This article is reproduced from the research of the Academia Sinica, and Pan-Science is the implementation unit of publicity and promotion.
- Interview and writing / Ou Yutian, Huang Xiaojun, Jian Kezhi
- Art Design / Lin Xun’an, Cai Wanjie
Neuroscience and Vision
How do we “see” colors and “perceive” things moving? How does the brain produce vision? Academia Sinica’s “Research” has an exclusive interview with Li Qihong, director of the Institute of Cell and Individual Biology in the academy. He is an internationally renowned neuroscientist. He used to do research at the National Institutes of Health in the United States for a long time. Contribute what you have learned. Li Qihong’s lab mainly uses the Drosophila visual system as a model to study how neurons form complex synaptic connections during development and how neural circuits generate vision to guide animal behavior.
Technology drives neuroscience research
How does the nervous system work? This was a black box to previous scientists. Because errors or problems in the brain will be directly reflected in external behavior, early scientists wanted to understand the working mechanism of the human brain. into the cellular level.
“In the development of biology, in addition to the need for intelligent thinking, everything else is driven by technology. You may think of an interesting topic, but it may take 30 years before sufficient technology appears to solve the problem.” Li Qihong gave an example , from light microscopy, electron microscopy, electrophysiological techniques, molecular biology to structural biology developments, each opening up new worlds at the cellular, molecular, and systems levels.
With the increasingly complete microscopic technology and genetic engineering, Drosophila has become a popular object of brain research today. Li Qihong pointed out, “Drosophila grows fast. Compared with mice, it takes a few months to mature, and Drosophila takes only two weeks. The brain complexity of Drosophila is between that of human and single-celled organisms, and its structure is highly similar to that of human beings. The results can be applied. on people.”
Therefore, in the past 10 years, neuroscience has taken off. Scientists use genetic methods to control the neuron activity of fruit flies and observe behaviors, so as to understand which genes affect the development and operation of the brain, and gradually crack the mystery of neural circuits.
“When I was doing postdoctoral research, I wanted to do nematodes, mice, fish, fruit flies, or other model organisms? I chose fruit flies in the end. In retrospect, I have just encountered fruit fly-related technologies booming in recent years, and choosing fruit flies is very important. Correct decision!” Li Qihong laughed.
Li Qihong cited the tri-level hypothesis of David Marr, a well-known neuroscientist, that the brain operates at three levels:
- Computation level: what the nervous system is doing, such as distinguishing colors, watching things move, recognizing whether an object is round or square, apple or orange, etc.
- Algorithm level (program): how the nervous system operates, how the program does it.
- Implementation level: How the nervous system implements this program through neurons, neural networks.
Li Qihong said, “In the past, most neuroscientists were discussing computation and then exploring the algorithm, but they couldn’t solve the implementation. Now, because of the technology, scientists can finally find the implementation, and then push back to the upper-level problem, and even found that the algorithm is different from what they originally thought. ”
How does the retinal perception system work?
There are also cases in which disputes have been resolved due to technological advances regarding how the nervous system operates (Algorithm level). Li Qihong, for example, used to study the mechanism by which neuroscientists perceive the movement of objects in the visual system. Several theories have emerged. The HR theory believes that neural signals use multiplication, and the other BL theory believes that it uses subtraction, which has been controversial for a long time.
In recent years, scientists have discovered that the original retinal perception system has a mixed operating mechanism, a total of three, called HR-BL Hybrid Vision Motion Detector. Both factions were only half right in the past.
The Hassenstein-Reichardt (HR) model: derived from studies of insect behavior.
- When a visual stimulus with a preferred direction (from left to right) appears, the photosensitive neuron on the left receives a signal, the signal is delayed (time τ), and then the photosensitive neuron on the right receives a signal, the signal of both will reach the downstream nerve cells (X) at the same time, and the signals will be multiplied to generate the motion signal.
- When a visual stimulus in a non-preferred direction (right to left) is present, the two signals arrive at different times and no motion signal is generated.
The Barlow-Levick (BL) model: derived from electrophysiological studies in rabbits.
- When a visual stimulus with a preferred direction (from left to right) appears, the photosensitive neuron on the left receives the signal, and then the photosensitive neuron on the right receives the signal, but it is an inhibitory signal and is delayed (time τ), The signal on the left will first reach the downstream nerve cells to generate motion signals.
- When a visual stimulus in a non-preferred direction (right to left) appears, the signals of the left and right light-sensing neurons will arrive at the same time, the stimulus signal and the inhibitory signal will cancel each other out, and no motor signal will be generated.
Continue to analyze the neural circuits of the Drosophila brain!
All operations of modern computers can be expressed by three logic gates of and, or, and Xor. Scientists want to know, is there a similar but higher-order neural circuit operation in the brain? “From the senses to the behavior, it is easier to observe and manipulate, and we currently know the most about the operation of the neural circuits in visual movement.”
Li Qihong has been doing research on insect vision and behavior in recent years, and found that when insects perceive colors, such as green light and ultraviolet light, the processing method of photoreceptor cells is to first compare the intensities of ultraviolet light and green light, and then subtract the intensities of the two lights. , so that the original two signals become one signal, the so-called “color antagonism”.
“This neural circuit can parse and compare the difference in the intensities of two colors, because it is the contrast that is most important visually. The antagonistic computing module can find out where the signal is strongest and the others are weaker. Other senses The mechanism is also the same. For example, when you touch an object, the protruding part is more important, and the auditory should find out which sound is particularly high, so that the most important signal can be highlighted.” Li Qihong added.
In 2021, Li Qihong’s team discovered for the first time that the Drosophila visual system stacks multiple sets of antagonistic computing modules to achieve the dual antagonistic effect of color and spatial receptive fields. The results were published in “Current Biology“. Such neural circuits can compare adjacent colors, creating a sense of contrast between color ranges. “Without such a function, we can’t see that red and green are tragic!” Li Qihong laughed.
Scientists are working hard to study the neural computing circuits of the fruit fly brain, hoping to gradually sort out the basic computing modules. Perhaps one day, seemingly complex brain functions may be cracked with basic circuits!
How did the teacher embark on the path of studying brain neuroscience?
“I started the road of scientific research late at night. I am interested in computers and like to write programs. I went to the medical department of the Chinese Medical College in college, and my family also wanted me to be a doctor. However, during my internship, I found that I had no interest in treating patients. Instead, I was more interested in the problem or the disease itself. After talking with a few teachers, I decided not to be a doctor, and went to Tsinghua University to study life sciences, and then to the Academia Sinica.”
Because of my medical background, I initially wanted to do research that could solve the problem immediately, such as treating cancer with a complex of proteins and toxins. But later I learned that without a deep understanding of the pathogenic mechanism and basic scientific research, it would be difficult to make a breakthrough.
Later, I went to the Rockefeller University to study for a Ph.D. During my study at Rockefeller, everyone often communicated with each other, which greatly inspired me. At that time, I was studying structural biology, hoping to understand the real physiological process of disease, and I had unraveled the protein structure of HIV and human signaling.
Before graduating from my Ph.D., I was exposed to neuroscience and was very interested, so I went to UCLA to do a postdoctoral study, studying developmental science in neuroscience, and wanted to understand how the brain uses different molecules to transmit between cells during development. message. At that time, I stayed in a large laboratory, and the teacher didn’t care about the students. They had to figure out their own way or learn from the people next to them. Many people were of high quality and the learning environment was very good.
After that, I entered the National Institutes of Health (NIH) and started to open a laboratory with my own team. After 16 years, I really entered the field of neuroscience, and I am still doing related research until now.
Everyone’s life choices are dominated by previous experiences. Without a medical background, I’m afraid I would not study structural biology or enter the field of brain neuroscience.
The teacher’s research in the United States went well, so what was the opportunity for you to decide to return to Taiwan? Did you feel uncomfortable when you came back?
“I went abroad at the age of 26 and stayed in the United States for 26 years. I was almost completely integrated into American life. The laboratory was working well, and even my wife was an American. But after many years in the United States, a deep feeling emerged in my heart: I am staying in Taiwan. After so long, Taiwan is the starting point for me to enter the sciences, maybe I should come back to teach the children in Taiwan.”
At the beginning, I had some ideas. I was invited to speak on stage a few times, but I didn’t make up my mind. Then came an important turning point. The Institute of Molecular Biology, Academia Sinica, invited me back to give a speech during the 30th anniversary celebration. At that time, I had the opportunity to chat with the former directors, many of whom were teachers I met at Academia Sinica in the past. After chatting, I felt deeply and found that each director has to face the growth or various problems of the shrine, and each director has unique insights and important contributions.
I was very moved when I saw that the shrine was working very well, and I thought to myself: maybe I can follow their example when I come back, and maybe I can make a little substantial contribution to the development of the Institute of Cell and Individual Biology, Academia Sinica.
Although if I stayed at the National Institutes of Health in the United States, I would have such an opportunity, but I still want to bring my own children and use my energy to make my country and organization progress. I want to try to bring back to Taiwan the lessons I learned at the NIH, like which organizations work and which don’t.
I am well aware of the possible problems, such as the impact of the scientific research community, and it will take a few years to re-establish the laboratory, but that opportunity gave me complete confidence. I used to joke with President Liao Junzhi that even if he didn’t give me money, I would probably come back. Because I really think this is a good opportunity to do something for Academia Sinica and Taiwan. After all, Academia Sinica has always been like my home!
However, after all, I used to speak English in the laboratory and at home in the United States, and I could only speak Taiwanese when I called my mother. Therefore, when I first returned to Taiwan in 2018, I was not fluent in Mandarin, but rather fluent in Taiwanese.
What advantages do teachers think of the research environment in the United States? What kind of new ideas and new trends do you hope to bring to Taiwan?
“The biggest feature of foreign countries is that academic exchanges are very frequent. Although they are also quite frequent in China, they have a deeper level of communication. That is to say, after I communicate with the teachers involved, I can often change my thoughts, ways of doing things or direction, and it is positive. Change.”
Foreign teachers are invited to give speeches, and they will be very active in talking for a few hours. They are completely immersed in it throughout the day. They not only tell what they are doing, but also ask the audience to give criticism or suggestions. They have in-depth exchanges with each other. Participants feel that they have gained a lot and have the possibility of cooperation.
My experience in China is that after the speech, there is relatively little opportunity to communicate with other teachers in depth. This may be the customary pattern in China, and I think it needs to be changed. Now I also ask everyone in the institute that since you have paid for the teacher to come, you must have in-depth exchanges and ask the other party to give advice.
What matters is not the format or inviting Nobel laureates, but after the speech, this person walks out of my office, after these people leave, is there any substantial change in what I do or how I do things? Have you been inspired to change your way of thinking or experimenting by talking to other scientists? Or listen to what others tell you, what else you didn’t expect?
Sharing is also a very important technique. In the process of communication, when we can explain one thing clearly, we will be enlightened and know where the problem is.
The current plan of the institute is to divide teachers into various interest groups, to communicate within the group or to have cross-group activities. The rest, like writing a plan, applying for a grant, running a lab, or writing and publishing an article, are basic technical issues.
To do any job, one is the basic core technology, if there is no “skill”, you cannot survive; the other is “art”, which can drive you to do it all the time. When training talents, in addition to cultivating technology, we also need to train art.
The teacher mentioned that art is needed for work, what part of the scientist’s art is it? Can you explain in more detail?
“I think in science, Art has many aspects. For example, how do you choose a problem, how do you find an entry point, how do you divide a big problem into several breakable parts, and solve it step by step, this is a kind of art. Especially in the selection of problems and entry points, it is necessary to have unique insights or opportunities to succeed.”
Scientists must create useful knowledge. What is useful knowledge? It is when you hear what you learn that will change the direction you think about things or the way you do things. Many things can be studied, and as long as the scientific method is rigorous enough, some knowledge can be obtained. But what topic to choose? What is an interesting question? Judging these is the art of science.
If it is said that there is a dark abyss in front of human beings, knowledge is like light that illuminates the road ahead of us, and scientists are like standing at the forefront, how do you know how to take that step? How to step out? This is Art.
When scientists see a problem and the problem takes shape, the most important key is how to choose a core problem to solve. Just like when you play a puzzle, you have to put down the core and most important piece of the puzzle.
After I returned to Taiwan, I felt that the research environment here is very good, the instruments are not inferior to others, and the teachers are excellent. But maybe most of us just focus on our own research and don’t take the time to think about it seriously. Where is the most important piece of the puzzle? When we have a deeper communication, we can find the most core piece and make the most important contribution.
How did the teacher lead the research team when he was in the foreign laboratory? What to expect from young scientists?
“The most important key in master’s and doctoral training is to change from “reading” science to actually “doing” science. We unfolded a textbook and saw that it talked about this and that, just reading other people’s science. Even if you read the original article, you are still watching how science is made by others. “
Only when I really do research can I realize that there may be thousands of articles behind every page and sentence in the textbook. Only then will I realize that I am very small, that I know how to be humble, and that I understand that what I can do in my life is limited.
Therefore, every time you take a small step, you need to figure out how to take the most efficient and effective way. I think the most important thing in a master’s or doctoral class is to understand that feeling.
Some students may think that I am very small anyway, the world is so big, even if I am the most successful scientist all my life, I will only get a sentence from the textbook. It doesn’t matter what I do. But we must lead students to understand that this project is not done by the teacher asking you to do it, but to make students feel that this project is their own, with room for progress and development, just like their own children, they must be responsible.
I used to be in the master and doctoral classes, and I was just beginning to learn techniques, experiments to produce results, or to publish articles like others. The kind of pride that I don’t know can really last for a long time. I still remember the joy of walking out of the lab at five in the morning knowing there was something in the world that only I knew!
When a student has felt the joy of discovering the truth, you don’t have to dictate what time he will come in the morning and what time he will leave in the evening, he will have the motivation to do it himself.
It’s a real joy when one thinks about what this thing should be like, and tries to find a way to prove it experimentally. I think this is unmatched by any other industry!
The student is to be trained to be a future scientist, to be on his own, and he should be allowed to go by himself. Even where you can see, let him come out on his own, and what he thinks of himself is more useful than what you tell him to come.
In fact, when I was the most excited as a teacher, it was the students who told me things I didn’t know, and they felt very happy. When the students thought of things I didn’t expect, they said they had made progress and were better than me, which was great!
Further reading
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