Fig 1. An introduction of Prof.Yuanping Han
Prof. Yuanping Han focuses on the integrated pathophysiology of cirrhosis, fatty liver, and metabolic syndrome development, and has deep insights into human digestive physiology and intestinal flora. He was engaged in new drug research at GSK GlaxoSmithKline skunkworks and Sichuan Antibiotics Research Institute and worked as a consultant for pharmaceutical companies for a long time during his stay in the US.
Probiotic preparations are the products we eventually hope to get. As an emerging drug, there are more things to considerate before product transformation. We were very fortunate to have Prof. Yuanping Han for an offline interview on the therapeutic aspects of this topic. We asked Prof. Han for advice and discussed several physiological and therapeutic related issues in the topic.
Professor Han also asked us some questions about the shortcomings of the subject and the direction of improvement.
“Have you ever tested the production of the beneficial products of your engineered probiotics? Are these products necessary for human body? What is the background level of such products in human body?”
“We will do fermentation experiments and measure the product concentration of PQQ, L-erythrose and other substances. Also, we plan to communicate with other iGEM teams conducting intestinal engineered probiotic related projects, hoping to find a more reliable application for our colonization platform.”
“Refer to your modeling data, first, the growth of probiotics obtained from your modeling after using erythritol is not significant. If you want to achieve the colonization effect you hope, you may do metabolic pathway optimization.”
“Yes, we've noticed this problem. The current modeling uses the same more general value for each gene in the erythritol gene cluster utilized. In the work later, we found that erythritol translocation and D-4-phosphate-erythritol isomerization are two key rate-limiting steps. In subsequent experiments, we will increase the expression of these two genes, expecting to increase the promotion of erythritol in engineered bacteria”
“ In addition, engineered probiotics colonize the wall of small intestine. The colonization density will not be very high due to the presence of natural barriers such as defensins from small intestine Paneth cell. At the same time, small intestine has a strong absorption effect on bacterial toxins, the colonization of engineered bacteria may have negative effects on humans, which can best be verified by animal experiments.”
Prof. Yuanping Han analyzed our project from various angles and gave us his insights and suggestions on several directions, which guided us to improve the feasibility statement of the project in terms of background. He also provided new thinking perspectives in terms of physiology, which provided valuable advice for the subsequent experimental design of the project.
Fig 2. Meeting with EPIC-China
In addition, we reached out to EPIC-China to ask them about the shortcomings and issues that need to be addressed in our project from entrepreneurship perspective. EPIC (Entrepreneurship Program Innovation Community) is the official non-profit entrepreneurship support organization of iGEM, dedicated to supporting entrepreneurs from the iGEM community. EPIC-China's entrepreneurial support is based on the local environment in China, and hopes to drive the entrepreneurship and development of synthetic biology-based enterprises to accelerate the world's development towards a more sustainable bioeconomy. The details of the exchange between SCU-China and EPIC-China are described in detail in the section "Improvement in Exchange".
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SCU-China
“Beverage advertisements claim that erythritol is a 0-calorie sugar substitute. But some people are still skeptical about this, what do you think?”
Han
“The first thing to consider is the amount of erythritol. I've noticed that one of the sugar-free drinks you've mentioned had 10 grams of erythritol per 100 ml, which is still a great amount of sugar at 10%. On the other hand, erythritol may be converted into sugar with some calories through a specific pathway after entering the cells. This conversion pathway has not been studied till now. So strictly speaking, it's still only a relatively 0 calorie sugar substitute from the biochemical view.”
SCU-China
“What do you think can be done to further improve the efficiency of engineered probiotic colonization in practical applications?”
Han
“The colonization of engineered bacteria is a very complex process, which involves many factors.
First is the location of colonization. Bacteria in the intestinal lumen are quickly eluted with defecation, while those on the mucosa can adhere more stably. For the latter, the bacteria can generally be adhered to the intestinal mucosa by negatively charged mucopolysaccharide, like a double-sided adhesive.
In addition to this, Bacteroides and E. coli are in different phylum. I have reservations whether the promotion effect of biomass growth on colonization by Bacteroides after using zymosan is also applicable in E. coli. However, considering they are both gram-negative bacteria with similar basic cell wall structure, the feasibility of the subject is also guaranteed.”
SCU-China
“We've noticed that many people are skeptical about probiotic therapy, what do you think?”
Han
“I know something about probiotics for cancer treatment. In general, due to the complexity of the kinetics of therapeutic substances in the body and the mechanism of cancer development, this technology is still a long way from practical application. However, if the focus of the subject is on health care products, I think it's still right.”