Following the light: He uses "photon imaging" to illuminate the biological world!

Fireflies are always an indispensable part of summer memories. At night, they often gather by the paths and fences, twinkling with fluorescence. From a distance, those silvery, lively lights float in the dark night, like stars sprinkled from the sky. Such a beautiful scene not only has a high appreciation value, but in fact, it is also very helpful in promoting the combined research of biology and optics, and the discipline of bio-optics was born. Since his doctoral studies, He Sicong has specialized in the development of optical microscopy technology in the optical discipline and its cross-cutting direction of application in the biomedical field. After joining the School of Life Sciences and the Department of Biomedical Engineering of Southern University of Science and Technology, he has been committed to developing new fluorescent microscopy technologies with high temporal and spatial resolution, large penetration depth, and low phototoxicity, and studying dynamic biological processes in living biological tissues through visualization. "Bio-optics is an emerging discipline formed by the intersection of life sciences and physics. Its main research object is the interaction between matter and light in organisms. It aims to develop optical and photonic technologies to enhance the understanding of the structure, function and dynamic processes in organisms. For this reason, bio-optics is also an exciting and challenging discipline. It is worthwhile for us to maintain a good habit of lifelong learning in order to explore new knowledge, to maximize the innovation engine of interdisciplinary studies, and to use optical technology to study cutting-edge scientific problems in the biomedical field." he said.

The power of the heart to follow the light

When talking about the beginning of He Sicong's relationship with optics, we must mention Zhejiang University (hereinafter referred to as "Zhejiang University"), which combines the magnificent academic style with the elegant spirit of the south of the Yangtze River. 2008 was the year when He Sicong pursued his dream of taking the college entrance examination, and it also coincided with the time when Zhejiang University began to fully implement the "general enrollment" training program. It is worth mentioning that this reform method for "general education" breaks through the boundaries of disciplines, encourages students to cross-learn, and gives students who have not yet chosen their development direction a buffer opportunity to "examine themselves" and clarify their interests. He Sicong is also one of the beneficiaries of this model. Since the subdivision of majors began in the second year of university, he could freely chase the wind and waves in the sea of ​​"big engineering" in his first year of school. But in fact, his eyes have always been attracted by optoelectronic information engineering. "Zhejiang University's School of Optoelectronics is the birthplace of my country's optical engineering discipline, and optoelectronics is one of the most influential and advantageous disciplines of the school." He Sicong has since opened a new chapter in his life that is closely related to optoelectronic information and optical imaging technology.

▲Group photo of He Sicong (fourth from left) and his team

From Zhejiang to Hong Kong, from the West Lake to Victoria Harbour, He Sicong spent several years studying with professional books such as "Geometric Optics" and "Physical Optics". Although he was still a blank sheet of paper when he first arrived at the Department of Electronics and Computer Science of the Hong Kong University of Science and Technology, and was once helpless in the development of the project because he had no academic background related to biology, but the trickle of water will eventually become a river. Under the earnest teachings and careful guidance of his mentor Professor Qu Jianan, he did not ignore any opportunity to accumulate experience, and especially realized that frequent exchanges with senior biologists were very important. "As a researcher with an optical research background, I need to jump out of my own inertial thinking circle, take the initiative to understand the research problems and needs in the biological field, and think about how to apply optics to it. The laboratories of different professional departments on the campus of the Hong Kong University of Science and Technology are all in the same academic building, and experts in various fields work under the same roof, which invisibly creates very convenient conditions for interdisciplinary exchanges and cooperation, and I have benefited from it." He Sicong said.

In terms of research, He Sicong also kept moving forward. After working hard at his desk day and night, he finally reaped the rewards in midsummer. At the end of his postdoctoral research, he submitted satisfactory answers to the two research projects "Research on high-resolution imaging technology of deep tissues of living organisms" and "Research on fluorescent labeling and tracing imaging technology of living single cells". The former plans and lays out key issues in the application of optical microscopy in biological tissues, focusing on solving the difficulties of wavefront distortion in the process of light penetrating biological tissues due to the complex structural components in biological tissues, resulting in unsatisfactory imaging effects. They try to use wavefront shaping to correct optical aberrations, with the goal of improving imaging depth and resolution. The latter focuses on achieving qualitative changes in the cognition of cell heterogeneity.

"In order to achieve high-resolution fluorescence imaging in deep biological tissues, we developed adaptive optical multiphoton fluorescence imaging technology (AO-TPEFM)." He Sicong introduced. The biggest advantage of this technology is that it can penetrate complex biological tissues under non-invasive or minimally invasive conditions to obtain high-resolution fluorescence images of cell structures. The reason is that He Sicong's team cleverly used multiphoton fluorescence to stimulate the instrument's inherent three-dimensional optical sectioning capability. "We assembled an ultra-high sensitivity wavefront detector to efficiently collect fluorescence as a guide star signal, and calculated the light wavefront distortion information introduced by the sample aberration based on this. Then, the calculated optical aberration value is immediately transmitted to a set of high-precision deformable mirror systems for real-time wavefront shaping, and a closed-loop feedback control system is used to quickly iterate and correct the residual aberration. This technology can achieve accurate measurement and rapid dynamic correction of aberrations in living biological tissues, thereby improving the resolution and contrast of deep tissue imaging." Although the research has been completed for some time, the details are still fresh in He Sicong's memory.

In addition, the study of cell heterogeneity has always been a major need in the field of biology and is essential for a comprehensive understanding of the complexity of individual development, dynamics, and functions of specific cell types. The advancement of imaging technology has enabled humans to clearly observe cell activities and biological processes in organisms. Coupled with the support of single-cell labeling technology that can track and observe the activity characteristics of the same cell and its progeny in organisms for a long time, it has undoubtedly laid a solid foundation for conducting heterogeneous research in cell behavior/development/function.

Talking about "single-cell optical labeling and tracing imaging technology", He Sicong mentioned the related projects in cooperation with the research group of Professor Wen Zilong of the Hong Kong University of Science and Technology. They have used advanced optical microscopy imaging technology, spectroscopy analysis and genetic modification tools to develop a new type of infrared laser heat shock single-cell labeling and tracing technology - single-cell IR-LEGO. The important innovation of this technology is that infrared lasers can be used to appropriately heat cells carrying heat-activated reporter genes and induce them to emit light, thereby achieving fluorescent labeling of single cells and all their progeny, facilitating subsequent long-term tracking of cell progeny activities and recording continuous and detailed activity data. He Sicong said: "Precise single-cell fluorescent labeling combined with high-resolution microscopy imaging technology has opened the door for us to intuitively understand the behavioral characteristics of each cell in the body."

New imaging tools help study disease

Undoubtedly, whether in the field of biological or medical research, scientists are looking forward to having an intuitive and clear static or dynamic image at any time to analyze the characteristics and status of specific areas of cells or organisms, or even the expression and distribution of specific molecules. Today, bio-optical imaging has entered the public eye with its mature detection instruments, high sensitivity and resolution, and fast imaging speed. Its emergence has important practical significance for the development of new diagnostic and treatment methods for some "difficult and complicated diseases" in the past. However, in the face of the pathological mechanisms and clinical manifestations that vary from person to person, bio-optics still has a broad room for improvement. This is also the fundamental motivation for He Sicong to join Southern University of Science and Technology to continue his research.

"When I was in Hong Kong, I learned that the founding spirit of Southern University of Science and Technology is 'daring to try, truth-seeking and pragmatic, reform and innovation, and pursuit of excellence'. Academician Zhang Mingjie, Dean of the School of Life Sciences, very much hopes to 'gather the strengths of various disciplines', build a distinctive discipline system, and develop the School of Life Sciences in a brand-new model. It is obvious that modern biomedical research is on the road of big data, quantification, multi-scale and multi-modality. Therefore, I believe that what I have learned in the past is still in a relatively high degree of fit with the needs of the school, and I fully agree with the development direction proposed by Academician Zhang." After hitting it off, the young scholar resolutely joined the team in 2020, and his research, like the new School of Life Sciences, has to start from scratch, but it also contains infinite hope.

Purchasing equipment, recruiting talents, balancing research, building platforms... These seemingly trivial and tedious things have occupied He Sicong's life in the past few years, but the power of persistence is often formed in these calm years. At present, after a little bit of precipitation and practice, He Sicong has developed a more meticulous and clear thinking about the future direction of his work. "I believe that if today's biomedical research is to make breakthroughs, it is critical to develop cross-scale, multi-modal high-resolution imaging technology tools. Therefore, the goal of my laboratory in SUSTech is to develop a high-resolution, large penetration depth optical microscope that can be widely used for imaging living tissues; at the same time, combine other technologies such as artificial intelligence and image processing to achieve multi-dimensional analysis of image data. We hope to help researchers in the biomedical field solve major scientific problems by developing cutting-edge imaging technology and scientific research equipment."

Time moves forward day and night, connecting the past and the future, and also engraving the footprints of unity and struggle. Looking back at yesterday, the scene of stepping into the Southern University of Science and Technology alone is still clear; based on the present, the days of working together with every diligent and thoughtful partner in the Bio-Optical Imaging Laboratory are enough to make He Sicong feel very happy. "What I am most proud of is this cross-disciplinary research team with talents from multidisciplinary professional backgrounds such as physics, biology, electronics, and computers. Scientific research can never rely on the strength of one person. In the future, we also welcome young scholars with professional backgrounds such as optics, biology, and instrument science to join our team and explore the mysteries of life with us using optical technology." He Sicong said.