CCB summer school at CSHL

by Kengo Watanabe
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This summer, I attended the Cold Spring Harbor Laboratory (CSHL) course program: Computational Cell Biology (CCB). Through this intensive course, I could obtain the systematic basic knowledge of CCB and realize current trends in this field. In addition, now that I learned and actually experienced practical computational simulation techniques, I can use a wide range of options to progress my research projects. Of course, I could also make many competent friends with common interests and aspirations. And so, I am feeling that I could make big strides toward my ultimate purpose: contribution to advance in life science and medicine. Here, I’d like to report my experience.
Cold Spring Harbor Laboratory & Computational Cell Biology Course
First of all, anyone would know UC Berkeley and Yale University, where the other recipients of FUTI Award went to study, but you might not know CSHL, which is located in the peaceful village to the east of New York City. Most biologists, however, know CSHL well because it has greatly contributed to the fundamental development of molecular biology, genetics and medicine. In fact, eight Nobel laureates including Dr. A. Hershey, who performed the famous Hershey-Chase experiments, have worked there. Furthermore, CSHL publishes many journals including Genes & Development, which all biologists have ever read.

And so, meetings and courses at CSHL are also in high repute. One of the reasons would be small class size and high ratio of faculty to student. In 2012 CCB summer school, 24 students, 4 teaching assistants, 4 regular instructors, and about 20 irregular lecturers participated. Among students, 1 was undergraduate, 16 were graduates, and 7 were PhDs. Half of them came from foreign countries: France, Germany, Netherlands, Denmark, Sweden, Russia, India, and Mexico. And about one-third had only theoretical experience, another had only experimental experience, and the other had both. As well as students, the faculty came from all over the U.S., and half of them were theoreticians and the other were experimentalists. Diverse scientists thus participated in this course.
Intensive Lectures
Because CCB covered a wide range of topics, the lectures were very intensive and hours were very long; the morning session was given from 9:00 to 12:00, afternoon session was from 13:30 to 16:30, and evening session was from 19:00 to 22:00!! Moreover, this schedule was applied not only to weekdays but also Saturdays and Sundays, and only one Sunday in three weeks was the free day. If you were me, you might have been fed up. Indeed, I was very busy with preparation and review of the lectures day after day because I had neither theoretical experience nor confidence with English, but I could really enjoy studying because everything was fresh and interesting.

In the beginning, we learned basic knowledge of CCB. In particular, I was impressed with the bifurcation theory; in short, it is a study relevant to the sudden radical changes of a system caused by small changes of parameters. I had never learned it, and I was ashamed to say that all I knew was that bifurcation was highly related to the chaos system. Although the bifurcation diagram was easy enough to understand for persons who learned fundamental calculus, I realized that it was important for us to understand dynamic biological systems. In fact, before studying at CSHL, I had felt that I could intuitively understand what the bifurcation diagram meant and wondered why it frequently appeared in papers related to bistability and oscillation. After studying, however, I noticed that it was a standard approach and included more information than I had interpreted. I think that it is too difficult to achieve this kind of realization by oneself and I wouldn’t find the true meaning if I didn’t attend the CSHL summer school.
As the course went on, the topics changed from basic theory to practical examples such as calcium signaling, gene regulatory network and signal transduction network. In this stage, lectures were omnibus, that is, various front-line lecturers gave us a lesson and explained their researches. For example, Dr. J. Hasty, who worked at UC San Diego and had published many papers in Nature and Science, introduced us to how powerful the synthetic biological approach was as a way to understand biological system quantitatively. And so, we had rich experiences being exposed to current trends in CCB. Also, I noticed that even though each hot topic seemed to be quite different from each other, there were common keywords: bistability, oscillation, stochasticity, and spatial model. This finding will be useful when I make a plan of future research projects.
At the same time as basic theory and practical examples, we took exercise lessons and learned practical computational simulation techniques. These lessons were very fruitful because we could reproduce and review what we learned. In addition, these were also valuable to experimentalists like myself since we could easily image actual situations. Although there are abundant numbers of softwares today, I feel that we can make many kinds of studies only by ones that we mainly used in this course: XPPAUT, Virtual Cell, COPASI, and MATLAB. And so, I can’t help but think whether the theoretical approach can be applied to progressing my current research projects.
Student Project

In addition to intensive lectures, the student project was also a remarkable feature in this course. We were asked to decide a short project based on our own interests, develop it during the course, and make a presentation of the results on the final day. I thought that this opportunity was precious for young scientists like ourselves because it was equivalent to a training to develop the essential skills for scientists, finding interesting problems and proposing new concepts, and I deeply thought about what theme was best. For three reasons, I decided to explain the specificity between two yeast MAPK pathways. Firstly, this is fairly related to my present researches, and I expected to obtain the most benefit from this activities. Secondly, although one group explained the specificity by mathematical model, other group denied it by experiment, and then the quantitative explanation remained to be accomplished. Finally, a few students chose the topics related to signal transduction pathway. In fact, when I consulted with a lecturer who was an expert in signal transduction pathway, he said that my theme seemed interesting.
Because a mathematical model was reported although denied already, I started to reproduce the simulation of this model at first. My lack of experience in computational simulation, however, prevented me from making good progress. By the help of TAs, I could finally reproduce it. I found that we couldn’t advance not only “wet” experiments but also “dry” experiments as we had expected. And so, I could experience closer situation to reality than one that I imagined through exercise lessons.
Even after that, out of frying pan into the fire; next, I tried modifying the model to agree in the reported experimental data, but was faced with failure many times. This time, I discussed with my new friends who have theoretical background. Although we couldn’t reach the direct solution, I came up with the idea that I introduce dynamics to the model because they simulated oscillatory model including positive feedback mechanism. And so, I tried applying positive feedback mechanism and acquired the most probable model. From this experience, I rediscovered the importance of communication with diverse persons.
Extracurricular Activities
Because CSHL was surrounded by nature, this course also included extracurricular activities such as sailing in the harbor, picnic on a beach and foot race while holding yeast plates. They were good for a change and also useful for deepening friendship with new friends. Even if they were not scheduled, however, we could bond with each other because we spent almost a whole day together; we took a meal together, studied together, and watched the Olympic games at a bar together.

Almost all friends hold high aspirations and had already decided to work in the academic field, and so, as well as lectures, the contents of the conversations cover a wide range of topics from funny stuff to serious scientific talk. Among talks with them, the most surprising thing for me was that all friends knew the University of Tokyo (UT). Since it was said that the UT was losing their presence and I had never talked with as many foreigners before, I had believed that most of them didn’t know my university, but I was glad to hear the fact that the UT was still famous. At the same time, I thought that this was the result of achievements of our predecessors and that I’d like to play some sort of role in carrying over this honorable name recognition into the next generation.
With regard to command of English, I keenly realized the necessity of improvement of daily conversational ability. Indeed, I had little problem listening to what lecturers said and ask a question in the lectures, but the situation was favorable for me; they naturally spoke slowly in order to explain. In addition, I could also use information from the eye; I understood the meaning of “nullcline” only after watching “dx/dt=0”, for example. In everyday conversation, on the other hand, I felt my lack of ability because I was faced with a lot of slang and proper nouns I didn’t know. Because I had the opportunities to listen to various pronunciations of non-native English speakers, I noticed that I was not good at catching the pronunciation of Russian friends. Also, I was irritated with myself when I couldn’t respond smoothly. Although I found that it is easier for me to bring up the topic, I must become able to get rid of the inconvenience because daily conversation is important for world-level scientists.
Conclusions
As mentioned above, I obtained many kinds of knowledge and skills. And I’d like to emphasize that I also realized what I should study and learn. Although realizing what is missing is still useless on practical side, I have the opportunity to continue to develop my knowledge and skills with a will of my own. And so, I conclude that this experience of studying abroad is priceless for me. Originally, because I felt the fact that molecular biology had the limitation to elucidate signal transduction pathway itself and thought that one of the solutions was applying mathematics and computational science to biology, I was eager to study quantitative approaches. After the attendance, my thought became much firmer. I’d like to become one of the best scientific leaders in the world who tackles the exhaustive understanding of intricate subcellular network systems, and ultimately who calculate the network under any conditions and contribute to drug discoveries. My road to this ambitions goal must be hard. I could, however, make big strides toward it in this summer, and I’d like to continue to go ahead.
Acknowledgement

First of all, I have great appreciation for my boss, Dr. Hidenori Ichijo (Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo). He wrote my recommendation letters and originally introduced CSHL summer school to me. Also, I’d like to thank Dr. Takayoshi Okabe (Open Innovation Center for Drug Discovery, The University of Tokyo), for writing my recommendation letter. Finally, I am deeply grateful to Friends of UTokyo, Inc. for financial support. In particular, I’d like to express my sincere gratitude to Dr. Hisashi Kobayashi, Dr. Masaaki Yamada, and Dr. Masako Osako. They kindly supported my procedure for my attendance. Moreover, Dr. Kobayashi also recommended a book related to CCB topics.