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From the Labs: Biotechnology

New publications, experiments and breakthroughs in biotechnology–and what they mean.
April 22, 2008

Engineering Enzymes from Scratch
Researchers design catalysts using a novel computational technique

Part of a model of a newly designed enzyme is shown above. The gray mesh represents a structural element that’s crucial to the enzyme’s catalytic properties.

Source: “De Novo Computational Design of Retro-Aldol Enzymes”
David Baker et al.
Science 319: 1387-1391

Results: Scientists from the University of Washington designed enzymes that cause a synthetic chemical to break down 10,000 times as quickly as it would on its own; then they built the enzymes from scratch. No natural enzymes perform the same task.

Why it matters: Novel enzymes that catalyze chemical reactions not normally seen in nature could lead to new ways to make drugs and biofuels and to clean up environmental toxins. Because enzymes are so structurally complex, however, designing new ones has proved extremely difficult.

Methods: In a biochemical reaction, an enzyme acts on a substrate. Small pockets in the enzyme that bind only to particular substrates give the molecule both its catalytic effect and its specificity. Researchers used a combination of methods, including some that involved quantum chemistry, to design a pocket that they predicted would catalyze the desired reaction. Then they used a series of novel algorithms to model candidate enzymes incorporating the pocket. Finally, the researchers synthesized the proteins and tested their catalytic activity.

Next steps: The researchers want to make the new enzymes as efficient as naturally occurring enzymes, which can increase the rate of a reaction a quadrillion-fold. To do that, they are both improving the algorithms used to generate model proteins and modifying the newly designed enzymes through directed evolution–making a variety of small changes to the enzymes and seeing which ones boost efficiency.

A Viral Attack on Brain Tumors
Rabies-related virus seeks out and destroys cancer cells

Source: “Systemic Vesicular Stomatitis Virus Selectively Destroys Multifocal Glioma and Metastatic Carcinoma in Brain”
Anthony N. van den Pol et al.
Journal of Neuroscience 28: 1882-1893

Results: Researchers at Yale University School of Medicine have shown that a specially evolved virus related to the one that causes rabies can rapidly home in on cancer cells. When injected into mice with brain tumors, the virus killed cancerous cells while leaving healthy tissue intact.

Why it matters: Surgery, chemotherapy, and radiation are often insufficient to eradicate brain tumor cells, which can replicate quickly and migrate throughout the brain. A virus that attacks cancer cells while leaving healthy cells unharmed could lead to more effective therapies.

Methods: Scientists had developed the cancer-­targeting virus by cultivating it for many generations, each time selecting for strains that quickly infected cancer cells while having little impact on healthy cells. In the new study, researchers used time-lapse laser confocal imaging to watch the virus (tagged fluorescent green) make its way to the brain and attack tumor cells (tagged fluorescent red).

Next steps: Researchers need to observe the virus’s behavior in the mice for a longer time to better assess its long-term safety. They also need to determine how well the virus survives in mice with intact immune systems: the animals used in the experi­ment were immunocompromised to allow cross-species transplantation of human brain cancer cells.

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