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Research in the Schmidt-Dannert Lab

Biosynthesis and Designer Microbes

more info is available at Claudia's Benefunder site

Microbes and plants synthesize a tremendous diversity of chemical compounds (natural products) that is unmatched by chemical synthetic methods. The structural complexity of these molecules is important for their bioactivities, but poses a challenge for their production using synthetic methodologies. Biological systems use myriads of enzymes with different functions as catalysts to achieve biosynthesis of complex molecules at room temperature and in the absence of organic solvents. With the sophistication of genetic methods for the manipulation of microbial cells and with increasing knowledge about biosynthetic processes on a molecular level, it became feasible to not only manipulate biosynthetic pathways for increased production levels in the natural producers, but also to combine genes encoding enzyme catalysts from different organisms into new routes for the production of novel compounds by engineered organisms.

We are interested in exploring and utilizing the metabolic machineries of plants and microorganisms to enable the discovery and synthesis of valuable microbial or plant-derived compounds in engineered microbial cells. We combine enzyme functions encoded by genes obtained from different sources into new biosynthetic pathways in engineered cells for the production of desired compounds.

Pharmaceuticals from Fungi and Plants

Currently, we investigate and engineer the biosynthesis of diverse isoprenoid- and phenylpropanoid derived natural products using enzymes isolated from plants and fungi, to produce chemicals with medicinal properties. A major research area in our group is the biosynthesis of isoprenoid compounds. Isoprenoids represent the largest class of natural products with over 20,000 compounds described. These compounds have a wide range of biological functions and are of industrial and pharmaceutical interest as pharmaceuticals, antioxidants, colorants, vitamins, and aroma compounds. We are currently investigating the biosynthesis of one group of pharmaceutically important isoprenoids – the sesquiterpenes. These cyclic molecules represent a rich source for the discovery of new pharmaceuticals. Well-known examples of current sesquiterpene-derived drugs are the anticancer and antimalarial compounds taxol® and artemisinin, respectively. We initially studied bacteria as new sources for these compounds, but realized that mushrooms represent an even greater and a completely untapped source for the discovery of bioactive sesquiterpenes.

Mushrooms have been used for centuries in traditional medicine, and they are known to produce a range of unique sesquiterpene structures, many of them with demonstrated antimicrobial, cytotoxic, immune-modulating and anti-inflammatory activities. A large effort in my research group is now focused on the identification and characterization of novel compounds in this fascinating class of organisms. We recently completed the genome sequence of one mushroom, the Jack-O-Lantern mushroom and identified the genes responsible for the biosynthesis of the anticancer illudin compounds by this mushroom. This gave us access to a large set of enzymes and their genes, which we now use to discover and clone genes encoding biosynthetic enzymes from the genomes of a range of mushrooms. Most of the mushrooms that have a sequenced genome have been sequenced because of their ability to break down plant material for biofuel production purposes. However, we are currently sequencing the genomes of mushrooms that have been used since millennia in traditional medicine and/or are known to make compounds useful as drugs. We are building a pipeline for the identification and subsequent engineered production of diverse natural products for screening and testing compounds with new pharmaceutical properties.

Rapid advances in entire genome sequencing, inexpensive DNA synthesis and in computational capabilities to analyze and study biological data and networks led to the emergence of a new multi-disciplinary field of study coined “Synthetic Biology.” It allows us to rapidly synthesize, assemble genes and other DNA parts in order to “refactor” entire biosynthetic routes taken from mushrooms into industrial production organisms like yeasts. These recombinant microorganisms can then be grown in large fermentation bioreactors for the synthesis of molecules (pharmaceuticals or other chemicals) of choice.

Engineering more efficient metabolic and biocatalytic functions and systems

The biosynthesis of complex specialty chemicals, pharmaceuticals and biofuels in native organisms often proceed through multifaceted secondary pathways requiring long reaction times and generating poor product yields. Thus, we are also interested in engineering more efficient metabolic functions in heterologous microbial hosts to generate designer microbes with optimized metabolisms for producing higher yields of desired product.

We are designing and constructing genetic circuits for value-added chemical production and engineering microbial cell-cell communication. Further, we are working to develop multi-cell systems that carry-out complex conversion processes by dividing the overall pathway among multiple engineered organisms that can communicate, modulate each-others growth and control relative population dynamics to maximize product yields. We are also investigating and engineering protein-based nano-compartments for biosynthetic processes in engineered microbes and for in vitro biocatalytic applications.

Ultimately, the techniques we are developing and employing to construct these designer microbes for our model systems can be broadly applied to engineer a wide number of new microbial systems. In this way we are working to develop a synthetic biology processing toolkit that can be used to aid the design of biorefineries. Our bioprocess toolkit will enhance the capability of biosynthesis, biocatalysis, and process separations that will drive a new bottom-up approach to bioprocess engineering and biorefinery design.