Douglas Clark
Professor of Chemical Engineering

We study biochemical engineering in Tan Hall. Some of our many projects include the development of new enzyme technology, the analysis of “extremophilic” microorganisms that have adapted to harsh living environments, and the study of cancer cell metabolism.

Much of our group’s recent research involves the development of new enzyme systems that have practical applications, from drug discovery to large-scale bioprocesses in industry. Enzymes are complex proteins produced by living cells that catalyze specific biochemical reactions under physiological conditions. Scientists have studied enzymes in test tubes for decades and have worked out many of their catalytic mechanisms. However, enzymes are not widely used in the chemical and pharmaceutical industries because once out of the cell, many enzymes lose their activity and stability. We have devised ways to greatly increase the activity and stability of enzymes under conditions suitable for the synthesis of chemicals and pharmaceuticals, namely under high pressure and temperature, and/or in organic solvents. These developments are particularly important for the large-scale application of enzymes in pharmaceutical, chemical, and agrochemical industries.

Combinatorial Biocatalysis
For example, we and coworkers pioneered combinatorial biocatalysis, a technique that uses enzymes and microbes to derive small-molecule lead compounds from a common starting compound. Combinatorial biocatalysis is an emerging technology in the field of drug discovery. The biocatalytic approach to combinatorial chemistry uses enzymatic and microbial transformations to generate libraries from lead compounds. Those derivative libraries can then be screened against various bacteria and diseases to look for a desired activity. This technology has had an immediate impact on the use of biocatalysis in drug discovery. Through research performed in Tan Hall and at several biotechnology and pharmaceutical companies, combinatorial biocatalysis has been used to generate many new drug candidates for clinical investigation, including new analogs of the anticancer drugs taxol and doxorubicin. Current biocatalysis projects involve the generation of new anti-cholesterol agents using unique compounds produced by a deep-sea organism as a starting point, and the biocatalytic synthesis of new anti-HIV compounds.

Learning from Extremophiles
We are also trying to find ways to practically exploit microorganisms that have been isolated from extreme environments, such as hydrothermal vents that lie deep in the ocean. These versatile “extremophiles” are able to grow and survive in harsh environments and could therefore be adapted to catalyze reactions in the broad range of process conditions that are used in industry. For this research, our group has built specialized equipment that can duplicate the most extreme conditions on Earth that are known to support life, i.e., high temperatures and greatly elevated pressures. By studying extremophiles under these conditions, we have been able to examine mechanisms by which these robust organisms adapt to stressful extremes, and to explore new bioprocesses at the outer limits of life.

Another major activity within the group, in collaboration with Professor Blanch, concerns the monitoring and modeling of complex metabolic reaction networks in breast cancer cells. This research involves the use of a relatively new technique, metabolic flux analysis, to study the major metabolic pathways, and complex
interactions among them, in cancer cells under different growth conditions and treatment regimens. This approach therefore enables comprehensive examination of cancer-cell metabolism and may reveal drug targets for new therapies to control cancer cell proliferation.
A high temperature-pressure bioreactor in Tan Hall designed to mimic extreme environments that can support life. The inset at the top left shows an extremophile isolated from a deep-sea hydrothermal vent.


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