QUANTITATIVE BIOLOGY OF METABOLISM
We focus on quantitative and systems study of mammalian metabolism. We take the approach of in vivo flux quantification by integrating animal experiments, mass spectrometry, and quantitative modeling. Fluxes are the most fundamental functional property of metabolism. Their systematic quantitation holds the potential to transform the field of mammalian physiology. Targeted understanding of key molecules and pathways such as cholesterol and insulin – despite their undisputed importance – is not enough. This is evident in the failure over the past decades to control obesity and diabetes, as well as other diseases with a metabolic component, such as cancer and neurodegeneration. Systematic flux quantitation in a mammal, however, poses two key challenges: (i) need for diverse expertise: animal experiments, analytical chemistry, and mathematical modeling; and (ii) multiple time and length scales involved, from enzymes and their reaction kinetics up to the level of tissue and animal physiology. The lab is unique in having the combination of mathematical and biological skills to successfully tackle these challenges.
The goal of the lab is to understand mammalian energy metabolism and develop treatment strategies for diseases with energy imbalance. To gain insights in how the body governs its energy metabolism, we study both sides of the coin of energy balance: the energy-surplus state (obesity) and the energy-deficit state (cachexia). This two pronged approach is valuable for generating and testing hypotheses, and for developing therapies for both diseases. E.g, knowing how the body loses weight in cachexia would certainly be useful for treating obesity! And vice versa!
In parallel, to achieve our overall research goal, the lab continues innovating methods that enable robust quantitative characterization of in vivo metabolism. We also vision a future where the technology of in vivo flux quantification has strong potentials in clinical settings.
QUANTITATIVE STUDY OF THE DIETARY DEPENDENCES OF ENERGY METABOLISM
Obesity is one of the most serious public health problems world wide. What we eat is an important determining factor: some foods tend to cause obesity while others do not. (E.g., high-fat diet is widely used in research to induce obesity in mice.) We want to ask this question: what is it that makes a diet unhealthy (i.e., causing obesity)? Does the diet contain too little of some ingredients or too much of them? What are these key ingredients? Or is the "balancing" of different ingredients the key for a healthy diet? To answer these questions, we systematically vary the composition of the diet and quantify the fate of different nutrients in the animal body. We aim to reveal the strategies the body uses to deal with different foods and the mechanisms for implementing these strategies.
PHYSIOLOGICAL UNDERSTANDING OF THE EFFECTS OF PATHOGEN/TUMOR ON HOST ENERGY METABOLISM
Cachexia refers to the involuntary weight loss and tissue wasting associated with many diseases, including cancer, heart failure, renal failure, chronic obstructive pulmonary disease, and infections. It is a strange metabolic phenomenon for an animal: eating less but burning more energy. What is the origin of this energy imbalance? How is wasting tissues physiologically good for the body? Why is supplementing energy nutrients not helpful? Is this imbalance due to the fact that the system is trying to balance something else (other than calories)? By making sense of this strange response by the host, we aim to reveal principles and mechanisms of energy metabolism of the body, and to develop disease treatment strategies. To study this phenomenon, we use established animal models of cancer cachexia.
IN VIVO FLUX QUANTIFICATION
A key approach we take to probe mammalian metabolism is quantifying metabolic fluxes in vivo. This is done by administering isotopic labeled nutrients to the animal and then inferring fluxes from the isotopic labeling patterns of many metabolites. While this approach of isotopic tracing has been used since decades ago, recent breakthroughs in mass spectrometry, flux modeling algorithms, and animal surgical techniques promise revolutionary advancement in in vivo flux determination technology, which will not only be valuable for research but also for clinical purposes such as diagnosing diseases.
C. Jang, S. Hui, X. Zeng, A. J. Cowan, L. Wang, L. Chen, R. J. Morscher, J. Reyes, C. Frezza, H. Y. Hwang, A. Imai, Y. Saito, K. Okamoto, C. Vaspoli, L. Kasprenski, G. A. Zsido II, J. H. Gorman III, R. C. Gorman and J. D. Rabinowitz. Metabolite Exchange between Mammalian Organs Quantified in Pigs. Cell Metabolism 30, 594-606 (2019)
M. D. Neinast*, C. Jang*, S. Hui, D. S. Murashige, Q. Chu, R. J. Morscher, L. Zhan, E. White, T. G. Anthony, J. D. Rabinowitz and Z. Arany. Whole-body metabolic fate of branched chain amino acids in health and insulin resistance. Cell Metabolism 29, 417- 429 (2019)
S. Hui and J. D. Rabinowitz. An unexpected trigger for calorie burning in brown fat. Nature 560, 38-39 (2018)
L. Liu, X. Su, W. J. Quinn III, S. Hui, K. Krukenberg, D. W. Frederick, P. Redpath, L. Zhan, K. Chellappa, Eileen White, M. Migaud, T. J. Mitchison, J. A. Baur and J. D. Rabinowitz. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell metabolism 27, 1067-1080 (2018)
C. Jang, S. Hui, W. Lu, A. J. Cowan, R. J. Morscher, G. Lee, W. Liu, G. J. Tesz, M. J. Birnbaum and J. D. Rabinowitz. The small intestine converts dietary fructose into glucose and organic acids. Cell metabolism 27, 351-361 (2018)
N. N. Pavlova, S. Hui, J. M. Ghergurovich, J. Fan, A. M. Intlekofer, R. M. White, J. D. Rabinowitz, C. B. Thompson and J. Zhang. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell metabolism 27, 1-11 (2018)
S. Hui, J. M. Ghergurovich, R. J. Morscher, C. Jang, X. Teng, W. Lu, L. A. Esparza, T. Reya, L. Zhan, J. Y. Guo, E. White and J. D. Rabinowitz. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115-118 (2017)
M. Basan, S. Hui and J. R. Williamson. ArcA overexpression induces fermentation and results in enhanced growth rates of E. coli. Scientific Reports 7:11866 (2017)
W. Lu, L. Wang, L. Chen, S. Hui and J. D. Rabinowitz. Extraction and quantitation of NAD(P)(H). Antioxidants and Redox Signaling (2017) doi:10.1089
M. Basan*, S. Hui*, H. Okano, Z. Zhang, Y. Shen, J. R. Williamson and T. Hwa. Overflow metabolism in E.coli results from efficient proteome allocation. Nature 528, 99-104 (2015) (*equal contribution)
S. Hui, J. M. Silverman, S. S. Chen, D. W. Erickson, M. Basan, J. Wang, T. Hwa#, and J. R. Williamson#. Quantitative proteomic analysis reveals a simple strategy of global resource allocation in bacterial metabolism and growth. Molecular Systems Biology 11.2 (2015) (#corresponding authors)
C. You, H. Okano*, S. Hui*, Z. Zhang, M. Kim, C. W. Gunderson, Y.-P. Wang, P. Lenz, D. Yan, and T. Hwa. Coordination of bacterial proteome with metabolism by cyclic AMP signalling. Nature 500, 301–306 (2013) (*equal contribution)
G. Alexe, R. Vijaya Satya, M. Seiler, D. Platt, T. Bhanot, S. Hui, M. Tanaka, A. J. Levine and G. Bhanot. PCA and Clustering Reveal Alternate mtDNA Phylogeny of N and M Clades. J. Mol. Evol. 67, 465-87 (2008)
S. Hui and L.-H. Tang. Ground state and glass transition of the RNA secondary structure. Eur. Phys. J. B 53, 77-84 (2006)
Postdoc positions are available for researchers with diverse backgrounds including biological sciences, chemistry, physics, and bioengineering. Experiences of mass spectrometry or animal experiments are a plus. You will need to work on animal experiments. Please contact Tony Hui with your CV, research interests, and why you are interested in joining the lab.
Positions are open to graduate students from any of the Harvard programs. No particular experience is required but you are passionate about understanding mammalian metabolism and metabolic diseases. You will need to work on animal experiments. Write to Tony Hui if you are interested in rotation (note that the lab will start in Jan 2020).