(7bc) From Integrative Metabolomics to Understanding Human Diseases and Enhancing CO2 Fixation

A growing concern for 21^st-century humanity is the irrevocable rise of carbon dioxide (CO₂). On a more personal level, many individuals today suffer from distressing diseases like cancer. Potential solutions to these disparate problems lie in metabolism. With these applications in mind, my research goal is to advance biotechnology and medicine by integrative metabolomics, which incorporates kinetic and thermodynamic information into characterization of metabolic processes.

My postdoctoral research with Prof. Gregory Stephanopoulos has focused on enhancing CO₂ fixation by employing thermodynamic and systems-level efficiency of non-photosynthetic carbon-fixing metabolism. I developed a rapid CO₂ fixation scheme that enables precise control over the rate of CO₂ fixation (i.e., productivity) and the proportion of CO₂ incorporated into the product (i.e., yield). Using this technology, fermentation of Moorella thermoacetica produced acetate as a product of CO₂ fixation at high specific productivities (0.54 g per g cell dry weight (gCDW) per hour) with nearly all acetate carbons (>98%) derived from CO₂.

In establishing this technology, my graduate and undergraduate training with Profs. Joshua Rabinowitz and Bernhard Palsson helped with quantitative characterization of metabolism. Using non-equilibrium thermodynamic principles and stoichiometric metabolic models, I was able to integrate forward-to-backward reaction flux ratios with reaction quotient-to-equilibrium constant ratios via Gibbs free energy. The upshot of the integrative analysis was internally consistent and comprehensive sets of metabolite concentrations and Gibbs energies in E. coli, yeast, and mammalian cells. Based on these results, I found efficient enzyme usage to be a design principle across kingdoms of life.

Collaborating with other researchers, I recognized that there is ample room for new discoveries by applying the integrative metabolomic approaches in other fields. Working with Profs. Mark Brynildsen and Stanislav Shvartsman, I contributed to understanding the underlying metabolic processes in bacterial persistence and in healthy embryonic development. The resulting knowledge pointed to potential drug targets in bacteria with high antibiotic tolerance and to an essential metabolic regulation that ensures normal development.

Going forward, I would like to incorporate comprehensive enzyme cost and efficiency information into the metabolic flux and pathway analysis paradigm. Lack of efficiency in certain cells (e.g., cancer cells) could suggest potential therapeutic targets. In metabolic engineering applications, the economics of cellular proteome partitioning must be compatible with our economic goals. Optimal and feasible solutions, then, would consist of metabolic modules that simultaneously permit maximum enzyme efficiency and maximum net value created. Such integrative approaches will help disentangle complex metabolic diseases and engineering challenges, thereby facilitating better therapeutic and engineering solutions.

Teaching Interests:

Teaching and research complement each other. Without proper training of young scientists, the future of research looks bleak. Oftentimes, new unanswered questions arise from teaching and current research findings enrich the teaching component. In both settings, the importance of interdisciplinary and collaborative problem solving cannot be overstated. Many of my research projects have been fruitful collaborative efforts involving several disciplines and I can readily apply my experience to my teaching.

My teaching goals also include promoting curiosity and encouraging the endeavor to pursue new knowledge and experience. From my experience teaching in lectures, discussion and laboratory sessions as well as mentoring students, I learned that, aside from answering students’ questions, I also have to ask them the ‘right’ questions to engage their minds. These questions could be laid out to guide students to solve problems on their own and eventually to render them more inquisitive. I would like to incorporate my teaching principles and goals into chemical and biological engineering core courses as well as new electives that introduce students to interdisciplinary/integrative problem solving.

Selected Publications:

1. Park JO, Rubin SA, Xu Y, Amador-Noguez D, Fan J, Shlomi T, Rabinowitz JD. Metabolite concentrations, fluxes and free energies imply efficient enzyme usage. Nature Chemical Biology 2016; 12:482-489
2. Schellenberger J, Park JO, Conrad TM, Palsson BØ. BiGG: A Biochemical Genetic and Genomic knowledgebase of large scale metabolic reconstructions. BMC Bioinformatics 2010; 11:213
3. Mok WWK, Park JO, Rabinowitz JD, Brynildsen MP. RNA futile cycling in model persisters derived from MazF accumulation. mBio 2015; 6(6):e01588-15
4. Song Y, Marmion R, Park JO, Biswas D, Rabinowitz JD, Shvartsman SY. Dynamic control of dNTP synthesis in early embryos. Developmental Cell 2017
5. Park JO, Liu N, Holinski KM, Emerson DF, Woolston BM, Vidoudez C, Islam MA, Girguis PR, Stephanopoulos G. Enhancing CO₂ fixation by balancing reducing power and ATP. in preparation