Career path, part 6 | Natural metabolism

Biology was one of my favorite courses when I was in high school, so I chose Biological Sciences as a major during my undergraduate studies. However, before my doctoral training, I would never have thought that my career would lead me to become a PI. I undertook my doctoral studies at the University of Science and Technology of China (USTC), where I worked on cell apoptosis and cancer biology under the supervision of Mian Wu. The training experience at during my doctoral studies motivated my personal decision to continue my studies as a postdoctoral researcher. I liked the uncertainty of scientific research and the journey that consists of going from an interesting initial phenomenon to the revelation of the processes that underlie it. In 2008, I joined Xiaolu Yang’s lab at the University of Pennsylvania as a post-doctoral fellow, where I continued my study of p53 in tumors. Xiaolu guided me and gave me the freedom and support to explore what interested me, which allowed me to develop my own research direction. During my postgraduate training I focused on how metabolic changes in NADPH production underlie p53-medicated tumor suppression and found that p53 unexpectedly regulates NADPH metabolism through the pentose phosphate pathway and the malic enzyme pathway, in a transcriptional or post-translational manner. One of the studies was published in Nature in 2013. It was the most exciting thing I had experienced since I started research. At that time, I realized my passion for research and wanted to continue working towards an academic career as an independent researcher.

Credit: Wenjing Du

In 2016, I was back in China and opened my own laboratory at the Institute of Basic Medical Sciences (IBMS), the Chinese Academy of Medical Sciences (CAMS) and the School of Medicine of base of Peking Union Medical College (PUMC). Starting my own lab as an IP was difficult, and running a new lab in China is different from the one in the US, especially in terms of waiting for funding and equipment from overseas. In the first year, I encountered unexpected challenges, such as starting a lab with a single small room that still needed to be furnished and equipped, recruiting people, and securing funds. Eventually, with the help of friends and colleagues, I overcame the difficulties and was fortunate to recruit talented people who wanted to work with me.

When everything calmed down, we started experimenting in early 2017. Laboratory research focused on a few topics, such as how cancer cells rewire their metabolism, the role of tumor suppressors, and oncogenes in their metabolic regulation; and how nutrient alteration is detected by cancer cells. Based on my previous study and the results of others, the scarcity of NADPH is considered to be a limiting step in cell proliferation. I have always been curious about the physiological role of NADPH in cells beyond its role in antioxidant defense and many biosynthetic reactions. To this end, we began to study how cells perceive the change in cellular NADPH. The manipulation of cellular NADPH levels was the important step of this project. We have reversed or overexpressed NADPH-producing enzymes (malic enzymes, glucose-6-phosphate dehydrogenase or methylenetetrahydrofolate dehydrogenase / mitochondrial cyclohydrolase) to reduce or increase cellular NADPH levels. However, since altering metabolic enzymes could affect intermediate metabolism beyond NADPH, we needed to find a way to directly manipulate the concentration of NADPH in cells. We could not add NADPH to the cell culture medium because NADPH is unable to cross the cell membrane. We wondered if NADPH could be transfected into cells like DNA. We tested this possibility from various angles and finally found a reagent that could actually transfect NADPH into cells. We tried it on several cell lines and looked at cell concentrations of NADPH after transfection, and it worked! In 2021, the first major article to come out of my lab, on how NADPH was detected and the function of NADPH in modulating cell epigenetic status (Li et al., Https:// -020-00330 -2), was published in Natural metabolism. The article describes an independent function of NADPH metabolism in modulating epigenetic status and transcription. Mechanically, NADPH interacts directly with histone deacetylase 3 (HDAC3) and disrupts the association between HDAC3 and its nuclear receptor co-activator 2 (Ncor2; SMRT) or Ncor1. By disrupting the complex between HDAC3 and Ncor, NADPH suppresses HDAC3 activity and reprograms histone acetylation and gene expression. Although how NADPH acts on HDAC3 requires further elucidation, NADPH may have broad impacts on cell physiology through modulation of epigenetic status and transcription.

The challenge for us during this project was that the COVID-19 pandemic forced us to shut down the lab for about two months while reviewing the manuscript. Then, with a gradual reopening, only one or two people were allowed to work simultaneously in the laboratory. Meanwhile, we were concerned about the slow progress. We were fortunate to meet caring editors who supported us and gave us ample time for us to fully respond to reviewers’ comments. And we were also fortunate to have the support of my collaborators, who helped us to perform docking and molecular dynamics simulation experiments between NADPH and HDAC3 during the review of the article. Additionally, we felt fortunate and encouraged to have the help of the editorial team and professional proofreaders. The reviewers’ comments were constructive and the editor summarized particularly important points, which was particularly helpful in showing a young lab how to review an article. I am also fortunate to have passionate interns who work hard and dedicate their careers to research.

The paper Natural metabolism gave my lab a good start and was also significant for my professional life as a junior PI. It brought a lot of positive things to my team and myself and opened up new direction and collaboration for my research team. After the article was published, he called attention to my work and my lab, including prizes and invitations to speak at conferences, and I hope that will manifest more in the future, in terms of recruiting people and funding.

Being an IP is not easy. Having my own laboratory is exciting but stimulating, because I have to assume my responsibilities towards my interns, my collaborators and my department. As a new IP, I encountered many challenges that I hadn’t anticipated, although these are probably common to most new IPs. Finding the right post-docs and students was more difficult than I expected; for example, when I recruited the first scientist for my lab, the candidate canceled the appointment a day before the interview. Fortunately, I managed to recruit talented and passionate scientists and students who wanted to join my lab and work with me. My lab has slowly grown from a small lab with one scientist and one student in 2017 to a larger lab with two scientists and six students today. I think recruiting people is the most important thing for a new IP and suggest being patient until you find the right people for your lab.

As a woman, I have always been asked how I am going to balance my personal life and my professional obligations. I must say that it is difficult to clearly separate personal and professional life. As an IP, it seems like you have tons of work to do all the time, like writing funding proposals, writing manuscripts, teaching, supervising interns, and attending seminars and meetings. Balancing the workload was particularly difficult during the COVID-19 pandemic in 2020, when schools were closed. My two children had to stay home and take their classes online. During the day I had to take care of them and take on the role of teacher, and it was only after they went to bed in the evening that I was able to start my own work. It has been a difficult time and I am proud of everything I have overcome. I am fortunate to have a very supportive family, which includes my particularly supportive husband, Peng Jiang, who is also my scientific collaborator. Therefore, I never try to separate my personal and professional life; I always take my work with me wherever I go. I think keeping those parts of your life separate doesn’t matter if your family is supporting you. However, I still believe that some work-life balance is necessary. The optimal work-life balance will vary over time, as we all have different priorities and obligations, and there is no one perfect model that works for everyone. The balance is right as long as you feel a sense of accomplishment and pleasure in your work or your life, and personally, I hope that I will progress far in my career and at the same time enjoy life with my family.

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