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Tony Forster, M.D., Ph.D., and colleagues are working to develop a synthetic cell. (photo by Susan Urmy)

Quest to create synthetic cell brings many parts together

BY: NICOLE MAJORAS

5/18/2007 - Vanderbilt's Tony Forster, M.D., Ph.D., is out to create a synthetic cell.

“This goal,” he said, “forces us to discover the remaining essential ingredients for protein synthesis, self-replication and basic life,” said Forster, assistant professor of Pharmacology. “And self-replication can be used to improve biopolymer syntheses and to evolve small molecule drugs in a manner analogous to monoclonal antibody technology.”

The first detailed blueprints for constructing a minimal cell, requiring 151 genes, were devised by Forster in collaboration with an internationally recognized guru in synthetic biology, Harvard Medical School's George Church, Ph.D.

“Life, like a machine, cannot be understood simply by studying it and its parts; it must also be put together from its parts,” Forster and Church wrote in their paper, “Towards synthesis of a minimal cell,” published last August in the journal Molecular Systems Biology.

Since arriving at Vanderbilt in 2005, Forster has continued his work, and this spring was awarded an anthrax-targeted R01 (individual research project) grant from the National Institute of Allergy and Infectious Diseases, and a Research Scholar Grant from the American Cancer Society. The grants total $2 million.

Forster attributed much of the credit for receiving the highly competitive grants to Pharmacology Chair Heidi Hamm, Ph.D., and Larry Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology, who recruited him to Vanderbilt and who have continued to support his work, and to Stephen Blacklow, M.D., Ph.D., who supervised his previous K08 (mentored clinical scientist development) award at Harvard Medical School.

Forster said that certain studies cannot be pursued with natural cells because cells are too complex. Scientists cannot determine the minimum genes sufficient for replication by just knocking out all genes that are individually non-essential because that kills the cell. And alternative combinations of fewer knockouts are too numerous to try.

“This problem will be solved by isolating cell processes — classical biochemistry,” he said, “because you don't have to get it right the first time. You can get a few parts working in the test tube and then debug until you get more things working. The complexity can be built up progressively.

“Isolating cell processes is biochemistry and has been going on forever,” Forster continued. “Amplifying DNA through PCR (the polymerase chain reaction) is an example of replicating DNA outside of a cell.”

What would a synthetic cell look like? Forster said it would be smaller than the smallest existing cell and very fragile.

In addition, creating a synthetic cell does not pose the same safety issues raised by engineering natural organisms. “It must have perfect conditions to survive,” Forster said, “and could only be sustained in the lab by feeding it dozens of special small molecules."

According to Forster, the hardest part of the project will be finding the few remaining essential genes for protein synthesis (translation) that make enzymes for modification of ribosomal and transfer RNAs. Currently, Forster is reconstituting translation from 31 purified proteins and looking at the regulation of the whole process.

A native of Australia, Forster earned a Ph.D. in biochemistry at the University of Adelaide in 1988, and his M.D. at Harvard in 1996. While in Adelaide, Forster discovered the textbook hammerhead-shaped ribozyme structure, which has advanced understanding of RNA self-cleavage, one of the tools useful for creating a synthetic cell.

Forster said he came to Vanderbilt “because of its outstanding pharmacology department and research institutes, which are equipped with the latest technology.”

“Vanderbilt has terrific people, tremendous resources and a new initiative in life sciences modeling,” he said. “I am happy to be here.”

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