Research
Biological rhythms orchestrate functions in space and time for organisms to develop, to adapt, and to survive. Our lab is interested in revealing hidden biological rhythms and in deciphering their underlying regulatory principles. Rhythmic systems that we investigate include oscillators, toggle switches and trigger waves, especially those that govern cellular survival, death, and differentiation. We take a multifaced quantitative approach integrating concepts and methods in biology, mathematics, engineering and informatics. Our ultimate goal is to reveal general principles in biology for its design and control.
Spatiotemporal coordination of large-scale cell death during embryogenesis
During embryonic development, cells proliferate and differentiate rapidly to form tissues and organs. Paradoxically, these processes that foster the formation of life is often accompanied by large-scale cell death, observed since the 19th century. Such death events can cover large areas of tissue, causing millions of cells to die. However, how large-scale cell death occurs during development remain a century-old mystery. We found that large-scale cell death can occur through propagation of ferroptosis, an iron-dependent form of cell death. We study how ferroptosis propagation can be utilized as a tissue-sculpting strategy to eliminate temporary tissues in developing embryos, and explore how global cell death events are coordinated in space and time via morphogen signaling to shape organisms during development. The image on the left depicts the occurrence of ferroptosis (yellow) to eliminate excess muscle fibers (magenta) in the developing limb.
Emergence of ROS trigger waves through multistability of cellular redox state
Upon metabolic stress, the level of reactive oxygen species (ROS) in individual cells can exhibit multistability and behave as a toggle switch, following an all-or-none response. When physically coupled, these ROS switches allow robust ROS propagation throughout a cell population as trigger waves, causing large-scale oxidative cell death. Different from simple diffusion whereby a signal dissipates quickly in space, trigger waves are self-regenerating chemical wave fronts that propagate at a constant speed over long distances. We are interested in identifying molecular regulators underlying the emergence of ROS multistability and the occurrence of ROS trigger waves. Our goal is to modulate and control ROS waves for therapeutic purposes. The movie on the right shows the propagation of lipid peroxidation (yellow) across cell populations.
What is a single cell pondering upon?
How cells make a decision is a fundamental but yet unresolved question. We reason that dynamics of proteins and metabolites represent cells' "thinking process“. Using single-cell time-lapse imaging and CRISPR-mediated gene targeting, we reveal signaling dynamics in single cells (e.g., left movie) during their decision-making process. Combined with mathematical modeling and time-series analysis, we investigate how these signaling dynamics emerge from genetic networks and non-genetic biochemcial noises. Functionally, we want to know how signaling dynamics encode information for cell fate determination. The movie on the left shows p53 (cyan) and MDM2 (yellow) dynamics in a single cell after DNA damage.
Designing synthetic circuits for cell fate control
By leveraging systems understanding of signaling networks, we design novel signaling molecules and bio-circuits to alter cellular state and cellular decisions for therapeutic purposes. Our goal is to promote physiological homeostasis through the prevention of cell death in aging-related pathological conditions (e.g., organ failure and tissue degeneration) and to eradicate cancer cells in the presence of genetic and non-genetic heterogeneities.
People
Sheng-hong (Sheng) Chen
Principal Investigator (Zoology/Artificial Life) shengchen@gate.sinica.edu.tw
Sheng-hong (Sheng) Chen was born and raised in Taipei, Taiwan. He was an undergraduate at National Taiwan University, where he majored in Zoology and worked with Alex Yu on the population genetics of Mus musculus. After graduation, he went to University of Sussex to do his M.Sc. in Artificial Life. For his thesis project, he worked with Inman Harvey to build an agent-based model to simulate the epidemic dynamics and evolution of the Foot-and-Mouth virus in a small-world network. He then did his Ph.D. at UC San Diego with Huilin Zhou, working on enzymology and quantitative proteomics of the DNA damage checkpoint. He received his Ph.D. in Biological Sciences in 2008 and moved to UC San Francisco and Harvard Medical School for postdoctoral training with Keith Yamamoto and Galit Lahav respectively. During this period, he worked on transcriptional dynamics of glucocorticoid receptor and p53 dynamics in single cells. He began his independent career in the Institute of Molecular Biology at Academia Sinica in 2016.
Feng-Shu Hsieh
Ph.D. Scientist (Cancer biology/Epigenetics) fengshu0430@gmail.com
Science should be ‘show me’, not ‘trust me’; it should be ‘help me if you can’, not ‘catch me if you can’. — Philip B. Stark
Feng-Shu Hsieh was born and raised in Taipei, Taiwan. She received a B.S. degree (2007) in Agricultural Chemistry from National Taiwan University, and pursued her Ph.D. at Dr. Wen-Ming Yang’s lab in the Institute of Molecular Biology, National Chung-Hsing University (2014). She worked with Dr. Yang on molecular mechanism of transcriptional repression. In Dr. Yang’s lab, she found her career passion in scientific research. After graduation, she moved back to Taipei and started her postdoctoral training with Dr. Kuen-Feng Chen in National Taiwan University Hospital. She participated in the basic science team to uncover potential targets of anti-cancer drugs. Now, she is eager to upgrade her knowledge in better understanding of cell behaviors and gain more insights in the better design of therapeutic strategies against cancer.
Chia-Chou Wu
Ph.D. Scientist (Biology/Electrical Engineering) ccwu19@gate.sinica.edu.tw
Chia-Chou Wu received the B.S. degree in life science (2006), the M.S. degree in biotechnology (2008) and the Ph.D. degree in electrical engineering (2016) from National Tsing Hua University, Hsinchu, Taiwan. During his Ph.D., he focused on a variety of biological datasets to understand the underlying mechanisms of various biological behaviors and to develop corresponding analyses for measuring information flow and systematic characteristics of biological systems. After that, he was funded by the Ministry of Science of Technology, Taiwan to conduct his postdoctoral research with Prof. Tom Freeman at the Roslin Institute in the University of Edinburgh. He worked on the melanoma classification based on the gene expression profiles and survival analysis. Now, he is funded by the Academia Sinica to conduct his postdoctoral research with Dr. Sheng-hong Chen. His current research interest is in modeling dynamic systems in cancer cells.
Ann Mikaela Lynne Ong Co
Junior Scientist（Biology/Immunology）annmikaela.co@gmail.com
TIGP Molecular & Cellular Biology PhD student
Mika was born and raised in Manila, Philippines. She recently graduated from the University of the Philippines with a Bachelor’s degree in Molecular Biology and Biotechnology. She is immensely interested in the workings of the immune system, and for her undergraduate research, she studied the T cell response against a candidate vaccine antigen against malaria. Currently, she is looking into how key players in the immune response, metabolism, and DNA damage response interact upon exposure of normal and cancer cells to genotoxic compounds.
Hao-Kuen Lin
M.D. Scientist（Medicine/Computation）b04401068@ntu.edu.tw
Long-term scientific collaborator
Currently: Resident Physician, Departmentof Medicine, Danbury Hospital
Hao-Kuen was studying at NTU medical school. He is intrigued by the unsolved questions in science and wishes to know it better through bioinformatics. He now focuses on modeling cancer metabolism to identify interesting properties!
Hannah Katrina Co
Junior Scientist（Biochemistry/Metabolism）hannahkatrinaco@gmail.com
TIGP Molecular & Cellular Biology PhD student
"...the scope of things I didn’t know wasn’t merely vast; it was, for all practical purposes, infinite. If our ignorance is infinite, the only possible course of action is to muddle through as best we can.” — Martin A. Schwartz
Hannah was born and raised in Manila, Philippines. She received her Bachelor's degree in Biochemistry from the University of the Philippines. During her undergraduate study, she found her love for understanding the intricate metabolic pathways involved in the complex interplay among biological processes. In LCD, she is drawn and amazed (!!) by cellular properties emerged from metabolic dynamics. Currently, she is investigating how cells talk with each other, and their language for communication. She hopes to learn their language, participate in their conversations to know them better, and finally decode their thinking processes that give rise to functional consequences.
Jen-Hao Cheng
Junior Scientist（Biology/Bioinformatics）chengjenhao@gate.sinica.edu.tw
AS-NTU Genomics & Systems Biology PhD student
Before I came here I was confused about this subject. Having listened to your lecture I am still confused. But on a higher level. — Enrico Fermi
Jen-Hao Cheng grew up in various places in Asia and the US. He studied Biology at Macalester College and Computational Biology at Carnegie Mellon University. Upon graduation, he returned to Taiwan and studied transcriptional regulation and molecular evolution at Huai-Kuang Tsai's lab in Academia Sinica. He then worked as a Bioinformatics Engineer at ACT Genomics, where he analyzed NGS data to improve cancer precision medicine. Jen-Hao is currently pursuing a PhD degree where he is interested in using computational approaches to study spatiotemporal dynamics of molecular changes and cell fate.
Yu-Hsiang Chen
Junior Scientist (Biomedical Engineering) sammy881127@gmail.com
Yu-Hsiang Chen graduated from National Taiwan University in 2023 with a Bachelor's degree in Biomedical Engineering and double major in Biochemical Science and Technology. During the undergraduate training, he has worked on developing an SPR-based medical sensor and studied macrophage polarization with transcriptomic data. He is interested in how to apply engineering tools to solve biological and medical problems. Currently, he is studying p53 oscillator at differnt cell cycle states utilizing mathematical modeling, and wondering how the predictive power of models can help to solve biological problems.
Ko-Wen (Kevin) Sun
Junior Scientist (Biomedical Engineering) kevinssun@gmail.com
TIGP Molecular & Cellular Biology PhD student
"The superpower of entrepreneur is they don't know how hard it is, and they only ask themselves how hard can it be." — Jensen Huang
Ko-Wen (Kevin) Sun was born and raised in Taipei, Taiwan. He studied Biomedical Science and Engineering at National Central University. During his undergraduate period, he joined Tumor Microenvironment Lab and worked with Dr. Shu-Chen Liu on the role of regulatory effects of cancer secreted cytokine. In 2022 summer, he joined LCD as an intern, where he worked on p53 dynamics under metabolic stress and realized his passion for research. After his graduation from college, he joined LCD as a PhD student. He is now trying to understand the dynamics of redox metabolism in various cellular processes.
Eclipse Ti LCD
Single-cell observer (Optics)
Elipse Ti LCD was born in Japan and raised in Taiwan. She joined LCD in December 2016 and has been spending all of her time observing dynamics of signaling molecules and single-cell behavior. Her current research interest is to find what dynamics encode cellular thoughts after metabolic and anti-cancer drug stresses by direct observation.
Zeiss Axio Observer 7 LCD
Single-cell and biological wave observer (Optics)
Zeiss Axo Observer 7 LCD was born in Germany and raised in Taiwan. He joined LCD in December 2019 and has been spending all of his time observing signaling dynamics in cell populations. His current research interest is to find what controls the occurrence and speed of ROS chemical wave fronts after metabolic stresses by direct observation.
Publication
Plausible, robust biological oscillations through allelic buffering. Cell Systems. 2024 Nov 20;Vol15(11):1018-1032.
Emergence of robust biological oscillators: We used quantitative single-cell imaging, stochastic simulations and chemcial perturbations to characterize an unexpected skipping event in the p53 oscillator and showed how this skipping event can be buffered to maintain robust p53 oscillations.
Emergence of large-scale cell death through ferroptotic trigger waves. Nature. 2024 Jul;631(8021):654-662.
Cell death spreads as wild fires: We showed that large-scale cell death can be achieved through the propagation of ferroptosis as self-regenerating trigger waves. Ferroptotic trigger waves can eliminate large areas of temporary tissues in the developing embryo, substantiating its utility as a tissue-sculpting strategy during embryogenesis.
Noted in:
Waves of ferroptotic cell death sculpt embryonic tissue. Nature. News and Views, 2024 July 10.
Ferroptosis disseminates afar in development. Nature Cell Biology, Research Highlight, 2024 Septermber 12.
Enhanced DNA repair through droplet formation and p53 oscillations. Cell. 2022 Nov 10;185(23):4394-4408.
Functional oscillations: We provided the first functional explanation for why p53 oscillates with a period of ~ 5 hours --- to enhance DNA damage repair via droplet formation of DNA damage repair proteins.
Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness. Scientific Reports. 2022 Feb 22;12(1):2974.
CEBU (Cell-specific Expression BUffering): Cell-specific gene expression can promote functional buffering for tissue homeostasis and cancer robustness.
Multistability maintains redox homeostasis in human cells. Molecular Systems Biology, 2021 October 6;17:e10480
Multistability: In-silico modeling of a nutrient-redox network and single-cell measurements of ROS demonstrate that ROS dynamics follow a bistable response to glucose deprivation in human cells.
Inferring leading interactions in the p53/Mdm2/Mdmx circuit through live-cell imaging and modeling. Cell Syst. 2019 Dec 18;9(6):548-558
Biological oscillator: p53/Mdm2 acts as an autonomous oscillator that is suppressed by Mdmx in proliferating cells.
Two is better than one; toward a rational design of combinatorial therapy. Curr Opin Struct Biol, 2016 Aug 10;41:145-150.
Drug combinations: A review paper on the emerging trend of using the dynamics of biological systems for the rational design of combinatorial therapy. Specifically, we focus how to leverage three properties of signaling networks including 1. single-cell signaling dynamics; 2. signal adaptation and 3. crosstalk among signaling pathways for the rational design of drug combinations.
Schedule-dependent interaction between anticancer treatments. Science 2016 Mar 11;351(6278):1204-8.
Single-cell dynamics: We showed how single cell approach reveals unexpected p53 dynamics and how to use these dynamics to guide the design of time-dependent cancer therapy. This work was featured in Harvard Medical School News, Xinhua News, le monde fr and Wiezmann !
Incoherent feed-forward regulatory logic underpinning glucocorticoid receptor action. Proc. Natl Acad Sci U S A. 2013 Jan 29;110(5):1964-9.
Transcriptional dynamics: Here we identified the regulatory logic underlying a pulsatile transcriptional activity of glucocorticoid receptor (GR) using systematic and quantitative perturbations of the GR transcriptional system.
A proteome-wide analysis of kinase-substrate network in the DNA damage response. J Biol Chem. 2010 Apr 23;285(17):12803-12.
Phospho-proteomics: Kinase-substrate network of the DNA damage checkpoint was mapped using quantitative phospho-proteomics.
Reconstitution of Rad53 activation by Mec1 through adaptor protein Mrc1. J Biol Chem. 2009 Jul 10;284(28):18593-604.
Enzyme kinetics: The DNA damage checkpoint signaling cascade was firstly reconstituted for identifying molecular mechanisms for checkpoint kinase activation.
Beauty
What we observed/created during our scientific journeys
