. The talent young man also got his Ph.D. in UCSD. Over the evening all we chat were about research and academic gossip, really very nerdy talks. I mentioned the story of Roger Tsien and Prasher, he said, “Ah, his lab located upstairs to my previous lab. Go find it in George Palade Laboratory building.” Bingo! I was happy to get this easy answer from drinking beer together!

The next morning, I went straight to George Palade Laboratory. This is a very weird building; there is no lobby, no main elevator, and no office in sight. I wandered around, walking in and out, just could not get to Room 301. I thought a Nobel Laureate in a building should be well known, so I entered a random lab to ask.

The first one I saw was a young guy who was dissecting a mouse. I myself am a mouse worker so really did not want to interrupt him. He stopped the cutting anyway and asked me what I was looking for. I asked back,

“Do you know where Roger Tsien’s lab was?”

He looked at me with a confused expression, “Roger… who?”

“Roger Tsien, 2008 Nobel Laureate.”

He shook his head, “Never heard before.”

I was totally shocked!

He tried to help and ask around people in the lab, but no one- not a single person- knew who Roger Tsien was, though they were obviously doing something very relevant to Roger Tsien’s research.

I went to the other side and asked a gentleman with wrinkles and gray hair. He did not know the name Roger Tsien, either. I did not know what to do but asking him to find me any office. I walked on the direction he instructed and entered an office, telling the staff the address that I was looking for. It existed in this building but the location obviously puzzled her. She googled and found a document, “Directions to Tsien Laboratory”. I read through it and the location still sounded tricky.

The staff lady was nice to print the instruction out for me. I thank her, handing this paper to continue my search but still confused. I stopped a student or postdoc, showing her the instruction. It took her like three minutes to point to the freight elevator outside: “That might be it.”

I walked toward the freight elevator and felt suspicious. At this moment, a FedEx guy towing a cart approached me. He asked, “Are you looking for a direction?”

I thought FedEx guy probably knew this building better than anyone else, so I told him I was trying to find Room 301. He stared at me and said, “Are you trying to find Dr. Tsien’s lab?”

I gave an ear-to-ear smile, “Yes, yes, could you show me the way?”

He laughed, “Finding direction? That’s my specialty. Follow me, and I will take you there.”

It took only one minute to arrive at the entrance of Tsien’s lab. His name plate was still by the door of his office, but no one in the whole space. I asked the courier’s help to take a few pictures with me in the view. He finished and told me,

“Roger was a very nice person.”

I was surprised, “Did you know him and talk to him?”

He said, “Sure! I have been around here for many years, talking to him often as delivering the items to his lab.”

I told him why I was here, he nodded and said, “Well done. He deserved respect from everyone.”

At that moment someone came close to unlock the door. Mr. FedEx said he was the professor who used the office space now. I introduced myself and mentioned my purpose of this visit. I asked him if Tsien’s group was dissolved. He said yes.

I kept asking, “Where was Prasher going?”

He answered, “Ah, you mean the guy who cloned GFP gene… he left one year before Roger passed away. I have no idea where he ended up with.”

I cannot stop all the sentiments in my mind. Like it said “Character is destiny” by Greek philosopher Heraclitus; so as Prasher, so as Roger Tsien, and so as every one of us.

In that afternoon I went visiting Birch Aquarium at Scripps. I found the aquarium with green fluorescent jellyfish, next to it was the plate to note Roger Tsien’s research in GFP was attributed to his Nobel Prize. I took a picture with it.

An outstanding, nice person like Roger Tsien, in the place where his career flourished, was remembered only by a FedEx courier. The history was ignored in our education, and the legacy was discarded from our mind setting. The consensus we have together is that science is just a manufacturing factory of our time, producing the disposable products that can be thrown away as soon as the profit is made.

On the way back, the sentimental thoughts still circled my head. I know it would not be easy to stop.

Chi-Ping Day

Staff Scientist, National Cancer Institute, NIH

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