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How did Daniel lay the foundation for scientific research?
All successful scientists must have one thing in common, that is, they must spend a lot of time and effort. This is a truth. In fact, no matter what kind of occupation you are engaged in in in society, you must spend more time than ordinary people if you want to be a leader in this industry.

About 10 years ago, a famous China biologist, Mr. Muming Poo, had an email that was widely circulated on the Internet. This email was written by Mr. Pu to all doctoral and postdoctoral students in his laboratory, and I totally agree with him. Whether in Princeton or Tsinghua, I forwarded this email to all the students in the lab to let them know. One of the paragraphs is like this:

"I think the most important thing is working hours in the laboratory. Today, a successful young scientist spends an average of 60 hours a week on research in the laboratory ... I suggest that everyone spend at least 6 hours a day on intense experimental operation and more than 2 hours on reading and other work directly related to scientific research. Documents and books should be read mainly outside these working hours. "

A classmate said to me after reading the email, "It seems that I am not academic material, because I really can't afford the pain." I often answer, "When I was your age, I would find it incredible to work like this for a long time." But unconsciously, you will gradually be moved by the subtlety of scientific research, be proud of your efforts and achievements, and gradually adapt to this lifestyle! "This answer actually comes from my own experience and understanding.

I especially like playing since I was a child, and I don't like studying, but the education and pressure from my school and parents forced me to study as hard as possible. High school students in Henan experimental middle school, with more efforts than others, comprehensive performance has been among the best. 1984 I won the first place in Henan Division of the National Senior High School Mathematics League, and I entered Tsinghua. At the university stage, I kept the tradition of studying hard, ranking first in my class in comprehensive scores, and graduated the year before last. However, in fact, I seldom really think independently and I am not interested in my major. When I graduated from college, I didn't intend to engage in scientific research, but I wanted to go into business wholeheartedly. As a result, I accidentally embarked on the road of studying in the United States.

It is conceivable that in the first year of studying abroad, my mood fluctuated greatly, impetuous and confused. I didn't intend to study or do research at all, but spent a lot of time working in a restaurant in China and taking computer courses. In the second year, I began to gradually adapt to the "boring" of scientific research and began to have a little experience of my own. Sometimes, after understanding some nuances, you can't help but be "complacent" and have the idea of "so much", and gradually have a little confidence in your scientific research ability. During this period, all the courses of doctoral students have been completed. I have a physical examination from 9 am to 7 pm every day, five days a week and two and a half days on weekends. In the third year, I have begun to understand the logic of scientific research, and I feel a little eager to try. I often ask questions in group meetings, and this feeling of "getting started" has increased my research interest. I often work until evening 1 1 to catch the last bus from Hopkins Medical College to Homewood Campus near my residence. In 1993, I marked "This is the second1day of my continuous work in the laboratory" next to the date of the experimental notebook to motivate myself. Actually, it's a bit of a show, because I only did five or six hours of experiments last weekend. In the fourth year, I completely adapted to the scientific research environment in the laboratory, and I won't feel bored anymore, and I won't have time pressure. The time schedule is completely subject to the needs of the experiment, and it should be as early as possible. In fact, the experimental time during this period is much longer than when I first entered the laboratory, but I feel much better.

In the later stage of graduate school, my efforts were famous in the laboratory. Being a postdoctoral fellow in new york was the hardest two years in my life. I do experiments until about 3 o'clock in the middle of the night, and it is often after 4 o'clock when I get back to my residence to lie down and sleep. But every morning at 8 o'clock, I will be awakened by the noise of cars on the First Avenue in new york, and return to the lab at around 9 o'clock to start a new day. Three meals a day are in the laboratory, at 9: 00, 3: 00 and 90: 00 respectively. This pace of life lasts 1 1 day. From Monday to Friday next week, I will take the Greyhound coach back to my home in Baltimore on Friday night. Sleep nearly 10 hours a day for two days on weekends to make up for the serious lack of sleep in the past 1 1 day, and then start the next 1 1 day on Monday morning. Although I am very tired, I am very satisfied and proud. I know that I am building the future with actions, starting a business, and sometimes encouraging myself in my diary. I live near the intersection of 65th Street and First Avenue in Manhattan, new york, close to the famous Central Park in new york, where there are cultural and entertainment activities, but I have worked in new york for two years, and I have never set foot in Central Park.

I will definitely tell this experience to all my students. Freshmen often ask me, "Teacher, do you feel bitter?" I usually answer: "I feel bitter only when I do things that I am not interested in, and it is not bitter at all when I am interested." Yes, a wonderful experiment brought me much more enjoyment than watching an American blockbuster. Looking back on the hard work at that time, I still feel very proud and excited! Sometimes I think: What would it be like if I didn't work hard for seven and a half years as a doctor and postdoctoral student, but watched movies, novels and sought entertainment freely (the Internet was far less abundant then)?

To be an excellent doctoral student, giving time is a necessary condition.

(2) If you want to make a breakthrough and success in scientific research, it is not enough to spend time assiduously, and critical analysis is a necessary quality.

The biggest difference between doctoral students and undergraduates is that undergraduates focus on learning and absorbing the accumulated knowledge of human beings, taking into account scientific research and skill training; The essence of doctoral students is to explore and create new knowledge through scientific research. The knowledge learned now and in the past is to better serve scientific research. In the undergraduate stage, it is very important to ask questions, but the answers often already exist, so whether the questions are critical or not is not so critical. Doctoral stage is completely different, you must have the ability of critical analysis, otherwise you can't become an excellent scientist. This, I call it a change in methodology.

In fact, the essence of the whole university and postgraduate education is to cultivate the ability of critical analysis and let students have the methodology to carry out innovative scientific research. There are many examples here, covering a wide range, so I want to give a few examples here.

Correct analysis of negative results is the key to success. As a doctoral student in life science, if every experiment goes smoothly, you can get positive results. Except for a few research fields, it usually takes only 6~24 months to get all the results needed for a doctoral degree. In fact, however, in the United States, it takes about six years for doctoral students in life sciences to get their doctorate. This figure itself shows that most experimental results will be inconsistent with expectations, or negative results. Most junior doctoral students hold a negative attitude towards negative results, which directly affects the cultivation of their critical analysis ability.

In fact, as long as there are appropriate controlled experiments, judging the correct negative experimental results is often the only way to success. Generally speaking, every step of any exploratory project has several or even a dozen possible ways of progress. The process of progress is basically the process of eliminating incorrect paths and finding the right direction. Many times, it is also a process of trying and eliminating these or even a dozen possible ways one by one until a feasible way is found. In this process, a credible negative result can often make us give up our current practice with confidence. If used properly, this division will ensure that we finally embark on the correct experimental method. From this perspective, the negative experimental results are not only normal, but also conducive to the ultimate success of the project. I warn and encourage all my students: as long as you keep getting credible negative results, your project will soon be on the right track; The powerful logical analysis ability mastered in the process of constantly analyzing negative results will make you mature quickly and grow into an excellent scientist.

I have always been worried about those students who are smooth sailing and rarely get negative results, because they have never really experienced the training of critical analysis in scientific research. Occasionally, there are such students in my laboratory, who have completed the required results in a very short time (about two years, sometimes even one year). For these students, I will definitely let them continue to undertake some challenging new topics and let them undergo the tempering of negative results. Without these trainings, it is difficult for them to really have the ability of critical analysis, and it is also difficult for them to become outstanding scientists who can lead a laboratory independently in the future.

So, don't be afraid of negative results. The key is how to get correct information from the process of analyzing negative results.

(3) "A person must choose what he wants to do, and it is impossible to cover everything. Whether reading scientific research literature or listening to academic lectures, the purpose is to learn relevant experience and better serve your own scientific research topics. " Never blindly pursue perfection.

Time-consuming perfectionism hinders innovation and progress. Nikolai Pavala Teach is my postdoctoral tutor and one of the most influential scientists. He has strong experimental judgment and thinking ability, made a series of landmark research work, and enjoys a high reputation in the field of structural biology. 3 1 year old was promoted to full professor. 1April, 1996, I just arrived in Nikolai's laboratory and purified a highly expressed protein Smad4. After two days, although protein was purified, the result was not satisfactory: the output may only be about 20% of what it should be. When I saw Nicholas, I said shyly, "The yield is very low. I intend to continue to optimize protein's purification methods and increase production. " He asked me, "Why should we increase production? Isn't the existing protein enough for you to do preliminary crystallization experiments? " I replied, "I have enough protein for crystallization screening, but I need to optimize the output to get more protein." He rudely interrupted me: "no .. the output is high enough." Your time is more important than your output. Please start crystallization as soon as possible. " Practice has proved the value of Nicholas's suggestion. I only used a few milligrams of protein for crystallization test, and soon realized that the length of this protein was not ideal, and dozens of amino acids with N-terminal flexibility needed to be removed by protein project. In fact, protein with dozens of amino acids removed from N-terminal is not only high in expression, but also stable in biochemical properties, so it is very easy to purify, and there is no need to worry about the yield.

In the initial stage of bold and innovative experiments, every step of the experiment should of course be designed as carefully as possible. But once we start as planned, we don't need to pursue perfection in the experimental results of the intermediate steps, but we should not hesitate to push the experiment to the end step by step to see if we can get the overall results that are roughly consistent with the hypothesis. If it is generally the same, you should go back and carefully improve the experimental design of each step. If it does not meet the requirements, and there is no mistake in the overall experimental design and operation, then your hypothesis (or overall direction) is likely to be very problematic.

This methodology is used in experiments every day. Since 1998 started its own independent laboratory, I have always warned all my classmates not to blindly pursue perfection.

Selection of scientific research documents and academic lectures

Let's start with the choice of literature and seminars. Nikolai Pavala Teach is a man of many talents. In the minds of many postdoctoral fellows, he must read many articles and often attend academic lectures. Unexpectedly, the facts greatly surprised us.

In my doctoral stage, my tutor Jeremy Berg attached great importance to the reading of relevant scientific research documents, and held literature seminars in the group every week to discuss important scientific research progress. When I first arrived in Nicholas's laboratory, I tried to show my knowledge of reading literature, and at the same time I wanted to discuss with Nicholas to get his "true biography". 1996 One day in spring, I read an article in Nature. When I met Nicholas before lunch, I described the subtlety of this article to him and looked forward to his comments. Nicholas looks a little embarrassed. "Sorry, I haven't read this article." At that time, I thought, oh, maybe this article is too new for him to understand. A few days later, I read a research article published in Science a few months ago and went to discuss it with Nicholas. I didn't expect him to say he hadn't seen it. After hitting a wall several times, I asked him inexplicably: "You are so knowledgeable, you must have read a lot of literature extensively." Why don't you read these papers I mentioned? " Nicholas looked at me and said, "I don't read much." I asked, "If you don't read widely, how can you do scientific research so well?" ? How can you quote so many documents in your paper? "Nicholas's answer surprised me:" I only read papers that are directly related to my research interests, and I only read a lot when writing papers. "

Si Long-Kettering Cancer Center, where I am a postdoctoral fellow, has a good series of academic lectures and often invites "Daniel" from all fields of life sciences to give lectures. On one occasion, a Nobel Prize winner came to give a lecture and asked to talk to Nicholas by name. For most people, this is a rare opportunity. Nicholas said to his secretary, "Please convey my apologies. I happened to go out on the day of the speech." We also feel sorry for Nicholas. What I never expected was that on the day of the Nobel Prize winner's speech, Nicholas shut himself in his office, never went out from morning till night, and naturally did not go to the lecture hall. Of course, this may be a coincidence-Nicholas canceled his travel plans. But from what we know about him, nine times out of ten, he is writing a paper. Later, we also realized that it was not unusual for such a thing to happen to Nicholas.

Before I left Nicholas's laboratory, I threw him a mystery that I never completely solved: "If you don't read much literature and don't listen to lectures, how can you be such an excellent scientist?" He replied that his time was limited and he only stayed in the laboratory 10 hours every day. After weighing the pros and cons, he can only spend limited time on what he thinks is the most important, such as analyzing the structure, discussing homework with students or writing articles.

Nicholas's answer expresses a simple truth: one must choose what one wants to do, and it is impossible to cover everything. Whether reading scientific research documents or listening to academic lectures, the purpose is to learn relevant experience and better serve their own scientific research topics.

(4) In the doctoral stage, especially in the first two years, I think it is necessary to spend enough time listening to academic lectures in various related fields and reading scientific research documents extensively to lay a solid foundation for critical thinking; However, with the deepening of scientific research, the choice of literature reading and academic lectures needs to be targeted and the allocation of time should be weighed.

Challenge traditional thinking. From the time I was sensible, I was taught that everything failed for a reason. I should find the reason for the failure and then start again. Until 1996, my experiments followed this principle. But in Nicholas's laboratory, this "basic principle" has been properly challenged.

Once, a complicated experiment failed. I'm depressed, and I'm going to spend a few days doing more controlled experiments to find out the problem. I didn't think Nicholas would stop me. He frowned and asked me, why do you want to find out why the experiment failed? I think this question is unreasonable, and I confidently answer:

"I need to know what went wrong to ensure success next time." Nicholas immediately commented: "No need. What you really need to do is to repeat the experiment, maybe you can do it next time. Instead of spending a lot of time figuring out why an experiment failed, it is better to repeat it first. In the face of a complicated one-time experiment failure, the best way is to do it again seriously. " Later, Nicholas sublimated his view: "Whether to find out the reason for the failure of an experiment is a philosophical problem. The habitual thinking of clarifying every small mistake is not necessarily the best way. " On second thought, these words still make sense. Not all failed experiments need to find reasons, especially life science experiments. Because the experimental process is complicated, most of the failures are caused by simple operational errors, so you can do it again carefully and often solve the problem. Only those key experiments that can't move forward without finding the cause of failure need to be traced back to the source.

These examples I have chosen are somewhat "extreme", but only in this way can we better shock everyone's thinking. In fact, in my own laboratory, these examples have been told to all the students many times, and after each lecture, I will tell you that the key to breaking superstition and doubt is to follow logic! Logically, this is a sentence that I am destined to repeat in the laboratory, and I have to say it to different students at least five times a day. Every time I discuss a topic with a doctoral student, I follow strict logic and find the next solution of the experiment through reasoning and exclusion. Strict logic is the basis of critical analysis.