Start-up Profiles

Published online: 23 June 2003, doi:10.1038/bioent747

METabolic EXplorer

Iterative rounds of modeling and wet biology yield industrially optimized bacteria.

Until now, engineering microorganisms to optimize the production of fine chemicals has been rather hit or miss. But METabolic EXplorer (METEX) believes that a combination of wet biology and metabolic modeling can dramatically improve the yield of such chemicals from engineered bacteria (See METabolic EXplorer profile).

METEX's iterative metabolic modeling approach.

The first step in METEX's approach involves the use of in silico modeling of the metabolism of strains of, for example, Escherichia coli and Corynebacterium glutamicum to increase the yield of desired end products. Predictive algorithms are linked up with a database of metabolic pathways of reference organisms (E. coli, Saccharomyces cerevisiae and Arabidopsis thaliana). With this knowledge in hand, METEX then targets key metabolic pathways by directed evolution of the bacteria's native genes or incorporation of foreign genes using transgenesis.

The next stage is really what makes METEX's solution innovative. The engineered bacteria are put to the test through a METEX proprietary analytical platform that quantifies in vivo metabolic fluxes. "We are looking at the repartition of carbon from [its stage as] raw material [used as feed] to [its incorporation into] the cell," explains CEO Benjamin Gonzalez. Such monitoring allows the METEX team to establish correlations between metabolic fluxes and altered culture parameters or defined genetic changes, leading to improved understanding of metabolic regulation.

The technology also makes it possible to assess whether the in vivo yield of the bacteria is close to the highest theoretical yield predicted in silico. If the effective yield is low, the engineered bacterial strain can be iteratively improved in vitro through one or more further rounds of optimization.

One limitation of the company's approach is the paucity of knowledge about certain metabolic pathways and regulatory mechanisms, which hampers the prediction ability of the computer model. However, because the company marries wet biology with computing, new data from the study of in vivo flux can be fed back into the model, thus allowing the database to keep refining and collating data on metabolic pathways.

The company now owns the patent relating to the model, transferred from the Institute of Biotechnology at the Forschungszentrum Jülich (Jülich, Germany) where it was initially developed. Two other patents on a method to stabilize cells when studying their metabolism with NMR are co-owned by METEX—transferred from the University of Auvergne (Clermont-Ferrand, France), where company founder Benjamin Gonzalez earned his PhD—and Bruker BioSpin (Billerica, MA, USA), a company specializing in NMR that helped develop the method.

With all the technology in place, METEX is now about to patent its first product: a strain of bacteria able to produce sulfur derivatives (used for food additives or as precursors in the organic synthesis of fine chemicals) that the company is planning to develop in a joint venture with partners. In parallel, METEX has signed research collaboration with Degussa (Duesseldorf, Germany) to improve their amino-acid fermentation process and with BioGemma (Paris), a subsidiary of agricultural crop producer Limagrain (Chappes, France), to characterize the metabolism of plants used to improve their nutritional content. METEX has also signed a fee-for-service agreement with Bayer (Leverkusen, Germany) to study the metabolic flux of some of the pharma company's in-house processes.

SL