Article｜China Science News reporter Feng Lifei
Two years ago, Yan Zhiqiang from the deep-rooted School of Life Sciences at Fudan University "jump" to the still nascent Shenzhen Bay Laboratory, "snail" in a commercial building, and the team here to find the last piece of the puzzle of human perception of the world.
Among the five senses defined by Aristotle, the receptor genes mediating the senses of smell, taste, vision, and touch have been successively identified. Among them, scientists' research on the five receptors has won the Nobel Prize three times. The most recent was the discovery of temperature and touch receptors by two American scientists in 2021.
But which gene encodes the ion channel responsible for auditory transduction, the heart of human sound perception, has been a mystery.
In 2020, Zhiqiang Yan and co-workers finally identified auditory transduction ion channels located in cochlear hair cells, providing an important basis for the identification of auditory receptors. Now, he and his team are continuing their research around this increasingly competitive international problem.
Although the economic strength of this coastal city is still weak research base, but he is very optimistic about the prospects of development here, because "all aspects of support are in place", not far from a research site of more than 200,000 square meters is planning to build.
Yan Zhiqiang and team
A "smooth" road to research
On the official website of Shenzhen Bay Laboratory, a simple five-line timeline summarizes Yan Zhiqiang's research experience over the past 22 years. A little closer look will reveal that his postdoctoral research will skip the assistant researcher, associate professor and most of the "young peasants" must go through the road to become a professor of the top universities in China.
"Compared with the growth environment, a person's life direction and their own relationship is greater." Yan Zhiqiang thinks so.
Yan Zhiqiang was born in an ordinary Shandong family, and after entering Fudan University in 2000, he became interested in the mysterious brain science as a young man ignorant of life sciences. At that time, China's brain science research has just begun, lack of knowledge base and professional training. This is considered to be the ultimate problem in the field of life sciences, a Chinese youngster can do well? No one knows the answer.
"The idea was in a state of 'naivety'. How much money to earn in the future? What house to buy? These are not thought of, just according to their own interests naturally forward." Yan Zhiqiang recalled.
In his sophomore year, he recommended himself to the Institute of Neurobiology founded by academician Yang Xiongli at Fudan University to do research in Prof. Li Baoming's lab; in the summer of his junior year, he was introduced by his teacher to the newly established Institute of Neuroscience of the Chinese Academy of Sciences (hereinafter referred to as the Institute of Neurology) for internship.
With this "breakthrough", he was exposed to the most cutting-edge scientific knowledge and professional training at the Neurology Institute. More importantly, in this research institute, which was established as a pilot project of the Chinese Academy of Sciences, he met many returnees who made beautiful research in the field of neuroscience, including Muming Pu, Yi Rao and Minmin Luo, who were the leaders of his biological experiments.
In 2004, he went to the Institute of Neurology as an exempt student for his master's degree, and a year later, he followed his supervisor Minmin Luo to another newly established and innovative institute, Beijing Institute of Life Sciences (BILS), to do research on olfactory neuron information transduction. This was a hot research area at that time, and the research on olfactory receptor molecular family had just won the Nobel Prize in 2004.
During that time, Yan Zhiqiang demonstrated for the first time that the olfactory bulb has precise and specific bilateral connections, which was the first report at that time to demonstrate that the forebrain has precise and specific bilateral connections. The related study was published in 2008 in Neuron (Neuron) Journal.
The beautiful research earned him a weighty letter of recommendation. In Rao Yi, Minmin Luo and Xiaodong Wang, three professors recommended Yan Zhiqiang to enter the University of California, San Francisco and Howard Hughes Medical Institute (HHMI) Yuh-Nung Jan's laboratory as a postdoctoral fellow. Yuh-Nung Jan and his wife, Lily Jan, are "double" members of the American Academy of Sciences and the American Academy of Arts and Sciences, and have a high reputation in the international field of neuroscience and have trained many famous scientists, such as Rao Yi and Luo Liqun.
In the eyes of Yan Zhiqiang, Mr. Zhan Yunong has the style of "old school scientists": completely in accordance with the independent scientists training young researchers. "The company's main business is to provide a wide range of products and services to the public. He doesn't care what direction you go, and he won't say anything if you ask him for specific advice. You tell him a stupid opinion, he will not say it is not good, but let you figure it out yourself." He says, "It's like watching your child about to hit the corner of the table and holding back from reminding him that he thinks the process of you finding your own direction is also the process of building competence."
This growth model has also allowed the lab to produce outstanding students, with more than 200 going on to become professors, which is also extremely rare in the United States.
Under such a nurturing environment, Yan Zhiqiang quickly determined his direction by reading the literature and discussing with colleagues to study the mechanisms of tactile and auditory transmission using Drosophila larvae. The mystery of the physiological basis of these two sensory systems, which have not yet been deciphered, is a frontier problem that scientists around the world are competing to explore, and is a new direction for the laboratory of Zhinong Yan.
In 2013, Yan Zhiqiang's research on the tactile transduction ion channel NompC was published in the leading international scientific journal Nature (NatureThe study, of which he was the first author, was also included in the textbook Principles of Neurobiology by Stanford University Professor Liqun Luo, a member of the National Academy of Sciences (Principles of Neurobiology). In addition, the research system constructed by Yan Zhiqiang and colleagues in a series of studies using Drosophila larvae as model organisms has attracted other international teams to follow suit.
In 2013, the then Vice President of Fudan University, Academician Jin Li of the Chinese Academy of Sciences in Yan Zhiqiang Fudan interview deliberately with a long talk with him, about the year Mr. Jiazhen to promote the progress of domestic research, despite his advanced age specifically to the United States to invite him back to the story, in order to inspire Yan Zhiqiang to return to his alma mater to teach. Fudan directly "broken" to this just out of the postdoctoral researcher to the PhD position. The following year, Yan Zhiqiang was awarded the title of "Oriental Scholar", a special professor of Shanghai universities, and received support from the Shanghai Young Scientist Program.
The next few years of research achievements, Yan Zhiqiang did not live up to the expectations of Fudan and the city of Shanghai for talent. 2019, he and the university's team of Professor Susuki Hattori and the team of Professor Rei Mochiki at the University of Tokyo collaborated to confirm the auditory primary mechanical force-gated ion channel for human perception of sound vibrations, solving a problem that has plagued the field of hearing for nearly 40 years. The related results were published as a cover story in the journal Neuron.
In the eyes of others, "smooth sailing", in Yan Zhiqiang's view, the key is to think about the direction of their lives and the management of personal behavior.
Like many people, Yan Zhiqiang's road to research has also encountered troubles. Although the second year of his master's degree in the experiments he made important discoveries, and then also quickly submitted a manuscript to the journal "Neuron", but over time, Yan Zhiqiang felt that the initial thought of "very interesting" research life is actually a bit boring. Every day is to do experiments, collect data ...... trivial daily routine let him feel boring: "I do the research is important? Is doing research the way I want to live?" In the process of reading articles of interest, it dawned on him: "As Russell said in his book The Road to Happiness, boredom is the basis of most great work, and Marx's Das Kapital, too, is to sit there a little bit slowly to write."
In response to some of the difficult problems encountered in research that can be a deterrent, his mantra is, "Difficulty is not the problem, doing it or not doing it is the biggest problem." In one of his experiments as a doctoral student, he had to inject a neural tracer dye into the brain of a mouse, and the injection had to be confined to the size of about 50 microns in the brain, which is only about 5-10 cells wide, and everyone said it was difficult to achieve and not to do it. So he took matters into his own hands and made an important discovery. In the haptic experiments during his postdoctoral period, there were few people in the world who could do the electrophysiology of the model animal larvae Drosophila and nowhere to learn, so he worked independently with his colleagues on how to solve it.
"The key thing is to look at the direction you choose to study."
In 2020, Yan Zhiqiang joined Shenzhen Bay Lab, and in the new environment, he and his team continue to explore the last piece of the puzzle of human perception of the world.
"The most critical thing in doing research is to look at the research direction you choose, choose problems that can be solved and are important, and ideally systematize the problems." He said.
Perceptual biology, one of the most central questions in neuroscience, is what he considers to be a "pragmatic and important" direction. Research on the physiological mechanisms surrounding the five senses defined by Aristotle - sight, hearing, smell, taste and touch - has been at the forefront of international research. The receptor genes mediating four of these senses have been identified, and three have been awarded the Nobel Prize in Physiology or Medicine.
Vision research rushed to the forefront, as early as the 19th century, the German physiologist Franz Christian Boll discovered the expression of the photoreceptor protein retinal rhodopsin on retinal optic rod cells, followed by the American scientist George Wald, who was awarded the Nobel Prize in 1967 for revealing the biochemical response of the protein to light sensitivity through biochemical means.
Entering the 21st century, American scientist Richard Axel and then postdoc Linda B. Buck were awarded the Nobel Prize in 2004 for their discovery of a family of olfactory receptor molecules.
Since then, international research on other sensory receptors has become increasingly competitive.
Yan Zhiqiang's research during his postdoc centered on tactile receptors, and in 2013 they discovered in their study that Drosophila tactile receptors are not conserved in humans, and the related results were published in Nature; while in 2014 Ardem Patapoutian, a professor at the Scripps Research Institute, discovered the human tactile receptor PIEZO2 in response to mechanical stimuli. eventually in 2021. Patapoutian shared the Nobel Prize in Physiology or Medicine that year with American scientist David Julius for this discovery.
On the taste side, three other U.S. scientists also assembled the molecular receptors for the five basic taste sensations of sweet, sour, bitter, salty and fresh in 2018 in a nearly 20-year white-hot competition.
The last piece of the puzzle of the physiological mechanism of hearing, which is second only to vision in the Aristotelian hierarchy of the five senses, has never been found.
In fact, in the field of hearing research, Hungarian-American scientist Georg von Bekesy was already awarded the Nobel Prize in Physiology or Medicine in 1961 for his discovery of the cochlea, the organ of hearing. However, the discovery of auditory receptors has plagued scientists for decades.
Yan Zhiqiang said that this is because the auditory sense is the most complex and delicate working mechanism among the five senses. "The senses of smell and taste are chemical reactions that are relatively simple, and the binding of the relevant receptors to chemical molecules can be demonstrated through in vitro cultured cell experiments. Hearing, on the other hand, requires the perception of mechanical forces, and it is important to understand the molecular mechanisms that convert such forces into electrical signals." He explains, "In contrast to touch, electrical signals induced by sound vibrations are more difficult to capture than receptors for pressure-induced electrical signals, and also require more elaborate protein complexes than touch, which are difficult to reconstitute or screen for in vitro in cultured cells."
Over the past few decades, hearing scientists have discovered that the TMC1 and TMC2 genes are important for hearing in humans and mice, and that these two genes have been found in deaf patients, but it has been unclear whether they are gating "switches" for the mechanical force of sound perception in the human ear. The 2020 study by Zhiqiang Yan and co-workers provides a key piece of evidence for this.
However, Yan Zhiqiang said that this only provides the basis for the determination of the auditory receptors, how the auditory conduction, how to feel the mechanical force stimulation, these issues have not been fully resolved. This means that related research is still facing fierce international competition. "There are laboratories internationally that have been doing this for 20 or 30 years. But we are also at the cutting edge." He says with a smile.
Despite his confidence in himself and his team, he is still very hardworking: sometimes like a demon, he can eat, sleep and go to the toilet 24 hours a day to think about a problem; he will also work in the laboratory until he is exhausted, until he can no longer work before he goes home to rest, and does not give himself a vacation for a year; occasionally he feels that his lifestyle is too unhealthy, he will also find colleagues and friends to play badminton, hiking, and relax. "People who do well (in research) work very hard, and you can't just look at luck." He said.
Although a little "hard" on their own, Yan Zhiqiang's requirements for team members is not so harsh. "Really interested, have the ability to solve problems, when working with full commitment to do a good job, is this requirement. Do not have to work every day, do research should be happy." He said.
Yan Zhiqiang and team
"The best thing about this place is that it is 'people oriented'."
In Shenzhen Bay Lab, Yan Zhiqiang is also expanding his research in other directions.
He hopes that further research on sensory receptors such as hearing, touch, humidity sensation, and thirst and their working mechanisms will lead to an understanding of the codes by which organisms perceive the outside world. Also, to understand the key nerve cell groups and neural circuits associated with the above senses, and to study the mechanisms by which they perform their physiological functions and their interactions with other important physiological functions. In addition, China has the largest number of hearing disabled people in the world, and hearing impairment affects about 27.8 million patients. He hopes to translate the relevant research results into the ground, to study the pathogenesis of deafness, and to develop genes and therapeutic drugs for diagnosing related diseases.
At present, after two years of construction, Yan Zhiqiang's team has four postdocs and one associate researcher, plus more than ten joint trainees with the University of Hong Kong and the Hong Kong University of Science and Technology. However, he admits that, due to the weak educational foundation in Shenzhen, the entire laboratory talent pool still needs to be strengthened.
"Shenzhen's biggest problem at the moment is the need to accumulate, just like Tsinghua, Peking University and Fudan, the educational foundation has been there for more than 100 years. But I believe Shenzhen will develop very fast, because it is very strong support in scientific research, education, will not let you have 'support or dedication' feeling." Yan Zhiqiang said.
He feels that the best thing about this place is that it is "people-oriented" and has a trusting attitude toward scientists. "Here to scientists funding support is not to see what your project application is, but to give you the autonomy to choose the good people, so you choose to see what to do, which is in line with the laws of science." Yan Zhiqiang said, and if the project-based, not only will involve a lot of energy of researchers in all kinds of project applications, and it is difficult to predict the final research results, because science itself is exploratory.
Yan Zhiqiang believes that another major advantage of the laboratory is the management model of administrative services for scientific research. For example, the platform construction committee composed of researchers have decision-making power on instrument purchases, etc., while the administration is the body to implement the decision, "everything revolves around research.
However, he said that the lack of PhD enrollment is a sore point for Shenzhen Bay Laboratory. This requires further deepening reform of China's education system, so that Shenzhen Bay Laboratory and institutions with high-level research such as the Beijing Institute of Life Sciences and the Beijing Brain Center can independently enroll doctoral students. In addition, provinces willing to make significant efforts to strengthen education and R&D should be given greater autonomy in admissions. For example, Shenzhen has a developed economy and is willing to invest huge amounts of money in education and scientific research, but because neither Shenzhen nor Guangdong can decide independently whether to enroll PhD students, there is a shortage of education and talent resources, thus creating a major obstacle to the development of first-class education in Shenzhen and the development of world-leading scientific research, which will have a negative impact on education, scientific research and future economic development in Shenzhen or Guangdong in the long run In the long run, this will have a negative impact on education, research and future economic development in Shenzhen and Guangdong.
Talking about the research career, Yan Zhiqiang felt that the overall environment of China's research and senior researcher salary and the developed countries in Europe and the United States have been similar. "Do not say how much money you earn, life is good on the line. In fact, the employment path to do research is also more, do a good job can be a professor, you can also open a company. It can be said that 'in can attack, can retreat', the development is not bad, as a career even to 'secular' vision is also good."
"One person in a thousand likes to do scientific research is enough, there are 1.4 billion people in China, one in a thousand is 1.4 million people, it is enough. Scientific research does not need so many people, only people who really like it." Yan Zhiqiang said.