Xu Keying, reporter of China Science News
"It's done!" When he saw the results of the experiment, Hao Nan knew that he had done something cool: after their "modification", the lifespan of a yeast cell was increased by 82%.
The molecular biology professor from the University of California, San Diego, has a soft spot for aging research. 10 YEARS AGO, HE ESTABLISHED HIS OWN QUANTITATIVE BIOLOGY LABORATORY, "HAO LAB," AND "AGING" BECAME THE MOST PRODUCTIVE BLACK PATCH IN RECENT YEARS.
Hao Nan
On April 28, he and postdoctoral fellow Zhou Zhen, as corresponding authors and first authors, respectively, published a new result in Science, which brought a subversive new idea to the field of aging science: using special oscillation methods to extend the lifespan of cells.
This means that humans may be able to manipulate cells the same way they manipulate electrical appliances or cars, including making them "die" more slowly.
Science reviewers commented that this research result is the "debut" of synthetic biology in the field of aging. Engineering-related research thinking and methods play a key role in this, which may have a revolutionary impact on biology.
Screenshot of the paper Source: Science website
Two Science papers 3 years apart
This latest achievement also has a prequel. Three years ago, Hao Nan's team published a paper in Science that successfully deciphered the two key aging mechanisms of yeast cells, that is, the two "death methods" of yeast cells.
As for why you decipher the "dead method" of yeast cells, there are two reasons. First, cell death is closely related to human aging, and in order to solve the mystery of human aging, it is necessary to understand the history of cell death. Second, the aging process of yeast cells is very similar to human epidermal cells and stem cells, which is a classic controllable model for studying human aging pathways.
Back to the path of death for yeast cells. In the past, biologists could only reach a partial causal consensus on cell aging, only knowing which damaging factors promote cell aging, such as chromatin instability, mitochondrial dysfunction, and reactive oxygen species. However, aging, as the "ancestor of all things", must be a very complex process, not determined by a single factor. Scientists are still confused about how these factors combine to contribute to aging.
Hao Nan's research three years ago took a step forward. They achieved observations of the intact aging process of yeast cells. At the same time, using time-lapse microscopy, microfluidic system and computer modeling technology, the two basic paths of yeast cells to death were successfully solved, and the relationship between key factors was clarified.
The researchers observed that even yeast cells with the same genetic material, in the same environment, exhibited two very different patterns of aging. In one mode, nucleoli enlarge and fragment, gradually losing their stability; In another mode, mitochondria accumulate before cell death, showing dysfunction. But either the former or the latter is a choice that yeast cells make early in their lives.
Schematic diagram of microfluidic system Source: Hao Lab
"Choose one of the two ways to die. Once the cell has made its choice, it goes all the way to the dark. Hao Nan explained.
Specifically, if the aging of yeast cells is thought of as a race to death, there are only two runways in front of each yeast cell: nucleoli and mitochondria. Although the materials, rhythms, and scenery along the two runways are not the same, the end point is death.
Immediately afterwards, Hao Nan naturally thought: How can we make this race end slowly?
If you can switch back and forth between two "tracks", one track runs too fast, switch to the other to grind for a while, and the time to reach the end may become longer.
The idea is great, but how do you make it happen?
"We've always been very interested in oscillation, which is a common concept in engineering. Oscillators are a good way to maintain stability because they limit movement to a certain range. Therefore, it is natural for us to think about whether the concept of oscillation can be used in cell modification to achieve the effect of prolonging life. ”
So, in this latest study, Hao Nan and they creatively customized a "synthetic oscillator device" for yeast cells. The researchers genetically rewired the circuitry that controls cell aging, designing a negative feedback loop that can drive cells to periodically switch between two "aging" states, avoiding being buried in either state for a long time, thereby slowing the degeneration of cells. Successfully turned the death "switch" that went all the way to the black into a "pendulum" that delays time through regular oscillations.
As a direct result of this "cheating," yeast cells lived 82 percent longer. "Our oscillator cells have lived longer than any of the longest-lived strains previously identified through unbiased genetic screening." Hao Nan said.
Take the "wild" path
In 2001, after graduating from Peking University with a bachelor's degree in molecular biology, Hao Nan went to the University of North Carolina at Chapel Hill for master's and doctoral studies. In the early days of graduate school, he didn't even set his ambition to do research.
Qualitative changes occur at the doctoral level. One afternoon, Hao Nan's mentor, Henrik Dohlman, went to a café as usual to handle work, and there happened to be a professor sitting next to him, a mathematician.
That was 20 years ago, systems biology was just beginning to gain traction, and many scientists were very interested in the direction of using computational methods to study biological systems. With a common interest, Henrik and the mathematician chatted happily, and finally hit it off: to do some research in systems biology together, and try to use mathematical modeling methods to optimize understanding of signaling in biology and other problems.
Henrik came back and found Hao Nan: "Nan, how is your math?" Hao Nan was a little confused at first: "Also... It's OK. The mentor told Hao Nan about his chance encounter with the mathematician and the interdisciplinary cooperation they wanted to promote, and Hao Nan was very interested. In this way, he naturally assumed the role of "threading the needle" between two laboratories and two disciplines, and enjoyed it.
"It is equivalent to two bosses in my doctoral stage, the boss of experimentation and the boss of computing. And the two of them are very good, not the kind of people who feel that they are very good and can't look at each other, but scholars who can really sit down and collaborate. This cooperation experience has benefited Hao Nan a lot, and it has also helped him find his field of passion and develop a unique academic style.
After graduating with a Ph.D., Hao chose to stay in a computational biology laboratory at the University of North Carolina at Chapel Hill for two years of postdoctoral training, which laid a foundation in computer science.
The biggest academic influence on Hao Nan was his postdoctoral supervisor at Harvard University, Erin O'Shea.
Erin O'Shea is a highly accomplished molecular biologist, a former recipient of the National Academy of Sciences Prize in Molecular Biology, and is now president of the Howard Sius Institute (HHMI). In addition, the biologist is a professional "dog trainer" who trained her pet dog "Zambo" to win the WUSV World Championship.
It is such a strong but distinctive mentor who led Hao Nan on a "wild" road of scientific exploration.
"She is a big bull, the kind of dragon that can't see the head and tail, and it's rare to see it. But a lot of ideas I learned from her. When I used to do those biological problems, I always thought that I had to do it all my life, compete with my peers, and the road became narrower and narrower. But my mentor's thinking is different, she thinks that as long as this biological problem makes sense, you will do it, we will accumulate experience without experience, and find ways to find resources if we need resources. This time it broadens the horizons, and it turns out that everything can be done! ”
During his years in Erin O'Shea's lab, Hao Nan enjoyed rare freedom and was deeply inspired, providing an excellent "demo" for him to build his own laboratory in the future.
Hao Nan said that the biggest influence of his mentor on him is that he sees another "way" to do scientific research. "Some scientists just study something, study it for a lifetime, drill it into the smallest detail. But Erin O'Shea's style is different, she is whimsical, as long as you have the right question, you can do it, and the scope is very wide. ”
This kind of science is really interesting, Hao Nan thought.
Hao Nan and Erin O'Shea
People who do "threading needles"
In 2013, he was hired by the University of California, San Diego, and Hao Nan established his own laboratory. At that time, he had grown into a composite scientist with a multidisciplinary background in biology, mathematics, and computers. After becoming a PI, Hao Nan began to try to do some cross-research that he was interested in, and "aging" was one of them.
"It's hard not to be interested in aging. I wanted to do aging a long time ago, but the conditions were not ripe. After having your own laboratory, all the conditions are met, and you can do it naturally. ”
How similar the history is. Like his doctoral supervisor Henrik, Hao Nan has also gained a group of like-minded cross-border friends in the process of exploring "aging".
It is an academic community that has spontaneously formed around aging. About 8 years ago, Hao Nan and three colleagues from different majors talked about aging-related research issues, and found that everyone was very interested, and they could form a clever complement in terms of professional ability and scientific research perspective. "There are physicists who do biological experiments, there are mathematical modeling, there are physicists who do engineering molds, and I have this cross-background and can play the role of threading needles in it."
Another hit it off! They spontaneously formed an interdisciplinary research group around aging, organizing seminars every two weeks.
This interdisciplinary group rubbed a lot of sparks. Hao Nan's team's latest scientific results, as well as research on two aging pathways in yeast cells 3 years ago, were inspired by the group.
Aging Research Group for 2020
Hao Nan's strong interest in interdisciplinary research also subtly infects his students, which is also the core concept of the laboratory. Hao Nan wrote on the lab's homepage: "Our goal is to establish a research environment that closely integrates experiment and theory while promoting the expansion of each member's scientific expertise. ”
Zhou Zhen, the first author of the latest study, came for this. Before coming to Hao Nan's lab, Zhou Zhen graduated from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and was a student with a "pure biology" background. Although he did not have a deep interdisciplinary foundation at that time, Hao Nan had a very high opinion of Zhou Zhen, believing that he had the quality he valued the most when selecting students - strong "motivation".
Hao Nan remembers that when Zhou Zhen first came to the laboratory for an interview, he expressed his abilities and interests to him very directly. This irrepressible internal drive surprised Hao Nan.
"Such students are particularly rare. When he came to me for an interview, he said that although he was a biology worker, he wanted to do crossovers and had done a lot of preparation before coming. I have been teaching modeling on my own since college, not two knives, but I really understand and do it well. He came to me with a clear purpose, which is to do synthetic biology. So it came and it went smoothly. ”
It took only two years before and after this study, and the super internal drive and execution of the first author Zhou Zhen played a key role in it.
Zhou Zhen
Hao Nan's lab currently has 16 members from different countries. The homepage of the official website has many photos taken by Hao Nan and the students during the party, and at first glance, Hao Nan, who hooks up with the students, looks like their "good brother".
He wants students to be able to "relax" a little in their labs. Chinese pays attention to "if you want to be fast, you can't reach it", Hao Nan hopes to guide students to master this wisdom. He believes that doing scientific research requires inspiration, and when you can't do it by racking your brains, you can take a step back and think about it, think about it and then launch a charge. Don't limit yourself too early, the sky of science is wide, you might as well fly far away.
Group photo of laboratory members
Group photo of laboratory members
But for students who are interested in interdisciplinary research, it is not enough to have good ideas, and it is easy to fall into the dilemma of talking on paper. "I often tell students that if you want interdisciplinarity to be your help, it's best to be the one who threaded the needle and get started on both sides, which is important. It's not enough to just work with others. You need a solid, concrete study plan. ”
Because doing cross-cutting research is likely to face some doubts. Hao Nan's research three years ago was questioned by some biologists. "At that time, some big players in the field asked us 'So What,' you can use mathematical models to explain these gene regulatory relationships, but so what?"
Three years later, the latest study led by Hao Nan and Zhou Zhen can undoubtedly give further answers. "I'm especially happy when the results come out because it can really answer 'So What.'" So'We can follow the mathematical model to find a way to change the aging path, and the method of this oscillator is unthinkable. Right? Hao Nan said with a smile.
Next, Hao Nan and his team will continue to deepen their research, further expanding from yeast cells to animal cells and even human cells.
Paper Link:
https://www.science.org/doi/10.1126/science.add7631
*Images in this article are provided by interviewees unless otherwise noted