In 2000, yan Ning, who was less than 23 years old, entered Princeton University as he wished, under the supervision of Professor Shi Yigong. But in the next two years, she unexpectedly lived a "dark day": not only was the schoolwork hard, the most important experimental link, Yan Ning was stuck, and her peers produced results, but she herself "did what she did, what could not be done".
She continued to observe, learn, and after repeated failures, she started from scratch, and finally completed an extremely complex experiment independently on a winter night. Mentor Shi Yigong said: Yan Ning, you will finally do the experiment. Since then, Yan Ning has been completely immersed in experiments, immersed in those ingenious and intricate molecular machines, scientific research has become an indispensable thing in life, and few things can bring her the same degree of joy and sorrow.
This is the purest thing a scientist can experience: put your curiosity into it, and science will reward you with wonder, fulfillment, and beauty. All this drives and attracts Yan Ning to move towards a major topic of molecular biology, the process is naturally difficult, but it is also full of naïve pleasure.
This article is an excerpt from Becoming a Scientist (published by CITIC Publishing House in May 2021) with the permission of the publishing house, and the text has been deleted and revised. Go to "Back to Park" and click on the mini program at the end of the article or "Read the original article" to purchase this book.
Written by | Guan Qi
One move kills
At the end of 2006, taking advantage of the end of the postdoctoral research project, Yan Ning returned to Beijing to visit her parents, and went to Tsinghua University to visit her former department head Zhao Nanming, who helped her write a letter of recommendation.
"How's your research?" Did you publish a paper in the journal Nature? When they met, Teacher Zhao asked her.
"I sent it." Yan Ning said proudly.
"Then do you want to come back and be a professor?"
"Yes." Yan Ning thought the teacher was joking and replied with a giggle.
Zhao Nanming did not joke, 10 days later, Yan Ning passed the interview at Tsinghua University School of Medicine, and at the age of 30, she became the youngest professor at Tsinghua University.
Yan Ning teaches at Tsinghua University (Courtesy photo: Yan Ning)
At that time, the domestic biological research environment was still quite different from that of foreign first-class universities. Young scientists like Yan Ning, who are already emerging and attracted academic attention, can often easily find a teaching position in the world's best-equipped laboratory, and then rise steadily until they get a tenured teaching position, and the future is visible. At this time, choosing to return to China to establish a laboratory from scratch means great uncertainty. Many people were surprised by Yan Ning's choice. In fact, Yan Ning is just being herself as she always has been— an adventurer who "can't keep up with the changes in the plan." She wants to study the most important questions—those that expand human cognition—and "steady rise" is not her concern.
Yan Ning's earliest batch of students at Tsinghua University feel lucky to this day. At that time, the laboratory had just been established, and a complete chain of "old with new" had not yet been formed, and each experiment was taught by Yan Ning by hand. Yan Ning likes to wear hoodies and jeans, and her hair is tied into a ponytail, which looks no different from a student. During the most intense stage of the project, the "little master" did experiments with the students in the laboratory every night. When everyone usually changes the pipette tip, they are used to seeing which one to change, but Yan Ning said no, it is easy to make mistakes, and it is necessary to strictly follow the order, so that if more or less solution is added, you can judge where the problem is from the number of gun heads. Yan Ning turned the most boring point crystal link into a competition with students, and she would proudly raise her chin when she gained a speed advantage, showing off: "Sister, I did your three-day job in less than a day, and I don't think you are out of school yet!" "When students argue with her about academic issues, Yan Ning will be particularly happy." "She was always like this," one PhD student recalled, "always saying that when you could convince her, she felt like she had brought out a real Ph.D. "Of course, there aren't many of these times. Most of the controversy still ended in Yan Ning's "victory".
From 2007 to 2011, in just 4 years, Yan Ning led the team to resolve 5 membrane protein structures, and the scientific research results were twice cited in the annual "Top Ten Advances in Science" selected by the American magazine "Science" in 2009 and 2012. This is almost impossible to achieve in the industry. A brother once asked her with surprise, why do you make things so fast? Yan Ning's answer was simple: "Without him, it is to avoid detours." No matter how smart and hard the students are, the lessons will always be inferior to yours. He stumbled and tossed around for half a day on his own, and maybe you worked with him for a few minutes to help him get around the trap. ”
By 2013, the lab was running smoothly and rhythmically, and the students who had been trained for several years had followed the team to publish papers in core journals, no longer under pressure to graduate. Yan Ning felt that he was ready. She stopped the research directions used to "practice" the laboratory and began to specialize in the pearl of the field of membrane proteins, the human glucose transporter GLUT1. A colleague advised her that you were risking it. Not to mention that the previous directions look bright, the future has a good application potential, not to continue to do it is a pity.
Even Deng Dong, a doctoral student in Yan Ning's own team, thinks his mentor made an unwise decision. He argued with Yan Ning about this for a long time. In Deng Dong's view, human glucose transporter is a structure that predecessors have worked hard for 50 years to make, and they should be more conservative, starting with the homologous protein of insects. He had already obtained an insect's glucose transporter, and had managed to make the protein grow into crystals, only the last step, X-ray diffraction, and success seemed to be close at hand.
However, this time, Yan Ning, who has always welcomed "confrontation", resolutely vetoed his students. She fully understands Deng Dong, first do homologous protein, the three most difficult levels of structural analysis he has passed two levels; and to directly overcome THE MULTI1, you have to start from the first level again. "But from my point of view, even if you pass this pass, you will directly climb Mount Everest, and your three passes will pass, and you will only reach the place of six thousand meters." Those who have the ability to climb Mount Everest should not climb the Jade Dragon Snow Mountain.
She said to Deng Dong, you have achieved this, there is no shortage of "Nature" or "Science" papers, I don't care, you shouldn't care so much. You now have the time, the energy, and the money to do something, why do you want to do that inferior, not the most important? Just kill it with one move and fight.
Later, a student told Yan Ning that the master brother came out of your office that day and "walked with a green face." Back in the laboratory, he sighed with his brothers and sisters that we had chosen a road of no return, and it might take four or five years to see the results.
Deng Dong is also a professor today and is still working on structural biology. The ending of the GLUT1 controversy is that he still admires Teacher Yan's determination and courage.
On June 5, 2014, the international top natural science journal "Nature" published the structure of the human glucose transporter GLUT1 analyzed by Yan Ning's team. Nobel laureate in chemistry Brian Kebilka, who described the achievement as a "great achievement," told Nature: "There are very few structures of mammalian membrane proteins obtained so far, but to develop drugs for human diseases, it is crucial to obtain the structure of human glucose transporters." Ronald Kabak, a member of the National Academy of Sciences and a professor at the University of California, Los Angeles, said that the academic community has been studying the structure of GLUT1 for half a century, and in a way, Yan Ning "has defeated all the scientists who have studied its structure in the past 50 years." ”
After winning the Sackler International Biophysical Prize for "making outstanding contributions to the structural biology of key membrane proteins including the landmark human glucose transporter GLUT1", Yan Ning's work caused a sensation in the mainstream media. She seems to have become a public figure, and although she doesn't care, she still goes her own way and is free on Weibo.
On the contrary, his friend Li Yinuo could not read the same and boring reports, and recalled the friendship between the two on his WeChat public account "Slave Society". "It seems that to do science, you have to be stretched, upright, and coldly serious," she wrote in the article, "in fact, scientists are also people, and the better scientists are, the more interesting people are." In her eyes, Yan Ning's innocence was as pure as ever.
At this time, Li Yinuo had also returned to China, quit her job at McKinsey, voluntarily cut her salary by two-thirds to become the chief representative of the Gates Foundation's Beijing representative office, eager to solve bigger problems. She also founded a primary school in Beijing dedicated to providing personalized education for children. Yan Ning was proud of her. After so many years, both people are still pursuing that little bit of "different". Throughout their long friendship, they continue to earn new respect for each other.
Infinite secrets
Around the same time that Yan Ning's own research made a breakthrough, the field of structural biology was also undergoing a great change. Since 2013, cryo-electron microscopy technology has made revolutionary advances, single-particle technology allows the structure of biological macromolecular complexes to be directly resolved with cryoelectron microscopy, and the resolution has reached an unprecedented atomic level. That is, structural biologists no longer have to work hard to find ways to obtain crystals. If structural biology is a mountain, advances in cryo-electron microscopy are like building a ropeway for it, making the mountain easier to climb.
From 2015 to 2017, Yan Ning used cryo-electron microscopy technology to analyze the structure of voltage-gated sodium ion channels and calcium ion channels (as shown below). These channels control a series of important physiological activities such as electrical signaling between nerves and muscle contraction, which are theoretically even more important than glucose transporters, but Yan Ning obviously felt a decline in happiness. While they're important and get a lot of attention, when the game gets too simple, it's not as fun for a player driven by curiosity and fulfillment.
Representative study of Yan Ning - sodium ion channel (right) and GLUT1 renderings (left) (Courtesy photo: Yan Ning)
In 2017, Yan Ning, who was about to enter the age of confusion, left Tsinghua University, where he had worked for 10 years, and accepted an invitation from another alma mater, Princeton University. As it was more than 10 years ago, the decision caused another uproar. But this time, the colleague who had advised her not to take too much risk fully understood her choice, and they had become friends by this time, and he knew that Yan Ning was such a person. Completely unrelated to the complex conjectures of the outside world, Yan Ning just wanted to break through herself in a new environment.
"She wanted to test where her boundaries were," the friend said in an interview, "and that desire was also a very important motivator for her to do things like research." I think that's a great place to start. ”
After doing life science research for a long time, Yan Ning often has a sense of humility. When she was 10 years old, she once looked at the starry sky outside the window and thought about the meaning of human life: Since the solar system will one day be destroyed, whether rich or poor, rich or poor, whether it is wise or foolish, in the end this body will not be able to escape that day, then why does human beings bustle and profit come and go? She still has no definite answer to this question. The emergence of life has accelerated the transformation of matter on earth, creating a large amount of matter that did not exist on earth, so what is the essence of life? What happens further down? Human beings have created culture and art, but from the perspective of life, they are not fundamentally different from animals. None of the machines invented by man can be more ingenious than the molecular machines in our cells. Compared with natural creation, human beings are very humble.
But it doesn't matter, for her, the real pleasure lies in understanding the world, in discovering something for herself and making it known. Knowing that there are infinite secrets waiting to be discovered in this world, she can explore and break through with great enthusiasm like the moment when she first learned about "cells" in biology in junior high school.
This is a reward for scientists alone.
Explanation of terms:
1. Glucose is the main source of energy for the human body, and can only be used by the human body when it enters the cells. Because glucose is hydrophilic, and the cell membrane is a hydrophobic lipid bilayer structure, glucose must use glucose transporters (GLUT) on the cell membrane to enter the cell and achieve the body's intake of glucose.
There are a total of 14 glucose transporters in the human body, and among these 14 GLUTs, GLUT1, 2, 3, and 4 are responsible for the most basic physiological functions, and the most extensively studied, of which GLUT1 is named after the earliest discovery. GLUT1 exists in almost every cell of the human body, is the main glucose transporter of epithelial cells such as red blood cells and blood-brain barrier, plays a key role in maintaining the stability of blood glucose concentration and brain energy supply, and is closely related to diseases such as diabetes and cancer. Since the 1980s, obtaining the three-dimensional structure of GLUT1 has been one of the most anticipated breakthroughs in structural biology.
2. For sodium, calcium and other ions that are essential to the human body, the cell membrane is impermeable and must pass through a class of transmembrane proteins on the cell membrane to enter and exit the cell. Voltage-Gated Ion Channels are like gates on the cell membrane for various ions to pass through, changing the potential on the cell membrane to regulate the opening or closing of the channel. While regulating, the inner and outer sides of the cell membrane will produce electrical signals due to changes in ion concentration, which is closely related to important physiological activities such as muscle contraction and nerve signal transmission. Sodium and calcium ion channels are important targets for the research of many international major pharmaceutical companies, and their abnormalities can lead to a series of neurological and cardiovascular diseases such as pain disorders, epilepsy, and heart rate disorders, and their structure is of common concern to the academic and pharmaceutical communities.