Caring for students
"Highly praised by students" is one of the many phrases people use to describe Yang Zhang.
As soon as the enrollment for the summer camp ended, students who wanted to enroll in Yang Zhang's group were inundated, and the number of applicants nearly doubled the original quota.
Kun Cao was one of the first students lucky enough to join Yang Zhang's group, and the latter impressed him with how approachable he was. Kun and the other first few members to join the group all had distinctive personalities and different colored hair at the time.
"Prof. Zhang doesn’t have so many restrictions on us, even if we put forward scientific research ideas that are still naive, he will listen carefully to everyone's ideas, and then try to guide us, instead of simply refuting us." Kun Cao said.
Yang keeps supplying different sorts of snacks and fruits on the public table, and quirky photos of members of the group are hanging on the wall. Not long ago, to celebrate the admission of one of the students to a doctor program and the birthday of some other fews, they have had altogether three birthday cakes in just one month, Kun Cao said a bit remorsefully, "I have gained thirty pounds.
However, Peishang Shi didn’t join the group just because of the lighthearted atmosphere, he chose Yang because he heard that he was "quite strict and pushing". One of the few things that impressed the sophomore the most took place the first time when he arrived at the lab. Yang Zhang, who was wearing a white lab coat, helped him to revive cells.
"Follow the teacher who works hard to have a better future," Almost every day, Peishang Shi and a few members of the group come to the laboratory early in the morning and work until eleven o'clock at night before going home, Yang rarely comes out of his office before their leaving.
For students who are just starting out in scientific research, it’s still somewhat difficult to develop the programs simply by themselves. To help these students, Yang would coach their research process step by step, "For their first subject, I will teach them hand by hand from the design of experiments to the analysis of results, explain the experimental methods and ideas very thoroughly.” In his consideration, Yang keeps a longer-term career development for his students, and what matters the most is to stimulate their interest and sense of achievement, so that they can carry on the scientific research.
Peishang is studying a new protein that can be used as a therapeutic target for cancer, and Yang always forwards to him some articles related to his topic that he didn’t notice himself, "Prof. Zhang will read a lot of essays, then inspires you to validate the main conclusions of the articles and helps you to design some reasonable experiments combined with your own topic." Each student in the group has his own independent project, and for each project, Yang would have enough preparation for the background research as well as the preliminary experiments to ensure that the general direction wouldn’t go wrong. By exchanging with different students every day, Yang Zhang's brain is switching channels constantly.
"He's always on standby, you can reach out to Prof. Zhang 7 or 8 times a day to discuss the details of the experiment,” said Mengya Cai, a student who just completed her role as a research assistant. As far as she is concerned, everyone could feel Yang's genuine concern for the future of each student, as he is very attentive to their projects, “when we students went out to give presentations and reports, he was the one too nervous to fall asleep.” In order to keep an eye on the students, Yang keeps his postdoctoral supervisor's advice in mind. “You must sit with the students so that you can understand their difficulties.” So, he chose to sit near them.
When the group was just founded, the quota of doctoral programs was still relatively scarce, Yang had to fight for places hither and thither and make all kinds of attempts. Under his efforts, the members of the group were all settled one by one.
For the weaker students, Yang will also teach in line with the students’ abilities, and guide them to develop good scientific habits and logical thinking abilities, so that the students with slower progress, can eventually complete the project independently. Behind Yang’s strictness and warmness, lies his deep concern for students.
In Yang’s opinion, the way he trains his students is a continuation of his mentor's words and teachings, and it is from his mentor that he draws on experiences and strenuous efforts.
The relationship with this life mentor began with a leap forward in Yang's scientific research career.
Leap into a new field
Yang Zhang, who had already graduated with a PhD and entered the workplace in 2015, decided to depart from the field of medical engineering that he had been studying for 10 years.
Seeing the human body as a precision instrument, although Yang had made some achievements in the past, it was as if he was tinkering with this precision instrument, and in order to completely revolutionize this instrument, he needed to understand its operating principles more thoroughly.
Yang's heart was no longer satisfied with superficial observation from the outside, and a strong desire sprouted in his heart –––– to solve those biological problems that had not been solved and to unravel those physiological phenomena that were still shrouded in fog.
This idea was like a seed that gradually took root in Yang's heart and completely changed his scientific research path. Interdisciplinary is a choice that requires "wisdom and courage," Yang set his sights on the other side of the ocean, "be a person with ambition, do something meaningful," Yang's parents, as always, encouraged and supported him.
At the crossroads of his academic career, Yang chose to step out of his comfort zone: he entered the completely unfamiliar field of ion and phospholipid transmembrane transport and joined Huanghe Yang's group at Duke University as a postdoctoral fellow.
At that time, Yang's engineering background filled the gap in Prof. Yang's group. Yang not only independently built the optical imaging system and animal behavior monitoring instruments, but also created many novel detection tools. These innovations provided important data support for in vivo molecular and cellular research. In addition, he wrote all the hardware control and data acquisition in the lab, as well as the programs for data processing in the lab, which greatly reduced the cost of purchasing instruments and greatly improved the efficiency of the entire staff.
What surprised Prof. Yang was not only Yang Zhang's engineering skills, but also his great passion for biology. For two months, he worked around the clock to brush up on the basics of biology, and with Professor Yang's patience, he was able to combine engineering problem-solving methods with biological research.
Walking through the gothic buildings of Duke University, Yang Zhang's research life can be described as "two o'clock and a line. He spent almost all his time in the lab from morning to night, and the only time he had off on weekends was to do housework and prepare meals for the week. Beef stew with potatoes has become his "specialty of the house", which he divided into seven small portions and put in the refrigerator to fill his appetite when necessary.
Over time, Yang Zhang used his advantages in engineering and gradually gnawed away at the interdisciplinary "hard bones". The first brand-new field he ventured into was the cold issue of ion channels.
For the regulation of neuronal membrane excitability, most studies have focused on cations such as sodium, potassium, and calcium ions, but the physiological importance of anions such as chloride ions in neurons has been neglected.
The brand-new question before Yang was about the function of chloride ions in neurons. Yang consulted a lot of literature and made various attempts to explore this unknown field bit by bit.
Despite the heavy workload of research, the group enjoyed it: "We only care about the research itself, though the daily life can be a bit monotonous.” For Yang, research is not only a job but also a place for the soul. Even if sometimes overnight to do experiments, whenever he entered the laboratory, his heart would emerge a kind of peace and joy.
The unknown world under the microscope dispels sleepiness and fatigue. The TMEM16B channel can be thought of as a "door" on the cell membrane that opens by the "key" of the calcium ion and allows chloride ions to pass through. Yang's research shows that this "gate" is active in neurons in the inferior olivary nucleus, where it works with other calcium channels to help regulate the firing of nerve signals, like an orchestra coordinating its performance so that the sounds of each instrument blend harmoniously into the music.
The imaging equipment area became Yang's second home, and the lights never went out at night. Yang often worked late into the night and came out to find Professor Yang's office still lit, a scenario that was repeated many times. At that time, Yang Zhang was still in the rooting stage of research on these cell membrane events, and Prof. Yang would patiently discuss the problems with him, often until two or three o'clock in the morning, which became their frequent "academic night talk".
"Scientific research must be done over time," Yang Zhang knows this very well. Ever since he was a child, he was the kind of person who could sit still. Once, he would turn over the covers of a book in order to read it thoroughly, holding obscure history books and immersing himself in them. He knew that true breakthroughs stemmed from the precipitation of time.
As data slowly emerged, the twists and turns of the experiment seemed to make sense. Yang Zhang found that when the TMEM16B channel was missing, the mice had significant difficulty with this motor learning, revealing the importance of the chloride channel. The study shed light on the role of TMEM16B channels in regulating neuronal excitability, which in turn affected motor learning in the cerebellum. (Neuron 2017).
If the discovery of chloride channels set Yang Zhang on an interdisciplinary path, his truly independent research began with a series of seemingly serendipitous events. These coincidences, like a path of necessity carefully laid out by fate, led him to follow the trail of questions and to profoundly inquire about the meaning of his scientific research.
The path becomes clear
Yang Zhang focused on TMEM16, a mysterious key that unlocks many important physiological functions and pathological mechanisms. TMEM16F of the TMEM16 family, a phospholipid flippase, has long been known to play an important role in platelet coagulation, but its other potential functions have remained a mystery.
To gain a more complete understanding of TMEM16F, the group knocked out the gene in mice, hoping to discover more interesting clues by comparing the performance of normal and knockout mice.
However, the first experimental results were disappointing. Whether observing brain, muscle or other routine physiological functions, the TMEM16F knockout mice showed little difference from normal mice.
The members began to wonder if TMEM16F might not be involved in some of the other complex functions. Yang Zhang was also a little perplexed, but he was still convinced that there must be something different hidden in the crevices of the unnoticed.
Yang decided to dissect a pregnant TMEM16F mouse, and to his surprise, he found that the placenta of a normal mouse had a healthy reddish color and was full of blood, while the placenta of a TMEM16F knockout mouse had abnormal white spots, as if it lacked the breath of life. He realized that this finding was highly unusual and could be an important clue to the important role of TMEM16F in placental development.
Yang began to delve deeper into the secrets of these white patchy placentas. He found that the placentas of mice lacking TMEM16F had almost completely lost their syncytial trophoblast cells on the side close to the fetus. Normally, these cells fuse to form a protective barrier that ensures the normal exchange of nutrients and immune substances between the fetus and the mother. However, in the absence of TMEM16F, the mouse placenta was unable to effectively form fused trophoblast cells, resulting in inadequate nutritional supply to the fetus and impaired vascular development, which ultimately led to fetal death in the perinatal period.
In exploring the unknown, Yang was often struck by the ingenuity of nature. It turned out that TMEM16F was not just a simple phospholipid flippase, but played a key role in the formation of the placenta –– cell fusion, a crucial biological process that seemed to be inextricably linked to it. Perhaps this white patch of the placenta was a whisper of fate, revealing the importance of TMEM16F in biological evolution and reproduction.
By restoring the TMEM16F gene in knockout mice, Yang found that the cells' ability to fuse was restored. Further studies showed that the externalization of phosphatidylserine is a key trigger signal for cell fusion mediated by TMEM16F.
Yang realized that phosphatidylserine was not only an apoptotic signal, but also played a more complex role in the cell fusion process. This novel mechanism provided the scientific community with a new perspective for understanding cell fusion, including cell-cell and virus-cell fusion, and several other complex biological processes (Science Advances 2020). Based on his research, the broad-spectrum antiviral effect of TMEM16F was subsequently verified.
This discovery made Yang Zhang realize that phospholipids are not only structural components of cell membranes, but their functions go far beyond traditional knowledge. Dynamic changes in phospholipids have profound effects on the physiological functions of cells.
Since the discovery of white plaques in the placenta, Yang has plunged headlong into the study of phospholipids. His research has gradually expanded into a global view of phospholipid dynamics.
Wandering through the academic halls of Duke University, Yang had many opportunities to interact with some of the best minds in science, and it was here that he met an important neighbor: Vann Bennett, an internationally renowned cell biologist known for his outstanding contributions to cytoskeletal research.
During several exchanges with Prof. Bennett, he repeatedly stressed to Yang, "You have to focus on what is really meaningful. Science is not just about solving the problem of a molecule, but about solving difficult problems that really bother people in the real world.
Prof. Bennett told Yang that a smart way to find valuable problems is to talk to clinicians more often: "Make sure you focus on what people need in the clinic. "
These words touched Yang deeply, and he realized that the details he was pursuing in the lab could be just a drop of water in the ocean of science. What can really promote the progress of science is research that can solve real problems and discoveries that can have a practical impact in the clinic.
He hopes that his research will not only reveal more fundamental mechanisms in the field of cell biology but also provide potential therapeutic solutions for many diseases related to abnormal cell membrane function.
In his next research, Yang focused more on the relationship between signaling at the cell membrane and disease. He began looking for partners who focused on disease research. Oncology was his first experimental field, where, in collaboration with Prof. Qing Zhang at UTSW, they discovered γ-butyryl-β-hydroxylase 1 (BBOX1), a key gene that regulates triple-negative breast cancer (TNBC), providing a new direction in the treatment of triple-negative breast cancer (Cancer Discovery 2020). In treating rare cases of absence epilepsy, Yang Zhang and his partners discovered that inhibiting the hyperactive state of BK channels effectively alleviated seizures and movement disorders (PNAS 2022).
Studying phospholipid signaling, Yang discovered that modulation of phospholipid flippase activity can regulate a variety of physiological processes (eLife 2022, eLife 2024). In erythrocytes from patients with hereditary stem cell hyperplasia (HX), Yang discovered an enhanced coupling of the mechanical force-sensitive ion channel PIEZO1 and the phospholipid flippase TMEM16F, which results in the exposure of a large amount of phosphatidylserine on the surface of erythrocytes and exacerbates the recycling of erythrocytes in the spleen, which can lead to anemia, enlarged spleen and blood clots. Yang successfully found an inhibitor of the PIEZO1 channel, solving the problem of the lack of medication for PIEZO-related diseases that had plagued the country for many years. (Blood 2024).
From these studies, Yang realized the importance of ion and phospholipid transport in cellular physiology. They are not only key regulators of a specific disease but also central controllers of multiple physiological processes covering a wide range of biological functions.
Yang Zhang understands that the progress of science lies not only in solving individual problems but also in discovering the common mechanisms behind these problems, thus proposing solutions that have the potential for widespread application.
In the future, Yang plans to further deepen these studies, not only exploring the underlying mechanisms in the laboratory but also hoping to apply these theories in the clinic to develop new diagnostic and therapeutic methods to alleviate patients' suffering. On the other hand, Yang will continue to cultivate the next generation of researchers with all his heart and soul, and be a beacon of light for them to move forward.
In every corner of the lab, Yang feels a deep connection –– his link to these microscopic worlds, the bonding between him and the patients waiting for treatment, as well as the legacy with the new generation of scientific researchers. The infinite possibilities continue to drive his efforts to turn every theoretical breakthrough into practical well-being and to truly bring the light of science to every place where it is needed.
Dr. Yang Zhang received his B.S. degree in biomedical engineering from Huazhong University of Science and Technology (HUST) in 2009 and his Ph.D. degree in biomedical engineering from HUST in 2014. He joined the Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS) as a research assistant in 2014. He has been in postdoctoral training at the Department of Biochemistry, Duke University since 2015, and joined the Institute of Molecular Physiology, Shenzhen Bay Laboratory as a full-time Distinguished Research Fellow in 2022. Dr. Zhang has published several papers as corresponding author or first author (including co-authors) in journals such as Neuron, Blood, Science Advances, eLife (2), and IEEE Transactions on Medical Imaging. Author of 4 patents for inventions. 2016 Joy Cappe Young Scientist Award, 2017 Burroughs Wellcome Fund Collaborative Research Award, 2019 Layton Holladay Memorial Fund Foundation Award, 2022 Gordon Research Conference Best Poster Presentation Award. Dr. Zhang major research achievements are 1. Understanding the physiological and pathological functions of TMEM16 calmodulin ion channels and calmodulin phospholipid flippase. a) Discovering the functions of novel calmodulin chloride channels in cerebellar motor learning; b) Revealing the functions of phospholipid signaling in the regulation of important physiological processes, such as cell fusion, coagulation, and immune response; and c) Elucidating the modulation of calcium signaling in physiological and pathological conditions. 2. Novel development of imaging technologies and monitoring methods. These include in vivo imaging methods for understanding ion and phospholipid transport across membranes, optical labeling techniques, and non-destructive behavioral monitoring tools.
Yang Zhang's group focuses on the physiological function of ion and phospholipid transport across membranes. The group uses a variety of biological methods combined with electrophysiology, optical imaging, and other technical means to study the functions of ion channels and phospholipid flippase in physiology and pathology and to develop therapeutic approaches for developmental abnormalities, coagulation disorders, tumors, and complex diseases during pregnancy.
Editor: Bai Bai
Executive Editor: Winston
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