Text: "China Science News" reporter Liu Runan
In 2018, Wei Yulei tried to build an embryonic stem cell line using mouse blastocysts, but failed.
In 2020, inspired by an article**, she and her husband Yu Leqian restarted the previous "failed" experiment, spent 3 months to complete and submit, and finally received a Nature cover ** in 2021. This ** took the first step of human "artificial embryo" and witnessed the birth of the world's first artificial human embryo-like structure. It was selected as one of the "Top Ten Scientific Breakthroughs" by Science that year.
In 2022, the couple returned to China for development. Wei Yulei, then 35 years old, joined the College of Biology of China Agricultural University and became a professor; Yu Leqian became a researcher at the Institute of Zoology of the Chinese Academy of Sciences. Recently, a study they collaborated on was featured in Cell. On the basis of the above research, the interaction relationship and mechanism of cells in early embryonic development in human beings are further analyzed.
Sometimes the results of the experiment are unsatisfactory or even failing, but don't give up easily. Perhaps the real breakthrough lies in this seemingly useless, casual detail. Wei Yulei told China Science News.
Wei Yulei. Photo provided by the interviewee (the same below).
"Husbands and wives are the best partners in scientific research".
Wei Yulei and Yu Leqian were college classmates and went to Kyoto University in Japan to study for a doctorate. After graduation, the two came to the University of Texas Southwestern Medical Center in the United States to do postdoctoral work.
After a bit of a detour in the 4 years of my Ph.D., I gradually discovered that I didn't like the study of chemical biology. Wei Yulei said that during the postdoctoral stage, she returned to her former field - cell biology to continue research, and felt much more handy.
Influenced by the domestic cultural atmosphere, Wei Yulei and Yu Leqian have always deliberately "kept their distance" in scientific research: although their bachelor's, master's and doctor's degrees are in the same school, they always choose different laboratories; When I went to the same laboratory during the postdoctoral stage, I also picked the two seats that were the farthest apart, and initially chose different topics.
The change happened in the summer of 2018. At that time, Wei Yulei had just joined the group, and she was faced with two choices: one was to join the subject that her husband had already started, which would undoubtedly be more efficient; The second is to join another colleague in the subject, which is a research that she enjoys very much.
When she was hesitant, the support of her mentor made her determined. "I recommend you to choose the first one, husband and wife are the best partners in scientific research, and no one will help each other better than you. Her mentor, Wu Jun, a professor at the University of Texas Southwestern Medical Center, said.
An inconspicuous "running along" experiment
In the follow-up research, Wei Yulei gradually discovered that there is no point in deliberately avoiding it, and common development and progress are the most important.
The topic for this research partner is related to cell development in the early embryonic period. Mammalian life develops from a fertilized egg, which cleavages to form a mulberry embryo, which polarizes and further develops into a blastocyst.
There are 3 cell types with different lineages in blastocysts, which are embryonic stem cells (ES), trophoblast stem cells (TS), and embryonic endoderm cells (Xen). ES and XEN will develop into fetus and amniotic membranes in the future, and TS will develop into placenta in the future.
The fate differentiation of the blastocyst stage has a profound impact on the beginning of life, the formation of tissues and organs, and the occurrence of diseases. However, due to ethical and material limitations, research on human blastocysts is relatively scarce. Scientists often adopt the method of in vitro culture to culture blastocysts in mice, monkeys and other experimental animals.
The initial task was to establish a culture system for equine ES, and after completion, they wanted to establish a mouse ES line with the same culture system.
The culture medium required for the ES line of different species may or may not be the same, and we thought that since the horse was made, it should be possible to build the line under the same conditions in mice. Wei Yulei said.
The result was unexpected. The same culture system was transferred to mice, and the cell types were disorganized and morphologically different. If you look closely, it seems to contain the ES line, so what are the other cells? Could it be the other two cell types in the early development blastocyst? They don't know for sure.
However, it is this inconspicuous "accompaniment" experiment, which contains the mystery of opening up the early development of the embryo, that has become the "masterpiece" of these two young people returning to China in the next two or three years.
Wei Yulei. 3 months to tackle the problem, completednatureCover ** Research
The daily experiment went on as usual. It wasn't until February 2020 that Yu Leqian saw a study from eLife**, which introduced that the human Na VE stem cell culture system - 5ILA can be differentiated into trophoblast stem cells.
He suddenly thought of the previous "accompaniment" experiment, and inspiration poured out: "Since 5ILA has the ability to differentiate into TS and Xen, and we have the culture conditions for co-culturing ES, TS and Xen, is it possible to establish three stem cell lines of early human embryos through this culture system, so as to establish a blastocyst-like structure?" Moreover, experiments a year ago have found that it seems to be feasible ...... in mice”
We realized that this was a great opportunity. The establishment of human blastocysts is equivalent to taking the first step towards human 'artificial blastocysts', which will be a top-level research. Wei Yulei said.
In order to win the competition in the same field, they set a goal: to complete the experiment and submit the paper in 3 to 4 months.
The spring and summer of 2020 coincided with the worst of the epidemic abroad. "The epidemic has slowed down everyone's work, and the whole building is basically empty. But we know that we must not stop, and we must seize the opportunity to storm the top magazine. There are not many such opportunities, not to mention that our research group has just been established, and PK is the world's top laboratory. Wei Yulei said.
After sending the mother and one-year-old child back to China, their scientific research began.
Trial-and-error, failure, give up or continue? The two partners asked themselves over and over again, suffering from the blows and torments of the results of the experiment.
Wei Yulei and Yu Leqian finally withstood this baptism, and used stem cells to cultivate three cell lines of ES, TS, and Xen at the blastocyst stage, and constructed early human blastocysts in vitro, which developed in vitro for 2 4 days.
We have opened the door for scientists to study early embryos and implantation time, which is helpful for scientists to study the best options for miscarriage, malformed babies, and female conception disorders caused by major diseases in early human beings. Wei Yulei said.
After several months of review and revision, the study was featured on the cover of Nature in 2021 and was selected by Science as one of the "Top Ten Scientific Breakthroughs" of that year.
Yu Leqian, Wu Jun and Wei Yulei (from left) celebrate together.
There are not many things and moments in life that can make you wholeheartedly and unreservedly strive for them, but if you have them, you must seize them. Today, Wei Yulei often uses this to encourage students.
The seeds that were not favored six years ago have now grown into big trees
The story of Mr. and Mrs. Wei's research continues. Since then, they and their collaborators have made several more studies, focusing on human blastocyst implantation models and the construction of bovine embryo models.
By this time, the cultivation of three stem cell lineages under the same culture system has been verified in human, bovine, mouse and other models, which also provides ideas for related applications. The next step of Wei Yulei and Yu Leqian's work turned to the study of the interaction and regulatory mechanism of intraembryonic and extraembryonic tissues composed of three cell lineages.
The interaction and regulatory mechanism of the two play an important role in maintaining stem cell self-renewal and embryonic development, and the abnormal interaction between the two is closely related to miscarriage, pregnancy failure and developmental diseases. Wei Yulei said.
In August 2022, Wei Yulei and Yu Leqian decided to return to China and join China Agricultural University and the Institute of Zoology of the Chinese Academy of Sciences respectively. "After wandering, you know that your family is good", Wei Yulei said, who has studied and worked abroad for many years, and has a deep understanding of this sentence.
The laboratory has changed, and the project cannot be stopped. They found that the proliferation rate of ES was significantly reduced after co-culturing ES and Xen from mice and cynomolgus monkeys, suggesting that extraembryonic stem cells had an inhibitory effect on the growth and proliferation of intraembryonic cells.
In other words, in the early stage of life development, the placenta, amniotic membranes and other initial cells control the development of the embryo itself. It is precisely because of the control of extraembryonic cells that the embryonic development becomes controllable and orderly, and does not grow into uncontrolled and wanton growth of tumor cells.
Through cross-species comparative analysis (human, mouse, cynomolgus monkey), Wei et al. also revealed the key genes that play a regulatory role among different species.
Looking back on the scientific research experience in the past few years, Wei Yulei sighed, "It's like planting a seed that is not favored 6 years ago, it was seen by a pair of eyes that are good at discovery, cultivated by a pair of dexterous hands, and then germinated and became a seedling." Later, it grew the most beautiful branch - Nature Cover**. Now, with this cell study, the trunk has become thicker and stronger. ”
Wei Yulei. Related**Information: