MEDICINE AND HEALTH

The first Nature paper was published after 8 years


In her 8th year as a postdoc at the famous “mecca of molecular biology”, Cold Spring Harbor Laboratory in the United States, Sun Xueqin published her first “Nature” paper.

Her research revealed how a deadly cancer with a 1-year survival rate of less than 50% and a 5-year survival rate plummeted to 5% used a mysterious mechanism to break through the body’s natural anti-cancer defense. More interestingly, this key mechanism she discovered could be reversed by drug intervention, and may in the future be used to repair the inhibited natural anti-cancer function in cancer cells.

In an interview with China Science News, Sun Xueqin reviewed her long research journey. In the process, she gained more than just a Nature paper.

The most dangerous cancer, how to break through the natural defense of the human body?

Glioblastoma multiforme (GBM) is one of the most common and deadly primary brain cancers. It is not only so dangerous that doctors sigh, but also mysterious that scientists scratch their heads. And one of the biggest secrets of this tumor is that it can escape the famous “cancer nemesis” – p53 gene.

The dreaded cancer cells were originally mutated from normal cells after they were damaged. P53 is the body’s natural line of defense against tumors, and when cells are severely damaged, it activates the cell’s potential suicide program, apoptosis, allowing these potentially dangerous cells to die rather than “blacken.” Therefore, the emergence of almost all tumors is accompanied by mutation and inactivation of the p53 gene.

But glioblastoma multiforme is an exception. Scientists have found that in more than 70% of glioblastoma, the normal p53 gene is still preserved.

“Intuition tells me that there must be something unknown in these glioblastomas that is preventing p53 from eliminating tumor cells.” Sun Xueqin told China Science News. That’s the scientific question she’s been trying to answer for the past few years.

To that end, she and her colleagues conducted CRISPR gene-editing screens in more than 30 cancer cell lines, and preliminary findings focused her on “epigenetic regulation.” The so-called “epigenetic regulation” refers to the fact that these genes are “booted and hatted” through DNA methylation, histone modification, chromosome structure changes and other effects without changes in the gene sequence itself, thereby affecting their functional performance.

On this basis, Sun Xueqin and others further screened and finally locked a special protein BRD8 containing the BRD domain.

BRD is a class of bromine domains with special sequences and structures, and there are at least 61 members in this large family, some of which have been studied in depth. The bromine domain is closely related to the occurrence and progression of a variety of diseases, including cancer. There are many small molecule drugs targeting the bromine domain in clinical trials. However, this BRD8 bromine domain is still quite unfamiliar to humans.

Next, they revealed the hidden mechanism of BRD8’s role in tumor formation: In glioblastoma, the bromine domain of BRD8 binds to a specific histone variant, H2AZ, which tightens chromosomes that carry specific genes like a ball of threads, preventing p53 from entering and regulating target genes.

“This never-before-seen mechanism, like a lock, keeps P53 out and prevents it from functioning properly.” Sun Xueqin said. What makes her even more pleased is that because epigenetic modification is reversible, the revelation of this mechanism also points out a way for treating glioblastoma with drugs.

“I think the reason why this paper was favored by Nature is probably because of these two points: first, it reveals a new mechanism that has never been reported before; Second, it brings new hope for people to conquer this very dangerous and difficult to treat cancer. Sun Xueqin said.

Mentor: This is one of the best manuscripts I’ve seen in 22 years

Sun Xueqin can’t forget the day she took the first draft of her paper to her supervisor, Alea Mills, a professor at the Cancer Center at Cold Spring Harbor Laboratory.

After reading the article, Mills was pleasantly surprised to say to Sun Xueqin: “This is one of the best manuscripts I have read in my 22 years in Cold Spring Port!” ”

Mills served as director of the T32 postdoctoral training program for cancer gene discovery and cancer biology in Cold Spring Harbor for 10 years and was a permanent member of the Cancer Molecular Pathology Research Group. The high evaluation from her made Sun Xueqin feel very excited.

So, as a non-native English speaker, how did Sun Xueqin write a beautiful first draft?

“First, whether it is Chinese writing or English writing, logic is the soul and essence of an article. Second, you need to read widely and pay attention to accumulation. I often make notes in my head, such as how this meaning can be expressed in English. It’s time-consuming and clumsy, but the more you remember and use it, it becomes your own expression. Sun Xueqin said.

But even such a manuscript encountered many obstacles in the submission process. After the manuscript was submitted to Nature magazine in September 2020, it was almost a year waiting due to the epidemic and the change of editor in the middle of the process.

Two out of three reviewers appreciated the work, but one reviewer kept coming up with new revisions. In response, Sun Xueqin accepted the suggestions she considered valuable, and argued for the rest with experimental results and literature data. In the end, the manuscript was notarized by a third-party expert invited by the editor of Nature.

The process also impressed Professor Mills. She said: “Sun’s handling was very convincing. ”

Despite several ups and downs, in Sun Xueqin’s view, every step is worth it. The large amount of data she generated in the process of supplementing the experiment, although not included in the Nature paper, also laid the groundwork for new research in the future.

It’s a long road, hard and rewarding

Sun Xueqin Photo courtesy of interviewee

“Do you think your scientific path is going well?” When hearing the reporter’s question, Sun Xueqin hesitated briefly.

On the one hand, after graduating from Wuhan University, she came to the famous Cold Spring Port Laboratory as a postdoctoral fellow, and her scientific research platform has always been very superior. And the two mentors she met successively also gave her strong support.

But on the other hand, she has been doing her PhD in Cold Spring Port for 7 and a half years, and she is expected to leave the station when she is 8 years old. During this time, she raised two children with her husband, who is also a postdoc. It has undoubtedly been a long and challenging time.

“It’s hard to simply say whether I’m going to go with it or not.” She finally replied calmly.

When she was at Wuhan University, she was one of the first doctoral students in Professor Huang Zan’s research group to graduate, and participated in the construction of the laboratory. Now when she goes to a job interview, she can answer the question “How do you build your own lab in your first year?” with confidence and methodology.

During her Ph.D., she worked hard to learn various techniques and developed strong hands-on skills. In this published work, she was able to solve many experimental operational problems, especially breaking through the traditional bottleneck of “BRD8 cannot be expressed with E. coli”, and also benefited from solid scientific research basic skills.

The 8 years of postdoctoral work in Cold Spring Port is indeed a bit long compared to most of his peers who have been postdoctoral fellows in China. But she said: “Here, I have had the opportunity to work productively with talented scientists in different fields and have benefited a lot. In addition to the published Nature article, she has a number of important work in the process of submission and research.

This is not an easy path, nor is it one that can be summed up as “smooth” or “not smooth.” But fortunately, Sun Xueqin looked back and found that in the past, none of these roads were taken in vain.

She told China Science News that she is interviewing for professorships at some top scientific research institutes, hoping to make more influential contributions to science. (Source: China Science News, Li Chenyang, Bu Jinting)

Related paper information:https://doi.org/10.1038/s41586-022-05551-x



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